Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment

Objective Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. Methods We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [11C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. Results Parietal and occipital lobar CMBs counts were higher in PiB+ ADCI with moderate WMH than PiB+ ADCI with minimal WMH, whereas PiB- patients with SVCI (ie, pure SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001). Interpretation Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs. Ann Neurol 2013;73:584-593This study was supported by the Korean Healthcare Technology R&D Project (A102065), a Korea Science and Engineering Foundation (KOSEF) National Research Laboratory (NRL) program grant (MEST; 20110028333), Samsung Medical Center (CRL-108011 and CRS110-14-1), and the Converging Research Center Program through the Ministry of Education, Science, and Technology (2010K001054).M.W.W.: scientific advisory boards, Lilly, Araclon and Institut Catala de Neurociencies Aplicades, Gulf War Veterans Illnesses Advisory Committee (VACO), Biogen Idec, Pfizer, BOLT International; consulting, Alzheimer's Drug Discovery Foundation (ADDF), Araclon, AstraZeneca, Bayer HealthCare, Biogen Idec, Easton Associates, Exonhit Therapeutics, Harvard University, INC Research, inThought, Ipsen, Janssen, KLJ Associates, Medivation/Pfizer, Pfizer, Servier, Synarc, TauRx Therapeutics, University of California at Los Angeles (UCLA); travel expenses, AD PD meeting, AstraZeneca, CHRU-Hopital Roger Salengro, CTAD (Clinical Trials on Alzheimer's Disease), CTAD ANT Congress, Danone Trading, Geneva University Hospitals, Institut Catala de Neurociencies Aplicades, Ipsen, Lilly, MCI Group (France), Neuroscience School of Advanced Studies (NSAS), NeuroVigil, Novartis, Paris University, Paul Sabatier University, Pfizer, Siemens, Tohoku University, Travel eDreams, University of California at San Diego-ADNI, University of New Mexico School of Medicine; editorial advisory boards, Alzheimer's & Dementia, MRI; honoraria, Danone Trading, Insitut Catala de Neurociencies Aplicades, NeuroVigil, Pfizer, Tohoku University; commercial entities research support, Merck, Avid; government entities research support, DOD, VA; stock options, Synarc, Elan. Organizations contributing to the Foundation for NIH and thus to the National Institute on Aging-funded Alzheimer's Disease Neuroimaging Initiative: Abbott, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Anonymous Foundation, AstraZeneca, Bayer HealthCare, BioClinica (ADNI 2), Bristol-Myers Squibb, Cure Alzheimer's Fund, Eisai, Elan, Gene Network Sciences, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly & Company, Medpace, Merck, Novartis, Pfizer, Roche, Schering Plough, Synarc, Wyeth