2023 American Academy of Neurology Abstract Website

Elena Herranz¹, Constantina Andrada Treaba¹, Valeria Barletta¹, Ambica Mehndiratta¹, Russell Ouellette², Eric Klawiter¹, Jacob Sloane³, Carolina Ionete⁴, Suma Babu¹, Marco Loggia¹, Jacob Hooker¹, Revere Kinkel⁵, Roberta Magliozzi⁶, Caterina Mainero⁷
¹Massachusetts General Hospital, ²Karolinska Institutet - Clinical Neuroscience, ³Beth Israel Deaconess Medical Center, ⁴UMass Memorial, ⁵University of California, San Diego, ⁶University of Verona, ⁷Massachusettes General Hospital

Objective:

To combine in vivo simultaneous MR-PET with ¹¹C-PBR28, a second-generation Translocator Protein (TSPO) radioligand, with ex vivo immunohistochemistry, to characterize meningeal TSPO expression in multiple sclerosis (MS).

Background:

Compartmentalized meningeal inflammation is thought to represent a key player in the pathogenesis of cortical demyelination in MS. Molecular imaging targeting of the 18kDa mitochondrial TSPO, overexpressed in activated glia/macrophages, represents a cell-specific approach to image in vivo meningeal inflammation in MS.

Design/Methods:

Forty-nine MS patients (SPMS=21; RRMS=28) underwent 90-min ¹¹C-PBR28 MR-PET. Tracer binding was measured using normalized standardized uptake values sampled at 4 mm above the cortex (meningeal tissue) and at mid cortical depth. Data in MS were compared to 21 age-matched healthy controls (HC).

To characterize the nature of ¹¹C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was quantified in post-mortem brain tissue of 15 SPMS cases and 3 age-matched controls (UK MS Tissue Bank).

Results:

Relative to HC, MS patients exhibited abnormally increased TSPO expression in the cortex and meningeal tissue, diffusively in SPMS and more localized in RRMS. In MS, increased meningeal TSPO levels were associated with increased EDSS scores and lower SDMT z scores (p=0.05, linear regression).

Immunohistochemistry revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post mortem SPMS cases relative to control tissue. In SPMS, increased TPSO expression was related to meningeal inflammation. The highest TSPO immunostaining was detected on meningeal MHC-classII+ macrophages (25-45% of examined cells) and on cortical activated MHC-classII+ microglia.

In vivo arterial blood data and neuropathology showed that endothelial binding did not represent a main factor accounting for increased TSPO cortico-meningeal expression in MS.

Conclusions:

Our findings support the use of TSPO-PET targeting for imaging in vivo meningeal inflammation in MS and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.