Advances in Vascular Cognitive Impairment

Abstract

HomeStrokeVol. 41, No. 2Advances in Vascular Cognitive Impairment Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBAdvances in Vascular Cognitive Impairment Philip B. Gorelick, MD, MPH, FACP and John V. Bowler, MD, FRCP Philip B. GorelickPhilip B. Gorelick From the Center for Stroke Research (J.B.G.), Department of Neurology and Rehabilitation, University of Illinois College of Medicine at Chicago, Chicago, Ill, and the Department of Neurology (J.V.B.), Royal Free Hospital, London, England. Search for more papers by this author and John V. BowlerJohn V. Bowler From the Center for Stroke Research (J.B.G.), Department of Neurology and Rehabilitation, University of Illinois College of Medicine at Chicago, Chicago, Ill, and the Department of Neurology (J.V.B.), Royal Free Hospital, London, England. Search for more papers by this author Originally published14 Jan 2010https://doi.org/10.1161/STROKEAHA.109.569921Stroke. 2010;41:e93–e98Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 14, 2010: Previous Version 1 Advances in our understanding of vascular cognitive impairment (VCI) have springboarded from further elucidation of the role of vascular risk factors, surgical procedures, medications, and neuroimaging studies that are related to this condition. The main focus of this VCI review will highlight the relation of diabetes mellitus and hippocampal dysfunction in VCI; coronary artery bypass surgery and cognitive decline; the role of cerebral amyloid angiopathy (CAA) in vascular dysfunction; and a discussion of other cardiovascular risk factors, treatment, and neuroimaging findings related to disease progression; and histopathologic and genetic correlates.Diabetes Mellitus, Hippocampal Function, Cerebral Blood Volume, Glucose, and InfarctsDiabetes increases the risk of both VCI and Alzheimer disease and may do so by the effects of insulin resistance, hyperglycemia-related increases in advanced glycation end products, and via oxidative stress, inflammation, and macrovascular or microvascular injury.1 Insulin is transported into the central nervous system through the blood-brain barrier by a saturable receptor-mediated process, and insulin receptors are located in astrocytes and neuronal synapses and are highly concentrated in the olfactory bulb, cerebral cortex, hippocampus, hypothalamus, amygdala, and septum.1 Of these structures, the hippocampus has been a focus of interest in relation to metabolic dysfunction and cognitive impairment in persons with diabetes.Wu et al2 have shown that in community-based, nondemented elderly who underwent magnetic resonance imaging (MRI) and high-resolution functional mapping of the hippocampus, both diabetes and brain infarcts were associated with hippocampal dysfunction but with separate hippocampal subregions suggestive of distinct underlying mechanisms. Specifically, blood glucose levels were inversely and selectively correlated with dentate gyrus cerebral blood volume, and blood glucose levels were selectively and inversely correlated with total recall on the Selective Reminding Test, whereas CA1 dysfunction was linked to the occurrence of cerebral infarcts, an area known to be differentially vulnerable to transient hypoperfusion. Therefore, these findings clarify how blood glucose levels and brain infarcts in later life may differentially target hippocampal formation and suggest possible mechanisms for prevention of late-life memory decline.Diabetes is nonetheless associated with a variety of types of cerebral damage. In the SMART study of MRI segmentation data in 1043 individuals, of whom 151 had type 2 diabetes, diabetes mellitus was associated with global atrophy, subcortical atrophy, leukoaraiosis, and lacunar infarcts (but not large infarcts) after correction for other common vascular risk factors.3In the Adult Changes in Thought Study, a longitudinal, population-based study of aging and cognitive decline, 2 different patterns of cerebral injury at brain necropsy were noted in patients with dementia: Individuals without diabetes had a greater amyloid-B peptide load and increased levels of F2-isoprostanes in the cerebral cortex, whereas those with diabetes had more microvascular infarcts and increased cortical interleukin-6.4 These patterns of injury in persons with dementia who do or do not have diabetes suggest possible distinct mechanisms and therapeutic implications.In addition, in a detailed MRI diffusion-weighted imaging study of hippocampal patterns in acute posterior cerebral artery territory stroke, Szabo et al5 identified 4 different patterns of acute ischemic lesions and mnestic neuropsychologic deficits with respect to the side of hippocampal infarction. Finally, among older adults with type 2 diabetes in the Kaiser Permanente Northern California Diabetes Registry, Whitmer et al6 showed a graded risk with single and multiple episodes of hypoglycemia severe enough to require hospitalization or an Emergency Department visit and risk of dementia. Specifically, there was a 2.39% increase in the absolute risk of dementia per year of follow-up.Coronary Artery Bypass Graft Surgery and Cognitive DeclineThere has been longstanding concern that patients undergoing coronary artery bypass grafting (CABG) may be at risk for both early (eg, 1 month) and late (eg, 5 or more years) cognitive decline.7 A recently published observational study suggests that late cognitive decline after CABG is not specific to the use of cardiopulmonary bypass, because nonsurgical cardiac comparison patients also showed mild late cognitive decline.7 Whereas early cognitive decline is common (estimates of 30% to 65%) but appears to improve in the months after surgery, ≈42% have been reported to have worse cognitive function at 5 years after CABG. A number of hypothetical mechanisms have been suggested to explain the cognitive decline associated with CABG, and these include but are not limited to the occurrence of stroke associated with surgery, influence of existent cardiovascular risk factors, effect of pump impurities or surgical anesthetics, and unmasking of Alzheimer disease.A recently published controlled study supports the contention that avoiding cardiopulmonary bypass may not materially affect cognitive outcomes.8 In a nonrandomized observational study among patients who underwent standard on-pump CABG, those who underwent off-pump procedures, and medically managed patients with coronary disease but no history of CABG (coronary controls) versus community controls without cardiovascular disease (healthy controls), Selnes et al9 reported that all 3 coronary disease groups showed similar declines in cognitive function over 6 years. Furthermore, they concluded that advanced age and atherosclerosis may be the key determinants of long-term cognitive decline rather than cardiac operations. A well-designed, randomized, large-scale clinical trial could provide more definitive data to answer important questions about long-term cognitive outcomes after CABG and other cardiac procedures.Risk Indices: Predictors of Maintenance of Cognitive Function or Occurrence of Dementia in the ElderlyThe absence of cardiovascular risk factors is proving to be an important component in the prediction of maintenance of cognitive function in the elderly.10 The Health, Aging and Body Composition (Health ABC) study is a prospective cohort of >3000 community-dwelling black and white women and men age 70 to 79 years at recruitment. In the Health ABC study, the following factors were identified as baseline variables significantly associated with maintenance of cognition during an 8-year period when compared with minor cognitive decline (cardiovascular factors underlined): age, white race, education, weekly moderate/vigorous exercise, and not smoking. The cardiovascular risk factors identified in this risk index could impact cognition prevention and treatment strategies.The Cardiovascular Health Cognition Study has published a late-life dementia risk index that elucidates factors most predictive of developing incident dementia within 6 years’ time in the elderly.11 Key summary predictor factors and point scores assigned to each of the factors are listed in Table 1. (Reference 11 includes a complete definition of predictor factors.) Several of the factors are cardiovascular disease lifestyle or associated factors that are potentially preventable or modifiable. Dementia was associated with low-risk index scores in 4%, moderate scores in 23%, and high scores in 56%.11Table 1. Summary Late-Life Dementia Risk Index Factors and Point Scores11**Cardiovascular or cardiovascular-related risk factors are underlined.Older age (1–2 points)Poor cognitive test performance (2–4 points)Body mass index <18.5 kg/m2 (2 points)≥1 Apolipoprotein E e4 allele (1 point)Cerebral MRI findings of white-matter disease (1 point) or ventricular enlargement (1 point)Internal carotid artery thickening on ultrasound (1 point)History of bypass surgery (1 point)Slow physical performance (1 point)Lack of alcohol consumption (1 point)CAA, Vascular Dysfunction, and Cognitive ConsequencesCerebral amyloid may have several deleterious effects on the brain vasculature. The AB-related form may lead to vascular dysfunction that manifests as impaired vascular responses to stimuli such as systemic blood pressure (ie, impaired autoregulation), arterial partial pressure of carbon dioxide, and neuronal activity.12 Vascular dysfunction mediated by endothelial dysfunction could result in cerebral microinfarction and small cortical infarcts. Furthermore, vascular B-amyloid deposition is toxic to smooth muscle cells, and such damage may result in vascular rupture and brain hemorrhage.12Cerebral microbleeds may be a consequence of CAA and may be associated with cognitive impairment13 independent of coexistent leukoaraiosis,14 although this point is disputed.15 Recently, concern has been raised that cerebral microbleeds may be associated with aspirin use in the elderly and also may be harbingers of brain macrohemorrhages.16 These findings could have important ramifications for cardiovascular disease prevention and cognitive maintenance in the elderly. Additional well-designed study is needed to clarify the role of antithrombotic use in the elderly and other persons at risk of CAA.16Other Cardiovascular Risk Factors and Cognition: Additional EvidenceIn 2009, several key articles were published in relation to other cardiovascular risk factors and cognition that are not addressed in the preceding text but that provide additional evidence for the importance of these factors. This additional information is reviewed in Table 2.17–34Table 2. Key Results About Other Cardiovascular Risk Factors in 2009AD indicates Alzheimer disease.Factor: Comment1. Diet: Higher Mediterranean-type diet adherence and higher physical activity were independently associated with a reduced risk of AD,17 and higher adherence to a Mediterranean-type diet was associated with a trend for a reduced risk of developing mild cognitive impairment and a reduced risk of mild cognitive impairment conversion to AD.18 In another study, higher adherence to a Mediterranean diet was associated with slower MMSE cognitive decline but was not consistently associated with other neuropsychometric tests or with the risk for incident dementia.192. Nonsteroidal Anti-Inflammatory Drugs: Heavy nonsteroidal anti-inflammatory drug users showed an increased incidence of dementia and AD, suggesting that a delay earlier in life could result in increased AD incidence in old age.203. Statin Therapy and Cholesterol: Pravastatin treatment in old age did not affect cognitive decline during a 3-year follow-up period in the randomized, placebo-controlled PROSPER study.21. Midlife serum total cholesterol was associated with an increased risk of AD and VCI.22 Furthermore, higher prediagnosis total cholesterol and LDL cholesterol concentrations and a history of diabetes were associated with faster cognitive decline in patients with incident AD.234. Social Isolation: Those widowed or divorced in midlife and still so at follow-up were at higher risk of showing cognitive impairment compared with persons married or cohabiting.245. Metabolic Syndrome and Adiposity: Metabolic syndrome prospectively predicted risk of developing cognitive impairment in older women25; higher levels of all adiposity measures were prospectively associated with worsening cognitive function in men26; and in midlife, there was an increased risk of dementia for obese persons, but the risk estimates were reversed in assessments of late-life body mass index.276. Diabetes Control: Higher glycosylated hemoglobin levels were associated with lower cognitive function in persons with diabetes.287. Hypertension and Treatment: From midlife to late life, Japanese-American men who went on to develop dementia had an increase in systolic blood pressure of 0.26 mm Hg/y, and over late-life examinations, they had an additional decline of systolic blood pressure of 1.36 mm Hg/y.29 Centrally acting angiotensin-converting enzyme inhibitors may be associated with a reduction in cognitive decline and may merit a randomized, clinical trial to study prevention of cognitive decline and dementia.308. Homocysteine, Folate, and Vitamin B12: In 124 patients with lacunar stroke, almost one third had B12 levels below the reference range, more than 15 times the proportion expected, and B12 was correlated with periventricular leukoaraiosis but not with deep white-matter lesions.31 However, additional data from the Rotterdam Scan Study that included measures of B12 biologic activity and homocysteine found the same association, with only a limited contribution from homocysteine.32 The Three-City study failed to identify any correlation between B12 and cognition but did find a correlation with low folate and with high homocysteine, although only when folate levels were low.33 The Framingham Offspring Study found that homocysteine was correlated with atrophy and silent infarcts, even after correction for folate, cyanocobalamin, and pyridoxine levels, which were all lower in those with higher homocysteine levels. There was no correlation between homocysteine and leukoaraiosis; although continuous data were available for leukoaraiosis, the analysis was limited to a dichotomized method based on “extensive” leukoaraiosis.34 Taken together, these studies indicate a role for B12, folate, and homocysteine, although the disparity among the results makes further interpretation difficult.Treatment and PreventionNew data on treatment and prevention have become available. In an observational study based on 1789 Mexican Americans followed up for 5 years, the Sacramento Area Latino Study on Aging found that the development of dementia (all types) or cerebral infarction, no dementia, was almost halved in those who had taken statins15. Although the authors reported that 13% had vascular dementia and 13% had mixed dementia, they did not provide results subdivided by dementia etiology. Conversely, in a small study of 94 subjects with recent lacunar stroke, 3 months of high-dose atorvastatin did not improve cerebral vasoreactivity.35In the Cardiovascular Health Study of 2313 individuals with MRI scans repeated after 5 years, the consumption of fish (especially tuna, but not fried fish) 3 or more times per week as opposed to once or less per month reduced the absolute risk of silent infarcts from 26.5% to 19.6% (relative risk=0.74). White-matter grade was also improved, but fish consumption had no effect on atrophy.36The Aspirin for Asymptomatic Atherosclerosis Trial studied the effect of 100 mg aspirin daily for 5 years in 3350 individuals from central Scotland with a mean age of 62 years at entry.37 These individuals were screened to be at higher risk for cardiovascular disease by use of the ankle-brachial index. No difference on a range of cognitive measures was found between those given aspirin and those taking placebo. The cognitive assessment included measures appropriate for VCI, and the trial cannot be faulted for duration or size. There was some tendency for those at higher risk of vascular events and with lower cognition at baseline to be lost to cognitive follow-up, but these differences were slight. The findings either indicate a true lack of benefit for aspirin at this dose or may reflect the slow progression of early VCI.38 PRoFESS studied cognition according to the Mini Mental State examination (MMSE) with 2.4 years of follow-up in 20 332 individuals with a mean age of 66 years receiving aspirin with dipyridamole, clopidogrel and telmisartan, or placebo in a factorial design and found no differences.39 Although this was a large trial, doubts remain about these findings because of the use of the MMSE, the short follow-up, and the relative youth of the subjects.Previous studies have shown surprisingly little benefit on cognition as a result of treatment of hypertension, and the HYVET-COG study of those age ≥80 years treated with indapamide with the option of perindopril, or placebo, found no effect on dementia.40 However, the progression of VCI in its early stages is slow, and this trial had been stopped early (at 2.2 years of follow-up) because of a clear benefit of treatment on stroke. Furthermore, cognition was assessed with the MMSE, which is insensitive to the domains commonly affected in VCI. A meta-analysis of antihypertensive treatment trials by the same authors favored treatment.40Imaging, Histopathology, and Genetics: Focus on LeukoaraiosisA longstanding problem in VCI has been that varying degrees of tissue damage short of infarction appear the same on standard MRI. In a study not restricted to those with any particular clinical diagnosis and with the advantage of antemortem MRI, a comparison with postmortem histopathology confirmed a vascular etiology for leukoaraiosis in this general population, because reduced vascular integrity was the best predictor of leukoaraiosis, with blood-brain barrier integrity also associated.41 A variety of structural elements, including myelin damage, microglial density, and vascular density, were not correlated with leukoaraiosis.The MRC CFAS study reported on changes in gene expression in areas of MRI-identified leukoaraiosis, in adjacent normal-appearing white matter, and in control subjects with no leukoaraiosis. They reported 502 genes that were differentially expressed between areas of leukoaraiosis and normal white matter from leukoaraiosis-free controls and that 409 genes related to the same pathways differed between areas of leukoaraiosis and normal-appearing white matter in those with leukoaraiosis. These genes were thought to reflect 8 main pathways (immune regulation, cell cycle, apoptosis, proteolysis, ion transport, cell structure, electron transport, and metabolism). The authors interpreted the pathways as favoring an ischemic etiology with additional factors like blood-brain barrier dysfunction,42 much in accordance with Young et al.41 Changes in normal-appearing white matter in those with leukoaraiosis have been reported previously from diffusion tensor MRI studies43 and given the high heritability of leukoaraiosis, suggest a field effect. Vascular risk factors also contribute, however, as diffuse changes in fractional anisotropy, most prominent frontally, have been demonstrated in otherwise-intact individuals with the metabolic syndrome.44 Nor are functional MRI changes limited to degenerative small-vessel disease, because similar findings have been reported in CAA.45 Factors driving leukoaraiosis do seem to be specific to cerebral vessels: whereas leukoaraiosis predicts stroke, it does not predict other vascular events.46 Another histopathologic study, the Baltimore Longitudinal Study of Aging, has emphasized the importance of microscopic infarcts, equating them in cognitive importance to hemispheric infarcts.47Although leukoaraiosis is highly heritable, the genetic basis of this condition is largely unknown except for some single-gene conditions, such as CADASIL. Paternoster et al48 reported a meta-analysis of studies of polymorphisms and leukoaraiosis and despite assembling 46 studies concerning 19 genes in 19 000 subjects, they found no persuasive associations. Some evidence of potential locations has been provided by the GENOA study investigating linkage with MRI parameters in white and black sibships. Total atrophy was closely linked to chromosomes 1 and 17 in whites, but in blacks evidence for chromosome 1 was weaker. Central atrophy (ventricular volume) was closely linked to chromosome 12, less strongly to chromosome 2, and only weakly to chromosomes 4, 13, and 20 in blacks. In whites, there was evidence for chromosomes 2, 3, and 10. Leukoaraiosis was linked to chromosomes 11 and 21 (weakly) in whites and 22 and 21 (weakly) in blacks (not at the same locus as in whites).49Imaging and ProgressionFurther data on progression have become available. In the Rotterdam Scan Study of 668 people with a mean age of 71 years at their first scan, 39% showed visible progression of leukoaraiosis at 3 years (32% subcortical, 27% periventricular) along with a 14% incidence of silent infarcts and a 2% incidence of symptomatic infarcts. As has previously been observed, baseline severity of leukoaraiosis strongly predicts progression, as do age, blood pressure, current smoking, and the presence of lacunar infarcts. Atrial fibrillation, carotid atherosclerosis, and homocysteine were not related to the progression of leukoaraiosis, although atherosclerosis was associated with lacunar infarcts. Periventricular leukoaraiosis and lacunar infarcts were correlated with declines in information processing speed and general cognition, and a marked progression of periventricular lesions was sufficient to produce a decline in MMSE, whereas subcortical leukoaraiosis had no cognitive correlates.50That severe leukoaraiosis predicts more rapid progression has been further confirmed by data from the PROGRESS trial, in which no leukoaraiosis at study entry was associated with a 4% risk of dementia or severe cognitive decline (as measured by the MMSE) after 4 years of follow-up, whereas 30% of those with severe leukoaraiosis at entry declined to this level.51 The LADIS study has also now reported 2.4-year follow-up data for its observational cohort of 633 74-year-olds and found a very similar transition rate of 29.5% to death or disability in activities of daily living for those with severe leukoaraiosis at entry, compared with 10% in those with only mild changes.52 It is the progression of leukoaraiosis rather than the baseline level that is correlated best with cognitive decline.53Lesion LocationThere has been a continuing debate on whether periventricular or deep leukoaraiosis is more damaging to cognition. Data published during the past year have favored periventricular lesions, because these best predicted the evolution of normal elderly individuals, or those with mild cognitive impairment, to dementia.53 In the Rotterdam Study, periventricular leukoaraiosis (and infarcts) but not subcortical white-matter lesions were correlated with a decline in speed.50 Periventricular lesions affect cholinergic projections, as assessed by positron emission tomography.54The LADIS study found that lacunar infarcts in the thalamus are especially likely to damage cognition in several domains, whereas those in the putamen and pallidum may have an effect on memory. Lacunes in the internal capsule, lobar white matter, and caudate had no detectable cognitive consequences.55 The same study also found that periventricular leukoaraiosis was most closely associated with falls, with some contribution from deep frontal lesions.56DisclosuresNone.FootnotesCorrespondence to Philip B. Gorelick, MD, MPH, FACP, Center for Stroke Research, Department of Neurology and Rehabilitation, University of Illinois College of Medicine at Chicago, 912 S Wood St, Room 855N, Chicago, IL 60612. E-mail [email protected] References 1 Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia. Arch Neurol. 2009; 66: 300–305.CrossrefMedlineGoogle Scholar2 Wu W, Brickman AM, Luchsinger J, Ferrazzano P, Pichiule P, Yoshita M, Brown T, DeCarli C, Barnes CA, Mayeux R, Vannucci SJ, Small SA. The brain in the age of old: the hippocampal formation is targeted differentially by diseases of late life. Ann Neurol. 2008; 64: 698–706.CrossrefMedlineGoogle Scholar3 Tiehuis AM, van der Graaf Y, Visseren FL, Vincken KL, Biessels GJ, Appelman APA, Kappelle LJ, Mali WPTM, for the Smart Study Group. Diabetes increases atrophy and vascular lesions on brain MRI in patients with symptomatic arterial disease. 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