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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We present an approach for head MR-based attenuation correction (MR-AC) based on the Statistical Parametric Mapping (SPM8) software that combines segmentation- and atlas-based features to provide a robust technique to generate attenuation maps (µ-maps) from MR data in integrated PET/MR scanners. Methods Coregistered anatomical MR and CT images acquired in 15 glioblastoma subjects were used to generate the templates. The MR images from these subjects were first segmented into 6 tissue classes (gray and white matter, cerebro-spinal fluid, bone and soft tissue, and air), which were then non-rigidly coregistered using a diffeomorphic approach. A similar procedure was used to coregister the anatomical MR data for a new subject to the template. Finally, the CT-like images obtained by applying the inverse transformations were converted to linear attenuation coefficients (LACs) to be used for AC of PET data. The method was validated on sixteen new subjects with brain tumors (N=12) or mild cognitive impairment (N=4) who underwent CT and PET/MR scans. The µ-maps and corresponding reconstructed PET images were compared to those obtained using the gold standard CT-based approach and the Dixon-based method available on the Siemens Biograph mMR scanner. Relative change (RC) images were generated in each case and voxel- and region of interest (ROI)-based analyses were performed. Results The leave-one-out cross-validation analysis of the data from the 15 atlas-generation subjects showed small errors in brain LACs (RC=1.38%±4.52%) compared to the gold standard. Similar results (RC=1.86±4.06%) were obtained from the analysis of the atlas-validation datasets. The voxel- and ROI-based analysis of the corresponding reconstructed PET images revealed quantification errors of 3.87±5.0% and 2.74±2.28%, respectively. The Dixon-based method performed substantially worse (the mean RC values were 13.0±10.25% and 9.38±4.97%, respectively). Areas closer to skull showed the largest improvement. Conclusion We have presented an SPM8-based approach for deriving the head µ-map from MR data to be used for PET AC in integrated PET/MR scanners. Its implementation is straightforward and only requires the morphological data acquired with a single MR sequence. The method is very accurate and robust, combining the strengths of both segmentation- and atlas-based approaches while minimizing their drawbacks.

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The cortical distribution of amyloid-β plaques in Alzheimer’s disease strikingly resembles frontal-parietal intrinsic functional connectivity networks. Using a novel method to trace the distribution of amyloid-β plaques within single patients, Myers et al. reveal a marked negative effect on intrinsic connectivity in several networks that have not typically been investigated.

IMPORTANCE Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. OBJECTIVE To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. MAIN OUTCOMES AND MEASURES Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤−1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. RESULTS Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%–7%] at 72 years and 21% [95% CI, 10%–33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, −1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%–20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%–17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. CONCLUSIONS AND RELEVANCE Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.