Background and Objectives

Multiple sclerosis (MS) is a chronic inflammatory disease coupled with neurodegenerative processes affecting both the white matter and gray matter (GM) in the CNS. Several histopathologic studies have reported a reduction in synaptic density in various areas of the brain. However, this pathologic feature is yet an unexplored entity among people with MS (pwMS). Therefore, we sought to investigate synaptic loss in vivo by quantifying the synaptic vesicle glycoprotein 2A using [¹¹C]UCB-J-PET imaging and to explore associations with clinical and cognitive measures.

Methods

Ten pwMS and 8 healthy controls (HCs) underwent high-resolution [¹¹C]UCB-J-PET imaging and MRI. SV2A availability was determined using the tissue-to-plasma concentration ratio at equilibrium (distribution volume; VT). We furthermore explored associations between PET imaging results and clinical and cognitive measures in pwMS (assessed with the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test [SDMT]). In addition, we considered volumetric, clinical, and cognitive measures during a 5-year period before PET imaging.

Results

Ten pwMS (7 women [70%], median [interquartile range] age, 53 [50-56]) years were compared with 8 HCs (6 women [75%]; age, 51 [50-70] years). PwMS had a significantly lower SV2A availability in the cortical GM (pwMS: mean [SD], V_T = 15.65 mL/cm3 [2.26]; HCs: V_T = 18.14 mL/cm³ [2.09]; p = 0.029, t test), as well as in several subcortical regions. Moreover, a lower SV2A availability in cortical GM correlated significantly with reduced SDMT values in pwMS (r = 0.071, p = 0.021; Spearman correlation coefficient). No association between physical disability (measured using EDSS) and SV2A availability was found.

Discussion

Using in vivo [¹¹C]UCB-J PET imaging, we provide evidence of reduced synaptic density in pwMS. Furthermore, the results reveal a link between synaptic loss and cognitive impairment. These findings highlight the potential of [¹¹C]UCB-J PET imaging as a promising tool for assessing clinically relevant aspects of GM pathology in MS.