Decoding neurotransmitter and genetic contributions to abnormal neuronal signal variability in Anti‑N‑Methyl‑D‑Aspartate receptor encephalitis: Implications for targeted therapies.

BACKGROUND

The molecular mechanisms linking brain function alterations to gene expression in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis remain unclear.

METHODS

We analyzed the coefficient of variation of blood oxygenation level dependent signal (CVBOLD) and functional connectivity (FC) in 30 healthy controls and 42 patients, with classification via 5 machine learning models. Transcriptomic profiles from the Allen Human Brain Atlas and neurotransmitter density maps from positron emission tomography were integrated. Partial least squares (PLS) regression determined gene expression relevant to the CVBOLD/FC changes. Multivariate linear regression evaluated neurotransmitter contributions.

RESULTS

Anti-NMDAR encephalitis patients exhibited increased CVBOLD in the right superior parietal gyrus, right fusiform gyrus, right lingual gyrus, left fusiform gyrus and left paracentral lobule meanwhile disrupted FC mainly in default mode and salience networks. PLS analysis revealed 2320 genes significantly associated with CVBOLD/FC (pbonferrni < 0.05), enriched in synaptic signaling (MAPK, cAMP), metabolic regulation (insulin resistance), and neurodegeneration pathways. Hub genes PPARGC1A (positive correlation with CVBOLD/FC) and UBA52 (negative correlation) were validated in key brain regions. Neurotransmitter analysis showed norepinephrine (NAT) strongly contributed to CVBOLD (weight = 0.57, pFDR < 0.001), meanwhile serotonin (5HT4), cannabinoid (CB1), noradrenaline (NAT), and glutamate (NMDA) influenced FC.

CONCLUSION

This study identifies a transcriptional signature that is spatially associated with CVBOLD/FC abnormalities and neurotransmitter distributions in anti-NMDAR encephalitis, thereby generating hypotheses about molecular targets that may be relevant for future mechanistic studies and precision medicine.