Amyloid plaques are depositions of amyloid β (Aβ) protein

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1 Topical Review Cerebrovascular Disease, Amyloid Plaques, and Dementia Wenyan Liu, MD; Adrian Wong, PhD; Andrew C.K. Law, MD, PhD; Vincent C.T. Mok, MD Amyloid plaques are depositions of amyloid β (Aβ) protein in the cerebral parenchyma and considered as one of the neuropathological diagnostic hallmarks of Alzheimer s disease (AD). 1 Cerebrovascular disease (CVD) is also highly prevalent among the elderly and is commonly found in patients with AD. 2 Autopsy studies conducted during the past 2 decades show that amyloid plaques frequently coexist with CVD, and the 2 may interact to modulate the risks and expression of clinical dementia. 2 Neuropathological examinations show that between 6% and 47% individuals with dementia had coexisting AD and CVD pathologies (Table) Indeed, mixed pathologies may account for the majority of dementia cases (38%). 11 Although autopsy study is considered the gold standard for determining the underlying pathology of dementia, it has inherent limitations with correlating pathological and clinical findings. In particular, uncertainties exist with regard to the temporal relationship between the development of brain lesions and dementia syndrome because of the time lag between dementia onset and autopsy. Moreover, the exact severity or extent of certain manifestations of CVD, in particular, white matter changes (WMC), is difficult to quantify in autopsy studies. 21 Also, heterogeneity in the definition of CVD lesions (eg, lacunar infarct) might contribute to inconsistency in assessments between neuropathologists. 21 Clinical in-vivo study investigating the relationship between amyloid plaques and cognitive impairment has only been made possible a decade ago with the advent of amyloid imaging, such as Carbon-11-labeled Pittsburgh Compound B (PiB) positron emission tomography (PET). Other amyloid ligands, such as flutemetamol (GE-067), florbetaben (BAY , AV-1), and florbetapir (AV-45) have also become available to the market in recent years. 22 Amyloid PET can detect comorbid amyloid deposition in patients with high vascular burden. 23 We reviewed the potential interactions between CVD and amyloid plaques and their relationships with cognitive impairment, with reference to in-vivo clinical studies using amyloid PET imaging and autopsy studies measuring amyloid plaques Prevalence of Amyloid Plaques in Subjects With CVD Using amyloid PET, AD-like PiB retention was found in 29.7% of patients with incident dementia after stroke or transient ischemic attack and 31.1% of patients with clinical diagnosis of subcortical vascular dementia (VaD). 24,25 These findings are in keeping with the prevalence reported in neuropathological studies showing that AD pathology, including both amyloid plaques and neurofibrillary tangles, was found between 25.8% and 55.6% of patients diagnosed with possible VaD Interactions Between CVD and Amyloid Plaques Being the 2 commonest causes for dementia, mounting evidence shows that CVD and AD share risk factors, including age, hypertension, diabetes mellitus, hypercholesterolaemia, ischemic heart disease, and smoking. 1 Research findings on the relationship between CVD and amyloid accumulation are discussed below. Neurovascular Unit and Amyloid Plaques Amyloid accumulation may occur a decade or more before the emergence of clinical symptoms of cognitive decline. 49 Alterations in neurovascular unit may take part in the process. 50 According to the 2-hit vascular hypothesis of AD, impaired blood brain barrier and reduced cerebral blood flow, caused by neurovascular unit dysfunction, may induce Aβ accumulation in addition to direct damage to neurons. 50,51 Apolipoprotein E-4, which is associated with both cerebrovascular lesions and late-onset sporadic AD, may also contribute to amyloid formation via vascular mechanisms. 52 Different from the direct neurotoxic effects of parenchymal amyloid plaques, amyloid deposits in vessels are associated with cerebral amyloid angiopathy (CAA). Vascular amyloid may disrupt blood brain barrier function and rupture the vessels, causing the leakage of the serum proteins and red blood cells into brain parenchyma. Together, these series of events set the stage for the formation of amyloid plaques. 50 This hypothesis is supported by pathological observations of an preferential accumulation of amyloid plaques around capillaries with CAA in patients with AD. 53 In young APP23 transgenic mouse (a mouse model for AD), vessels deformation and attachment by small amyloid deposits were found before the presence of amyloid plaques in the parenchyma, suggesting that microvasculature alternations may be an early event in the formation of amyloid plaques. 54 Received October 15, 2014; accepted February 23, From the Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China (W.L., A.W., V.C.T.M.); and Neural Dysfunction Research Laboratory, Department of Psychiatry, The University of Hong Kong, Hong Kong, China (A.C.K.L.). Correspondence to Adrian Wong, PhD, Department of Medicine and Therapeutics, 10/F Clinical Sciences Bldg, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. adrianwong@cuhk.edu.hk (Stroke. 2015;46: DOI: /STROKEAHA ) 2015 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Liu et al Cerebrovascular Disease, Amyloid, and Cognition 1403 Table. Pathology Findings in Dementia Author Setting No. Mean Age, y AD+CVD (%) Pure AD (%) Pure VaD (%) LBD (%) FTD (%) Others (%) Victoroff 3 Hospital 196 d (12.8%) 88 (44.9%) 9 (4.6%) 13 (6.6%) NA 61 (31.1%) Snowdon 4 Convents 45 d (47%) NA NA NA NA NA Nolan 5 Hospital 87 d NA 32 (37%) 44 (50.6%) NA NA 11 (12.6%) Seno 6 Nursing home 122 d 83.6± (11%) 41 (34%) 42 (35%) NA NA 25 (20%) Barker 7 Hospital 382 d 79±13 43 (11%) 159 (42%) 12 (3%) 99 (25.9%)* 21 (5.5%) 48 (12.6%) Akatsu 8 Geriatric 158 d 81.2±8.3 9 (6%) 73 (46%) 34 (22%) 28 (18%) 14 (8%) hospital Riekse 9 Community 124 d (14.5%) 30 (24.2%) 8 (6.5%) NA NA 124 (54.8%) Petrovitch 10 Community 333 (120 d) (18.3%) 37 (30.8%) 35 (29.2%) 26 (21.7%) (HAAS) Schneider 11 Community 141 (50 d) 87.8± (38%) 15 (30%) 6 (12%) NA 10 (20%) (the Rush MAP) Brunnström 12 Hospital 524 d 80 (39 102) 113 (21.6%) 220 (42%) 124 (23.7%) 1 (0.2%) 21 (4%) 45 (8.6%) Schneider 13 Community 179 d (30.2%) 76 (42.4%) 8 (4.5%) 30 (16.8%)* NA 11 (6.2%) (the Rush ROS and MAP) Brayne 14 Community 213 (113 d) 91.1 (81 101) 25 (22.1%) 76 (67.2) 4 (3.5%) 1 (1%) NA 7 (6%) (CC75C study) White 15 Community 443 (183 d) (14.2%) 34 (18.6%) 62 (33.8%) 20 (10.9%) 41 (22.4%) (HAAS) Jellinger 16 Hospital 1700 d 84.3± (27.8%) 775 (45.6%) 209 (12.3%) 158 (9.3%) NA 85 (5%) Sinka 17 Hospital 93 (86 d) (19.7%) 48 (55.8%) 21 (24.4%) Echavarri 18 Hospital 200 d 78.7 (15 100) 31 (16%) 52 (26%) 4 (2%) 1 (0.5%) 4 (2%) 113 (56.5%) Grinberg 19 Community 1291 (113 d) 78.3± (13.3%) 40 (35.4%) 24 (21.2%) NA NA 34 (30.1%) (BBBABSG) Magaki 20 Hospital 218 d (11%) 123 (56.4%) 1 (0.5%) 31 (14.2%)* 14 (6.4%) 25 (11.5%) AD indicates Alzheimer s disease; BBBABSG, Brain Bank of the Brazilian Aging Brain Study Group; CC75C, Cambridge City Over-75s Cohort; CVD, cerebrovascular disease; d, number of patients with dementia; FTD, frontotemporal dementia; HAAS, Honolulu-Asia Aging Study; LBs, Lewy bodies; LBD, Lewy body disease; MAP, Rush Memory and Aging Project; NA, not available; ROS, Religious Order Study; and VaD, vascular dementia. *Including LBs+others. Including FTD+others. AD+others, but most are AD+CVD. However, an unresolved issue remains on the temporal relationship between the development of vascular and amyloid pathologies as other potential factors, such as the overproduction of Aβ caused by genetic mutations in APP and presenilin genes might also take part in the abnormal amyloid accumulation. 1 Atherosclerosis and Amyloid Plaques Atherosclerosis in large cerebral arteries can compromise cerebral blood flow and cause cerebral hypoperfusion. Patients with AD had a higher proportion and more pronounced atherosclerosis in the circle of Willis than those patients with non- AD dementias (except VaD) as shown in autopsy studies. 41,55 58 Moreover, there was a high concordance between the ratings of atherosclerosis with amyloid plaques and CAA ratings. 41 Through [18F] AV-45 PET examination, amyloid deposition in patients with dementia having unilateral carotid artery stenosis was increased. More importantly, the distribution of the amyloid disposition was found to be lateralized to the side of stenosis. 26 Together, these clinical and pathological findings suggest that there is a shared cause between atherosclerosis and amyloid deposition. Infarcts and Amyloid Plaques Most amyloid PET studies did not find significant relationships between infarcts and amyloid deposition. 27,28 In fact, a study showed that in patients with subcortical vascular cognitive impairment, the number of lacunes was negatively related with the PiB retention ratio. 29 In patients with recent ischemic stroke, although a relatively increased PiB retention was found in peri-infarct region comparing to the contralateral mirror region, this increased regional PiB retention did not translate into a higher global PiB retention. 30 In experimental stroke models in transgenic mouse with amyloid deposition (APPswe/PS1dE9), increase in new amyloid plaques around the infarcted area was only transient, in which the accumulation most probably reflected an impaired amyloid clearance pathway caused by infarcted tissue. 59 Moreover, the possibility that the observed increase in local PiB retention being a result of leakage of free PiB because of the blood brain barrier damage could not be excluded. 30 Overall, thus far, there is no solid evidence of a significant interaction between cerebral infarcts and global amyloid burden.

3 1404 Stroke May 2015 WMC and Amyloid Plaques Pathogenesis of WMC could be multifactorial. Here, we specify WMC as age-related WMC, which is suggested to represent incomplete infarct related to small vessel disease. WMC is generally hypothesized to be associated with demyelination, loss of oligodendrocytes, and axonal damage. 60 Findings about the relationship between WMC and amyloid accumulation seem to be inconsistent. In general, most studies showed a lack of correlation between WMC and amyloid load ,31,32 However, there were also studies showing positive relationships between WMC and amyloid. 33,34 For instance, in sporadic AD patients, WMC at baseline was significantly related to the progression of amyloid deposition in 28 months, 33 suggesting that WMC might accelerate the aggregation of amyloid protein produced in situ. However, the positive association between WMC and amyloid burden seemed to be predominant in the posterior brain regions, which are not the typical topography of AD but CAA. 34 Another study also reported that the volume of WMC was independently related to amyloid retention in patients with CAA but not in patients with AD. 35 On the basis of these findings, it can be speculated that WMC may be more closely linked to vascular amyloid deposition associated with CAA rather than parenchymal amyloid deposition characteristic of AD. Noteworthy is that a study among cognitively normal individuals showed that gray matter regions with more WMC had lower amyloid deposition. 36 It was hypothesized that WMC might disrupt the entry of misfolded proteins from white matter tracts and thus resulted in lower amyloid load in gray matter regions. 36 In view of these conflicting results, further investigation between WMC and amyloid is warranted. Microbleeds and Amyloid Plaques The number of studies on the association of microbleeds and amyloid burden are limited. 37,38,42 Two studies revealed positive findings. 37,42 In a postmortem study using immunohistochemical staining, the majority of Aβ deposits were found to be at or near the capillary hemorrhage sites. 42 The Australian Imaging, Biomarkers, and Lifestyle Study of Aging Research group showed that the prevalence and incidence of microbleeds were both significantly higher in AD than in cognitively normal individuals. 37 However, converging evidence showed that microbleeds in AD were more linked to CAA and related increased blood brain barrier permeability, rather than amyloid disposition. 38 Autopsy study showed that microbleeds in AD with CAA were found in all brain sections, whereas in AD without CAA, microbleeds were only predominate in the central coronal sections. 61 This observed discrepancy on topographical distribution of microbleeds may differentiate AD patients with and without CAA. Interactions Between CVD, Amyloid Plaques on Cognition Comorbid CVD and Amyloid Plaques on Expression of Dementia The Nun study was a landmark study that revealed a concerted effect of lacunes and AD pathologies on clinical expression of dementia. It suggested that concurrent cerebral infarcts might significantly amplify the risk and severity of dementia in patients with neuropathologically confirmed AD. 4 More recent studies using amyloid PET also showed converging findings. For example, PiB-positive (PiB+) subcortical patients with VaD had lower cognitive performance than those who were PiB-negative (PiB ). 25 Interestingly, there seems to be a dynamic balance between amyloid deposition and CVD pathologies on the expression of dementia because on a given level of cognitive impairment, less amount of one kind of pathology is found when the amount of other kind of pathology increases. For example, in neuropathological studies, amyloid plaques were found to be fewer in those with CVD lesions Among patients with poststroke dementia, PiB+ patients had fewer old infarcts than their PiB counterparts. 24,25 Although findings from above studies raised the possibility of a synergistic effect between the 2 pathologies, other study suggested that CVD largely contributed an additive, rather than synergistic, effect on the expression of dementia against the background of amyloid burden. 29 Note that synergistic effects between the 2 pathologies might be specific to cognitive domains such as visuospatial functions. 39 Contributions of Comorbid CVD and Amyloid Plaques on Expression of Dementia The amyloid hypothesis posits that the amyloid deposition on its own is an early step in the development of cognitive impairment. 49 The accumulation of amyloid in the aging brain causes oxidative and inflammatory effects, which lead to neuronal death and synaptic failure, and eventually result in brain atrophy and cognitive impairment. Although the detrimental effects of Aβ on neuron and synapse have been observed in animal models, it remains unclear how much Aβ deposition is required to instigate the neurodegenerative process and finally results in cognitive dysfunction. Given that amyloid burden could be found in 20% to 30% cognitively normal older adults, 62,63 the threshold of amyloid plaques for cognitive manifestation is likely to be modulated by individual differences, such as brain and cognitive reserve, and other environmental factors. 49 Concurrent CVD lesions may catalyze or trigger the onset of clinical dementia in asymptomatic or subclinical individuals with amyloid plaques by several ways. First, CVD may impair cognition directly via neuronal death and synaptic failure independent of amyloid. 2 According to laboratory research, the neurovascular dysfunction could cause oxidative stress and inflammation via nonamyloidogenic pathway, leading to neuronal loss. 2,50 Second, according to the aforementioned 2-hit vascular hypothesis, the neurovascular dysfunction is also associated with an increased accumulation of amyloid plaques. 50 Third, decreased number of viable neurons caused by the CVD lesions may reduce brain reserve and subsequently the resilience of the brain against the detrimental effects from amyloid-mediated neurotoxicity. Therefore, concurrent CVD lesions may lower the threshold for clinical manifestation of cognitive impairment with amyloid burden.

4 Liu et al Cerebrovascular Disease, Amyloid, and Cognition 1405 In addition to possible pathological mechanisms mentioned above, in clinical setting, the presence of concurrent CVD may increase the likelihood for patients to receive a diagnosis of dementia. In the early stage of amyloid deposition, a diagnosis of dementia is more likely to be established in the presence of deficits on multiple cognitive domains contributed concurrently by frontal dysfunction associated with cerebrovascular lesions. 64 When the invasion of amyloid progresses to later stage and involves in all areas of the isocortex, the superimposed cognitive dysfunction caused by CVD will be difficult to distinguish. 65 This may be one of the reasons why CVD lesions play a greater role in the development of dementia in people with fewer amyloid plaques than those with more severe deposition. Comorbid CVD and Amyloid Plaques on Cognitive Profile of Dementia In AD, amyloid has most robust effects on episodic memory among the cognitive domains. 66 In contrast, executive dysfunction tends to be typically more prominent in patients with subcortical vascular disease, such as individuals exhibiting lacunes and WMC, in which their effects are more pronounced on the frontosubcortical system. 67 Such dissociations have been demonstrated in patients with mixed pathologies. For example, in patients with subcortical VaD and mild cognitive impairment, amyloid burden seemed to be more related to episodic memory decline, whereas WMC was associated with poor executive function. 25,29,39 A path analysis study showed that memory deficits related to amyloid burden was mediated by hippocampal atrophy, whereas WMC affected executive function via frontal thinning. 40 However, the relationships between cognitive domains and pathologies may not be straightforward. For example, WMC could also affect episodic memory by affecting working memory and executive retrieval with frontal dysfunction. 40 In addition, amyloid and CVD might influence memory and executive function independent of brain atrophy. 40 Several possibilities may explain the overlaps of the cognitive domains associated with amyloid deposition and CVD. First, cerebral regions affected by amyloid deposition and CVD may overlap. Distribution of amyloid deposition is typically observed in the frontal cortex, posterior cingulate, precuneus, caudate, parietal cortex, and lateral temporal cortex, which are brain regions involved in a wide range of cognitive processes, including executive functions, attention, and memory. Locations of cerebrovascular lesions in individuals are variable in CVD. In addition to executive dysfunction, cerebrovascular lesions in posterior cerebral artery territory may also affect the medial temporal lobe with consequential memory failure. 68 Second, distinct cerebral regions are associated with multiple cognitive processes rather than a single cognitive function. For instance, both executive functions and memory are subserved by the frontal lobes and related pathways. 69 Third, in addition to brain atrophy, functional network disruptions may also impair cognition. 70 Therefore, given that differences in neuropsychological profiles between AD, VaD, and mixed dementia are less distinct than expected, it may be clinically difficult to distinguish pathologies based on cognitive profile alone. Conclusions and Future Directions Autopsy and amyloid PET studies showed the existence of comorbid CVD and amyloid deposition in patients with cognitive impairment. Underlying microvasculature alternation may contribute to an early accumulation of amyloid. With aging, emergence of CVD could further affect cognition in those patients with preexisting amyloid by causing direct neuronal damage and accelerating the amyloid deposition. Concurrent CVD may also lower the brain reserve against cognitive effects from amyloid disposition, and vice versa. Nevertheless, relationships between amyloid deposition and different kinds of cerebrovascular lesions are still unclear. Longitudinal studies with repeated amyloid and MRI in young subjects with high risks of CVD or AD will be helpful to study the evolution in the development and interactions between CVD and amyloid deposition. In addition, the validity of neuropsychological paradigms such as intraindividual variability measures may be examined in conjunction with the use of computerized testing technology as a way to differentiate underlying pathology and predict clinical course. In clinical practice, aggressive control of risk factors of CVD will probably prevent or delay onset of dementia in elderly subjects harboring amyloid plaques. Furthermore, active lifestyle engagement, such as physical activities and mental stimulation has been found to be associated with reduced CVD risks and amyloid burden. 71,72 Clinical trials are needed to study the modulating effects of lifestyle intervention on clinical and neuroimaging markers of CVD and AD for primary prevention of dementia in our rapidly aging populations. Sources of Funding This work was supported by Health and Health Services Research Fund and Lui Che Woo Institute of Innovative Medicine. None. Disclosures References 1. Blennow K, de Leon MJ, Zetterberg H. Alzheimer s disease. 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