340. Synaptic density in psychiatric and neurodegenerative disorders: a systematic review of in vivo SV2A PET studies

Abstract

Abstract Background Over four decades of research have linked synaptic pathology to a broad range of brain disorders. Postmortem studies in conditions like psychosis spectrum disorders, Parkinson’s and Alzheimer’s Disease (AD) show changes in synaptic integrity but are confounded by factors such as illness duration or disease stage. Genetic research further suggests synaptic dysfunction via alterations in gene networks. Structural MRI studies reveal consistent patterns of gray matter changes, but these are indirect measures and lack specificity. Synaptic vesicle glycoprotein 2A (SV2A) has emerged as a superior molecular target for direct in vivo quantification of synaptic density (SD) due to its ubiquitous presynaptic expression. Positron Emission Tomography (PET) ligands targeting SV2A strongly correspond with synaptic terminal density, establishing SV2A PET as the first noninvasive, quantitative approach to map SD in the living brain. Aims & Objectives (1) Determine whether SV2A PET-measured alterations in SD are brain-region specific across brain disorders (2) Explore how regional SD relates to cognitive performance and functional outcomes. Method We systematically searched MEDLINE, Embase, APA PsycINFO, Web of Science, and the Cochrane Library from inception to November 2025, including all original peer-reviewed articles measuring SD using SV2A PET (Prospero ID: CRD42024562887). Meta-analyses of reported synaptic measures, percentage differences, and correlations with clinical severity and illness duration are ongoing and expected to be completed by the end of February 2026. Results 111 studies met the inclusion criteria: neurodegenerative (k=60), neuropsychiatric (k=16), epileptiform (k=7), neurodevelopmental (k=2), neuroinflammatory (k=1) disorders and studies in non-clinical populations (k=25). Of the 25 distinct disorders examined, 17 were represented by a single study or by studies with overlapping samples, limiting the ability to assess reproducible patterns across independent datasets. No consistent patterns were observed in mood disorders, potentially reflecting substantial heterogeneity within these conditions. The most consistent reductions in SD in Parkinson’s Disease (k=10) were in brainstem (k=2), caudate (k=6), frontal cortex (k=3), occipital lobe (k=3), substantia nigra (k=6), and thalamus (k=4); however, no associations were observed with disease stage. In the psychosis-spectrum studies (k=7), convergent reduction patterns were observed in the anterior cingulate cortex (k=7), hippocampus (k=6), occipital cortex (k=4), temporal cortex (k=6), parietal lobe (k=4), and frontal cortex (k=5). Associations between reduced SD and clinical/cognitive measures were observed in psychosis studies (k=4). Significant reductions were observed in the hippocampus in temporal lobe epilepsy (k=3). Links between Aβ deposition and reduced hippocampal SD (k=4) were noted in a sample of AD and mild cognitive impairment (k=33). Discussion & Conclusions This systematic analysis of SV2A PET studies across all brain disorders shows SD loss across disorders with disease-specific patterns. Consistent with postmortem and genetic findings, regionally selective synaptic alterations within disorders point to circuit-level vulnerability rather than uniform global synaptic loss. By integrating SV2A PET findings across disorders, this analysis will help clarify how SD relates to disease stage, clinical/cognitive impairment, and functional outcomes, informing future research on therapeutic approaches.