Recent developments in multiple sclerosis neuropathology

Abstract

Purpose of review: Neuropathological studies in human brain tissue are indispensable for our understanding of disease mechanisms in multiple sclerosis (MS). They inform concepts of lesion evolution, tissue regeneration and disease progression, and ideally reveal new disease mechanisms and therapeutic targets. Here we review recent neuropathological studies that have advanced our knowledge of MS pathogenesis.

Recent findings: Recent cohort studies support the notion that different clinical MS disease phenotypes share underlying pathological features, and that clinical and pathological heterogeneity is derived from a variable combination of innate and adaptive inflammation, demyelinating activity, and neuroaxonal loss. Importantly, emerging technologies for spatial transcriptome analysis enable an unprecedented glimpse into the cellular composition and molecular mechanisms involved in lesion evolution. These promising technologies will help identify the identification of molecular hubs governing tissue damage and regeneration.

Summary: Recent neuropathological studies helped to identify tissue correlates of disability and disease progression. Substantial progress in molecular brain tissue analysis revealed the complexity of MS-related tissue features. Close collaboration between tissue-based, molecular, bioinformatic, pharmacologic, imaging and clinical experts is needed to continue to advance the field, particularly for the benefit of people with progressive MS.

Keywords: cortical demyelination; microglia; multiple sclerosis; neuropathology; remyelination.

Box 1

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FIGURE 1

Cortical disease activity in progressive multiple sclerosis. Iba1+ microglia cells in a subpial cortical demyelinated area (a and c). MHCII immunohistochemistry (IHC) indicates pronounced microglia activation at the border of the demyelinated upper cortical layers to the adjacent regularly myelinated tissue (b and d). Frame (a) is magnified in (c). Double immunofluorescent IHC (a and c) for myelin basic protein (MBP) and the myeloid cell marker Iba1 (Iba1: yellow; MBP: cyclamen); light microscopic double-labellings (b and d) for MBP (blue) and MHCII (brown).

FIGURE 2

Ongoing and established cortical remyelination. BCAS1 IHC (a–d) identifies myelin sheaths and process-bearing oligodendrocytes indicative of ongoing remyelination (b). Established cortical remyelination is characterized by a reduced density of thin myelin sheaths (d). IHC, immunohistochemistry; NAC, normal-appearing cortex (a and c); RM, remyelination.