Bateman, Randall J.

AbstractIntroduction18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C‐Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET.MethodsFDG, early frames of PiB images, and relative PiB delivery rate constants (PiB‐R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross‐sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history.ResultsMetabolism and perfusion images were spatially correlated. Regional PiB‐R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity.DiscussionHypometabolism estimated by PiB‐R1 may provide a measure of brain perfusion without increasing radiation exposure.

AbstractIntroductionLittle is known about effects of physical activity (PA) in genetically driven early‐onset autosomal dominant Alzheimer's disease (AD).MethodsA total of 372 individuals participating at the Dominantly Inherited Alzheimer Network study were examined to evaluate the cross‐sectional relationship of PA with cognitive performance, functional status, cognitive decline, and AD biomarkers in cerebrospinal fluid. Mutation carriers were categorized as high or low exercisers according to WHO recommendations.ResultsMutation carriers with high PA showed significantly better cognitive and functional performance and significantly less AD‐like pathology in cerebrospinal fluid than individuals with low PA. Mutation carriers with high PA scored 3.4 points better on Mini Mental State Examination at expected symptom onset and fulfilled the diagnosis of very mild dementia 15.1 years later compared with low exercisers.DiscussionThese results support a beneficial effect of PA on cognition and AD pathology even in individuals with genetically driven autosomal dominant AD.

ObjectivePrevious studies suggest that the brain‐derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross‐sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181, and whether these increases are associated with accelerated brain volume loss and memory decline.MethodsA total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network.ResultsIn mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181increases (6×) than Val66 homozygotes.BDNFdid not influence rates of cortical β‐amyloid accumulation or change in CSF Aβ42levels in mutation carriers. In mutation noncarriers,BDNFgenotype had no effect on change in cognition, brain volume, cortical β‐amyloid accumulation, or change in any CSF measures of tau, ptau181, and CSF Aβ42.InterpretationAs in sporadic AD, the deleterious effects of β‐amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. TheBDNFVal66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424–435