Objective: To quantify the frequency of NMDA receptor (NMDAR) antibodies (Abs) in Parkinson’s disease (PD) and characterise their relationship with the cognitive and neuropsychiatric symptoms.

Background: NMDAR encephalitis is an IgG antibody-mediated syndrome with prominent cognitive and psychiatric symptoms. NMDAR Abs, particularly of IgA and IgM isotype, are also found outside encephalitis and have been implicated in cognitive impairment.1,2 The prevalence and potential contribution of NMDAR Abs to the neuropsychiatric and cognitive symptoms in PD is unknown.

Method: The plasma from 106 patients with PD and 40 age and sex-matched healthy controls was screened for IgA, IgM and IgG NMDAR Abs using fixed cell-based immunoassays. PD patients were assessed at baseline with measures including MMSE, Hamilton Anxiety Depression Score (HADS) and Non-Motor Symptom Scale (NMSS). 58% (n=61) were followed up annually for up to 6 years.

Results: 10 (9.4%) PD patients tested positive for NMDAR Abs; 5 IgA, 6 IgM, 0 IgG. 2 controls (5%) tested positive for IgM NMDAR Abs. PD patients had IgA NMDAR Abs more frequently than controls (4.8% vs 0%; OR 1.4; 95% CI 1.26–1.56). No difference in gender, age of PD onset or age at Ab testing was seen with NMDAR Ab seropositivity. There was no difference in MMSE score with NMDAR Ab seropositivity (Ab+) at baseline but during follow up MMSE scores became significantly lower in Ab+ PD patients (Ab+ mean MMSE 24.6 SD 5.0; Ab- mean MMSE 27.2 SD 3.23, p = 0.049). There was no difference between groups in length of follow up, years of education or duration with PD symptoms. IgA NMDAR Abs were also independently associated with lower MMSE scores during follow up (IgA+ mean 23.4 SD 5.6, IgA- mean MMSE 27.2 SD 3.2, p = 0.025) but not at baseline. Depression and psychotic symptoms were not more common in patients with NMDAR Abs at baseline (depression Ab+ 30%, Ab- 26%, p = 0.72; psychosis Ab+ 20%, Ab- 30.2%, p=0.72) or follow up (depression Ab+ 71.4%, Ab- 50% p = 0.43; psychosis Ab+ 43%, Ab- 46.3%, p = 1.0).

Conclusion: IgA NMDAR Ab were seen more frequently in PD patients versus controls. NMDAR Ab were associated with greater cognitive impairment over time in PD patients, with IgA NMDAR Ab primarily driving this association. There was no observed relationship with NMDAR Ab and neuropsychiatric symptoms in PD. These findings require replication in a larger sample.

References: 1. Doss, S., Wandinger, K. P., Hyman, B. T., Panzer, J. A., Synofzik, M., Dickerson, B., Mollenhauer, B., Scherzer, C. R., Ivinson, A. J., Finke, C., Schöls, L., Müller Vom Hagen, J., Trenkwalder, C., Jahn, H., Höltje, M., Biswal, B. B., Harms, L., Ruprecht, K., Buchert, R., Höglinger, G. U., … Prüss, H. (2014). High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types. Annals of clinical and translational neurology, 1(10), 822–832. https://doi.org/10.1002/acn3.120 2. Bartels F, Strönisch T, Farmer K, Rentzsch K, Kiecker F, Finke C. (2019). Neuronal autoantibodies associated with cognitive impairment in melanoma patients. Ann Oncol,1;30(5):823-829.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nmda-receptor-antibodies-and-neuropsychiatric-symptoms-in-parkinsons-disease/