In vivo NMDA receptor function in people with NMDA receptor antibody encephalitis

In N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis, NMDAR-autoantibodies are hypothesised to cause prominent neuropsychiatric symptoms by internalizing NMDARs. However, supporting evidence comes chiefly from in vitro and rodent data with scant direct evidence from affected humans. Here, we used in vivo positron emission tomography (PET) with [18F]GE-179 to show a mean 30% reduction of the density of open, activated NMDARs in grey matter of persistently NMDAR-autoantibody seropositive patients following NMDAR-antibody encephalitis compared to healthy controls. The reduction was most prominent in the anterior temporal and superior parietal cortices. These patients had normal structural MRIs and mild residual symptoms. In contrast, one symptom-free patient who recovered from NMDAR-antibody encephalitis and was not NMDAR-autoantibody seropositive had normal density of active NMDARs. These findings reveal a functional deficit of open, activated NMDARs in humans with NMDAR-autoantibodies. Moreover, we observed a functional NMDAR deficit for up to 8 months following the disease peak, despite only mild residual symptoms, highlighting the considerable compensatory capacity of the human brain.One Sentence SummaryReductions of activated NMDA receptors detected in vivo in female patients following NMDA-receptor-antibody encephalitis.