Neuronal Autoantibodies Associated with Cognitive Impairments in Lung Cancer Patients

A full one-third of patients with small cell (SCLC) and non-small cell lung cancer (NSCLC) had neuronal autoantibodies associated with cognitive impairment, according to a study published in JAMA Oncology. Researchers are hopeful that with further study, these autoantibodies can become a potential therapeutic target in the battle against immune-mediated cognitive impairment in these patients—and others—with cancer.

“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,” wrote Frederik Bartels, MD, of Universitätsmedizin Berlin, Berlin, Germany, and fellow researchers.

“A high prevalence of neuronal autoantibodies was observed in a 2017 retrospective study of 323 patients with different types of cancer, including SCLC and NSCLC. These serum autoantibodies mainly targeted neuronal cell surface proteins and were associated with mild cognitive impairment. This finding was replicated in a prospective blinded study indicating that neuronal autoantibodies were associated with deficits in all cognitive domains among patients with melanoma. Some of these autoantibodies (immunoglobin A [IgA] and immunoglobin M [IgM] autoantibodies targeting the N-methyl-D-aspartate receptor [NMDAR]) had previously been associated with slow cognitive impairment and were also detected in a subgroup of patients with dementia,” they added.

Bartels and colleagues conducted this prospective, cross-sectional study in 167 patients (median age: 66.0 years; 62.9% men) with SCLC (n=40) and NSCLC (n=127) from a single lung cancer center in Berlin. Immunohistochemical analysis revealed brain-directed autoantibodies in 36.5% of all patients, known autoantibodies in 19.8%, and autoantibodies against a currently unknown antigen in 16.8%.

SCLC patients had a higher prevalence of autoantibodies compared with NSCLC patients (45.0% versus 33.9%, respectively). In patients with SCLC, researchers also found 11-fold greater odds of cognitive impairment for those with autoantibodies (OR: 11.0; 95% credible interval [CrI]: 1.2-103.6) compared with patients who were autoantibody-negative. This increase was independent of age, sex, and neurological deficit.

Most SCLC patients had A1C autoantibodies (30.0%), the presence of which was associated with a significantly higher odds of cognitive impairment (OR: 8.3; 95% CrI: 0.7-91.5), verbal memory deficits (OR: 44.0; 95% CrI: 1.4-1,345.4), and attention deficits (OR: 36.8; 95% CrI: 2.9-474.1).

Among NSCLC patients, most autoantibodies targeted the NMDAR, and the presence of IgA NMDAR autoantibodies was associated with significantly higher risks of verbal memory deficits (OR: 182.8; 95% CrI: 3.1-10,852.4).

Finally, researchers found that the presence of autoantibodies against currently unknown antigens were associated with an increased odds of cognitive impairment (OR: 2.8; 95% CrI: 0.6-12.1).

A subgroup of 97 carefully selected patients underwent neuropsychological testing after researchers excluded all patients with potential confounding factors such as brain metastases and other severe neurological or psychiatric disorders. Among these patients, 67.0% had cognitive impairment, with the most common deficits including those in executive function (45.8%) and attention (43.3%).

Patients with SCLC and NSCLC in this select group had a similar prevalence of cognitive impairment (61.5% versus 69.0%, respectively), as did men and women (69.6% versus 63.4%) and the various treatment groups and tumor stages. Finally, depression and mental health scale scores were also similar in patients with and without cognitive impairment.

“How might the findings in this study help address cognitive impairments in patients with lung cancer and lead to better treatment? First, the high rate of cognitive impairments in patients with lung cancer means that most patients are, at one point or another, negatively affected by a reduced ability to concentrate, remember, or efficiently communicate. In the US, comprehensive neuropsychological testing for patients with cancer is not often accessible or covered by managed care clinicians. Bartels et al highlight the importance of such testing for patients, especially those who have subjective complaints,” wrote Shawn L. Hervey-Jumper, MD, of the University of California, San Francisco, and Michelle Monje, MD, PhD, Stanford University, in an accompanying editorial.

They also concluded that these results highlight the importance of future studies to “understand the associations of disease activity and cancer therapy with cognition, including the cognitive effects of immunomodulation therapies. As the underlying mechanisms of cancer-related and cancer therapy-related cognitive impairments become clearer, this study lays the foundation for forthcoming clinical and mechanistic studies, and ultimately, therapeutic intervention.”

1. In this cross-sectional study of patients with lung cancer, 37% had neuronal autoantibodies, and 45% of patients with small cell lung cancer and 34% of patients with non–small cell lung cancer were autoantibody positive.

2. Researchers suggested that, with further study, these autoantibodies can become a potential therapeutic target in the battle against immune-mediated cognitive impairment in cancer patients.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

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