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Original Investigation
July 1, 2021

Association Between Neuronal Autoantibodies and Cognitive Impairment in Patients With Lung Cancer

Author Affiliations
  • 1Department of Neurology, Charité–Universitätsmedizin Berlin, Berlin, Germany
  • 2Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
  • 3Berlin School of Mind and Brain, Humboldt–Universität zu Berlin, Berlin, Germany
  • 4Institute of Biometry and Clinical Epidemiology, Charité–Universitätsmedizin Berlin, Berlin, Germany
  • 5Institute of Experimental Immunology, EUROIMMUN, Lübeck, Germany
  • 6Department of Respiratory Diseases, Evangelische Lungenklinik Berlin, Berlin, Germany
JAMA Oncol. 2021;7(9):1302-1310. doi:10.1001/jamaoncol.2021.2049
Key Points

Question  Are neuronal autoantibodies associated with impaired cognitive function in patients with lung cancer?

Findings  In this cross-sectional study of 167 consecutive patients with lung cancer, 37% of patients had neuronal autoantibodies; 45% of patients with small cell lung cancer and 34% of patients with non–small cell lung cancer were autoantibody positive. Patients with neuronal autoantibodies had increased odds of cognitive impairment compared with patients without autoantibodies; 17% of patients had autoantibodies against currently unknown neuronal antigens, which were also associated with higher odds of cognitive impairment.

Meaning  The study’s findings suggested that neuronal autoantibodies might represent a pathogenic factor in cancer-related cognitive impairment among patients with lung cancer; autoantibodies against currently unknown epitopes have potentially relevant consequences for cognitive function, which warrants further characterization.


Importance  Paraneoplastic neurological syndromes are associated with neuronal autoantibodies, and some of these autoantibodies are associated with neuropsychological symptoms. The most common underlying tumor is lung cancer. The association of neuronal autoantibodies with cognitive deficits has not been systematically investigated in patients with small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC).

Objective  To assess the frequency of neuronal autoantibodies in patients with lung cancer and analyze their association with cognitive function.

Design, Setting, and Participants  This prospective, cross-sectional study included 167 patients with lung cancer (both SCLC and NSCLC) recruited at a single lung cancer center in Berlin, Germany, between June 2015 and April 2016. Detailed neuropsychological testing was performed in a carefully selected subgroup of 97 patients (from which patients with potential confounding factors were excluded). Investigators were blinded to patients’ autoantibody status and cognitive test results. Data were analyzed from May 2016 to December 2019.

Main Outcomes and Measures  Prevalence of neuronal autoantibodies and their association with cognitive impairment. The evaluation of autoantibodies as potential risk factors for cognitive impairment was performed using bayesian logistic regression models.

Results  Among 167 patients with lung cancer (median age, 66.0 years [interquartile range, 59.0-72.0 years]; 105 men [62.9%]), 127 had NSCLC, and 40 had SCLC. Brain-directed autoantibodies were detected in 61 of 167 patients (36.5%); 33 patients (19.8%) had known autoantibodies and 28 patients (16.8%) had autoantibodies against currently unknown antigens that were detected through immunohistochemical analysis. Cognitive impairment was found in 65 of 97 patients (67.0%). Among patients with SCLC, the odds of cognitive impairment for those with any autoantibodies was 11-fold higher (odds ratio [OR], 11.0; 95% credible interval [CrI], 1.2-103.6) than that of autoantibody-negative patients, and the increased odds were independent of age, sex, and neurological deficit. Among patients with NSCLC, those with immunoglobin A autoantibodies targeting the N-methyl-d-aspartate receptor had a relevantly increased odds of verbal memory deficits (OR, 182.8; 95% CrI, 3.1-10 852.4). Autoantibodies against currently unknown antigens were also associated with increased odds of cognitive impairment (OR, 2.8; 95% CrI, 0.6-12.1).

Conclusions and Relevance  In this prospective, cross-sectional study, more than one-third of patients with lung cancer had neuronal autoantibodies that were found to be associated with cognitive impairment. These autoantibodies might represent a potentially treatable mechanism of immune-mediated cognitive impairment among patients with lung cancer.

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