Hippocampal hub failure is linked to long-term memory impairment in anti-NMDA-receptor encephalitis - Insights from structural connectome graph theoretical network analysis

Abstract Introduction Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is characterized by distinct structural and functional brain alterations, predominantly affecting the medial temporal lobes and the hippocampus. Structural connectome analysis with graph-based investigations of network properties allows for an in-depth characterization of global and local network changes and their relationship with clinical deficits in NMDAR encephalitis. Objective To investigate changes in structural connectivity and network efficiency in NMDAR encephalitis by use of probabilistic whole-brain tractography and graph theoretical analysis of structural brain networks. Methods Structural networks from sixty-one NMDAR encephalitis patients in the post-acute stage (median time from acute hospital discharge: 18 months) and sixty-one age- and sex-matched healthy controls (HC) were analyzed using diffusion-weighted imaging (DWI)-based probabilistic anatomically-constrained tractography and spherical deconvolution-informed filtering of tractograms. We calculated global, modular, and nodal graph measures indicative of structural connectivity and network reorganization with special focus on default-mode network, medial temporal lobe, and hippocampus. Pathologically altered metrics were included in multiple regression analyses to investigate their potential association with clinical course, disease severity, and cognitive outcome. Results Patients with NMDAR encephalitis showed regular global graph metrics, but bilateral reductions of hippocampal node strength (left: p =0.049; right: p =0.013) and increased node strength of right precuneus ( p =0.013) compared to HC. Betweenness centrality was decreased for left-sided entorhinal cortex ( p =0.042) and left caudal middle frontal gyrus (p = 0.037). Correlation analyses showed a significant association between reduced left hippocampal node strength and verbal long-term memory impairment ( p =0.021) Conclusion Focal network property changes of the medial temporal lobes indicate hippocampal hub failure that is associated with memory impairment in NMDAR encephalitis at the post-acute stage, while global structural network properties remain unaltered. Graph theory analysis provides new pathophysiological insight into structural network changes and their association with persistent cognitive deficits in NMDAR encephalitis.