Disentangling the Heterogeneity of Multiple Sclerosis Through Identification of Independent Neuropathological Dimensions

Medical Laboratory Science Neurology Life Sciences Immunology Medicine Cell Biology
multiple sclerosis neuropathology genetics factor analysis lesions immune system disease heterogeneity

Research Background

Multiple Sclerosis (MS) is a common disease involving lesions in the central nervous system, characterized mainly by demyelination of neuronal axons and neuronal damage. The heterogeneity of the disease is extremely high, meaning that different patients exhibit varying symptoms and pathological mechanisms, which greatly complicates treatment and prognosis assessment. Therefore, this study aims to identify independent neuropathological dimensions within the disease through exploratory factor analysis of brain pathological data from 226 MS donors, thereby achieving more precise pathological classification.

Source of the Paper

This paper was jointly written by Alyse de Boer, Aletta M.R. van den Bosch, Nienke J. Mekkes, Nina L. Fransen, and other researchers affiliated with multiple research institutions including the University Medical Center Groningen, and the Amsterdam University Medical Centers. The paper was published in 2024 in the journal Acta Neuropathologica.

Research Process

The study identified three independent dimensions through factor analysis of neuropathological data from 226 MS donors, followed by further validation with clinical, neuropathological, and genetic data.

a) Detailed Introduction of the Research Process: 1. Brain Pathological Anatomy and Sample Processing:
Starting from 2001, autopsy MRI guidance was used to increase sampling of active demyelinating lesions and reactive sites. Tissue was classified based on double immunostaining of proteolipids and human leukocyte antigens. 2. Types of White Matter Lesions Included:
Active lesions, mixed lesions, inactive lesions, and remyelinated lesions. 3. Microglial Morphological Analysis:
Major morphologies of microglia in different active lesions were identified and activation scores were calculated. 4. Data Preparation and Factor Analysis (FAMD):
Data cleaning and transformation were performed, ultimately selecting three dimensions for in-depth analysis. 5. Validation of Clinical, Neuropathological, and Genetic Data:
Statistical methods were used to validate the relationship between the dimensions and clinical manifestations, neuropathological features, and genetic factors.

Presentation of Research Results

b) Main Research Results:
The study identified three independent anatomical dimensions, each reflecting different pathological features associated with MS.

Dimension 1: Shorter disease course and higher disease severity with higher lesion load, more active and mixed lesions, and foamy microglia presence. This dimension is also related to cortical lesions and the presence of B and T cells, suggesting it may be associated with immune cell activity and the progression of demyelinating lesions.

Dimension 2: Longer disease course with milder disease, more active lesions, and reactive regions. At the molecular level, this dimension is associated with MS risk variations in the human leukocyte antigen region, suggesting it may be related to lesion initiation.

Dimension 3: Reduced lesion activity and relatively longer disease course, with increased cortical lesion load and mixed lesion ratio. Biomarker data analysis revealed this dimension is associated with low involvement of the adaptive immune system and lesser neuronal axon damage, indicating it may reflect the loss of lesion activity and scar formation.

Conclusion and Significance of the Study

c) Conclusion and Value of the Study:
The study provides a deeper understanding of the heterogeneity of MS by identifying multi-dimensional pathological features. The three independent dimensions reveal the roles of various factors in immune cell activity, demyelination progression, and the loss of lesion activity, offering new perspectives for individualized treatment and prognosis.

These findings highlight the importance of the interaction of multiple pathological features and generate associations between MS, its genetic predictors, and disease outcomes. The results can help more accurately identify patients in clinical practice and develop individualized treatment plans, further advancing the study of MS heterogeneity and providing important insights for the observation and intervention in living patients.

d) Research Highlights:
- Identified three independent anatomical dimensions, fully reflecting the heterogeneity of MS. - Detailed data analysis process and multi-dimensional validation ensure the reliability of the research results. - The association analysis with clinical severity, neuronal axon damage, and genetic screening results highlights the clinical relevance of each dimension.

Other Valuable Information

Although the study demonstrates the independence of the three dimensions, these dimensions are not completely independent in individual patients, which will provide a basis for further combined analysis. Considering that the research data mainly focus on white matter pathology, future studies should include gray matter pathology and other cell types to enhance the comprehensive understanding of MS.

Further understanding of these dimensions and their associations with clinical, biological, and genetic markers will aid in classifying MS patients based on pathological biology, applying this knowledge in research and clinical practice, and ultimately improving patient treatment outcomes and quality of life.