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. 2018 Apr;135(4):511-528.
doi: 10.1007/s00401-018-1818-y. Epub 2018 Feb 13.

Progressive Multiple Sclerosis Patients Show Substantial Lesion Activity That Correlates With Clinical Disease Severity and Sex: A Retrospective Autopsy Cohort Analysis

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Free PMC article

Progressive Multiple Sclerosis Patients Show Substantial Lesion Activity That Correlates With Clinical Disease Severity and Sex: A Retrospective Autopsy Cohort Analysis

Sabina Luchetti et al. Acta Neuropathol. .
Free PMC article

Abstract

Multiple sclerosis (MS) is a highly heterogeneous disease with large inter-individual differences in disease course. MS lesion pathology shows considerable heterogeneity in localization, cellular content and degree of demyelination between patients. In this study, we investigated pathological correlates of disease course in MS using the autopsy cohort of the Netherlands Brain Bank (NBB), containing 182 MS brain donors. Using a standardized autopsy procedure including systematic dissection from standard locations, 3188 tissue blocks containing 7562 MS lesions were dissected. Unbiased measurements of lesion load were made using the tissue from standard locations. Lesion demyelinating and innate inflammatory activity were visualized by immunohistochemistry for proteolipid protein and human leukocyte antigen. Lesions were classified into active, mixed active/inactive (also known as chronic active), inactive or remyelinated, while microglia/macrophage morphology was classified as ramified, amoeboid or foamy. The severity score was calculated from the time from first symptoms to EDSS-6. Lesion type prevalence and microglia/macrophage morphology were analyzed in relation to clinical course, disease severity, lesion load and sex, and in relation to each other. This analysis shows for the first time that (1) in progressive MS, with a mean disease duration of 28.6 ± 13.3 years (mean ± SD), there is substantial inflammatory lesion activity at time to death. 57% of all lesions were either active or mixed active/inactive and 78% of all patients had a mixed active/inactive lesion present; (2) patients that had a more severe disease course show a higher proportion of mixed active/inactive lesions (p = 6e-06) and a higher lesion load (p = 2e-04) at the time of death, (3) patients with a progressive disease course show a higher lesion load (p = 0.001), and a lower proportion of remyelinated lesions (p = 0.03) compared to patients with a relapsing disease course, (4) males have a higher incidence of cortical grey matter lesions (p = 0.027) and a higher proportion of mixed active/inactive lesions compared to females across the whole cohort (p = 0.007). We confirm that there is a higher proportion of mixed active/inactive lesions (p = 0.006) in progressive MS compared to relapsing disease. Identification of mixed active/inactive lesions on MRI is necessary to determine whether they can be used as a prognostic tool in living MS patients.

Keywords: Chronic active lesions; Lesion activity; Multiple sclerosis; Neuropathology; Remyelination; Sex characteristics.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Scoring MS lesion subtypes. Double immunostaining for human leukocyte antigen (HLA, in black), detecting microglia/macrophages, and proteolipid protein (PLP, in brown), detecting myelin on tissue samples from MS patients. ae white matter lesions. a Normal-appearing white matter (NAWM). b Reactive site. c Active lesion, with foamy microglia/macrophages. d Mixed active/inactive (chronic active) lesion with rounded microglia/macrophages. e Inactive lesion (arrow) and inactive remyelinated lesion (arrowhead). f Microglia/macrophage morphology score used for all active (2) and mixed active/inactive (3) lesions. 0: Ramified 0.5: Amoeboid 1: Foamy. gi Cortical grey matter lesions, g: leukocortical lesion (I), h: intracortical lesion (II, arrow). i Subpial lesions (III, arrowhead and IV arrow). Scale bar ae and gi 0.5 mm. Scale bar f 0.025 mm. Scale bar inset in c: 0.020 mm
Fig. 2
Fig. 2
Relationship between lesion activity and clinical disease severity. Patients with a more severe disease course have a higher lesion load (a) and a higher proportion of mixed active/inactive (chronic active) lesions (b) than patients with a less severe disease course. The disease severity did not correlate with the proportion of active lesions (c), the reactive load (d), the proportion of remyelinated lesions (e) or the MMAS (f). Severity score is calculated as 5-log (years to EDSS-6 +1), with shorter time to EDSS-6 the patient has a higher severity score. The relationship between each parameter and severity score is shown as a loess-smoothed fit with 95% confidence intervals. Where a significant correlation was found, the straight-line fit is shown (black-dotted line). Pearson’s product-moment correlation coefficient was used
Fig. 3
Fig. 3
Mixed active/inactive lesion presence relates to severity and lesion load. Patients with a mixed active/inactive (chronic active) lesion present (n = 141) have a more severe disease course (a) and a higher lesion load (b) compared to patients without a mixed active/inactive lesion present (n = 41). t test with unequal variances was used
Fig. 4
Fig. 4
Lesion activity in clinical MS types. Relapsing patients have a significantly lower lesion load (a), a lower proportion of mixed active/inactive (chronic active) lesions (b) and a higher proportion of remyelinated lesions (c) as compared to PP and SP MS. The proportion of active lesions (d) MMAS (e) and reactive site load (f) were not significantly different between the clinical MS types. Lesion load and reactive load were transformed as log(x + 1). The Kruskall–Wallis and Wilcoxon tests of pairs were used for lesion load and reactive load. For lesion subtype proportions and MMAS, a quasibinomial-generalized linear model was used with Tukey’s post hoc tests
Fig. 5
Fig. 5
Sex differences in MS lesion activity and cortical grey matter lesions. Males have a higher proportion of mixed active/inactive (chronic active) lesions (a, t test with unequal variances was used) and a higher incidence of cortical grey matter lesions (b, Fisher’s exact test) as compared to females
Fig. 6
Fig. 6
The relationship between lesion load and lesion activity. The lesion load positively correlates with the proportion of mixed active/inactive (chronic active) lesions (a), MMAS (b), and reactive load (c), whereas it negatively correlates with the proportion of remyelinated lesions (d). The proportion of active lesions (e) did not significantly correlate with lesion load. The relationship between each parameter and lesion load is shown as a loess-smoothed fit with 95% confidence intervals. Where a significant correlation was found, the straight-line fit is shown (black-dotted line). Pearson’s product-moment correlation coefficient was used
Fig. 7
Fig. 7
The relationship between the presence of cortical grey matter lesions and white matter lesion activity. Patients with cortical grey matter lesions have a significantly higher lesion load (a), higher reactive load (c), higher proportion of mixed active/inactive (chronic active) lesions (b) and a lower proportion of remyelinated lesions (d). Lesion load and reactive load were determined in standardly dissected brainstem tissue blocks and proportions of chronic active and remyelinated lesions were determined in white matter. t test with unequal variance was used
Fig. 8
Fig. 8
The relationship between active lesion proportion and mixed active/inactive lesion proportion with lesion activity. The proportion of active lesions significantly correlated with the MMAS (a) and the reactive site load (log transformed) (b). There is no relationship between the proportion of active lesions and mixed active/inactive (chronic active) lesions (c), whereas the proportion of mixed active/inactive lesions inversely correlated with the proportion of remyelinated lesions (d). Pearson’s product-moment correlation coefficient was used
Fig. 9
Fig. 9
Overview of lesion activity scoring and correlates shown in analysis. Examples are shown of each subtype of white and grey matter lesions, and of microglial/macrophage morphology scoring. Alongside are shown their definitions and significant correlations

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