Whole brain grey matter synaptic terminal density, age and intellectual functioning in schizophrenia: an in vivo [11C]UCB-J positron emission tomography study

In vivo SV2A PET imaging reveals reduced global synaptic density in schizophrenia and age-related decline, independent of intellectual functioning

Authors: Ellis Chika Onwordi; Thomas Whitehurst; Ekaterina Shatalina; Ayla Mansur; Atheeshaan Arumuham; Martin Osugo; Tiago Reis Marques; Sameer Jauhar; Ravi Mehrotra; Maja Ranger; Nikola Rahaman; Steve M. Church; Eugenii A. Rabiner; Roger N. Gunn; Sridhar Natesan; Abraham Reichenberg; Oliver D. Howes

Synaptic dysfunction has long been implicated in the cognitive impairment associated with schizophrenia, yet direct in vivo measures of synaptic terminal density have been limited. In this study, the authors use [11C]UCB-J PET imaging targeting synaptic vesicle glycoprotein 2A (SV2A) to quantify whole-brain grey matter synaptic density in patients with schizophrenia and healthy volunteers.

Across 43 patients and 26 controls, whole-brain SV2A binding was significantly lower in schizophrenia, consistent with a global reduction in synaptic terminal density. SV2A levels declined with age in both groups, indicating similar age-related synaptic changes regardless of diagnosis. Notably, synaptic density did not correlate with current or premorbid IQ measures, suggesting that global synaptic terminal loss alone may not explain intellectual impairment in schizophrenia. Together, the findings position SV2A PET as a powerful translational biomarker for synaptic pathology, while refining our understanding of how synaptic changes relate to cognition in neuropsychiatric disease.

Why read this article

• ILargest [11C]UCB-J PET study in schizophrenia to date, providing robust in vivo quantification of synaptic terminal density
• Demonstrates global synaptic deficits, extending prior regional findings to whole-brain grey matter
• Defines age-related synaptic decline, offering important context for longitudinal and clinical trial interpretation
• Highlights translational implications of SV2A PET, supporting its use as a biomarker for disease biology, target engagement, and therapeutic development

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