ASSOCIATION BETWEEN CEREBRAL AMYLOID ACCUMULATION AND SYNAPTIC DENSITY IN ALZHEIMER'S DISEASE: A MULTITRACER PET STUDY

Abstract

Introduction Alzheimer's Disease (AD) pathology is traditionally characterized by the accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau. However, an equally important pathology, synaptic loss, has been demonstrated to be an early event in the disease process and a major structural correlate of cognitive impairment. Recently, positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a novel biomarker of synaptic density. We have previously demonstrated extensive synaptic loss that is more widespread than reductions in gray matter volume in cortical and subcortical brain regions of participants with AD. The current study further investigates the association of local and global cortical amyloid burden with synaptic density. Methods [11C]UCB-J binding to SV2A and [11C]PiB binding to amyloid were measured in 38 participants with AD (14 amnestic MCI and 24 mild dementia) and 20 cognitively normal (CN) participants aged 55-85?years. For [11C]PiB image analysis, parametric images of the binding potential (BPND) were generated using SRTM2 with whole cerebellum as a reference region and converted to distribution volume ratios (DVR). For [11C]UCB-J, parametric images of BPND were first computed using SRTM2 with a shrunken (2 mL) centrum semiovale (CS) reference region. BPND was then converted to DVR with a cerebellum reference region. Brain amyloid and synaptic density were measured in frontal, posterior cingulate/precuneus, lateral parietal, lateral temporal, medial temporal, lateral occipital, medial occipital, and pericentral regions of interest (ROIs). For [11C]PiB parametric images, a composite cortical DVR (representative of global amyloid burden) was calculated by combining the frontal, posterior cingulate/precuneus, lateral parietal, and lateral temporal regions. Results The study sample consisted of 58 participants (38 AD and 20 CN) with no group differences observed in sex (p=0.85), age (p=0.46), or education (p=0.06). AD participants had clinical characteristics typical of amnestic MCI and mild AD with CDR-global = 0.74±0.25 (p Conclusions Using [11C]UCB-J PET, widespread reductions of synaptic density in cortical and subcortical regions were observed in AD compared to CN participants. This included regions not traditionally associated with fibrillar amyloid pathology, such as the pericentral cortex. Interestingly, the cortical regions associated with the least robust accumulation of fibrillar amyloid (medial temporal cortex) were associated with the most pronounced reductions in synaptic density. Although significant negative associations between both global and local amyloid burden and regional synaptic density were observed for the pooled sample, this was driven by differences between diagnostic groups and was not significant within the AD group alone. Our findings are therefore consistent with previous postmortem studies describing the patterns of fibrillar amyloid burden and synaptic loss in AD. This research was funded by: NIA (P50AG047270 [CHvD], K23AG057784 [APM], R01AG052560 [REC, CHV], R01AG062276 [CHvD], and The Dana Foundation [MKC]), NIMH R25MH071584 and T32MH019961 (RSO), and the Detre T. Memorial Fellowship (RSO).