Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise

Area of Science:

• Neuroimaging and Demyelinating Diseases
• Multiple Sclerosis Pathophysiology
• White Matter Abnormalities

Background:

• Normal-appearing white matter (NAWM) in multiple sclerosis (MS) exhibits subtle abnormalities.
• The precise pathology and spatial distribution of these NAWM alterations remain poorly understood.
• Understanding these early changes is crucial for predicting lesion formation and disease progression.

Purpose of the Study:

• To evaluate NAWM abnormalities in brain regions that subsequently develop MS lesions.
• To investigate the spatial distribution of NAWM abnormalities in individuals with MS.
• To identify early indicators of tissue alteration preceding clinical or MRI-detected lesion development.

Main Methods:

• Analysis of brain MRIs from three large clinical trials (SYNERGY, ASCEND, ADVANCE) involving patients with MS.
• Focus on pre-lesion NAWM using normalized magnetization transfer ratio (nMT) and T2-weighted (nT2) intensities.
• Comparison of pre-lesion NAWM with overall NAWM and spatially matched contralateral NAWM using linear mixed-effects models.

Main Results:

• Pre-lesion NAWM showed significantly higher nT2 intensity and lower nMT compared to overall and contralateral NAWM up to 2 years before new T2 lesion onset.
• Contralateral NAWM also exhibited higher nT2 intensity compared to overall NAWM in the pre-lesion phase.
• Generated brain atlases revealed that the spatial distribution of NAWM abnormalities mirrors the anatomical distribution of T2 hyperintense lesions.

Conclusions:

• Intrinsic spatial properties and longstanding precursory abnormalities in NAWM are implicated in MS.
• These early NAWM changes may contribute to the risk of acute demyelination in multiple sclerosis.
• Findings highlight the importance of studying NAWM for understanding MS pathogenesis and predicting lesion development.