Browsing by Author "Niimi, Yoshiki"

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    Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage
    (Wiley, 2024) Joseph-Mathurin, Nelly; Feldman, Rebecca L.; Lu, Ruijin; Shirzadi, Zahra; Toomer, Carmen; Saint Clair, Junie R.; Ma, Yinjiao; McKay, Nicole S.; Strain, Jeremy F.; Kilgore, Collin; Friedrichsen, Karl A.; Chen, Charles D.; Gordon, Brian A.; Chen, Gengsheng; Hornbeck, Russ C.; Massoumzadeh, Parinaz; McCullough, Austin A.; Wang, Qing; Li, Yan; Wang, Guoqiao; Keefe, Sarah J.; Schultz, Stephanie A.; Cruchaga, Carlos; Preboske, Gregory M.; Jack, Clifford R., Jr.; Llibre-Guerra, Jorge J.; Allegri, Ricardo F.; Ances, Beau M.; Berman, Sarah B.; Brooks, William S.; Cash, David M.; Day, Gregory S.; Fox, Nick C.; Fulham, Michael; Ghetti, Bernardino; Johnson, Keith A.; Jucker, Mathias; Klunk, William E.; la Fougère, Christian; Levin, Johannes; Niimi, Yoshiki; Oh, Hwamee; Perrin, Richard J.; Reischl, Gerald; Ringman, John M.; Saykin, Andrew J.; Schofield, Peter R.; Su, Yi; Supnet-Bell, Charlene; Vöglein, Jonathan; Yakushev, Igor; Brickman, Adam M.; Morris, John C.; McDade, Eric; Xiong, Chengjie; Bateman, Randall J.; Chhatwal, Jasmeer P.; Benzinger, Tammie L. S.; Dominantly Inherited Alzheimer Network; Pathology and Laboratory Medicine, School of Medicine
    Introduction: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. Methods: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. Results: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. Discussion: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. Highlights: Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.