Imaging the Innate Immune Repsonse in MS: PET & MRI
Susan Gauthier1
1Neurology, Weill Cornell Medicine, NY, United States

Synopsis

This talk will discuss imaging methods, including both PET and MRI, used to assess CNS inflammation in MS and highlight the technical challenges and validation studies to provide a comprehensive review. Furthermore, it will be demonstrated how imaging is being utilized to explore the role of the innate immune response on the pathological mechanisms of disease in MS and the impact on clinical disability.

Objectives and Purpose:

CNS inflammation, which is based upon the innate immune system, plays a pivotal role in the pathophysiology of multiple sclerosis (MS), and important cell types involved in this process are CNS resident microglia and blood-derived macrophages[1]. Activated microglia and macrophages (m/M) are involved in demyelination and are the source of reactive nitrogen and oxygen species, which induce oxidative injury to mitochondria, oligodendrocytes and degenerating neurons[2-6]. This talk will discuss imaging methods, including both PET and MRI, used to assess CNS inflammation in MS and highlight the technical challenges and validation studies to provide a comprehensive review. Furthermore, it will be demonstrated how imaging is being utilized to explore the role of the innate immune response on the pathological mechanisms of disease in MS and the impact on clinical disability.

Methods and Discussion:

Measuring innate immune activity via PET. Positron emission tomography imaging (PET), in combination with the first generation 18kDa translocator protein (TSPO) ligand 11C-PK11195 (PK-PET), has been validated as in-vivo measure of activated m/M[7]. A number of PK-PET studies in MS have demonstrated the occurrence of activated m/M within chronic lesions, normal appearing white matter (NAWM) and gray matter (GM)[8-14]. Newer generation TSPO ligands, with improved specificity and brain penetration, have provided more consistent findings across studies, however these ligands still remain limited by heterogeneous binding due genetic polymorphisms[15-19]. A relatively new TSPO ligand, [11C]ER176, has been reported to bind all three genotypes (high, mixed and low affinity) [20] and novel microglia targets (P2X7 and P2Y212), which are early stage development, are likely to enhance our assessment of the phenotypic differences among chronic microglia activity in MS[21]. Importantly, PET TSPO studies should be interpreted with caution given cross binding with astrocytes, small studies, and the lack of consensus regarding TSPO quantification. As we move forward with novel inflammatory targets, efforts should be taken to determine the most effective quantification method for each individual ligand. Furthermore, the feasibility of utilizing 11C as radioisotope is clearly limited by a short half-life and the requirement of an on-site cyclotron. As fluorinated (18F) radiotracers are developed, large multi-center studies, similar to those for oncology and Alzheimer’s disease, may be feasible in MS. Measuring innate immune activity via MRI. Chronic CNS inflammation in the MS lesion is maintained with pro-inflammatory m/M, which have been demonstrated to be present at the rim of chronic active MS lesions and at the site of ongoing demyelination [22-25]. The majority of the m/M found at the rim of chronic active multiple sclerosis lesions contain iron [22, 25], and conversely iron-enriched microglia and macrophages are not found at the rim of remyelinated or shadow plaques[26]. MRI with a gradient echo (GRE) sequence is sensitive to iron[27] and has been utilized by many investigators to detect an iron rim in chronic active multiple sclerosis lesions.[2, 23, 25, 28-31] Quantitative susceptibility mapping (QSM) provides an effective means to directly map the distribution of susceptibility sources by solving the field-to-source inversion problem using a phase-based magnetic field deconvolution technique[32, 33]. Utilizing PK11195-PET, it has been demonstrated that lesions with a rim of hyperintensity on QSM (rim+) have a significantly higher level of inflammation as compared on lesions lacking this rim[34]. QSM rim+ lesions were also found to have more tissue injury, as measured by myelin water imaging, [35] which is consistent with other GRE studies showing that phase rim lesions are more likely to develop into a chronic T1w hypointense lesions[31] and demonstrate slow expansion over time[25]. Essential next steps include examining the impact of paramagnetic rim lesions on the disease course and on-going tissue damage. Finally, GRE MRI can identify a subset of chronic lesions with retained CNS inflammation and a potential target for future therapeutic studies.

Conclusions:

In conclusion, there have been significant advances in imaging innate immune response utilizing both PET and MRI in MS, which will provide new biomarkers for novel treatment targets and contribute to the study of CNS inflammation across many neurodegenerative diseases.

Acknowledgements

My lab: Ulrike Kaunzner MD PhD, Neha Safi MD, Melanie Marcille, Lily Zexter, Nicole Zinger, and Nara Michaelson MD

Collaborators: Yi Wang PhD, Thanh Nguyen PhD, Yeona Kang PhD, Sandra Hurtado Rua, Elizabeth Sweeney, Yihao Yao MD, Shun Zhang MD, and Pascal Spincemaille PhD

Pathology collaborator: David Pitt MDMembers of the

Judith Jaffe MS Center: Timothy Vartanian MD PhD, Jai Perumal MD, Nancy Nealon MD and Ulrike Kaunzner MD,PhD

Funding agencies: NINDS: RO1 NS104283 (Gauthier), RO1 105144 (mPI: Wang, Gupta, Gauthier), R01NS090464 (Wang) and R01 NS102267 (Pitt); NMSS RG-1602-07671 (Nguyen), Biogen (Gauthier)

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Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)