Ringman, John M.

AbstractIntroductionFour less well‐studied but promising “emerging” cerebrospinal fluid (CSF) biomarkers are elevated in late‐onset Alzheimer disease (AD): neurogranin, synaptosomal‐associated protein‐25 (SNAP‐25), visinin‐like protein 1 (VILIP‐1), and chitinase‐3‐like protein 1 (YKL‐40).MethodsCSF neurogranin, SNAP‐25, VILIP‐1, and YKL‐40 were measured in families carrying autosomal‐dominant AD mutations.ResultsThe four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP‐25, VILIP‐1, and YKL‐40 were altered very early in the AD time course, approximately 15–19 years before estimated symptom onset. All CSF biomarkers predicted important AD‐related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset.DiscussionEarly abnormalities in CSF tTau, pTau, SNAP‐25, VILIP‐1, and YKL‐40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.

Aβ deposition in the basal ganglia is common in autosomal dominant Alzheimer’s disease. Vöglein et al. report an increased severity of motor symptoms in autosomal dominant versus sporadic disease in advanced disease stages. Motor symptoms are more severe in post-codon 200 presenilin 1 mutation carriers and correlate with basal ganglia Aβ.

Abstract Introduction Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B–based and florbetapir‐based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter‐individual variability of the two tracers were compared using multivariate linear models both cross‐sectionally and longitudinally. Results Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.

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.