Exploring synaptic density patterns in cerebral small vessel disease: insights from [¹⁸F]SynVesT-1 PET imaging

PURPOSE: Cognitive dysfunction caused by cerebral small vessel disease (CSVD) is the most common cause of vascular dementia. [18F]SynVesT-1 is a promising PET tracer binding Synaptic vesicle glycoprotein 2 A (SV2A) which is a potential biomarker for CSVD diagnosis. This study aimed to discern distinct synaptic density patterns associated with CSVD using [18F]SynVesT-1 PET, and to elucidate the correlation between synaptic density and cognitive performance. METHODS: Sixteen CSVD patients and ten age- and sex-matched healthy controls (HCs) underwent [18F]SynVesT-1 PET imaging to quantify synaptic density. Comparative analyses were conducted between CSVD and HCs, as well as within different CSVD subgroups based on burden scores and cognitive status. Moreover, associations between regional synaptic density and neuropsychological assessment outcomes in CSVD patients were explored. RESULTS: CSVD patients exhibited decreased [18F]SynVesT-1 uptake in the bilateral hippocampus-insula region and the left postcentral gyrus compared to HCs (P < 0.001, cluster size > 50). Neuropsychological performance correlated with regional standardized uptake values (P < 0.05). Specifically, CSVD patients with burden scores of 0–1 demonstrated reduced synaptic density in the left insula and lingual gyrus compared to HCs. Conversely, patients with burden scores of 2–4 manifested diminished uptake in the bilateral insula, left parahippocampal gyrus, and right anterior cingulate and paracingulate gyri (P < 0.001, cluster size > 50). Moreover, CSVD patients without cognitive impairment exhibited decreased uptake in the left hippocampus-insula region relative to HCs, while those with cognitive impairment displayed synaptic loss in the bilateral insula, left hippocampus, and anterior cingulate and paracingulate gyri (P < 0.001, cluster size > 50). DISCUSSION: This study represents the first in vivo investigation of synaptic density in CSVD utilizing [18F]SynVesT-1 PET imaging. Our findings suggest the potential of synaptic density as a biomarker for diagnosing CSVD and assessing cognitive impairment and disease progression.