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O2‐01‐05: A cortical signature of familial Alzheimer's disease: Cross‐sectional and longitudinal study of presymptomatic changes
Author(s) -
Weston Philip S.J.,
Lehmann Manja,
Nicholas Jennifer M.,
Harper Lorna,
Ryan Natalie S.,
MacPherson Kirsty,
Woodward Felix,
Schott Jonathan M.,
Rossor Martin N.,
Fox Nick C.
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.07.134
Subject(s) - precuneus , supramarginal gyrus , entorhinal cortex , inferior parietal lobule , atrophy , medicine , cortex (anatomy) , longitudinal study , psychology , neuroscience , hippocampus , cardiology , pathology , cognition , functional magnetic resonance imaging
Background: White matter hyperintensities (WMH) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans thought to reflect small vessel cerebrovascular disease. Previous work demonstrated that increased WMH volume is associated with risk and progression of AD. According to current pathogenic models, these observations are interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not a core feature of AD. We examined the severity and distribution of WMH in presymptomatic presenilin 1, presenilin 2, and amyloid precursor protein mutation carriers to determine the extent towhich small vessel cerebrovascular disease manifests in individuals genetically determined to develop AD. Methods: Participants (n1⁄4299, mean age1⁄439.03+10.13, 56% women) came from the Dominantly Inherited Alzheimer’s Network (DIAN), where there is a 100% probability of developing AD if an autosomal dominant, fully penetrant mutation for AD is present. The DIAN study includes both symptomatic and asymptomatic participants; 61.5% carried a genetic mutation for AD. We calculated the estimated years from expected symptom onset by subtracting the parent’s age at symptom onset from the participant’s age. Baseline high-resolution T2-weighted MRI data were analyzed with inhouse developed software to determine the total and regional (by lobe) WMH volume. Mixed effects piecewise linear regression was used to examine the total and regional WMH volumes with respect to estimated years from symptom onset, controlling for participant age, APOE-ε4, and participant family as a random factor. Results: Total WMH volumes appeared to increase significantly approximately 6 years prior to expected symptom onset in mutation carriers (Mutation Status X estimated age of onset interaction, estimate1⁄40.03, t1⁄42.06, p1⁄40.040, knot1⁄4-6). These effects were most dramatic in the parietal and occipital lobes, where there were changes in mutation carriers compared with non-carriers as much as 18 years prior to estimated symptom onset. Conclusions: Autosomal dominant AD is associated with increased small vessel cerebrovascular disease well before expected symptom onset. The findings highlight the possibility that small vessel cerebrovascular disease is a core feature of AD, a potential therapeutic target, and a factor that should be incorporated into pathogenic models of the disease. Support: NIH/NIA AG032438.