Vascular Dementia

Etiology

Vascular dementia is distinguished from other forms of MND in that it results from brain ischemia or hemorrhage and not from one or more underlying neurodegenerative proteinopathies. However, the temporal relationship between causative ischemic events and subsequent cognitive decline may be subtle or go unnoticed. The pathogenesis of vascular dementia is understood as follows: vascular risk factors lead to cerebrovascular disease that, in turn, causes brain injury; the resulting disruption of cognitive networks culminates in vascular dementia.

Recent reports in the neuropathological and neuropsychological literature posit that vascular dementia and Alzheimer disease frequently co-occur, making so-called pure cases of either condition comparatively rare. Indeed, cerebrovascular dysfunction may potentiate Alzheimer disease pathology, and pathological changes in Alzheimer disease may, likewise, induce vascular dysfunction.[1]

Epidemiology

Historically, the incidence of vascular dementia has been believed to increase, more or less linearly, with age. However, recent work is beginning to challenge this received knowledge: one report with more than 1.4 million person-years of follow-up concluded that cerebrovascular disease is no longer a risk factor for dementia among older adults.[2] Estimates vary, but consensus traditionally considers vascular dementia the second most common cause of dementia—after AD—in North America and Europe, accounting for as much as 15 to 20% of clinically diagnosed MND cases. The disease burden may be higher in Asia and some developing countries.[3] Estimates are complicated, however, by the prevalence of mixed dementias, often vascular dementia in combination with Alzheimer disease pathology, with considerably less than 15% of cases arising from “pure” vascular pathologies in neuropathological studies.[4]

Pathophysiology

Neuropathologic studies illustrate vascular dementia's high degree of heterogeneity, with multiple and overlapping types of cerebrovascular disease damaging multiple sites in the vascular tree.[5] Thus, etiologic precision in vascular dementia is complicated by the varying distributions of vascular involvement and their sequelae. Historically, multiple and overlapping descriptive terms have been applied to vascular dementia; the continuing absence of any formal consensus-based clinical diagnostic criteria for vascular dementia has underscored the resulting nosological confusion. Cardiovascular risk factors for vascular dementia include smoking, hyperlipidemia, hypertension, diabetes, atrial fibrillation, obesity, and physical inactivity, among others. Disparities in the prevalence of these risk factors may appear linked to race, but evidence is mounting that they likely arise instead from social determinants of health.[6]

A brief précis of patterns of damage in the vascular tree that can result in cognitive impairment include:

• Atherosclerosis of large feeding arteries, often associated with smoking and hyperlipidemia, can cause territorial infarcts via cerebrovascular arterial occusion or thromboembolism, resulting in the classic "step-wise" cognitive and functional decline of vascular dementia.
• Arteriolosclerosis, mainly linked to hypertension, can cause occlusive disease of small arteries that feed deep, penetrating structures, leading to lacunar infarcts, central hemorrhage, and cerebral microbleeds.
• Microvascular disease, most closely associated with diabetes, commonly disrupts metabolic function at the capillary level.  
• Finally, the APOE ε4 genotype and cerebral amyloid angiopathy (in which amyloid-β accumulates primarily in pial and cortical arteries and capillaries, causing lobar hemorrhage, cortical microinfarcts, and white matter hyperintensities) are also risk factors for vascular cognitive impairment and dementia. 
• Mixed vascular disease is more likely to cause cognitive and functional decline than pure atherosclerosis or arteriolosclerosis.[5]

History and Physical

Diagnosis of vascular dementia requires a thorough history and physical/neurologic examination, including mental status. An overview of management, with guidance for the importance of mood and function, can be found in the American Academy of Neurology's (AAN) set of clinical quality measures for managing dementia.[7] Interviewing the care partner can provide salient supplemental details about history and current functioning, as care partners often possess additional details and, as the care partner, they will become an integral part of the patient-partner dyad. However, note that it is never acceptable to rely solely on information from the care partner, assuming that the actual patient lacks all insight or concern about their clinical situation.  

 The history and physical should include: 

• A review of any vascular risk factors present—including their duration, severity, and response to current pharmacologic treatment or lifestyle changes—is an essential starting place. History should also be reviewed for previous cardiac surgeries or interventions for peripheral vascular disease.
• Details should be sought about the patterns of cognitive difficulty, especially noting dysexecutive patterns or problems with attention, as these may be salient clues about underlying vascular dementia, compared to Alzheimer disease, where memory and word-finding difficulty usually predominate. Temporal association between cognitive/functional change and any ischemic/hemorrhagic insult should be sought. Descriptions of progression patterns are also important, with slow progression suggestive of subcortical vascular disease or possible Alzheimer disease/mixed pathology and a pattern of step-wise progression suggestive of possible underlying lacunar or territorial infarction(s).
• Social history should be reviewed for past or current tobacco use, obesity, physical activity habits, and social networks.
• Family history should be sought for any form of dementia, but especially if thought to have been related to cerebrovascular disease.
• Medication review is vital to ascertain the use of medications to modify vascular risk factors and seek medications that are relatively contraindicated in older adults with cognitive concerns.[8]
• Mood should be assessed for complicating symptoms of anxiety or depression. In particular, depression at midlife can act as a risk factor for later-life dementia, and later-life depression can be seen as a dementia prodrome.[9]
• Functional ability for both instrumental (ie, cooking, driving, financial assistance, and medication management) and more basic activities of daily living (ie, dressing, bathing, and toileting) should be assessed using activity questionnaires with demonstrated reliability and validity in dementia care.[10]

The general physical examination of the older adult with possible vascular dementia should seek findings suggesting significant underlying cardiovascular disease. Pulse and blood pressure must be checked at every visit. Extremity examination should seek signs of peripheral vascular disease, eg, decreased skin temperature, brittle/shiny skin on the legs and feet, and weak pulses in the legs and feet; pitting lower extremity edema may indicate heart failure. Examination of the fundus may reveal signs of hypertensive retinopathy.

The cardiopulmonary examination is essential to assess for arrhythmia (especially the irregularly irregular rhythm that indicates atrial fibrillation), carotid bruit indicating possible atherosclerosis and evidence of fluid overload on pulmonary examination. On neurological examination, the aim is to unearth signs of focal neurological deficit: most commonly encountered are upper motor neuron patterns of facial weakness, hemiparesis, hemisensory loss, or visual field cuts. Spasticity or increased deep tendon reflexes may point to a prior neurological insult. Evidence of gait impairment, bradykinesia, and rigidity should also be sought. 

As with all MND presentations, the cognitive assessment is the most important element of the initial clinical evaluation. As noted, the underlying site of vascular injury often yields typical patterns of cognitive impairment. The Vascular Impairment of Cognition Classification Consensus Study (VICCS)[11] posited the existence of 4 phenotypic subtypes, noting that any 1 of the 4 has the potential for (or likely has) underlying mixed pathology:

• Subcortical ischemic vascular dementia: this phenotype is typically characterized by a slowly progressive decline in the speed of information processing, complex attention, and other executive abilities (eg, working memory, set-shifting, planning, organizing, and self-monitoring/awareness). Most commonly, the underlying pathophysiology is either (1) hypertension-induced arteriolosclerosis of long, penetrating vessels causing chronic ischemia of periventricular and deep white matter or (2) diabetes-induced microvascular disease.

• Poststroke dementia: VICCS criteria carry forward older definitions here, requiring as they do that there be a history of actual stroke, with cognitive deficits emerging as early as immediately after the insult but not later than six (6) months. Cortical and deep brain structures known to have significant cognitive sequelae after stroke include the angular gyrus, thalamus, basal forebrain, basal ganglia, posterior cerebral artery territory (including the hippocampus, a central structure for memory and navigation), and anterior cerebral artery territory.[12]

• Multi-infarct dementia: VICCS defines this phenotype as one of multiple large cortical infarcts, usually arising from territorial infarcts caused by cerebrovascular arterial occlusion or thromboembolism. Cognitive evaluation may reveal cortical signs such as apraxia, aphasia, visual field cuts, or sensorimotor phenomena of hemineglect. 

• Mixed dementia: Mixed dementia most commonly denotes a combination of vascular dementia and AD pathologies, although other MND combinations are possible. Such patients may even present with what appears to be a purely amnestic syndrome suggestive of AD; neuroimaging and, increasingly, biomarkers may help distinguish the two. 

The initial evaluation of a patient with possible cognitive impairment of vascular origin must include a formal cognitive assessment. In current practice, an emerging consensus supports the preferential use of the Montreal Cognitive Assessment (MoCA) over the use of the Mini-Mental State Examination (MMSE), as the former is better able to assess executive function and the latter possesses troublesome ceiling effects and cultural biases; both instruments have copyrights that are infrequently observed. However, the MoCA is insufficiently sensitive to slowed informational processing and visual memory impairments, and its sensitivity to right-hemisphere lesions is notably poor.[13] Some evidence suggests that other assessments, eg, the Memory and Executive Screening, may have superior performance.[14]

Evaluation

The standard workup for vascular dementia includes neuroimaging, laboratory assessment, and, if at all possible, neuropsychological testing. 

Laboratory Evaluation

Laboratory assessment should include basic labs, such as a complete blood count and a comprehensive metabolic panel. Unless there is suspicion after a medical history review, there is no need to obtain testing for c-reactive protein, HIV, or treponemal antibodies. In addition to basic laboratory tests, obtaining vitamin B12 and homocysteine levels is recommended. Homocysteine, in particular, has been associated with an increased risk of vascular dementia.[15]

Neuroimaging 

Neuroimaging is essential for making rigorous diagnoses of MND. MRI is the preferred imaging modality because its different sequences and orientations provide essential insights in evaluating cognitive impairment. Contrast is not necessary unless one is concerned about possible hemorrhage or infection. 

Noncontrast MRI has multiple sequences and many different orientations. The salient sequences for a dementia evaluation include:

• T1-weighted sequence: This is the preferred sequence for evaluating brain anatomy and atrophy patterns, which can be regional. Coronal sequences are best for assessing hippocampal atrophy, which can be important for determining the likelihood of mixed Alzheimer disease and vascular dementia, as hippocampal volume should be all or primarily preserved in cases of "pure" vascular dementia. Generalized cerebral atrophy can be associated with underlying cardiovascular disease; therefore, such atrophy has low specificity for vascular dementia.[16]

• FLAIR (fluid-attenuated inversion recovery sequences): White matter ischemia causes damaged areas to appear bright on FLAIR; FLAIR is also a helpful sequence for identifying lacunar infarcts. The severity of white matter ischemia can be graded using the Fazekas scale;[17] using this scale, severe white matter disease has been reported to predict rapid global functional decline.[18] 

• Gradient echo (GRE) or susceptibility-weighted imaging (SWI): Either of these sequences can aid in identifying cerebral microbleeds. Such bleeds in deep subcortical structures usually arise from underlying hypertension; when microbleeds occur at the gray-white junction, in the subarachnoid space, or along the surface of the cortex (superficial siderosis), underlying CAA is usually the culprit. 

• Diffusion-weighted imaging (DWI): This sequence brightly and whitely highlights acute stroke and should always be reviewed. 

Neuropsychological Testing 

Neuropsychological testing is invaluable for fleshing out the full scope of cognitive and behavioral changes in all cases of MND, including vascular dementia.[13] Domain-specific cognitive assessment can aid in distinguishing vascular dementia from Alzheimer disease based on neuropsychological profile; mixed dementia is more challenging to assess, making longitudinal assessment necessary in some cases.

Neuropsychologists are also adept at sussing out the presence and burden of the so-called behavioral and psychiatric adverse effects of dementia (BPSD) in vascular dementia. The evidence base for BPSD in vascular dementia lags well behind that for Alzheimer disease, meaning that the need for prospective, cross-sectional, and longitudinal studies of BPSD in vascular dementia is great. A recent expert panel strongly recommended using standardized protocols to address BPSD and care partner burden; the Neuropsychiatric Inventory (NPI) was recommended for the former[19] and the Zarit Burden Index for the latter.[13] 

Current Trends in Evaluation

Currently, imaging modalities beyond MRI, such as FDG-, amyloid-, or tau-PET, have little utility in the clinical evaluation of MND and thus are best reserved for the research setting. This may change, however, as the emergence of new drugs for the treatment of Alzheimer disease may lead to some relaxation in the restrictions on the clinical availability of such tests.

Similarly, the utility of biomarkers—whether in CSF or blood—in vascular dementia lags behind that of Alzheimer disease at this time. For example, interleukin 6 is a biomarker with the potential for discriminating between Alzheimer disease and vascular dementia, but minimal evidence and high inconsistency across studies limit its utility at this time.[20]

Treatment / Management

Prevention and control of vascular risk factors constitute the central approaches to managing vascular dementia, for which there is currently no curative pharmacologic treatment. Once vascular dementia is present, treatment requires both pharmacologic and nonpharmacologic approaches. 

Prevention includes control of modifiable vascular risk factors. Notably, aspirin is no longer recommended for primary prevention, although it may still be used for secondary prevention.[21] A 2019 meta-analysis revealed nonsuperiority among antihypertensives for dementia prevention among older adults; diuretic use suggested benefit in some studies, but results were inconsistent, and data in individuals younger than 65 were too limited to produce meaningful analyses.[22] A recent data analysis from the Health and Retirement Study (HRS) revealed that low LDL-C levels (<70 mg/dL, and especially <55 mg/dL) were associated with significantly slower cognitive decline.[23] Despite concerns about cognitive impairment associated with statin use exemplified by the  FDA's changes to the safety label for statins, no evidence base has emerged to support this concern. Current guidance favors using statins because of their known cardiovascular benefit and LDL reduction for secondary prevention.[12](A1)

Lifestyle modification is under intense study for its preventive promise in MND. In a recent retrospective analysis of long-term Korean data, exercise was significantly associated with a lower risk of incident dementia and, more specifically, a lower risk of post-stroke dementia development.[24] As important lifestyle modifications, a healthy diet, regular exercise, and active social engagement should all be emphasized.[25][26] Potential geriatric syndromes such as falls, failure to thrive, malnutrition or undernutrition, elder abuse, and urinary incontinence should be evaluated and managed appropriately. Safety concerns should be addressed, which minimally should include assessing potential risks if the patient is living alone, still driving, or has routine access to firearms.

No pharmacologic approaches are FDA-approved explicitly for vascular dementia. Cholinesterase inhibitors, which increase the availability of acetylcholine in the synaptic cleft and may have a salubrious effect on cerebral blood flow, are often used in an off-label fashion in vascular dementia. In contrast, they form the backbone of pharmacotherapy in Alzheimer disease. These agents have a mild-to-moderate benefit of slowing the progression of cognitive decline in some patients, but they also have a significant adverse effect profile, including gastrointestinal distress, symptomatic bradycardia, sleep disturbances, and weight loss. Cholinesterase inhibitors are not specific to treating vascular dementia but are reasonable to consider as there is considerable overlap of mixed Alzheimer dementia with vascular dementia. 

Memantine, an NMDA receptor antagonist, is also used off-label for treating vascular dementia; its most common adverse effects include dizziness and headache. Newer monoclonal antibody agents (eg, aducanumab, lecanemab, and likely soon, donanemab) are approved for the treatment of mild Alzheimer dementia and remain controversial with significant adverse effects and unclear degree of benefit. They are not recommended for the treatment of vascular dementia.[27][28] 

Nonpharmacologic approaches have been markedly less studied than pharmacologic, but this does not diminish their potential to help the vascular dementia dyad in some cases and to some extent. Such approaches include the collaboration of nutritionists, clinical social workers, cognitive rehabilitation, therapists (physical, occupational, and speech/language), audiologists, companion care services, and geriatric case managers to improve patient care. Ensuring that resources are in place for capacity for both financial and healthcare decisions is crucially important. Advance care planning is prudent. When vascular dementia has progressed to its later or end stages, referral for palliative care or hospice. 

Differential Diagnosis

The main differential diagnosis for vascular dementia is Alzheimer Disease and mixed dementia presentations are quite common. In addition, the differential diagnosis process should review the patient's presentation for signs and symptoms of normal pressure hydrocephalus, excess alcohol consumption, emergence or exacerbation of bipolar and other mood disorders, and metabolic derangement (especially B12 and homocysteine). 

Prognosis

Like all MND, vascular dementia is ultimately a terminal diagnosis.[29] Vascular dementia appears to have a poorer prognosis than Alzheimer disease.[30] 

In one study of MND patients, those who experienced rapid mortality were slightly older at diagnosis, with lower MMSE scores and more depressive symptoms, plus a higher prevalence of cardiovascular risk factors, all of which had P values less than 0.05. Alzheimer disease was most common among individuals with rapid mortality, but it was relatively less common in the group without rapid mortality. Among those with rapid mortality, vascular dementia, frontotemporal dementia, and Creutzfeldt-Jakob disease occurred more frequently than Alzheimer disease.[31] For vascular dementia, published papers note a life expectancy range of 3 to 5 years. 

Complications

As vascular dementia progresses from mild to moderate, challenging behaviors often become more common, and the care partner burden often increases. Challenging behaviors can include the emergence of delusions, visual hallucinations, and paranoia, among others. Care partner counseling is essential here, and care partners can benefit greatly from instruction about redirection and other soothing approaches; it is crucial to underscore that there is simply no such thing as one pill or any medication combination that can alleviate all challenging behaviors. As vascular dementia enters its end stages, functional concerns often predominate, as patients may develop problems with gait, aspiration, falls, pressure sores or ulcers, and burdensome hospitalizations.