Evolutionary implications of NOTCH2NLC mutations: brain structural changes in neuronal intranuclear inclusion disease revealed by comprehensive morphometry.

This study investigated brain structural changes associated with NOTCH2NLC gene mutations in neuronal intranuclear inclusion disease (NIID) patients, focusing on the evolutionary implications of this human-specific gene in brain development. We analysed 41 NIID patients and 21 healthy controls using voxel-based morphometry and surface-based morphometry to assess differences in grey matter volume and cortical complexity. Spatial relationships between brain atrophy and white matter hyperintensity volume as well as cerebrospinal fluid fraction were examined. Additionally, we conducted exploratory Spearman correlation analyses to evaluate associations between regional grey matter volume and clinical variables, including GGC repeat length, disease duration, age at onset and cognitive scores. NIID patients exhibited extensive reductions in grey matter volume and cortical thinning in multiple brain regions, with pronounced effects in the prefrontal cortex and cerebellum. The parietal lobe, insula and posterior cingulate gyrus showed decreased gyrification index and fractal dimension, while certain regions of the temporal and frontal lobes showed increased gyrification index and fractal dimension. Furthermore, in the NIID group, white matter hyperintensity volume and cerebrospinal fluid fraction were negatively correlated with grey matter volume in the olfactory cortex, orbital gyrus, anterior cingulate gyrus, insula, amygdala and temporal pole. Exploratory analyses suggested that longer GGC repeats were associated with greater atrophy in the striatum, middle cingulate cortex, sensorimotor cortex and cerebellum; earlier age at onset with thalamic (mediodorsal/pulvinar), occipital and cerebellar atrophy; and poorer cognitive scores with atrophy in the anterior cingulate cortex, superior occipital gyrus and superior temporal pole. This study uncovers widespread and complex cerebral structural changes in NIID patients, predominantly affecting the prefrontal cortex, cerebellum, insula and limbic system structures. These findings provide new insights into the neuroanatomical basis of NIID and support the hypothesis that human-specific genetic innovations driving cortical expansion may concurrently confer selective vulnerability to neurodegeneration.