Autoantibodies against the NMDAR subunit NR1 are associated with neuropsychiatric outcome after ischemic stroke.

Abstract Background and Purpose Preexisting autoantibodies against N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB) in acute ischemic stroke patients with previously intact blood-brain-barrier were associated with smaller evolution of lesion size. Effects of chronic exposure to NMDAR1-AB long after stroke, however, have remained unclear. We investigated in a prospective follow-up study whether long-term neuropsychiatric outcome after stroke differs depending on NMDAR1-AB status. Methods Blood samples for NMDAR1-AB analysis were collected within 24h after ischemic stroke from n=114 patients. Outcome was assessed 1-3 years later using NIHSS, modified Rankin-scale, Barthel-Index, RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) subcategories (immediate/delayed memory, attention, visuoconstruction), anamnesis evaluating neuropsychiatric symptoms (e.g. hallucinations, psychomotor slowing, reduced alertness, depressiveness, fatigue) and questionnaires (Beck's Depression Inventory-BDI, Fatigue Impact Scale-FIS). Scores were generated to cover RBANS plus neuropsychiatric symptoms (Score A; n=96) or only neuropsychiatric symptoms (Score B; n=114, including patients unable to conduct RBANS). Depression/fatigue were measured in patients, capable to perform questionnaires (n=86). Results NMDAR1-AB (IgM, IgA, IgG) were detected in n=27 patients (23.7%). NMDAR1-AB seropositive patients showed inferior results in Score A (p=0.006), Score B (p=0.004), BDI (p=0.013) and FIS (p=0.018), compared to seronegative patients. Multiple regression analysis including covariates age, NIHSS at day 7 post-stroke, and days from stroke to follow-up, showed NMDAR1-AB seropositivity associated with worse outcome in Scores A (b: 1.517, 95%CI: 0.505-2.529, p=0.004) and B (b: 0.803, 95%CI: 0.233-1.373; p=0.006). Also FIS was unfavorably associated with NMDAR1-AB seropositivity (binary logistic regression: OR: 3.904, 95%CI: 1.200-12.695; p=0.024). Conclusions Even though the numbers of included patients are low, our data apparently indicate that NMDAR1-AB seropositivity at the time point of acute ischemic stroke is associated with neuropsychiatric symptoms including cognitive dysfunction and fatigue years after stroke. Preclinical proof of a causal relation provided, targeted immunosuppression may be a future prophylactic option to be clinically evaluated. AHA subject terms: Ischemic Stroke, Cerebrovascular Disease/Stroke, Blood-Brain- Barrier, Cognitive Impairment, Quality and Outcomes