Marina Dauar

Dissociation between Brain Amyloid Deposition and Metabolism in Early Mild Cognitive Impairment

Background The hypothetical model of dynamic biomarkers for Alzheimer’s disease (AD) describes high amyloid deposition and hypometabolism at the mild cognitive impairment (MCI) stage. However, it remains unknown whether brain amyloidosis and hypometabolism follow the same trajectories in MCI individuals. We used the concept of early MCI (EMCI) and late MCI (LMCI) as defined by the Alzheimer’s disease Neuroimaging Initiative (ADNI)-Go in order to compare the biomarker profile between EMCI and LMCI. Objectives To examine the global and voxel-based neocortical amyloid burden and metabolism among individuals who are cognitively normal (CN), as well as those with EMCI, LMCI and mild AD. Methods In the present study, 354 participants, including CN (n = 109), EMCI (n = 157), LMCI (n = 39) and AD (n = 49), were enrolled between September 2009 and November 2011 through ADNI-GO and ADNI-2. Brain amyloid load and metabolism were estimated using [18F]AV45 and [18F]fluorodeoxyglucose ([18F]FDG) PET, respectively. Uptake ratio images of [18F]AV45 and [18F]FDG were calculated by dividing the summed PET image by the median counts of the grey matter of the cerebellum and pons, respectively. Group differences of global [18F]AV45 and [18F]FDG were analyzed using ANOVA, while the voxel-based group differences were estimated using statistic parametric mapping (SPM). Results EMCI patients showed higher global [18F]AV45 retention compared to CN and lower uptake compared to LMCI. SPM detected higher [18F]AV45 uptake in EMCI compared to CN in the precuneus, posterior cingulate, medial and dorsal lateral prefrontal cortices, bilaterally. EMCI showed lower [18F]AV45 retention than LMCI in the superior temporal, inferior parietal, as well as dorsal lateral prefrontal cortices, bilaterally. Regarding to the global [18F]FDG, EMCI patients showed no significant difference from CN and a higher uptake ratio compared to LMCI. At the voxel level, EMCI showed higher metabolism in precuneus, hippocampus, entorhinal and inferior parietal cortices, as compared to LMCI. Conclusions The present results indicate that brain metabolism remains normal despite the presence of significant amyloid accumulation in EMCI. These results suggest a role for anti-amyloid interventions in EMCI aiming to delay or halt the deposition of amyloid and related metabolism impairment.

Association between cortical thickness and CSF biomarkers in mild cognitive impairment and Alzheimer’s disease

Sara Mohades, Jonathan Dubois, Maxime Parent, Laksanun Cheewakriengkrai, Jared Rowley, Monica Shin, Thomas Beaudry, Simon Eskildsen, Antoine Leuzy, Marina Tedeschi Dauar, Vladimir Fonov, Serge Gauthier, Pedro RosaNeto, McGill Center-McGill Centre for Studies in Aging, Montreal, Quebec, Canada; McGill Universtiy, Montreal, Quebec, Canada; McGill University, Verdun, Quebec, Canada; McGill Centre for Studies in Aging, Montreal, Quebec, Canada; Aarhus University, Aarhus, Denmark; Montreal Neurological Institute, Montreal, Quebec, Canada; Alzheimer’s Disease Research Unit, McGill Center for Studies in Aging, Montreal, Quebec, Canada; McGill Universtiy-McGill Center for Studies in Aging, Montreal, Quebec, Canada. Contact e-mail: sara.mohades@gmail.com

In vivo characterization of glutamatergic vulnerability in behavioral variant FTD: An [11C]ABP688 PET/ VBM /DBM study

Background: Pathological examination of the brain is used to confirm Alzheimer’s disease (AD) diagnosis. In AD, the second earliest site where pathology occurs after the entorhinal cortex is the hippocampus. Hippocampal atrophy is the most established AD imaging biomarker.Methods:Temporal lobes of 10 deceased AD subjects and 5 deceased cognitively normal controls (NC) were obtained from the AD Research Center Brain Bank at the University of California, Los Angeles and scanned with a Bruker Biospec 7 Tesla MRI machine at the UCLA Brain Mapping Center. Hippocampal MRI scans were manually registered to the International Consortium for Brain Mapping template. Hippocampal structures were manually traced and converted into 3D mesh models. Radial distance maps and volumes were computed for each hippocampal structure. Temporal lobes were sectioned coronally in 5mm blocks, embedded in paraffin and cut into 6 mm slices, mounted, and stained for amyloid beta 40, tau, and Cresyl Violet. Aperio ScanScope CS was used to scan the slides digitally at 20x. The CA1 hippocampal subfield was manually traced. To quantify disease burden in the CA1 subfield, in-house nuclear and positively immunostaining pixel algorithms were used to determine neuronal counts and amyloid beta 40 and tau burden. Results: We found significant correlations between amyloid beta 40 burden and hippocampal volume (r1⁄4-0.55, p corrected 1⁄40.035) andmean hippocampal radial distance (r1⁄4-0.58, p corrected1⁄40.025). In addition, neuronal count per CA1 m m 2 was positively correlated with mean radial distance (r1⁄40.61, p corrected 1⁄40.016). Conclusions: As expected, our findings suggest that amyloid burden is inversely related to hippocampal volume and radial distance. Lower CA1 neuronal count also showed a significant association with hippocampal atrophy. The observed associations provide pathological confirmation of hippocampal morphometry as a valid biomarker for AD pathology.

Confrontation naming deficits are associated with amyloidosis in early MCI and with synaptic dysfunction in late MCI and Alzheimer's disease: An [18F]AV45/[18F]FDG-PET study

microstructure 4. Of specific interest in this study is the extra-axonal radial diffusivity (i.e., De,t), an index of myelin integrity. Regions of interest (ROI’s) in the genu, body, and splenium of the CC were drawn based on a standardWM atlas, and their parameter values were correlated with neuropsychological measures of CPS (i.e., WAIS Digit-Symbol Coding [DSC] and Trails A). Results: Strong correlations were obtained between De,t in the three ROI’s and WAIS-DSC (gCC r 1⁄4-0.70, P<0.05; bCC r 1⁄4-0.82, P<0.01; sCC r 1⁄4-0.58, P1⁄40.08) and Trails A (gCC r 1⁄40.68, P<0.05; bCC r1⁄40.65,P<0.05; sCC r1⁄40.44, ns) in theMCI group, whereas correlations between these variables in the NC and AD groups were non-significant.Conclusions:This is the first demonstration of a strong clinical correlation between DKI-derived WM microstructural metrics and neuropsychological function.While these results are preliminary and limited by its cross-sectional design, scatterplots of these associations suggest that CPS decline in MCI via myelin degeneration may serve as a biomarker of incipient AD. Confirmation of these findings through larger longitudinal studies and in other regions involved in AD is needed.

Association between brain amyloidosis, synaptic dysfunction and cognitive performance measured with ADAS-cog and MMSE scores in early MCI, late MCI and Alzheimer's disease

dorsal anterior cingulate, posterior cingulate and the insula were associated with the main effects of depression, increased GM atrophy in the thalamus, and default mode, executive control and medial temporal lobe (MTL) regions were related to the main effects of aMCI. Depression-aMCI interactive effects were associated with global GM volume loss involving cortical and MTL structures (P<0.05 FDR corrected; Figure 1). Depressive symptoms were negatively correlated and episodic memory performances were positively associated with GMV in similar brain regions as observed with LLD and aMCI respectively. Depressive symptom-memory deficit interactive effects were also seen globally, especially in the DMN and MTL regions. Conclusions: The interactive effects of LLD and aMCI are associated with GMV loss in crucial cognition and mood regulation structures. The co-existence of these clinical phenotypes may be a marker of AD. IC-P-083 ASSOCIATION BETWEEN BRAIN AMYLOIDOSIS, SYNAPTIC DYSFUNCTION AND COGNITIVE PERFORMANCE MEASUREDWITH ADAS-COG AND MMSE SCORES IN EARLY MCI, LATE MCI AND ALZHEIMER’S DISEASE Marina Dauar, Jared Rowley, Liyong Wu, Monica Shin, Sara Mohades, Vladimir Fonov, Antoine Leuzy, Serge Gauthier, Pedro Rosa-Neto, McGill Center for Studies in Aging, Montreal, Quebec, Canada; 2 McGill University, Verdun, Quebec, Canada; 3 McGill Center for Studies in Aging, Verdun, Quebec, Canada; 4 McGill University, Verdun, Quebec, Canada; Montreal Neurological Institute, Montreal, Quebec, Canada; McGill Centre for Studies in Aging, Montreal, Quebec, Canada; 7 Alzheimer Disease Research Unit, McGill Center for Studies in Aging, Montreal, Quebec, Canada; 8 McGill University, Montreal, Quebec, Canada.

Association of brain amyloidosis and metabolism with the Trail Making Test in MCI and Alzheimer's disease

METABOLISM WITH THE TRAIL MAKING TEST IN MCI AND ALZHEIMER’S DISEASE Sara Mohades, Jared Rowley, Antoine Leuzy, Liyong Wu, Marina Tedeschi Dauar, Vladmir Fonov, Monica Shin, Christine Zaccaria, Serge Gauthier, Pedro Rosa-Neto, McGill Centre for Studies in Aging, Montreal, Quebec, Canada; 2 McGill University, Verdun, Quebec, Canada; McGill University, Montreal, Quebec, Canada; McGill Center for Studies in Aging, Quebec, China; McGill Center for Studies in Aging, Montreal, Quebec, Canada; 6 Alzheimer Disease Research Unit, McGill Center for Studies in Aging, Montreal, Quebec, Canada.