Some of the most scientifically challenging neurodegenerative diseases feature pathology that effects the function and density of synapses, such as Alzheimer's disease (AD). Until now, in vivo measurements of synaptic density have primarily focused on cerebral spinal fluid (CSF) levels of synaptic proteins. CSF measures are surrogate markers of the brain. With new advances in PET imaging we can now quantify synapses in specific brain regions, providing a view of the density of synapses and their decline. The PET imaging markers currently available, Aβ and tau, focus on early indicators of disease and so far, do not correlate with clinical decline. Alternatively, synapse loss has shown to be an optimal biomarker for brain integrity and cognitive function as it correlates strongly with cognitive decline in AD. Recently, a PET radioligand has been developed that binds with the synaptic vesicle glycoprotein 2A (SV2A), an integral glycoprotein located in the membrane of synaptic vesicles widely distributed throughout the brain, providing accurate measurements of synaptic proteins in the living brain. Recent SV2A PET studies have demonstrated promising disease-specific regional reductions in SV2A binding in persons with AD, but still require thorough analytical validation before wide-spread use.

This three-year project will demonstrate SV2A PET imaging as a reliable biomarker of synaptic density in AD and accelerate the application as a treatment response marker in disease-modifying clinical trials. The project is comprised of three stages: procurement and qualification; ex vivo/postmortem validation; and in vivo SV2A PET and tissue characterization. Key outputs include: biological understanding of SV2A binding within the synapse; comparison of SV2A in healthy control, MCI, and AD in-vivo and post-mortem; filling a crucial need for a robust clinical validation to confirm that SV2A signals reflect synaptic density; and indication of utility for use as a treatment response biomarker in clinical trials.