Transdiagnostic hippocampal damage patterns in neuroimmunological disorders

Abstract

Hippocampal damage and associated cognitive deficits are frequently observed in neuroimmunological disorders, but comparative analyses to identify shared hippocampal damage patterns are missing. Here, we adopted a transdiagnostic analytical approach and investigated hippocampal shape deformations and associated cognitive deficits in four neuroimmunological diseases. We studied 120 patients (n = 30 in each group), including patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), anti-NMDAR and anti-LGI1 encephalitis. A control group was matched to each patient sample from a pool of 79 healthy participants. We performed an MRI-based vertex-wise hippocampal shape analysis, extracted hippocampal volume estimates and scalar projection values as a measure of surface displacement. Cognitive testing included assessment of verbal memory and semantic fluency performance. Our cross-sectional analyses revealed characteristic patterns of bilateral inward deformations covering up to 32% of the hippocampal surface in MS, anti-NMDAR encephalitis, and anti-LGI1 encephalitis, whereas NMOSD patients showed no deformations compared to controls. Significant inversions were noted mainly on the hippocampal head, were accompanied by volume loss, and correlated with semantic fluency scores and verbal episodic memory in autoimmune encephalitis and MS. A deformation overlap analysis across disorders revealed a convergence zone on the left anterior hippocampus that corresponds to the CA1 subfield. This convergence zone indicates a shared downstream substrate of immune-mediated damage that appears to be particularly vulnerable to neuroinflammatory processes. Our transdiagnostic morphological view sheds light on mutual pathophysiologic pathways of cognitive deficits in neuroimmunological diseases and stimulates further research into the mechanisms of increased susceptibility of the hippocampus to autoimmunity.

Keywords: Autoimmune encephalitis; Hippocampal shape; Memory disorders; Multiple sclerosis; Neuroinflammation; Neuromyelitis optica spectrum disorder.

Fig. 1

Hippocampal shape deformations. Upper panels: Colored regions show significant inward deformation of the hippocampal surface (p < .05; multiple-comparison corrected). Top row: Surface deformations of the left hippocampus are shown in a dorsolateral perspective. Bottom row: Deformations of the left and right hippocampus are shown in ventral and dorsal view. Lower panel: Scalar projection values of the hippocampus show the average displacement of the hippocampal surface with respect to the control groups (in mm; *p < .05; **p < .01). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Receiver operating characteristics (ROC) for hippocampal scalar values, hippocampal volumes, and their combined classification performance. 1-specificity and sensitivity of the derived displacement measure are plotted on the x and y axes. The average scalar values of the left and right hippocampi (solid lines) show comparable diagnostic performance to that of conventional volumetric measures (dotted lines). Combining shape and volume information yielded the best classification performance across all diseases.

Fig. 3

Pairwise overlaps of surface deformations in ventral (upper panel) and dorsal view (lower panel). (A) Multiple sclerosis (yellow) and NMDAR encephalitis (blue) overlapped strongly on the left hippocampus (Φ = 0.440; contingency coefficient). More than 70% of the affected vertices in multiple sclerosis were also affected in NMDAR encephalitis. (B) LGI1 encephalitis (red) and multiple sclerosis (yellow) overlapped with moderate contingency on the left (Φ = 0.386) and right (Φ = 0.260) hippocampus. Surface deformations overlap around 50% on both sides. (C) Overlap of NMDAR (blue) and LGI1 encephalitis (red) was stronger for the left (Φ = 0.268) than for the right hippocampus (Φ = 0.108). Around 50% of the surface inversions overlapped. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Overlap analyses reveal an area of the left anterior hippocampus that is affected across diseases and sensitive to cognitive alterations.

Supplementary Fig. 1