In vivo measurement of widespread synaptic loss and associated tau accumulation in early Alzheimer's disease: Molecular imaging of novel biomarkers for neurodegeneration and ADRD. (7th December 2020)

• Record Type: Journal Article
• Authors: Mecca, Adam P.; O'Dell, Ryan S.; Chen, Ming‐Kai; Naganawa, Mika; Toyonaga, Takuya; Godek, Tyler A.; Harris, Joanna E.; Bartlett, Hugh H.; Zhao, Wenzhen; Gallezot, Jean‐Dominique; Nabulsi, Nabeel B.; Ropchan, Jim R.; Ye, Yunpeng; Wyk, Brent C. Vander; Arnsten, Amy F.T.; Huang, Yiyun; Carson, Richard E.; van Dyck, Christopher H.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.037791
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Using [ 11 C]UCB‐J–PET we have shown significant reductions in hippocampal SV2A specific binding as a marker of synaptic density in participants with early Alzheimer's disease (AD). However, postmortem studies have suggested more widespread neocortical reductions in synaptic density that are associated with fibrillary tau accumulation. Methods: We measured SV2A binding with [ 11 C]UCB‐J‐PET in 34 participants with early AD (MMSE=23.1±4.1, CDR=0.5‐1.0) and 19 cognitively normal (CN) participants (MMSE=29.3±1.1, CDR=0). Amyloid status was confirmed by [ 11 C]PiB‐PET. For [ 11 C]UCB‐J‐PET, we calculated the distribution volume ratio ( DVR ) using a cerebellum reference. In a subset of 10 CN and 10 AD participants, we measured tau accumulation using [ 18 F]flortaucipir‐PET. [ 18 F]Flortaucipir standardized uptake value ratios ( SUVR s) were calculated using an inferior cerebellum reference. Results: Our primary analysis of group differences in SV2A binding demonstrated a significant effect of group (F(1, 51)=33.4, P <0.00001) and group*region (F(10, 510)=2.4, P =0.01) as predictors of SV2A binding ( DVR ). Post‐hoc comparisons revealed significant group differences in all medial temporal regions and more broadly in neocortical regions (Figure 1). SV2A reductions in AD were most pronounced in the hippocampus ( DVR –17.3%, P<0.00001; BP ND –19.8%) and entorhinal cortex ( DVR –15.7%, P<0.00001; BP ND –17.6%), but also present in parahippocampal, amygdala, lateral temporal, prefrontal, posterior cingulate/precuneus, lateral parietal, and pericentral regions. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume. In a smaller sample of participants with tau PET, AD participants demonstrated significantly higher entorhinal cortical (ERC) [ 18 F]flortaucipir binding compared to CN participants (CN SUVR =1.11±0.12, AD SUVR =1.68±0.16, p<0.00001). ERC‐tau was inversely associated with hippocampal synaptic density (r=‐0.63, P =0.005). Synaptic density and tau were inversely associated in regions of early and later Braak stages (r=‐0.45 to ‐0.59, P <0.05). Conclusion: We observed widespread reductions of synaptic density with [ 11 C]UCB‐J‐PET in medial temporal and neocortical regions in early AD. ERC tau accumulation was associated with lower hippocampal synaptic density. This inverse association may reflect synaptic failure due to tau pathology in ERC neurons projecting to the hippocampus. Further longitudinal studies are needed to elucidate the chronology and topography of tau accumulation and synaptic loss in AD and their relationship.