NMDA Receptor Antibodies and Neuropsychiatric Symptoms in Parkinson's Disease

Lucy L. Gibson; Thomas A. Pollak; Melanie Hart; Amanda Heslegrave; Abdul Hye; Andrew J. Church; Neghat Lakdawala; Timothy R. Nicholson; Lucia Batzu; Silvia Rota; Dhaval Trivedi; Henrik Zetterberg; Kallol Ray Chaudhuri; Dag Aarsland

doi:10.1176/appi.neuropsych.20220107

NMDA Receptor Antibodies and Neuropsychiatric Symptoms in Parkinson's Disease

Lucy L. Gibson^*, Thomas A. Pollak, Melanie Hart, Amanda Heslegrave, Abdul Hye, Andrew J. Church, Neghat Lakdawala, Timothy R. Nicholson, Lucia Batzu, Silvia Rota, Dhaval Trivedi, Henrik Zetterberg, Kallol Ray Chaudhuri, Dag Aarsland

^*Corresponding author for this work

King's College London

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

OBJECTIVE: N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoantibody-mediated neurological syndrome with prominent cognitive and neuropsychiatric symptoms. The clinical relevance of NMDAR antibodies outside the context of encephalitis was assessed in this study.

METHODS: Plasma from patients with Parkinson's disease (PD) (N=108) and healthy control subjects (N=89) was screened at baseline for immunoglobulin A (IgA), IgM, and IgG NMDAR antibodies, phosphorylated tau 181 (p-tau181), and the neuroaxonal injury marker neurofilament light (NfL). Clinical assessment of the patients included measures of cognition (Mini-Mental State Examination [MMSE]) and neuropsychiatric symptoms (Hospital Anxiety and Depression Scale; Non-Motor Symptoms Scale for Parkinson's Disease). A subgroup of patients (N=61) was followed annually for up to 6 years.

RESULTS: Ten (9%) patients with PD tested positive for NMDAR antibodies (IgA, N=5; IgM, N=6; IgG, N=0), and three (3%) healthy control subjects had IgM NMDAR antibodies; IgA NMDAR antibodies were detected significantly more commonly among patients with PD than healthy control subjects (χ2=4.23, df=1, p=0.04). Age, gender, and disease duration were not associated with NMDAR antibody positivity. Longitudinally, antibody-positive patients had significantly greater decline in annual MMSE scores when the analyses were adjusted for education, age, disease duration, p-tau181, NfL, and follow-up duration (adjusted R2=0.26, p=0.01). Neuropsychiatric symptoms were not associated with antibody status, and no associations were seen between NMDAR antibodies and p-tau181 or NfL levels.

CONCLUSIONS: NMDAR antibodies were associated with greater cognitive impairment over time in patients with PD, independent of other pathological biomarkers, suggesting a potential contribution of these antibodies to cognitive decline in PD.

Original language	English
Pages (from-to)	236-243
Number of pages	8
Journal	The Journal of neuropsychiatry and clinical neurosciences
Volume	35
Issue number	3
Early online date	30 Jan 2023
DOIs	https://doi.org/10.1176/appi.neuropsych.20220107
Publication status	Published - 1 Jul 2023

Keywords

Immunology (Neuropsychiatric Aspects)
Parkinson’s Disease

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10.1176/appi.neuropsych.20220107

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Gibson, L. L., Pollak, T. A., Hart, M., Heslegrave, A., Hye, A., Church, A. J., Lakdawala, N., Nicholson, T. R., Batzu, L., Rota, S., Trivedi, D., Zetterberg, H., Chaudhuri, K. R., & Aarsland, D. (2023). NMDA Receptor Antibodies and Neuropsychiatric Symptoms in Parkinson's Disease. The Journal of neuropsychiatry and clinical neurosciences, 35(3), 236-243. https://doi.org/10.1176/appi.neuropsych.20220107

@article{de544e615aff4f2d8f3889065ce25a23,

title = "NMDA Receptor Antibodies and Neuropsychiatric Symptoms in Parkinson's Disease",

abstract = "OBJECTIVE: N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoantibody-mediated neurological syndrome with prominent cognitive and neuropsychiatric symptoms. The clinical relevance of NMDAR antibodies outside the context of encephalitis was assessed in this study. METHODS: Plasma from patients with Parkinson's disease (PD) (N=108) and healthy control subjects (N=89) was screened at baseline for immunoglobulin A (IgA), IgM, and IgG NMDAR antibodies, phosphorylated tau 181 (p-tau181), and the neuroaxonal injury marker neurofilament light (NfL). Clinical assessment of the patients included measures of cognition (Mini-Mental State Examination [MMSE]) and neuropsychiatric symptoms (Hospital Anxiety and Depression Scale; Non-Motor Symptoms Scale for Parkinson's Disease). A subgroup of patients (N=61) was followed annually for up to 6 years. RESULTS: Ten (9%) patients with PD tested positive for NMDAR antibodies (IgA, N=5; IgM, N=6; IgG, N=0), and three (3%) healthy control subjects had IgM NMDAR antibodies; IgA NMDAR antibodies were detected significantly more commonly among patients with PD than healthy control subjects (χ2=4.23, df=1, p=0.04). Age, gender, and disease duration were not associated with NMDAR antibody positivity. Longitudinally, antibody-positive patients had significantly greater decline in annual MMSE scores when the analyses were adjusted for education, age, disease duration, p-tau181, NfL, and follow-up duration (adjusted R2=0.26, p=0.01). Neuropsychiatric symptoms were not associated with antibody status, and no associations were seen between NMDAR antibodies and p-tau181 or NfL levels. CONCLUSIONS: NMDAR antibodies were associated with greater cognitive impairment over time in patients with PD, independent of other pathological biomarkers, suggesting a potential contribution of these antibodies to cognitive decline in PD.",

keywords = "Immunology (Neuropsychiatric Aspects), Parkinson{\textquoteright}s Disease",

author = "Gibson, {Lucy L.} and Pollak, {Thomas A.} and Melanie Hart and Amanda Heslegrave and Abdul Hye and Church, {Andrew J.} and Neghat Lakdawala and Nicholson, {Timothy R.} and Lucia Batzu and Silvia Rota and Dhaval Trivedi and Henrik Zetterberg and Chaudhuri, {Kallol Ray} and Dag Aarsland",

year = "2023",

month = jul,

day = "1",

doi = "10.1176/appi.neuropsych.20220107",

language = "English",

volume = "35",

pages = "236--243",

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Gibson, LL , Pollak, TA, Hart, M, Heslegrave, A, Hye, A, Church, AJ, Lakdawala, N, Nicholson, TR , Batzu, L , Rota, S , Trivedi, D, Zetterberg, H, Chaudhuri, KR & Aarsland, D 2023, 'NMDA Receptor Antibodies and Neuropsychiatric Symptoms in Parkinson's Disease', The Journal of neuropsychiatry and clinical neurosciences, vol. 35, no. 3, pp. 236-243. https://doi.org/10.1176/appi.neuropsych.20220107

TY - JOUR

T1 - NMDA Receptor Antibodies and Neuropsychiatric Symptoms in Parkinson's Disease

AU - Gibson, Lucy L.

AU - Pollak, Thomas A.

AU - Hart, Melanie

AU - Heslegrave, Amanda

AU - Hye, Abdul

AU - Church, Andrew J.

AU - Lakdawala, Neghat

AU - Nicholson, Timothy R.

AU - Batzu, Lucia

AU - Rota, Silvia

AU - Trivedi, Dhaval

AU - Zetterberg, Henrik

AU - Chaudhuri, Kallol Ray

AU - Aarsland, Dag

PY - 2023/7/1

Y1 - 2023/7/1

N2 - OBJECTIVE: N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoantibody-mediated neurological syndrome with prominent cognitive and neuropsychiatric symptoms. The clinical relevance of NMDAR antibodies outside the context of encephalitis was assessed in this study. METHODS: Plasma from patients with Parkinson's disease (PD) (N=108) and healthy control subjects (N=89) was screened at baseline for immunoglobulin A (IgA), IgM, and IgG NMDAR antibodies, phosphorylated tau 181 (p-tau181), and the neuroaxonal injury marker neurofilament light (NfL). Clinical assessment of the patients included measures of cognition (Mini-Mental State Examination [MMSE]) and neuropsychiatric symptoms (Hospital Anxiety and Depression Scale; Non-Motor Symptoms Scale for Parkinson's Disease). A subgroup of patients (N=61) was followed annually for up to 6 years. RESULTS: Ten (9%) patients with PD tested positive for NMDAR antibodies (IgA, N=5; IgM, N=6; IgG, N=0), and three (3%) healthy control subjects had IgM NMDAR antibodies; IgA NMDAR antibodies were detected significantly more commonly among patients with PD than healthy control subjects (χ2=4.23, df=1, p=0.04). Age, gender, and disease duration were not associated with NMDAR antibody positivity. Longitudinally, antibody-positive patients had significantly greater decline in annual MMSE scores when the analyses were adjusted for education, age, disease duration, p-tau181, NfL, and follow-up duration (adjusted R2=0.26, p=0.01). Neuropsychiatric symptoms were not associated with antibody status, and no associations were seen between NMDAR antibodies and p-tau181 or NfL levels. CONCLUSIONS: NMDAR antibodies were associated with greater cognitive impairment over time in patients with PD, independent of other pathological biomarkers, suggesting a potential contribution of these antibodies to cognitive decline in PD.

AB - OBJECTIVE: N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoantibody-mediated neurological syndrome with prominent cognitive and neuropsychiatric symptoms. The clinical relevance of NMDAR antibodies outside the context of encephalitis was assessed in this study. METHODS: Plasma from patients with Parkinson's disease (PD) (N=108) and healthy control subjects (N=89) was screened at baseline for immunoglobulin A (IgA), IgM, and IgG NMDAR antibodies, phosphorylated tau 181 (p-tau181), and the neuroaxonal injury marker neurofilament light (NfL). Clinical assessment of the patients included measures of cognition (Mini-Mental State Examination [MMSE]) and neuropsychiatric symptoms (Hospital Anxiety and Depression Scale; Non-Motor Symptoms Scale for Parkinson's Disease). A subgroup of patients (N=61) was followed annually for up to 6 years. RESULTS: Ten (9%) patients with PD tested positive for NMDAR antibodies (IgA, N=5; IgM, N=6; IgG, N=0), and three (3%) healthy control subjects had IgM NMDAR antibodies; IgA NMDAR antibodies were detected significantly more commonly among patients with PD than healthy control subjects (χ2=4.23, df=1, p=0.04). Age, gender, and disease duration were not associated with NMDAR antibody positivity. Longitudinally, antibody-positive patients had significantly greater decline in annual MMSE scores when the analyses were adjusted for education, age, disease duration, p-tau181, NfL, and follow-up duration (adjusted R2=0.26, p=0.01). Neuropsychiatric symptoms were not associated with antibody status, and no associations were seen between NMDAR antibodies and p-tau181 or NfL levels. CONCLUSIONS: NMDAR antibodies were associated with greater cognitive impairment over time in patients with PD, independent of other pathological biomarkers, suggesting a potential contribution of these antibodies to cognitive decline in PD.

KW - Immunology (Neuropsychiatric Aspects)

KW - Parkinson’s Disease

UR - http://www.scopus.com/inward/record.url?scp=85164846481&partnerID=8YFLogxK

U2 - 10.1176/appi.neuropsych.20220107

DO - 10.1176/appi.neuropsych.20220107

M3 - Article

C2 - 36710627

AN - SCOPUS:85164846481

SN - 0895-0172

VL - 35

SP - 236

EP - 243

JO - The Journal of neuropsychiatry and clinical neurosciences

JF - The Journal of neuropsychiatry and clinical neurosciences

IS - 3

ER -

NMDA Receptor Antibodies and Neuropsychiatric Symptoms in Parkinson's Disease

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