Frischer, Josa M.

ObjectiveHistology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I–III). In patterns I and II, a T‐cell‐ and macrophage‐associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers.MethodsWe evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow‐up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112).ResultsA strong association of a ringlike enhancement and a hypointense T2‐weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients.InterpretationWe provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440–454

ObjectiveMultiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains, suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown.MethodsWe used synchrotron X‐ray fluorescence imaging, histology, and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients.ResultsImmunopattern II early active lesions contain 64% more iron (95% confidence interval [CI] = 17–127%, p = 0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95% CI = 3–64%, p = 0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95% CI = −40 to −14%, p < 0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p < 0.001). Microfocused X‐ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, whereas macrophages in immunopattern III lesions contain little iron.InterpretationIron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions. This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin, or different demyelination mechanisms, and paves the way for developing new or using existing iron‐sensitive magnetic resonance imaging techniques to differentiate among immunopatterns in the general nonbiopsied MS patient population. ANN NEUROL 2021;89:498–510

ObjectiveAn extensive analysis of white matter plaques in a large sample of multiple sclerosis (MS) autopsies provides insights into the dynamic nature of MS pathology.MethodsOne hundred twenty MS cases (1,220 tissue blocks) were included. Plaque types were classified according to demyelinating activity based on stringent criteria. Early active, late active, smoldering, inactive, and shadow plaques were distinguished. A total of 2,476 MS white matter plaques were identified. Plaque type distribution was analyzed in relation to clinical data.ResultsActive plaques were most often found in early disease, whereas at later stages, smoldering, inactive, and shadow plaques predominated. The presence of early active plaques rapidly declined with disease duration. Plaque type distribution differed significantly by clinical course. The majority of plaques in acute monophasic and relapsing–remitting MS (RRMS) were active. Among secondary progressive MS (SPMS) cases with attacks, all plaque types could be distinguished including active plaques, in contrast to SPMS without attacks, in which inactive plaques predominated. Smoldering plaques were frequently and almost exclusively found in progressive MS. At 47 years of age, an equilibrium was observed between active and inactive plaques, whereas smoldering plaques began to peak. Men displayed a higher proportion of smoldering plaques.InterpretationDisease duration, clinical course, age, and gender contribute to the dynamic nature of white matter MS pathology. Active MS plaques predominate in acute and early RRMS and are the likely substrate of clinical attacks. Progressive MS transitions to an accumulation of smoldering plaques characterized by microglial activation and slow expansion of pre‐existing plaques. Whether current MS therapeutics impact this pathological driver of disease progression remains uncertain. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696

Objective Multiple sclerosis (MS) lesions demonstrate immunopathological heterogeneity in patterns of demyelination. Previous cross‐sectional studies reported immunopatterns of demyelination were identical among multiple active demyelinating lesions from the same individual, but differed between individuals, leading to the hypothesis of intraindividual pathological homogeneity and interindividual heterogeneity. Other groups suggested a time‐dependent heterogeneity of lesions. The objective of our present study was to analyze tissue samples collected longitudinally to determine whether patterns of demyelination persist over time within a given patient. Methods Archival tissue samples derived from patients with pathologically confirmed central nervous system inflammatory demyelinating disease who had undergone either diagnostic serial biopsy or biopsy followed by autopsy were analyzed immunohistochemically. The inclusion criteria consisted of the presence of early active demyelinating lesions—required for immunopattern classification—obtained from the same patient at 2 or more time points. Results Among 1,321 surgical biopsies consistent with MS, 22 cases met the study inclusion criteria. Twenty‐one patients (95%) showed a persistence of immunopathological patterns in tissue sampled from different time points. This persistence was demonstrated for all major patterns of demyelination. A single patient showed features suggestive of both pattern II and pattern III on biopsy, but only pattern II among all active lesions examined at autopsy. Interpretation These findings continue to support the concept of patient‐dependent immunopathological heterogeneity in early MS and suggest that the mechanisms and targets of tissue injury may differ among patient subgroups. These observations have potentially significant implications for individualized therapeutic approaches. Ann Neurol 2014;75:728–738