17 - Neurocognitive Disorders

Neurocognitive Disorders

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Neurocognitive Disorders The neurocognitive disorders (NCDs) begin with delirium, followed by the syndromes of major NCD, mild NCD, and their etiological subtypes. The major or mild NCD subtypes are NCD due to Alzheimer’s disease; vascular NCD; NCD with Lewy bodies; NCD due to Parkinson’s disease; frontotemporal NCD; NCD due to traumatic brain injury; NCD due to HIV infection; substance/medication-induced NCD; NCD due to Huntington’s disease; NCD due to prion disease; NCD due to another medical condition; NCD due to multiple etiologies; and unspecified NCD. The NCD category encompasses the group of disorders in which the primary clinical deficit is in cognitive function, and that are acquired rather than developmental. Although cognitive deficits are present in many if not all mental disorders (e.g., schizophrenia, bipolar disorders), only disorders whose core features are cognitive are included in the NCD category. The NCDs are those in which impaired cognition has not been present since birth or very early life, and thus represents a decline from a previously attained level of functioning. The NCDs are unique among DSM-5 categories in that these are syndromes for which the underlying pathology, and frequently the etiology as well, can potentially be determined. The various underlying disease entities have all been the subject of extensive research, clinical experience, and expert consensus on diagnostic criteria. The DSM-5 criteria for these disorders have been developed in close consultation with the expert groups for each of the disease entities and align as closely as possible with the current consensus criteria for each of them. The potential utility of biomarkers is also discussed in relation to diagnosis. Dementia is subsumed under the newly named entity major neurocognitive disorder, although the term dementia is not precluded from use in the etiological subtypes in which that term is standard. Furthermore, DSM-5 recognizes a less severe level of cognitive impairment, mild neurocognitive disorder, which can also be a focus of care. Diagnostic criteria are provided for both these syndromic entities, followed by diagnostic criteria for the different etiological subtypes. Several of the NCDs frequently coexist with one another, and their relationships may be multiply characterized under different chapter subheadings, including “Differential Diagnosis” (e.g., NCD due to Alzheimer’s disease vs. vascular NCD), “Risk and Prognostic Factors” (e.g., vascular pathology increasing the clinical expression of Alzheimer’s disease), or “Comorbidity” (e.g., mixed Alzheimer’s disease–vascular pathology). The term dementia is retained in DSM-5 for continuity and may be used in settings where physicians and patients are accustomed to this term. Although dementia is the customary term for disorders like the degenerative dementias that usually affect older adults, the term neurocognitive disorder is widely used and often preferred for conditions affecting younger individuals, such as impairment secondary to traumatic brain injury or HIV infection. Furthermore, the major NCD definition is somewhat broader than the term dementia, in that a diagnosis of major NCD can be made if there is a significant cognitive decline in only one cognitive domain, whereas a diagnosis of dementia in ICD-10 and ICD-11 (and formerly in

DSM-IV) requires multiple cognitive deficits. Thus, cases that would qualify in ICD-10 and ICD-11 (and formerly DSM-IV) for a diagnosis of amnestic disorder (memory impairment in the absence of other cognitive deficits) are diagnosed as major NCD in DSM-5. Neurocognitive Domains The criteria for the various NCDs are based on defined cognitive domains. Table 1 provides for each of the key domains a working definition, examples of symptoms or observations regarding impairments in everyday activities, and examples of assessments. The domains thus defined, along with guidelines for clinical thresholds, form the basis on which the NCDs, their levels, and their subtypes may be diagnosed. TABLE 1 Neurocognitive domains Cognitive domain Examples of symptoms or observations Examples of assessments Complex attention (sustained attention, divided attention, selective attention, processing speed) Major: Has increased difficulty in environments with multiple stimuli (TV, radio, conversation); is easily distracted by competing events in the environment. Is unable to attend unless input is restricted and simplified. Has difficulty holding new information in mind, such as recalling phone numbers or addresses just given, or reporting what was just said. Is unable to perform mental calculations. All thinking takes longer than usual, and components to be processed must be simplified to one or a few. Mild: Normal tasks take longer than previously. Begins to find errors in routine tasks; finds work needs more double-checking than previously. Thinking is easier when not competing with other things (radio, TV, other conversations, cell phone, driving). Sustained attention: Maintenance of attention over time (e.g., pressing a button every time a tone is heard, and over a period of time). Selective attention: Maintenance of attention despite competing stimuli or distractors: hearing numbers and letters read and asked to count only letters. Divided attention: Attending to two tasks within the same time period: rapidly tapping while learning a story being read. Processing speed can be quantified on any task by timing it (e.g., time to put together a design of blocks; time to match symbols with numbers; speed in responding, such as counting speed or serial 3 speed). Executive function (planning, decisionmaking, working memory, responding to feedback/error correction, overriding habits/inhibition, mental flexibility) Major: Abandons complex projects. Needs to focus on one task at a time. Needs to rely on others to plan instrumental activities of daily living or make decisions. Mild: Increased effort required to complete multistage projects. Has increased difficulty multitasking or difficulty resuming a task interrupted by a visitor or phone call. May complain of increased fatigue from the extra effort required to organize, plan, and make decisions. May report that large social gatherings are more taxing or less enjoyable because of increased effort required to follow shifting conversations. Planning: Ability to find the exit to a maze; interpret a sequential picture or object arrangement. Decision-making: Performance of tasks that assess process of deciding in the face of competing alternatives (e.g., simulated gambling). Working memory: Ability to hold information for a brief period and to manipulate it (e.g., adding up a list of numbers or repeating a series of numbers or words backward). Feedback/error utilization: Ability to benefit from feedback to infer the rules for solving a problem. Overriding habits/inhibition: Ability to choose a more complex and effortful solution to be correct (e.g., looking away from the direction indicated by an arrow; naming the color of a word’s font rather than naming the word)

670 Major: Repeats self in conversation, often within the same conversation. Cannot keep track of short list of items when shopping or of plans for the day. Requires frequent reminders to orient to task at hand. Mild: Has difficulty recalling recent events, and Learning and memory (immediate memory, recent memory [including free recall, cued recall, and recognition memory], very-long-term memory [semantic; autobiographical], implicit learning) relies increasingly on list making or calendar. Needs occasional reminders or re-reading to keep track of characters in a movie or novel. Occasionally may repeat self over a few weeks to the same person. Loses track of whether bills have already been paid. Note: Except in severe forms of major neurocognitive disorder, semantic, autobiographical, and implicit learning are relatively preserved, compared with recent memory. Major: Has significant difficulties with Language (expressive language [including naming, word finding, fluency, and grammar, and syntax] and receptive language) expressive or receptive language. Often uses general-use phrases such as “that thing” and “you know what I mean,” and prefers general pronouns rather than names. With severe impairment, may not even recall names of closer friends and family. Idiosyncratic word usage, grammatical errors, and spontaneity of output and economy of utterances occur. Stereotypy of speech occurs; echolalia and automatic speech typically precede mutism. Mild: Has noticeable word-finding difficulty. May substitute general for specific terms. May avoid use of specific names of acquaintances. Grammatical errors involve subtle omission or incorrect use of articles, prepositions, auxiliary verbs, etc. Major: Has significant difficulties with previously familiar activities (using tools, driving motor vehicle), navigating in familiar environments; is often more confused at dusk, when shadows and lowering levels of light change perceptions. Mild: May need to rely more on maps or others Perceptual-motor (includes abilities subsumed under the terms visual perception, visuoconstructional, perceptual-motor, praxis, and gnosis) for directions. Uses notes and follows others to get to a new place. May find self lost or turned around when not concentrating on task. Is less precise in parking. Needs to expend greater effort for spatial tasks such as carpentry, assembly sewing or knitting word s font rather than naming the word). Mental/cognitive flexibility: Ability to shift between two concepts, tasks, or response rules (e.g., from number to letter, from verbal to keypress response, from adding numbers to ordering numbers, from ordering objects by size to ordering by color). Immediate memory span: Ability to repeat a list of words or digits. Note: Immediate memory sometimes subsumed under “working memory” (see “Executive Function”). Recent memory: Assesses the process of encoding new information (e.g., word lists, a short story, or diagrams). The aspects of recent memory that can be tested include 1) free recall (the individual is asked to recall as many words, diagrams, or elements of a story as possible); 2) cued recall (examiner aids recall by providing semantic cues such as “List all the food items on the list” or “Name all of the children from the story”); and 3) recognition memory (examiner asks about specific items— e.g., “Was ’apple’ on the list?” or “Did you see this diagram or figure?”). Other aspects of memory that can be assessed include semantic memory (memory for facts), autobiographical memory (memory for personal events or people), and implicit (procedural) learning (unconscious learning of skills). Expressive language: Confrontational naming (identification of objects or pictures); fluency (e.g., name as many items as possible in a semantic [e.g., animals] or phonemic [e.g., words starting with “f”] category in 1 minute). Grammar and syntax (e.g., omission or incorrect use of articles, prepositions, auxiliary verbs): Errors observed during naming and fluency tests are compared with norms to assess frequency of errors and compare with normal slips of the tongue. Receptive language: Comprehension (word definition and object-pointing tasks involving animate and inanimate stimuli): performance of actions/activities according to verbal command. Visual perception: Line bisection tasks can be used to detect basic visual defect or attentional neglect. Motor-free perceptual tasks (including facial recognition) require the identification and/or matching of figures—best when tasks cannot be verbally mediated (e.g., figures are not objects); some require the decision of whether a figure can be “real” or not based on dimensionality. Visuoconstructional: Assembly of items requiring hand-eye coordination, such as drawing, copying, and block assembly.

assembly, sewing, or knitting. Perceptual-motor: Integrating perception with purposeful movement (e.g., inserting blocks into a form board without visual cues; rapidly inserting pegs into a slotted board). Praxis: Integrity of learned movements, such as ability to imitate gestures (wave goodbye) or pantomime use of objects to command (“Show me how you would use a hammer”). Gnosis: Perceptual integrity of awareness and recognition, such as recognition of faces and colors. Social cognition (recognition of emotions, theory of mind) Major: Behavior clearly out of acceptable social range; shows insensitivity to social standards of modesty in dress or of political, religious, or sexual topics of conversation. Focuses excessively on a topic despite group’s disinterest or direct feedback. Behavioral intention without regard to family or friends. Makes decisions without regard to safety (e.g., inappropriate clothing for weather or social setting). Typically, has little insight into these changes. Mild: Has subtle changes in behavior or attitude, often described as a change in personality, such as less ability to recognize social cues or read facial expressions, decreased empathy, increased extraversion or introversion, decreased inhibition, or subtle or episodic apathy or restlessness. Recognition of emotions: Identification of emotion in images of faces representing a variety of both positive and negative emotions. Theory of mind: Ability to consider another person’s mental state (thoughts, desires, intentions) or experience—story cards with questions to elicit information about the mental state of the individuals portrayed, such as “Where will the girl look for the lost bag?” or “Why is the boy sad?” Delirium Diagnostic Criteria A. A disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) accompanied by reduced awareness of the environment. B. The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day. C. An additional disturbance in cognition (e.g., memory deficit, disorientation, language, visuospatial ability, or perception). D. The disturbances in Criteria A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma. E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (i.e., due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies.

Specify if: Acute: Lasting a few hours or days. Persistent: Lasting weeks or months. Specify if: Hyperactive: The individual has a hyperactive level of psychomotor activity that may be accompanied by mood lability, agitation, and/or refusal to cooperate with medical care. Hypoactive: The individual has a hypoactive level of psychomotor activity that may be accompanied by sluggishness and lethargy that approaches stupor. Mixed level of activity: The individual has a normal level of psychomotor activity even though attention and awareness are disturbed. Also includes individuals whose activity level rapidly fluctuates. Specify whether: Substance intoxication delirium: This diagnosis should be made instead of substance intoxication when the symptoms in Criteria A and C predominate in the clinical picture and when they are sufficiently severe to warrant clinical attention. Coding note: The ICD-10-CM codes for the [specific substance] intoxication delirium are indicated in the table below. Note that the ICD-10-CM code depends on whether or not there is a comorbid substance use disorder present for the same class of substance. If a mild substance use disorder is comorbid with the substance intoxication delirium, the 4th position character is “1,” and the clinician should record “mild [substance] use disorder” before the substance intoxication delirium (e.g., “mild cocaine use disorder with cocaine intoxication delirium”). If a moderate or severe substance use disorder is comorbid with the substance intoxication delirium, the 4th position character is “2,” and the clinician should record “moderate [substance] use disorder” or “severe [substance] use disorder,” depending on the severity of the comorbid substance use disorder. If there is no comorbid substance use disorder (e.g., after a one-time heavy use of the substance), then the 4th position character is “9,” and the clinician should record only the substance intoxication delirium. ICD-10-CM Substance intoxication delirium With mild use disorder With moderate or severe use disorder Without use disorder Alcohol F10.121 F10.221 F10.921 Cannabis F12.121 F12.221 F12.921 Phencyclidine F16.121 F16.221 F16.921 Other hallucinogen F16.121 F16.221 F16.921

Inhalant F18.121 F18.221 F18.921 Opioid F11.121 F11.221 F11.921 Sedative, hypnotic, or anxiolytic F13.121 F13.221 F13.921 Amphetamine-type substance (or other stimulant) F15.121 F15.221 F15.921 Cocaine F14.121 F14.221 F14.921 Other (or unknown) substance F19.121 F19.221 F19.921 Substance withdrawal delirium: This diagnosis should be made instead of substance withdrawal when the symptoms in Criteria A and C predominate in the clinical picture and when they are sufficiently severe to warrant clinical attention. Coding note: The ICD-10-CM codes for the [specific substance] withdrawal delirium are indicated in the table below. Note that the ICD-10-CM code depends on whether or not there is a comorbid substance use disorder present for the same class of substance. If a mild substance use disorder is comorbid with the substance withdrawal delirium, the 4th position character is “1,” and the clinician should record “mild [substance] use disorder” before the substance withdrawal delirium (e.g., “mild alcohol use disorder with alcohol withdrawal delirium”). If a moderate or severe substance use disorder is comorbid with the substance withdrawal delirium, the 4th position character is “2,” and the clinician should record “moderate [substance] use disorder” or “severe [substance] use disorder,” depending on the severity of the comorbid substance use disorder. If there is no comorbid substance use disorder (e.g., after regular use of an anxiolytic substance taken as prescribed), then the 4th position character is “9,” and the clinician should record only the substance withdrawal delirium. ICD-10-CM Substance withdrawal delirium With mild use disorder With moderate or severe use disorder Without use disorder Alcohol F10.131 F10.231 F10.931 Opioid F11.188 F11.288 F11.988 Sedative, hypnotic, or anxiolytic F13.131 F13.231 F13.931 Other (or unknown) substance F19.131 F19.231 F19.931 Medication-induced delirium: This diagnosis applies when the symptoms in Criteria A and C arise as a side effect of a medication taken as prescribed. Code [specific medication]–induced delirium: F11.921 opioid taken as prescribed (or F11.988 if during withdrawal from opioid taken as prescribed); F12.921 pharmaceutical cannabis receptor agonist taken as prescribed; F13.921 sedative, hypnotic, or anxiolytic taken as prescribed (or F13.931 if

Substance intoxication delirium. during withdrawal from sedative, hypnotic, or anxiolytic taken as prescribed); F15.921 amphetamine-type substance or other stimulant taken as prescribed; F16.921 ketamine or other hallucinogen taken as prescribed or for medical reasons; F19.921 for medications that do not fit into any of the classes (e.g., dexamethasone) and in cases in which a substance is judged to be an etiological factor but the specific class of substance is unknown (or F19.931 if during withdrawal from medications that do not fit into any of the classes, taken as prescribed). F05 Delirium due to another medical condition: There is evidence from the history, physical examination, or laboratory findings that the disturbance is attributable to the physiological consequences of another medical condition. Coding note: Include the name of the other medical condition in the name of the delirium (e.g., F05 delirium due to hepatic encephalopathy). The other medical condition should also be coded and listed separately immediately before the delirium due to another medical condition (e.g., K72.90 hepatic encephalopathy; F05 delirium due to hepatic encephalopathy). F05 Delirium due to multiple etiologies: There is evidence from the history, physical examination, or laboratory findings that the delirium has more than one etiology (e.g., more than one etiological medical condition; another medical condition plus substance intoxication or medication side effect). Coding note: Use multiple separate codes reflecting specific delirium etiologies (e.g., K72.90 hepatic encephalopathy; F05 delirium due to hepatic failure; F10.231 alcohol withdrawal delirium). Note that the etiological medical condition both appears as a separate code that precedes the delirium code and is substituted into the delirium due to another medical condition rubric. Recording Procedures The name of the substance intoxication delirium begins with the specific substance (e.g., cocaine) that is presumed to be causing the delirium. The diagnostic code is selected from the table included in the criteria set, which is based on the drug class and presence or absence of a comorbid substance use disorder. For substances that do not fit into any of the classes (e.g., dexamethasone), the code for “other substance” should be used; and in cases in which a substance is judged to be an etiological factor but the specific class of substance is unknown, the category “unknown substance” should be used. When recording the name of the disorder, the comorbid substance use disorder (if any) is listed first, followed by the word “with,” followed by the name of the substance intoxication delirium, followed by the course (i.e., acute, persistent), followed by the specifier indicating level of psychomotor activity (i.e., hyperactive, hypoactive, mixed level of activity). For example, in the case of acute hyperactive intoxication delirium occurring in a man with a severe cocaine use disorder, the diagnosis is F14.221 severe cocaine use disorder with cocaine intoxication delirium, acute, hyperactive. A separate diagnosis of the comorbid severe cocaine use disorder is not given. If the intoxication delirium occurs without a comorbid substance use disorder (e.g., after a one-time heavy use of the substance), no accompanying substance use disorder is noted (e.g.,

Substance withdrawal delirium. Medication-induced delirium. F16.921 phencyclidine intoxication delirium, acute, hypoactive). The name of the substance withdrawal delirium begins with the specific substance (e.g., alcohol) that is presumed to be causing the withdrawal delirium. The diagnostic code is selected from substance-specific codes in the coding note included in the criteria set. When recording the name of the disorder, the comorbid substance use disorder (if any) is listed first, followed by the word “with,” followed by the substance withdrawal delirium, followed by the course (i.e., acute, persistent), followed by the specifier indicating level of psychomotor activity (i.e., hyperactive, hypoactive, mixed level of activity). For example, in the case of acute hyperactive withdrawal delirium occurring in a man with a severe alcohol use disorder, the diagnosis is F10.231 severe alcohol use disorder with alcohol withdrawal delirium, acute, hyperactive. A separate diagnosis of the comorbid severe alcohol use disorder is not given. The name of the medication-induced delirium begins with the specific substance (e.g., dexamethasone) that is presumed to be causing the delirium. The name of the disorder is followed by the course (i.e., acute, persistent), followed by the specifier indicating level of psychomotor activity (i.e., hyperactive, hypoactive, mixed level of activity). For example, in the case of acute hyperactive medication-induced delirium occurring in a man using dexamethasone as prescribed, the diagnosis is F19.921 dexamethasone-induced delirium, acute, hyperactive. Specifiers Regarding course, in hospital settings, delirium usually lasts about 1 week, but some symptoms often persist even after individuals are discharged from the hospital. Individuals with delirium may rapidly switch between hyperactive and hypoactive states. The hyperactive state may be more common or more frequently recognized and often is associated with medication side effects and drug withdrawal. The hypoactive state may be more frequent in older adults and is often unrecognized among older individuals in emergency departments and hospitals. Diagnostic Features The essential feature of delirium is an acute impairment of consciousness characterized by a disturbance in attention accompanied by reduced awareness of the environment, both core features of normal consciousness. Because these deficits reflect an altered state of consciousness affecting many higher cerebral cortical functions of the cerebral cortex, they are accompanied by a change from baseline in other cognitive functions that cannot be better explained by a preexisting or evolving neurocognitive disorder (NCD). The disturbance in attention (Criterion A) is manifested by reduced ability to direct, focus, sustain, and shift attention. Questions must be repeated because the individual’s attention wanders, or the individual may perseverate with an answer to a previous question rather than appropriately shift attention. The individual is easily distracted by irrelevant stimuli. The disturbance in awareness affects both internal thinking and insight as well as difficulty making sense of what is happening in the external environment. The disturbance develops over a short period of time, usually hours to a few days, and tends

to fluctuate during the course of the day, often with worsening in the evening and night when external orienting stimuli decrease (Criterion B). There is evidence from the history, physical examination, or laboratory findings that the disturbance is a physiological consequence of an underlying medical condition, substance intoxication or withdrawal, use of a medication, or a toxin exposure, or a combination of these factors (Criterion E). The etiology should be coded according to the etiologically appropriate subtype (i.e., substance or medication intoxication, substance withdrawal, another medical condition, or multiple etiologies). Delirium often occurs in the context of an underlying NCD. The impaired brain function of individuals with mild and major NCD renders them more vulnerable to developing a delirium. There is an accompanying change in at least one other area that may include memory and learning (particularly recent memory), disorientation (particularly to time and place), alteration in language (particularly semantic comprehension), or perceptual distortion or a perceptual-motor disturbance (Criterion C). The perceptual disturbances accompanying delirium include misinterpretations, illusions, or hallucinations; these disturbances are typically visual, but may occur in other modalities as well, and range from simple and uniform to highly complex. Normal attention/arousal, delirium, and coma lie on a continuum. Coma is defined as a state of unconsciousness with an absence of cognition or sleep-wake cycle, along with the lack of any meaningful response to verbal or physical stimuli. Delirium is an impaired state of consciousness in the setting of an aroused cortex. The ability to evaluate cognition to diagnose delirium depends on there being a level of cortical arousal and wakefulness sufficient for response to verbal stimulation; hence, delirium should not be diagnosed in the context of coma (Criterion D). Stuporous individuals also have a reduced level of brain arousal, but not to the extent of the complete unconsciousness of coma. Coma and stupor can be due to neurological conditions or drug-induced as with iatrogenic deep sedation in intensive care unit (ICU) settings or general anesthesia. Those individuals who show only minimal responses to verbal or physical stimulation are incapable of engaging with attempts at standardized testing or even interview. This inability to engage should be classified as a disorder of arousal such as coma or stupor, and not as delirium. However, delirium can be a stage that follows emergence from coma or stupor, especially when coma is the result of a neurological condition. Further, the sleep-wake cycle disturbance characteristic of the circadian rhythm disturbance in delirium can interfere with full assessment of the individual if in a sleep phase, which should be distinguished from a disorder of brain arousal. Associated Features Delirium is often associated with a disturbance in the sleep-wake cycle. This disturbance can include daytime sleepiness, nighttime agitation, difficulty falling asleep, excessive sleepiness throughout the day, or wakefulness throughout the night. In some cases, complete reversal of the night-day sleep-wake cycle can occur. Sleep-wake cycle disturbances are very common in delirium and have been proposed as a core criterion for the diagnosis. The individual with delirium may exhibit emotional disturbances, such as anxiety, fear, depression, irritability, anger, euphoria, and apathy. There may be rapid and unpredictable shifts

from one emotional state to another. The disturbed emotional state may also be evident in calling out, screaming, cursing, muttering, moaning, or making other sounds. These behaviors are especially prevalent at night and under conditions in which stimulation and environmental cues are lacking. Prevalence The prevalence of delirium is highest among hospitalized older individuals and varies depending on the individuals’ characteristics, setting of care, and sensitivity of the detection method. Data from the United States and Finland indicate that the prevalence of delirium in the community overall is low (1%–2%). The prevalence is 8%–17% in older individuals presenting to North American emergency departments, where the delirium often indicates a medical illness. Based on data from various countries, the prevalence of delirium when individuals are admitted to the hospital ranges from 18% to 35%, and estimates of the occurrence of delirium arising during hospitalization range from 29% to 64% in general hospital populations. Internationally, delirium occurs in 11%–51% of older individuals postoperatively and in up to 81% of those in intensive care. The prevalence of delirium ranges from 20% to 22% in individuals in nursing homes or post–acute care settings and occurs in up to 88% of individuals with terminal illness at the end of life. Despite having higher risk factors for delirium, such as cardiovascular disease, sepsis, and respiratory failure, younger African Americans tended to have lower rates of the occurrence of delirium compared with White individuals of similar age in a large case series of ICU patients in the United States. Development and Course The majority of individuals with delirium have a full recovery with or without treatment, especially those who are not elderly. Delirium may progress to stupor, coma, seizures, or death, particularly if undetected and the underlying cause(s) remains untreated. There is increasing evidence that delirium may be associated in long-term follow-up with cognitive decline or major NCD in the elderly, particularly in those with preexisting underlying cognitive impairment. Mortality among hospitalized individuals with delirium is high; as many as 38%–41% of individuals with delirium die within 1 year after diagnosis; the risk of death is particularly great among those with malignancies and other significant underlying medical illness. Risk and Prognostic Factors Delirium may be increased in the context of functional impairment, preexisting cognitive impairment, sensory impairment (e.g., vision/hearing), increasing age, illness severity or comorbidity, infection, depression, history of stroke, and history of alcohol use. Both major and mild NCDs can increase the risk for delirium and complicate the course. Falls may be an outcome of delirium but are not found to be a risk factor. In a meta-analysis of studies from 1990 through 2016, anticholinergic use was not a validated predictor of delirium. Older individuals are especially susceptible to delirium compared with younger adults.

Psychotic disorders and bipolar and depressive disorders with psychotic features. Acute stress disorder. Malingering and factitious disorder. Other neurocognitive disorders. Among children, susceptibility to delirium in infancy and through childhood may be associated with significant childhood morbidity and mortality, whereas individuals in early adulthood through mid-adulthood may have less susceptibility to delirium and lower mortality risk. Sex- and Gender-Related Diagnostic Issues The symptoms associated with delirium may vary in men and women. Men more commonly manifest motor agitation and affective lability, whereas women more commonly manifest hypoactive delirium. Male sex is a risk factor for delirium, and sex- or gender-related factors may interact with other risk factors. Diagnostic Markers In addition to laboratory findings characteristic of underlying medical conditions (or intoxication or withdrawal states), there is often generalized irregular theta slowing on electroencephalography, and fast activity is occasionally found (e.g., in some cases of alcohol withdrawal delirium). However, electroencephalography is unable to detect slowing associated with delirium without comparison to premorbid baseline alpha rhythms unless the slowing is in the abnormal theta or delta frequency range. Functional Consequences of Delirium Delirium itself is associated with increased functional decline and risk of institutional placement. Hospitalized individuals 65 years or older with delirium are at greater risk for poor outcomes following discharge, including mortality, institutionalization, and dementia. Differential Diagnosis Delirium that is characterized by vivid hallucinations, delusions, language disturbances, and agitation must be distinguished from brief psychotic disorder, schizophrenia, schizophreniform disorder, and other psychotic disorders, as well as from manic or major depressive episodes, with psychotic features. Delirium associated with fear, anxiety, and dissociative symptoms, such as depersonalization, must be distinguished from acute stress disorder, which is precipitated by exposure to a severely traumatic event. Delirium can be distinguished from these disorders on the basis of the often atypical symptomatic presentation in malingering and factitious disorder and the absence of another medical condition or substance that is etiologically related to the apparent cognitive disturbance. The most common differential diagnostic issue when evaluating confusion in older adults is disentangling symptoms of delirium and major NCD. The clinician must determine whether the individual has delirium; a delirium superimposed on a preexisting NCD, such as that due to Alzheimer’s disease; or an NCD without delirium. The traditional

distinction between delirium and major NCD according to acuteness of onset and temporal course is particularly difficult in those elderly individuals who had a prior NCD that may not have been recognized, or who developed persistent cognitive impairment following an episode of delirium. When delirium and major NCD are comorbid, the management of the delirium should generally be given priority. Other Specified Delirium R41.0 This category applies to presentations in which symptoms characteristic of delirium that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning predominate but do not meet the full criteria for delirium or any of the disorders in the neurocognitive disorders diagnostic class. The other specified delirium category is used in situations in which the clinician chooses to communicate the specific reason that the presentation does not meet the criteria for delirium or any specific neurocognitive disorder. This is done by recording “other specified delirium” followed by the specific reason (e.g., “subsyndromal delirium”). An example of a presentation that can be specified using the “other specified” designation is the following: Subsyndromal delirium: A delirium-like presentation involving disturbances in attention, higher-level thought, and circadian rhythm, in which the severity of cognitive impairment falls short of that required for the diagnosis of delirium. Unspecified Delirium R41.0 This category applies to presentations in which symptoms characteristic of delirium that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning predominate but do not meet the full criteria for delirium or any of the disorders in the neurocognitive disorders diagnostic class. The unspecified delirium category is used in situations in which the clinician chooses not to specify the reason that the criteria are not met for delirium, and includes presentations for which there is insufficient information to make a more specific diagnosis (e.g., in emergency room settings). Major and Mild Neurocognitive Disorders

Major Neurocognitive Disorder Diagnostic Criteria A. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on:

1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function; and
2. A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment. B. The cognitive deficits interfere with independence in everyday activities (i.e., at a minimum, requiring assistance with complex instrumental activities of daily living such as paying bills or managing medications). C. The cognitive deficits do not occur exclusively in the context of a delirium. D. The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia). Specify whether due to: Note: Each subtype listed has specific diagnostic criteria and corresponding text, which follow the general discussion of major and mild neurocognitive disorders. Alzheimer’s disease Frontotemporal degeneration Lewy body disease Vascular disease Traumatic brain injury Substance/medication use HIV infection Prion disease Parkinson’s disease Huntington’s disease Another medical condition Multiple etiologies Unspecified etiology Coding note: Code based on medical or substance etiology. In most cases of major neurocognitive disorder, there is need for an additional code for the etiological medical condition, which must immediately precede the diagnostic code for major neurocognitive disorder, as noted in the coding table on pp. 682–683.

Specify (see coding table for details): Without behavioral disturbance: If the cognitive disturbance is not accompanied by any clinically significant behavioral disturbance. With behavioral disturbance (specify disturbance): If the cognitive disturbance is accompanied by a clinically significant behavioral disturbance (e.g., psychotic symptoms, mood disturbance, agitation, apathy, or other behavioral symptoms). Coding note: Use additional code(s) to indicate clinically significant psychiatric symptoms due to the same medical condition causing the major neurocognitive disorder (e.g., F06.2 psychotic disorder due to Alzheimer’s disease, with delusions; F06.32 depressive disorder due to Parkinson’s disease, with major depressive–like episode). Note: Mental disorders due to another medical condition are included with disorders with which they share phenomenology (e.g., for depressive disorders due to another medical condition, see the chapter “Depressive Disorders”). Specify current severity: Mild: Difficulties with instrumental activities of daily living (e.g., housework, managing money). Moderate: Difficulties with basic activities of daily living (e.g., feeding, dressing). Severe: Fully dependent. Coding and Recording Procedures The following are examples of coding and recording major neurocognitive disorders due to an etiological subtype (for more information, see coding table on pp. 682–683 and coding notes in the specific diagnostic criteria for each major and mild neurocognitive disorder subtype): Major neurocognitive disorder due to probable Alzheimer’s disease, without behavioral disturbance, mild: G30.9 Alzheimer’s disease, F02.80 major neurocognitive disorder due to probable Alzheimer’s disease, without behavioral disturbance, mild. Major neurocognitive disorder due to traumatic brain injury, with behavioral disturbance, moderate: S06.2X9S diffuse traumatic brain injury with loss of consciousness of unspecified duration, sequela; F02.81 major neurocognitive disorder due to traumatic brain injury, with behavioral disturbance, moderate; F06.34 bipolar and related disorder due to traumatic brain injury, with mixed features. Mild Neurocognitive Disorder Diagnostic Criteria

A. Evidence of modest cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on:

1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a mild decline in cognitive function; and
2. A modest impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment. B. The cognitive deficits do not interfere with capacity for independence in everyday activities (i.e., complex instrumental activities of daily living such as paying bills or managing medications are preserved, but greater effort, compensatory strategies, or accommodation may be required). C. The cognitive deficits do not occur exclusively in the context of a delirium. D. The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia). Specify whether due to: Note: Each subtype listed has specific diagnostic criteria and corresponding text, which follow the general discussion of major and mild neurocognitive disorders. Alzheimer’s disease Frontotemporal degeneration Lewy body disease Vascular disease Traumatic brain injury Substance/medication use HIV infection Prion disease Parkinson’s disease Huntington’s disease Another medical condition Multiple etiologies Unspecified etiology Coding note: For mild neurocognitive disorder due to any of the medical etiologies listed above, code G31.84. Do not use additional codes for the presumed etiological medical conditions. For substance/medication-induced mild neurocognitive disorder, code based on type of substance; see “Substance/Medication-Induced Major or Mild Neurocognitive Disorder.” For unspecified mild neurocognitive disorder, code R41.9.

Specify (behavioral disturbance cannot be coded but should still be recorded): Without behavioral disturbance: If the cognitive disturbance is not accompanied by any clinically significant behavioral disturbance. With behavioral disturbance (specify disturbance): If the cognitive disturbance is accompanied by a clinically significant behavioral disturbance (e.g., psychotic symptoms, mood disturbance, agitation, apathy, or other behavioral symptoms). Coding note: Use additional code(s) to indicate clinically significant psychiatric symptoms due to the same medical condition causing the mild neurocognitive disorder (e.g., F06.2 psychotic disorder due to traumatic brain injury, with delusions; F06.32 depressive disorder due to HIV disease, with major depressive–like episode). Note: Mental disorders due to another medical condition are included with disorders with which they share phenomenology (e.g., for depressive disorders due to another medical condition, see the chapter “Depressive Disorders”). Coding and Recording Procedures The following are examples of coding and recording mild neurocognitive disorders due to an etiological subtype (for more information, see coding table on pp. 682–683 and coding notes in the specific diagnostic criteria for each major and mild neurocognitive disorder subtype): G31.84 Mild neurocognitive disorder due to Alzheimer’s disease, without behavioral disturbance. G31.84 Mild neurocognitive disorder due to traumatic brain injury, with behavioral disturbance; F06.34 bipolar and related disorder due to traumatic brain injury, with mixed features. Etiological subtype Associated etiological medical code for major neurocognitive disordera Major neurocognitive disorder code Mild neurocognitive disorder code Alzheimer’s disease G30.9 F02.8xb G31.84c Do not use additional code for Alzheimer’s disease. Frontotemporal degeneration G31.09 F02.8xb G31.84c Do not use additional code for frontotemporal degeneration. Lewy body disease G31.83 F02.8xb G31.84c Do not use additional code for Lewy body disease. Vascular disease No additional medical code. F01.5xb Do not use additional code for the vascular disease. G31.84c Do not use additional code for the vascular disease. Traumatic brain injury S06.2X9S F02.8xb G31.84c Do not use additional code for the traumatic brain injury. Substance/medicationinduced No additional medical code. Code based on the type of substance causing the major Code based on the type of substance causing the mild neurocognitive disorder.d

causing the major neurocognitive disorder.d HIV infection B20 F02.8xb G31.84c Do not use additional code for HIV infection. Prion disease A81.9 F02.8xb G31.84c Do not use additional code for prion disease. Parkinson’s disease G20 F02.8xb G31.84c Do not use additional code for Parkinson’s disease. Huntington’s disease G10 F02.8xb G31.84c Do not use additional code for Huntington’s disease. Due to another medical condition Code the other medical condition first (e.g., G35 multiple sclerosis). F02.8xb G31.84c Do not use additional codes for the presumed etiological medical conditions. Due to multiple etiologies Code all of the etiological medical conditions first (with the exception of vascular disease). F02.8xb (code once for major neurocognitive disorder due to all etiologies that apply) Code also major vascular NCD (F01.5x), if present. Code also the relevant substance/medicationinduced major neurocognitive disorders if substances or medications play a role in the etiology. G31.84c Do not use additional codes for the presumed etiological medical conditions. Code also the relevant substance/medication-induced mild neurocognitive disorders if substances or medications play a role in the etiology. Unspecified neurocognitive disorder No additional medical code. R41.9c R41.9c aCode first, before code for major neurocognitive disorder. bCode fifth character based on symptom specifier: .x0 without behavioral disturbance; .x1 with behavioral disturbance (e.g., psychotic symptoms, mood disturbance, agitation, apathy, or other behavioral symptoms). Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded. cNote: “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded. dSee coding table in “Substance/Medication-Induced Major or Mild Neurocognitive Disorder” for ICD-10-CM code. Note: The severity specifiers “mild,” “moderate,” and “severe” (for substance/medication-induced major neurocognitive disorder) and the accompanying symptom specifiers “with behavioral disturbance” and “without behavioral disturbance” (for substance/medication-induced major or mild neurocognitive disorder) cannot be coded but should still be recorded. Subtypes Major and mild neurocognitive disorders (NCDs) are primarily subtyped according to the known or presumed etiological/pathological entity or entities underlying the cognitive decline. These subtypes are distinguished on the basis of a combination of time course, characteristic domains affected, and associated symptoms. For certain etiological subtypes, the diagnosis depends substantially on the presence of a potentially causative entity, such as Parkinson’s or

Huntington’s disease, or a traumatic brain injury or stroke in the appropriate time period. For other etiological subtypes (generally the neurodegenerative diseases like Alzheimer’s disease, frontotemporal degeneration, and Lewy body disease), the diagnosis is based primarily on the cognitive, behavioral, and functional symptoms. Typically, the differentiation among these syndromes that lack an independently recognized etiological entity is clearer at the level of major NCD than at the level of mild NCD, but sometimes characteristic symptoms and associated features are present at the mild level as well. NCDs are frequently managed by clinicians in multiple disciplines. For many subtypes, multidisciplinary international expert groups have developed specialized consensus criteria based on clinicopathological correlation with underlying brain pathology. The subtype criteria here have been harmonized with those expert criteria. Specifiers Evidence for distinct behavioral features in NCDs has been recognized, particularly in the areas of psychotic symptoms and depression. Psychotic features are common in many NCDs, particularly at the mild-to-moderate stage of major NCDs due to Alzheimer’s disease, Lewy body disease, and frontotemporal degeneration. If the psychotic symptoms are judged to be due to the Alzheimer’s disease, Lewy body disease, or frontotemporal degeneration, an additional diagnosis of psychotic disorder due to Alzheimer’s disease, psychotic disorder due to Lewy body disease, or psychotic disorder due to frontotemporal degeneration may be given. Paranoia and other delusions are common features, and often a persecutory theme may be a prominent aspect of delusional ideation. In contrast to psychotic disorders with onset in earlier life (e.g., schizophrenia), disorganized speech and disorganized behavior are not characteristic of psychosis in NCDs. Hallucinations may occur in any modality, although visual hallucinations are more common in NCDs than in depressive, bipolar, or psychotic disorders. Mood disturbances, including depression, anxiety, and elation, may occur. Depression is common early in the course (including at the mild NCD level) of NCD due to Alzheimer’s disease and Parkinson’s disease, while elation may occur more commonly in frontotemporal degeneration. If the mood disturbance is judged to be due to the Alzheimer’s disease, Parkinson’s disease, or frontotemporal degeneration, an additional diagnosis of depressive disorder due to Alzheimer’s disease, depressive disorder due to Parkinson’s disease, or bipolar and related disorder due to frontotemporal degeneration may be given. Mood symptoms are increasingly recognized to be a significant feature in the earliest stages of mild NCDs such that clinical recognition and intervention may be important. Agitation is common in a wide variety of NCDs, particularly in major NCD of moderate to severe severity, and often occurs in the setting of confusion or frustration. It may arise as combative behaviors, particularly in the context of resisting caregiving duties such as bathing and dressing. Agitation is characterized as disruptive motor or vocal activity and tends to occur with advanced stages of cognitive impairment across all of the NCDs. Individuals with NCD can present with a wide variety of behavioral symptoms that are the focus of treatment. Sleep disturbance is a common symptom that can create a need for clinical attention and may include symptoms of insomnia, hypersomnia, and circadian rhythm disturbances.

685 Apathy is common in mild and major NCD. It is observed particularly in NCD due to Alzheimer’s disease and may be a prominent feature of NCD due to frontotemporal degeneration. Apathy is typically characterized by diminished motivation and reduced goaldirected behavior accompanied by decreased emotional responsiveness. Symptoms of apathy may manifest early in the course of NCDs when a loss of motivation to pursue daily activities or hobbies may be observed. Other important behavioral symptoms include wandering, disinhibition, hyperphagia, and hoarding. Some of these symptoms are characteristic of specific disorders, as discussed in the relevant sections. When more than one behavioral disturbance is observed, each type should be noted in writing with the specifier “with behavioral disturbance.” Diagnostic Features Major and mild NCDs exist on a spectrum of cognitive and functional impairment. Major NCD roughly corresponds to the condition labeled in ICD-10 and ICD-11 (as well as in DSM-IV) as dementia. The core feature of NCDs is acquired cognitive decline in one or more cognitive domains (Criterion A) based on both 1) a concern about cognition on the part of the individual, a knowledgeable informant, or the clinician, and 2) performance on an objective assessment that falls below the expected level or that has been observed to decline over time. Both a concern and objective evidence are required because they are complementary. When there is an exclusive focus on objective testing, a disorder may go undiagnosed in high-functioning individuals whose currently “normal” performance actually represents a substantial decline in abilities, or an illness may be incorrectly diagnosed in individuals whose currently “low” performance does not represent a change from their own baseline or is a result of extraneous factors like test conditions or a passing illness. Alternatively, excessive focus on subjective symptoms may fail to diagnose illness in individuals with poor insight, or whose informants deny or fail to notice their symptoms, or it may be overly sensitive in the so-called worried well. A cognitive concern differs from a complaint in that it may or may not be voiced spontaneously. Rather, it may need to be elicited by careful questioning about specific symptoms that commonly occur in individuals with cognitive deficits (see Table 1 in the introduction to this chapter). For example, memory concerns include difficulty remembering a short grocery list or keeping track of the plot of a television program; executive concerns include difficulty resuming a task when interrupted, organizing tax records, or planning a holiday meal. At the mild NCD level, the individual is likely to describe these tasks as being more difficult or as requiring extra time or effort or compensatory strategies. At the major NCD level, such tasks may only be completed with assistance or may be abandoned altogether. At the mild NCD level, individuals and their families may not notice such symptoms or may view them as normal, particularly in the elderly; thus, careful history taking is of paramount importance. The difficulties must represent changes rather than lifelong patterns: the individual or informant may clarify this issue, or the clinician can infer change from prior experience with the individual or from occupational or other clues. It is also critical to determine that the difficulties are related to cognitive loss rather than to motor or sensory limitations. Neuropsychological testing, with performance compared with norms appropriate to the

individual’s age, sex, educational attainment, and cultural background, is part of the standard evaluation of NCDs and is particularly critical in the evaluation of mild NCD. The use of culturally validated assessment instruments is preferred, which are available for many racial/ethnic and linguistic populations. For major NCD, performance is typically 2 or more standard deviations below appropriate norms (3rd percentile or below). For mild NCD, performance typically lies in the 1–2 standard deviation range (between the 3rd and 16th percentiles). However, neuropsychological testing is not available in all settings, and neuropsychological thresholds are sensitive to the specific test(s) and norms employed, as well as to test conditions, sensory limitations, and intercurrent illness. A variety of brief office-based or “bedside” assessments, as described in Table 1, can also supply objective data in settings where such testing is unavailable or infeasible. In any case, as with cognitive concerns, objective performance must be interpreted in light of the individual’s prior performance. Optimally, this information would be available from a prior administration of the same test, but often it must be inferred based on appropriate norms, along with the individual’s educational history, occupation, and other factors. Norms are more challenging to interpret in individuals with very high or very low levels of education and in individuals being tested outside their own language or cultural background. Criterion B relates to the individual’s level of independence in everyday functioning. Individuals with major NCD will have impairment of sufficient severity so as to interfere with independence, such that others will have to take over tasks that the individuals were previously able to complete on their own. Individuals with mild NCD will have preserved independence, although there may be subtle interference with function or a report that tasks require more effort or take more time than previously. The distinction between major and mild NCD is inherently arbitrary, and the disorders exist along a continuum. Precise thresholds are therefore difficult to determine. Careful history taking, observation, and integration with other findings are required, and the implications of making a diagnosis should be considered when an individual’s clinical manifestations lie at a boundary. Associated Features Typically the associated features that support a diagnosis of major or mild NCD will be specific to the etiological subtype (e.g., neuroleptic sensitivity and visual hallucinations in NCD due to Lewy body disease). Diagnostic features specific to each of the subtypes are found in the relevant sections. Prevalence The prevalence of NCD varies widely by age and by etiological subtype. Overall prevalence estimates are generally only available for older populations. Among individuals older than 60 years, prevalence increases steeply with age, so prevalence estimates are more accurate for narrow age bands than for broad categories such as “over 65” (where the mean age can vary greatly with the life expectancy of the given population). For those etiological subtypes occurring across the life span, prevalence estimates for NCD are likely to be available, if at all,

only as the fraction of individuals who develop NCD among those with the relevant condition (e.g., traumatic brain injury, HIV infection). Female gender is associated with higher prevalence of dementia overall, and especially Alzheimer’s disease, but this difference is largely, if not wholly, attributable to greater longevity in females. Overall, international prevalence estimates for dementia (which is largely congruent with major NCD) are approximately 1%–2% at age 65 years and as high as 30% by age 85 years. The prevalence of mild NCD is very sensitive to the definition of the disorder, particularly in community settings, where evaluations are less detailed. In addition, in contrast with clinical settings, where cognitive concern must be high to seek and locate care, there may be a less clear decline from baseline functioning. Estimates of the prevalence of mild cognitive impairment (which is substantially congruent with mild NCD) among older individuals are fairly variable, ranging from 2% to 10% at age 65 and 5% to 25% by age 85. Prevalence and incidence of dementia vary cross-nationally and among ethnic and racialized populations in the United States, although methodological differences complicate rate comparisons. Some U.S. studies found that incidence is highest in African Americans followed, in decreasing order, by American Indians/Alaska Natives, Latinx, Pacific Islanders, non-Latinx Whites, and Asian Americans. Among four Asian American populations, Filipino Americans had the highest incidence, followed by Japanese Americans, Chinese Americans, and Asian-Indian Americans. Latinx subpopulations in the United States have been found to vary considerably in prevalence and incidence of dementia; Caribbean Hispanics have much higher rates than Mexican Americans in some U.S. studies. Development and Course The course of NCD varies across etiological subtypes, and this variation can be useful in differential diagnosis. Some subtypes (e.g., those related to traumatic brain injury or stroke) typically begin at a specific time and (at least after initial symptoms related to inflammation or swelling subside) remain static. Others may fluctuate over time (although if this occurs, the possibility of delirium superimposed on NCD should be considered). NCDs due to neurodegenerative diseases like Alzheimer’s disease or frontotemporal degeneration typically are marked by insidious onset and gradual progression, and the pattern of onset of cognitive deficits and associated features helps to distinguish among them. NCDs with onset in childhood and adolescence may have broad repercussions for social and intellectual development, and in this setting intellectual developmental disorder (intellectual disability) or other neurodevelopmental disorders may also be diagnosed to capture the full diagnostic picture and ensure the provision of a broad range of services. In older individuals, NCDs often occur in the setting of medical illnesses, frailty, and sensory loss, which complicate the clinical picture for diagnosis and treatment. When cognitive loss occurs in youth to midlife, individuals and families are likely to seek care. NCDs are typically easiest to identify at younger ages, although in some settings malingering or factitious disorder may be a concern. Very late in life, cognitive symptoms may

not cause concern or may go unnoticed. In late life, mild NCD must also be distinguished from the more modest deficits associated with “normal aging,” although a substantial fraction of what has been ascribed to normal aging likely represents prodromal phases of various NCDs. In addition, it becomes harder to recognize mild NCD with age because of the increasing prevalence of medical illness and sensory deficits. It becomes harder to differentiate among subtypes with age because there are multiple potential sources of neurocognitive decline. Risk and Prognostic Factors Risk factors vary not only by etiological subtype but also by age at onset within etiological subtypes. Some subtypes are distributed throughout the life span, whereas others occur exclusively or primarily in late life. Even within the NCDs of aging, the relative prevalence varies with age: Alzheimer’s disease is uncommon before age 60 years, and the prevalence increases steeply thereafter, while the overall less common frontotemporal degeneration has earlier onset and represents a progressively smaller fraction of NCDs with age. The strongest risk factor for major and mild NCDs is age, primarily because age increases the risk of neurodegenerative and cerebrovascular disease. Risk of NCDs varies by ethnic and racialized background and is associated with variation in risk of underlying diseases (e.g., hypertension, diabetes), predisposing conditions (e.g., head injury), environment (e.g., access to nutritious food, safe spaces for exercise), and other factors. For example, in the United States, African Americans and Latinx tend to be at higher risk for vascular dementia than Whites. Lower education and literacy are risk factors for NCDs that also can vary by ethnoracial group because of differential exposure to adverse social determinants of health. Culture-Related Diagnostic Issues Individuals’ and families’ level of awareness and concern about neurocognitive symptoms may vary across ethnic, racialized, and occupational groups. Cultural differences regarding whether decreased cognitive ability is seen as a normal part of aging (“normalization”) and in dementiarelated stigma can delay families’ recognition of a problem and decrease help seeking for individuals in the early stages of cognitive loss. For example, social stigma appears to be associated with underutilization of services for cognitive impairment among some underserved ethnic and racialized groups (e.g., Chinese Americans, Korean Americans). Neurocognitive symptoms are more likely to be noticed, particularly at the mild level, in individuals who engage in complex occupational, domestic, or recreational activities. In addition, norms for neuropsychological testing tend to be available only for broad populations, and thus they may not be easily applicable to individuals with less than high school education or those being evaluated outside their primary language or culture. Culturally related diagnostic challenges include accounting for intraethnic variation in the interpretation of assessments; evaluating the effect on neuropsychological testing of a) the test taker’s stereotype threat (i.e., anxiety from concerns that he or she will confirm the negative stereotype of the ethnic or racialized group by underperforming) and/or b) the clinician’s implicit (unconscious) bias on test

interpretation; and selecting the appropriate language when assessing bilingual individuals. Bilingual individuals with dementia may lose their facility with acquired nonnative languages, which might affect their ability to communicate with caregivers. The caregiving environment may be influenced by cultural norms of family responsibility to care for the elderly, for example, by affecting the decision whether to care for the elder with NCD at home or in a care facility. In some cultures, adult children are expected to provide care for their older parents (e.g., filial piety) so that a functional limitation may not be as obvious to the dependent elder or the family. Sex- and Gender-Related Diagnostic Issues Some studies show that men and women experience major and mild NCD differently. Sex- and gender-related factors may influence incidence and prevalence, the etiology (risk and protective factors), and the clinical manifestations of major and mild NCD. More women than men experience major NCD because of their longer life span. Thus, a woman of a given age has a higher cumulative risk of developing major NCD before death than a man of the same age. The difference in incidence rates is less clear and may vary across populations and over time because of gender-related factors (e.g., education, occupation, family role, stress). For example, the incidence of dementia in several higher-income countries has declined in the past 30 years, and the decline was different in men and women across countries. Women tend to express a broader range of symptoms. In particular, women tend to manifest more psychiatric symptoms such as depression, anxiety, and delusions. Men tend to manifest more aggression, apathy, and vegetative symptoms. Like age, culture, and occupation, sex and gender issues may affect the level of concern and awareness of cognitive symptoms. In addition, for late-life NCDs, women are likely to be older, to have more medical comorbidity, and to live alone, which can complicate evaluation and treatment. In addition, there are sex and gender differences in the frequency of some of the etiological subtypes. Diagnostic Markers In addition to a careful history, neuropsychological assessments are the key measures for diagnosis of NCDs, particularly at the mild level, where functional changes are minimal and symptoms more subtle. Ideally, individuals will be referred for formal neuropsychological testing, which will provide a quantitative assessment of all relevant domains and thus help with diagnosis; provide guidance to the family on areas where the individual may require more support; and serve as a benchmark for further decline or response to therapies. When such testing is unavailable or not feasible, the brief assessments in Table 1 can provide insight into each domain. More global brief mental status tests may be helpful but may be insensitive, particularly to modest changes in a single domain or in those with high premorbid abilities, and may be overly sensitive in those with low premorbid abilities. In distinguishing among etiological subtypes, additional diagnostic markers may come into play, particularly neuroimaging studies such as magnetic resonance imaging scans and positron

Normal cognition. Delirium. Major depressive disorder. Specific learning disorder and other neurodevelopmental disorders. emission tomography scans. In addition, specific markers may be involved in the assessment of specific subtypes and may become more important as additional research findings accumulate over time, as discussed in the relevant sections. Association With Suicidal Thoughts or Behavior Large-scale studies indicate elevated rates of suicidal behavior in individuals with NCD due to a variety of etiologies compared with persons without an NCD. A nationwide study in Taiwan reported that attempted suicide in late life is associated with subsequent dementia. Functional Consequences of Major and Mild Neurocognitive Disorders By definition, major and mild NCDs affect functioning, given the central role of cognition in human life. Thus, the criteria for the disorders, and the threshold for differentiating mild from major NCD, are based in part on functional assessment. Within major NCD there is a broad range of functional impairment, as implemented in the severity specifiers. In addition, the specific functions that are compromised can help identify the cognitive domains affected, particularly when neuropsychological testing is not available or is difficult to interpret. Differential Diagnosis The differential diagnosis between normal cognition and mild NCD, as between mild and major NCD, is challenging because the boundaries are inherently arbitrary. Careful history taking and objective assessment are critical to these distinctions. A longitudinal evaluation using quantified assessments may be key in detecting mild NCD. Both mild and major NCD may be difficult to distinguish from a persistent delirium, which can co-occur. Careful assessment of attention and arousal will help to make the distinction. The distinction between mild NCD and major depressive disorder, which may co-occur with NCD, can also be challenging. Specific patterns of cognitive deficits may be helpful. For example, consistent memory and executive function deficits are typical of Alzheimer’s disease, whereas nonspecific or more variable performance is seen in major depression. Alternatively, treatment of the depressive disorder with repeated observation over time may be required to make the diagnosis. A careful clarification of the individual’s baseline status will help distinguish an NCD from a specific learning disorder or other neurodevelopmental disorders. Additional issues may enter the differential for specific etiological subtypes, as described in the relevant sections. Comorbidity NCDs are common in older individuals and thus often co-occur with a wide variety of agerelated diseases that may complicate diagnosis or treatment. Most notable of these is delirium, for which NCD increases the risk. In older individuals, a delirium during hospitalization is, in many cases, the first time that an NCD is noticed, although a careful history will often reveal evidence of earlier decline. Mixed NCDs are also common in older

690 individuals, as many etiological entities increase in prevalence with age. In younger individuals, NCD often co-occurs with neurodevelopmental disorders; for example, a head injury in a preschool child may also lead to significant developmental and learning issues. Additional comorbidity of NCD is often related to the etiological subtype, as discussed in the relevant sections. Major or Mild Neurocognitive Disorder Due to Alzheimer’s Disease Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. There is insidious onset and gradual progression of impairment in one or more cognitive domains (for major neurocognitive disorder, at least two domains must be impaired). C. Criteria are met for either probable or possible Alzheimer’s disease as follows: For major neurocognitive disorder: Probable Alzheimer’s disease is diagnosed if either of the following is present; otherwise, possible Alzheimer’s disease should be diagnosed.

1. Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing.

2. All three of the following are present: a. Clear evidence of decline in memory and learning and at least one other cognitive domain (based on detailed history or serial neuropsychological testing). b. Steadily progressive, gradual decline in cognition, without extended plateaus. c. No evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease, or another neurological, mental, or systemic disease or condition likely contributing to cognitive decline). For mild neurocognitive disorder: Probable Alzheimer’s disease is diagnosed if there is evidence of a causative Alzheimer’s disease genetic mutation from either genetic testing or family history. Possible Alzheimer’s disease is diagnosed if there is no evidence of a causative Alzheimer’s disease genetic mutation from either genetic testing or family history, and all three of the following are present:

3. Clear evidence of decline in memory and learning.

4. Steadily progressive, gradual decline in cognition, without extended plateaus.

5. No evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease, or another neurological or systemic disease or condition likely contributing to cognitive decline). D. The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder. Coding note (see coding table on pp. 682–683): For major neurocognitive disorder due to probable or possible Alzheimer’s disease, with behavioral disturbance, code first G30.9 Alzheimer’s disease, followed by F02.81. For major neurocognitive disorder due to probable or possible Alzheimer’s disease, without behavioral disturbance, code first G30.9 Alzheimer’s disease, followed by F02.80. Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded. For mild neurocognitive disorder due to Alzheimer’s disease, code G31.84. (Note: Do not use the additional code for Alzheimer’s disease. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild neurocognitive disorder due to Alzheimer’s disease: Use additional code(s) to indicate clinically significant psychiatric symptoms due to Alzheimer’s disease (e.g., F06.2 psychotic disorder due to Alzheimer’s disease, with delusions; F06.32 depressive disorder due to Alzheimer’s disease, with major depressive–like episode). Diagnostic Features Beyond the neurocognitive disorder (NCD) syndrome (Criterion A), the core features of major or mild NCD due to Alzheimer’s disease include an insidious onset and gradual progression of cognitive and behavioral symptoms (Criterion B). The typical presentation is amnestic (i.e., with impairment in memory and learning). Unusual nonamnestic presentations, particularly visuospatial and logopenic aphasic variants, also exist. A significant proportion of individuals, likely more than half, first present with behavioral symptoms before the onset of cognitive symptoms; the presence of behavioral disturbance should be noted using the appropriate specifier codes. At the mild NCD phase, Alzheimer’s disease manifests typically with impairment in memory and learning, sometimes accompanied by deficits in executive function. At the major NCD phase, visuoconstructional/perceptual-motor ability and language (e.g., word retrieval) will also be impaired, particularly when the NCD is moderate to severe. Social cognition tends to be preserved until late in the course of the disease with the exception of individuals who have the less common variants with significant dysexecutive and behavioral disturbance. A level of diagnostic certainty must be specified denoting Alzheimer’s disease as the “probable” or “possible” etiology (Criterion C). Probable Alzheimer’s disease is diagnosed in

both major and mild NCD if there is evidence of a causative Alzheimer’s disease gene, either from genetic testing or from an autosomal dominant family history coupled with autopsy confirmation or a genetic test in an affected family member. At present, the designation of “probable” represents the highest level of diagnostic certainty within the current criteria framework. However, current developments in biomarkers continue to increase diagnostic certainty (e.g., when brain positron emission tomography [PET] scans may indicate the presence of Alzheimer’s pathology, such as evidence of amyloid and/or tau deposition by imaging or cerebrospinal [CSF] analysis). For major NCD, a typical clinical picture, without extended plateaus or evidence of mixed etiology, can also be diagnosed as due to probable Alzheimer’s disease. However, in some individuals there may be prolonged periods of very slow or minimal progression. For mild NCD, given the lesser degree of certainty that the deficits will progress, these features are only sufficient for a possible Alzheimer’s etiology. As stated above, however, new biomarker methods may affect the use of “probable” and “possible” in mild NCD. If the etiology appears mixed, mild NCD due to multiple etiologies should be diagnosed. In any case, for both mild and major NCD due to Alzheimer’s disease, the clinical features must not suggest another primary etiology for the NCD (Criterion D). As biomarker data continue to inform the nature of underlying pathologies, it is likely that the existence of multiple etiologies will be more systematically mapped in the future to better identify diagnostic variations in NCD due to multiple etiologies. Associated Features For individuals with NCD due to Alzheimer's disease, symptoms extend beyond cognitive deficits to include neuropsychiatric symptoms such as agitation, apathy, depression, delusions, and sleep disorders. Neuropsychiatric symptoms may also be described as behavioral and psychological symptoms of dementia and have been observed in neurocognitive disorders of all etiologies. These symptoms are nearly universal in Alzheimer's disease as confirmed in two U.S. population samples, with 5-year follow-up in one reporting that 98% of individuals with NCD due to Alzheimer's disease develop neuropsychiatric symptoms. Neuropsychiatric symptoms lead to disability, worsening quality of life, greater impairment in activities of daily living, faster cognitive and functional decline, greater caregiver burden, earlier institutionalization, and accelerated mortality. Neuropsychiatric symptoms are often more distressing than cognitive manifestations and are frequently the reason that health care assistance is sought. These symptoms are also frequently present at the mild NCD stage, with evidence suggesting that more than half of individuals who develop dementia begin with neuropsychiatric symptoms. At the mild NCD stage or the mildest level of major NCD, depression, irritability, and/or apathy are most often seen. With moderately severe major NCD, delusions, agitation, combativeness, and wandering are common. Late in the illness, gait disturbance, dysphagia, incontinence, myoclonus, and seizures are observed. Prevalence The prevalence of overall NCD due to Alzheimer’s disease rises steeply with age. In high-

income countries, it ranges from 5% to 10% in individuals ages 60–69 years to at least 25% thereafter. An estimated 5.4 million Americans of all ages had dementia due to Alzheimer’s disease in 2016, including about 200,000 individuals with disease onset before age 65. Dementia due to Alzheimer’s disease is found in 11% of individuals age 65 and older and 32% of those age 85 and older. Estimates applying incidence rates of dementia due to Alzheimer’s disease to U.S. census data indicate that 81% of those with the disease are age 75 or older. The percentage of dementias attributable to Alzheimer’s disease ranges from about 60% to over 90%, depending on the setting and diagnostic criteria. Mild NCD due to Alzheimer’s disease is likely to represent a substantial fraction of mild cognitive impairment (MCI) as well. Studies show that prevalence of dementia due to Alzheimer’s disease tends to vary by ethnoracial background; for example, in the United States, prevalence in individuals age 65 years and older ranges from 3.5% to 14.4%, depending on ethnoracial group, age, and assessment methodology. Higher prevalence has been found among African Americans and U.S. Latinx of Caribbean origin, after adjustment for gender and clinical comorbidities. Development and Course Major or mild NCD due to Alzheimer’s disease progresses gradually, at times with plateaus, through severe dementia to death. The mean duration of survival after diagnosis is approximately 10 years, reflecting the advanced age of the majority of individuals rather than the course of the disease; some individuals can live with the disease for as long as 20 years. Late-stage individuals are eventually mute and bedbound. Death most commonly results from aspiration in those who survive through the full course. In mild NCD due to Alzheimer’s disease, impairments increase over time, and functional status gradually declines until symptoms reach the threshold for the diagnosis of major NCD. The onset of symptoms is usually at ages 70 through 89; early-onset forms seen in individuals ages 40–59 are often, but not always, related to known causative mutations. Symptoms and pathology do not differ much by onset ages. However, younger individuals are more likely to survive the full course of the disease, while older individuals are more likely to have numerous medical comorbidities that affect the course and management of the illness. Diagnostic complexity is higher in older adults because of the increased likelihood of comorbid medical illness and mixed pathology. Age at symptom onset, rate of cognitive decline, and survival rates appear to vary by ethnoracial background. For example, compared with non-Latinx Whites, U.S. Latinx can develop Alzheimer’s disease symptoms up to 4 years earlier, African Americans tend to show slower cognitive decline, and both underserved groups may have longer survival periods. Risk and Prognostic Factors A number of risk factors have been identified, including low educational status, midlife hypertension, obesity, and hearing loss, as well as late-life smoking, depression, physical inactivity, social isolation, and diabetes. The co-occurrence of multiple vascular risk factors also increases risk for Alzheimer’s disease and may act by increasing cerebrovascular pathology or

Genetic and physiological. also through direct effects on Alzheimer’s pathology. Traumatic brain injury, especially in men, may increase risk for major or mild NCD due to Alzheimer’s disease, although this relationship remains controversial. Age is definitively the strongest risk factor for Alzheimer’s disease, as the prevalence estimates demonstrate. A strong genetic predisposition (60%–80% of attributable risk) has been demonstrated. Rare mutations on chromosomes 1, 14, and 21 follow Mendelian inheritance, leading to autosomal dominant forms. Individuals with Down syndrome (trisomy 21) may develop Alzheimer’s disease if they survive to midlife. The most common risk factors are polygenic, with more than 45 risk genes/loci having been identified, typically with small effects on risk. The strongest genetic susceptibility polymorphism, apolipoprotein E4 (APOEE4), increases risk and decreases age at onset, particularly in homozygous individuals, although some homozygous individuals survive to advanced ages without developing symptoms. Ethnoracial and national origin are related to the genetic susceptibility profile for Alzheimer’s disease. While APOEE4 is associated with Alzheimer’s disease risk, this association has not been consistently found across all ethnic and racialized groups. For example, some studies have identified a unique mutation in the Gly206Ala presenilin 1 gene among individuals of Puerto Rican descent with Alzheimer’s disease, which is also related to early onset. Moreover, some studies have found a stronger association with ABCA7, a protein transporter gene, among individuals who identify as African American than among U.S. Whites. Culture-Related Diagnostic Issues Detection of an NCD may be more difficult in cultural and socioeconomic settings where memory loss is considered normal in old age, where older adults face fewer cognitive demands in everyday life, or where very low educational levels pose greater challenges to objective cognitive assessment. Sex- and Gender-Related Diagnostic Issues Women were found to have a higher incidence of Alzheimer’s disease than men in several European studies, but the incidence was similar in men and women in most North American studies. Some studies suggested that the symptoms of dementia progress faster in women than in men. However, because women perform better than men of the same age on some verbal memory tests, it is also possible that gender differences reflect the cut-off scores of tests used to support a diagnosis. Different cut-off scores may be useful in men and women when assessing for mild cognitive impairment. Diagnostic Markers Amyloid-predominant neuritic plaques, tau-predominant neurofibrillary tangles, and neuronal loss observed microscopically or manifested in regional cortical atrophy (e.g., hippocampal, parietal, frontal) are hallmarks of the pathological diagnosis of Alzheimer’s disease and may be confirmed via postmortem histopathological examination. For early-onset cases with apparent autosomal dominant inheritance, a mutation in one of the known

Other neurocognitive disorders. causative Alzheimer’s disease genes—amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2)—may be involved, and genetic testing for such mutations is commercially available, although usually without clinical utility. While APOE E*4 cannot serve as a diagnostic marker because it is a risk factor (i.e., neither necessary nor sufficient for disease occurrence), in rare instances genetic testing at this locus may have utility in clinical settings. Since amyloid beta-42 deposition in the brain occurs early in the pathophysiological cascade, amyloid-based diagnostic tests such as amyloid imaging on brain PET scans and reduced levels of amyloid beta-42 in the CSF may have diagnostic value. Similarly, tau PET imaging or CSF analyses for elevated total tau or phospho-tau levels are available for clinical use. Signs of neuronal injury, such as hippocampal and temporoparietal cortical atrophy on a magnetic resonance image scan and temporoparietal hypometabolism on a fluorodeoxyglucose PET scan, provide evidence of neuronal damage but are less specific for Alzheimer’s disease. Most of these biomarkers have been validated and are widely available in tertiary care settings. Blood-derived biomarkers for Alzheimer’s disease are being developed and are likely to become clinically available as diagnostic, prognostic, and theranostic indicators. Association With Suicidal Thoughts or Behavior Alzheimer’s disease is associated with a moderate risk of suicide even many years after the diagnosis; thus, ongoing assessment of mood and suicidality is appropriate. A large population study in Denmark found that the risk of suicide in individuals with a hospital-determined diagnosis of dementia was three- to eightfold greater compared with persons without dementia. In contrast, several other studies found mixed results regarding suicide risk in individuals with Alzheimer’s disease. A review of the neurobiology of suicide in the elderly found preliminary evidence of an association with cognitive deficits and elderly suicidal behavior, especially regarding impaired decision-making and reduced cognitive inhibition. Functional Consequences of Major or Mild Neurocognitive Disorder Due to Alzheimer’s Disease Because of the effect on cognition, behavior, and functioning, NCD due to Alzheimer’s disease has a serious and substantial impact on individuals, their caregivers, and families. Early in the disease course, memory loss, disorientation, and mood symptoms adversely impact independence, and create safety concerns (e.g., around driving). For individuals with onset at younger ages, NCD due to Alzheimer’s disease can lead to early retirement. As the disease advances, individuals become increasingly disabled in instrumental and basic daily living activities, slowly becoming fully dependent on others. Caregivers for individuals with NCD due to Alzheimer’s disease often see their social network deteriorate and develop a series of health and mental health problems that can adversely affect outcomes for both the caregiver and the individual with the NCD. Differential Diagnosis Major and mild NCDs due to other neurodegenerative processes (e.g., Lewy body disease, frontotemporal degeneration) share the insidious onset and gradual decline caused by Alzheimer’s disease but have distinctive core features of their own (which are

Other concurrent, active neurological or systemic illness. Major depressive disorder. not always present). For example, NCD with Lewy bodies is typically characterized by frequent fluctuations in cognition early in the disease, parkinsonian features, gait imbalances, and visual hallucinations. Individuals with frontotemporal NCD may present with a distinct behavioral or language variant. The behavioral variant typically first manifests with prominent changes in social behavior, such as disinhibition, apathy, or perseverative behavior, that may not infrequently lead to a primary psychiatric diagnosis. In contrast, the language variant of frontotemporal NCD may manifest with impairments in expressive language or word comprehension. In major or mild vascular NCD, there is typically a history of stroke temporally related to the onset of cognitive impairment, and infarcts or hemosiderin deposits observed on brain imaging can be judged sufficient to account for the clinical picture. However, major or mild vascular NCD shares many clinical features with Alzheimer’s disease; frequently Alzheimer’s pathology is present alone or in combination with vascular pathologies. It should be noted that white matter change alone does not constitute enough evidence of cerebrovascular disease to propose a mixed etiology if the other diagnostic considerations support the diagnosis of NCD due to Alzheimer’s disease. The presence of subcortical ischemic changes on neuroimaging must be interpreted carefully in view of whether concurrent Alzheimer’s pathology is present. Other neurological or systemic illness should be considered if there is an appropriate temporal relationship and severity to account for the clinical picture. At the mild NCD level, it may be difficult to distinguish an Alzheimer’s disease etiology from that of another medical condition (e.g., thyroid disorders, vitamin B12 deficiency). Particularly at the mild NCD level, the differential diagnosis also includes major depression. The presence of depression may be associated with reduced daily functioning and poor concentration that may resemble an NCD, but improvement with treatment of depression may be useful in making the distinction. If the symptoms meeting criteria for a major depressive episode are judged to be due to the physiological effects of Alzheimer’s disease, a diagnosis of depressive disorder due to Alzheimer’s disease, with major depressive– like episode, should be given instead of major depressive disorder. Comorbidity Most individuals with Alzheimer’s disease are elderly and have multiple medical conditions that can complicate diagnosis and influence the clinical course. Major or mild NCD due to Alzheimer’s disease commonly co-occurs with cerebrovascular disease, which contributes to the clinical picture. When a comorbid condition contributes to the NCD in an individual with Alzheimer’s disease, then NCD due to multiple etiologies should be diagnosed. Major or Mild Frontotemporal Neurocognitive Disorder

Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. The disturbance has insidious onset and gradual progression. C. Either (1) or (2):

1. Behavioral variant: a. Three or more of the following behavioral symptoms: i. Behavioral disinhibition. ii. Apathy or inertia. iii. Loss of sympathy or empathy. iv. Perseverative, stereotyped or compulsive/ritualistic behavior. v. Hyperorality and dietary changes. b. Prominent decline in social cognition and/or executive abilities.
2. Language variant: a. Prominent decline in language ability, in the form of speech production, word finding, object naming, grammar, or word comprehension. D. Relative sparing of learning and memory and perceptual-motor function. E. The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder. Probable frontotemporal neurocognitive disorder is diagnosed if either of the following is present; otherwise, possible frontotemporal neurocognitive disorder should be diagnosed:
3. Evidence of a causative frontotemporal neurocognitive disorder genetic mutation, from either family history or genetic testing.
4. Evidence of disproportionate frontal and/or temporal lobe involvement from neuroimaging. Possible frontotemporal neurocognitive disorder is diagnosed if there is no evidence of a genetic mutation, and neuroimaging has not been performed. Coding note (see coding table on pp. 682–683): For major neurocognitive disorder due to probable or possible frontotemporal degeneration, with behavioral disturbance, code first G31.09 frontotemporal degeneration, followed by F02.81. For major neurocognitive disorder due to probable or possible frontotemporal degeneration, without behavioral disturbance, code first G31.09 frontotemporal degeneration, followed by F02.80. Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded.

For mild neurocognitive disorder due to frontotemporal degeneration, code G31.84. (Note: Do not use the additional code for frontotemporal degeneration. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild frontotemporal neurocognitive disorder: Use additional code(s) to indicate clinically significant psychiatric symptoms due to frontotemporal degeneration (e.g., F06.33 bipolar and related disorder due to frontotemporal degeneration, with manic features; F07.0 personality change due to frontotemporal degeneration, disinhibited type). Diagnostic Features Major or mild frontotemporal neurocognitive disorder (NCD) comprises a number of syndromic variants characterized by the progressive development of behavioral and personality change and/or language impairment. The behavioral variant and two language variants (semantic and agrammatic/nonfluent) exhibit distinct patterns of brain atrophy and some distinctive neuropathology. The criteria must be met for either the behavioral or the language variant to make the diagnosis, but many individuals present with features of both. Individuals with behavioral-variant major or mild frontotemporal NCD present with varying degrees of apathy or disinhibition. They may lose interest in socialization, self-care, and personal responsibilities, or display socially inappropriate behaviors. Insight is usually impaired, and this often delays medical consultation. The first referral is often to a psychiatrist. Individuals may develop changes in social style, and in religious and political beliefs, with repetitive movements, hoarding, changes in eating behavior, and hyperorality. In later stages, loss of sphincter control may occur. Cognitive decline is less prominent, and formal testing may show relatively few deficits in the early stages. Common neurocognitive symptoms are lack of planning and organization, distractibility, and poor judgment. Deficits in executive function, such as poor performance on tests of mental flexibility, abstract reasoning, and response inhibition, are present, but learning and memory are relatively spared, and perceptualmotor abilities are almost always preserved in the early stages. Individuals with language-variant major or mild frontotemporal NCD present with primary progressive aphasia with gradual onset, with two subtypes commonly described: semantic variant and agrammatic/nonfluent variant; each variant has distinctive features and corresponding neuropathology. A third form of progressive language decline, called logopenic progressive aphasia, is associated with left temporoparietal dysfunction and is often caused by Alzheimer’s disease pathology. “Probable” is distinguished from “possible” frontotemporal NCD by the presence of causative genetic factors (e.g., mutations in the gene coding for microtubule-associated protein tau) or by the presence of distinctive atrophy or reduced activity in frontotemporal regions on structural or functional imaging. Associated Features

Genetic and physiological. Extrapyramidal features may be prominent in some cases, with an overlap with syndromes such as progressive supranuclear palsy and corticobasal degeneration. Features of motor neuron disease may be present in some cases (e.g., muscle atrophy, weakness). A subset of individuals develop visual hallucinations. Prevalence Major or mild frontotemporal NCD is a common cause of early-onset NCD in individuals younger than 65 years. In international studies, population prevalence estimates are in the range of 2–31 per 100,000, with overall rates generally noted to be equal in men and women, although variation exists among studies. Approximately 20%–25% of cases of frontotemporal NCD occur in individuals older than 65 years. Frontotemporal NCD accounts for about 5% of all cases of dementia in unselected autopsy series. The behavioral variant is the most common presentation of NCD due to frontotemporal degeneration, occurring in approximately 60% of cases. Development and Course Individuals with major or mild frontotemporal NCD commonly present in their 50s, although the age at onset varies from the 20s through the 80s. The disease is gradually progressive, with median survival being 6–11 years after symptom onset and 3–4 years after diagnosis. Survival is shorter and decline is faster in major or mild frontotemporal NCD than in typical Alzheimer’s disease. Risk and Prognostic Factors Approximately 40% of individuals with major or mild frontotemporal NCD have a family history of early-onset NCD, and approximately 10% show an autosomal dominant inheritance pattern. A number of genetic factors have been identified, such as mutations in the gene encoding the microtubule-associated protein tau (MAPT), the granulin gene (GRN), and the C9ORF72 gene (C9orf72). A number of families with causative mutations have been identified (see the section “Diagnostic Markers” for this disorder), but many individuals with known familial transmission do not have a known mutation. The presence of motor neuron disease is associated with a more rapid deterioration. Diagnostic Markers Computed tomography (CT) or structural magnetic resonance imaging (MRI) may show distinct patterns of atrophy. In behavioral-variant major or mild frontotemporal NCD, both frontal lobes (especially the medial frontal lobes) and the anterior temporal lobes are atrophic. In semantic language–variant major or mild frontotemporal NCD, the middle, inferior, and anterior temporal lobes are atrophic bilaterally but asymmetrically, with the left side usually being more affected. Nonfluent language–variant major or mild frontotemporal NCD is associated with predominantly left posterior frontal-insular atrophy. Functional imaging demonstrates hypoperfusion and/or cortical hypometabolism in the corresponding brain regions, which may be present in the early stages in the absence of structural abnormality. Emerging biomarkers for Alzheimer’s disease

Other neurocognitive disorders. Other neurological conditions. (e.g., cerebrospinal fluid amyloid-beta and tau levels, and amyloid imaging) may help in the differential diagnosis, but the distinction from Alzheimer’s disease can remain difficult. In familial cases of frontotemporal NCD, the identification of genetic mutations may help confirm the diagnosis. Mutations associated with frontotemporal NCD include the genes encoding microtubule-associated protein tau (MAPT) and granulin (GRN), C9ORF72, transactive response DNA-binding protein of 43 kDa (TDP-43, or TARDBP), valosin-containing protein (VCP), chromatin modifying protein 2B (CHMP2B), and fused in sarcoma protein (FUS). Functional Consequences of Major or Mild Frontotemporal Neurocognitive Disorder Because of the relative early age at onset of the disorder, the disorder often affects workplace and family life. Because of the involvement of language and/or behavior, function is often more severely impaired relatively early in the course. For individuals with the behavioral variant, prior to diagnostic clarification there may be significant family disruption, legal involvement, and problems in the workplace because of socially inappropriate behaviors. The functional impairment attributable to behavioral change and language dysfunction, which can include hyperorality, impulsive wandering, and other disinhibited behaviors, may far exceed that attributable to the cognitive disturbance and may lead to nursing home placement or institutionalization. These behaviors can be severely disruptive, even in structured care settings, particularly when the individuals are otherwise healthy, nonfrail, and free of other medical comorbidities. Differential Diagnosis Other neurodegenerative diseases may be distinguished from major or mild frontotemporal NCD by their characteristic features. In major or mild NCD due to Alzheimer’s disease, decline in learning and memory is an early feature. However, 10%–30% of individuals presenting with a syndrome suggestive of major or mild frontotemporal NCD are found at autopsy to have Alzheimer’s disease pathology. This occurs more frequently in individuals who present with progressive dysexecutive syndromes in the absence of behavioral changes or movement disorder or in those with the logopenic variant. In major or mild NCD with Lewy bodies, core and suggestive features of Lewy bodies must be present. In major or mild NCD due to Parkinson’s disease, spontaneous parkinsonism emerges well before the cognitive decline. In major or mild vascular NCD, depending on affected brain regions, there may also be loss of executive function and behavioral changes such as apathy, and this disorder should be considered in the differential diagnosis. However, history of a cerebrovascular event is temporally related to the onset of cognitive impairment in major or mild vascular NCD, and neuroimaging reveals infarctions or white matter lesions sufficient to account for the clinical picture. Major or mild frontotemporal NCD overlaps with progressive supranuclear palsy, corticobasal degeneration, and motor neuron disease clinically as well as

Other mental disorders and medical conditions. pathologically. Progressive supranuclear palsy is characterized by supranuclear gaze palsies and axial-predominant parkinsonism. Pseudobulbar signs may be present, and retropulsion (losing balance in a backward direction) is often prominent. Neurocognitive assessment shows psychomotor slowing, poor working memory, and executive dysfunction. Corticobasal degeneration presents with asymmetric rigidity, limb apraxia, postural instability, myoclonus, alien limb phenomenon, and cortical sensory loss. Many individuals with behavioral-variant major or mild frontotemporal NCD show features of motor neuron disease, which tend to be mixed upper and predominantly lower motor neuron disease. Behavioral-variant major or mild frontotemporal NCD may be mistaken for a primary mental disorder, such as major depression, bipolar disorders, or schizophrenia, and individuals with this variant often present initially to psychiatry. Over time, the development of progressive neurocognitive difficulties will help to make the distinction. A careful medical evaluation will help to exclude treatable causes of NCDs, such as metabolic disturbances, nutritional deficiencies, and infections. If the symptoms characteristic of a primary mental disorder (e.g., delusions) are judged to be due to the physiological effects of frontotemporal degeneration, a diagnosis of the appropriate mental disorder due to frontotemporal degeneration should be given instead of the primary psychotic disorder (e.g., psychotic disorder due to frontotemporal degeneration, with delusions). Major or Mild Neurocognitive Disorder With Lewy Bodies Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. The disorder has an insidious onset and gradual progression. C. The disorder meets a combination of core diagnostic features and suggestive diagnostic features for either probable or possible neurocognitive disorder with Lewy bodies. For probable major or mild neurocognitive disorder with Lewy bodies, the individual has two core features, or one suggestive feature with one or more core features. For possible major or mild neurocognitive disorder with Lewy bodies, the individual has only one core feature, or one or more suggestive features.

1. Core diagnostic features: a. Fluctuating cognition with pronounced variations in attention and alertness. b. Recurrent visual hallucinations that are well formed and detailed. c. Spontaneous features of parkinsonism, with onset subsequent to the development of cognitive decline.
2. Suggestive diagnostic features: a. Meets criteria for rapid eye movement sleep behavior disorder.

b. Severe neuroleptic sensitivity. D. The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder. Coding note (see coding table on pp. 682–683): For major neurocognitive disorder with probable or possible Lewy bodies, with behavioral disturbance, code first G31.83 Lewy body disease, followed by F02.81. For major neurocognitive disorder with probable or possible Lewy bodies, without behavioral disturbance, code first G31.83 Lewy body disease, followed by F02.80. Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded. For mild neurocognitive disorder with Lewy bodies, code G31.84. (Note: Do not use the additional code for Lewy body disease. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild neurocognitive disorder with Lewy bodies: Use additional code(s) to indicate clinically significant psychiatric symptoms due to Lewy body disease (e.g., F06.0 psychotic disorder due to Lewy body disease, with hallucinations; F06.31 depressive disorder due to Lewy body disease, with depressive features). Diagnostic Features Major neurocognitive disorder with Lewy bodies corresponds to the condition known as dementia with Lewy bodies (DLB). The overall major or mild neurocognitive disorder with Lewy bodies (NCDLB) category includes not only progressive cognitive impairment (with early changes in attention, executive function, and visuoperceptual ability, rather than learning and memory) but also recurrent, complex, visual hallucinations; and concurrent symptoms of rapid eye movement (REM) sleep behavior disorder (which can be a very early manifestation); as well as hallucinations in other sensory modalities, apathy, anxiety, depression, and delusions. The cognitive symptoms may fluctuate in a pattern that can resemble a delirium, for which an adequate precipitating factor may or may not be found. The variable presentation of NCDLB symptoms reduces the likelihood of all symptoms being observed in a brief clinic visit and necessitates a thorough assessment, including caregiver observations. The use of assessment scales specifically designed to assess fluctuation may aid in diagnosis. Another core feature is spontaneous parkinsonism; this can often be relatively mild, and the degree of response to levodopa therapy is variable. Up to 25% of individuals with probable NCDLB may never develop extrapyramidal signs, and they are not essential for diagnosis. The parkinsonism must be distinguished from neuroleptic-induced extrapyramidal signs. Accurate diagnosis is essential to safe treatment planning, as up to 50% of individuals with NCDLB have severe sensitivity to neuroleptic drugs, and these medications should be used with extreme caution in individuals suspected of having an NCDLB diagnosis. The diagnosis of mild NCDLB is appropriate for individuals who present with the core

Genetic and physiological. clinical features at a stage when cognitive or functional impairments are not of sufficient severity to fulfill criteria for major NCD, particularly if nonamnestic cognitive deficits are prominent. However, as for all mild NCDs, there will often be insufficient evidence to justify any single etiology, and use of the unspecified diagnosis may be more appropriate. Associated Features Individuals with NCDLB frequently experience repeated falls, syncope, or other transient episodes of unresponsiveness. Autonomic dysfunction may be observed, including orthostatic hypotension, constipation, and urinary incontinence; hypersomnia and hyposmia may also be observed. Prevalence Limited data from several high-income and low- and middle-income countries show that the population-based prevalence estimates for NCDLB range from 0% to 1.2% of the general elderly population, and from 0% to 9.7% of all dementia cases. The mean prevalence of major NCDLB was 4.2% of all dementias in the community, and in clinic-based studies this increased to 7.5% of all dementias. The clinical prevalence of major NCDLB among individuals with dementia does not appear to be significantly affected by either age or sex. In studies from the United States and United Kingdom, the pathological lesions known as Lewy bodies are present in 20%–35% of cases of dementia. In a population-based study in Minnesota that relied on medical records, the incidence of NCDLB was approximately three times higher in men than in women age 65 or older. Development and Course NCDLB is a gradually progressive disorder with insidious onset. However, there is often a prodromal history of confusional episodes (delirium) of acute onset, which may be precipitated by illness or surgery. The distinction between NCDLB, in which Lewy bodies are primarily limbic in location (with or without neocortical involvement), and major or mild NCD due to Parkinson’s disease, which starts in the brain stem, is the order in which the cognitive and motor symptoms emerge. In NCDLB, the cognitive decline is manifested early in the course of illness (see the section “Differential Diagnosis” for this disorder). Onset of symptoms is typically observed in individuals ages 50–89, with most cases having onset in individuals in the mid-70s. Disease course may be characterized by occasional plateaus but eventually progresses through severe dementia to death. Average duration of survival is 5.5– 7.7 years from the onset of cognitive decline. Risk and Prognostic Factors Familial aggregation may occur, and several risk genes have been identified; but in most cases of NCDLB, there is no family history. The available studies suggest that genetic risk factors are as important in NCDLB as in Alzheimer’s disease or Parkinson’s

Major or mild neurocognitive disorder due to Parkinson’s disease. disease. Diagnostic Markers Biomarkers indicative of NCDLB may be considered to carry diagnostic weight equivalent to core clinical features; these include low striatal dopamine transporter uptake on single photon emission computed tomography (SPECT) or positron emission tomography (PET) scan, abnormal (low uptake) (MIBG) myocardial scintigraphy suggesting cardiac sympathetic denervation, and polysomnographic confirmation of REM sleep without atonia. The associated condition REM sleep behavior disorder may be diagnosed through a formal sleep study or identified by questioning the individual or informant about relevant symptoms. The underlying neurodegenerative disease is primarily associated with misfolding and aggregation of αsynuclein, which may be confirmed via postmortem histopathological examination. Neuropsychological testing beyond the use of a brief screening instrument may be necessary to define cognitive deficits clearly. Assessment scales developed to measure fluctuation can be useful. Biomarkers supportive of NCDLB but with more limited evidence of diagnostic value include the following: preservation of medial temporal volume relative to Alzheimer’s disease on magnetic resonance imaging (MRI), generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity with or without the cingulate island sign (sparing of the posterior cingulate cortex relative to the precuneus plus cuneus on fluorodeoxyglucose-PET imaging), and prominent slow-wave activity on electroencephalogram with periodic fluctuations in the prealpha/theta range. Functional Consequences of Major or Mild Neurocognitive Disorder With Lewy Bodies Individuals with NCDLB are more functionally impaired than would be expected for their cognitive deficits when contrasted to individuals with other neurodegenerative diseases, such as Alzheimer’s disease. This is largely a result of motor and autonomic impairments, which cause problems with toileting, transferring, and eating. Sleep disorders and prominent psychiatric symptoms may also add to functional difficulties. Consequently, the quality of life of individuals with NCDLB is often significantly worse than that of individuals with Alzheimer’s disease. Differential Diagnosis The distinction between NCDLB and NCD due to Parkinson’s disease is based on the timing and sequence of motor symptoms and cognitive symptoms. Consensus criteria for DLB separate NCDLB from NCD due to Parkinson’s disease by specifying that for dementia to be attributed to Parkinson’s disease, the Parkinson’s disease diagnosis is present for at least 1 year before cognitive decline has reached the level of major NCD, whereas for NCDLB, the cognitive symptoms may begin before, with, or in the absence of parkinsonism. By contrast, expert consensus criteria for Parkinson’s disease propose that if cognitive decline occurs prior to a motor diagnosis, the diagnosis of Parkinson’s

disease may still be made; therefore, a clinician may attribute the cognitive decline to the Parkinson’s disease and diagnose NCD due to Parkinson’s disease. Consequently, the clinician may choose to diagnose NCD due to Parkinson’s disease or NCDLB for individuals with major NCD that starts either before or within 12 months of Parkinson’s disease. In such circumstances, the clinician decides which diagnosis is more appropriate. If Parkinson’s disease has been diagnosed for at least 1 year prior to the onset of cognitive symptoms, then both expert criteria agree that NCD due to Parkinson’s disease would typically be the appropriate diagnosis. The timing and sequence of parkinsonism and mild NCD may be particularly difficult to determine, and unspecified NCD may need to be diagnosed until the order of clinical progression becomes evident. Comorbidity Lewy body pathology frequently coexists with Alzheimer’s disease, transactive response DNA‐ binding protein 43 (TDP‐43)–related pathology, and cerebrovascular disease pathology, particularly in the oldest age groups. TDP-43 is a protein that has been identified as a source of the proteinopathies across a range of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal degeneration. The presence of multiple pathological lesions has implications for disease prognosis and may be associated with a more rapid cognitive decline and shorter survival time. Major or Mild Vascular Neurocognitive Disorder Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. The clinical features are consistent with a vascular etiology, as suggested by either of the following:

1. Onset of the cognitive deficits is temporally related to one or more cerebrovascular events.

2. Evidence for decline is prominent in complex attention (including processing speed) and frontal-executive function. C. There is evidence of the presence of cerebrovascular disease from history, physical examination, and/or neuroimaging considered sufficient to account for the neurocognitive deficits. D. The symptoms are not better explained by another brain disease or systemic disorder. Probable vascular neurocognitive disorder is diagnosed if one of the following is present; otherwise possible vascular neurocognitive disorder should be diagnosed:

3. Clinical criteria are supported by neuroimaging evidence of significant parenchymal injury attributed to cerebrovascular disease (neuroimagingsupported).

4. The neurocognitive syndrome is temporally related to one or more documented cerebrovascular events.

5. Both clinical and genetic (e.g., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) evidence of cerebrovascular disease is present. Possible vascular neurocognitive disorder is diagnosed if the clinical criteria are met but neuroimaging is not available and the temporal relationship of the neurocognitive syndrome with one or more cerebrovascular events is not established. Coding note (see coding table on pp. 682–683): For major neurocognitive disorder probably or possibly due to vascular disease, with behavioral disturbance, code F01.51. For major neurocognitive disorder probably or possibly due to vascular disease, without behavioral disturbance, code F01.50. An additional medical code for the vascular disease is not used. Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded. For mild vascular neurocognitive disorder, code G31.84. (Note: Do not use an additional code for the vascular disease. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild vascular neurocognitive disorder: Use additional code(s) to indicate clinically significant psychiatric symptoms due to the cerebrovascular disease (e.g., F06.31 depressive disorder due to cerebrovascular disease, with depressive features). Diagnostic Features The diagnosis of major or mild vascular neurocognitive disorder (NCD) requires the establishment of an NCD (Criterion A) and the determination that cerebrovascular disease is the dominant if not exclusive pathology that accounts for the cognitive deficits (Criteria B and C). Vascular etiology may range from large vessel stroke to microvascular disease; the presentation is therefore very heterogeneous, stemming from the types of vascular lesions and their extent and location. The lesions may be focal, multifocal, or diffuse and occur in various combinations. Pathogenic mechanisms responsible for brain parenchymal injury include hypoperfusion and hypoxia, oxidative stress and inflammation leading to endothelial dysfunction, impairment of autoregulation, and disruption of neurovascular coupling. Many individuals with major or mild vascular NCD present with multiple infarctions, with an acute stepwise or fluctuating decline in cognition, and intervening periods of stability and even some improvement. Others may have gradual onset with slow progression, a rapid development of deficits followed by relative stability, or another complex presentation. Major or mild vascular

NCD with a gradual onset and slow progression is generally attributable to small vessel disease leading to lesions in the white matter, basal ganglia, or thalamus. The gradual progression in these cases is often punctuated by acute events that leave subtle neurological deficits. The cognitive deficits in these cases can be attributed to disruption of cortical-subcortical circuits; complex attention, particularly speed of information processing, and executive function are likely to be affected. Clinical subtypes of vascular NCD have been described and include 1) poststroke NCD, manifesting immediately after a stroke; 2) subcortical ischemic vascular NCD; 3) multi-infarct (cortical) NCD; and 4) cortical-subcortical vascular NCD. Assessing for the presence of sufficient cerebrovascular disease relies on history, physical examination, and neuroimaging (Criterion C). Etiological certainty requires the demonstration of abnormalities on neuroimaging. The lack of neuroimaging can result in significant diagnostic inaccuracy by overlooking “silent” brain infarction and white matter lesions. However, if the neurocognitive impairment is temporally associated with one or more well-documented strokes, a probable diagnosis can be made in the absence of neuroimaging. Clinical evidence of cerebrovascular disease includes documented history of stroke, with cognitive decline temporally associated with the event, or physical signs consistent with stroke (e.g., hemiparesis; pseudobulbar syndrome, visual field defect). Neuroimaging (magnetic resonance imaging [MRI] or computed tomography [CT]) evidence of cerebrovascular disease comprises one or more of the following: one or more large vessel infarcts or hemorrhages, a strategically placed single infarct or hemorrhage (e.g., in angular gyrus, thalamus, basal forebrain), two or more lacunes outside the brain stem, or extensive and confluent white matter lesions. The latter is often termed small vessel disease or subcortical ischemic changes on clinical neuroimaging evaluations. MRI is the preferred mode of neuroimaging, and there has been interest in using specialized MRI techniques to detect cerebral microbleeds, cortical microinfarcts, dilated perivascular spaces, and diffusion-based analyses of white matter tracts and network connectivity. For mild vascular NCD, history of a single stroke or extensive white matter disease is generally sufficient. For major vascular NCD, two or more strokes, a strategically placed stroke, or a combination of white matter disease and one or more lacunes is generally necessary. However, the relationship between identifiable vascular pathology in the brain on neuroimaging and the cognitive symptoms is imperfect, and clinical judgment is generally needed to relate the vascular lesions to the cognitive syndrome. The neurocognitive symptoms must not be better explained by another medical condition or mental disorder. For example, prominent memory deficit early in the course might suggest NCD due to Alzheimer’s disease, early and prominent parkinsonian features would suggest NCD due to Parkinson’s disease, and a close association between onset of cognitive and depressive symptoms would suggest cognitive impairment as a result of depression. A number of expert international groups have similarly defined and categorized the vascular NCDs, with which DSM-5 criteria generally display good correspondence. Associated Features

Environmental. A neurological assessment often reveals history of stroke or transient ischemic episodes, and signs indicative of brain infarctions. Also commonly associated are personality and mood changes, abulia, depression, and emotional lability. The development of late-onset depressive symptoms accompanied by psychomotor slowing and executive dysfunction is a common presentation among older adults with progressive small vessel ischemic disease (so-called vascular depression). Prevalence Vascular disease is the second most common cause of NCD after Alzheimer’s disease. In the United States, population prevalence estimates for vascular dementia are 0.98% for individuals ages 71–79 years, 4.09% for those ages 80–89 years, and 6.19% for those age 90 years or older. Within 3 months following stroke, 20%–30% of individuals are diagnosed with dementia. In a European autopsy series of decedents ages 60–103 years, the prevalence of pure vascular dementia was 12.3%. Among those ages 60–69 years, the prevalence was higher (15.0%) compared with those older than 90 years (8.7%). Mixed dementia (Alzheimer’s plus vascular pathology) was present in 5.5% of the overall cohort, with a higher prevalence in those older than 90 years (10.6%) compared with those ages 60–69 years (5.2%). Higher prevalence of vascular dementia has been found among African Americans, Mexican Americans, and South Asian Americans compared with non-Latinx Whites, possibly because of higher rates of risk factors such as diabetes and cardiovascular disease. In Japan and several other Asian countries, the prevalence of dementia due to Alzheimer’s disease has increased over time relative to vascular dementia. Currently, the prevalence of dementia due to Alzheimer’s disease among Japanese Americans is 2.6 times higher than that of vascular dementia. Stroke is more common in men through age 65 years, but more common in women after age 65 years. Overall, the rate of vascular NCD was higher in men in some studies. Development and Course Major or mild vascular NCD can occur at any age, although the prevalence increases exponentially after age 65 years. In older individuals, additional pathologies are almost always present and partly account for the neurocognitive deficits. The course may vary from acute onset with partial improvement to stepwise decline to progressive decline, with fluctuations and plateaus of varying durations. Pure subcortical major or mild vascular NCD can have a slowly progressive course that simulates major or mild NCD due to Alzheimer’s disease. The risk of an ischemic stroke progressing to vascular NCD within 5 years was almost twice as high among African Americans as among non-Latinx Whites in the United States and occurred at younger ages. This is possibly a result of the impact of higher rates of hypertension, diabetes, and adverse social determinants of mental health known to worsen dementia risk, such as limited formal education and low socioeconomic status. Risk and Prognostic Factors The neurocognitive outcomes of vascular brain injury are influenced by

Genetic and physiological. Other neurocognitive disorders. Other medical conditions. Other mental disorders. neuroplasticity factors such as education, physical exercise, and mental activity. The major risk factors for major or mild vascular NCD are the same as those for cerebrovascular disease and stroke, including hypertension, diabetes, smoking, obesity, high cholesterol levels, high homocysteine levels, other risk factors for atherosclerosis and arteriolosclerosis, atrial fibrillation, and other conditions increasing the risk of cerebral emboli. Cerebral amyloid angiopathy, leading to cerebral hemorrhage, is an important risk factor in which amyloid deposits occur within arterial vessels. A genetic risk factor is the hereditary condition cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL. Other rarer forms of genetic disorders linked to vascular NCD exist, but overall the contribution of genetics is small. Diagnostic Markers Structural neuroimaging, using MRI or CT, has an important role in the diagnostic process. There are no other established biomarkers of major or mild vascular NCD. Functional Consequences of Major or Mild Vascular Neurocognitive Disorder Major or mild vascular NCD is commonly associated with physical deficits that cause additional disability. Differential Diagnosis Since incidental brain infarctions and white matter lesions are common in older individuals, it is important to consider other possible etiologies when an NCD is present in an individual with white matter lesions. A history of memory deficit early in the course, and progressive worsening of memory, language, executive function, and perceptualmotor abilities in the absence of corresponding focal lesions on brain imaging, are suggestive of Alzheimer’s disease as the primary diagnosis. Potential biomarkers currently being validated for Alzheimer’s disease, such as cerebrospinal fluid levels of β-amyloid and phosphorylated tau, and amyloid and tau imaging, may prove to be helpful in the differential diagnosis. NCD with Lewy bodies is distinguished from major or mild vascular NCD by its core features of fluctuating cognition, visual hallucinations, and spontaneous parkinsonism. While deficits in executive function and language occur in major or mild vascular NCD, the insidious onset and gradual progression of behavioral features or language impairment are characteristic of frontotemporal NCD and are not typical of vascular etiology. A diagnosis of major or mild vascular NCD is not made if other diseases (e.g., brain tumor, multiple sclerosis, encephalitis, toxic or metabolic disorders) are present and are of sufficient severity to account for the cognitive impairment. A diagnosis of major or mild vascular NCD is inappropriate if the symptoms can be entirely attributed to delirium, although delirium may sometimes be superimposed on a preexisting major or mild vascular NCD, in which case both diagnoses can be made. If the criteria for major depressive disorder are met and the cognitive impairment is

temporally related to the likely onset of the depression, major or mild vascular NCD should not be diagnosed. However, if the NCD preceded the development of the depression, or the severity of the cognitive impairment is out of proportion to the severity of the depression, depressive disorder due to cerebrovascular disease should be diagnosed instead of major depressive disorder. Comorbidity Major or mild NCD due to Alzheimer’s disease commonly co-occurs with major or mild vascular NCD, in which case both diagnoses should be made. Major or mild vascular NCD and depression frequently co-occur. Major or Mild Neurocognitive Disorder Due to Traumatic Brain Injury Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. There is evidence of a traumatic brain injury—that is, an impact to the head or other mechanisms of rapid movement or displacement of the brain within the skull, with one or more of the following:

1. Loss of consciousness.
2. Posttraumatic amnesia.
3. Disorientation and confusion.
4. Neurological signs (e.g., neuroimaging demonstrating injury; visual field cuts; anosmia; hemiparesis; hemisensory loss; cortical blindness; aphasia; apraxia; weakness; loss of balance; other sensory loss that cannot be accounted for by peripheral or other causes). C. The neurocognitive disorder presents immediately after the occurrence of the traumatic brain injury or immediately after recovery of consciousness and persists past the acute post-injury period. Coding note (see coding table on pp. 682–683): For major neurocognitive disorder due to traumatic brain injury, with behavioral disturbance: code first S06.2X9S diffuse traumatic brain injury with loss of consciousness of unspecified duration, sequela; followed by F02.81 major neurocognitive disorder due to traumatic brain injury, with behavioral disturbance. For major neurocognitive disorder due to traumatic brain injury, without behavioral

disturbance: code first S06.2X9S diffuse traumatic brain injury with loss of consciousness of unspecified duration, sequela; followed by F02.80 major neurocognitive disorder due to traumatic brain injury, without behavioral disturbance. Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded. For mild neurocognitive disorder due to traumatic brain injury, code G31.84. (Note: Do not use the additional code for traumatic brain injury. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild neurocognitive disorder due to traumatic brain injury: Use additional code(s) to indicate clinically significant psychiatric symptoms due to the traumatic brain injury (e.g., F06.34 bipolar and related disorder due to traumatic brain injury, with mixed features; F07.0 personality change due to traumatic brain injury, apathetic type). Specifiers Rate the severity of the neurocognitive disorder (NCD), not the underlying traumatic brain injury (see the section “Development and Course” for this disorder). Diagnostic Features Major or mild NCD due to traumatic brain injury (TBI) denotes an acquired and persistent disorder of cognition resulting from a traumatic brain injury. Traumatic brain injury is defined as disruption of brain structure and/or function resulting from the application of biomechanical forces (including acceleration/deceleration forces and blast-related forces), as manifested immediately by one or more of the following clinical signs: loss of consciousness, loss of memory for events immediately before or after the injury (posttraumatic amnesia), alteration in mental state (e.g., confusion, disorientation, slowed thinking), or focal neurological signs (e.g., hemiparesis, hemisensory loss, cortical blindness, aphasia, apraxia, weakness, loss of balance, other sensory loss that cannot be accounted for by peripheral or other causes) (Criterion B). These manifestations of TBI must not be due to alcohol or other drugs or medications, other injuries or treatment(s) for other injuries (e.g., facial injuries, intubation, or bodily/systemic injuries), or psychological trauma, language barrier, or coexisting medical conditions. The severity of a TBI is classified as mild, complicated mild, moderate, or severe according to the thresholds in Table 2. An individual whose injury phenomenologically meets criteria for mild TBI but whose computed tomographic or magnetic resonance imaging in the acute period after TBI reveals traumatic intracranial abnormalities (i.e., traumatic epidural or subdural hematoma, subarachnoid or intracerebral hemorrhage, cerebral contusions or laceration) is classified as complicated mild TBI. Outcomes of individuals with complicated mild TBI are more like those with moderate TBI than those with uncomplicated mild TBI. TABLE 2 Classification of traumatic brain injury (TBI) severity

TBI severity Mild TBI Complicated mild TBI Moderate TBI Severe TBI Loss of consciousness duration ≤ 30 minutes ≤ 30 minutes

 30 minutes to < 24 hours ≥ 24 hours Posttraumatic amnesia duration (densely impaired new learning) ≤ 1 day ≤ 1 day  1 day to < 7 days ≥ 7 days Alteration of consciousness duration (e.g., confusion, disorientation, slowed thinking) ≤ 1 day ≤ 1 day  1 day to < 7 days ≥ 7 days Glasgow Coma Scale score (30 minutes after the event) 13–15 13–15 9–12 3–8 Computed tomography or magnetic resonance imaging of the brain Normal Abnormal Normal or abnormal Normal or abnormal To be attributable to TBI, the NCD must manifest either immediately after the brain injury occurs or immediately after the individual recovers consciousness after the injury, and persist past the acute postinjury period (Criterion C). While the specific cognitive impairments associated with major or mild NCD due to TBI are variable, impairments in complex attention, processing speed, learning and memory, and executive function are common, as are disturbances in social cognition. In more severe TBI in which there is brain contusion, intracranial hemorrhage, or penetrating injury, there may be additional neurocognitive impairments associated with the affected region of the brain and the volume of brain tissue lost (e.g., aphasia, apraxia, disturbances in perceptual-motor function). Associated Features The diagnosis may also be supported by subtle neurological signs (e.g., multiple primitive reflexes such as glabellar sign, snout response, palmomental reflex) or deficits in saccades and smooth-pursuit eye movements co-occurring with frontally mediated cognitive impairments such as complex attention problems, slow processing speed, impaired memory retrieval, or executive dysfunction. Particularly in some cases of penetrating TBI, the diagnosis of NCD due to TBI may be supported by posttraumatic epilepsy with focal onset in a location that corresponds to the anatomy of a cognitive domain in which an individual demonstrates impairment (e.g., medial temporal lobe–onset seizures and episodic memory impairment; frontal lobe seizures and executive dysfunction or social cognitive impairment). Prevalence The prevalence of major and mild NCD due to TBI varies with injury severity and time since injury, with the highest frequencies among individuals with more severe injury and during the acute/subacute post-injury period. In the United States, more than 2.87 million TBIs occur annually, including more than 837,000 TBIs in children. These TBIs account for 2.5 million emergency department visits, 288,000 hospitalizations, and more than 56,000 deaths annually. Among individuals presenting to an emergency department with TBI, the rates for men are 547.6 per 100,000 and for women are 385.9 per 100,000. The TBI rate is higher for men than women in every age group up to age 75 years, after which the rates of TBI between

men and women approach parity. The leading causes of TBI in the United States are falls (178.4 per 100,000), collision with a moving or stationary object (termed “struck by/against” events) (92.7 per 100,000), motor vehicle crashes (74.7 per 100,000), and assaults (50.6 per 100,000 persons). Concussion in sport is increasingly recognized as a cause of mild TBI. Men are approximately 40% more likely to experience a TBI compared with women in the young and adult populations; however, women may have higher risk of TBI after age 65 years. It has been suggested that men with moderate or severe TBI may have a worse prognosis than women with the same level of severity; however, the findings have been mixed. The cause of TBI also differs by sex and gender. Men are more likely to experience injuries at work, in motor vehicle accidents, and during military activities, whereas women are more likely to experience injuries from assault and domestic violence. Development and Course The course of recovery from TBI is variable, depending not only on the specifics of the injury but also on pre-injury and postinjury factors. These factors may favor or impede recovery and include age; prior history of TBI; neurological, psychiatric, and substance use comorbidities and complications; genetics; the timeliness and effectiveness of medical and rehabilitative interventions; and psychosocial support, among others. Neurocognitive impairments are most severe in the acute period following the TBI and may be accompanied by disturbances of emotion and behavior. Across the spectrum of TBI severity, substantial improvement in neurocognitive and associated psychiatric and neurological symptoms and signs is expected. The extent of recovery and the variability in neurocognitive outcomes tend to reflect the severity of TBI, with complete recovery being typical after mild TBI and more variable, and often incomplete, recovery following more severe TBI. Neurocognitive impairments associated with mild TBI typically resolve within days to weeks after the injury, with complete resolution within 3–12 months post-injury. Other symptoms (e.g., depression, irritability, fatigue, headache, photosensitivity, sleep disturbance) that may potentially co-occur with the neurocognitive symptoms also tend to resolve in the weeks following mild TBI. Persistent symptoms after mild TBI or subsequent neurocognitive deterioration should trigger consideration of other potential causes of neurocognitive symptoms and functional limitations, including major depressive disorder, posttraumatic stress disorder (PTSD), anxiety disorders, substance use disorders, sleep disturbances, negative injury perceptions, and poor expectations for recovery. When neurocognitive symptoms and functional limitations persist after mild TBI (including repetitive mild TBI) despite treatment of their other potential causes, diagnosis of an NCD due to TBI may be appropriate. Neurocognitive impairments and associated functional limitations produced by moderate and severe TBI typically improve over weeks to months after the injury, although long-term neurocognitive recovery is often incomplete among individuals with more severe injuries. Nonetheless, neurocognitive and functional improvement may continue for years after moderate or severe TBI, with more individuals cognitively improving than declining during the first 5 years postinjury. With moderate and severe TBI, in addition to persistence of neurocognitive deficits, there may be associated neurological, medical, emotional, and behavioral complications. These include seizures (particularly in the first year), photosensitivity, hyperacusis, irritability, aggression, depression, sleep disturbance, fatigue, apathy, inability to resume occupational and

social functioning at preinjury level, and deterioration in interpersonal relationships. Moderate and severe TBI have been associated with increased risk of depression, aggression, and possibly neurodegenerative diseases such as Alzheimer’s disease, Lewy body disease, and frontotemporal degeneration. The features of persisting major or mild NCD due to TBI will vary by age, specifics of the injury, and cofactors. Persisting TBI-related impairment in an infant or child may be reflected in delays in reaching developmental milestones (e.g., language acquisition), worse academic performance, and possibly impaired social development. Among older teenagers and adults, persisting symptoms may include various neurocognitive deficits, irritability, hypersensitivity to light and sound, easy fatigability, and mood changes, including depression, anxiety, hostility, or apathy. In older individuals, mild TBI may produce neurocognitive outcomes like those associated with moderate or severe TBI in younger adults. Risk and Prognostic Factors Risk factors for adverse cognitive outcomes after TBI include age older than 40 years, lower preinjury cognitive abilities (especially as indexed by education or academic competence), preinjury depressive symptoms, possibly pre-injury unemployment, and injury severity. Other risk factors for adverse cognitive outcomes include a longer duration of posttraumatic amnesia, evidence of traumatic intracranial abnormalities on early computed tomography or magnetic resonance imaging (MRI) studies (i.e., traumatic epidural or subdural hematoma, subarachnoid or intracerebral hemorrhage, cerebral contusions or laceration, diffuse axonal injury) and neurogenetic profile (e.g., APOE*E4 allele carrier status, catechol-O-methyltransferase genotype, ANKK1 Taq1A allele status). Pre-injury alcohol or substance use disorders increase the risk of sustaining a TBI as well as the risk of adverse cognitive outcomes, including memory impairment and executive dysfunction. Diagnostic Markers The diagnosis of major or mild NCD due to TBI may be supported by contemporaneous computed tomographic or MRI findings (e.g., focal atrophy, encephalomalacia, gliosis, white matter abormalities) in brain areas or networks subserving specific cognitive domains in which an individual demonstrates impairment. The diagnosis may also be supported by subtle neurological signs (e.g., multiple primitive reflexes such as glabellar sign, snout response, palmomental reflex) or deficits in saccades and smooth-pursuit eye movements co-occurring with frontally mediated cognitive impairments such as complex attention problems, slow processing speed, impaired memory retrieval, or executive dysfunction. Particularly in some cases of penetrating TBI, the diagnosis of NCD due to TBI may be supported by posttraumatic epilepsy with focal onset in a location that corresponds to the anatomy of a cognitive domain in which an individual demonstrates impairment (e.g., medial temporal lobe–onset seizures and episodic memory impairment; frontal lobe seizures and executive dysfunction or social cognitive impairment). Performance on commonly used general cognitive screening measures, particularly when

interpreted using large-scale, population-based normative data, may usefully identify individuals in need of further neurodiagnostic assessment. However, the diagnosis of major or mild NCD due to TBI rests on performance on domain-specific cognitive assessment interpreted in light of the individual’s prior performance (e.g., neuropsychological estimates of pre-injury cognitive ability or appropriate norms) and assessment of functional status. While neuroimaging and other clinical assessments (e.g., subtle neurological signs) may provide supportive information, they cannot independently diagnose NCD due to TBI. At present, there are no other established biomarkers of major or mild NCD due to TBI. Association With Suicidal Thoughts or Behavior Individuals with TBI, including moderate or severe TBI, are at increased long-term risk for suicide. While depression is a substantial contributor to this risk, it does not fully account for it. Rates of suicidal ideation are as high as 10%, and rates of suicide attempt are 0.8%–1.7% over the first 20 years after TBI. The development of depression and/or suicidal behavior at 1year post-injury is associated with consistently elevated rates of depression and suicidal behavior 5 years after TBI. While the relationship between cognitive impairments and suicide risk after TBI is complex, assessing suicide risk is an important element in the evaluation of individuals with major or mild NCD due to TBI. Youth who have had concussions may be at higher risk for suicidal behavior. There is an increased risk of suicide among both veteran and civilian cohorts with TBI, and individuals seeking mental health care may have a history of TBI. Individuals seeking rehabilitative services for TBI are also at heightened risk for suicidal thoughts and behavior. Functional Consequences of Major or Mild Neurocognitive Disorder Due to Traumatic Brain Injury Approximately 3.17 million individuals in the United States (approximately 1.1% of the population) live with a TBI-related disability, including neurocognitive impairments that compromise the ability to work or perform daily activities and that are associated with the need for ongoing medical care, rehabilitation, support, and services. Cognitive impairments interfere with functional independence, productive employment, and community participation and may reduce satisfaction with life. The influence of cognitive impairments on functional status varies with the type and severity of those impairments; with the presence and severity of co-occurring psychiatric, substance use, neurological, and medical conditions; and with family, other psychosocial, and medical support. With mild NCD due to TBI, individuals may report reduced cognitive efficiency, difficulty concentrating, and lessened ability to perform usual activities. With major NCD due to TBI, an individual may have difficulty in independent living and self-care. Prominent neuromotor features, such as severe incoordination, ataxia, and motor slowing, may be present in major NCD due to TBI and may add to functional difficulties. Individuals with TBI histories report more depressive and anxious symptoms, and these can amplify cognitive complaints and worsen functional outcome. Additionally, loss of emotional

Other mental disorders and medical conditions. Factitious disorder and malingering. control, including aggressive or inappropriate affect and apathy, may be present after more severe TBI with greater neurocognitive impairment. These features may compound difficulties with functional independence and self-care. Differential Diagnosis Mental disorders (e.g., major depressive disorder, anxiety disorders, PTSD, alcohol and other substance use disorders, sleep disturbances), prescribed medications (e.g., typical antipsychotics, benzodiazepines, drugs with anticholinergic properties, antiepileptic drugs), and other medical conditions may contribute to or account for cognitive impairments among individuals with TBI, and need to be considered in the differential diagnosis of major or mild NCD due to TBI. Alternative explanations for neurocognitive symptoms should be considered when the severity of neurocognitive symptoms and functional limitations are inconsistent with the cognitive outcomes expected after TBI—and particularly mild TBI—and when neuropsychological assessment reveals poor effort or is otherwise not valid for interpretation. In such circumstances, the possibility of factitious disorder or malingering (especially in situations in which there might be external incentives such as obtaining financial compensation) should be considered. Comorbidity Major or mild NCD due to TBI may be accompanied by other specified or unspecified depressive or anxiety disorders characterized by disturbances in emotional function (e.g., irritability, easy frustration, tension and anxiety, affective lability). Other specified or unspecified personality disorders may also occur as a result of symptoms such as disinhibition, apathy, suspiciousness, or aggression. Medical comorbidities may occur with neurological and physical disturbances characterized by headache, fatigue, sleep disorders, vertigo or dizziness, tinnitus or hyperacusis, photosensitivity, anosmia, reduced tolerance to psychotropic medications, and, particularly in more severe TBI, neurological symptoms and signs (e.g., seizures, hemiparesis, visual disturbances, cranial nerve deficits) and evidence of orthopedic injuries. The most common medical and psychiatric comorbidities associated with moderate-tosevere TBI are (in order of frequency) back pain, depression, hypertension, anxiety, fractures, high blood cholesterol, sleep disorders, panic attacks, osteoarthritis, and diabetes. Among individuals with substance use disorders, the neurocognitive effects of the substance contribute to or compound the TBI-associated cognitive disturbances, particularly among individuals with two or more TBIs. PTSD can co-occur with TBI in civilian, military, and veterans populations. TBI and PTSD produce similar neurocognitive symptoms (e.g., disturbances of complex attention, processing speed, learning and memory, and executive function), and either or both conditions, as well as co-occurring depression and sleep disturbances, may explain neurocognitive symptoms in individuals with such comorbidities.

Substance/Medication-Induced Major or Mild Neurocognitive Disorder Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. The neurocognitive impairments do not occur exclusively during the course of a delirium and persist beyond the usual duration of intoxication and acute withdrawal. C. The involved substance or medication and duration and extent of use are capable of producing the neurocognitive impairment. D. The temporal course of the neurocognitive deficits is consistent with the timing of substance or medication use and abstinence (e.g., the deficits remain stable or improve after a period of abstinence). E. The neurocognitive disorder is not attributable to another medical condition or is not better explained by another mental disorder. Coding note (see also coding table on pp. 682–683): The ICD-10-CM codes for the [specific substance/medication]-induced neurocognitive disorders are indicated in the table below. Note that the ICD-10-CM code depends on whether or not there is a comorbid substance use disorder present for the same class of substance. In any case, an additional separate diagnosis of a substance use disorder is not given. Substance-induced major neurocognitive disorder: If a mild substance use disorder is comorbid with the substance-induced major neurocognitive disorder, the 4th position character is “1,” and the clinician should record “mild [substance] use disorder” before the substance-induced major neurocognitive disorder (e.g., “mild inhalant use disorder with inhalant-induced major neurocognitive disorder”). For alcohol and sedative, hypnotic, or anxiolytic substances, a mild substance use disorder is insufficient to cause a substance-induced major neurocognitive disorder; thus, there are no available ICD-10-CM codes for this combination. If a moderate or severe substance use disorder is comorbid with the substance-induced major neurocognitive disorder, the 4th position character is “2,” and the clinician should record “moderate [substance] use disorder” or “severe [substance] use disorder,” depending on the severity of the comorbid substance use disorder. If there is no comorbid substance use disorder, then the 4th position character is “9,” and the clinician should record only the substance-induced major neurocognitive disorder. Substance-induced mild neurocognitive disorder: If a mild substance use disorder is comorbid with the substance-induced mild neurocognitive disorder, the 4th position character is “1,” and the clinician should record “mild [substance] use disorder” before the substance-induced mild neurocognitive disorder (e.g., “mild

cocaine use disorder with cocaine-induced mild neurocognitive disorder”). If a moderate or severe substance use disorder is comorbid with the substance-induced mild neurocognitive disorder, the 4th position character is “2,” and the clinician should record “moderate [substance] use disorder” or “severe [substance] use disorder,” depending on the severity of the comorbid substance use disorder. If there is no comorbid substance use disorder, then the 4th position character is “9,” and the clinician should record only the substance-induced mild neurocognitive disorder. The severity specifiers “mild,” “moderate,” and “severe” (for major neurocognitive disorder) and the accompanying symptom specifiers “with behavioral disturbance” and “without behavioral disturbance” (for major or mild neurocognitive disorder) cannot be coded but should still be recorded. ICD-10-CM With mild use disorder With moderate or severe use disorder Without use disorder Substance-induced major neurocognitive disorder (NCD) Alcohol (major NCD), nonamnesticconfabulatory type NA F10.27 F10.97 Alcohol (major NCD), amnesticconfabulatory type NA F10.26 F10.96 Inhalant (major NCD) F18.17 F18.27 F18.97 Sedative, hypnotic, or anxiolytic (major NCD) NA F13.27 F13.97 Other (or unknown) substance (major NCD) F19.17 F19.27 F19.97 Substance-induced mild neurocognitive disorder (NCD) Alcohol (mild NCD) F10.188 F10.288 F10.988 Inhalant (mild NCD) F18.188 F18.288 F18.988 Sedative, hypnotic, or anxiolytic (mild NCD) F13.188 F13.288 F13.988 Amphetamine-type substance (or other stimulant) (mild NCD) F15.188 F15.288 F15.988 Cocaine (mild NCD) F14.188 F14.288 F14.988 Other (or unknown) substance (mild NCD) F19.188 F19.288 F19.988 Specify if: Persistent: Neurocognitive impairment continues to be significant after an extended period of abstinence. Recording Procedures The name of the substance/medication-induced neurocognitive disorder (NCD) begins with the specific substance (e.g., alcohol) that is presumed to be causing the neurocognitive symptoms. The ICD-10-CM code that corresponds to the applicable drug class is selected from the table included in the criteria set. For substances that do not fit into any of the classes (e.g., intrathecal methotrexate), the ICD-10-CM code for the other (or unknown) substance class should be used and the name of the specific substance recorded (e.g., F19.988 intrathecal methotrexate-induced

mild neurocognitive disorder). In cases in which a substance is judged to be an etiological factor but the specific substance is unknown, the ICD-10-CM code for the other (or unknown) substance class is used, and the fact that the substance is unknown is recorded (e.g., F19.97 unknown substance-induced major neurocognitive disorder). When recording the name of the disorder, the comorbid substance use disorder (if any) is listed first, followed by the word “with,” followed by the name of the disorder (i.e., [specific substance]–induced major neurocognitive disorder or [specific substance]–induced mild neurocognitive disorder), followed by the type in the case of alcohol (i.e., nonamnesticconfabulatory type, amnestic-confabulatory type), followed by specification of duration (i.e., persistent). For example, in the case of persistent amnestic-confabulatory symptoms in a man with a severe alcohol use disorder, the diagnosis is F10.26 severe alcohol use disorder with alcohol-induced major neurocognitive disorder, amnestic-confabulatory type, persistent. A separate diagnosis of the comorbid severe alcohol use disorder is not given. If the substanceinduced neurocognitive disorder occurs without a comorbid substance use disorder (e.g., after a sporadic heavy use of inhalants), no accompanying substance use disorder is noted (e.g., F18.988 [specific inhalant]–induced mild neurocognitive disorder). Diagnostic Features Substance/medication-induced major or mild NCD is characterized by neurocognitive impairments that persist beyond the usual duration of intoxication and acute withdrawal (Criterion B). Initially, these manifestations can reflect slow recovery of brain functions from a period of prolonged substance use, and improvements in neurocognitive as well as brain imaging indicators may be seen over many months. If the disorder continues for an extended period, persistent should be specified. The given substance and its use must be known to be capable of causing the observed impairments (Criterion C). While nonspecific decrements in a range of cognitive abilities can occur with nearly any substance of abuse and a variety of medications, some patterns occur more frequently with selected drug classes. For example, NCD due to sedative, hypnotic, or anxiolytic drugs (e.g., benzodiazepines, barbiturates) may show greater disturbances in memory than in other cognitive functions. NCD induced by alcohol frequently manifests with a combination of impairments in executive-function and memory and learning domains. The temporal course of the substance-induced NCD must be consistent with that of use of the given substance (Criterion D). Alcohol-induced, amnestic-confabulatory type (Korsakoff’s) NCD is characterized by an impairment in recent memory that is out of proportion to additional NCD symptoms. Features include prominent amnesia (severe difficulty learning new information with rapid forgetting) and a tendency to confabulate, although confabulation can be seen with any severe diminution of recent memory. These manifestations may co-occur with signs of thiamine encephalopathy (Wernicke’s encephalopathy) with associated features such as nystagmus and ataxia. Ophthalmoplegia of Wernicke’s encephalopathy is typically characterized by a lateral gaze paralysis. The neurocognitive deficits associated with inhalant misuse include diminished executive functioning, slower cognitive speed, and additional impaired performance on aspects of the Wisconsin Card Sorting and the Stroop tests. Neurocognitive symptoms associated with stimulant use include difficulties with learning and memory and executive function. Methamphetamine use can also be associated with

715 evidence of vascular injury (e.g., focal weakness, unilateral incoordination, asymmetrical reflexes). The most common neurocognitive profile approximates that seen in vascular NCD. Substances that cause NCD included in the other (or unknown) substance category include intrathecal methotrexate and organophosphate insecticides, as well as compounds that are misused and known to induce adverse cognitive effects but are less well characterized (e.g., kratom/Mitragyna speciosa). When one is determining the relationship between NCD conditions and any group of drugs, it is important to consider whether the deficit was present before the use of the substance and consequently would not be attributable to the substance—and may have even contributed to poor judgment that resulted in the substance use. For example, evidence of decreased impulse control and related impairment of executive functions have been reported as associated with the onset of the use of stimulants and other drugs. In studies in which neurocognitive function is carefully assessed prior to substance use, and then subjects are followed up over several months or more, the ability of drugs other than alcohol, other depressants, and inhalants to cause clinically significant persistent NCDs is not clear. Associated Features Inhalant-induced NCD conditions may be associated with the smell of the inhalant on an individual’s breath or a rash around the individual’s nose or mouth from “huffing” the drug from a container. These are most often seen in individuals with limited access to other drugs who have histories of inhalant use as well as the early onset of use of multiple substances, especially if their symptoms fulfill criteria for conduct or antisocial personality disorders. A high risk is also seen in workers exposed to solvents in the workplace. Mild NCD induced by drugs with central nervous system depressant effects may manifest with added symptoms of increased irritability, anxiety, sleep disturbance, and dysphoria. NCD induced by stimulant drugs may manifest with rebound depression, hypersomnia, and apathy. In severe forms of substance/medication-induced major NCD (e.g., associated with long-term alcohol use), there may be prominent neuromotor features, such as incoordination, ataxia related to cerebellar damage, and motor slowing, as well as medical complications such as hypokalemia and cardiac arrhythmias. There may also be loss of emotional control, including aggressive or inappropriate affect, or apathy. Prevalence The prevalence of these conditions is not well known. Prevalence figures are more available for the use of these substances and for associated substance use disorders rather than for the neurocognitive conditions. Substance/medication-induced major or mild NCDs are more likely in those who are older, have longer duration of use, and have other risk factors such as nutritional deficits. For alcohol use disorder, the rate of mild NCD is approximately 30%–40% in the first 2 months of abstinence. Mild NCD may persist, particularly in those who do not achieve stable abstinence until after age 50 years. Major NCD is rare and may result from concomitant nutritional deficits, as in alcohol-induced amnestic-confabulatory NCD. Alcohol-induced major NCD may be more common in men.

Few studies are available regarding the prevalence of NCD from other brain depressant drugs (i.e., sedatives, hypnotics, or anxiolytics), likely reflecting the relative rarity of studies of substance use disorders on these drugs and the relatively low level of heavy and persistent “recreational” use of sedative, hypnotic, or anxiolytic drugs compared with alcohol, cannabis, and many other drugs. More data are available on the prevalence of inhalant use. Such exposure has been linked to both major and mild NCD of varied duration in both higher- and lower-income populations. However, persistent use to the point of developing an NCD is estimated to be less than 1% of the U.S. population. In the case of stimulants (methamphetamines and cocaine), cerebrovascular disease can also occur, resulting in diffuse or focal brain injury that can be of mild or major neurocognitive levels. Development and Course The onset of substance use disorders tends to occur during late adolescence and peak in the 20s and 30s. Although longer history of severe substance use disorder is associated with greater likelihood of NCD, the relationships are not straightforward, with substantial and even complete recovery of neurocognitive functions being common among persons who achieve stable abstinence prior to age 50 years. Substance/medication-induced major or mild NCD is most likely to become persistent in individuals who continue to have substance use disorders past the age of 50 years, presumably because of a combination of lessened neural plasticity and the onset of other age-related brain changes. NCD conditions may involve a fairly rapid onset of neurocognitive impairment in individuals whose history includes the use of multiple types of drugs of abuse, especially with an early onset of substance use. Earlier commencement of heavy use, particularly of alcohol, may lead to defects in later neural development (e.g., later stages of maturation of frontal circuitries), which may have effects on social cognition as well as other neurocognitive abilities. For alcoholinduced NCD, there may be an additive effect of aging and alcohol-induced brain injury. Risk and Prognostic Factors Risk factors for substance/medication-induced NCDs include older age, longer duration of use, and persistent use past age 50 years. For alcohol-induced NCD, long-term nutritional deficiencies, liver disease, vascular risk factors, and cardiovascular and cerebrovascular disease may contribute to risk. An increased risk for alcohol-induced, amnestic confabulatory–type NCD occurs in the context of a genetic transketolase deficiency as well as in the context of poor nutrition. Sedative-, hypnotic-, or anxiolytic-induced NCDs have not been well studied, but these problems may be increased in individuals with long-term anxiety disorders or sleep impairment who have been taking benzodiazepines or other hypnotic medications in increasing amounts for months or years.

Diagnostic Markers Magnetic resonance imaging (MRI) of individuals with chronic alcohol use disorder frequently reveals cortical thinning, white matter loss, and enlargement of sulci and ventricles. While neuroimaging abnormalities are more common in those with NCDs, it is possible to observe NCDs without neuroimaging abnormalities, and vice versa. Specialized techniques (e.g., diffusion tensor imaging) may reveal damage to specific white matter tracts. Magnetic resonance spectroscopy may reveal reduction in N-acetylaspartate, and increase in markers of inflammation (e.g., myoinositol) or white matter injury (e.g., choline). Many of these brain imaging changes and neurocognitive manifestations reverse following successful abstinence. In individuals with methamphetamine use disorder, MRI may also reveal hyperintensities suggestive of microhemorrhages or larger areas of infarction. Functional Consequences of Substance/Medication-Induced Major or Mild Neurocognitive Disorder The functional consequences of substance/medication-induced mild NCD are sometimes augmented by reduced cognitive efficiency and difficulty concentrating beyond that seen in many other NCDs. In addition, at both major and mild levels, substance/medication-induced NCDs may have associated motor syndromes that increase the level of functional impairment. Differential Diagnosis Individuals with substance use disorders, substance intoxication, and substance withdrawal are at increased risk for other conditions that may independently, or through a compounding effect, result in neurocognitive disturbance. These include history of traumatic brain injury and infections that can accompany substance use disorder (e.g., HIV, hepatitis C virus, syphilis). Therefore, presence of substance/medication-induced major or mild NCD should be differentiated from NCDs arising outside the context of substance use, intoxication, and withdrawal, including these accompanying conditions (e.g., traumatic brain injury). Comorbidity Substance use disorders, substance intoxication, and substance withdrawal are highly comorbid with other mental disorders. In general, the higher the exposure to drugs of abuse, the greater the risk for a substance- or medication-induced NCD. Comorbid posttraumatic stress disorder, psychotic disorders, depressive and bipolar disorders, and neurodevelopmental disorders can contribute to neurocognitive impairment in substance users. Traumatic brain injury occurs more frequently with substance use, complicating efforts to determine the etiology of NCD in such cases. Severe, long-term alcohol use disorder can be associated with major organ system disease, including cerebrovascular disease and cirrhosis; inhalant use disorder is associated with higher rates of kidney and liver damage; and amphetamine- and cocaine-induced NCD may be accompanied by major or mild vascular NCD secondary to stimulant use.

Major or Mild Neurocognitive Disorder Due to HIV Infection Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. There is documented infection with human immunodeficiency virus (HIV). C. The neurocognitive disorder is not better explained by non-HIV conditions, including secondary brain diseases such as progressive multifocal leukoencephalopathy or cryptococcal meningitis. D. The neurocognitive disorder is not attributable to another medical condition and is not better explained by a mental disorder. Coding note (see coding table on pp. 682–683): For major neurocognitive disorder due to HIV infection, with behavioral disturbance, code first B20 HIV infection, followed by F02.81 major neurocognitive disorder due to HIV infection, with behavioral disturbance. For major neurocognitive disorder due to HIV infection, without behavioral disturbance, code first B20 HIV infection, followed by F02.80 major neurocognitive disorder due to HIV infection, without behavioral disturbance. Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded. For mild neurocognitive disorder due to HIV infection, code G31.84. (Note: Do not use the additional code for HIV infection. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild neurocognitive disorder due to HIV infection: Use additional code(s) to indicate clinically significant psychiatric symptoms due to HIV infection (e.g., F06.34 bipolar and related disorder due to HIV infection, with mixed features; F07.0 personality change due to traumatic brain injury, apathetic type). Diagnostic Features HIV disease is caused by infection with human immunodeficiency virus type-1 (HIV-1), which is acquired through exposure to bodily fluids of an infected individual through injection substance use, unprotected sexual contact, or accidental or iatrogenic exposure (e.g., needle puncture injury to medical personnel). HIV infects several types of cells, most particularly “Thelper” (CD4) lymphocytes and monocytes. Over time, the infection can cause severe decreases in the CD4 count, resulting in severe immunocompromise, often leading to opportunistic infections and neoplasms. Infected monocytes can enter the central nervous system, leading to infection of macrophages and microglia. A small percentage of astrocytes may harbor productive

HIV infection. The advanced form of HIV infection is termed acquired immune deficiency syndrome (AIDS). Diagnosis of HIV is confirmed by established laboratory methods, such as the reverse-transcription polymerase chain reaction (RT-PCR) assay for HIV RNA and the antibody/antigen combination test. Of note, in-home self-testing for HIV is available. Some individuals with HIV infection develop a neurocognitive disorder (NCD), which generally shows a “subcortical pattern” with prominently impaired executive function, slowing of processing speed, problems with more demanding attentional tasks, and difficulty in learning new information, but fewer problems with recall of learned information. In major NCD, slowing may be prominent. Language difficulties, such as aphasia, are uncommon, although reductions in fluency may be observed. HIV pathogenic processes can affect any part of the brain; therefore, other patterns are possible. Associated Features Major or mild NCD due to HIV infection is more prevalent in individuals of increasing age, lower educational level, or female sex, and among those with major depressive disorder, alcohol or other substance use disorders, and medical comorbidities (particularly diabetes and hypertension). The NCD risk due to HIV infection is also increased with any of the following: prior episodes of immunosuppression, high viral loads in the cerebrospinal fluid, and increased levels of tumor necrosis factor–alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein, D-dimer, sCD14, sCD163, and neurofilament light chain in the peripheral blood or clinical laboratory indicators of advanced HIV disease, such as a low CD4 cell nadir, anemia, and hypoalbuminemia. Individuals with major NCD may show more prominent neuromotor features, such as severe incoordination, ataxia, and motor slowing. These features may become more prominent with NCD disease progression. Prevalence Depending on the clinical stage of HIV disease, approximately one-third to over one-half of HIV-infected individuals have at least some evidence of a neurocognitive disturbance, but most of these disturbances would not meet criteria for mild NCD and would instead represent individuals with asymptomatic neurocognitive impairment (ANI), who may have substandard performance on one or more tests of neurocognitive abilities but do not have any impairment in functional status. Rates in North America and Western Europe have largely shown that ANI accounts for the majority of neurocognitive disturbances, whereas mild NCD due to HIV accounts for approximately one-quarter of individuals, and major NCD criteria are met for typically less than 5% of individuals with HIV-related neurocognitive disturbances. In Germany, the overall prevalence of HIV-associated NCDs among HIV clinic participants was 43%, 90% of whom were in treatment: 20% had ANI, 17% had mild NCD, and 6% had HIV-associated dementia. In low- and middle-income countries, prevalence of HIV-associated NCDs is higher among untreated individuals with HIV. In other parts of the world, and in cohorts composed mostly of individuals infected with HIV on effective antiretroviral treatment tested with comprehensive cognitive test batteries, the overall rates of

cognitive impairment were found to be around 25%–35%. In the United States, the incidence of HIV infection is higher in men than in women in every ethnic group. However, evidence supports a sex difference in NCD due to HIV infection, with more frequent neurocognitive impairment in women, including when sex is maintained as a risk factor in a multivariate analysis. The higher rate of impairment in women may be associated with differences in educational quality. Development and Course In the development and course of NCD due to HIV, individuals may have neurocognitive impairment when the HIV infection is asymptomatic; the Centers for Disease Control and Prevention classifies the underlying HIV infection in three stages: asymptomatic, early symptomatic, and late symptomatic/AIDS. The course of NCD due to HIV infection can resolve, improve, remain stable, slowly worsen, rapidly worsen, or have a fluctuating course. Rapid progression of neurocognitive impairment is uncommon in the context of currently available combination antiretroviral treatment, although it may still occur in the context of a subgroup associated with older age, as well as in association with specific comorbidities promoting cognitive impairment. Nevertheless, for the predominant proportion of individuals with HIV, an abrupt change in mental status warrants an evaluation of other medical sources for the cognitive change, including secondary infections. Because HIV infection preferentially affects subcortical regions over the course of illness, including deep white matter, the progression of the disorder follows a subcortical pattern. The subcortical pattern of cognitive impairment is characterized by mental slowing associated with motor dysfunction, procedural learning deficits, and free recall deficits, with relative sparing of recognition memory, verbal abstraction, and naming. Because HIV infection can affect a variety of brain regions and the illness can take on many different trajectories depending on associated comorbidities and the consequences of HIV infection, the overall course of an NCD due to HIV infection has considerable heterogeneity. A subcortical neurocognitive profile may interact with age over the life course, such that an interaction occurs between age and clinical stage of HIV disease in the domains of episodic memory and motor impairment (e.g., slowed gait). This interaction increases the overall prevalence of neurocognitive impairment and the likelihood that it will be more pronounced in later life. Acquisition of HIV infection typically occurs in adults in high-income countries, via highrisk behaviors (e.g., unprotected sex; injection substance use) beginning in late adolescence and peaking during young and middle adulthood, with a significant contribution persisting into older age. In lower-income regions, where HIV testing and antiretroviral treatments for pregnant women are not readily available, perinatal transmission is common. The NCD in such infants and children may manifest primarily as neurodevelopmental delay. As individuals treated for HIV survive into older age, additive and interactive neurocognitive effects of HIV and aging, including other NCDs (e.g., due to Alzheimer’s disease, due to Parkinson’s disease), are possible. More than 50% of individuals with HIV in the United States are older than 50 years. Long-term antiretroviral therapy is indicated for the ongoing control of HIV infection. However, some antiretroviral therapy may be associated with inflammation, neurotoxic effects, and metabolic changes that can lead to vascular compromise and indirectly increase neurocognitive impairment in conjunction with aging and medical comorbidities that may worsen cognition.

720 Risk and Prognostic Factors Paradoxically, NCD due to HIV infection has not declined significantly with the advent of effective antiretroviral therapy, although the most severe presentations (consistent with the diagnosis of major NCD) have decreased sharply. Contributory factors may include inadequate control of HIV in the central nervous system (CNS), the evolution of antiretroviral drug-resistant viral strains, the effects of chronic long-term systemic and brain inflammation, and the effects of comorbid factors such as aging, substance use disorder, hypertension, diabetes, past history of CNS trauma, and co-infections, such as with the hepatitis C virus. Chronic exposure to antiretroviral drugs has also been associated with neurotoxicity in its own right. Diagnostic Markers An HIV diagnosis may be made from a test conducted on the blood, oral fluids, or urine. In addition, HIV characterization of the cerebrospinal fluid may be helpful if it reveals a disproportionately high viral load in the cerebrospinal fluid versus in the plasma or if there are indicators of a high level of neuroinflammation. Neuroimaging (e.g., magnetic resonance imaging [MRI]) may reveal reduction in total brain volume, cortical thinning, reduction in white matter volume, and patchy areas of abnormal white matter (hyperintensities). MRI of the brain or lumbar puncture may be helpful to exclude a specific medical condition (e.g., cryptococcal meningitis, meningoencephalitis, herpes simplex virus type 1 or type 2 encephalitis, progressive multifocal leukoencephalopathy) that might contribute to CNS changes in the context of AIDS. Specialized techniques such as diffusion tensor imaging may reveal damage to specific white matter tracts. Arterial spin-labeling (ASL) developed as a new type of MRI (ASL-MRI) may reveal regional changes in brain perfusion in 3–5 minutes without infusion of extrinsic tracers, and translocator protein 18-kDa (TSPO) positron emission tomography scanning may reveal neuroinflammation. Functional Consequences of Major or Mild Neurocognitive Disorder Due to HIV Infection Functional consequences of major or mild NCD due to HIV infection are variable across individuals. Thus, impaired executive functions and slowed information processing may substantially interfere with adherence to the effective antiretroviral therapy regimens, although these regimens have been greatly simplified since their inception. Thus, functional status must be assessed and mapped directly to neurocognitive impairment in order to determine the severity of the NCD. Functional status related to neurocognitive impairment due to HIV should be separated from dysfunction attributable to other concomitant disorders that can affect neurocognitive function. Differential Diagnosis In the presence of comorbidities, such as other infections (e.g., hepatitis C virus, syphilis), substance use disorder (e.g., methamphetamine use disorder), prior traumatic brain injury, or neurodevelopmental conditions, major or mild NCD due to HIV infection can be diagnosed

provided there is evidence that infection with HIV has worsened any NCDs because of such preexisting or comorbid conditions. Among older adults, onset of neurocognitive decline related to cerebrovascular disease or primary neurodegeneration (e.g., major or mild NCD due to Alzheimer’s disease) may need to be differentiated; these conditions may be suggested by a relatively more progressive course of decline than is seen in NCD due to HIV. HIV infection itself has been shown to increase the risk of cerebrovascular disease. Because more severe immunodeficiency can result in opportunistic infections of the brain (e.g., toxoplasmosis; cryptococcosis) and neoplasia (e.g., CNS lymphoma), sudden onset of an NCD or sudden worsening of an NCD demands active investigation of non-HIV etiologies. Delirium is important to consider because it occurs frequently over the disease course of individuals with HIV and may be due to multiple etiologies (including SARS-CoV-2 coinfection). Comorbidity HIV disease is accompanied by chronic systemic and CNS inflammation and diseases that can be associated with an NCD. These complications can be part of the pathogenesis of major or mild NCD as well as ANI due to HIV infection. HIV frequently co-occurs with conditions such as substance use disorders and other sexually transmitted infections. Both medical and psychiatric comorbidities have been identified that increase the likelihood of a diagnosis of NCD due to HIV infection. Women and members of underserved ethnic and racialized groups may show variation in the rates of the comorbidities associated with NCD due to HIV infection. Major or Mild Neurocognitive Disorder Due to Prion Disease Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. There is insidious onset, and rapid progression of impairment is common. C. There are motor features of prion disease, such as myoclonus or ataxia, or biomarker evidence. D. The neurocognitive disorder is not attributable to another medical condition and is not better explained by another mental disorder. Coding note (see coding table on pp. 682–683): For major neurocognitive disorder due to prion disease, with behavioral disturbance, code first A81.9 prion disease, followed by F02.81 major neurocognitive disorder due to prion disease, with behavioral disturbance. For major neurocognitive disorder due to prion disease, without behavioral

disturbance, code first A81.9 prion disease, followed by F02.80 major neurocognitive disorder due to prion disease, without behavioral disturbance. Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded. For mild neurocognitive disorder due to prion disease, code G31.84. (Note: Do not use the additional code for prion disease. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild neurocognitive disorder due to prion disease: Use additional code(s) to indicate clinically significant psychiatric symptoms due to prion disease (e.g., F06.2 psychotic disorder due to prion disease, with delusions; F06.32 depressive disorder due to prion disease with major depressive–like episode). Diagnostic Features The classification of major or mild neurocognitive disorder (NCD) due to prion disease includes NCDs due to a group of subacute spongiform encephalopathies (including sporadic CreutzfeldtJakob disease, genetic Creutzfeldt-Jakob disease, iatrogenic Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, variably protease-sensitive prionopathy, kuru [found among the Fore people in Papua New Guinea], Gerstmann-Sträussler-Scheinker syndrome, and fatal insomnia) caused by transmissible agents known as prions. Given that the most common type is sporadic Creutzfeldt-Jakob disease, it is typically referred to as simply Creutzfeldt-Jakob disease (CJD). Variant CJD is much rarer and is associated with transmission of bovine spongiform encephalopathy, also called “mad cow disease.” Typically, individuals with CJD present with neurocognitive deficits, ataxia, and abnormal movements such as myoclonus, chorea, or dystonia; a startle reflex is also common. The history often reveals rapid progression to major NCD over as little as 6 months, and thus the disorder is typically seen only at the major level. However, many individuals with the disorder may have atypical presentations, and the disease can be confirmed only by biopsy or at autopsy. For example, individuals with variant CJD may present with a greater preponderance of psychiatric symptoms than do individuals with other types of prion disease, characterized by low mood, withdrawal, and anxiety. Although biomarker evidence is not necessarily required for the diagnosis if the motor features of prion disease (e.g., myoclonus, ataxia) are present, confidence that the NCD is due to prion disease is greatly increased if characteristic biomarkers are present. Prevalence Prevalence is unknown but very low given the short survival. Based on data from nine highincome countries, the annual incidence of sporadic CJD is approximately one or two cases per million people. Incidence varies by age and is highest in those age 65 years or older (4.8/1,000,000 individuals) and is higher in Whites compared with Blacks. Incidence among ethnic Chinese in Taiwan is lower than general population rates in the United States and other reporting countries.

Environmental. Genetic and physiological. Development and Course Prion disease may develop at any age in adults—the peak age for sporadic CJD is approximately 67 years—although it has been reported to occur in individuals spanning the teenage years to late life. Non-Latinx Whites were found to have an older mean age at onset compared with other ethnic and racialized populations in the United States. Prodromal symptoms of prion disease may include fatigue, anxiety, problems with appetite or sleeping, or difficulties with concentration. After several weeks, these symptoms may be followed by incoordination, altered vision, or abnormal gait or other movements that may be myoclonic, choreoathetoid, or ballistic, along with a rapidly progressive dementia. The disease typically progresses very rapidly to the major level of impairment over several months. More rarely, it can progress over 2 years and appear similar in its course to other NCDs. Risk and Prognostic Factors Cross-species transmission of prion infections, with agents that are closely related to the human form, has been demonstrated (e.g., the outbreak of bovine spongiform encephalopathy inducing variant CJD in the United Kingdom during the mid-1990s). Transmission by corneal transplantation, cadaveric dura mater grafts, contaminated neurosurgical instruments, cadaver-derived human growth hormone and pituitary gonadotropin injections, and blood transfusion (only in the case of variant CJD) has been documented. Studies have not demonstrated an increased risk of sporadic CJD in health care professionals. In up to 15% of prion disease cases, there are autosomal dominant genetic mutations in the prion protein gene (PRNP), which encodes for a normal neuronal membrane–bound protein. The codon 129 polymorphism of PRNP mediates the risk of sporadic and acquired prion diseases as well as modifies clinical manifestation, age at disease onset, and disease duration. Diagnostic Markers Prion disease can be definitively confirmed only by brain biopsy or at autopsy. There are several cerebrospinal fluid (CSF) proteins that are markers of neuronal injury and are frequently elevated in prion disease; the ones most commonly used for diagnostic purposes are 14-3-3 and tau, which have high sensitivity but variable specificity. Real-time quaking induced conversion (RT-QuIC) is another CSF diagnostic test that is able to amplify minute amounts of disease-causing prion proteins and has extremely high specificity. Magnetic resonance brain imaging is currently considered the most sensitive diagnostic test when DWI (diffusion-weighted imaging) is performed, with the most common finding being multifocal gray matter hyperintensities in subcortical and/or cortical regions. In some individuals, the electroencephalogram reveals periodic sharp, often triphasic and synchronous discharges at a rate of 0.5–2 Hz at some point during the course of the disorder. It is important to note that the above diagnostic markers vary across prion disease type (e.g., sporadic CJD, genetic CJD, variant CJD).

Other major neurocognitive disorders. Differential Diagnosis Major NCD due to prion disease may appear similar in its course to other NCDs, but prion diseases are typically distinguished by their rapid progression and prominent cerebellar and motor symptoms. Major or Mild Neurocognitive Disorder Due to Parkinson’s Disease Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. The disturbance occurs in the setting of established Parkinson’s disease. C. There is insidious onset and gradual progression of impairment. D. The neurocognitive disorder is not attributable to another medical condition and is not better explained by another mental disorder. Major or mild neurocognitive disorder probably due to Parkinson’s disease should be diagnosed if 1 and 2 are both met. Major or mild neurocognitive disorder possibly due to Parkinson’s disease should be diagnosed if 1 or 2 is met:

1. There is no evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease or another neurological, mental, or systemic disease or condition likely contributing to cognitive decline).
2. The Parkinson’s disease clearly precedes the onset of the neurocognitive disorder. Coding note (see coding table on pp. 682–683): For major neurocognitive disorder probably or possibly due to Parkinson’s disease, with behavioral disturbance, code first G20 Parkinson’s disease, followed by F02.81. For major neurocognitive disorder probably or possibly due to Parkinson’s disease, without behavioral disturbance, code first G20 Parkinson’s disease, followed by F02.80. Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded. For mild neurocognitive disorder due to Parkinson’s disease, code G31.84. (Note: Do not use the additional code for Parkinson’s disease. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild neurocognitive disorder due to Parkinson’s disease: Use additional code(s) to indicate clinically significant psychiatric symptoms due to Parkinson’s

disease (e.g., F06.0 psychotic disorder due to Parkinson’s disease, with hallucinations; F06.31 depressive disorder due to Parkinson’s disease, with depressive features; F07.0 personality change due to traumatic brain injury, apathetic type). Diagnostic Features The essential feature of major or mild neurocognitive disorder (NCD) due to Parkinson’s disease is cognitive decline observed at the time of or following the onset of idiopathic Parkinson’s disease. The disturbance must occur in the setting of established Parkinson’s disease (Criterion B), and deficits must have developed gradually (Criterion C). The rate of progression of cognitive deficits may vary; for some individuals with mild deficits there may be very minimal change over time. The NCD is viewed as probably due to Parkinson’s disease when there is no evidence of another disorder that might be responsible for the cognitive decline and when the Parkinson’s disease precedes onset of the NCD. The NCD is considered possibly due to Parkinson’s disease when only one of these conditions is met but not both conditions. A diagnosis of Parkinson’s disease prior to the onset of the cognitive change increases the diagnostic confidence that the NCD is attributable to Parkinson’s disease, as denoted by the probable designation. Associated Features Frequently present features include apathy, depressed mood, anxious mood, hallucinations, delusions, personality changes, rapid eye movement (REM) sleep behavior disorder, excessive daytime sleepiness, freezing of gait, falls, bilateral involvement early in disease, postural instability and gait disturbance (PIGD) subtype, and hyposmia. The combination of postural and gait instability may occur early in the disease and may be described by the term PIGD subtype to distinguish from tremor-predominant Parkinson’s disease. Prevalence The prevalence of Parkinson’s disease in the United States steadily increases with age from approximately 0.4% between ages 60 and 69 years to 1.4% between ages 80 and 89 years. Parkinson’s disease is more common in men than in women. Similarly, the prevalence of NCD due to Parkinson’s disease is higher in men than in women. However, it is not clear if the incidence of NCD due to Parkinson’s disease is higher in men than in women. Among individuals with Parkinson’s disease, as many as 80% will eventually develop a major NCD. Among those without a major NCD, the prevalence of mild NCD in Parkinson’s disease has been estimated at 25%–27%. For individuals with incident-untreated Parkinson’s disease, a range of 9%–19% have mild NCD, whereas other studies have reported major NCD occurring in 24% of newly diagnosed untreated Parkinson’s disease. Among African Americans, the risk of Parkinson’s disease tends to be lower than among non-Latinx Whites, but the risk of dementia among those with the disease tends to be higher. Development and Course Onset of Parkinson’s disease is typically between ages 50 and 89 years, with most expression in

Environmental. Genetic and physiological. Major or mild neurocognitive disorder with Lewy bodies (NCDLB). the early 60s. Mild NCD often develops relatively early in the course of Parkinson’s disease, whereas major impairment typically does not occur until individuals are older. Risk and Prognostic Factors Risk factors for Parkinson’s disease include exposure to pesticides, solvents, and possibly traumatic brain injury. Potential risk factors for NCD among individuals with Parkinson’s disease include older age at disease onset, increasing severity of disease, prominent gait symptoms, severe autonomic disturbance (particularly orthostatic hypotension), REM sleep behavior disorder, and possibly being a man and having fewer years of formal education. Individuals with Parkinson’s disease with glucocerebrosidase gene (GBA) mutations and APOE*E4 genotype have been demonstrated to have worse cognition in cross-sectional and longitudinal research. Culture-Related Diagnostic Issues Guam dementia is a late-onset NCD observed among 8.8% of Chamorros (the indigenous population of Guam) age 65 years and older. Characterized by neurofibrillary tangles but without the amyloid plaques found in Alzheimer’s disease, it is thought to be possibly related to a unique parkinsonism-dementia complex and amyotrophic lateral sclerosis. An association has been found with processing and eating fadang made with cycad seeds. Diagnostic Markers Neuropsychological testing, with a focus on tests that are not affected by motor slowing (i.e., not timed or requiring use of hands), is critical in detecting the core cognitive deficits, particularly at the mild NCD phase. Characteristic features observed in neuropsychological testing early in the disorder may include reduced attention, executive dysfunction, slowed information processing, and deficits in memory and visuospatial function, whereas many language skills may remain intact. Dopamine transporter scans, such as DaT scans, may differentiate Lewy body–related dementias (i.e., NCD due to Parkinson’s disease, NCD with Lewy bodies) from non–Lewy body–related dementias (e.g., NCD due to Alzheimer’s disease). Differential Diagnosis The distinction between NCDLB and NCD due to Parkinson’s disease is based on the timing and sequence of motor symptoms and cognitive symptoms. Consensus criteria for dementia with Lewy bodies separate NCDLB from NCD due to Parkinson’s disease by specifying that for dementia to be attributed to Parkinson’s disease, the Parkinson’s disease diagnosis must be present for at least 1 year before cognitive decline has reached the level of major NCD, whereas for NCDLB, the cognitive

Major or mild neurocognitive disorder due to Alzheimer’s disease. Major or mild vascular neurocognitive disorder. Neurocognitive disorder due to another medical condition (e.g., neurodegenerative disorders). Antipsychotic (or other dopamine receptor–blocking drug)–induced parkinsonism. symptoms may begin before, with, or in the absence of parkinsonism. By contrast, expert consensus criteria for Parkinson’s disease propose that if cognitive decline occurs prior to a motor diagnosis, the diagnosis of Parkinson’s disease may still be made; therefore, a clinician may attribute the cognitive decline to the Parkinson’s disease and diagnose NCD due to Parkinson’s disease. Consequently, the clinician may choose to diagnose NCD due to Parkinson’s disease or NCDLB for individuals with major NCD that starts either before or within 12 months of Parkinson’s disease. In such circumstances, the clinician decides which diagnosis is more appropriate. If Parkinson’s disease has been diagnosed for at least 1 year prior to the onset of cognitive symptoms, then both expert criteria agree that NCD due to Parkinson’s disease would typically be the appropriate diagnosis. The timing and sequence of parkinsonism and mild NCD may be particularly difficult to determine, and unspecified NCD may need to be diagnosed until the order of clinical progression becomes evident. The motor features are the key to distinguishing major or mild NCD due to Parkinson’s disease from major or mild NCD due to Alzheimer’s disease. However, the two disorders can co-occur, and individuals with wellestablished Alzheimer’s disease can develop mild parkinsonism. Major or mild vascular NCD may manifest with parkinsonian features that may occur as a consequence of diffuse cortical or subcortical small vessel disease. However, the parkinsonian features typically are not sufficient for a diagnosis of Parkinson’s disease, and the course of the NCD usually has a clear association with cerebrovascular changes. When a diagnosis of major or mild NCD due to Parkinson’s disease is being considered, the distinction must also be made from other brain disorders, such as progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, tumors, and hydrocephalus. Antipsychotic (or other dopamine receptor–blocking drug)–induced parkinsonism can occur in individuals with other NCDs, particularly when antipsychotic medications are prescribed for the behavioral manifestations of such disorders. Comorbidity Parkinson’s disease may coexist with Alzheimer’s disease and cerebrovascular disease, especially in older individuals. Individuals with NCD due to Parkinson’s disease may display clinical or biomarker features that suggest the presence of both Parkinson’s disease and other pathologies. Evidence for mixed etiology does not preclude the contribution of Parkinson’s disease to an NCD. The compounding of multiple pathological features may diminish the functional abilities of individuals with Parkinson’s disease. Motor symptoms and frequent cooccurrence of depression, psychosis, REM sleep behavior disorder, or apathy can make functional impairment worse. Major or Mild Neurocognitive Disorder Due to Huntington’s Disease

Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. There is insidious onset and gradual progression. C. There is clinically established Huntington’s disease, or risk for Huntington’s disease based on family history or genetic testing. D. The neurocognitive disorder is not attributable to another medical condition and is not better explained by another mental disorder. Coding note (see coding table on pp. 682–683): For major neurocognitive disorder due to Huntington’s disease, with behavioral disturbance, code first G10 Huntington’s disease, followed by F02.81 major neurocognitive disorder due to Huntington’s disease, with behavioral disturbance. For major neurocognitive disorder due to Huntington’s disease, without behavioral disturbance, code first G10 Huntington’s disease, followed by F02.80 major neurocognitive disorder due to Huntington’s disease, without behavioral disturbance. Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded. For mild neurocognitive disorder due to Huntington’s disease, code G31.84. (Note: Do not use the additional code for Huntington’s disease. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild neurocognitive disorder due to Huntington’s disease: Use additional code(s) to indicate clinically significant psychiatric symptoms due to Huntington’s disease (e.g., F06.31 depressive disorder due to Huntington’s disease with depressive features; F06.4 anxiety disorder due to Huntington’s disease). Diagnostic Features Progressive cognitive impairment is a core feature of Huntington’s disease, with early changes in executive function (i.e., processing speed, organization, and planning) typically being more prominent than decline in learning and memory. Cognitive and associated behavioral changes often precede the emergence of the typical motor abnormalities of bradykinesia (i.e., slowing of voluntary movement) and chorea (i.e., involuntary jerking movements). A diagnosis of definite Huntington’s disease is given in the presence of unequivocal, extrapyramidal motor abnormalities in an individual with either a family history of Huntington’s disease or genetic testing showing a CAG trinucleotide repeat expansion in the HTT gene, located on chromosome 4. Associated Features Irritability, apathy, anxiety, obsessive-compulsive symptoms, depression, and, more rarely,

Genetic and physiological. psychosis can all be associated with Huntington’s disease and often precede the onset of motor symptoms. Prevalence Neurocognitive deficits are an eventual outcome of Huntington’s disease; the worldwide prevalence is estimated to be 2.7 per 100,000. The prevalence of Huntington’s disease in North America, Europe, and Australia is 5.7 per 100,000, with a much lower prevalence of 0.40 per 100,000 in Asia. Development and Course The age at diagnosis of Huntington’s disease varies widely, but symptoms are most often observed between ages 35 and 45 years. Age at onset is inversely correlated with CAG expansion length. Juvenile Huntington’s disease (onset before age 20) may present more commonly with bradykinesia, dystonia, and rigidity than with the choreic movements characteristic of the adult-onset disorder. The disease is gradually progressive, with the average length of survival after clinical diagnosis estimated to be approximately 10–20 years, although affected individuals may demonstrate significant variability in disease progression. Phenotypic expression of Huntington’s disease varies by presence of motor, cognitive, and psychiatric symptoms. Psychiatric and cognitive abnormalities can predate the motor abnormality by a decade or more. Initial symptoms requiring care often include irritabity, anxiety, or depressed mood. Other behavioral disturbances may include pronounced apathy, disinhibition, impulsivity, and impaired insight, with apathy often becoming more progressive over time. Early movement symptoms may involve the appearance of fidgetiness of the extremities as well as mild apraxia (i.e., difficulty with purposeful movements), particularly with fine motor tasks. As the disorder progresses, other motor problems include impaired gait (ataxia) and postural instability. Motor impairment eventually affects speech production (dysarthria) such that the speech becomes very difficult to understand, which may result in significant distress resulting from the communication barrier in the context of comparatively intact cognition. Advanced motor disease severely affects gait with progressive ataxia. Eventually individuals become nonambulatory. End-stage motor disease impairs motor control of eating and swallowing, typically a major contributor to the death of the individual from aspiration pneumonia. Risk and Prognostic Factors The genetic basis of Huntington’s disease is a fully penetrant autosomal dominant expansion of the CAG trinucleotide, often called a CAG repeat in the huntingtin gene. A repeat length of 40 or more is invariably associated with Huntington’s disease, with longer repeat lengths associated with early age at onset. A CAG repeat length in the 36–39 range is considered to be partially penetrant, which means that this length could or could not lead to Huntington’s disease. If Huntington’s disease does occur with repeat lengths in this range, it is more often associated with onset late in life (diagnosis after age 70).

Diagnostic Markers Genetic testing is the primary laboratory test for the determination of Huntington’s disease, which is an autosomal dominant disorder with complete penetrance. The trinucleotide CAG is observed to have a repeat expansion in the gene that encodes huntingtin protein on chromosome 4. A diagnosis of Huntington’s disease is not made in the presence of the gene expansion alone, but the diagnosis is made only after motor symptoms become manifest. Some individuals with a positive family history request genetic testing in a presymptomatic stage. Associated features may also include neuroimaging changes; volume loss in the basal ganglia, particularly the caudate nucleus and putamen, is well known to occur and progresses over the course of illness. Other structural and functional changes have been observed in brain imaging but remain research measures. Association With Suicidal Thoughts or Behavior In Huntington’s disease, an elevated suicide risk compared with the general population has been well documented. A literature review and report of data from a large observational study found that suicide is among the leading causes of death in Huntington’s disease. The elevated risk of suicidal thoughts in Huntington’s disease has been shown in diagnosed individuals both prior to and after manifesting the motor symptoms of Huntington’s disease. Risk factors for suicidal thoughts include depressive symptoms, anxiety, irritability, psychosis, and apathy—emphasizing the importance of treating depressive symptoms and assessing suicidal thoughts during clinical monitoring. A large European cohort study of Huntington’s disease similarly found that the most frequent causes of death were pneumonia (19.5%), other infections (6.9%), and suicide (6.6%). Functional Consequences of Major or Mild Neurocognitive Disorder Due to Huntington’s Disease In the prodromal phase of illness and at early diagnosis, occupational decline is most common, with most individuals reporting some loss of ability to engage in their typical work. The emotional, behavioral, and cognitive aspects of Huntington’s disease, such as disinhibition and personality changes, are highly associated with functional decline. Cognitive deficits that contribute most to functional decline may include speed of processing, initiation, and attention rather than memory impairment. Given that Huntington’s disease onset occurs in productive years of life, it may have a very disruptive effect on performance in the work setting as well as social life, family life, and important aspects of daily functioning such as driving. As the disease progresses, disability from problems such as impaired gait, dysarthria, and impulsive or irritable behaviors may substantially add to the level of impairment and daily care needs, over and above the care needs attributable to cognitive decline. Severe choreic movements may substantially interfere with provision of care such as bathing, dressing, and toileting. Differential Diagnosis

Other mental disorders. Other neurocognitive disorders. Other movement disorders. Early symptoms of Huntington’s disease may include instability of mood, irritability, or compulsive behaviors that may suggest another mental disorder. However, genetic testing or the development of motor symptoms will distinguish the presence of Huntington’s disease. In such cases, if the mood symptoms are a focus of clinical attention, they may be indicated by an additional diagnosis of depressive disorder due to Huntington’s disease, with depressive features. The early symptoms of Huntington’s disease, particularly symptoms of executive dysfunction and impaired psychomotor speed, may resemble other neurocognitive disorders (NCDs), such as major or mild vascular NCD. Huntington’s disease must also be differentiated from other disorders or conditions associated with chorea, such as Wilson’s disease, drug-induced tardive dyskinesia, Sydenham’s chorea, systemic lupus erythematosus, or senile chorea. Rarely, individuals may present with a course similar to that of Huntington’s disease but without positive genetic testing; this is considered to be a Huntington’s disease phenocopy that results from a variety of potential genetic factors. Major or Mild Neurocognitive Disorder Due to Another Medical Condition Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. There is evidence from the history, physical examination, or laboratory findings that the neurocognitive disorder is the pathophysiological consequence of another medical condition (e.g., multiple sclerosis). C. The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder) or another specific neurocognitive disorder (e.g., major neurocognitive disorder due to Alzheimer’s disease). Coding note (see coding table on pp. 682–683): For major neurocognitive disorder due to another medical condition, with behavioral disturbance, code first the other medical condition, followed by the major neurocognitive disorder due to another medical condition, with behavioral disturbance (e.g., G35 multiple sclerosis, F02.81 major neurocognitive disorder due to multiple sclerosis, with behavioral disturbance). For major neurocognitive disorder due to another medical condition, without behavioral disturbance, code first the other medical condition, followed by the major neurocognitive disorder due to another medical condition, without behavioral disturbance (e.g., G35 multiple sclerosis, F02.80 major neurocognitive disorder due to multiple sclerosis, without behavioral disturbance). Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded.

Other major or mild neurocognitive disorder. For mild neurocognitive disorder due to another medical condition, code G31.84. (Note: Do not use the additional code for the other medical condition. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild neurocognitive disorder due to another medical condition: Use additional code(s) to indicate clinically significant psychiatric symptoms due to another medical condition (e.g., F06.32 depressive disorder due to multiple sclerosis, with major depressive–like episode). Diagnostic Features A number of medical conditions can cause neurocognitive disorders (NCDs) other than those specific etiologies (e.g., Alzheimer’s disease) already included in prior NCD criteria sets in this chapter. These conditions include structural lesions (e.g., primary or secondary brain tumors, subdural hematoma, slowly progressive or normal-pressure hydrocephalus), hypoxia related to hypoperfusion from heart failure, endocrine conditions (e.g., hypothyroidism, hypercalcemia, hypoglycemia), nutritional conditions (e.g., deficiencies of thiamine or niacin), other infectious conditions (e.g., neurosyphilis, cryptococcosis), immune disorders (e.g., temporal arteritis, systemic lupus erythematosus), hepatic or renal failure, metabolic conditions (e.g., Kufs’ disease, adrenoleukodystrophy, metachromatic leukodystrophy, other storage diseases of adulthood and childhood), and other neurological conditions (e.g., epilepsy, multiple sclerosis). Unusual causes of central nervous system injury, such as electrical shock or intracranial radiation, are generally evident from the history. The temporal association between the onset or exacerbation of the medical condition and the development of the cognitive deficit offers the greatest support that the NCD is a pathophysiological consequence of the medical condition. Diagnostic certainty regarding this relationship may be increased if the neurocognitive deficits ameliorate partially or stabilize in the context of treatment of the medical condition. Development and Course Typically the course of the NCD progresses in a manner that is commensurate with progression of the underlying medical condition. In circumstances where the medical condition is treatable (e.g., hypothyroidism), the neurocognitive deficit may improve or at least not progress. When the medical condition has a deteriorative course (e.g., secondary progressive multiple sclerosis), the neurocognitive deficits will progress along with the temporal course of illness. Diagnostic Markers Associated physical examination and laboratory findings and other clinical features depend on the nature and severity of the medical condition. Differential Diagnosis The presence of an attributable medical condition does not entirely exclude the possibility of another etiological type of major or mild NCD. If cognitive

deficits persist following successful treatment of an associated medical condition, then another etiology may be responsible for the cognitive decline. Major or Mild Neurocognitive Disorder Due to Multiple Etiologies Diagnostic Criteria A. The criteria are met for major or mild neurocognitive disorder. B. There is evidence from the history, physical examination, or laboratory findings that the neurocognitive disorder is the pathophysiological consequence of more than one etiological process, excluding substances (e.g., neurocognitive disorder due to Alzheimer’s disease with subsequent development of vascular neurocognitive disorder). Note: Refer to the diagnostic criteria for the various neurocognitive disorders due to specific medical conditions for guidance on establishing the particular etiologies. C. The cognitive deficits are not better explained by another mental disorder and do not occur exclusively during the course of a delirium. Coding note (see coding table on pp. 682–683): For major neurocognitive disorder due to multiple etiologies, code first all of the etiological medical conditions (with the exception of vascular disease, which is not coded), followed by either F02.81 for major neurocognitive disorder due to multiple etiologies, with behavioral disturbance; or F02.80 for major neurocognitive disorder due to multiple etiologies, without behavioral disturbance. If vascular disease is among the multiple etiological medical conditions, code next either F01.51 for major vascular neurocognitive disorder, with behavioral disturbance; or F01.50 for major vascular neurocognitive disorder, without behavioral disturbance. Note: The severity specifiers “mild,” “moderate,” and “severe” cannot be coded for major neurocognitive disorder but should still be recorded. For example, for a presentation of major neurocognitive disorder, moderate, with a behavioral disturbance, that is judged to be due to Alzheimer’s disease, vascular disease, and HIV infection, and in which heavy chronic alcohol use is judged to be a contributing factor, code the following: G30.9 Alzheimer’s disease, B20 HIV infection; F02.81 major neurocognitive disorder due to Alzheimer’s disease and HIV infection, moderate, with behavioral disturbance; F01.51 major vascular neurocognitive disorder, moderate, with behavioral disturbance; and F10.27 severe alcohol use disorder with alcohol-induced major neurocognitive disorder, moderate, nonamnestic-confabulatory type.

For mild neurocognitive disorder due to multiple etiologies, code G31.84. (Note: Do not use the additional codes for the etiologies. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.) For major or mild neurocognitive disorder due to multiple etiologies: Use additional code(s) to indicate clinically significant psychiatric symptoms due to the various etiologies (e.g., F06.2 psychotic disorder due to Alzheimer’s disease, with delusions; F06.31 depressive disorder due to cerebrovascular disease, with depressive features). This category is included to cover the clinical presentation of a neurocognitive disorder (NCD) for which there is evidence that multiple medical conditions have played a probable role in the development of the NCD. In addition to evidence indicative of the presence of multiple medical conditions that are known to cause NCD (i.e., findings from the history and physical examination, and laboratory findings), it may be helpful to refer to the diagnostic criteria and text for the various medical etiologies (e.g., NCD due to Parkinson’s disease) for more information on establishing the etiological connection for that particular medical condition. Unspecified Neurocognitive Disorder R41.9 This category applies to presentations in which symptoms characteristic of a neurocognitive disorder that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning predominate but do not meet the full criteria for any of the disorders in the neurocognitive disorders diagnostic class. The unspecified neurocognitive disorder category is used in situations in which the precise etiology cannot be determined with sufficient certainty to make an etiological attribution. Coding note: For unspecified major or mild neurocognitive disorder, code R41.9. (Note: Do not use additional codes for any presumed etiological medical conditions. “With behavioral disturbance” and “without behavioral disturbance” cannot be coded but should still be recorded.)