# 14 - 444 Vascular Dementia

### 444 Vascular Dementia

Steven M. Greenberg, William W. Seeley

Vascular Dementia
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. 442), and is especially common in populations with 
limited access to medical care, where vascular risk factors are under­
treated. 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 com­
monly 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 sur­
vivors and progressively increases with longer periods of follow-up. 
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 cumu­
lative 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 contri­
butions to cognitive dysfunction and decline from both grossly vis­
ible 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 target­
ing 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 cogni­
tive 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 nota­
ble 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.

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■GLOBAL CONSIDERATIONS
A review of data from across the globe indicates good evidence for vari­
ability 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 dis­
ease. The causes of these disparities remain under investigation but 
likely include access to health care, lifestyle factors such as diet, and 
possible genetic influences.

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■SUBTYPES OF CEREBROVASCULAR DISEASE 
ASSOCIATED WITH VCID
Large Cerebral Strokes 
Symptomatic strokes, whether ischemic 
(Chap. 438) or hemorrhagic (Chap. 439), reflect irreversible injury 
to discrete areas of cerebral cortex, subcortical white matter, or other 
subcortical and infratentorial structures and produce cognitive impair­
ment 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 suffi­
ciently 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 perfor­
mance that fall under the broader VCID concept. Multiple strokes and 
larger volumes of infarcted territory are associated with a higher likeli­
hood of poststroke cognitive dysfunction.
CHAPTER 444
Vascular Dementia
Stroke patients who make good cognitive recovery nonetheless 
demonstrate accelerated poststroke cognitive decline. Communitybased 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 post­
stroke 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 ves­
sels (Chap. 438) 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 arteriolo­
sclerosis 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, hyper­
tension, 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 penetrat­
ing vessels such as thalamus, basal ganglia, or brainstem. Cerebral amy­
loid angiopathy is defined by deposition of the β-amyloid peptide in the 
walls of small cerebral arteries, arterioles, and capillaries, with conse­
quent loss of normal wall structure. Its primary risk factor is advancing 
age. Cerebral amyloid angiopathy is most often recognized symptom­
atically as a cause of intracerebral hemorrhage (Chap. 439), commonly 
located in cerebral cortex, subcortical white matter (collectively known 
as lobar hemorrhages), or the cerebral convexity subarachnoid space. 
This small-vessel pathology also appears to confer increased risk for 
the adverse amyloid-related imaging abnormalities (ARIA) associ­
ated with recently approved immunotherapies for Alzheimer’s disease 
(Chap. 442). 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. 444-1). 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

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PART 13
Neurologic Disorders
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FIGURE 444-1  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.
3–15 mm (Fig. 444-1A), but this characteristic appearance evolves in 
only a subset of small infarctions, and many cannot be readily identi­
fied 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 hyper­
intense 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, pri­
marily in deep penetrating brain regions if caused by arteriolosclerosis 
(Fig. 444-1C) or lobar regions if caused by cerebral amyloid angiopathy 
(Fig. 444-1D).
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. 444-1E) 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 vas­
cular injury is commonly referred to as Binswanger’s disease or subcor­
tical 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 

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(see Fig. 31-2), with hypoperfusion and hypometabolism. More subtle 
alterations in white matter structure can be sensitively and quantita­
tively detected by diffusion tensor MRI (Chap. 434) as increased water 
diffusivity or decreased diffusion directionality. Diffusion tensor mea­
sures 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 cere­
bral 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. Functional MRI measurement of cerebrovascu­
lar reactivity to physiologic stimuli is generally not performed in clini­
cal practice, but it may become abnormal decades before appearance of 
structural brain injury and therefore represents a promising outcome 
marker for identifying disease-modifying interventions aimed to slow 
or prevent vascular brain injury.
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. 442). 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