# 15 - 445 Dementia with Lewy Bodies

### 445 Dementia with Lewy Bodies

considered independently. Interactions between cerebrovascular and 
neurodegenerative processes may also contribute to dementia. Such 
interactions might involve loss of blood-brain barrier integrity (pos­
sibly allowing brain penetration of neurotoxic or inflammatory agents) 
and impaired clearance of β-amyloid or other pathogenic molecules 
from the brain (postulated to occur along perivascular drainage path­
ways driven by physiologic vascular motion).
APPROACH TO THE PATIENT
Vascular Dementia
Identifying vascular contributors to a patient’s cognitive impair­
ment can clarify the etiologic diagnosis and point to specific 
interventions aimed at slowing progression. Clinical evaluation is 
focused on identifying vascular risk factors (hypertension, diabetes 
mellitus, dyslipidemia, tobacco use, atrial fibrillation, coronary 
artery disease, or peripheral vascular disease), history of prior 
symptoms of stroke or transient ischemic attack, and family history 
of early stroke or vascular disease. Although stepwise progression 
and certain cognitive deficits such as loss of executive function 
are particularly suggestive, most individuals with VCID follow the 
more typical pattern of gradual progression of impaired episodic 
memory.
The mainstay for detection and subtyping of cerebrovascular 
disease is brain MRI. The MRI should include FLAIR, diffusionweighed, and T2∗-weighted sequences to detect the range of lesions 
noted above: large and small chronic infarcts, acute microinfarcts, 
microbleeds, and white matter hyperintensities. Vessel imaging 
studies such as computed tomography or magnetic resonance angi­
ography are not required for initial evaluation of cognitive impair­
ment, though they may be useful for determining the cause of any 
macroscopic infarcts that are identified. Genetic testing for rare 
hereditary forms of VCID such as cerebral autosomal dominant 
arteriopathy with subcortical infarcts and leukoencephalopathy 
(CADASIL) (Chap. 438) or hereditary cerebral amyloid angiopathy 
can be considered for cases in which there is a particularly young 
onset, positive family history, or suggestive neuroimaging, but is 
otherwise unnecessary.
TREATMENT
Vascular Dementia
Very few trials have addressed the optimal treatment for individuals 
with asymptomatic large- or small-vessel cerebrovascular disease, 
leaving uncertainty as to whether to follow primary or secondary 
stroke prevention guidelines. At a minimum, treatment should 
assiduously follow primary stroke prevention guidelines. The 
American Heart Association recommends the prudent approach 
for vascular health of managing blood pressure, controlling choles­
terol, reducing blood sugar, maintaining an active lifestyle, adhering 
to a heart-healthy diet, losing weight, discontinuing tobacco, and 
getting healthy sleep (Life’s Essential 8, https://www.heart.org/en/
healthy-living/healthy-lifestyle/lifes-essential-8). Blood pressure tar­
gets are <140/90 mmHg for all individuals and <130/80 mmHg 
for those with estimated 10-year cardiovascular disease risk ≥10%, 
which likely applies to many individuals with imaging evidence of 
asymptomatic brain infarcts or advanced small-vessel disease. The 
usefulness of other treatments for secondary stroke prevention such 
as antiplatelet or statin therapy has not been established for asymp­
tomatic infarcts. These agents are reasonable to consider, however, 
when the imaging appearance suggests embolic or large-vesselrelated strokes. All individuals with asymptomatic infarcts should 
be screened for atrial fibrillation, and those with embolic-appearing 
infarcts can be considered for prolonged cardiac monitoring. Simi­
larly, patients with infarcts in the territories of large arteries should 
be considered for vascular imaging.
The few trials of symptomatic medications for cognitive impair­
ment due to vascular etiologies have suggested modest cognitive 

benefits comparable to those found in Alzheimer’s disease patients. 
Therefore, it may be reasonable in VCID to consider agents such 
as the cholinesterase inhibitors donepezil, rivastigmine, or galan­
tamine for mild to moderate cognitive impairment and high-dose 
donepezil or the N-methyl-d-aspartate receptor antagonist meman­
tine for moderate to severe impairment (Chap. 442). A shared 
decision-making approach in considering these medications is use­
ful, given their relatively small impact on daily function.

■
■FURTHER READING
Boyle PA et al: Person-specific contribution of neuropathologies to 
cognitive loss in old age. Ann Neurol 83:74, 2018.
Corriveau RA et al: The science of vascular contributions to cogni­
tive impairment and dementia (VCID): A framework for advancing 
research priorities in the cerebrovascular biology of cognitive decline. 
Cell Mol Neurobiol 36:281, 2016.
Dichgans M, Leys D: Vascular cognitive impairment. Circ Res 
CHAPTER 445
120:573, 2017.
Düering M et al: Neuroimaging standards for research into small ves­
sel disease-advances since 2013. Lancet Neurol 22:602, 2023.
Greenberg SM et al: Cerebral amyloid angiopathy and Alzheimer dis­
ease: One peptide, two pathways. Nat Rev Neurol 16:30, 2020.
Levine DA et al: Trajectory of cognitive decline after incident stroke. 
Dementia with Lewy Bodies 
JAMA 314:41, 2015.
Smith EE et al: Prevention of stroke in patients with silent cerebro­
vascular disease: A scientific statement for healthcare professionals 
from the American Heart Association/American Stroke Association. 
Stroke 48:e44, 2017.
Snowdon DA et al: Brain infarction and the clinical expression of 
Alzheimer disease. The Nun Study. JAMA 277:813, 1997.
Vermeer SE et al: Silent brain infarcts and the risk of dementia and 
cognitive decline. N Engl J Med 348:1215, 2003. 
Irene Litvan, William W. Seeley, 

Bruce L. Miller

Dementia with 

Lewy Bodies
Lewy body disease (LBD), manifesting as Parkinson’s disease dementia 
(PDD) or dementia with Lewy bodies (DLB), is the second most com­
mon cause of neurodegenerative dementia, after Alzheimer’s disease 
(AD) (Chap. 442). Approximately 10% of patients with Parkinson’s 
disease (PD) develop PDD per year, with the majority of PD patients 
developing PDD over time. The incidence of DLB is ~7 per 100,000 
person-years. The prevalence of both PDD and DLB increases with 
aging, and both affect men more often than women. The development 
of increasingly useful biomarkers for PD and DLB is making possible 
new operational definitions, classifications, and staging for these disor­
ders, and these are likely to continue to evolve over time.
CLINICAL MANIFESTATIONS
Most investigators conceptualize PDD and DLB as points on a spec­
trum of LBD pathology. Cognitively, PDD and DLB usually manifest 
with severe executive, attentional, and visuospatial deficits but pre­
served episodic memory. Cognitive decline in LBD affects performance 
of daily living activities beyond other PD symptoms. Early psychosis 
including well-formed visual hallucinations, fluctuating cognition, 
rapid eye movement sleep behavior disorder (RBD), and parkinson­
ism are the main diagnostic features in DLB. The sense of a presence 
behind the person may precede well-formed hallucinations. Delusions

are less frequent than hallucinations and are usually related to mis­
identification, infidelity, theft, or persecution. Fluctuating attention 
and concentration are other characteristic features. Minor day-to-day 
variation in cognitive functioning is common across dementias, but in 
DLB, these fluctuations can be marked, with short periods of confusion 
or severe lethargy that may rapidly resolve. Patients with PDD and DLB 
are highly sensitive to infectious or metabolic disturbances. The first 
manifestation of DLB in some patients is delirium, often precipitated 
by an infection, new medicine, or other systemic disturbance. Parkin­
sonism in DLB is usually associated with early postural instability and 
can present early or later in the course. RBD is a characteristic, often 
prodromal, feature. Normally, dreaming is accompanied by skeletal 
muscle paralysis, but patients with RBD enact dreams, often violently, 
leading to injuries to themselves or their bed partners. Both PDD and 
DLB may be accompanied or preceded by anosmia, constipation, RBD, 
depression, and anxiety.

The symptom profile in DLB and PDD can provide clues for the 
differential diagnosis at the clinic. Clinically, the time interval between 
parkinsonism and dementia differentiates PDD and DLB. PDD presents 
in patients with long-standing PD, who manifest dementia often with 
visual hallucinations, fluctuating attention or alertness, and RBD. On 
the other hand, when the dementia and the neuropsychiatric symptoms 
precede or co-emerge with the parkinsonism, the patient is diagnosed 
with DLB. Patients with DLB, more frequently than those with PDD, 
also have AD co-pathology, making the prediction of underlying pathol­
ogy challenging for clinicians. Episodic memory disturbance points to 
the diagnosis of comorbid AD. Orthostatic hypotension that can lead to 
syncopal events, erectile dysfunction, and constipation can be present 
early in DLB, at times making it challenging to differentiate DLB from 
multiple system atrophy (MSA). In MSA, the autonomic disturbances 
occur early and are usually more severe than in DLB, and cognition 
is relatively preserved. Anosmia is also more characteristic of LBD 
than MSA. Skin biopsy and serum with biomarkers for α-synuclein 
oligomers, a major component of Lewy bodies, have shown potential 
for differentiating PD from MSA, and if validated for clinical use, this 
type of test may also differentiate DLB or PDD from MSA in the future.
PART 13
Neurologic Disorders
■
■PRODROMAL PHASE
Both DLB and PDD have a prodromal phase where patients have a 
mild cognitive impairment (MCI), with cognitive deficits that do not 
have a substantial impact on daily life. PD-MCI is characterized by def­
icits in executive, attention, and visuospatial disturbances, but can also 
present with an amnestic or multiple-domain MCI. Prodromal DLB is 
characterized by similar cognitive disturbances but is also associated 
with either hallucinations unrelated to medications, RBD, fluctuations 
in attention, or parkinsonism. It is at times challenging to differentiate 
prodromal MCI-DLB and PD-MCI when the major features are RBD 
and parkinsonism, for which the term prodromal MCI–Lewy body 
(MCI-LB) was recently proposed. RBD may precede the development 
of an LBD-related syndrome by many years, usually evolving into 
either PD or DLB. The clinical profile and several biomarkers can help 
differentiate MCI due to LBD versus AD pathology (Table 445-1).
PATHOLOGY
The key neuropathologic feature in LBD is the presence of Lewy bod­
ies and Lewy neurites throughout specific brainstem nuclei, substan­
tia nigra, amygdala, cingulate gyrus, and, ultimately, the neocortex. 
Lewy bodies are intraneuronal cytoplasmic inclusions that stain with 
periodic acid–Schiff (PAS) and ubiquitin but are now identified with 
antibodies to the presynaptic protein α-synuclein. Lewy bodies are 
composed of straight neurofilaments 7–20 nm long with surrounding 
amorphous material and contain epitopes recognized by antibodies 
against phosphorylated and nonphosphorylated neurofilament pro­
teins, ubiquitin, and α-synuclein. The presence of α-synuclein aggre­
gates in neurons and glia in PDD and DLB molecularly classifies these 
diseases as synucleinopathies. In general, neuronal and synaptic loss, 
rather than Lewy pathology per se, best predicts the clinical deficits.
Formal criteria identify three stages of progression: (1) brainstem 
predominant; (2) transitional limbic; and (3) diffuse neocortical. 

TABLE 445-1  Distinguishing MCI Due to Lewy Body Disease or 
Alzheimer’s Disease
CLINICAL 
FEATURES
PRODROMAL MCI-LB 
PATHOLOGY
PRODROMAL MCI-AD 
PATHOLOGY
MCI
MCI usually affecting 
executive, attention, and/or 
visuospatial functions
MCI with impaired memory 
and semantic naming
Fluctuating 
cognition with 
variations in 
attention
Frequent and severe
Rare or not severe
Sleep
REM sleep behavior 
disorder
Insomnia, frequent 
awakenings
Recurrent visual 
hallucinations
Frequent
Rare
Biomarkers
Polysomnogram
REM sleep behavior 
disorder without atonia
Normal
CSF
Decreased CSF α-synuclein 
by RT-QuIC
Decreased CSF β-amyloid 
and increased phospho-tau. 
This can now be performed 
in blood.
MRI
Atrophy of the amygdala
Atrophy of the 
parahippocampal/
hippocampal areas
18F-deoxyglucose 
PET scan
Hypometabolism in occipital 
lobe and increased 
in posterior cingulate 
(cingulate island sign)
Hypometabolism in 
parietotemporal lobes
Amyloid PET scan
Normal, unless associated 
with AD
Abnormal parietotemporal 
areas
MIBG myocardial 
scintigraphy
Postganglionic sympathetic 
denervation
Normal
DAT scan or PET 
dopamine scan
Reduced dopamine 
transporter in the basal 
ganglia, particularly 
putamen
Normal
Abbreviations: AD, Alzheimer’s disease; CSF, cerebrospinal fluid; DAT, dopamine 
transporter; LB, Lewy bodies; MCI, mild cognitive impairment; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; PET, positron emission 
tomography; REM, rapid eye movement; RT-QuIC, real-time quaking-induced 
conversion.
Importantly, healthy older individuals may also show isolated scattered 
Lewy body pathology in the substantia nigra, amygdala, or olfactory 
bulb. Pathologic studies have shown that PD usually starts in the 
enteric nervous system and spreads through the vagus nerve to the heart, 
lower brainstem, substantia nigra, limbic system, and lastly the cerebral 
cortex. PD may also begin in the olfactory bulb and spread through 
olfactory system connections or start independently in enteric and 
olfactory bulb areas. Evidence from human anatomic pathology and 
animal models suggests that LBD may similarly propagate via a prionlike mechanism. Abnormally folded α-synuclein aggregates propagate 
transneuronally following connection pathways of the nervous system. 
This pathologic propagation from the periphery to the brain correlates 
with the evolution of clinical symptoms; PD usually manifests first 
with nonmotor features characterized by constipation and/or hypos­
mia, followed by anxiety, depression, RBD, parkinsonism, and lastly 
dementia. PDD is manifested clinically when limbic and cortical areas 
are involved.
A profound cholinergic deficit, owing to basal forebrain and pedun­
culopontine nucleus involvement, is present in most patients with DLB 
and may be associated with the characteristic fluctuations, inattention, 
and visual hallucinations. Adrenergic deficits from locus coeruleus 
involvement further undermine arousal and alerting.
PATHOGENESIS
Both genes and environmental factors are thought to contribute to 
the development of LBD. The presence of α-synuclein aggregates in 
Lewy bodies led to the discovery of α-synuclein duplications and