Assessment of Gray Matter Microstructure and Synaptic Density in Alzheimer's Disease: A Multimodal Imaging Study With DTI and SV2A PET

Objective: Multimodal imaging techniques have furthered our understanding of how different aspects of Alzheimer's disease (AD) pathology relate to one another. Diffusion tensor imaging (DTI) measures such as mean diffusivity (MD) may be a surrogate measure of the changes in gray matter structure associated with AD. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has been used to quantify synaptic loss, which is the major pathological correlate of cognitive impairment in AD. In this study, we investigated the relationship between gray matter microstructure and syn-aptic density. Methods: DTI was used to measure MD and [11C]UCB-J PET to measure synaptic density in 33 amyloid-positive participants with AD and 17 amyloid-negative cognitively normal (CN) participants aged 50-83. Univari-ate regression analyses were used to assess the association between synaptic density and MD in both the AD and CN groups. Results: Hippocampal MD was inversely associated with hippocampal synaptic density in participants with AD (r = -0.55, p <0.001, df = 31) but not CN (r = 0.13, p = 0.62, df = 15). Explor-atory analyses across other regions known to be affected in AD suggested wide-spread inverse associations between synaptic density and MD in the AD group. Conclusion: In the setting of AD, an increase in gray matter MD is inversely asso-ciated with synaptic density. These co-occurring changes may suggest a link between synaptic loss and gray matter microstructural changes in AD. Imaging studies of gray matter microstructure and synaptic density may allow important insights into AD-related neuropathology. (Am J Geriatr Psychiatry 2024; 32:17-28)