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

Abstract

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 MEASURESPrevalence 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,. 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 RELEVANCEIn 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.

Band-Like Brainstem Lesion in a Patient With a History of Lung Adenocarcinoma

“…The second important clinical point is that concurrent with identifying the brainstem lesion, our patient showed a rapid cognitive decline, primarily a deficit in object-naming ability. Bartels et al showed that a high proportion of patients with lung cancer (67.0%) had cognitive impairment, with a similar prevalence between patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) [ 18 ]. Here, we can assume the following two mechanisms of cognitive decline in our patient.…”

“…A second possible mechanism is that paraneoplastic anti-neuronal antibodies may lead to cognitive decline. Bartels et al reported that more than one-third of patients with lung cancer had neuronal autoantibodies that were found to be associated with cognitive decline [ 18 ]. We examined patient sera using a commercially available paraneoplastic neurological syndrome antibody panel and found no antibodies.…”

“…However, most of the antibodies in the panel target intracellular antigens and are associated with SCLS. Bartles et al reported that, among patients with NSCLC, immunoglobin A autoantibodies targeting the N-methyl-D-aspartate receptor, which is a neuronal surface antigen, and autoantibodies against currently unknown antigens are associated with cognitive decline [ 18 ]. As we did not probe for these antibodies, we are unable to exclude the possibility that paraneoplastic anti-neuronal antibodies were involved in our patient’s cognitive decline.…”

Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune related adverse events

“…Detection of brain-reactive autoantibodies was performed using c o m m e r c i a l a s s a y s ( a l l E U R O I M M U N M e d i z i n i s c h e Labordiagnostika AG, Germany) including cell-based assays (CBA) and immunohistochemistry (IHC) of frozen brain tissue (rat hippocampus, rat cerebellum, and monkey cerebellum). To that end, indirect immunofluorescence using BIOCHIP mosaics ™ was performed as described previously (24). To confirm CBA or IHC results for intracellular antigens, immunoblot assays (EUROLINE) were additionally performed.…”

Editorial: Insights in neuroinflammation and neuropathy

“…The presence of neuronal autoantibodies is associated with neuropsychological syndromes and cognitive impairment (Bartels et al, 2019(Bartels et al, , 2021. In a study conducted by Hansen et al, the application of methylprednisolone immunotherapy was assessed in patients with neural autoantibodies.…”