# 21 - 31 Dementia

### 31 Dementia

and therefore, serial examinations and multimodal prognostication 
approaches are advised. For example, the absence of the cortical 
responses of the somatosensory evoked potentials has been shown 
to be a strong indicator of poor outcome following hypoxic injury, as 
has high elevations of serum neuron-specific enolase drawn at estab­
lished intervals after anoxia.
The poor outcome of persistent vegetative and minimally conscious 
states has already been mentioned, but reports of a small number of 
patients displaying cortical activation on functional MRI in response 
to salient stimuli have begun to alter the perception of such individu­
als. In one series, about 10% of vegetative patients (mainly following 
traumatic brain injury) could activate their frontal or temporal lobes 
in response to requests by an examiner to imagine certain visuospatial 
tasks. Another series demonstrated that up to 15% of patients with 
various forms of acute brain injury and absence of behavioral responses 
to motor commands showed EEG activation in response to these com­
mands. It is prudent to avoid generalizations from these findings, but 
the need for future studies of novel techniques to help communication 
and possibly recovery is needed.
■
■FURTHER READING
Claasen J et al: Detection of brain activation in unresponsive patients 
with acute brain injury. N Engl J Med 380:2497, 2019.
Edlow JA et al: Recovery from disorders of consciousness: Mechanisms, 
prognosis and emerging therapies. Nat Rev Neurol 17:135, 2021.
Greer DM et al: Pediatric and adult brain death/death by neurologic 
criteria consensus guideline: Report of the AAN guidelines subcom­
mittee, AAP, CNS, and SCCM. Neurology 101:1112, 2023.
Posner JB et al: Plum and Posner’s Diagnosis of Stupor and Coma, 5th ed. 
New York, Oxford University Press, 2019.
Wijdicks EFM: Predicting the outcome of a comatose patient at the 
bedside. Pract Neurol 20:26, 2020.
Gil D. Rabinovici, William W. Seeley, 

Bruce L. Miller

Dementia
Dementia, a syndrome with many causes, affects over 6 million people 
in the United States and results in a total annual health care cost in 
excess of $300 billion. Dementia is defined as an acquired deterioration 
in cognitive abilities that impairs the successful performance of activi­
ties of daily living. Episodic memory, the ability to recall events specific 
in time and place, is the cognitive function most commonly lost; 10% 
of persons age >70 years and 20–40% of individuals age >85 years have 
clinically identifiable memory loss. In addition to memory, dementia 
may erode other mental faculties, including language, visuospatial, 
praxis, calculation, judgment, and problem-solving abilities. Neuropsy­
chiatric and social deficits also arise in many dementia syndromes, 
manifesting as depression, apathy, anxiety, hallucinations, delusions, 
agitation, insomnia, sleep disturbances, compulsions, or disinhibition. 
The clinical course may be slowly progressive, as in Alzheimer’s disease 
(AD); static, as in anoxic encephalopathy; or may fluctuate from day to 
day or minute to minute, as in dementia with Lewy bodies (DLB). Most 
patients with AD, the most prevalent form of dementia, begin with 
episodic memory impairment, but in other dementias, such as fron­
totemporal dementia (FTD), memory loss is not typically a presenting 
feature. When dementia is caused by a progressive neurodegenerative 
disease, it is preceded by a prodromal clinical stage called mild cogni­
tive impairment (MCI), in which individuals experience cognitive 
decline but remain independent in most daily activities. Increasingly, 

a preclinical stage is recognized for AD and other dementing illnesses, 
in which brain pathology is present but clinical symptoms are not yet 
manifest. Focal cerebral disorders are discussed in Chap. 32 and 
illustrated in a video library in Chap. V2; detailed discussions of AD 
can be found in Chap. 442; FTD and related disorders in Chap. 443; 
vascular dementia in Chap. 444; DLB in Chap. 445; Huntington’s 
disease (HD) in Chap. 447; and prion diseases in Chap. 449. 

FUNCTIONAL ANATOMY OF 
THE DEMENTIAS
Dementia syndromes result from the disruption of specific large-scale 
neuronal networks by initially focal brain lesions, including neurode­
generative changes and vascular injury. Ultimately, the location and 
severity of synaptic and neuronal loss combine to produce the clinical 
features (Chap. 32). Behavior, mood, and attention are also modu­
lated by ascending noradrenergic, serotonergic, and dopaminergic 
pathways, whereas cholinergic signaling is critical for attention and 
memory functions. The dementias differ in the underlying molecular 
pathology and relative neurotransmitter deficit profiles; accordingly, 
accurate diagnosis guides effective therapy.
Dementia
CHAPTER 31
AD typically begins in the entorhinal region of the medial temporal 
lobe, spreads to the hippocampus and other limbic structures, moves 
through the basal temporal areas, and then into lateral and posterior 
temporal and parietal neocortex, eventually causing a more widespread 
degeneration. Vascular dementia is associated with focal damage in a 
variable patchwork of cortical and subcortical regions or white matter 
tracts that disconnects nodes within distributed networks. In keeping 
with its anatomy, AD typically presents with episodic memory loss 
accompanied later by aphasia, executive dysfunction, or navigational 
problems. In contrast, dementias that begin in frontal or subcortical 
regions, such as FTD or HD, are less likely to begin with memory prob­
lems and more likely to present with difficulties with judgment, mood, 
executive control, movement, and behavior.
Lesions of frontal-striatal1 pathways produce specific and predict­
able effects on behavior. The dorsolateral prefrontal cortex has con­
nections with a central band of the caudate nucleus. Lesions of either 
the caudate or dorsolateral prefrontal cortex, or their connecting white 
matter pathways, may result in executive dysfunction, manifesting 
as poor organization and planning, decreased cognitive flexibility, 
and impaired working memory. The lateral orbital frontal cortex 
connects with the ventromedial caudate, and lesions of this system 
cause impulsiveness, distractibility, and disinhibition. The anterior 
cingulate cortex and adjacent medial prefrontal cortex project to the 
nucleus accumbens, and interruption of this system produces apathy, 
poverty of speech, emotional blunting, or even akinetic mutism. All 
corticostriatal systems also include topographically organized projec­
tions through the globus pallidus and thalamus, and damage to these 
nodes can likewise reproduce the clinical syndrome associated with 
the corresponding cortical or striatal injuries. Lesions in nodes of the 
dominant hemisphere speech and language networks can present as a 
primary progressive aphasia, with deficits in naming, word retrieval, 
motor speech, grammar, and comprehension of single words or more 
complex phrases (Chap. 443). Involvement of brainstem nuclei and 
cerebellar structures can further contribute to cognitive, behavioral, 
motor and autonomic manifestations.
■
■THE CAUSES OF DEMENTIA
The single strongest risk factor for dementia is increasing age. The 
prevalence of disabling memory loss increases with each decade over 
age 50 and is usually associated with the microscopic changes of AD 
at autopsy. Yet some centenarians have intact memory function and 
no evidence of clinically significant dementia. Whether dementia is an 
inevitable consequence of normal human aging remains controversial, 
although the prevalence increases with every decade of life.
The many causes of dementia are listed in Table 31-1. The frequency 
of each condition depends on the age group under study, access of the 
1The striatum comprises the caudate/putamen.

TABLE 31-1  Differential Diagnosis of Dementia
Most Common Causes of Dementia
Alzheimer’s disease
Alcoholisma
Vascular dementia
PDD/LBD spectrum
  Multi-infarct
Drug/medication intoxicationa’
  Diffuse white matter disease 
Limbic-predominant age-related 
TDP-43 encephalopathy
(Binswanger’s)
Less Common Causes of Dementia
Vitamin deficiencies
  Thiamine (B1): Wernicke’s 
Toxic disorders
  Drug, medication, and narcotic 
PART 2
Cardinal Manifestations and Presentation of Diseases
encephalopathya
poisoninga
  B12 (subacute combined 
  Heavy metal intoxicationa
degeneration)a
  Organic toxins
Psychiatric
  Depression (pseudodementia)a
  Nicotinic acid (pellagra)a
Endocrine and other organ failure
  Hypothyroidisma
  Schizophreniaa
  Adrenal insufficiency and Cushing’s 
  Conversion disordera
syndromea
Degenerative disorders
  Huntington’s disease
  Multisystem atrophy
  Hereditary ataxias (some forms)
  Frontotemporal lobar degeneration 
  Hypo- and hyperparathyroidisma
  Renal failurea
  Liver failurea
  Pulmonary failurea
Chronic infections
  HIV
  Neurosyphilisa
spectrum
  Multiple sclerosis
  Adult Down’s syndrome with 
  Papovavirus (JC virus) (progressive 
Alzheimer’s disease
  ALS-parkinsonism-dementia 
multifocal leukoencephalopathy)
  Tuberculosis, fungal, and protozoala
complex of Guam
  Prion (Creutzfeldt-Jakob and 
  Whipple’s diseasea
Gerstmann-Sträussler-Scheinker 
diseases)
Miscellaneous
  Sarcoidosisa
Head trauma and diffuse brain damage
  Chronic traumatic encephalopathy
  Chronic subdural hematomaa
  Postanoxia
  Postencephalitis
  Normal-pressure hydrocephalusa
  Vasculitisa
  CADASIL, etc.
  Acute intermittent porphyriaa
Intracranial hypotension
Neoplastic
  Primary brain tumora
  Recurrent nonconvulsive seizuresa
Additional conditions in children or 
adolescents
  Pantothenate kinase–associated 
  Metastatic brain tumora
  Paraneoplastic/autoimmune limbic 
neurodegeneration
  Subacute sclerosing panencephalitis
  Metabolic disorders (e.g., Wilson’s and 
encephalitisa
Leigh’s diseases, leukodystrophies, 
lipid storage diseases, mitochondrial 
mutations)
aPotentially reversible dementia.
Abbreviations: ALS, amyotrophic lateral sclerosis; CADASIL, cerebral autosomal 
dominant arteriopathy with subcortical infarcts and leukoencephalopathy; LBD, 
Lewy body disease; PDD, Parkinson’s disease dementia.
group to medical care, country of origin, and perhaps racial or ethnic 
background. AD is the most common cause of dementia in Western 
countries, accounting for more than half of all patients. Vascular dis­
ease is the second most frequent cause for dementia and is particularly 
common in elderly patients or populations with limited access to medi­
cal care, where vascular risk factors are undertreated. Often, vascular 
brain injury is mixed with neurodegenerative disorders, particularly 
AD, making it difficult, even for the neuropathologist, to estimate the 
contribution of cerebrovascular disease to the cognitive disorder in 
an individual patient. Dementias associated with Parkinson’s disease 
(PD) are common and may develop years after onset of a parkinsonian 
disorder, as seen with PD-related dementia (PDD), or can occur con­
currently with or preceding the motor syndrome, as in DLB. A recently 
characterized dementia is limbic-predominant aging-related TDP-43 

encephalopathy (LATE), which is common after age 70 and has been 
linked to declining episodic memory function. Chronic traumatic 
encephalopathy (CTE), a unique disease found in individuals with 
high exposure to repetitive head impacts (e.g., professional athletes 
in collision or fighting sports, military veterans exposed to multiple 
blasts), presents with changes in cognition, mood, behavior, or motor 
function. Mixed pathology is common, especially in older individuals. 
In patients under the age of 65, FTD rivals AD as the most common 
cause of dementia. Chronic intoxications, including those resulting 
from alcohol and prescription drugs, are an important and often treat­
able cause of dementia. Other disorders listed in Table 31-1 are uncom­
mon but important because many are reversible. The classification of 
dementing illnesses into reversible and irreversible disorders is a useful 
approach to differential diagnosis.
In a study of 1000 persons attending a memory disorders clinic, 
19% had a potentially reversible cause of the cognitive impairment 
and 23% had a potentially reversible concomitant condition that may 
have contributed to the patient’s impairment. The three most com­
mon potentially reversible diagnoses were depression, normal pres­
sure hydrocephalus (NPH), and alcohol dependence; medication side 
effects are also common and should be considered in every patient 
(Table 31-1).
The term rapidly progressive dementia (RPD) is applied to illnesses 
that progress from initial symptom onset to dementia within a year 
or less; confusional states related to toxic/metabolic conditions are 
excluded. Although the prion proteinopathy Creutzfeldt-Jakob disease 
(CJD) (Chap. 449) is the classic cause of a rapidly progressive demen­
tia, especially when associated with myoclonus, more often cases of 
RPD are due to AD or another neurodegenerative disorder, or to an 
autoimmune encephalitis (Chap. 99).
Subtle cumulative decline in episodic memory is a common part of 
aging. This frustrating experience, often the source of jokes and humor, 
has historically been referred to as benign forgetfulness of the elderly. 
Benign means that it is not so progressive or serious that it impairs 
successful and productive daily functioning, although the distinction 
between benign and significant memory loss can be subtle. At age 85, 
the average person is able to learn and recall approximately one-half of 
the items (e.g., words on a list) that they could at age 18. The term sub­
jective cognitive decline is used to refer to individuals who experience 
a subjective decline from their cognitive baseline but perform within 
normal limits for their age and educational attainment on formal neu­
ropsychological testing. As noted earlier, MCI is defined as a decline 
in cognition that is confirmed on objective cognitive testing but does 
not disrupt normal daily activities. MCI can be further subcategorized 
based on the presenting complaints and deficits (e.g., amnestic MCI, 
dysexecutive MCI). Factors that predict progression from MCI to an 
AD dementia include a prominent memory deficit, family history 
of dementia, presence of an apolipoprotein ε4 (Apo ε4) allele, small 
hippocampal volumes on brain imaging, and positive AD biofluid or 
imaging biomarkers (see below). The term mild behavioral impairment 
(MBI) refers to the emergence of sustained and impactful neuropsychi­
atric symptoms in older adults (e.g., apathy, emotional dysregulation, 
impulse control, social inappropriateness, hallucinations, or delusions). 
Like its cognitive counterpart (MCI), MBI can reflect a neuropsychiat­
ric prodrome to a neurodegenerative dementia.
The major degenerative dementias include AD, DLB, LATE, FTD 
and related disorders, HD, and prion diseases, including CJD. These 
disorders are all associated with the abnormal aggregation of a specific 
protein: Aβ and tau in AD; α-synuclein in DLB; TAR DNA-binding 
protein of 43 kDa (TDP-43) in LATE; tau, TDP-43, or the FET fam­
ily of proteins (fused in sarcoma [FUS], Ewing sarcoma [EWS], and 
TBP-associated factor 15 [TAF15]) in FTD; huntingtin in HD; and 
misfolded prion protein (PrPsc) in CJD (Table 31-2).
The risk of developing dementia in late life is associated with 
numerous exposures that can happen across the lifespan. Modifi­
able risk factors based on large-scale epidemiologic studies include 
low education, hearing loss, social isolation, traumatic brain injury, 
hypertension, diabetes mellitus, obesity, heavy alcohol use, smoking, 
depression, physical inactivity, and air pollution exposure. Improved

TABLE 31-2  The Molecular Basis for Degenerative Dementia
DEMENTIA
MOLECULAR BASIS
CAUSAL GENES (CHROMOSOME)
SUSCEPTIBILITY GENES PATHOLOGIC FINDINGS
AD
Aβ/tau
APP (21), PS-1 (14), PS-2 (1) (<2% carry these 
mutations, most often in PS-1)
DLB
α-Synuclein
Very rare SNCA (4)
Unknown
α-Synuclein neuronal inclusions (Lewy 
bodies)
LATE
TDP-43
None identified
TMEM106B, GRN
TDP-43 neuronal “inclusion bodies” and 
neurites in neurons and glia, with or 
without hippocampal sclerosis
FTD
Tau
MAPT exon and intron mutations (17) (~10% of 
familial cases)
TDP-43
GRN (10% of familial cases), C9ORF72 (20–30% 
of familial cases), rare VCP, very rare TARDBP, 
TBK1, TIA1
FUS
Very rare FUS
FUS neuronal and glial inclusions varying in 
morphology and distribution
CJD
PrPSC
PRNP (20) (up to 15% of patients carry these 

dominant mutations)
Abbreviations: AD, Alzheimer’s disease; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; LATE, limbic-predominant age-related 
TDP-43 encephalopathy.
management of mid-life cardiovascular risk factors has been credited 
with a decreasing incidence of dementia noted in North America and 
western European countries.
APPROACH TO THE PATIENT
Dementias
Three major issues should be kept at the forefront: (1) What is the 
clinical diagnosis? (2) What component of the dementia syndrome 
is treatable or reversible? (3) Can the physician help to alleviate the 
burden on caregivers? A broad overview of the approach to demen­
tia is shown in Table 31-3. The major degenerative dementias can 
usually be distinguished by the initial symptoms; neuropsycho­
logical, neuropsychiatric, and neurologic findings; neuroimaging 
features; and other biomarkers (Table 31-4).
HISTORY
The history should concentrate on the onset, duration, and tempo 
of progression. An acute or subacute onset of confusion may be 
due to delirium (Chap. 29) and should trigger a search for intoxi­
cation, infection, or metabolic derangement. An elderly person 
with slowly progressive memory loss over several years is likely 
to suffer from AD and/or LATE. Nearly 75% of patients with AD 
begin with memory symptoms, but other early symptoms include 
anxiety or depression and difficulty with managing money, driv­
ing, shopping, following instructions, finding words, or navigating. 
Personality change, disinhibition, and weight gain or compulsive 
eating suggest FTD, not AD. FTD is also suggested by prominent 
apathy, compulsivity, loss of empathy for others, or progressive loss 
of speech fluency or single-word comprehension with relative spar­
ing of memory and visuospatial abilities. The diagnosis of DLB is 
suggested by early visual hallucinations; parkinsonism; proneness 
to delirium or sensitivity to psychoactive medications; rapid eye 
movement (REM) behavior disorder (RBD; dramatic, sometimes 
violent, limb movements during dreaming [Chap. 33]); or Capgras 
syndrome, the delusion that a familiar person has been replaced by 
an impostor.
A history of stroke with irregular stepwise progression suggests 
vascular dementia. Vascular dementia is also commonly seen in the 
setting of hypertension, atrial fibrillation, peripheral vascular dis­
ease, smoking, and diabetes. In patients suffering from cerebrovas­
cular disease, it can be difficult to determine whether the dementia 
is due to AD, vascular disease, or a mixture of the two because 
many of the risk factors for vascular dementia, including diabetes, 
high cholesterol, elevated homocysteine, and low exercise, are also 

Apo ε4 (19)
Amyloid plaques, neurofibrillary tangles, 
and neuropil threads
H1 MAPT haplotype
Tau neuronal and glial inclusions varying in 
morphology and distribution
Dementia
CHAPTER 31
TDP-43 neuronal and glial inclusions 
varying in morphology and distribution
Codon 129 homozygosity 
for methionine or valine
PrPSC deposition, panlaminar spongiosis
TABLE 31-3  Evaluation of the Patient with Dementia
OPTIONAL FOCUSED 
TESTS
OCCASIONALLY 
HELPFUL TESTS
ROUTINE EVALUATION
History
Physical examination
Laboratory tests
  Thyroid function (TSH)
  Vitamin B12
  Complete blood count
  Complete metabolic panel
  CT/MRI
Psychometric testing
HIV, RPR, or VDRL
Lumbar puncture
PET (FDG, amyloid, tau)
Chest x-ray
Urine toxin screen
Apolipoprotein E
Blood-based AD 
biomarkers
EEG
Parathyroid 
function
Adrenal function
Urine heavy 

metals
RBC sedimentation 
rate
Lab screen for 
autoantibodies
Angiogram
Brain biopsy
Diagnostic Categories
IRREVERSIBLE/
DEGENERATIVE 
DEMENTIAS
PSYCHIATRIC 
DISORDERS
REVERSIBLE CAUSES
Examples
  Hypothyroidism
  Thiamine deficiency
  Vitamin B12 deficiency
  Normal-pressure 
Examples
  Alzheimer’s
  Frontotemporal 
Depression
Schizophrenia
Conversion 
reaction
dementia
  Huntington’s
  Dementia with Lewy 
hydrocephalus
  Subdural hematoma
  Chronic infection
  Brain tumor
  Drug intoxication
  Autoimmune 
bodies
  Vascular
  Leukoencephalopathies
  Parkinson’s
  LATE
encephalopathy
Associated Treatable Conditions
Depression
Seizures
Insomnia
Agitation
Caregiver 
“burnout”
Drug side effects
Abbreviations: CT, computed tomography; EEG, electroencephalogram; LATE, 
limbic-predominant age-related TDP-43 encephalopathy; MRI, magnetic resonance 
imaging; PET, positron emission tomography; RBC, red blood cell; RPR, rapid plasma 
reagin (test); TSH, thyroid-stimulating hormone; VDRL, Venereal Disease Research 
Laboratory (test for syphilis).

TABLE 31-4  Clinical Differentiation of the Major Dementias
DISEASE
FIRST SYMPTOM
MENTAL STATUS
NEUROPSYCHIATRY
NEUROLOGY
IMAGING
AD
Memory loss
Episodic memory loss
Executive, language, and 
visuospatial functions variably 
affected
Vascular
Often but not always sudden; 
variable; apathy, falls, focal 
weakness
Frontal/executive, cognitive 
slowing; can spare memory
DLB
Visual hallucinations, REM sleep 
behavior disorder, delirium, 
Capgras syndrome, parkinsonism
Drawing and frontal/
executive; spares memory; 
delirium-prone
PART 2
Cardinal Manifestations and Presentation of Diseases
LATE
Memory loss
Episodic memory loss
Mild semantic deficits
FTD
Apathy; poor judgment/insight, 
speech/language; hyperorality
Frontal/executive and/or 
language; spares drawing
CJD
Dementia, mood, anxiety, 
movement disorders
Variable, frontal/executive, 
focal cortical, memory
Abbreviations: AD, Alzheimer’s disease; CBD, cortical basal degeneration; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FLAIR, fluid-attenuated 
inversion recovery; FTD, frontotemporal dementia; LATE, limbic-predominant age-related TDP-43 encephalopathy; MND, motor neuron disease; MRI, magnetic resonance 
imaging; PSP, progressive supranuclear palsy; REM, rapid eye movement.
risk factors for AD. Moreover, many patients with a major vascular 
contribution to their dementia lack a history of stepwise decline.
The age at symptom onset can also aid in the differential diag­
nosis of dementia. AD and FTD are the most common neuro­
degenerative causes of “early-onset” (age at symptom onset <65) 
dementia. The most common causes of “late-onset” dementia (age 
at symptom onset >65) are AD, DLB, and vascular dementia. LATE 
neuropathological changes are increasingly common with older 
age and are found in ~20% of individuals with dementia who die at 
age <70 versus >50% of individuals with dementia who die at age 
>90. Most late-onset dementia is associated with multiple patho­
logical entities; it is common for individuals who suffered from 
dementia to show three or four different pathologies at autopsy. 
In one large community-based autopsy cohort of individuals 
who presented with an amnestic dementia during life (mean age 
at death 89.7 years), 39% of the attributable risk for dementia 
was explained by AD neuropathology, 25% by cerebrovascular 
disease, 17% by LATE, and 12% by Lewy body disease.
Rapid progression with motor rigidity and myoclonus suggests 
CJD (Chap. 449). Seizures may indicate strokes or neoplasm but 
also occur in AD, particularly early-age-of-onset AD. Gait distur­
bance is common in vascular dementia, PD/DLB, or NPH. A history 
of high-risk sexual behaviors or intravenous drug use should trig­
ger a search for central nervous system (CNS) infection, especially 
HIV or syphilis. A history of recurrent head trauma could indicate 
chronic subdural hematoma, CTE, intracranial hypotension, or 
NPH. Subacute onset of severe amnesia and psychosis with mesial 
temporal T2/fluid-attenuated inversion recovery (FLAIR) hyperin­
tensities on magnetic resonance imaging (MRI) should raise con­
cern for autoimmune (paraneoplastic) encephalitis, sometimes in 
long-term smokers or other patients at risk for cancer. The spectrum 
of autoimmune etiologies producing RPD has rapidly expanded 
and includes antibodies targeting leucine-rich glioma-inactivated 
1 (LGI1; faciobrachial dystonic seizures); contactin-associated 
protein-like 2 (Caspr2; insomnia, ataxia, myotonia); N-methyl-d-

aspartate (NMDA) receptor (psychosis, insomnia, dyskinesias); and 
α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) 
receptor (limbic encephalitis with relapses), among others (Chap. 99). 
Alcohol abuse creates risk for malnutrition and thiamine deficiency. 
Pernicious anemia, veganism, bowel irradiation, a remote history 

Irritability, anxiety, 
depression
Initially normal
Entorhinal cortex and 
hippocampal atrophy; 
posterior-predominant 
cortical atrophy
Apathy, delusions, 
anxiety
Usually motor slowing, 
spasticity; can be normal
Cortical and/or subcortical 
infarctions, confluent white 
matter disease
Visual hallucinations, 
depression, sleep 
disorder, delusions
Parkinsonism
Posterior parietal atrophy; 
hippocampi larger than in AD
None described
Normal
Medial temporal and 
hippocampal atrophy, anterior 
predominant
Apathy, disinhibition, 
overeating, compulsivity
May have vertical gaze 
palsy, axial rigidity, 
dystonia, alien hand, or 
MND
Frontal, insular, and/or 
temporal atrophy; usually 
spares posterior parietal lobe
Depression, anxiety, 
psychosis in some
Myoclonus, rigidity, 
parkinsonism
Cortical ribboning and 
basal ganglia or thalamus 
hyperintensity on diffusion/
FLAIR MRI
of gastric surgery, and chronic therapy with histamine H2-receptor 
antagonists for dyspepsia or gastroesophageal reflux are causes of 
B12 deficiency. Certain occupations, such as working in a battery or 
chemical factory, might indicate heavy metal intoxication. Careful 
review of medication intake, especially for sedatives and analgesics, 
may raise the issue of chronic drug intoxication. An autosomal 
dominant family history is found in HD and in familial forms of 
AD, FTD, DLB, or prion disorders. A history of mood disorder, the 
recent death of a loved one, or depressive signs such as insomnia 
or weight loss raise the possibility of depression-related cognitive 
impairment. 
PHYSICAL AND NEUROLOGIC EXAMINATION
A thorough general and neurologic examination is essential, in the 
setting of dementia, to look for signs of nervous system involvement 
and to search for clues suggesting a systemic disease that might be 
responsible for the cognitive disorder. Typical AD spares motor sys­
tems until later in the course. In contrast, patients with FTD often 
develop axial rigidity, supranuclear gaze palsy, or a motor neuron 
disease reminiscent of amyotrophic lateral sclerosis (ALS). In DLB, 
the initial symptoms may include the new onset of a parkinsonian 
syndrome (resting tremor, cogwheel rigidity, bradykinesia, festinat­
ing gait), but DLB often starts with visual hallucinations or cogni­
tive impairment, and symptoms referable to the lower brainstem 
(RBD, gastrointestinal or autonomic problems) may arise years or 
even decades before parkinsonism or dementia. Corticobasal syn­
drome (CBS) features asymmetric akinesia and rigidity, dystonia, 
myoclonus, alien limb phenomena, pyramidal signs, and prefrontal 
deficits such as nonfluent aphasia with or without motor speech 
impairment, executive dysfunction, apraxia, or a behavioral disor­
der. Progressive supranuclear palsy (PSP) is associated with unex­
plained falls, axial rigidity, dysphagia, and vertical gaze deficits. CJD 
is suggested by the presence of diffuse rigidity, an akinetic-mute 
state, and prominent, often startle-sensitive myoclonus.
Hemiparesis or other focal neurologic deficits suggest vascu­
lar dementia or brain tumor. Dementia with a myelopathy and 
peripheral neuropathy suggests vitamin B12 deficiency. Peripheral 
neuropathy could also indicate another vitamin deficiency, heavy 
metal intoxication, thyroid dysfunction, Lyme disease, or vasculitis. 
Dry cool skin, hair loss, and bradycardia suggest hypothyroidism.

Fluctuating confusion associated with repetitive stereotyped move­
ments may indicate ongoing limbic, temporal, or frontal seizures. 
In the elderly, hearing impairment or visual loss may produce 
confusion and disorientation misinterpreted as dementia. Profound 
bilateral sensorineural hearing loss in a younger patient with short 
stature or myopathy, however, should raise concern for a mitochon­
drial disorder. 
COGNITIVE AND NEUROPSYCHIATRIC EXAMINATION
Brief screening tools such as the Mini-Mental State Examination 
(MMSE) and the Montreal Cognitive Assessment (MOCA) can be 
used to capture dementia and follow progression. None of these 
tests is highly sensitive to early-stage dementia or reliably discrimi­
nates between dementia syndromes. The MMSE is a 30-point test 
of cognitive function, with each correct answer being scored as 1 
point. It includes tests of orientation (e.g., identify season/date/
month/year/floor/hospital/town/state/country); registration (e.g., 
name and restate three objects); recall (e.g., remember the same 
three objects 5 min later); and language (e.g., name pencil and 
watch; repeat “no ifs, ands, or buts”; follow a three-step command; 
obey a written command; and write a sentence and copy a design). 
In most patients with MCI and some with clinically apparent AD, 
bedside screening tests may be normal, and a more challenging 
and comprehensive set of neuropsychological tests will be required. 
When the etiology for the dementia syndrome remains in doubt, 
a specially tailored evaluation should be performed that includes 
tasks of working and episodic memory, executive function, lan­
guage, and visuospatial and perceptual abilities. In AD, the early 
deficits involve episodic memory, category generation (“Name as 
many animals as you can in 1 minute”), and visuoconstructive abil­
ity. Usually deficits in verbal or visual episodic memory are the first 
neuropsychological abnormalities detected, and tasks that require 
the patient to recall a long list of words or a series of pictures after 
a predetermined delay will demonstrate deficits in most patients. 
Patients with LATE also present with prominent deficits in epi­
sodic memory and can be identified by sparing of other cognitive 
domains and relatively slow progression. Patients with PDD or DLB 
have more severe deficits in executive and visuospatial function but 
do better on episodic memory tasks than patients with AD. Patients 
with vascular dementia often demonstrate a mixture of executive 
and visuospatial deficits, with prominent psychomotor slowing. In 
delirium, the most prominent deficits involve attention, working 
memory, and executive function, making the assessment of other 
cognitive domains challenging and often uninformative. In FTD, 
the earliest deficits on cognitive testing involve executive control or 
language (speech or naming) function, but some patients lack either 
finding despite profound social-emotional deficits.
A functional assessment should also be performed to help the 
physician determine the day-to-day impact of the disorder on the 
patient’s memory, community affairs, hobbies, judgment, dressing, 
and eating. Knowledge of the patient’s functional abilities will help 
the clinician and the family to organize a therapeutic approach.
Neuropsychiatric assessment is important for diagnosis, prog­
nosis, and treatment. In the early stages of AD, mild depressive 
features, social withdrawal, and irritability or anxiety are the most 
prominent psychiatric changes, but patients often maintain core 
social graces into the middle or late stages, when delusions, agita­
tion, and sleep disturbance may emerge. In FTD, dramatic person­
ality changes with apathy, overeating, compulsions, disinhibition, 
and loss of empathy are early and common. DLB is associated with 
visual hallucinations, delusions related to person or place identity, 
RBD, and excessive daytime sleepiness. Dramatic fluctuations occur 
not only in cognition but also in arousal. Vascular dementia can 
present with psychiatric symptoms such as depression, anxiety, 
delusions, disinhibition, or apathy. 
LABORATORY TESTS
The choice of laboratory tests in the evaluation of dementia is com­
plex and should be tailored to the individual patient. The physician 

must take measures to avoid missing a reversible or treatable cause, 
yet no single treatable etiology is common; thus, a screen must use 
multiple tests, each of which has a low yield. Cost/benefit ratios 
are difficult to assess, and many laboratory screening algorithms 
for dementia discourage multiple tests. Nevertheless, even a test 
with only a 1–2% positive rate is worth undertaking if the alterna­
tive is missing a treatable cause of dementia. Table 31-3 lists most 
screening tests for dementia. The American Academy of Neurol­
ogy recommends the routine measurement of a complete blood 
count; electrolytes; glucose; renal, liver, and thyroid functions; 
a vitamin B12 level; and a structural neuroimaging study (MRI or 
computed tomography [CT]).
Dementia
CHAPTER 31
Neuroimaging studies, especially MRI, help to rule out primary 
and metastatic neoplasms, locate areas of infarction or inflam­
mation, detect subdural hematomas, and suggest NPH or diffuse 
white matter disease. They also help to establish a regional pattern 
of atrophy. Support for the diagnosis of AD includes hippocampal 
atrophy in addition to posterior-predominant cortical atrophy 
(Fig. 31-1). Marked hippocampal and medial temporal lobe 
atrophy is also the MRI signature of LATE. Focal frontal, insular, 
and/or anterior temporal atrophy suggests FTD (Chap. 443). DLB 
often features less prominent atrophy, with greater involvement 
of amygdala than hippocampus. In CJD, magnetic resonance 
diffusion-weighted imaging reveals restricted diffusion within the 
cortical ribbon and/or basal ganglia in most patients. Extensive 
multifocal white matter abnormalities suggest a vascular etiology 
(Fig. 31-2). Communicating hydrocephalus with vertex efface­
ment (crowding of dorsal convexity gyri/sulci), gaping Sylvian 
fissures despite minimal cortical atrophy, and additional features 
shown in Fig. 31-3 suggest NPH. 18F-fluorodeoxyglucose positron 
emission tomography (FDG-PET) scanning shows temporal-pari­
etal or hypometabolism in AD, often with early and prominent 
involvement of the posterior cingulate cortex and precuneus. 
Conversely, patients with FTD show hypometabolism in frontal 
and anterior temporal cortices. The FDG signature of DLB fea­
tures hypometabolism in the occipital cortex and precuneus with 
sparing of the posterior cingulate (“cingulate island sign”), while 
LATE is characterized by severe medial temporal hypometabo­
lism with sparing of association cortices. Single-photon emission 
computed tomography (SPECT) demonstrates spatial patterns 
of hypoperfusion that mirror the FDG hypometabolic patterns 
described above.
Amyloid and tau PET imaging can support the diagnosis of AD 
by directly detecting amyloid plaques and neurofibrillary tangles, 
the neuropathological lesions that define the disease. There are cur­
rently three amyloid PET ligands (18F-florbetapir, 18F-florbetaben, 
18F-flutametamol) and one tau PET ligand (18F-flortaucipir) 
approved by the U.S. Food and Drug Administration (FDA) for 
clinical use. Amyloid PET ligands bind to diffuse and neuritic 
amyloid plaques as well as to vascular amyloid deposits (cerebral 
amyloid angiopathy), while tau PET ligands bind to the paired 
helical filaments of tau characteristic of neurofibrillary tangles in 
AD. Current tau PET ligands do not reliably detect tau deposits in 
non-AD conditions. Because amyloid plaques are also commonly 
found in cognitively normal older persons (~25% of individuals at 
age 70), the main clinical value of amyloid imaging is to exclude 
AD as the likely cause of dementia in patients who have negative 
scans. In older patients presenting with a progressive amnestic 
disorder and hippocampal atrophy, a negative amyloid PET scan 
strongly suggests LATE as the underlying neuropathology. The 
spread of tau is more tightly linked to cognitive state (Chap. 442), 
and thus tau PET may be more useful for “ruling in” AD, as well 
as for disease staging. Amyloid PET is also useful to identify can­
didates for novel anti-Aβ monoclonal antibodies (e.g., lecanemab, 
donanemab) that reduce amyloid plaque load and slow cognitive 
decline in patients in early clinical stages of AD. Amyloid and tau 
PET can also assist with prognosis, as patients who are positive 
on both modalities show the most rapid decline in cognition and

62 y.o. HC
60 y.o. AD
PART 2
Cardinal Manifestations and Presentation of Diseases
A
B
C
D
FIGURE 31-1  Alzheimer’s disease (AD). Axial T1-weighted MRI and 18F-florbetapir amyloid PET images from a 62-year-old healthy control (left) and 60-year-old with 
dementia due to AD (right panels). Note the reduction in medial temporal volumes and prominent sulci on MRI in the patient with AD. Amyloid PET demonstrates a white 
matter only binding pattern in the healthy control (negative scan), whild the patient with AD demonstrates diffuse neocortical binding and blurring of gray/white matter 
contrast (positive scan). (Images courtesy of Gil Rabinovici, University of California, San Francisco.) 
function. Use of amyloid and tau PET in cognitively unimpaired 
older adults should for now be restricted to research studies and 
clinical trials testing interventions aimed at reducing the risk of 
MCI and dementia in asymptomatic individuals who are positive 
for AD biomarkers.
Lumbar puncture is indicated when CNS infection or inflamma­
tion is a credible diagnostic possibility or to assess molecular bio­
markers for AD in lieu of PET imaging. A cerebrospinal fluid (CSF) 
pattern that shows low levels of Aβ42 (or a low Aβ42/Aβ40 ratio), mild 
to moderately elevated CSF total tau, and elevated CSF phosphory­
lated tau (p-Tau at residues 181 or 217) is highly suggestive of AD 
and sufficient for selecting patients for anti-Aβ antibody treatment. 
Novel fully automated CSF Aβ and tau assays perform comparably 
to amyloid PET, with the Aβ42/Aβ40 or p-Tau181/Aβ42 ratios show­
ing higher concordance with amyloid PET and neuropathology 
than any single CSF AD biomarker. Blood-based AD biomarkers, 
such as plasma Aβ42/Aβ40, p-Tau181 and p-Tau217 measured with 
FIGURE 31-2  Diffuse white matter disease. Axial fluid-attenuated inversion 
recovery (FLAIR) magnetic resonance image through the lateral ventricles reveals 
multiple areas of hyperintensity (arrows) involving the periventricular white matter 
as well as the corona radiata and striatum. Although seen in some individuals with 
normal cognition, this appearance is more pronounced in patients with dementia of 
a vascular etiology.

mass spectrometry or highly sensitive immunoassays, are evolving 
rapidly and are likely to be approved for clinical use in the near 
future, greatly enhancing the scalability and cost effectiveness of 
biomarker testing in patients with suspected AD (Chap. 442).
Recently, there has been significant progress in developing bio­
markers of α-synuclein pathology, enabling a molecular diagnosis 
of PD or DLB. A CSF seed amplification assay for α-synuclein 
shows high sensitivity and specificity in clinically diagnosed PD 
patients and also detects pathology in a subset of individuals at 
risk for PD based on the presence of anosmia or RBD. α-Synuclein 
can also be detected with high sensitivity and specificity in living 
patients with PD and DLB with skin biopsies immunostained for 
phosphorylated α-synuclein colocalizing with nerve fiber bundles. 
While still in early stages of validation, these biomarkers hold 
A
B
FIGURE 31-3  Normal-pressure hydrocephalus. A. Sagittal T1-weighted magnetic 
resonance image (MRI) demonstrates dilation of the lateral ventricle and stretching 
of the corpus callosum (arrows), depression of the floor of the third ventricle (single 
arrowhead), and enlargement of the aqueduct (double arrowheads). Note the diffuse 
dilation of the lateral, third, and fourth ventricles with a patent aqueduct, typical of 
communicating hydrocephalus. B. Axial T2-weighted MRIs demonstrate dilation 
of the lateral ventricles. This patient underwent successful ventriculoperitoneal 
shunting.

great promise for enhancing diagnostic accuracy and accelerating 
drug development for α-synuclein disorders. Active work is being 
done to develop PET tracers for α-synuclein and to discover both 
imaging and fluid-based biomarkers for other aggregated disease 
proteins underlying neurodegenerative dementias, such as non-AD 
tau and TDP-43.
Electroencephalogram (EEG) is not routinely used but can help 
to suggest CJD (repetitive bursts of diffuse high-amplitude sharp 
waves, or “periodic complexes”) or an underlying nonconvulsive 
seizure disorder (epileptiform discharges). Brain biopsy (including 
meninges) is not advised except to diagnose vasculitis, potentially 
treatable neoplasms, or unusual infections when the diagnosis is 
uncertain. Systemic disorders with CNS manifestations, such as 
sarcoidosis, can often be confirmed through biopsy of lymph node 
or solid organ rather than brain. Magnetic resonance angiography 
should be considered when cerebral vasculitis or cerebral venous 
thrombosis is a possible cause of the dementia.
■
■GLOBAL CONSIDERATIONS
Vascular dementia (Chap. 444) is more common in Asian countries, 
due to the higher prevalence of intracranial atherosclerosis. Rates 
of vascular dementia are also on the rise in developing countries as 
vascular risk factors such as hypertension, hypercholesterolemia, and 
diabetes mellitus become more widespread. CNS infections, HIV 
(and associated opportunistic infections), syphilis, cysticercosis, and 
tuberculosis likewise represent major contributors to dementia in the 
developing world. Systemic infection with SARS-CoV-2 may, in some 
individuals, have lasting effects on cognition due to involvement of 
brain microvasculature or due to immunologically mediated white 
matter injury (acute disseminated encephalomyelitis [ADEM]) 
(Chap. 456). Some individuals infected with SARS-CoV-2 complain 
of lasting fatigue, changes in mood, and cognitive difficulties, but the 
long-term prognosis for SARS-CoV-2–related cognitive impairment 
remains unknown. Isolated populations have also contributed to our 
understanding of neurodegenerative dementia. Kuru, the cannibalismassociated rapidly progressive dementia seen in tribal New Guinea, 
played a role in the discovery of human prion disease. ALS-parkin­
sonism-dementia complex of Guam (or lytico-bodig disease) is a poly­
proteinopathy, often with tau, TDP-43, and α-synuclein aggregation. 
The root cause of the disease remains uncertain, but its incidence has 
declined sharply over the past 60 years.
TREATMENT
Dementia
The major goals of dementia management are to treat reversible 
causes and to provide comfort and support to the patient and 
their caregivers. Treatment of underlying causes includes thyroid 
replacement for hypothyroidism; vitamin therapy for thiamine or 
B12 deficiency or for elevated serum homocysteine; antimicrobials 
for opportunistic infections or antiretrovirals for HIV; ventricular 
shunting for NPH; or surgical, radiation, and/or chemotherapeutic 
treatment for CNS neoplasms. Removal of cognition-impairing 
drugs or medications is critical when appropriate. If the patient’s 
cognitive complaints stem from a psychiatric disorder, vigorous 
treatment of the condition should be sought to eliminate the cogni­
tive complaint or to confirm that it persists despite adequate resolu­
tion of the mood or anxiety symptoms. Patients with degenerative 
diseases may also be depressed or anxious, and those aspects of 
their condition often respond to therapy, while not necessarily 
improving cognition. Antidepressants, such as selective serotonin 
reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake 
inhibitors (SNRIs) (Chap. 463), which feature anxiolytic properties 
but few cognitive side effects, provide the mainstay of treatment 
when necessary. Anticonvulsants are used to control seizures, with 
levetiracetam and lamotrigine being the preferred agents based on 
their efficacy in animal models of AD and favorable cognitive side 

effect profiles. Furthermore, a small clinical trial found a potential 
cognitive benefit for levetiracetam over placebo in AD patients 
found to have epileptiform activity on electroencephalogram or 
magnetoencephalography.

Agitation, hallucinations, delusions, and confusion are difficult 
to treat. These behavioral problems represent major causes for 
nursing home placement and institutionalization. Before treating 
these behaviors with medications, the clinician should aggres­
sively seek out modifiable environmental or metabolic factors. 
Hunger, lack of exercise, toothache, constipation, urinary tract or 
respiratory infection, electrolyte imbalance, and drug toxicity all 
represent easily correctable causes that can be remedied without 
psychoactive drugs. Drugs such as phenothiazines and benzodiaz­
epines may ameliorate the behavior problems but have untoward 
side effects such as sedation, rigidity, dyskinesia, and occasion­
ally paradoxical disinhibition (benzodiazepines). Despite their 
unfavorable side effect profile, second-generation antipsychotics 
such as quetiapine (starting dose, 12.5–25 mg daily) can be used 
for patients with agitation, aggression, and psychosis, although 
the risk profile for these compounds is significant, including 
increased mortality in patients with dementia. Brexpiprazole, an 
atypical antipsychotic that acts on noradrenergic, serotonergic, and 
dopaminergic neurotransmitter systems, recently became the first 
FDA-approved drug for the treatment of agitation in patients with 
AD dementia based on evidence of short-term efficacy and safety 
in a 12-week, double-blind, placebo-controlled randomized clini­
cal trial. When patients do not respond to treatment, it is usually a 
mistake to advance to higher doses or to use anticholinergic drugs 
(e.g., diphenhydramine) or sedatives (e.g., barbiturates or ben­
zodiazepines). It is important to recognize and treat depression; 
treatment can begin with a low dose of an SSRI (e.g., escitalopram, 
starting dose 5 mg daily, target dose 5–10 mg daily) while monitor­
ing for efficacy and toxicity. Sometimes apathy, visual hallucina­
tions, depression, and other psychiatric symptoms respond to the 
cholinesterase inhibitors, especially in DLB, obviating the need for 
other more toxic therapies.
Dementia
CHAPTER 31
Cholinesterase inhibitors are being used to treat AD (donepezil, 
rivastigmine, galantamine) and PDD (rivastigmine). Memantine, 
which acts on N-methyl-D-aspartate (NMDA) glutamate receptors, 
proves useful when treating some patients with moderate to severe 
AD; its major benefit relates to decreasing caregiver burden, most 
likely by decreasing resistance to dressing and grooming support. 
In moderate to severe AD, the combination of memantine and a 
cholinesterase inhibitor delayed nursing home placement in several 
studies, although other studies have not supported the efficacy of 
adding memantine to the regimen. Memantine should be used 
with great caution, or not at all, in patients with DLB, due to risk of 
worsening agitation and confusion.
In recent years, a novel class of drugs, monoclonal antibod­
ies that target Aβ, have been approved for the treatment of MCI 
and mild dementia due to AD. These drugs reduce amyloid 
plaque burden as measured by PET, and some have been found 
to modestly slow clinical decline. In 2021, aducanumab became 
the first anti-Aβ monoclonal antibody to receive accelerated 
FDA approval, based on strong biomarker evidence of amyloid 
plaque lowering on PET. However, clinical benefits were ques­
tionable based on discordant results in two identically designed 
phase 3 randomized clinical trials (RCTs). In 2023, lecanemab 
received traditional FDA approval based on evidence of clinical 
efficacy in a phase 3 RCT, with treated patients showing 27% 
less decline over 18 months compared to placebo on the Clinical 
Dementia Rating–Sum of Boxes, a clinical scale that measures 
changes in cognition and function. A third antibody, donanemab, 
reported similar positive clinical results in a phase 3 RCT, and was 
approved by the FDA in 2024. All three drugs are infused intrave­
nously every 2 weeks (lecanemab) or monthly (aducanumab and 
donanemab). Significant side effects of this class of medications 
include infusion reactions and amyloid-related imaging abnor­
malities (ARIA), which manifest as edema or sulcal effusions