[Multiple sclerosis; review].

Pathological evaluation is the gold standard for identifying processes related to multiple sclerosis that explain disease manifestations, and for guiding the development of new treatments. However, there are limitations to the techniques used, including the small number of donors available, samples often representing uncommon cases, and impossibility of follow-up. Correlative studies have demonstrated that MRI is sensitive to the different pathological substrates of multiple sclerosis (inflammation, demyelination, and neuro-axonal loss). The role of MRI in evaluating other pathological processes, such as leptomeningeal involvement, central vein and rim of lesions, microstructural abnormalities, iron accumulation, and recovery mechanisms, has been investigated. Although techniques used for quantifying pathological processes in different regions of the CNS have advanced diagnosis and monitoring of disease course and treatment of multiple sclerosis, new perspectives and questions have emerged, including how different pathological processes interact over the disease course and when remyelination might occur. Addressing these questions will require longitudinal studies using MRI in large cohorts of patients with different phenotypes.

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Association between pathological and MRI findings in multiple sclerosis

During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus In addition, imaging methods as well as biomarkers are not well established Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches

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Progressive multiple sclerosis: from pathogenic mechanisms to treatment.

Oligodendrocytes generate multiple layers of myelin membrane around axons of the central nervous system to enable fast and efficient nerve conduction. Until recently, saltatory nerve conduction was...

Myelin in the Central Nervous System: Structure, Function, and Pathology.

This article provides a comprehensive overview of the pathology of multiple sclerosis (MS), including recent insights into its molecular neuropathology and immunology It shows that all clinical manifestations of relapsing and progressive MS display the same basic features of pathology, such as chronic inflammation, demyelination in the white and gray matter, and diffuse neurodegeneration within the entire central nervous system However, the individual components of the pathological spectrum vary quantitatively between early relapsing and late progressive MS Widespread confluent and plaque-like demyelination with oligodendrocyte destruction is the unique pathological hallmark of the disease, but axonal injury and neurodegeneration are additionally present and in part extensive Remyelination of existing lesions may occur in MS brains; it is extensive in a subset of patients, while it fails in others Active tissue injury in MS is always associated with inflammation, consistent with T-cell and macrophage infiltration and microglia activation Recent data suggest that oxidative injury and subsequent mitochondrial damage play a major pathogenetic role in neurodegeneration Finally we discuss similarities and differences of the pathology between classical MS and other inflammatory demyelinating diseases, such as neuromyelitis optica, concentric sclerosis, or acute disseminated encephalomyelitis

Pathology of multiple sclerosis and related inflammatory demyelinating diseases.

Objective:

The study was undertaken to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis brains.



Methods:

Brain tissues were obtained through a rapid postmortem protocol that included in situ magnetic resonance imaging (MRI). Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) regions that were abnormal on all images (T2T1MTR lesions); (2) NAWM regions with slightly abnormal MTR located close to white matter lesions (sa-WM Close); (3) NAWM regions with slightly abnormal MTR located far from lesions (sa-WM Far); and (4) NAWM regions with normal MTR (NAWM). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins, and blood vessels.



Results:

Forty-eight ROIs from 4 secondary progressive MS brains were analyzed. sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged major histocompatibility complex II+ microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area, and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in nonlesional white matter (WM) were correlated with activated microglia, but not with axonal or myelin integrity.



Interpretation:

The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities. ANN NEUROL 2011

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Amy J. Ransohoff

Papers

Multiple sclerosis normal-appearing white matter: pathology-imaging correlations.

Decision regret after failed autologous in vitro fertilization in women ≥42 years of age.