Preprint Normal appearing white matter and disability in multiple sclerosis, 2025, Stepanov et al.

[SNT Gatchaman]

Normal appearing white matter and disability in multiple sclerosis

Spoiler: Authors / NYU

Valentin N Stepanov; Santiago Coelho; Benjamin Ades-aron; Jenny Chen; Timothy M Shepherd; Dmitry S Novikov; Ilya Kister; Els Fieremans

BACKGROUND AND OBJECTIVES
Multiple sclerosis (MS) is characterized by lesions and atrophy on conventional MRI, yet these often fail to explain disability. Diffusion MRI (dMRI) detects microstructural injury with diffusion tensor (DTI) and kurtosis imaging (DKI) offering sensitivity, and Standard Model Imaging (SMI) providing biologically interpretable parameters. We evaluated whether these clinically feasible dMRI metrics are associated with disability beyond volumetric and lesion measures, and whether effects arise from normal-appearing white matter (NAWM).

METHODS
This cross-sectional study included MS patients who underwent 3T MRI including T1-and T2-weighted and a ~7-minute multi-shell dMRI protocol. Brain volumes (gray matter, white matter, thalamus) and lesion load were derived using FreeSurfer and Icobrain. Diffusion metrics included radial diffusivity (RD) from DTI, radial kurtosis (RK) from DKI, intra-axonal water fraction (f) and fiber dispersion (p2) from SMI. Clinical outcomes were the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), 9-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), and disease duration. Voxelwise and tract-based regions of interest analyses were adjusted for sex and age at onset and repeated after excluding lesions.

RESULTS
Ninety-two patients (68 women; mean age 48, range 24-73; median disease duration 14 years; EDSS 3.0, range 0-8.5) were included. dMRI revealed widespread associations with all clinical measures that persisted after lesion exclusion, implicating NAWM. Functional outcomes were tract-specific: 9HPT correlated with corticospinal tract and optic radiations (RD r=0.45; RK r=-0.44; f r=-0.42); MSFC with brainstem and optic radiations (RD r=-0.52; RK r=0.40; f r=0.39). SDMT showed widespread correlation with diffusion and atrophy (white matter r=0.49; thalamus r=0.47). EDSS showed weaker diffusion highlighting commissural disorganization (forceps major/minor r=(-0.30 to -0.32) and was most strongly associated to infratentorial lesion load (r=0.42). Disease duration was dominated by gray-matter atrophy (r=-0.54) with commissural p2 reductions (r-0.45).

DISCUSSION
dMRI detects NAWM injury underlying functional impairment beyond atrophy and lesions. SMI adds specificity (f for axonal loss/demyelination; p2 for inflammation). Structural measures capture the effect of cumulative burden in terms of disease duration and EDSS. Together, diffusion, volumetric, and lesion metrics offer complementary insights, supporting multimodal imaging for MS monitoring and stratification.

Keywords: Multiple Sclerosis (MS), Diffusion Tensor Imaging (DTI), Diffusion Kurtosis Imaging (DKI), Standard Model of Diffusion (SMI), Brain Volume, Microstructural Pathology, Disease Progression.

Web | PDF | Preprint: MedRxiv | Open Access

 

[SNT Gatchaman]

DTI- and DKI-derived measures showed robust, tract-specific associations with motor and cognitive outcomes, largely driven by NAWM pathology.

In interpreting the MRI associations, we noted that the outcome measures could be grouped based on both their clinical nature and the patterns of correlations observed. EDSS and disease duration showed broad, non-specific diffusion associations, consistent with cumulative burden. In contrast, MSFC and 9HPT, composed of timed performance tasks, displayed more focal, tract-specific associations, justifying their classification as ‘functional’ outcomes. SDMT showed distributed associations across diffusion and structural metrics, in line with its multifactorial demands on processing speed, attention, and motor output. These distinctions motivated the use of terms such as “cumulative disease burden” for EDSS and disease duration, and “functional” for MSFC and 9HPT.

EDSS reflects both motor disability, whereas disease duration primarily tracks long-term structural damage. Structural measures were less strongly associated with motor performance but captured cumulative effects.

These findings support the hypothesis that microstructural degeneration in NAWM precedes measurable atrophy, with diffusion abnormalities explaining functional impairment, while volumetric atrophy and lesion burden reflect cumulative damage. This temporal sequence provides a unifying framework for interpreting the complementary roles of diffusion and structural imaging in MS. These results suggest that microstructural changes may precede measurable atrophy, although longitudinal studies are needed to confirm this sequence.

So much for MS with functional overlay / comorbid FND. The symptoms and disability are driven by pathology in the normal appearing white matter.

FND may simply be a structural problem (that we're only now beginning to see) where the function can be abnormal in unusual/non-standard ways: not a fixed defect (a binary of always working vs always broken) but non-deterministic.

It would be similar to the "normal appearing white matter" (NAWM) in MS, which absolutely isn't at autopsy, now able to be shown in vivo with advanced MRI techniques. This gets diagnosed as "MS with FND overlay".

Functional neurological disorder in multiple sclerosis: A prospective study (2025)

The borderland of multiple sclerosis and functional neurological disorder: A call for clinical research and vigilance (2022)

Functional neurological disorder and multiple sclerosis: a systematic review of misdiagnosis and clinical overlap (2021)