Alterations of long-range association fibers in patients with anti-N-methyl-D-aspartate receptor encephalitis

Patients with anti-NMDAR encephalitis typically exhibit impaired cognitive integration, which relies on the integrity of long-range association fibers connecting diverse brain regions. However, the microstructural integrity of long-range association fibers in this population remains unknown.

Diffusion tensor imaging (DTI) data were collected from 32 patients with anti-NMDAR encephalitis and 30 healthy controls. Patients were further categorized into early and delayed immunotherapy subgroups based on a 2-week threshold for immunotherapy initiation. The diffusion properties of major long-range association fibers were quantified at both the bundle and node levels.

Compared with healthy controls, patients exhibited widespread microstructural damage within long-range association fibers, with more severe alterations in the delayed immunotherapy subgroup (FDR-corrected p < 0.05). In this subgroup(n = 14), radial diffusivity (RD) of left inferior fronto-occipital fasciculus (IFOF), left inferior longitudinal fasciculus (ILF), left superior longitudinal fascicles (SLF), and bilateral arcuate fascicles correlated significantly with global cognition (MMSE, FDR-corrected p < 0.05). Notably, RD also strongly correlated with working memory in the delayed immunotherapy subgroup, showing bundle-wise associations for IFOF (left: r = -0.8315, p = 0.0112; right: r = -0.7044, p = 0.0295), ILF (left: r = -0.7473, p = 0.0243), SLF (left: r = -0.7562, p = 0.0243; right: r = -0.6599, p = 0.0391), and arcuate fasciculus (left: r = -0.7240, p = 0.0272; right: r = -0.6835, p = 0.0333), with left-hemisphere predominance confirmed by node-wise analyses of IFOF, ILF, SLF, and arcuate fasciculus (FDR-corrected p < 0.05).

Our findings highlight widespread microstructural damage in long-range association fibers in patients with anti-NMDAR encephalitis, particularly in those with delayed immunotherapy. This damage may serve as the neurophysiological basis for cognitive impairments, with working memory being most affected.