AIMS: Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is characterized by widespread neural dysfunction, yet the underlying neurochemical and molecular mechanisms remain poorly understood. This study aimed to investigate whether functional alterations in anti-NMDAR encephalitis are spatially associated with neurotransmitter receptor distributions and transcriptomic profiles, to uncover their neurochemical, molecular, and cellular signatures.
METHODS: A total of 25 patients diagnosed with anti-NMDA receptor encephalitis and 30 healthy controls (HCs) were recruited in this study. All participants underwent resting-state functional MRI (rs-fMRI) scanning, with patients being scanned during the recovery phase of the disease. To explore the neurochemical, molecular and cellular signatures underlying altered brain functional activity, we conducted neuroimaging-neurotransmitter, neuroimaging-transcriptome regression analyses and cell type enrichment analysis, linking aberrant fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) patterns with PET-derived receptor maps and transcriptomic profiles from the Allen Human Brain Atlas (AHBA).
RESULTS: Patients exhibited significant alterations in fALFF/ReHo across the frontal, temporal, and occipital cortices. Neuroimaging-neurotransmitter regression analyses revealed that these functional abnormalities were significantly associated with neurotransmitter receptor maps, particularly involving serotonin (5-HT2a) and dopamine (D1) systems. Neuroimaging-transcriptome regression analyses further demonstrated that the genes associated with fALFF/ReHo alterations were primarily enriched in biological processes related to neuron projection development, oligodendrocyte specification and differentiation leading to myelin components for central nervous system. The oligodendrocytes and astrocytes were considered key cellular contributors to the functional alterations.
CONCLUSIONS: Our findings demonstrate that neural dysfunction during the recovery phase of anti-NMDAR encephalitis are closely linked to neurotransmitter systems and transcriptomic profiles. This multiscale integration bridges molecular mechanisms with neural dysfunction and may inform novel therapeutic strategies.
