Stroke remains the number one cause of disability and the third leading cause of death in the USA. Similarly, one in three Americans will have a stroke or develop dementia in their lifetime . The prevalence of dementia in developed countries is 5–10% in people older than 65 years of age, but this increases rapidly by a decade with a prevalence of as much as 50% of the population over age 85 [2▪]. Similarly, the prevalence of Alzheimer disease doubles every 4.3 years and that of vascular dementia (VaD) doubles every 5.3 years . This startling statistic, coupled with the expectation that the number of people over 65 in the US will double by the year 2030, means an increasing proportion of healthcare dollars will be spent treating people with these age-related conditions. However, the prevalence of these disorders may be even higher because original studies used definitions such as VaD or ‘multiinfarct dementia’ (MID) that reflect the extreme of the spectrum and do not include prodromal stages. More recently, the term ‘vascular cognitive impairment’ (VCI) was introduced to explain all forms of cognitive dysfunction caused by vascular disease, including forms that range from mild cognitive dysfunction to overt dementia . Though the full impact of VCI on public health is unknown, the prevalence of VCI without dementia may be as many as three million persons in the USA, a number similar to the prevalence of VCI with overt dementia . This is of great importance because the costs of VCI are high and, unlike Alzheimer disease, are not dependent on severity .
Historically, the first term used in relation to dementia following stroke was MID  and VaD took hold once other forms, such as strategic infarct dementia, were appreciated . Vascular disease may affect cognition in ways that have been systematically underestimated because of the historical evolution of diagnostic criteria for VaD from those for Alzheimer disease . Second, dementia implies a decline in function to the point of no longer being able to carry out the usual activities of a cognitively healthy person. This concept is very important, as the design of interventions to potentially prevent disability requires a definition that allows for the detection of disease prior to the development of dementia. Finally, it is important to understand that vascular and degenerative causes of dementia are often commingled because they are both prevalent in the elderly. VaD can coexist with multiple cerebral and systemic diseases that can affect brain function and cognition, especially Alzheimer disease. In certain circumstances, it may be difficult to determine whether the cognitive decline is based on vascular factors, Alzheimer disease, or both (mixed forms). Though the presence of Alzheimer disease pathology could be confirmed by biomarkers such as amyloid PET, amyloid and tau biomarkers in CSF, or, in early onset cases, genetic studies such as the PS1 mutation [10▪▪], the differentiation of VCI from pure Alzheimer disease remains challenging and has low specificity when using a purely clinical approach. On the basis of the clinical criteria, Alzheimer disease and VCI have been differentiated by the degree of memory impairment in the past, as Alzheimer disease is often characterized by deficits in recall memory (episodic memory) or factual memory (semantic memory) . On the other hand, VCI has been associated with executive dysfunction demonstrated by lack of performance in planning and execution of an activity . In reality, however, many memory tests, such as those depending on free recall, involve executive abilities. The newly appreciated relevance of executive dysfunction is based on its independent association with disability. Even so, a synergy exists between Alzheimer disease and vascular damage as suggested by the evidence that less Alzheimer disease pathology is required to bring about dementia in those with comorbid cerebrovascular lesions . To this end, the concept of VCI represents a shift in thinking about vascular effects on cognition by being inclusive of the breadth of cognitive deficits seen. Therefore, the term VCI defines a syndrome characterized by the evidence of clinical stroke or subclinical vascular brain injury with cognitive impairment affecting at least one cognitive domain, characterizing all forms of cognitive deficits from mild cognitive impairment of vascular origin (VaMCI) to the extreme of the spectrum VaD [10▪▪,14] as recently clarified by the American Heart Association and American Stroke Association in their statement [10▪▪] (Table 1). A last group of VaMCI, termed ‘unstable VaMCI’, may be applied to patients with a diagnosis of probable or possible VaMCI whose symptoms revert to normal . Such patients may have multiple underlying disease processes such as depression , chronic heart failure (CHF) , or autoimmune disorders  that have been associated with fluctuations in cognitive function and activities of daily living depending on disease activity.
The definitive diagnosis of Alzheimer disease or VCI is based on histopathology. Theories surrounding the onset of Alzheimer disease describe either a pathological deposition of amyloid protein resulting in neuronal damage and Alzheimer disease  or chronic vascular damage leading to cerebral hypoperfusion, a neuroglial energy crisis, and neuronal damage ultimately leading to Alzheimer disease . The pathological changes seen in Alzheimer disease and VCI are quite specific, however. Alzheimer disease is characterized by the deposition of extraneuronal neuritic plaques and development of intracellular neurofibrillary tangles. Neuritic plaques are structurally based on amyloid-beta (β) fibrils that are a product of amyloid precursor protein cleavage by β and gamma (γ) secretases such as the presenilins. This proteolytic action generates highly hydrophobic amyloid-β fibrils that are prone to aggregation and thus deposition in the extracellular matrix. On the other hand, neurofibrillary tangles are intraneuronal protein aggregates of tau proteins that are thought to be the toxic effects of amyloid plaques on surrounding neurons. Separately, tau protein mutations are also associated with other neurodegenerative disorders described as ‘tauopathies’ [frontotemporal dementia (FTD), corticobasal degeneration, and progressive supranuclear palsy]. The pathological characteristics of VCI are more diverse and include discrete infarction, hemorrhage, and white matter lesions. Pathological studies have demonstrated an overlap of histopathological findings between Alzheimer disease and VCI and the prevalence of both conditions in patients that undergo autopsy ranges from 25 to 50% [21,22]. Increasing evidence suggests the relationship between amyloid and ischemia is bidirectional, with amyloid deposition causing vascular damage and ischemia causing an increase in amyloid deposition .
Vascular risk factors have been associated with the onset of cognitive impairment. As with most vascular and neurocognitive disorders, VCI is more common in older patients. The presence of atheromatous formations in the extracranial and intracranial vessels predisposes the patient to ischemic events, both subclinical brain infarction (SBI) and stroke, and small vessel disease as well as amyloid angiopathy cause white matter damage and the latter causes hemorrhage as well. The presence of SBI, white matter lesions, hemorrhage, and brain atrophy seen on brain imaging in large population-based studies has been linked with the vascular risk factors in vivo and vascular pathology on autopsy [24,25]. Further, vascular damage has been linked to loss of brain microstructural integrity (as measured by diffusion tensor imaging – DTI) in normal appearing white matter, but few population-based studies exist . In turn, subclinical cerebrovascular damage increases the risk of stroke and predicts VCI [14,15,27–35]. The number and volume of lesions is also a predictor of dementia. Clinical–pathological correlations have suggested that larger volumes and greater numbers of lesions are associated with a greater risk of VaD [7,36]. Increasing evidence suggests that exposure to risk factors in midlife is associated with VCI later on, making the length of exposure a key factor.
Several studies have examined the association between hypertension and cognitive impairment. High blood pressure in midlife has been shown to be associated with cognitive impairment 14, 25, and 30 years later, and high diastolic blood pressure at age 50 has been found to predict poor cognitive outcomes at age 70 [37–39]. High blood pressure has also been associated with impairment on tests of executive function . In addition, control of blood pressure decreased the incidence of dementia in a controlled trial . High blood pressure may damage small blood vessels and affect cognition by disrupting subcortical circuits. This is supported by the finding that white matter hyperintensity (WMH) and subclinical infarcts are associated with elevated blood pressure [32,42]. But the relationship between blood pressure and VCI is likely age-dependent as low blood pressure has been associated with a greater risk of dementia in the oldest old, underscoring the importance of midlife exposure [43,44]. Longstanding hypertension impairs vasomotor reactivity and shifts the cerebral autoregulation curve such that reducing blood pressure later on may result in an increased risk of stroke because of an increase in the minimum blood pressure required for adequate cerebral perfusion . This argues in favor of hypoperfusion as a possible cause of VCI but requires further study. Conversely, VCI may lead to damage of autonomic systems that regulate blood pressure and this could cause further worsening of cognition in a feed forward manner.
There is some evidence suggesting that treating hypertension to prevent heart disease and stroke decreases the risk of cognitive impairment. In the Heart Outcomes Prevention Evaluation (HOPE) study, the effect of the angiotensin-converting enzyme inhibitor (ACE-I) ramipril was compared against placebo in 1013 high-risk patients with a history of stroke or transient ischemic attack (TIA). Beyond the 24% relative risk reduction in stroke, myocardial infarction, and vascular death among patients treated with ramipril, the study showed a 59% relative risk reduction of cognitive decline [46,47]. Similarly, in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) , 6105 patients with stroke or TIA within 5 years were randomized to the ACE-Inhibitor Perindopril versus the combination of perindopril plus the diuretic indapamide. The combination resulted in a 43% relative reduction of risk of recurrent stroke, a 40% relative reduction in vascular events, and a 23% risk reduction of VCI , without a significant difference for the ACE-I group alone. Finally, the European Systolic Hypertension (SYST-EUR) trial, which randomized patients to receive the calcium channel blocker (CCB) enalapril or placebo, showed a 42% relative reduction in the incidence of stroke in the treatment group  and a 55% relative reduction in the risk of dementia .
The ongoing Systolic Pressure Intervention Trial Memory and cognition IN Decreased hypertension (SPRINT-MIND) study is designed to determine if a systolic blood pressure goal of less than 120 mmHg compared to 140 mmHg will decrease the rate of incident dementia and MCI, global and domain-specific cognitive function, and small vessel ischemic disease .
Diabetes is an established risk factor for cardiovascular disease and stroke  but can also affect cognitive function independent of its role as a risk factor for cerebrovascular disease. The effect of both hypoglycemic and hyperglycemic events has been linked to cognitive impairment [54,55]. Histopathological studies have shown that the prevalence of neuritic plaques, neurofibrillary tangles, amyloid angiopathy, and atrophy particularly in the hippocampi, are greater in diabetics compared to nondiabetics [56,57]. Similarly, several population-based studies have shown associations between measures of diabetes mellitus and cognitive impairment, dementia with stroke, and Alzheimer disease . Cross-sectional data from Sweden showed that both insulin resistance and diabetes were related to cognitive impairment, especially in untreated men . Similarly diabetes, hyperinsulinemia, and impaired glucose tolerance were associated with poor cognitive performance, and doubling of the risk of Alzheimer disease and VCI in the Rotterdam study . However, few studies have specifically addressed the relationship between fasting glucose levels and measures of insulin resistance on patterns of cognitive dysfunction, although patients with type 2 diabetes have been shown to perform worse on executive tests in several studies [60–62]. Interestingly, the presence of Apoε4 in diabetics may be associated with a greater risk of dementia and Alzheimer disease [56,63]. There is no evidence suggesting that aggressive glycemic control prevents cognitive impairment or the onset of dementia in diabetic populations. A recent systematic review  showed that treatment strategies for diabetes were not associated with meaningful changes in the risk of dementia.
The abnormalities of serum lipids (dyslipidemia) have been found to be a risk factor for coronary artery disease (CAD) but less so for cerebrovascular disease. Dyslipidemia has been found to be an important risk factor for dementia and Alzheimer disease, especially in those who are Apoε4 negative [65▪]. However, data from long-term population-based studies suggest that elevated total cholesterol in midlife increases the risk of both Alzheimer disease and VCI later in life [66–69]. Similarly, data from the Rotterdam Study suggests that treatment with statins, but not other lipid-lowering agents, was associated with a lower risk of dementia . However, the association between statins and dementia is unclear and a recent meta-analysis showed no net effect of statins on the risk of dementia .
There is increasing evidence that those with the metabolic syndrome, a composite of several risk factors including abdominal obesity, elevated triglycerides and LDL-cholesterol, low HDL-cholesterol, raised blood pressure, insulin resistance, and prothrombotic and proinflammatory states, have a greater incidence of vascular outcomes, and this may place these people at greater risk of cognitive dysfunction through VCI. For example, in the Honolulu–Asia Aging study of Japanese–American men, the metabolic syndrome predicted VaD but not Alzheimer disease . Few studies have been done on VCI, but waist circumference has been associated with worse executive function in one study . Race–ethnic disparities in the association between the metabolic syndrome and VCI are understudied, and many of the components are highly prevalent in Hispanic and black individuals. For example, the population-based Northern Manhattan Study found the metabolic syndrome to be associated with worse cognitive performance [74▪▪].
Though cigarette smoking is an independent determinant of stroke even after adjusting for known risk factors , the association with cognitive impairment and Alzheimer disease is controversial, based on the negative association between the number of smoked pack-year and the incidence of dementia . This finding was confirmed in the Rotterdam Study in patients with the Apoε4 genotype . Whether tobacco provides a protective effect for the onset of dementia, or is an artifact of residual confounding, remains controversial and recent studies have suggested a positive association between smoking and the onset of Alzheimer disease and VCI, particularly in heavy smokers (more than two packs per day) [78,79▪▪]. Evidence is lacking that smoking cessation prevents cognitive impairment or the onset of dementia.
Consumption of alcohol is also a potential mediator of the effects of vascular disease on cognition. Moderate consumption has been associated with better cognitive function or a lower risk of dementia compared to abstainers in some studies [80–83], but other studies have shown a U-shaped relationship with heavy drinkers having decreased cognitive function or an increased risk of dementia [82–84]. The connection between alcohol and VCI is suggested by the data showing that moderate alcohol consumption is related to a lower burden of WMH and subclinical infarcts, supporting the idea that it may diminish vascular damage to the brain [82,85]. However, study results have varied in relation to the amount of alcohol associated with a positive effect on the development of VCI.
This is a risk factor for heart disease and stroke [86,87]. However, the association between elevated homocysteine and cognition and the mechanism through which it may act is less clear. Some case–control and cross-sectional studies have found associations between homocysteine and cognitive impairment and dementia [88,89]. However, prospective data from the Rotterdam study did not confirm a relationship between plasma homocysteine and cognitive impairment or decline, while data from Framingham found a robust association with incident dementia as well as Alzheimer disease . Total homocysteine levels can be lowered with B vitamin and folate supplementation and this has led to several clinical trials, none of which have shown a benefit to treatment [91,92]. A recent randomized trial of homocysteine-lowering therapy versus placebo to prevent dementia was negative . However, the only test that discriminated between the two groups was one of executive function, suggesting that further research should focus not on dementia but on VCI more broadly, taking into account the MRI measures of cerebrovascular damage that will allow clarification of the relative importance of small vessel disease and brain atrophy in the effects of homocysteine on cognition. Total homocysteine lowering may also have limited benefit in areas where folic acid is added to foods as part of federal nutrition programs.
Atrial fibrillation is present in approximately 1% of the U.S. population and the incidence increases with age, with a prevalence of 6% in individuals older than 65 and of 10% in those older than 75 years . Both persistent and paroxysmal atrial fibrillation are potent predictors of first and recurrent stroke, and the annual risk of stroke in untreated individuals with nonvalvular atrial fibrillation is about 5% per year . Atrial fibrillation-related stroke is associated with greater severity, disability, and mortality than stroke because of other causes , and the risk of stroke is even greater in patients with concomitant hypertension, diabetes, prior stroke or TIA, CAD, or CHF . Several studies show that atrial fibrillation is more common among patients with cognitive impairment, and the Rotterdam Study found atrial fibrillation was an independent predictor for the development of Alzheimer disease and VCI [96–98]. Moreover, even in the absence of manifest stroke, atrial fibrillation is a risk factor for cognitive impairment and hippocampal atrophy . The causal mechanisms by which atrial fibrillation may predispose to dementia in those without stroke need clarification, but subclinical embolic infarction is a likely cause.
These glycoproteins are responsible for lipid transport in the central nervous system and other organs. Three main isoforms (ε2, ε3, and ε4) are encoded in chromosome 19. The ε4 allele is a well-known genetic factor associated with the onset of Alzheimer disease  and cardiovascular disease . Though it is known that Apoε4 increases the risk of Alzheimer disease, the mechanisms are unclear and the presence of this genotype does not imply that the carrier will develop Alzheimer disease, and, moreover, some Alzheimer disease patients are not carriers of the Apoε4 genotype. In relation to VaD, several studies report no association with Apoε4 genotype [102,103].
Stroke or dementia will affect 30% of the aging population. About 90% of patients with dementia have either VCI or Alzheimer disease and about 50% of these patients have mixed dementia (overlap Alzheimer disease and VCI). Even though the definition of VCI requires further validation, the term represents a useful shift in thinking about the vascular effects on cognition by taking into account people with the early cognitive effects of vascular damage in whom risk factors may be treated to prevent progression of disease. The term VCI will allow researchers to better understand who is affected and find appropriate targets for intervention. The role of such risk factors in the development of VCI and Alzheimer disease is extremely important as they seem to confer a higher risk for VCI and dementia independent of their inherent risk of stroke. The role of risk factor modification for hypertension, diabetes, dyslipidemia, smoking, and atrial fibrillation, and the impact of such prevention strategies on the onset of VCI need to be demonstrated in future studies. Clinical trials of prevention strategies are also needed to show that limiting vascular brain injury prevents progression of VCI and overt dementia.
Conflicts of interest
Dr Rincon: None.
Dr Wright: royalties from UpToDate, Inc. for review articles related to vascular dementia.
Funding: Dr Rincon – American Heart Association (12CRP12050342); Dr Wright – National Institutes of Neurological Disorders and Stroke (K02 NS 059729) and National Heart Lung and Blood (R01 HL 108623).
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 104).
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