Exploratory Associations Between Multimodal MRI-Derived Features and Neurological Symptoms in Wolfram Syndrome: A Spanish Cohort Pilot Study

Background/Objectives: Wolfram syndrome is an ultra-rare, progressive multisystem disorder in which endocrine and sensory manifestations coexist with neurological involvement. Quantitative magnetic resonance imaging (MRI) may help characterize central nervous system involvement in this condition; however, evidence derived from small imaging cohorts requires cautious interpretation. This study aimed to examine the relationships between different MRI-derived attributes and neurological symptoms in Wolfram syndrome, with the goal of identifying exploratory imaging patterns that may suggest the involvement of specific neural systems. Methods: We analyzed a Spanish cohort of 45 genetically confirmed patients with Wolfram syndrome. A homogeneous subset of 15 patients with standardized 3-Tesla multimodal MRI and adequate image quality was included in the quantitative imaging analysis. T1-weighted MRI, T2-weighted/fluid-attenuated inversion recovery (FLAIR) imaging, and diffusion tensor imaging (DTI) were processed using a standardized workflow for brain extraction, anatomical segmentation, cortical reconstruction, and quantitative feature extraction. A total of 172 MRI-derived features were examined in relation to neurological phenotypes, including dysphagia, ataxia, gait instability, and cognitive impairment. Analyses included principal component analysis, exploratory factor analysis, correlation analyses, and symptom-specific group comparisons. Given the small MRI sample size and the high feature-to-subject ratio, all analyses were considered exploratory and hypothesis-generating, and the findings should be interpreted cautiously pending validation in larger, independent cohorts. Results: Multimodal MRI-derived features showed distributed associations with neurological manifestations. The most recurrent exploratory imaging correlates involved the thalamus, lateral geniculate nucleus, cerebellum, brainstem, ventricular system, corpus callosum, posterior cortical regions, and white-matter pathways. FLAIR-derived signal heterogeneity in the thalamus and lateral geniculate nucleus appeared repeatedly across several clinical manifestations. Dysphagia was associated with a distributed pattern involving cortical thinning, thalamic and brainstem volume reduction, reduced cerebellar white-matter integrity, increased FLAIR heterogeneity, and ventricular enlargement. Ataxia and gait instability showed overlapping but partially distinct imaging profiles, whereas cognitive impairment was associated with broader cortical, subcortical, callosal, cerebellar, and ventricular alterations. Conclusions: In this exploratory pilot study, multimodal MRI-derived features showed clinically plausible associations with neurological manifestations in Wolfram syndrome. The findings support a distributed model of neurological involvement affecting cerebello-thalamo-cortical circuits, visual relay structures, brainstem pathways, and long-range white-matter connections. These results should be interpreted as exploratory MRI-derived attributes rather than as validated biomarkers, prognostic indicators, or clinically applicable imaging signatures. Confirmation in future longitudinal, multicenter studies with harmonized imaging protocols and external validation will be required.