Evidence before this study Using PubMed and Google Scholar the authors reviewed prior work on longitudinal neuroimaging markers of Alzheimer pathology with a focus on autosomal dominant Alzheimer disease (ADAD). We searched for all articles prior to October 31 st , 2017 with no language restrictions for the keywords Alzheimer's, Alzheimer, longitudinal, positron emission tomography, PET, MRI, atrophy, FDG, hypometabolism, familial, and autosomal. Theories proposed initially in 2010 by Jack and colleagues and revised in 2013 posited temporal trajectories of Alzheimer biomarkers relative to each other and clinical decline. Work by Bateman and colleagues in 2012, Benzinger and colleagues in 2013, and Fleisher and colleagues in 2015 depict such temporal ordering of biomarkers in ADAD populations derived from cross-sectional analyses. There was also a small subset of longitudinal ADAD studies, but these had one or more limitation such as small populations (n<50), examination of only one biomarker, not accounting for regional differences or correlations in the brain, or had a short duration of longitudinal followup. Added value of this studyOur study presents the first known work examining both the longitudinal temporal trajectories and spatial patterns of Alzheimer pathology in ADAD cohorts using neuroimaging. This work also presents the largest known cohort to date of ADAD individuals studied longitudinally with multiple neuroimaging biomarkers. Longitudinal analyses can provide a more accurate and powerful way to model the temporal emergence of pathology in ADAD. We find that mutation carriers first display Aβ accumulation, followed by hypometabolism, and finally structural atrophy; this is consistent with theoretical models and cross-sectional estimates from ADAD. Most importantly we consider such temporal relationships not in one singular summary measure, but characterize these trajectories throughout the brain. We found that the accrual of pathology varied throughout the brain and by modality in terms of the time of initial emergence and the rates of longitudinal change. These findings suggest region specific vulnerabilities to β-amyloidosis, metabolic decline, and atrophy that change over the course of the disease. Implications of all the available evidenceOur results build upon existing evidence characterizing biomarkers in clinical and preclinical Alzheimer disease. Our findings suggest that imaging biomarkers follow a sequential pattern, with β-amyloidosis, hypometabolism, and structural atrophy emerging more than twenty, fifteen, and ten years respectively before the expected onset of dementia. Although there is a general hierarchical pattern, there was considerable regional heterogeneity. Most commonly, regions demonstrated an increase in β-amyloidosis and structural atrophy, but there was not evidence of metabolic declines. Further, rather than being homogenous, the same biomarker often demonstrates different longitudinal trajectories across brain regions. Characterizing the temporal and regional dynamics...

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Objective White matter hyperintensities(WMH) are areas of increased signal on magnetic resonance imaging(MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer’s disease(AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically-determined to develop AD. Methods The study comprised participants(n=299, age=39.03±10.13) from the Dominantly Inherited Alzheimer Network, including 184(61.5%) with a mutation that results in AD and 115(38.5%) first-degree relatives who were non-carrier controls. We calculated the estimated years from expected symptom onset(EYO) by subtracting the affected parent’s symptom onset age from the participant’s age. Baseline MRI data were analyzed for total and regional WMH. Mixed effects piecewise linear regression was used to examine WMH differences between carriers and non-carriers with respect to EYO. Results Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years prior to expected symptom onset. The effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years prior to estimated onset. Interpretation Autosomal dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMH are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease.

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