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. 2022 Dec;18(12):2527-2536.
doi: 10.1002/alz.12582. Epub 2022 Feb 17.

Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [11 C]UCB-J

Adam P Mecca  1   2 , Ryan S O'Dell  1   2 , Emily S Sharp  1   3 , Emmie R Banks  1   2 , Hugh H Bartlett  1   2 , Wenzhen Zhao  1   2 , Sylwia Lipior  1   2 , Nina G Diepenbrock  1   2 , Ming-Kai Chen  4 , Mika Naganawa  4 , Takuya Toyonaga  4 , Nabeel B Nabulsi  4 , Brent C Vander Wyk  5 , Amy F T Arnsten  1   6 , Yiyun Huang  5 , Richard E Carson  5 , Christopher H van Dyck  1   2   3   6
Affiliations

Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [11 C]UCB-J

Adam P Mecca et al. Alzheimers Dement. 2022 Dec.

Abstract

Introduction: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo.

Methods: We examined the relationship between synaptic density measured by [11 C]UCB-J PET and neuropsychological test performance in 45 participants with early AD.

Results: Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume.

Conclusion: These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.

Keywords: Alzheimer's disease; [11C]UCB-J; cognition; synaptic density; synaptic vesicle glycoprotein 2A.

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Conflict of interest statement

APM, REC, and CHvD report grants from National Institutes of Health (NIH) for the conduct of the study. APM, ESS, TT, BCV, AFTA, YH, and REC report grant support from the NIH for work not related to this manuscript. APM reports grants for clinical trials from Genentech, Eisai, and Eli Lilly outside the submitted work. MKC reports research support from the Dana Foundation and Eli Lilly outside the submitted work. YH reports research grants from UCB and Eli Lilly outside the submitted work. REC reports grants from Bristol Myers Squibb, Cerevel Therapeutics, Invicro, and UCB outside the submitted work. CHvD reports grants for clinical trials from Biogen, Novartis, Eli Lilly, Eisai, Biohaven, and the Alzheimer's Association outside the submitted work. YH, REC, and NBN have a patent for a newer version of the SV2A tracer. MKC reports consulting fees from Eisai and Actinum. AFTA reports consulting fees from Vallon, Supernus, and Ludbeck. CHvD reports consulting fees from Roche, Esai, and Ono Pharmaceuticals. APM received honoraria for presentations at University of Connecticut and Stanford University. NBN received honoraria for presentations from UCLA Semel Institute for Neuroscience & Human Behavior. AFTA received honoraria for presentations at McGill University, Killam Institute, Montreal Neurological Institute, Harvard, Massachusetts General Hospital, Western Connecticut State University, and the University of Massachusetts. APM received support from ACTC/ATRI for travel to ACTC/ATRI meetings. TT received travel support from the conference for the 2019 Brain and Brain PET meeting. AFTA received support from the conference for travel to give a presentation at ACNP. APM is a member of the ISTAART Neuroimaging PIA executive committee. NN receives royalties from MD Anderson Cancer Center. AFTA and Yale receive royalties from Shire/Takada from USA sales of Intuniv. ERB, HHB, WZ, SL, NGD, and MN have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Correlation of synaptic density (DVR) and cognition in participants with AD. Global synaptic density in a composite of AD‐affected regions, represented as DVR, was plotted with (A) global cognition, (B) verbal memory, (C) language, (D) executive function, (E) processing speed, or (F) visuospatial ability. Multiple variable linear regression analysis included predictors of synaptic density, years of education, age, and sex. η is displayed for the main explanatory variable of synaptic density as it contributes to the overall model (*P < 0.05). Data points and line of best fit (dotted line) are unadjusted values. AD, Alzheimer's disease; DVR, distribution volume ratio of [11C]UCB‐J calculated with a whole cerebellum reference region
FIGURE 2
FIGURE 2
Correlation maps of synaptic density (DVR) and global cognition in all regions for participants with AD. (A) Pearson's r was calculated for the correlation between synaptic density ([11C]UCB‐J DVR) and global cognition in all FreeSurfer regions. A similar analysis was conducted (B) after PVC of [11C]UCB‐J PET images, and (C) with gray matter volume. Brain maps were created by producing images with the voxels in each FreeSurfer region set uniformly to the calculated Pearson's r for that region and overlaid on an MNI template T1 MRI. The color scale represents Pearson's r, which is displayed only for regions that had an uncorrected P < 0.05. AD, Alzheimer's disease; DVR, distribution volume ratio of [11C]UCB‐J calculated with a whole cerebellum reference region; MNI, Montreal Neurological Institute; MRI, magnetic resonance imaging; PET, positron emission tomography; PVC, partial volume correction
FIGURE 3
FIGURE 3
Correlation maps of synaptic density (DVR) and domain specific cognitive performance in all regions for participants with AD. Pearson's r was calculated for the correlation between synaptic density ([11C]UCB‐J DVR) and (A) verbal memory, (B) language, (C) executive function, (D) processing speed, and (E) visuospatial ability domain scores. Brain maps were created by producing images with the voxels in each FreeSurfer region set uniformly to the calculated Pearson's r for that region and overlaid on an MNI template T1 MRI. The color scale represents Pearson's r, which is displayed only for regions that had an uncorrected P < 0.05. AD, Alzheimer's disease; DVR, distribution volume ratio of [11C]UCB‐J calculated with a whole cerebellum reference region; MNI, Montreal Neurological Institute; MRI, magnetic resonance imaging
FIGURE 4
FIGURE 4
Correlation of synaptic density with PVC (PVC–DVR) and cognition in participants with AD. PVC was applied to [11C]UCB‐J PET images. Global synaptic density in a composite of AD‐affected regions, represented as DVR, was plotted with (A) global cognition, (B) verbal memory, (C) language, (D) executive function, (E) processing speed, or (F) visuospatial ability. Multiple variable linear regression analysis included predictors of synaptic density, years of education, age, and sex. η is displayed for the main explanatory variable of synaptic density as it contributes to the overall model (*P < 0.05). Data points and line of best fit (dotted line) are unadjusted values. AD, Alzheimer's disease; DVR, distribution volume ratio of [11C]UCB‐J calculated with a whole cerebellum reference region; PET, positron emission tomography; PVC, partial volume correction
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References

    1. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990;27:457‐464. - PubMed
    1. Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572‐580. - PubMed
    1. Masliah E, Ellisman M, Carragher B, et al. Three‐dimensional analysis of the relationship between synaptic pathology and neuropil threads in Alzheimer's disease. J Neuropathol Exp Neurol. 1992;51:404‐414. - PubMed
    1. Scheff SW, DA Price, Schmitt FA, Mufson EJ. Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment. Neurobiol Aging. 2006;27:1372‐1384. - PubMed
    1. Bajjalieh SM, Peterson K, Linial M, Scheller RH. Brain contains two forms of synaptic vesicle protein 2. Proc Natl Acad Sci U S A. 1993;90:2150‐2154. - PMC - PubMed

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