Positron Emission Tomography (PET)-Derived Measurement of Brain Synaptic Vesicle Glycoprotein 2A (SV2A) – a Potential Biomarker in Patients with Essential Tremor - Project Summary/Abstract Essential tremor (ET) is a chronic, progressive neurologic disease affecting 7 million Americans (2.2% of the entire US population). Recent evidence suggests that ET is neurodegenerative. Despite its high prevalence, there are no established biomarkers, serological or imaging, for ET. As a result, the diagnosis is solely based on neurologic history and exam, and there is no method to track underlying disease progression in clinical trials or clinical practice settings. This stands in stark contrast to the options available for Alzheimer’s and Parkinson’s disease (PD). Synaptic vesicle glycoprotein 2A (SV2A) is presynaptically located and ubiquitously expressed in the central nervous system. Positron emission tomography (PET)-derived measurement of brain SV2A has the potential to serve as an in vivo biomarker of synaptic density, and reductions in synaptic density in relevant brain regions have been demonstrated in several neurodegenerative diseases. Considerable data have linked ET to the cerebellum, with evidence of degeneration in the cerebellar cortex. Our preliminary data suggest that there is an in vivo reduction in synaptic density in the cerebellar cortex in ET. In this 5-year proposal, we explore the value of SV2A as a biomarker and diagnostic tool in ET. There are 3 aims. Aim 1a: To measure synaptic density with SV2A PET imaging in 30 ET cases and 30 matched controls. We hypothesize that there will be lower SV2A PET binding in the cerebellar cortex of ET cases compared to controls. Aim 1b: To perform several focused clinical correlational studies to assess the construct validity of the notion that a reduction in cerebellar cortex SV2A PET binding is a valid metric of symptomology in ET. We hypothesize the presence of significant correlations between synaptic density and key clinical features of ET. Aim 1c: To examine synaptic density in the cerebral cortex with SV2A PET in ET vs. controls. We hypothesize that whole brain analyses will uncover lower SV2A PET binding in ET in motor areas (e.g., motor cortex). Aim 2: To assess cerebellar cortex SV2A PET binding as a diagnostic marker for ET by comparing ET to a select number of other related movement disorders with overlapping clinical features: PD (n = 15) and dystonia (n = 15). We hypothesize that a reduction in cerebellar cortex SV2A PET binding, along with its binding in other regions (e.g., substantia nigra), will facilitate imaging-based distinction between these different diagnostic entities. Aim 3: Autoradiographic studies indicate that in vivo SV2A binding correlates with tissue levels of SV2A in postmortem samples. Therefore, SV2A autoradiography will be performed post-mortem in ET (n = 20) and control (n = 20) cerebellar tissue from the New York Brain Bank to determine if a lower postmortem tissue SV2A signal is apparent in ET. We hypothesize that tissue SV2A signal will be lower in ET, serving to independently validate the PET imaging data. This proposal is a highly novel study to rigorously examine whether in-vivo synaptic density can be used to provide important information in ET patients. The particular need we now seek to address, developing a biomarker for ET, is a fundamental unmet need in the field.
