Association Between Plasma Biomarkers of Amyloid, Tau, and Neurodegeneration with Cerebral Microbleeds

Article type: Research Article

Authors: McCarter, Stuart J.^{a; b; *} | Lesnick, Timothy G.^{c; 1} | Lowe, Val J.^d | Rabinstein, Alejandro A.^a | Przybelski, Scott A.^{c; 1} | Algeciras-Schimnich, Alicia^e | Ramanan, Vijay K.^a | Jack Jr., Clifford R.^d | Petersen, Ronald C.^a | Knopman, David S.^a | Boeve, Bradley F.^a | Kantarci, Kejal^d | Vemuri, Prashanthi^d | Mielke, Michelle M.^{a; c} | Graff-Radford, Jonathan^a

Affiliations: [a] Department of Neurology, Mayo Clinic, Rochester, MN, USA | [b] Center for Sleep Medicine, Mayo Clinic, Rochester, MN, USA | [c] Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA | [d] Department of Radiology, Mayo Clinic, Rochester, MN, USA | [e] Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

Correspondence: [*] Correspondence to: Stuart J. McCarter, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1 507 284 2511; Fax: +1 507 538 6012; E-mail: mccarter.stuart@mayo.edu.

Note: [1] Performed statistical analysis.

Abstract: Background:Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting. Objective:To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs. Methods:712 participants from the Mayo Clinic Study of Aging with T2* GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models. Results:Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8–116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC –53.0). Conclusion:Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

Keywords: Amyloid-β, biomarker, cerebral microbleed, PiB-PET, plasma, tau

DOI: 10.3233/JAD-220158

Journal: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1537-1547, 2022