Comprehensive mapping of synaptic vesicle protein 2A (SV2A) in health and neurodegenerative diseases: a comparative analysis with synaptophysin and ground truth for PET-imaging interpretation

• Published in: Acta neuropathologica 2024-10, Vol.148 (1), p.58, Article 58
• Main Authors: Shanaki Bavarsad, Mahsa, Spina, Salvatore, Oehler, Abby, Allen, Isabel E., Suemoto, Claudia K., Leite, Renata E. P., Seeley, William S., Green, Ari, Jagust, William, Rabinovici, Gil D., Grinberg, Lea T.
• Format: Article
• Language: English
• Subjects: Age; Aged; Aged, 80 and over; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Brain - diagnostic imaging; Brain - metabolism; Brain - pathology; Brain mapping; Cognitive ability; Comparative analysis; Disease; Female; Frontal gyrus; Frontotemporal dementia; Frontotemporal Lobar Degeneration - diagnostic imaging; Frontotemporal Lobar Degeneration - metabolism; Frontotemporal Lobar Degeneration - pathology; Hippocampus; Humans; Immunohistochemistry; Male; Medicine; Medicine & Public Health; Membrane Glycoproteins - metabolism; Middle Aged; Nerve Tissue Proteins - metabolism; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - diagnostic imaging; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neuroimaging; Neurosciences; Original Article; Pathology; Peptide mapping; Positron emission tomography; Positron-Emission Tomography - methods; Progressive supranuclear palsy; Supranuclear Palsy, Progressive - diagnostic imaging; Supranuclear Palsy, Progressive - metabolism; Supranuclear Palsy, Progressive - pathology; Synaptic density; Synaptophysin; Synaptophysin - metabolism; Temporal gyrus; Therapeutic targets; Western blotting
• ISSN: 1432-0533; 0001-6322; 1432-0533
• DOI: 10.1007/s00401-024-02816-9

Synaptic dysfunction and loss are central to neurodegenerative diseases and correlate with cognitive decline. Synaptic Vesicle Protein 2A (SV2A) is a promising PET-imaging target for assessing synaptic density in vivo, but comprehensive mapping in the human brain is needed to validate its biomarker potential. This study used quantitative immunohistochemistry and Western blotting to map SV2A and synaptophysin (SYP) densities across six cortical regions in healthy controls and patients with early-onset Alzheimer’s disease (EOAD), late-onset Alzheimer’s disease (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-GRN). We identified region in SV2A density among controls and observed disease- and region-specific reductions, with the most severe in FTLD-GRN (up to 59.5%) and EOAD. EOAD showed a 49% reduction in the middle frontal gyrus (MFG), while LOAD had over 30% declines in the inferior frontal gyrus (IFG) and hippocampus (CA1). In PSP, smaller but significant reductions were noted in the hippocampal formation, with the inferior temporal gyrus (ITG) relatively unaffected. A strong positive correlation between SV2A and SYP densities confirmed SV2A’s reliability as a synaptic integrity marker. This study supports the use of SV2A PET imaging for early diagnosis and monitoring of neurodegenerative diseases, providing essential data for interpreting in vivo PET results. Further research should explore SV2A as a therapeutic target and validate these findings in larger, longitudinal studies.