Abstract Details

Title In Vivo And Ex Vivo Characterization Of Meningeal Translocator Protein Expression In Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) S9 - MS Biomarkers, Immunology, and Basic Science (5:18 PM-5:30 PM)

Poster/Presentation
Number 010

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.

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).

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.

Authors/Disclosures
Caterina Mainero, MD, PhD (Massacgusetts General Hospital) PRESENTER	The institution of Dr. Mainero has received research support from Genentech.
Elena Herranz, PhD (Massachusetts General Hospital/Harvard Medical School)	Dr. Herranz has received personal compensation for serving as an employee of Invicro .
Constantina Andrada Treaba, MD, PhD (Massachusetts General Hospital, Harvard Medical School)	Dr. Treaba has nothing to disclose.
Valeria T. Barletta, MD, PhD (MGH)	Dr. Barletta has nothing to disclose.
	No disclosure on file
Russell A. Ouellette IV (Karolinska Institutet - Clinical Neuroscience)	Mr. Ouellette has nothing to disclose.
Eric Klawiter, MD, FAAN (Massachusetts General Hospital)	Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Galen/Atlantica. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Banner Life Sciences. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Greenwich Biosciences. Dr. Klawiter has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for OM1. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. The institution of Dr. Klawiter has received research support from Biogen. The institution of Dr. Klawiter has received research support from Abbvie. The institution of Dr. Klawiter has received research support from Genentech.
Jacob A. Sloane, MD, PhD (Beth Israel Deaconess Medical Center)	Dr. Sloane has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for biogen. Dr. Sloane has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Sloane has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi.
Carolina Ionete, MD (UMass Memorial)	Dr. Ionete has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Ionete has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. The institution of Dr. Ionete has received research support from Genetech. The institution of Dr. Ionete has received research support from Biogen. The institution of Dr. Ionete has received research support from NIH.
Suma Babu, MD, MPH (Massachusetts General Hospital, Brigham, Harvard)	The institution of Dr. Babu has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for OrphAI therapeutics. The institution of Dr. Babu has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. The institution of Dr. Babu has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Uniqure Therapeutics. Dr. Babu has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Medscape. The institution of Dr. Babu has received research support from Biogen. The institution of Dr. Babu has received research support from Novartis. The institution of Dr. Babu has received research support from Ionis. The institution of Dr. Babu has received research support from OrphAI therapeutics. The institution of Dr. Babu has received research support from Denali Therapeutics. Dr. Babu has a non-compensated relationship as a Appointed Member of the Committee on ALS: Accelerating Treatments and Improving Quality of Life with National Academies of Sciences, Engineering and Medicine that is relevant to AAN interests or activities.
	No disclosure on file
	No disclosure on file
Revere Kinkel, MD, FAAN (University of California San Diego)	Dr. Kinkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Kinkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Kinkel has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Kinkel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. Kinkel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Janssen. Dr. Kinkel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion. The institution of Dr. Kinkel has received research support from Department of Defense. The institution of Dr. Kinkel has received research support from PCORI. The institution of Dr. Kinkel has received research support from Sanofi.
	No disclosure on file