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.

多发性硬化症（MS）是一种高度异质性的疾病，其病程存在较大的个体差异。MS 病变病理学显示患者之间在定位、细胞含量和脱髓鞘程度方面存在相当大的异质性。在这项研究中，我们利用荷兰脑库 (NBB) 的尸检队列（包含 182 名 MS 脑捐献者）调查了 MS 病程的病理相关性。使用标准化尸检程序，包括从标准位置进行系统解剖，解剖了包含 7562 个 MS 病变的 3188 个组织块。使用来自标准位置的组织对病变负荷进行无偏测量。通过蛋白脂质蛋白和人白细胞抗原的免疫组织化学观察病变脱髓鞘和先天炎症活动。病变分为活动性、混合性活动/非活动性（也称为慢性活动性）、非活动性或髓鞘再生，而小胶质细胞/巨噬细胞形态分为分枝状、变形虫状或泡沫状。严重程度评分是从首次出现症状到 EDSS-6 的时间计算的。分析病变类型患病率和小胶质细胞/巨噬细胞形态与临床病程、疾病严重程度、病变负荷和性别的关系以及彼此之间的关系。该分析首次表明 (1) 在平均病程为 28.6 ± 13.3 年（平均值 ± 标准差）的进行性多发性硬化症中，死亡时存在大量炎症病变活动。57% 的所有病变为活动性或混合性活动/非活动性病变，78% 的患者存在混合性活动/非活动性病变；(2) 病程较严重的患者 在死亡时表现出较高比例的混合活动性/非活动性病变 ( p  = 6e−06) 和较高的病变负荷 ( p = 2e−04)，(3) 患者与复发性病程的患者相比，具有进展性病程的患者病变负荷较高（p  = 0.001），髓鞘再生病变比例较低（p =  0.03），（4）男性皮质灰质病变发生率较高( p  = 0.027)，并且与整个队列中的女性相比，混合活动/非活动病变的比例更高 ( p  = 0.007)。 我们证实，与复发性疾病相比，进行性 MS 中混合活动/非活动病变的比例更高 ( p = 0.006)。MRI 上识别混合活动/非活动病变对于确定它们是否可以用作活着的多发性硬化症患者的预后工具是必要的。