Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease
Nelly Joseph‐Mathurin, Guoqiao Wang, Kejal Kantarci, Clifford R. Jack, Eric McDade, Jason Hassenstab, Tyler Blazey, Brian A. Gordon, Yi Su, Gengsheng Chen, Parinaz Massoumzadeh, Russ C. Hornbeck, Ricardo Allegri, Beau M. Ances, Sarah Berman, Adam M. Brickman, William S. Brooks, David M. Cash, Jasmeer P. Chhatwal, Helena C. Chui, Stephen Correia, Carlos Cruchaga, Martin R. Farlow, Nick C. Fox, Michael Fulham, Bernardino Ghetti, Neill R. Graff‐Radford, Keith A. Johnson, Celeste M. Karch, Christoph Laske, Athene Lee, Johannes Levin, Colin L. Masters, James M. Noble, Antoinette O’Connor, Richard J. Perrin, Gregory M. Preboske, John M. Ringman, Christopher C. Rowe, Stephen Salloway, Andrew J. Saykin, Peter R. Schofield, Hiroyuki Shimada, Mikio Shoji, Kazushi Suzuki, Victor L. Villemagne, Chengjie Xiong, Igor Yakushev, John C. Morris, Randall J. Bateman, Tammie L.S. Benzinger, Douglas Galasko, Takeshi Ikeuchi, Mathias Jucker, Jae‐Hong Lee, Ralph N. Martins, Martin N. Rossor, Raquel Sanchez- Valle
Abstract
OBJECTIVE: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD). METHODS: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease. RESULTS: ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year). CONCLUSION: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.