Serum anti-NMDA receptor antibodies are linked to memory impairment 12 months after stroke

Abstract

Patients suffering from strokes are at increased risk of developing post-stroke dementia. Serum anti-NMDA receptor autoantibodies (NMDAR1-abs) have been associated with unfavorable post-stroke outcomes. However, their effect on specific cognitive domains remains unclear. We used data from the prospective multicenter DZNE-mechanisms after stroke (DEMDAS) cohort, and measured NMDAR1-abs in serum at baseline. Cognitive function was assessed with a comprehensive neuropsychological test battery at 6- and 12-months follow-up. We employed crude and stepwise confounder adjusted linear and logistic regression models as well as generalized estimating equation models (GEE) to determine the relevance of NMDAR1-abs seropositivity on cognitive function after stroke. 10.2% (58/569) DEMDAS patients were NMDAR1-abs seropositive (IgM:n = 44/IgA:n = 21/IgG:n = 2). Seropositivity was not associated with global cognitive impairment after stroke. However, NMDAR1-abs seropositive patients performed lower in the memory domain (β_adjusted = -0.11; 95%CI = -0.57 to -0.03) and were at increased risk for memory impairment (OR_adjusted = 3.8; 95%CI = 1.33-10.82) compared to seronegative patients, 12 months after stroke. Further, NMDAR1-abs were linked to memory impairment over time in GEE from 6- to 12-months follow-up (OR_adjusted = 2.41; 95%CI = 1.05-5.49). Our data suggests that NMDAR1-abs contribute to memory dysfunction 1 year after stroke while not affecting other cognitive subdomains. Hence, antineuronal autoimmunity may be involved in distinct mechanisms of post-stroke memory impairment. Clinical trial name and registration number: The Determinants of Dementia After Stroke (DEMDAS; study identifier on clinical trials.gov: NCT01334749).

Fig. 1. Flowchart of patient inclusion and exclusion.

Gray boxes indicate that participants were included in the analysis, while red boxes represent participants that were excluded from the analysis. Autoantibody indicates anti-NMDAR1 (GluN1) autoantibodies. MFU months follow-up.

Fig. 2. Global and subdomain scoring from the Consortium to Establish a Registry for Alzheimer’s Disease Plus’–battery (CERAD-Plus) from anti-NMDAR1 autoantibody seronegative and seropositive patients.

Red dots represent single participants’ z-scores of anti-NMDAR1 autoantibody seronegative patients while blue dots display single participants’ z-scores of anti-NMDAR1 autoantibody seropositive patients, with a boxplot overlay and emphasized zero-line (red dashed line). A Global cognitive test performance. B Test performance in the language domain. C Test performance in the memory domain. D Test performance in the visuo-spatial domain. E Test performance in the executive domain. F Test performance in the attention domain. Age, sex, and education standardized z-scores were calculated from a reference normative population. MFU months follow-up.

Fig. 3. Global and domain-specific cognitive impairment in association to anti-NMDAR1 autoantibody serostatus.

Forest plots representing odds ratios (dots) and corresponding 95% confidential intervals (lines) assessing the association of anti-NMDAR1 autoantibody seropositivity and global and domain-specific binary outcomes in propensity score-adjusted logistic regression models at 6-months follow-up (A), at 12-months follow-up (B), and in logistic GEE analysis from 6- to 12-months follow-up (C). Propensity scores were calculated from logistic regression models including age (continuous), sex (dichotomous), education (continuous), ever smoking (dichotomous), habitual alcohol consumption (dichotomous), severe disease (dichotomous), previous stroke or transitory ischemic attack (dichotomous), cardiovascular diseases (dichotomous), and other organic brain diseases (dichotomous), with NMDAR1-abs serostatus as dependent variable. MFU months follow-up. * Indicates statistical significance with the p-value threshold set at <0.05.

Fig. 4. Scatter plots and correlation coefficients for depression and fatigue with memory function at both follow-up timepoints.

A + B x-axis: Center for Epidemiological Studies Depression (CES-D), y-axis: z-scores for memory function at 6- and 12-months, respectively. R: correlation coefficient. C + D x-axis: Fatigue Assessment Questionnaire (FAQ), y-axis: z-scores for memory function at 6- and 12-months respectively. R correlation coefficient, MFU months follow-up.

Fig. 5. Scatter plots and correlation coefficients for baseline hippocampal volumes with memory function at both follow-up timepoints: X-axis.

Baseline hippocampal volume, y-axis: z-scores for memory function at (A) 6- and (B) 12-months, R correlation coefficient, MFU months follow-up.