Evidence of skull bone translocator protein overexpression linked to multiple sclerosis progression

The skull bone marrow contributes to brain immune homeostasis via recently discovered skull-meningeal channels, enabling the bidirectional trafficking of immune cells between skull bone and underlying dura mater. In multiple sclerosis, autoreactive T cells migrate to the bone marrow and shift its hematopoietic output toward myeloid differentiation, contributing to disease progression. However, the role of the skull bone marrow in multiple sclerosis pathophysiology, and its relationship to brain damage and clinical disability remain largely unexplored. We utilized simultaneous MR-PET with the second-generation radioligand ¹¹C-PBR28 to characterize within the skull bone of multiple sclerosis patients the in vivo expression of the translocator protein (TSPO), an 18-kilodalton mitochondrial membrane protein largely expressed by microglia, astrocytes, and peripheral myeloid cells. Sixty-five multiple sclerosis subjects (46 relapsing-remitting, 19 secondary progressive) and 26 healthy controls underwent ¹¹C-PBR28 MR-PET to acquire 60-90-minute post-injection standardized uptake value maps and anatomical scans for brain volumetrics. Voxel-wise analyses of skull TSPO signal were conducted to assess group differences and associations with demographic, clinical, and brain volumetrics. Voxel-wise analyses revealed a divergent association between age and skull TSPO signal, with a negative correlation in healthy controls in bilateral frontal and right parietal regions (r=-0.67, p0.550). We provide in vivo evidence of skull TSPO overexpression in multiple sclerosis, observed in progressive disease and associated with clinical disability and structural brain damage. Overall, these findings suggest a role for the skull bone marrow in disease-related processes and highlight its potential as a novel radiological marker and therapeutic target.