Genetic associations with brain microbleeds

Maxwell, Susanne; Jackson, Caroline; Paternoster, Lavinia; Cordonnier, Charlotte; Thijs, Vincent; Salman, Rustam Al-Shahi; Sudlow, Cathie

doi:10.1212/wnl.0b013e318224afa3

Cited by 64 publications

(48 citation statements)

References 30 publications

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“…31 The APOE ε4 gene was associated with the presence of strictly lobar CMBs. 31,32 Overall, prevalence of CMBs in our study confirms the age-stratified prevalence of CMBs reported in the Rotterdam Scan Study (mean age of our study population, 66 years; age range, 46-85 years). 31 Prevalence of CMBs was similar in offspring and control subjects, suggesting that the propensity of familial longevity is not associated with a lower susceptibility to CMBs.…”

supporting

confidence: 89%

Lower Susceptibility to Cerebral Small Vessel Disease in Human Familial Longevity

Altmann-Schneider

Slagboom

Westendorp

et al. 2013

Stroke

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Subjects were included from the Leiden Longevity Study, which has been described in more detail elsewhere. 13 In short, 421 Dutch white families were enrolled in the study between 2002 and 2006 based on the following inclusion criteria: (1) there were at least 2 living Background and Purpose-On MRI, cerebral white matter lesions, lacunar infarcts, and cerebral microbleeds are common imaging correlates of cerebral small vessel damage in apparently healthy elderly individuals. We investigated whether middle-aged to elderly offspring of nonagenarian siblings, who are predisposed to become long-lived as well, have a lower prevalence of white matter lesions, lacunar infarcts, and cerebral microbleeds than control subjects. Methods-All subjects were from the Leiden Longevity Study. In this study, middle-aged to elderly offspring of nonagenarian siblings, who are predisposed to become long-lived as well, were contrasted to their spouses. Cerebral small vessel disease was assessed using 3-T MRI. Results-Offspring were less likely to have severe periventricular frontal caps (odds ratio [OR], 0.3; 95% confidence interval[CI], 0.1-1.1; P trend=0.01) and severe periventricular bands (OR, 0.4; 95% CI, 0.2-0.8; P trend=0.02). Moreover, offspring were less likely to have frontal (OR, 0.4; 95% CI, 0.2-0.9; P trend=0.05), parietal (OR, 0.4; 95% CI, 0.1-0.9; P trend=0.001), temporal (OR, 0.3; 95% CI, 0.1-0.8]; P trend=0.004), and occipital subcortical white matter lesions (OR, 0.3; 95% CI, 0.1-0.6; P trend=0.001). Prevalence of lacunar infarcts also was lower in offspring (OR, 0.3; 95% CI, 0.1-1.1; P=0.07). Prevalence of microbleeds was not significantly different in offspring and control subjects. Conclusions-Exceptional familial longevity is associated with a lower susceptibility to white matter lesions and lacunar infarcts, but not cerebral microbleeds. (Stroke. 2013;44:9-14.)

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supporting

confidence: 89%

Lower Susceptibility to Cerebral Small Vessel Disease in Human Familial Longevity

Altmann-Schneider

Slagboom

Westendorp

et al. 2013

Stroke

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“…56 In line with our results, they found that APOE e4 carriers had a significantly increased risk of having at least one CMB compared to APOE e33 carriers, 56 with a stronger association for lobar CMB. They did not find a significant relationship between APOE e2 and CMB, regardless of their location.…”

supporting

confidence: 88%

APOE genotype and MRI markers of cerebrovascular disease

et al. 2013

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Objective: We aimed to examine the association of APOE e genotype with MRI markers of cerebrovascular disease (CVD): white matter hyperintensities, brain infarcts, and cerebral microbleeds.Methods: We performed a systematic review and meta-analysis of 42 cross-sectional or longitudinal studies identified in PubMed from 1966 to June 2012 (n 5 29,965). This included unpublished data from 3 population-based studies: 3C-Dijon, Framingham Heart Study, and Sydney Memory and Ageing Study. When necessary, authors were contacted to provide effect estimates for the meta-analysis. Conclusions: APOE e4 and APOE e2 were associated with increasing burden in MRI markers for both hemorrhagic and ischemic CVD. While the association of APOE e4 with an increased burden of CVD could be partly contributing to the relationship between APOE e4 and AD, APOE e2 was associated with MRI markers of CVD in the opposite direction compared to AD. The e4 allele of the APOE gene is a major risk factor for dementia and Alzheimer disease (AD). Results 1-6The association of APOE with cerebrovascular disease (CVD) is more controversial.7 APOE e4 is a risk factor for cerebral amyloid angiopathy (CAA), a major determinant of intracerebral hemorrhage (ICH) in older individuals.1 Recent data from the International Stroke Genetics Consortium suggest an association of APOE e4 with an increased risk of ICH, mostly lobar, 8 and an association of the APOE e2 allele with an increased risk and size of lobar ICH. 8,9 Whether the epsilon polymorphism is also associated with an increased risk of ischemic stroke and MRI markers of CVD is unclear.7 MRI markers of CVD-white matter hyperintensities (WMH), brain infarcts (BI), and cerebral microbleeds (CMB)-are powerful predictors of stroke and dementia.10-13 They are highly prevalent in older community-dwelling persons, [14][15][16] and can be assessed noninvasively and quantitatively in large population-based samples. Dissecting the relationship between APOE and MRI

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“…In terms of CMB, this report does not align with recent meta‐analyses that concluded significant deleterious effects of APOE ε4 6, 7. Of those meta‐analyses, Schilling et al .…”

Section: Discussioncontrasting

confidence: 85%

“…6 (‘healthy’ n = 5387; P = 0·002) and Maxwell et al . 7 (total n = 7351; P < 0·01). These two reports also had a degree of overlapping datasets.…”

Section: Introductionmentioning

confidence: 98%

APOE/TOMM40 Genetic Loci, White Matter Hyperintensities, and Cerebral Microbleeds

Lyall

Maniega

Harris

et al. 2015

International Journal of Stroke

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BackgroundTwo markers of cerebral small vessel disease are white matter hyperintensities and cerebral microbleeds, which commonly occur in people with Alzheimer's disease.Aim and/or hypothesisTo test for independent associations between two Alzheimer's disease‐susceptibility gene loci – APOE ε and the TOMM 40 ‘523’ poly‐T repeat – and white matter hyperintensities/cerebral microbleed burden in community‐dwelling older adults.MethodsParticipants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε and TOMM 40 523, and detailed structural brain magnetic resonance imaging at a mean age of 72·70 years (standard deviation = 0·7; range = 71–74).ResultsNo significant effects of APOE ε or TOMM 40 523 genotypes on white matter hyperintensities or cerebral microbleed burden were found amongst 624 participants.ConclusionsLack of association between two Alzheimer's disease susceptibility gene loci and markers of cerebral small vessel disease may reflect the relative health of this population compared with those in other studies in the literature.

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Genetic associations with brain microbleeds

Abstract: Given the known associations of APOE alleles with lobar intracerebral hemorrhage and cerebral amyloid angiopathy, these findings support the concept that strictly lobar BMBs may be an imaging biomarker of cerebral amyloid angiopathy.

Cited by 64 publications

References 30 publications

Lower Susceptibility to Cerebral Small Vessel Disease in Human Familial Longevity

Lower Susceptibility to Cerebral Small Vessel Disease in Human Familial Longevity

APOE genotype and MRI markers of cerebrovascular disease

APOE/TOMM40 Genetic Loci, White Matter Hyperintensities, and Cerebral Microbleeds

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