Innate immune cells and myelin profile in multiple sclerosis: a multi-tracer PET/MR study

Neuropathological studies have demonstrated distinct profiles of microglia activation and myelin injury among different multiple sclerosis (MS) phenotypes and disability stages. PET imaging using specific tracers may uncover the in vivo molecular pathology and broaden the understanding of the disease heterogeneity.

We used the 18-kDa translocator protein (TSPO) tracer (R)-[¹¹C]PK11195 and [¹¹C]PIB PET images acquired in a hybrid PET/MR 3 T system to characterize, respectively, the profile of innate immune cells and myelin content in 47 patients with MS compared to 18 healthy controls (HC). For the volume of interest (VOI)-based analysis of the dynamic data, (R)-[¹¹C]PK11195 distribution volume (V_T) was determined for each subject using a metabolite-corrected arterial plasma input function while [¹¹C]PIB distribution volume ratio (DVR) was estimated using a reference region extracted by a supervised clustering algorithm. A voxel-based analysis was also performed using Statistical Parametric Mapping. Functional disability was evaluated by the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Symbol Digit Modality Test (SDMT).

In the VOI-based analysis, [¹¹C]PIB DVR differed between patients and HC in the corpus callosum (P = 0.019) while no differences in (R)-[¹¹C]PK11195 V_T were observed in patients relative to HC. Furthermore, no correlations or associations were observed between both tracers within the VOI analyzed. In the voxel-based analysis, high (R)-[¹¹C]PK11195 uptake was observed diffusively in the white matter (WM) when comparing the progressive phenotype and HC, and lower [¹¹C]PIB uptake was observed in certain WM regions when comparing the relapsing-remitting phenotype and HC. None of the tracers were able to differentiate phenotypes at voxel or VOI level in our cohort. Linear regression models adjusted for age, sex, and phenotype demonstrated that higher EDSS was associated with an increased (R)-[¹¹C]PK11195 V_T and lower [¹¹C]PIB DVR in corpus callosum (P = 0.001; P = 0.023), caudate (P = 0.015; P = 0.008), and total T₂ lesion (P = 0.007; P = 0.012), while better cognitive scores in SDMT were associated with higher [¹¹C]PIB DVR in the corpus callosum (P = 0.001), and lower (R)-[¹¹C]PK11195 V_T (P = 0.013).

Widespread innate immune cells profile and marked loss of myelin in T₂ lesions and regions close to the ventricles may occur independently and are associated with disability, in both WM and GM structures.