Spatial and Temporal Distribution of White Matter Lesions in NOTCH2NLC-Related Neuronal Intranuclear Inclusion Disease.

Background and objectives: NOTCH2NLC-related neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease with characteristic white matter lesions (WMLs) visible on MRI. However, the distribution of WMLs and their clinical correlations remain poorly understood in NIID. This study aims to investigate the spatial and temporal distribution of WMLs in the brain of patients with NOTCH2NLC-related NIID.

Methods: We retrospectively evaluated patients diagnosed with NOTCH2NLC-related NIID in Zhongshan Hospital, Fudan University. Detailed clinical information, including retrospective MRI data, was collected. Spatial distribution of WMLs with fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) hyperintensities was quantified, and the relationship between WML distribution and clinical presentations was analyzed by the Fisher exact test. The volume of whole-brain WMLs was quantified using ITK-SNAP software. The relationship between phenotypes and WML volume was analyzed by the Student t test, Mann-Whitney test, or correlation analysis. WML development patterns were summarized based on the longitudinal observation of MRI characteristics.

Results: This study evaluated 45 patients with NOTCH2NLC-related NIID, with a median age of 66 years (range 55-82 years) and consisting of 30 women. Patients exhibited diverse clinical manifestations, with cognitive decline, autonomic dysfunction, and tremor being the 3 most frequent presentations. Severe WMLs were observed in 43 patients, with FLAIR hyperintensities predominantly in the corona radiata, centrum semiovale, and other brain regions. The presence of DWI hyperintensities was common in the corticomedullary junction (91.1%) and corpus callosum (53.3%). Analysis showed significant correlations between FLAIR hyperintensity volume and both age (r = 0.312, p = 0.042) and Montreal Cognitive Assessment scores (r = -0.371, p = 0.048). Longitudinal MRI retrospection in 7 patients over an average of 9.6 ± 2.9 years revealed 3 gradually progressed WML patterns: periventricular-subcortical, periventricular-dominant, and corticomedullary junction-dominant. In addition, 3 patients experienced rapid WML expansion associated with mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS)-like episodes.

Discussion: Our analysis revealed the radiologic characteristics and spatial distribution of WMLs and demonstrated significant correlations between FLAIR hyperintensity volume and age/cognitive levels in NIID. Long-term retrospection revealed 3 types of gradual WML expansion patterns while MELAS-like episodes cause rapid WML aggravation. Although results should be confirmed in a larger cohort, these insights enhance understanding of NIID's clinical-radiologic relationships and pathogenesis.