To characterize regional brain atrophy patterns, evaluate their association with regional leucine-rich glioma-inactivated-1 (LGI1) gene expression, and identify clinical predictors of hippocampal atrophy in LGI1-IgG autoimmune encephalitis (AE).

Residual brain atrophy associates with worse functional outcomes in LGI1-AE. The regional distribution of atrophy and its clinical determinants remain incompletely characterized.

This observational study compared regional brain volumes in an LGI1-AE cohort versus age-and-sex matched healthy controls (HC) and patients with Alzheimer’s disease (AD). LGI1 gene expression was derived from the Allen Human Brain Atlas. Multivariable linear regression and generalized linear models were used for association studies.

A total of 55 LGI1-AE patients were included. Median age was 68 years (IQR 62.5, 74.2) at volumetric analysis, after a median of 19 months (IQR 11, 45) from symptom onset. Compared to HC and AD, LGI1-AE had greater regional atrophy of the hippocampus, medial temporal lobe, insula, caudate, and putamen (p<0.002). Longitudinal analyses (n=17) demonstrated hippocampal and pallidal volume decline, remaining significant after co-variate adjustment. Regions with greatest differential atrophy, relative to comparators, corresponded with higher LGI1 gene expression (Spearman ρ = 0.7, p=0.005). Severe cognitive deficits at diagnosis (i.e., higher clinical dementia rating [CDR], β= -0.56; p=0.002) and longer disease duration at time of MRI (β= -0.01; p=0.001) independently predicted total hippocampal volume (R² = 0.31). Smaller temporal (p=0.01), frontal (p=0.04), and parietal (p=0.03) volumes were associated with a higher proportion of impaired neuropsychological tests.

LGI1-AE is associated with a distinct pattern of limbic and striatal atrophy that differs from AD and aligns with regional LGI1 expression, supporting a model of selective network vulnerability involving limbic and striatal circuits. Greater baseline cognitive impairment and longer disease duration independently associated with hippocampal atrophy, underscoring the potential importance of early diagnosis and treatment to limit structural brain injury.