MS lesion characterization

Characterization and analysis of MS lesions of the NBB autopsy cohort

Nina L. Fransen, PhD student

Figure 1: HLA-PLP immunohistochemistry on tissue samples from MS cases, PLP is brown, HLA is black (DAB-nickel). a NAWM b Reactive site c active lesion d mixed active/inactive (chronic active) lesion e inactive lesion and inactive remyelinated lesion f microglia-macrophage morphology subscore used for all active and mixed active/inactive lesions. 0 Ramified 0.5 Rounded 1 Foamy. g leukocortical lesion 5I h intracortical lesion 5II i subpial lesions 5III and 5IV. Scalebar A-G and I-K represents 0.5mm, in H 0.025 mm.

Multiple sclerosis (MS) is a heterogeneous disease with large inter-individual differences in disease course, response to therapies and MS lesion pathology. We hypothesize that heterogeneity in the disease course is correlates with demyelination and microglia/macrophage activity at the end stage of the disease at autopsy. We studied 182 clinically well documented MS cases that came to autopsy at Netherlands Brain Bank (NBB) between 1990 and 2015. Using a standardized autopsy procedure including dissection of MS lesions apparent macropscopically or on post mortem MRI guidance and systematic dissection of axial slices from the spinal cord and brain stem, 3188 tissue blocks containing 7562 MS lesions were analyzed. Demyelinating and innate inflammatory activity were visualized by immunohistochemistry for proteolipid protein (PLP) and human leukocyte antigen (HLA). 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. In addition, reactive sites with activated microglia/macrophages but absence of demyelination were distinguished. Cortical grey matter demyelination was scored and classified into leukocortical, intracortical, and subpial lesions (Fig. 1).

The 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 cases had a mixed active/inactive lesion present; (2) cases 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) cases 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 cases 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.¹

We are currently quantifying T cells, B cells and axonal damage in relation to lesion activity and clinical characteristics, and also analyze SNPs that previously showed an associated with clinical disease severity in relation to pathological characteristics.

¹Luchetti & Fransen et al. , Acta Neuropathologica, in revision.