Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions

Abstract

Chronic active multiple sclerosis lesions, characterized by a hyperintense rim of iron-enriched, activated microglia and macrophages, have been linked to greater tissue damage. Post-mortem studies have determined that chronic active lesions are primarily related to the later stages of multiple sclerosis; however, the occurrence of these lesions, and their relationship to earlier disease stages may be greatly underestimated. Detection of chronic active lesions across the patient spectrum of multiple sclerosis requires a validated imaging tool to accurately identify lesions with persistent inflammation. Quantitative susceptibility mapping provides efficient in vivo quantification of susceptibility changes related to iron deposition and the potential to identify lesions harbouring iron-laden inflammatory cells. The PET tracer 11 C-PK11195 targets the translocator protein expressed by activated microglia and infiltrating macrophages. Accordingly, this study aimed to validate that lesions with a hyperintense rim on quantitative susceptibility mapping from both relapsing and progressive patients demonstrate a higher level of innate immune activation as measured on 11 C-PK11195 PET. Thirty patients were enrolled in this study, 24 patients had relapsing remitting multiple sclerosis, six had progressive multiple sclerosis, and all patients had concomitant MRI with a gradient echo sequence and PET with 11 C-PK11195. A total of 406 chronic lesions were detected, and 43 chronic lesions with a hyperintense rim on quantitative susceptibility mapping were identified as rim + lesions. Susceptibility (relative to CSF) was higher in rim + (2.42 AE 17.45 ppb) compared to rimÀ lesions (À14.6 AE 19.3 ppb, P 5 0.0001). Among rim + lesions, susceptibility within the rim (20.04 AE 14.28 ppb) was significantly higher compared to the core (À5.49 AE 14.44 ppb, P 5 0.0001), consistent with the presence of iron. In a mixed-effects model, 11 C-PK11195 uptake, representing activated microglia/macrophages, was higher in rim + lesions compared to rimÀ lesions (P = 0.015). Validating our in vivo imaging results, multiple sclerosis brain slabs were imaged with quantitative susceptibility mapping and processed for immunohistochemistry. These results showed a positive translocator protein signal throughout the expansive hyperintense border of rim + lesions, which co-localized with iron containing CD68 + microglia and macrophages. In conclusion, this study provides evidence that suggests that a hyperintense rim on quantitative susceptibility measure within a chronic lesion is a correlate for persistent inflammatory activity and that these lesions can be identified in the relapsing patients. Utilizing quantitative susceptibility measure to differentiate chronic multiple sclerosis lesion subtypes, especially chronic active lesions, would provide a method to assess the impact of these lesions on disease progression.

Microglia in Multiple Sclerosis: Friend or Foe?

“…The interaction between QSM and TSPO was explored in a study that found that 11C-(R)-PK11195 uptake was higher in rim positive lesions compared to rim negative lesions and this was also confirmed with post mortem immunohistochemistry for iron containing CD68 positive cells (63). These findings suggest that QSM detectable rims do contain activated microglia.…”

Clinical Integration of Automated Processing for Brain Quantitative Susceptibility Mapping: Multi‐Site Reproducibility and Single‐Site Robustness

“…The QSM reconstruction itself is fully automated, including the referencing of the susceptibility values with respect to the ventricular CSF, chemically close to pure water. This automated zero‐reference during reconstruction improves image quality, provides absolute susceptibility values, and allows longitudinal and cross‐center studies, which are important for monitoring disease progression and therapy of many neurological diseases, including MS, cerebral cavernous malformation, and Parkinson's disease, and for mapping cerebral metabolic rate of oxygen consumption and biodistribution of magnetic theranostics …”

Imaging Mechanisms of Disease Progression in Multiple Sclerosis: Beyond Brain Atrophy

“…Most of the activated macrophages and microglia found at the rim of chronic active MS lesions contain iron, 51‐53 which causes a paramagnetic susceptibility shift and makes them visible on phase images generated from susceptibility‐weighted MRI at high field strength or on R2*/T2* maps generated from multi‐echo gradient echo (GRE) sequences 52,54‐59 . 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 60‐63 . Using TSPO‐PET, it has been demonstrated that lesions with a rim of hyperintensity on QSM (rim+) have a significantly higher level of inflammation as compared with lesions lacking this rim (Fig 1A).…”