3379 Frontotemporal Dementia CHAPTER 432

pathology. Microscopic findings seen

across all patients with FTLD include

gliosis, microvacuolation, and neuronal loss, but the disease is subtyped

according to the protein composition

of neuronal and glial inclusions, which

contain either tau or TDP-43 in ~90%

of patients, with the remaining ~10%

showing inclusions containing the FET

family of proteins (FUS, Ewing sarcoma

protein, TAF-15) (Fig. 432-2).

■ PATHOGENESIS

In FTLD-tau, the toxicity and spreading

capacity of misfolded tau are critical

for the pathogenesis of inherited and

sporadic tauopathies, although loss of

tau microtubule stabilizing function may

also play a role. In recent years, the

characteristic structures of the misfolded tau in each FTLD tauopathy

have been resolved using cryo-electron microscopy, opening up new

approaches to diagnosis and treatment. TDP-43 and FUS, in contrast,

are RNA/DNA binding proteins whose roles in neuronal function are

still being actively investigated. TDP-43 is a master regulator of gene

expression, and loss of TDP-43 function results in mis-splicing events

leading to mRNA degradation (via nonsense-mediated decay) or

aberrant transcripts that give rise to stable but dysfunctional peptides.

One key role of TDP-43 and FUS proteins may be the chaperoning of

mRNAs to the distal neuron for activity-dependent translation within

dendritic spines. Because these proteins also form intracellular aggregates and produce similar anatomic progression, protein toxicity and

spreading may also factor heavily in the pathogenesis of FTLD-TDP

and FTLD-FET.

Increasingly, misfolded proteins in neurodegenerative disease are

recognized as having “prion-like” properties in that they can template

the misfolding of their natively folded (or unfolded) protein counterparts, a process that creates exponential amplification of protein

misfolding within a cell and may promote transcellular and even

transsynaptic protein propagation between cells. This hypothesis could

provide a unifying explanation for the stereotypical patterns of disease

spread observed in each syndrome (Chap. 424).

Although the term Pick’s disease was once used to describe a progressive degenerative disorder characterized by selective involvement

of the anterior frontal and temporal neocortex and pathologically

by intraneuronal cytoplasmic inclusions (Pick bodies), it is now used

only in reference to a specific FTLD-tau histopathologic subtype.

Classical Pick bodies are argyrophilic, staining positively with the

Bielschowsky silver method (but not with the Gallyas method) and

also with immunostaining for hyperphosphorylated tau. Recognition

of the three FTLD major molecular classes has allowed delineation of

distinct FTLD subtypes within each class. These subtypes, based on the

morphology and distribution of the neuronal and glial inclusions (Fig.

432-3), account for the vast majority of patients, and some subtypes

show strong clinical or genetic associations (Fig. 432-2). Despite this

progress, clinical features do not allow reliable prediction of the underlying FTLD subtype, or even the major molecular class, for all clinical

syndromes. Molecular PET imaging with ligands chosen to bind misfolded tau protein shows promise, but at the moment these ligands only

show robust and specific binding to AD-related misfolded tau. Because

FTLD-tau and FTLD-TDP account for 90% of FTLD patients, the

ability to detect pathologic tau (or TDP-43) protein deposition in vivo

would greatly improve prediction accuracy, especially when amyloid

PET imaging is negative.

■ TREATMENT

Caregivers for patients with FTD carry a heavy burden, especially when

the illness disrupts core emotional and personality functions of the

loved one. Treatment is symptomatic, and there are currently no therapies known to slow progression or improve symptoms. Many of the

FIGURE 432-1 Three major frontotemporal dementia (FTD) clinical syndromes. Coronal MRI sections from

representative patients with behavioral variant FTD (left) and the semantic (center) and nonfluent/agrammatic (right)

variants of primary progressive aphasia (PPA). Areas of early and severe atrophy in each syndrome are highlighted

(white arrowheads). The behavioral variant features anterior cingulate and frontoinsular atrophy, spreading to orbital

and dorsolateral prefrontal cortex. Semantic variant PPA shows prominent temporopolar atrophy, more often on the

left. Nonfluent/agrammatic variant PPA is associated with dominant frontal opercular and dorsal insula degeneration.

■ GENETIC CONSIDERATIONS

Autosomal dominant forms of FTD can result from mutations in

C9orf72 (chromosome 9), GRN (chromosome 17), and MAPT

(chromosome 17) genes. A hexanucleotide (GGGGCC) expansion in a noncoding exon of C9ORF72 is the most common genetic

cause of familial or sporadic FTD (usually presenting as bvFTD with or

without MND) and amyotrophic lateral sclerosis (ALS). The expansion

is associated with C9orf72 haploinsufficiency, nuclear mRNA foci containing transcribed portions of the expansion and other mRNAs, neuronal cytoplasmic inclusions containing dipeptide repeat proteins

translated from the repeat mRNA, and TDP-43 neuronal cytoplasmic

and glial inclusions. The pathogenic significance of these various features is a topic of vigorous investigation. MAPT mutations lead to a

change in the alternate splicing of tau or cause loss of function in the

tau molecule, thereby altering microtubule binding. With GRN, mutations in the coding sequence of the gene encoding progranulin protein

result in mRNA degradation due to nonsense-mediated decay, leading

to a ~50% reduction in circulating progranulin protein levels. Intriguingly, homozygous GRN mutations cause neuronal ceroid lipofuscinosis, focusing investigators on the lysosome as a site of molecular

dysfunction in GRN-related FTD. Progranulin is a growth factor that

binds to tumor necrosis factor (TNF) and sortilin receptors and participates in tissue repair and tumor growth. How progranulin mutations

lead to FTD remains unknown, but the most likely mechanisms

include lysosomal dysfunction and neuroinflammation. Often, MAPT

and GRN mutations are associated with parkinsonian features, whereas

ALS is rare. Infrequently, mutations in the valosin-containing protein

(VCP, chromosome 9), TANK binding kinase 1 (TBK-1), T cell–restricted

intracellular antigen-1 (TIA1), and charged multivesicular body protein 2b (CHMP2b, chromosome 3) genes also lead to autosomal dominant familial FTD. Mutations in the TARDBP (encoding TDP-43) and

FUS (encoding fused in sarcoma [FUS]) genes (see below) cause familial ALS, sometimes in association with an FTD syndrome, although a

few patients presenting with FTD alone have been reported.

■ NEUROPATHOLOGY

The pathologic hallmark of FTLD is a focal atrophy of frontal, insular,

and/or temporal cortex, which can be visualized with neuroimaging

studies (Fig. 432-1) and is often profound at autopsy. Neuroimaging

studies suggest that atrophy often begins focally in one hemisphere

before spreading to anatomically interconnected cortical and subcortical regions. Loss of cortical serotonergic innervation is seen in many

patients. In contrast to AD, the cholinergic system is relatively spared

in FTD, which accounts for the poor efficacy of acetylcholinesterase

inhibitors in this group.

Although early studies suggested that 15–30% of patients with

FTD showed underlying AD at autopsy, progressive refinement in

clinical diagnosis has improved prediction accuracy, and most patients

diagnosed with FTD at a dementia clinic will show underlying FTLD

3380 PART 13 Neurologic Disorders

behaviors that may accompany FTD, such as depression, hyperorality,

compulsions, and irritability, can be ameliorated with antidepressants,

especially SSRIs. Because FTD is often accompanied by parkinsonism,

antipsychotics, which can exacerbate this problem, must be used with

caution. A general approach to the symptomatic management of

dementia is presented in Chap. 29.

■ PROGRESSIVE SUPRANUCLEAR PALSY

SYNDROME

PSP-RS is a degenerative disorder that involves the brainstem, basal

ganglia, diencephalon, and selected areas of cortex. Clinically, PSP-RS

begins with falls and executive or subtle personality changes (such as

mental rigidity, impulsivity, or apathy). Shortly thereafter, a progressive oculomotor syndrome ensues that begins with square wave jerks,

followed by slowed saccades (vertical worse than horizontal) before

resulting in progressive supranuclear ophthalmoparesis. Dysarthria,

dysphagia, and symmetric axial rigidity can be prominent features that

emerge at any point in the illness. A stiff, unstable posture with hyperextension of the neck and a slow, jerky, toppling gait are characteristic.

Frequent unexplained and sometimes spectacular falls are common

secondary to a combination of axial rigidity, inability to look down, and

impaired judgment. Even once patients have severely limited voluntary

eye movements, they retain oculocephalic reflexes (demonstrated

using a vertical doll’s head maneuver); thus, the oculomotor disorder

is supranuclear. The dementia overlaps with bvFTD, featuring apathy,

frontal-executive dysfunction, poor judgment, slowed thought processes, impaired verbal fluency, and difficulty with sequential actions

and with shifting from one task to another. These features are common

at presentation and often precede the motor syndrome. Some patients

with a pathologic diagnosis of PSP begin with a nonfluent aphasia or

motor speech disorder and progress to classical PSP-RS. Response to

l-dopa is limited or absent; no other treatments exist. Death occurs

within 5–10 years of onset. Like Pick’s disease, increasingly the

term PSP is used to refer to a specific histopathologic entity within

the FTLD-tau class. In PSP, accumulation of hyperphosphorylated

4-repeat tau is seen within neurons and glia. Tau neuronal inclusions

often appear tangle-like and may be large, spherical (“globose”) and

coarse in subcortical and brainstem structures. The most prominent

involvement is in the subthalamic nucleus, globus pallidus, substantia

nigra, periaqueductal gray, tectum, oculomotor nuclei, pontine nuclei,

and dentate nucleus of cerebellum. Neocortical tangle-like inclusions,

like those in AD, often take on a more flame-shaped morphology, but

on electron microscopy PSP tangles can be shown to consist of straight

tubules rather than the paired helical filaments found in AD. Furthermore, PSP is associated with prominent tau-positive glial inclusions,

such as tufted astrocytes (Fig. 432-3), coiled oligodendroglial inclusions (“coiled bodies”), or, least often, thorny astrocytes. Most patients

with PSP-RS show PSP at autopsy, although small numbers will show

another tauopathy (corticobasal degeneration [CBD] or Pick’s disease;

Fig. 432-2).

In addition to its overlap with FTD and CBS (see below), PSP is often

confused with idiopathic Parkinson’s disease (PD). Although elderly

patients with PD may have restricted upgaze, they do not develop

downgaze paresis or other abnormalities of voluntary eye movements

typical of PSP. Dementia ultimately occurs in most patients with PD,

often due to the emergence of a full-blown DLB-like syndrome or

comorbid AD-type dementia. Furthermore, the behavioral syndromes

seen with DLB differ from PSP (see below). Dementia in PD becomes

more likely with increasing age, increasing severity of extrapyramidal

signs, long disease duration, and the presence of depression. Patients

with PD who develop dementia also show cortical atrophy on brain

imaging. Neuropathologically, there may be AD-related changes in the

cortex or Lewy body disease (LBD)-related α-synuclein inclusions in

both the limbic system and cerebral cortex. DLB and PD are discussed

in Chaps. 434 and 435, respectively.

■ CORTICOBASAL SYNDROME

CBS is a slowly progressive dementia-movement disorder associated

with severe degeneration in the perirolandic cortex and basal ganglia

(substantia nigra and striatopallidum). Patients typically present with

asymmetric rigidity, dystonia, myoclonus, and apraxia that render a

progressively incapacitated limb, at times associated with alien limb

phenomena in which the limb exhibits unintended motor actions such

as grasping, groping, drifting, or undoing. Eventually CBS becomes

bilateral and leads to dysarthria, slow gait, action tremor, and a

frontal-predominant dementia. Whereas CBS refers to the clinical

Pick’s

3R tau

FTDP-17

MAPT

Other: CTE,

AGD, MST, GGT

CBD

4R tau

PSP

4R tau aFTLD-U BIBD

NIFID/

NIBD

FUS NOS

FUS

Type U

(C9ORF72)

(TARDBP)

Type D

VCP

Type A

(PGRN)

(C9ORF72)

Type B

(C9ORF72) Type C

Alzheimer’s

disease

bvFTD svPPA nfvPPA FTD-MND CBS PSP-RS

FTLD-tau FTLD-TDP* FTLD-FET FTLD-3

CHMP2B

Frontotemporal lobar degeneration (FTLD)

FIGURE 432-2 Frontotemporal dementia syndromes are united by underlying frontotemporal lobar degeneration pathology, which can be divided according to the

presence of tau, TDP-43, or FUS-containing inclusions in neurons and glia. Correlations between clinical syndromes and major molecular classes are shown with colored

shading. Despite improvements in clinical syndromic diagnosis, a small percentage of patients with some frontotemporal dementia syndromes will show Alzheimer’s

disease neuropathology at autopsy (gray shading). aFTLD-U, atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions; AGD, argyrophilic grain

disease; BIBD, basophilic inclusion body disease; bvFTD, behavioral variant frontotemporal dementia; CBD, corticobasal degeneration; CBS, corticobasal syndrome; CTE,

chronic traumatic encephalopathy; FET, FUS, Ewing sarcoma protein, TAF-15 family of proteins; FTD-MND, frontotemporal dementia with motor neuron disease; FTDP-17,

frontotemporal dementia with parkinsonism linked to chromosome 17; FUS, fused in sarcoma; GGT, globular glial tauopathy; MST, multisystem tauopathy; nfvPPA, nonfluent/

agrammatic variant primary progressive aphasia; NIBD, neurofilament inclusion body disease; NIFID, neuronal intermediate filament inclusion disease; PSP, progressive

supranuclear palsy; PSP-RS, progressive supranuclear palsy–Richardson syndrome; svPPA, semantic variant primary progressive aphasia; Type U, unclassifiable type.

3381Vascular Dementia CHAPTER 433

A B C

D E F

FIGURE 432-3 Neuropathology in frontotemporal lobar degeneration (FTLD). FTLD-tau (A–C) and FTLD-TDP (D–F) account for >90% of patients with FTLD, and

immunohistochemistry reveals characteristic lesions in each of the major histopathologic subtypes within each class: A. Pick bodies in Pick’s disease; B. a tufted astrocyte

in progressive supranuclear palsy; C. an astrocytic plaque in corticobasal degeneration; D. small compact or crescentic neuronal cytoplasmic inclusions and short, thin

neuropil threads in FTLD-TDP, type A; E. diffuse/granular neuronal cytoplasmic inclusions (with a relative paucity of neuropil threads) in FTLD-TDP, type B; and F. long,

tortuous dystrophic neurites in FTLD-TDP, type C. TDP can be seen within the nucleus in neurons lacking inclusions but mislocalizes to the cytoplasm and forms inclusions

in FTLD-TDP. Immunostains are 3-repeat tau (A), phospho-tau (B and C), and TDP-43 (D–F). Sections are counterstained with hematoxylin. Scale bar applies to all panels and

represents 50 μm in A, B, C, and E and 100 μm in D and F.

syndrome, CBD refers to a specific histopathological FTLD-tau entity

(Fig. 432-2). Although CBS was once thought to be pathognomonic for

CBD, increasingly it has been recognized that CBS can be due to CBD,

PSP, FTLD-TDP, and AD, the latter accounting for up to 30% of CBS

in some series. In CBD, the microscopic features include ballooned,

achromatic, tau-positive neurons; astrocytic plaques (Fig. 432-3); and

other dystrophic glial tau pathomorphologies that overlap with those

seen in PSP. Most specifically, CBD features a severe tauopathy burden in the subcortical white matter, consisting of axonal threads and

oligodendroglial coiled bodies. As shown in Fig. 432-2, patients with

bvFTD, nonfluent/agrammatic PPA, and PSP-RS may also show CBD

at autopsy, emphasizing the importance of distinguishing clinical and

pathologic constructs and terminology. Treatment of CBS remains

symptomatic; no disease-modifying therapies are available.

■ FURTHER READING

Irwin DJ et al: Frontotemporal lobar degeneration: Defining phenotypic diversity through personalized medicine. Acta Neuropathol

129:469, 2015.

Mackenzie I et al: Nomenclature and nosology for neuropathologic

subtypes of frontotemporal lobar degeneration: An update. Acta

Neuropathol 119:1, 2010.

Olney NT et al: Frontotemporal dementia. Neurol Clin 35:339, 2017.

Onyike CU, Diehl-Schmid J: The epidemiology of frontotemporal

dementia. Int Rev Psychiatry 25:130, 2013.

Roberson ED: Mouse models of frontotemporal dementia. Ann Neurol 72:837, 2012.

Seeley WW: Behavioral variant frontotemporal dementia. Continuum

(Minneap Minn) 25:76, 2019.

The term vascular dementia has traditionally been used to describe a

subset of dementia cases due primarily to one or more symptomatic

strokes. Considered as such, vascular dementia is usually ranked the

second most frequent cause of dementia, exceeded only by Alzheimer’s

disease (Chap. 431), and is especially common in populations with

limited access to medical care, where vascular risk factors are undertreated. More recently, this relatively narrow definition of vascular

dementia has been substantially broadened to encompass the full

impact of cerebrovascular disease on age-related cognitive decline.

The term vascular contributions to cognitive impairment and dementia

(VCID) reflects the observation that pathologic changes involving the

cerebral vasculature are highly prevalent in the elderly and contribute

to cognitive impairment, whether occurring in isolation or—more

commonly—in conjunction with other neurodegenerative processes.

The concept of VCID is one facet of the contemporary understanding

of age-related cognitive decline as due to cumulative effects of distinct

and overlapping neuropathologic changes. Multifactorial or “mixed”

dementias appear to be more prevalent than single-etiology dementias

and thus represent the rule rather than the exception.

Symptomatic stroke and asymptomatic vascular lesions, most commonly detected with brain magnetic resonance imaging (MRI) scans,

both contribute importantly to cognitive impairment. At least some

cognitive impairment is present in approximately half of stroke survivors and progressively increases with longer periods of follow-up.

433 Vascular Dementia

Steven M. Greenberg, William W. Seeley

3382 PART 13 Neurologic Disorders

Population-based studies also demonstrate substantially increased

risk of cognitive impairment among individuals without symptomatic

stroke but with MRI evidence of cerebrovascular disease. The high risk

for subsequent cognitive impairment or dementia conferred by MRI

markers of otherwise silent vascular brain injury highlights the cumulative impact of small distributed brain injuries—often associated with

small-vessel brain disease—on compromising brain function. Further

support for this framework comes from the correlation of cognitive

performance during life with postmortem neuropathology. Analysis

of large community-based samples demonstrates independent contributions to cognitive dysfunction and decline from both grossly visible

infarcts and pathologic markers of overall cerebrovascular disease

severity such as atherosclerosis, arteriolosclerosis, and cerebral amyloid

angiopathy scores. The Religious Orders Study and Memory and Aging

Project analysis of 1079 community-based participants, for example,

found each of these cerebrovascular entities to be moderate to severe

in >30% of postmortem brains and, when present, to each account for

~20% of an individual’s premortem cognitive decline.

Recent epidemiologic evidence of a decline in age-adjusted dementia

incidence hints at the potential public impact of improving vascular health.

The population-based Framingham Study reported 5-year age- and sex

-adjusted cumulative hazard rates for dementia of 3.6 per 100 persons

during the late 1970s to early 1980s, 2.8 in the late 1980s to early 1990s,

2.2 in the late 1990s to early 2000s, and 2.0 in the late 2000s to early 2010s.

These time intervals coincide with parallel trends in hypertension control

and stroke prevention, though the associations do not prove causation.

Evidence supporting a potential causative effect of blood pressure control

came from the SPRINT-MIND trial targeting systolic blood pressure

(SBP) of <120 mmHg versus 140 mmHg in hypertensive individuals aged

≥50 years. The study ended prematurely because of effective prevention

of cardiovascular outcomes in the lower SBP target group but nonetheless

demonstrated that SBP reduction reduced rates of mild cognitive impairment (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.69–0.95)

and combined mild cognitive impairment or probable dementia (HR,

0.85; 95% CI, 0.74–0.97), although not dementia alone (HR, 0.83; 95% CI,

0.67–1.04). It is notable that both these studies measured all-cause cognitive impairment rather than just a vascular dementia subset, underlining

the potential importance of VCID as a target for dementia prevention.

■ GLOBAL CONSIDERATIONS

A review of data from across the globe indicates good evidence for variability in vascular dementia. Intracranial atherosclerosis, for example,

is higher in Asians, Hispanics, and American blacks than it is in European

and American whites, while whites may have more extracranial disease. The causes of these disparities remain under investigation but

likely include access to health care, lifestyle factors such as diet, and

possible genetic influences.

■ SUBTYPES OF CEREBROVASCULAR DISEASE

ASSOCIATED WITH VCID

Large Cerebral Strokes Symptomatic strokes, whether ischemic

(Chap. 427) or hemorrhagic (Chap. 428), reflect irreversible injury

to discrete areas of cerebral cortex, subcortical white matter, or other

subcortical and infratentorial structures and produce cognitive impairment as a function of their size and location. Rare individual infarcts in

specific strategic locations such as thalamus, medial temporal cortex,

anterior corpus callosum, or dominant-side angular gyrus can sufficiently impair episodic memory and functional skills to meet memorybased criteria for dementia. More commonly, strokes occur outside

these strategic territories and affect various other aspects of cognition

such as executive function, processing speed, and visuospatial performance that fall under the broader VCID concept. Multiple strokes

and larger volumes of infarcted territory are associated with a higher

likelihood of poststroke cognitive dysfunction.

Stroke patients who make good cognitive recovery nonetheless

demonstrate accelerated poststroke cognitive decline. Community

-based individuals in the longitudinal Reasons for Geographic and

Racial Differences in Stroke study, for example, changed trajectory from

an average prestroke cognitive gain of 0.021 points/year to poststroke

cognitive loss of –0.035 points/year on the six-item screener global cognitive function scale. Mechanisms for poststroke cognitive decline likely

include ongoing effects of the cerebrovascular disease that gave rise to

the index stroke as well as loss of cognitive reserve that makes the brain

less resilient to any additional age-related disorders.

Cerebral Small-Vessel Disease Diseases of the brain’s small vessels (Chap. 427) can also cause symptomatic ischemic or hemorrhagic

stroke but are more often clinically asymptomatic and recognized only

during evaluation for cognitive decline or other symptoms. The two

common age-related cerebral small-vessel pathologies are arteriolosclerosis and cerebral amyloid angiopathy. Arteriolosclerosis represents

thickening of arterioles due to infiltration of plasma proteins into the

vessel wall. The primary risk factors for this process are age, hypertension, and diabetes mellitus. Cerebrovascular arteriolosclerosis can

present as a cause of ischemic or hemorrhagic symptomatic stroke,

both most commonly centered in territories supplied by deep penetrating vessels such as thalamus, basal ganglia, or brainstem. Cerebral amyloid angiopathy is defined by deposition of the β-amyloid peptide in the

walls of small cerebral arteries, arterioles, and capillaries, with consequent loss of normal wall structure. Its primary risk factor is advancing

age. Cerebral amyloid angiopathy is most often recognized symptomatically as a cause of intracerebral hemorrhage (Chap. 428), commonly

located in cerebral cortex, subcortical white matter (collectively

known as lobar hemorrhages), or the cerebral convexity subarachnoid

space. The distinction between the deep penetrating territories most

commonly affected by arteriolosclerosis and superficial lobar brain

regions affected by cerebral amyloid angiopathy often allows the two

small-vessel diseases to be radiographically distinguished.

Despite differences in their underlying pathogenic mechanisms, the

two cerebral small-vessel diseases produce a similar range of ischemic

and hemorrhagic brain lesions detectable by histopathology at autopsy

or MRI scan during life (Fig. 433-1). Small (lacunar) infarcts are a

common feature of arteriolosclerosis and less commonly of cerebral

amyloid angiopathy. Chronic lacunar infarcts can appear on MRI fluidattenuated inversion recovery (FLAIR) sequences as a hyperintense

rim surrounding a hypointense cavitated core with diameters typically

3–15 mm (Fig. 433-1A), but this characteristic appearance evolves in

only a subset of small infarctions, and many cannot be readily identified

in the chronic stage. Microinfarcts <3 mm are characteristic of both

small-vessel diseases. They are substantially more numerous than lacunar infarcts but less easily visualized. Acute microinfarcts may be visible

as punctate hyperintensities on diffusion-weighted MRI images (Fig.

433-1B), whereas a small subset of chronic microinfarcts is detectable on

high-resolution T2-weighted MRI sequences as hyperintense lesions in

the cerebral cortex. Cerebral microbleeds are less numerous than lacunes

or microinfarcts but readily detected in their chronic stage because of the

paramagnetic effects of iron products. These appear as round hypointense lesions on T2*

-weighted MRI, primarily in deep penetrating brain

regions if caused by arteriolosclerosis (Fig. 433-1C) or lobar regions if

caused by cerebral amyloid angiopathy (Fig. 433-1D).

Other MRI markers of small-vessel disease identify diffuse injury

of the white matter. White matter hyperintensities on T2-weighted or

FLAIR MRI sequences (Fig. 433-1E) are an almost ubiquitous feature

of aging. Although these lesions are readily visible on clinical MRI, they

represent a nonspecific marker of white matter gliosis, demyelination,

or increased water content. Extremely severe diffuse white matter vascular injury is commonly referred to as Binswanger’s disease or subcortical arteriosclerotic encephalopathy, recognized as a clinical syndrome

with gradual cognitive deterioration and notable white matter changes

of small-vessel ischemic disease. On neuroimaging, a progressive confluent subcortical and periventricular white matter disease is seen (see

Fig. 29-2), with hypoperfusion and hypometabolism. More subtle

alterations in white matter structure can be sensitively and quantitatively detected by diffusion tensor MRI (Chap. 423) as increased water

diffusivity or decreased diffusion directionality. Diffusion tensor measures of white matter structural integrity show a consistent association

with cognitive performance and gait speed, reflecting the central role

of disconnection of key brain networks in mediating the effects of

3383Vascular Dementia CHAPTER 433

A B

C D

FIGURE 433-1 Magnetic resonance imaging (MRI) markers of cerebral small vessel disease. A. Lacunar infarct: fluid-attenuated inversion recovery (FLAIR) sequence

showing hyperintense rim surrounding a hypointense cavitated core in the left thalamus (arrowhead). B. Acute microinfarct: diffusion-weighted sequence showing small

hyperintense lesion in the left centrum semiovale (arrowhead). C. Cerebral microbleeds in deep penetrating brain region: T2*-weighted sequence showing multiple small

hypointense lesions in the pons (arrowheads). D. Cerebral microbleeds in lobar brain regions: T2*-weighted sequence showing multiple small hypointense lesions lobar

brain regions (arrowheads). E. White matter hyperintensities: FLAIR sequence showing confluent diffuse hyperintensities in white matter.

cerebral small-vessel disease. These diffusion tensor–based methods

often require complex processing and are typically used in research

rather than clinical settings. A relatively simple diffusion tensor–based

metric defined by the peak width of the skeletonized mean diffusivity

(PSMD) histogram has emerged as a candidate method for quantifying

white matter disconnection.

Role of Accompanying Brain Pathologies The concept of

VCID posits that large strokes and small-vessel disease often occur in

combination with neurodegenerative brain diseases, most commonly

Alzheimer’s disease (Chap. 431). Many clinicopathologic correlation

studies have established that the co-occurrence of cerebrovascular and

neurodegenerative lesions produces more cognitive and functional

impairment than expected from the effects of each disease mechanism

considered independently. Interactions between cerebrovascular and

neurodegenerative processes may also contribute to dementia. Such

interactions might involve loss of blood-brain barrier integrity (possibly 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 pathways driven by physiologic vascular motion).

APPROACH TO THE PATIENT

Vascular Dementia

Identifying vascular contributors to a patient’s cognitive impairment

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

3384 PART 13 Neurologic Disorders

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,

diffusion-weighed, 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 angiography are not required for initial evaluation of

cognitive impairment though 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. 427) 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 cholesterol, reducing blood sugar, maintaining an active lifestyle, adhering to a heart-healthy diet, losing weight, and discontinuing

smoking (Life’s Simple 7, https://www.heart.org/en/healthy-living/

healthy-lifestyle/my-life-check--lifes-simple-7). Blood pressure targets

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

E

FIGURE 433-1 (Continued)

asymptomatic 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. Similarly, patients with infarcts in the territories of large arteries should

be considered for vascular imaging.

The few trials of symptomatic medications for cognitive impairment 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 galantamine for mild to moderate cognitive impairment and high-dose

donepezil or the N-methyl-d-aspartate receptor antagonist memantine for moderate to severe impairment (Chap. 431). A shared

decision-making approach in considering these medications is

useful, 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 cognitive 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

120:573, 2017.

Greenberg SM et al: Cerebral amyloid angiopathy and Alzheimer disease: One peptide, two pathways. Nat Rev Neurol 16:30, 2020.

Levine DA et al: Trajectory of cognitive decline after incident stroke.

JAMA 314:41, 2015.

Smith EE et al: Prevention of stroke in patients with silent cerebrovascular 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.

Wardlaw JM et al: Neuroimaging standards for research into small

vessel disease and its contribution to ageing and neurodegeneration.

Lancet Neurol 12:822, 2013.

3385 Dementia with Lewy Bodies CHAPTER 434

Lewy body disease (LBD), manifesting as Parkinson’s disease and

dementia (PDD) or dementia with Lewy bodies (DLB), is the second

most common cause of neurodegenerative dementia, after Alzheimer’s

disease (AD) (Chap. 431). Approximately 10% of patients with PD

develop PDD per year, with the majority of PD patients developing

PDD over time. The incidence of DLB is approximately 7 per 100,000

person-years. The prevalence of both PDD and DLB increases with

aging, and both affect men more often than women.

CLINICAL MANIFESTATIONS

Most researchers conceptualize PDD and DLB as points on a spectrum

of LBD pathology. Cognitively, PDD and DLB usually manifest with

severe executive, attentional, and visuospatial deficits but preserved

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 parkinsonism 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 misidentification, 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. Parkinsonism 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 differentiate 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

pathology 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.

■ PRODROMAL PHASE

Both PDD and DLB 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

deficits in executive, attention, and visuospatial disturbances, but can

also present with an amnestic or multiple-domain MCI. Prodromal

DLB is also characterized by similar cognitive disturbances but is also

434

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 vs. AD pathology

(Table 434-1).

PATHOLOGY

The key neuropathologic feature in LBD is the presence of Lewy bodies

and Lewy neurites throughout specific brainstem nuclei, substantia

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 proteins, ubiquitin, and α-synuclein. The presence of α-synuclein aggregates 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.

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

Dementia with

Lewy Bodies

Irene Litvan, William W. Seeley,

Bruce L. Miller

TABLE 434-1 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

with atonia

Normal

CSF Decreased CSF α-synuclein by

RT-QuIC

Decreased CSF

β-amyloid and increased

phospho-tau. This can be

performed in blood now.

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

parieto-temporal lobes

Amyloid PET scan Normal, unless associated

with AD

Abnormal parietotemporal areas

MIBG myocardial

scintigraphy

Post-ganglionic sympathetic

denervation

Normal

DAT scan or PET

dopamine scan

Reduced dopamine transporter

in the basal ganglia,

particularly putamen

Normal

AD, Alzheimer’s disease; CSF, cerebrospinal fluid; DAT, dopamine transporter; LB,

Lewy bodies; MIBG, meta-iodobenzylguanidine; MRI, magnetic resonance imaging;

PET, positron emission tomography; RT-QuIC, real-time quaking-induced conversion.