Cerebral Amyloid Angiopathy Burden and Cerebral Microbleeds: Pathological Evidence for Distinct Phenotypes

Article type: Research Article

Authors: Graff-Radford, Jonathan^{a; *} | Lesnick, Timothy G.^b | Mielke, Michelle M.^{a; b} | Constantopoulos, Eleni^c | Rabinstein, Alejandro A.^a | Przybelski, Scott A.^b | Vemuri, Prashanthi^d | Botha, Hugo^a | Jones, David T.^a | Ramanan, Vijay K.^a | Petersen, Ronald C.^a | Knopman, David S.^a | Boeve, Bradley F.^a | Murray, Melissa E.^f | Dickson, Dennis W.^f | Jack, Clifford R.^d | Kantarci, Kejal^d | Reichard, R. Ross^c

Affiliations: [a] Department of Neurology, Mayo Clinic, Rochester, MN, USA | [b] Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA | [c] Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA | [d] Department of Radiology, Mayo Clinic, Rochester, MN, USA | [e] Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA | [f] Department of Pathology and Laboratory Medicine, Mayo Clinic, Jacksonville, FL, USA

Correspondence: [*] Correspondence to: Jonathan Graff-Radford, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1 507 284 2511; Fax: +1 507 538 6012; E-mail: [email protected].

Abstract: Background:The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia. Objective:To determine whether CMBs on antemortem MRI correlate with CAA. Methods:We reviewed 54 consecutive participants with antemortem T2*GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By a clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores from these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs. Results:MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal/cortical components correlated with number of lobar CMBs. Conclusion:Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOE ɛ4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA.

Keywords: Alzheimer’s disease, capillaries, cerebral amyloid angiopathy, neuropathology

DOI: 10.3233/JAD-201536

Journal: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 113-122, 2021