Structural and molecular substrates underlying functional dysconnectivity and cognitive impairment in neuronal intranuclear inclusion disease.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a complex neurodegenerative disorder characterized by progressive cognitive decline. However, the patterns of functional network reorganization, as well as the underlying structural white matter (WM) damage and molecular mechanisms contributing to cognitive impairment, remain poorly understood.

METHODS: Nine patients with genetically-confirmed NIID (following the exclusion of one patient due to excessive head motion) and 10 age- and sex-matched healthy controls underwent multimodal MRI. We integrated voxel-level functional connectivity strength (FCS) with DTI-derived metrics (FA, AD, RD, and MD) across 20 major WM tracts. Cognitive performance was assessed via Montreal Cognitive Assessment (MoCA). We employed a "structure-function-metabolism" analytical pipeline to examine how WM disintegration relates to cortical dysconnectivity and how these changes align with normative receptor maps (via JuSpace) and cerebral blood flow.

RESULTS: NIID patients demonstrated a distinct pattern of functional reorganization, marked by decreased FCS in the right opercular part of the inferior frontal gyrus (IFGoperc) and increased FCS in the left gyrus rectus; notably, the reduced FCS in the right IFGoperc was positively correlated with MoCA scores. Significant WM degeneration was observed in the bilateral anterior thalamic radiation (ATR) and the forceps minor, with FA values in the latter showing a significant positive correlation with MoCA scores. Crucially, the severity of WM damage (reduced FA; elevated AD, RD, and MD) in the left ATR was significantly correlated with functional disconnection in the IFGoperc, suggesting a structural-functional cascade may underlie cognitive deterioration. Molecular enrichment analysis further demonstrated that these functional deficits were spatially coupled with specific serotonergic (5-HT1b/2a) and glutamatergic (mGluR5) receptor profiles, as well as regional hyperperfusion.

CONCLUSION: Our findings suggest a potential multi-level pathophysiological framework in NIID, where structural disintegration of thalamo-cortical and interhemispheric tracts may serve as a topographical substrate for downstream functional network reorganization. This structural-functional-molecular axis, characterized by the convergence of network dysfunction, regional hyperperfusion, and specific neurotransmitter profiles, provides preliminary insights into the neurobiological mechanisms potentially underlying cognitive decline in NIID.