Cerebral microbleeds and cognition in cerebrovascular disease: An update

Journal of the Neurological Sciences 322 (2012) 50–55

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Cerebral microbleeds and cognition in cerebrovascular disease: An update Andreas Charidimou, David J. Werring ⁎ Stroke Research Group, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom

a r t i c l e

i n f o

Article history: Received 7 March 2012 Accepted 27 May 2012 Available online 18 June 2012 Keywords: Cerebral microbleeds MRI Vascular cognitive impairment Cerebral amyloid angiopathy

a b s t r a c t Sporadic cerebral small vessel disease is a major cause of cognitive impairment. MRI is an important tool for detecting and mapping cerebral small vessel disease in vivo. Lacunes and white matter changes are recognized as characteristic MRI manifestations of small vessel disease. Cerebral microbleeds (CMBs) – small, perivascular haemorrhages seen as well-demarcated, hypointense, rounded lesions on MRI sequences sensitive to magnetic susceptibility – are a more recently recognized MRI marker of small vessel pathology. CMBs are increasingly found in various patient populations and disease settings, including first-ever and recurrent ischaemic or haemorrhagic stroke, Alzheimer's disease, vascular cognitive impairment and healthy elderly individuals. Increasing evidence suggests that the anatomical distribution of CMBs (lobar or deep) may have diagnostic value in detecting small vessel disease subtypes including hypertensive arteriopathy and cerebral amyloid angiopathy. However, the relevance of CMBs for cognitive impairment remains uncertain. The study of CMBs and cognition in populations with cerebrovascular disease presents a special challenge as they coexist and correlate with other cerebrovascular pathologies. This review updates current thinking on how CMBs may be relevant in the study of cognitive impairment in populations with cerebrovascular disease, and how they can contribute in understanding the links between cerebrovascular and degenerative pathologies. © 2012 Elsevier B.V. All rights reserved.

1. Introduction As people live longer, cognitive impairment is becoming an increasing healthcare challenge facing all societies worldwide [1]. Although Alzheimer's disease (AD) is considered the most common cause of cognitive dysfunction in the elderly, vascular cognitive impairment (VCI) has emerged as an important contributor to the burden of cognitive dysfunction [2]. The construct of VCI comprises a spectrum of cognitive disorders related to all forms of cerebral vascular disease and was introduced to replace earlier concepts of “multi-infarct dementia” and “poststroke dementia” [2,3]. It recognizes that overt dementia defined according to traditional criteria represents only a fraction of the total cognitive morbidity, and emphasizes the complexity of the mechanisms and overlap between cerebrovascular and neurodegenerative pathologies in the elderly [2,4]. Cerebral small vessel disease plays a critical role in VCI. Magnetic resonance imaging (MRI) has become the most important tool for detecting and mapping cerebral small vessel disease in vivo [2,3,5]. Lacunes and white matter changes (WMC, also known as leukoaraiosis) have been recognized for many years as characteristic MRI manifestations of small vessel disease (Fig. 1). In addition, cerebral microbleeds (CMBs) – small, perivascular haemorrhages seen as well-demarcated, ⁎ Corresponding author at: Clinical Senior Lecturer in Neurology, National Hospital for Neurology and Neurosurgery, Box 6, Queen Square, London WC1N 3BG, United Kingdom. Tel.: + 44 207 829 8753. E-mail address: [email protected] (D.J. Werring). 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.05.052

hypointense, rounded lesions on MRI sequences sensitive to magnetic susceptibility (Fig. 1) – have emerged as an important new manifestation and diagnostic marker of small vessel pathology [6,7]. However, their clinical impact on cognition remains an active field of research [6]. This review considers recent evidence on how CMBs may be relevant in the study of cognitive impairment in populations of individuals with – or at risk of – cerebrovascular disease (Table 1). 1.1. Sporadic cerebral small vessel disease: definitions and MRI-clinical correlations Cerebral small vessel disease is one of the most prevalent brain conditions described, and a major cause of VCI [8,9]. Small vessel disease refers to a group of pathological processes which affect the small arteries, arterioles and capillaries of the brain [9]. The main sporadic forms include: (a) hypertensive arteriopathy, which causes thickening of and damage to the arteriole wall, and typically affects the small perforating end-arteries of the deep grey nuclei and deep white matter; and (b) cerebral amyloid angiopathy (CAA), a common age-related condition characterised by the progressive deposition of amyloid-β in the media and adventitia of small arteries, arterioles and capillaries in the cerebral cortex, overlying leptomeninges and grey–white matter junction (Fig. 2A) [10]. Since small vessels cannot be easily directly visualised in vivo, the parenchymal MRI lesions which they are thought to cause have been adopted as markers of small vessel damage [9]. Despite extensive research, the correlation of some well known imaging markers of small vessel disease with cognition (such as WMC), has

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B1

A

White matter changes

B2

Lacunar infarct

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C

Cerebral microbleeds

Fig. 1. MRI manifestations of cerebral small vessel disease with relevance to cognitive function. (A) Coronal FLAIR (fluid attenuated inversion recovery) MRI showing confluent periventricular and deep white matter hyperintensities (leukoaraiosis). (B1–2) The left panel (B1) is an axial T2-weighted image showing a lacunar infarct in the right basal ganglia (arrow) — with the corresponding coronal FLAIR appearance (inset; circle); the right panel (B2) is an axial diffusion-weighted MR image which illustrates an acute lacunar infarct. (C) Multiple cortical-subcortical cerebral microbleeds (dark, rounded lesions) detected by axial T2*-weighted gradient-recalled echo.

often been modest - particularly in patients with symptomatic cerebrovascular disease [11,12]. The limited correlations in some studies may be a reflection of both the pathological heterogeneity of small vessel diseases and lack of pathological specificity of conventional MRI [12,13]: for example T2-weighted or FLAIR MRI dichotomises white matter as either ‘hyperintense’ (WMC) or ‘normal,’ but WMC areas may reflect varying degrees of different pathological tissue changes (including infarction, ischaemic demyelination and gliosis), which may have different functional consequences [13]. Small vessel disease also has histopathological manifestations which may not be readily detectable by currently available imaging techniques (e.g. cerebral microinfarcts; Fig. 2B) [13]. There is thus a need for a better understanding of the pathological basis of MRI changes, and for more specific imaging markers to detect and quantify the various expressions of small vessel disease throughout the brain.

brainstem), whereas CAA is characterised by CMBs in a lobar (corticalsubcortical) distribution and is not related to traditional cardiovascular risk factors such as hypertension (Fig. 2) [7,17]. The population-based Rotterdam scan study [18] showed a strong association between strictly lobar (but not deep) CMBs and APOE ε4 (confirmed in a meta-analysis [19]), consistent with the well-known relation of this allele with CAA [10] A recent imaging study in clinically probable CAA, using noninvasive amyloid imaging with 11C-Pittsburgh Compound B (PiB), found that lobar CMBs correspond to areas with a high concentration of amyloid [20]. Even in healthy elderly people, multiple lobar CMBs were recently found to be associated with higher amyloid-β burden, as detected by PiB imaging [21]. Thus, CMBs have promise to detect, quantify and map the effects of cerebral small vessel diseases in patients with cognitive impairment. 2. Rationale for studying CMBs in relation to cognition

1.2. Cerebral microbleeds: an overview 2.1. How might CMBs influence cognitive function? The introduction of blood sensitive MRI sequences, including T2*-weighted gradient-recalled echo (T2*-GRE) has enabled the detection of CMBs, defined radiologically as small, rounded, homogeneous, hypointense lesions, not detected with conventional spin echo sequences [7]. CMBs are increasingly detected in various patient populations and disease settings, including first-ever and recurrent ischaemic or haemorrhagic stroke, Alzheimer's disease, VCI and healthy older people [6,14,15]. Histopathological correlation has shown that radiologically-defined CMBs are quite specific for small collections of blood-breakdown products (in particular, haemosiderin contained within perivascular macrophages), adjacent to abnormal small vessels — mainly affected by hypertensive arteriopathy or CAA [16]. Consequently, CMBs are unique among current MRI manifestations of small vessel disease, in that they seem to provide direct evidence of microvascular blood leakage (by contrast to WMC, which lack pathological specificity) [6]. Several lines of evidence support the hypothesis that CMB have different underlying aetiologies depending on the basis of their location in the brain [6]:it is hypothesized that hypertensive arteriopathy is associated with CMBs in deep brain regions (basal ganglia, thalamus and Table 1 Search strategy and selection criteria. References for this review were identified through PubMed using the search terms: “microbleed(s)”; or “micro(−)h(a)emorrhage(s); or “petechial h(a)emorrhage(s)”; or “gradient-echo”, “T2*”, or “susceptibility” from January 1970 to January 2012. The reference list from identified articles, related review articles and the authors’ own files were also searched for relevant publications. Only papers published in English were reviewed. The final reference list was chosen on the basis of relevance to the topics covered in this article.

The mechanism(s) by which CMBs might influence cognitive function remain speculative, but may include one or more of the following: (a) CMBs may cause direct structural damage to surrounding brain tissue, leading to disconnection of functionally important cortical and subcortical structures, although it remains unclear whether the microscopic perivascular haemosiderin deposition associated with CMBs is sufficient to result in tract degeneration [6,22]; (b) CMBs may induce functional disturbances in surrounding tissue, since experimental microbleeding has been shown to disturb the function of nearby neurons [23]; or (c) CMBs might relate to cognition via an indirect effect (e.g. arteriolar narrowing causing hypoperfusion and micro-ischaemic damage). Finally, CMBs may simply be a general marker for the severity and type of small vessel disease and not have a direct independent impact on cognitive function. CMBs are of particular interest because they are linked with both small vessel and neurodegenerative (AD) pathology in the elderly [1,6]. 2.2. Vascular cognitive impairment, Alzheimer's disease and CAA Traditionally, AD and VCI have been considered as separate entities; however, this dichotomy is clearly an artificial one: dementia and cognitive impairment are now conceptualised as a continuum of overlapping syndromes in older people, in who underlying neurodegenerative and cerebrovascular pathology often co-exist, and “mixed” pathology is probably the commonest substrate of cognitive impairment [4,24]. Moreover, an interaction between vascular and neurodegenerative processes is increasingly recognized: for example, the “Nun study” showed that lacunes are associated with worse cognition in those with AD-type pathology

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Lobar microbleeds

A

B

DWI

Cerebral microinfarct

Cerebral amyloid angiopathy

A2

Deep microbleeds

Hypertensive arteriopathy

Leukoaraiosis

Lacunes

A. Charidimou

Fig. 2. The topography of sporadic cerebral small vessel disease and its MRI features are shown in this schematic representation (Panel A). The small vessels of the brain can mainly be affected by two types of pathological process: (1) hypertensive arteriopathy — which typically affects small deep arterial perforators (black); or (2) cerebral amyloid angiopathy (CAA) — which preferentially affects the small arteries and arterioles of the cerebral cortex and gray–white matter junction by the deposition of amyloid-β in the vessel walls (purple). Cerebral microbleeds (CMBs) are a marker for the severity and type of small vessel disease; their anatomic distribution is meant to reflect the underlying pathological vessel damage. Hence, CMBs located in cortical-subcortical regions are presumably caused by CAA (Panel A1), whereas CMBs located in deep brain regions mainly result from hypertensive arteriopathy (Panel A2). Panel B shows an acute cerebral microinfarct detected on diffusion weighted MRI (DWI). Recent studies show that microinfarcts often result from small vessel pathologies, their often numerous (especially in patients with advanced CAA) and might affect cognition.

[25]. Other clinical-pathological studies also indicate that cerebrovascular and neurodegenerative pathologies are not simply coincidental, but interact to heighten the risk and produce more severe cognitive dysfunction than either process alone [26,27]. For example, pre-existing AD pathology may make people with stroke more vulnerable to poststroke cognitive decline [28]. Exactly how cerebrovascular and neurodegenerative pathologies are linked remains a critical question in understanding mechanisms of dementia. CAA (for which CMBs are an increasingly important imaging marker) may provide an intriguing link between these processes [1,15],.yet has received very little attention in comparison to the parenchymal amyloid deposits seen in AD. Pathologically-defined CAA is very common with advancing age (being found in 20–40% of non-demented, and 50–60% of demented elderly populations) [29], as well as being a major cause of spontaneous lobar intracerebral haemorrhage in the elderly [10]. In AD, CAA is almost invariable, being found at autopsy in more than 90% of cases [30,31], with severe CAA found in about onequarter [32]. Neuroimaging evidence further corroborates these neuropathological findings: population-based studies with optimized imaging protocols have detected lobar CMBs (suggesting of sub-clinical CAA) in up to about 25% healthy elderly individuals [33,34]. Lobar CMBs have also recently been observed in more than 20% of AD patients [15]. In both the Medical Research Council Cognitive Function and Aging Study (MRC CFAS) and Honolulu-Asia Aging Study, CAA pathology was significantly associated with ante-mortem dementia, even after controlling for age and AD-type pathology [35,36]. More recently, the Religious Orders Study found that moderate-to-severe CAA was associated with lower performance in specific cognitive domains, notably perceptual speed and episodic memory, after accounting for AD pathology and other potential covariates [37]. The precise pathophysiological mechanisms responsible for the associations between CAA and cognition are yet to be

established. One possibility is that vascular amyloid-β deposition progressively affects the function of the neurovascular unit, a key player in microvascular and neurodegenerative processes [4,27].and critical supporting structure for healthy neuronal function. CAA also causes impaired vascular reactivity which might result in chronic ischaemia [38] or acute focal ischaemic lesions (i.e. microinfarcts; Fig. 1B) [39] which could potentially contribute to clinical impairment. In parallel, small vessel damage (including hypertensive arteriopathy) can lead to impaired clearance of amyloid-β resulting in its further deposition in vessel wall. CMBs may be particularly interesting as they appear to be at the centre of these complex processes, relating to both CAA (with or without AD), and hypertensive small vessel damage). 3. Studies of cerebral microbleeds and cognition Table 2 provides a summary of studies that evaluate the impact of CMBs on cognition in different populations with – or at risk of – cerebrovascular disease. Studies in Alzheimer's disease are not considered further here; please see van der Flier et al. (ref separate article in the same issue) for further details of CMBs in this setting. 3.1. Recent insights from population-based studies CMBs are very common in the general elderly population [33,40]. Their prevalence increases with age and is affected by the imaging method used: in the Rotterdam scan study which used an optimised susceptibility-weighted imaging sequence, the prevalence of CMBs was around 40% in participants over 80 years old [40]. Despite their high prevalence, studies of how CMBs could affect cognitive function in healthy populations have been scarce [41–44]. Nevertheless, two studies in Japanese populations used the Mini Mental State examination

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Table 2 Associations between cerebral microbleeds and cognitive function in different populations of patients with, or at risk of, cerebrovascular disease. Study

Design

HEALTHY ADULTS Poels et al., Cross2012 sectional Takashima Crosset al., 2011 sectional Qiu et al., 2010

Crosssectional

Yakushiji Crosset al., 2008 sectional

Population

Main findings

Healthy people (The Rotterdam Scan Study; n = 3979 Community-dwelling healthy people (n = 368) Community-based (AGES-Reykjavik Study; n = 3906) Healthy self-funded adults (n = 678)

Higher number of CMBs associated with worse performance on information Brain atrophy, WMC volume, processing speed and motor speed; multiple strictly lobar CMBs significantly presence of lacunes associated with worse performance in all non-memory cognitive domains Lower scores on MMSE associated with CMBs WMC, silent brain infarcts

SPORADIC CEREBROVASCULAR DISEASES van Norden CrossNon-demented elderly et al., 2011 sectional with SVD (RUN DMC Study; n = 500) van Es et al., CrossElderly with increased 2011 sectional vascular risk (PROSPER Study; n = 439) Werring CrossIschaemic stroke/TIA et al., 2004 sectional clinic (n = 55) Seo et al., CrossMemory clinic; 2007 sectional subgroup with subcortical vascular dementia (n = 86) CADASIL Liem et al., 2009

Longitudinal; n = 25 7-year follow-up Viswanathan Crossn = 147 et al., 2008 sectional

Other MRI markers adjusted for

Lower score on executive function and processing speed associated with multiple CMBs

–

Lower scores on MMSE associated with CMBs

WMC

Presence and number of MBs were related to global cognitive function, psychomotor speed and attention

Total brain volume, WMC volume, and lacunar and territorial infarcts WMC volume, infarcts

Lower score on the Immediate Picture-Word Learning test, Delayed Picture-Word Learning associated with infratentorial CMBs

Executive dysfunction more common in the group with CMB than in control Groups matched for WML group MB associated with MMSE score and tests in a range of cognitive domains WMC, lacunes with exception of language

Global cognitive decline, executive function and memory associated with an WMH, lacunes; no independent increase in CMBs associations reported Association with global measures (MMSE. Mattis Dementia Rating Scale)

(MMSE) and found lower scores (>1.5 standard deviations below the age-related mean) associated with the presence of CMBs [42,44]. Recently, the population-based AGES-Reykjavik study assessed the associations of CMBs and retinal microvascular lesions (suggestive of retinalblood barrier breakdown), with cognitive impairment and dementia in 3906 older adults (mean age 76 years) [43]. Using a battery of neuropsychological tests, this study found that multiple CMBs were associated with lower scores on tests sensitive to processing speed and executive function (even after adjusting for potential confounders such as WMC, infarcts and major cardiovascular risk factors) [43]. These associations were stronger in patients with multiple CMBs located in deep or infratentorial regions. Markedly lower scores on processing speed and executive functions were noted in patients with strictly lobar CMBs and retinopathy [43]. More recently, the Rotterdam scan study investigated the association between the number of CMBs (additionally distinguishing between the presence of no, 1, 2–4 and ≥5 CMBs) and different cognitive domains in 3979 individuals without dementia (mean age, 60.3 years) [41]. One or more CMBs were detected in a total of 609 people (15.3%); of these, 413 (67.8%) had CMBs in a strictly lobar location. Analysed as a continuous variable, the number of CMBs was associated with worse performance on tests of information processing speed and motor speed. The presence of ≥5 CMBs was significantly associated with worse performance in all cognitive domains, except memory. After adjusting for brain atrophy, WMC volume, and lacunar infarcts, these associations were found to be more robust for participants with strictly lobar CMBs, compared to those with deep or infratentorial CMBs, suggesting a possible independent role for subclinical CAA in cognitive impairment [41].

WMC, lacunes; No independent association demonstrated except a small strategic effect for caudate/internal capsule CMBs

3.2. Cerebrovascular diseases: stroke and vascular dementia cohorts CMBs are increasingly found as MRI is used more frequently in patients with stroke. CMBs are more prevalent in patients with recurrent stroke than in patients with first-ever stroke, indicating that they are associated with the progression of cerebrovascular disease [14]. A number of studies have examined the relation between CMBs and cognitive function in selected groups of patients with various types of cerebrovascular disease [22,45–47]. The demonstration of a direct relationship between CMBs and cognition, particularly in these patient populations, is challenging because of the association between CMBs and other neuroimaging markers of small vessel disease (including WMC and lacunes). A small study in a neurovascular clinic population compared detailed cognitive function in consecutive patients with CMBs (n= 25) versus a control group without CMBs (n = 30) closely matched for age, WMC severity, prevalence and location of cortical infarcts and ischaemic stroke subtype (factors likely to influence cognition) [22]. A difference in the prevalence of executive dysfunction was found between the two groups: 60% of patients with CMBs were impaired in frontal executive function compared to only 30% in the control group (p = 0.03). In a memory clinic cohort with subcortical vascular dementia, Seo et al. [47] demonstrated that the number of CMBs was an independent predictor of cognition in multiple domains and dementia severity. Recently, the presence and location of CMBs in relation to cognition were investigated in 439 elderly individuals with vascular risk factors in the nested MRI substudy of the PROSPER study (Prospective Study of Pravastatin in the Elderly at Risk) [46]. The main and rather unexpected

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finding was that infratentorial CMBs were associated with cognitive impairment (lower scores in: memory, assessed by Immediate Picture-Word Learning test and Delayed Picture-Word Learning; and Instrumental Activities of Daily Living), after adjusting for sex, age, WMC volume, infarction, and the presence of CMBs at other anatomic regions. The associations of this post-hoc analysis should be interpreted with caution: as the authors acknowledged, the selected population included in the PROSPER study consists of subjects with or at high risk for developing vascular disease and might not be representative of the general elderly populations or stroke populations [46]. The inclusion criteria may have led to a bias in favour of atherosclerotic cerebrovascular disease and a lower prevalence of CAA. The Radboud (RUN-DMC) study recently investigated 500 nondemented elderly patients with small vessel disease (defined by the presence of lacunar infarcts and/or WMC) [45]. In analyses adjusted for age, sex, education, depressive symptoms, total brain volume, WMC volume, and lacunar and territorial infarcts, they found that presence and number of CMBs were related to global cognitive function, psychomotor speed and attention. Relations with cognitive performance were mainly driven by frontal, temporal, and strictly deep located CMBs [45]. In CADASIL, a “pure” form of cerebral small vessel disease and vascular dementia (with affected individuals progressing to dementia at 40–60 years of age), in which the presence of coexistent AD pathology and CAA is unlikely, CMBs were associated with lower MMSE scores [48,49], but had no independent effects except for a possible strategic effect when located in the caudate nucleus [48]. For a more comprehensive discussion on the role of CMBs in cognitive function in CADASIL the interested reader is referred to a recent summary of this field [50]. There are very few prospective studies addressing the prognostic value of CMBs for longer term cognitive function. CMBs may be a useful prognostic marker for post-stroke cognitive decline, which affects around 60% of stroke survivors at three months and has been hypothesized to be related to pre-existing small vessel damage or neurodegenerative pathology [51]. Longitudinal data from a small 5-year follow-up study of stroke patients from our neurovascular clinic supports this hypothesis: the presence of baseline CMBs predicted frontal-executive impairment at follow-up (OR 8.40, 95%CI 1.27–55.39, p = 0.027), suggesting that they may help to identify individuals at highest risk of cognitive decline [52], and perhaps target aggressive preventative therapy.

4. Conclusions and future research directions There are several challenges in interpreting the studies reporting associations between CMBs and cognition so far (Table 2): (a) most of them focused on different cohorts (e.g. varied disease inception points, different severities of cerebrovascular disease) in a range of clinical settings (e.g. population or hospital), which may affect generalizability to other populations; (b) some have used the presence of one or more CMBs, although the biological significance of a single lesion is unclear and a graded relationship between CMBs and cognition would strengthen the biological plausibility of a link; (c) almost all studies are cross-sectional so cannot prove causation; and (d) the cognitive tests used were different between studies and were sometimes insensitive to subtle or focal cognitive deficits (e.g. the MMSE). Nevertheless, based on the available evidence some preliminary conclusions can be drawn: (a) Evidence suggests that CMBs are not clinically “silent” for cognition in a range of populations: that a relationship between CMBs and cognition even with insensitive cognitive measures in some studies suggests a clinically relevant impact of CMBs on cognition. (b) A pattern emerging from cerebrovascular cohorts is the association of CMBs with executive and speed and attention

dysfunction, although there is considerable heterogeneity in the tests used and the finding is not consistent. (c) Regional associations between CMBs and cognition are also inconsistent, which may be related to differences in the clinical cohorts. For example, associations between CAA (suggested by multiple lobar CMBs) and cognition might be attenuated by the high prevalence of vascular risk factors in some studies (e.g. the PROSPER study [46]). Some large studies [41,43] suggest that lobar CMBs have a strong link to processing speed or executive function, consistent with a role for CAA pathology in cognitive impairment. (d) The potential mechanisms underlying associations between CMBs and cognition remain uncertain. Given the small amount of tissue damage associated with CMBs, a direct effect of CMBs on local tract integrity and disconnection seems unlikely. Nevertheless, CMBs may be a new link to explore how small vessel diseases (especially CAA) influence neurodegeneration. Further studies of CMBs in large carefully controlled representative cohorts and more sophisticated analyses, particularly in conjunction with other imaging manifestations of cerebrovascular disease and neurodegeneration are needed to clarify their potential relevance in cognitive dysfunction. Future research directions are summarised in Table 3. For the moment, it seems clear that CMBs should be an important component of future studies investigating mechanisms of cognitive impairment, particularly in elderly populations. Conflict of interest None. Acknowledgements and role of funding source Andreas Charidimou receives research support from the Greek State Scholarship Foundation. David Werring is supported by a Department of Health and Higher Educational and Funding Council for England Clinical Senior Lectureship Award. This work was undertaken at UCLH/UCL who received a proportion of funding from the UK Department of Health's National Institute for Health Research Biomedical Research Centers funding scheme (UCLH/UCL Comprehensive Biomedical Research Trust). The funding sources had no role in any study design, collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Table 3 Cerebral microbleeds (CMBs) and cognition: Future research directions. ➢More pathological correlations to understand relation between CMB anatomical distribution and underlying angiopathies ➢Consistent use of appropriate test batteries rather than screening tests of global cognitive function such as the MMSE ➢Standardization of MRI acquisitions parameters and terminology ➢Incorporation of newer MRI methods sensitive to CMBs– e.g. susceptibilityweighted imaging (SWI) ➢Investigation of multiple imaging markers of cerebrovascular disease and neurodegeneration: ○ Relevance of other types of bleeding (e.g. superficial cortical siderosis – commonly associated with CAA) ○ Significance of cerebral microinfarcts ○ Role of medial temporal lobe atrophy as a marker of Alzheimer pathology ➢Automated identification of CMBs, white matter changes and atrophy ➢Lesion-symptom mapping ➢Use of quantitative MRI techniques (e.g. diffusion tensor imaging or magnetization transfer imaging) to investigate tissue damage not visible on conventional structural MRI

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