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ISSN: 1524-4628 Copyright © 2006 American Heart Association. All rights reserved. Print ISSN: 0039-2499. Online Stroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514 DOI: 10.1161/01.STR.0000195177.61184.49 2006;37;248-255; originally published online Dec 8, 2005; Stroke Gabrielle G. Leblanc, James F. Meschia, Donald T. Stuss and Vladimir Hachinski Challenges Genetics of Vascular Cognitive Impairment: The Opportunity and the http://stroke.ahajournals.org/cgi/content/full/37/1/248 located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/reprints Reprints: Information about reprints can be found online at journalpermissions@lww.com 410-528-8550. E-mail: Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters http://stroke.ahajournals.org/subscriptions/ Subscriptions: Information about subscribing to Stroke is online at by on November 3, 2010 stroke.ahajournals.orgDownloaded from Genetics of Vascular Cognitive Impairment The Opportunity and the Challenges Gabrielle G. Leblanc, PhD; James F. Meschia, MD; Donald T. Stuss, PhD; Vladimir Hachinski, MD Background and Purpose—This review considers the current state of knowledge of genetic factors underlying vascular cognitive impairment (VCI). Summary of Review—We argue here that genes conferring susceptibility to VCI must be of 2 nonmutually exclusive classes: (1) genes that confer susceptibility to cerebrovascular disease, and (2) genes that determine brain tissue responses to cerebrovascular disease (ie, render parenchymal tissue more or less susceptible to injury or able to repair itself after injury). Although some progress has been made in identifying genes of the first class, little has been done to explore genes of the second class. Evidence for the existence of such genes is presented. We discuss the advantages and disadvantages of different forms of cerebrovascular disease for studying these genes, and different study designs that might be used. Conclusion—The most critical challenge for genetic studies of VCI is to identify quantifiable phenotypes that can be reliably and effectively determined in large samples of subjects. (Stroke. 2006;37:248-255.) Key Words: cerebrovascular disorders � cognition � dementia � ischemia Cognitive impairment attributable to cerebrovascular dis-ease is a rapidly escalating public health problem. For example, up to one third of all stroke survivors exhibit dementia within 3 months after their stroke.1–3 In addition, postmortem pathological studies4–9 indicate that 15% to 34% of dementia cases (of which there are currently �4 million in the United States) show significant vascular pathology, either alone or in combination with Alzheimer disease (AD) pathol- ogy. However, dementia represents only a portion of the burden of cognitive dysfunction associated with cerebrovas- cular disease. In addition to patients who develop dementia, there are those who develop cognitive impairment that does not fulfill traditional criteria for dementia but that nonetheless has a significant impact on quality of life and ability to carry out activities of daily living. As a result, the older term “vascular dementia” is being replaced with a new one: “vascular cognitive impairment” (VCI), in which frank de- mentia may or may not be a feature.4–6 Recent studies indicate that the prevalence of VCI without dementia is equal to that of VCI with dementia,7,8 suggesting that the total prevalence of VCI (with or without dementia) could be as high as 3 million cases in the United States. The Opportunity: Genetics of VCI So Far Unexplored Although the prevalence of VCI approaches that of AD, research on VCI has lagged considerably behind that on AD, particularly with regard to pathogenic mechanisms. Our un- derstanding of the pathobiology of AD vaulted forward with the discovery of genes that produce monogenic forms of the illness or contribute to polygenic forms. Similarly, the iden- tification of genes contributing to VCI would no doubt provide insight into the cellular and molecular basis of VCI. The genes underlying VCI must be of 2 nonmutually exclusive classes: (1) genes that predispose individuals to cerebrovascular disease, and (2) genes that determine tissue responses to cerebrovascular disease (eg, genes conveying ischemic tolerance or susceptibility, or the ability to recover from ischemic insult). With regard to the first class of genes, some progress has been made in the past few years in identifying genes that confer suscep- tibility to hypertension and stroke.9 –14 In addition, several monogenic forms of cerebrovascular disease have been identified. The 2 best studied of these are cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoen- cephalopathy (CADASIL) and hereditary cerebral hemor- rhage with amyloidosis-Dutch type (HCHWA-D). CADASIL is a syndrome of subcortical small vessel disease accompa- nied by lacunar strokes, migraine, and dementia.15 The disease results from mutations in the Notch 3 gene,16,17 which is normally expressed in vascular smooth muscle cells and pericytes (including those of the cerebral vasculature).18,19 The gene appears to be involved in directing smooth muscle Received May 11, 2005; final revision received September 2, 2005; accepted September 27, 2005. From the Neurogenetics Group, National Institute of Neurological Disorders and Stroke (G.G.L.), Bethesda, Md; Department of Neurology (J.F.M.), Mayo Clinic, Jacksonville, Fla; Baycrest Centre for Geriatric Care (D.T.S.), The Rotman Research Institute, University of Toronto, Ontario, Canada; London Health Sciences Center (V.H.), University of Western Ontario, London, Ontario, Canada. Correspondence to Gabrielle G. Leblanc, PhD, National Institute for Neurological Disorders and Stroke, 6001 Executive Blvd, Room 2114, Bethesda, MD 20892. E-mail leblancg@ninds.nih.gov © 2005 American Heart Association, Inc. Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000195177.61184.49 248 Comments, Opinions, and Reviews by on November 3, 2010 stroke.ahajournals.orgDownloaded from cell proliferation and differentiation.20–24 HCHWA-D is a syndrome of primarily hemorrhagic strokes and dementia.25,26 It is caused by a mutation in the gene for amyloid precursor protein (APP) that causes abnormal deposition of amyloid in the walls of leptomeningeal arteries and cortical arterioles (a pathological condition known as cerebral amyloid angiopathy [CAA]).27,28 Mouse models have been developed for CADA- SIL28,29 and HCHWA-D28–30 and have contributed critical insights into the cell biology of the pathogenic processes underlying them. In contrast, little attention has been paid to the second class of genes: those that render the brain more or less susceptible to injury in response to cerebrovascular disease. Evidence for the existence of such response genes is that patients with apparently similar loads of vascular pathology (with regard to lesion type, number, and location) may range from no cognitive impairment to severely cognitively impaired.31–35 Such differences could be attributable to either genetic or environmental factors. Direct evidence for a role of genetic factors comes from studies of the heritability of white matter hyperintensities (WMH). Studies in older male twins,36 in a family-based sample of middle-aged and older men and women (the Framingham Study cohort37), and in hypertensive sibships38 have shown that WMH volume is a highly heritable trait, indicating a large genetic contribution to development of this condition. Does the heritability of WMH volume simply reflect the heritability of underlying cerebrovascular disease? Two lines of evidence suggest not. First, in the Framingham study group, high heritability of WMH volume was seen even in younger patients in whom the prevalence of cerebrovas- cular injury was relatively low. Second, in the study of hypertensive sibships, levels of hypertension were controlled for. Thus, these studies suggest that there are genetic factors affecting cellular responses to cerebrovascular pathology that are different from those that cause cerebrovascular pathology itself. One class of genes that must influence tissue responses to cerebrovascular disease are the AD genes. As was first shown in the Nun Study,39 there is an additive or synergistic interaction between AD and cerebrovascular pathologies, such that individuals with both of these pathologies show greater cognitive impairment than those exhibiting either pathology alone. This finding has been replicated.40,41 In addition, at least 3 sets of genes in the AD pathway, the presenilins, APP, and apolipoprotein E (apoE), are known to interact with the VCI disease pathway. The presenilins, mutations of which cause AD, have been shown to interact directly with Notch proteins, including Notch 3 (mutations of which cause CADASIL).42 Mutations in the APP gene can lead either to AD or to hemorrhagic stroke and dementia (as in HCHWA-D) depending on the site of the mutation and the subsequent cellular site of amyloid accumulation.28,43,44 Vari- ants of the apoE gene appear to affect not only susceptibility to cerebrovascular disease but also recuperative responses to it (see below). Thus, there appear to be links in the biochem- ical pathways underlying VCI and AD pathologies, which could be responsible for the observed interactive effects of these pathologies on cognitive function. Genes that influence brain responses to cerebrovascular disease do not appear to be limited to those within AD pathway. First, it has been shown that VCI can occur in the complete absence of AD pathology in sporadic VCI and in hereditary forms.34,45,46 In addition, the cognitive sequelae of pathogenic processes associated with VCI are different from those seen in “pure” AD, in that executive function appears more strongly affected in VCI than is memory.6,47,48–51 Consis- tent with these observations, different brain regions seem differ- entially affected in VCI and AD, with prefrontal circuits being more affected in VCI and the hippocampus in AD.52–56 There is direct evidence from both human and animal studies for specific non-AD genes that play a role in tis- sue responses in ischemia. First, studies in humans suggest that variants in the genes for platelet glycoprotein and �-fibrinogen affect poststroke outcomes without affecting stroke risk per se.57–61 Furthermore, studies in animal models have demonstrated that a number of proteins outside the AD pathway contribute to (or protect against) tissue injury after ischemia. These include glutamate and �-aminobutyric acid receptors, acid-sensing ion channels, proteases, growth fac- tors and their receptors, and transcription factors.62–64 Genes that affect an individual’s premorbid level of cog- nitive ability also seem likely to affect performance in the wake of cerebrovascular disease. For example, several studies have shown now that subjects who in their youth perform better on measures of linguistic or mental ability are less likely to develop cognitive impairment or dementia later in life.65–67 Baseline cognitive function in “healthy” individuals at all ages clearly has a strong genetic component.68–70 Indeed, the heritability of certain cognitive measures (includ- ing measures of executive function) actually increases with increasing age, raising the possibility that genetic influences become even more important in later life.71 With respect to specific genes that may influence cognitive function, candidate gene studies have indicated strong asso- ciations between measures of prefrontal function and poly- morphisms in the catechol-o-methyl transferase gene.70 Ge- netic studies of attention deficit hyperactivity disorder suggest statistically significant associations of this disorder with genes in the dopaminergic and serotonergic neurotrans- mitter systems;72 it remains to be determined to what extent these findings are applicable to prefrontal function in aging “normal” individuals. Studies in genetically engineered ani- mal models have also identified specific genes that may be involved in human cognition,68 although much of the focus in those studies has been on hippocampal memory formation; executive function has been far less studied. Finally, some of the genes underlying VCI are likely to affect both susceptibility to cerebrovascular disease and the response of the brain to ischemic or hemorrhagic injury. ApoE appears to be an example of gene that affects disease incidence and disease responses. On the disease incidence side, apoE genotype influences risk of intracerebral hemorrhage. In the Greater Cincinnati/Northern Kentucky population, about one third of all cases of lobar intracerebral hemorrhage are attributable to the possession of the e2 or e4 allele.73 E4 allele carriers also have a nearly 4-fold higher risk of lobar warfarin-related intracerebral hemorrhage.74 On the Leblanc et al Genetics of Vascular Cognitive Impairment 249 by on November 3, 2010 stroke.ahajournals.orgDownloaded from injury response side, the presence of the e4 allele has been associated with reduced survival in intracerebral hemor- rhage.58,75 Conversely, an increasing dose of the e4 allele has been associated with improved survival in patients after ischemic stroke, even after adjusting for baseline severity of neurological impairment.76 Although a useful conceptual model, differentiating inci- dence from injury-response genes may be difficult experi- mentally. This is especially true for genes encoding for or affecting the expression of vascular growth factors such as ephrins, which have overlapping effects with neural growth factors.77 Because there are gene products that can have vasculotrophic and neurotropic effects, human studies should encompass not only information on the presence or absence of stroke (whether symptomatic or not) but also on markers of neural injury or response to injury (such as measures of neurological deficit or cognition). Challenge 1: Choice of Subject Population and Study Design Acute Large Vessel Infarct The cerebrovascular pathologies that cause VCI are hetero- geneous. Hence, there are several different patient popula- tions that could be used for genetic studies. The first of these is patients with acute ischemic stroke enrolled at the time of admission to hospital. Because only a subpopulation of these patients will develop a clinically diagnosable cognitive im- pairment subsequent to their stroke, one could compare the genotypes of patients with different cognitive outcomes. Use of this patient population would have distinct practical advantages: patient collection would be straightforward and would generate a cohort enriched with individuals destined for cognitive decline. There are several obvious confounders that would have to be addressed with this patient population. Symptomatic cerebral infarction is heterogeneous with regard to lesion volume, location, and laterality. Hence, the degree of cogni- tive impairment seen may reflect these factors as well as the genetic factors that render neural tissue more or less resilient to injury. However, these factors could be controlled for with a sufficiently large sample size of patients with large vessel strokes in similar brain regions. A second confounding issue is that the cognitive status of the patients before stroke would be variable and could not be measured directly at the time of presentation with stroke. Using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), investigators estimate the rate of prestroke dementia at 12% to 16%.78,79 The confound of premorbid cognitive impairment might be controlled for by testing cognition at �2 time points after the stroke and using rates of change in cognitive ability as the phenotype to be measured. The timing of cognitive testing after stroke would de- pend on what phase of the postischemic tissue injury re- sponse one wished to analyze and what classes of genes one thereby hoped to target. After a discrete ischemic event, there is an acute phase of tissue injury, and it is typically during this phase that the individual presents at the hospital with clinical symptoms. Over the first 6 to 12 months after infarct, a large proportion (up to 50%) of patients with early presen- tation of cognitive impairment exhibit significant recov- ery.80,81 However, over the subsequent months and years, progressive deterioration is seen in the overall population of stroke patients.82–84 This long-term cognitive deterioration may reflect additional ischemic events (which may or may not be attended by acute symptoms), the interaction of the acquired cognitive impairment with normal aging changes, progressive nonvascular dementias such as AD, or some combination. The likely occurrence of nonvascular cognitive impairment in a subset of individuals complicates the analysis of long- term cognitive outcomes considerably. There are neuropsy- chometric tools that could potentially help identify patients with significant AD; these are discussed in a later section of this article. Insights could also be gained through serial MRI, amyloid imaging, or testing for AD-related genes. However, such long-term studies ideally would be performed over a period of at least several years and would carry considerable per-patient costs. An alternative solution would be to target the initial phase of poststroke recovery. It is possible that the degree of short-term recovery would be less influenced by concomitant AD pathology than would long-term outcome. This approach might also uncover genes that promote tissue repair as well as ones that render it susceptible to damage. Such a study could be hospital based and loss to follow-up would be minimal. Subcortical Small Vessel Disease It has been suggested that subcortical small vessel disease produces a more homogeneous set of cognitive deficits than do large vessel infarcts,85 although the deficits may be milder and slower in onset. In this regard, subcortical small vessel disease could be particularly well suited to genetic studies. The major challenge with this population would be subject recruitment. Large-scale imaging studies have shown that most subcortical small vessel disease does not produce acute symptoms but rather an insidious decline in neurological function or no symptoms at all.31,35,86 In theory, one could screen a large number of “normal” subjects for MRI signs of small vessel disease and then compare the genotypes of subjects who do and do not subsequently develop cognitive impairment. However, only�15% to 25% of elderly subjects show MRI signs of small vessel disease,86–89 and only a subpopulation of these then go on to develop cognitive impairment. Because it has been estimated that about a thousand cases and a thousand controls would be needed for a case/control study design (John Hardy and Don Bowden, personal communications, 2004), this kind of longitudinal study design would be extremely costly. CADASIL and CAA CADASIL patients are another intriguing population for studying the genetics of VCI. There are 2 potential advan- tages in using this population. First, the population is rela- tively homogeneous with respect to underlying vascular disease (small artery angiopathy causing degeneration of the smooth muscle cell layer) and type of infarct (primarily subcortical lacunar). Second, despite this homogeneity in the 250 Stroke January 2006 by on November 3, 2010 stroke.ahajournals.orgDownloaded from nature of the vascular disease, there is a high degree of variability in penetrance and age of onset of stroke and cogni