Subventricular Zone Microstructure in Pediatric-Onset Multiple Sclerosis

Abstract

Objective: The aim of this study was to explore the microstructural dynamics of the subventricular zone (SVZ) with aging and their associations with clinical disability and brain structural damage in pediatric-onset multiple sclerosis (MS) patients.

Methods: One-hundred and forty-one pediatric-onset MS patients (67 pediatric and 74 adults with pediatric-onset) and 233 healthy controls (HC) underwent neurological and 3.0 T MRI assessment. Fractional anisotropy (FA) and mean diffusivity (MD) were extracted from the SVZ and the thalamus (as control region).

Results: In HC, SVZ FA was higher until age 40 then declined, whereas MD was lower until age 35 before rising (false discovery rate p value [pFDR] ≤ 0.008). Thalamic FA was higher until age 30 and then declined, whereas MD was higher until age 50 (pFDR ≤ 0.007). Pediatric MS patients showed significantly higher SVZ FA than pediatric HC (pFDR < 0.001), while adult patients showed no differences compared to adult HC (pFDR ≤ 0.724). Adult patients had lower thalamic FA and higher MD (pFDR < 0.001). Adults had lower SVZ FA and MD, but higher thalamic MD compared to pediatric patients (pFDR < 0.001). In pediatric MS, higher SVZ FA and MD were associated with higher white matter (WM) lesion volume (LV) and choroid plexus volume and lower brain and thalamic volumes (pFDR ≤ 0.047). In adult patients, higher SVZ MD associated with higher WM LV, lower brain volumes, and lower z-SDMT (pFDR≤0.019). Thalamic microstructural abnormalities were associated with more severe disability and brain damage in both groups (pFDR ≤ 0.018).

Interpretation: Our findings suggest that microstructural changes in the SVZ occur early in pediatric MS and are associated with brain structural damage but not with clinical impairment. ANN NEUROL 2025;97:979-992.

FIGURE 1

Identification of the subventricular zone and thalamic control region and methodological workflow. (A) Anatomical localization of the subventricular zone (red) located in‐between the caudate nucleus (light blue) and the CSF; in blue the band of the thalamus (green) close to the CSF which serves as region of control (created with biorender.com). (B) Coronal plane of T1‐weighted sequence showing the thalamus and caudate nucleus with superimposed the created masks for the subventricular zone and thalamic region. (C) The masks created on T1‐weighted sequence were co‐registered to the b0 image and then superimposed on FA (D) and MD (E) maps. See text for further details. CSF = cerebrospinal fluid; FA = fractional anisotropy; MD = mean diffusivity [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 2

Estimated sex‐adjusted DTI metrics lifespan trajectories in the subventricular zone and thalamic region of healthy controls. The figure shows mean estimated sex‐adjusted DTI values (solid lines with 95% shaded CIs) in the (A, B) subventricular zone and (C, D) thalamus. CI = confidence interval; FA = fractional anisotropy; DTI = diffusion tensor imaging; MD = mean diffusivity; SVZ = subventricular zone [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 3

DTI z‐score distribution in pediatric multiple sclerosis and adults with pediatric‐onset multiple sclerosis patients compared to their relative healthy controls. Violin plots show the distribution of FA and MD z‐scores in the (A, B) subventricular zone and (C, D) thalamus, in pediatric healthy controls and pediatric multiple sclerosis and adult healthy controls and adults with pediatric‐onset multiple sclerosis. FDR correction (Benjamini–Hochberg procedure) was applied. See main text and Table 3 for further details. DTI = diffusion tensor imaging; FA = fractional anisotropy; FDR = false discovery rate; HC = healthy controls; MD = mean diffusivity; MS = multiple sclerosis [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 4

Representations of the subventricular zone in the normal brain and of the possible changes occurring in multiple sclerosis. The subventricular zone is located directly beneath the ependymal layer on the lateral wall of the lateral ventricles. The control subventricular zone (green box) is composed of a ribbon of astrocytes separated from the ependymal wall by a hypocellular gap, containing few early progenitors. In multiple sclerosis subventricular zone (red box), the density of astrocytes and early progenitors is increased. The presence of progenitors with a bipolar morphology suggests their potential migration away from the subventricular zone. SVZ = subventricular zone [Color figure can be viewed at www.annalsofneurology.org]