Neuronal autoantibodies associated with cognitive impairment in melanoma patients

Abstract

Background Cancer-related cognitive impairment is an important complication in cancer patients, yet the underlying mechanisms remain unknown. Over the last decade, the field of paraneoplastic neurological syndromes has been dramatically changed by the discovery of new neuronal autoantibodies, some of them associated with cognitive impairment. We aimed to assess the prevalence of neuronal autoantibodies in melanoma patients and their association with neurological and cognitive dysfunction. Patients and methods A total of 157 consecutive melanoma patients with a median age of 63 years were recruited at the Department of Dermatology, Charité—Universitätsmedizin Berlin and tested for neuronal autoantibodies. A comprehensive neuropsychological assessment was carried out in a selected subgroup of 84 patients after exclusion of patients with confounding factors for a cognitive dysfunction, including brain metastases, relevant medication, and neurological disorders. Results Neuronal autoantibodies were found in 22.3% of melanoma patients. The most frequent antibodies were IgA/IgM anti-NMDAR antibodies. Applying the International Cognition and Cancer Task Force criteria, 36.9% had cognitive impairment, however, with a threefold higher odds in antibody-positive compared with antibody-negative patients (57.1% versus 30.2%, OR = 3.1, 95% CI: 1.1 to 8.6; P = 0.037). In patients with anti-NMDAR antibodies, this impairment increased with higher antibody titers ( P = 0.007). Antibody-positive patients had a significantly impaired overall cognitive performance ( z -value: −0.38 ± 0.69 versus 0.00 ± 0.56; P = 0.014) as well as significant impairments in tests of memory, attention, and executive function. In a multiple linear regression analysis, autoantibodies were an independent risk factor for cognitive impairment (B = −0.282; 95% CI: −0.492 to −0.071; P = 0.009). Autoantibody seropositivity was associated with immune checkpoint inhibitor treatment and a history of autoimmune diseases. Conclusions A large number of melanoma patients harbor neuronal autoantibodies that are associated with significant cognitive impairment affecting memory, attention, and executive function. Neuronal autoantibodies might represent a pathophysiological factor and possible biomarker in the development of cancer-related cognitive impairment.

Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: a translational study from chronic life stress to brain injury

“…In a first search of cellular mechanisms relevant for (patho)physiological autoimmunity in general, and NMDAR1-AB in particular, we focused here on the gene encoding CTLA4, an Ig-superfamily member and dampener of T-cell activation, with recognized susceptibility to various autoimmune diseases [35][36][37][38][39][40][41][42]. Correspondingly, anti-CTLA4 treatment of cancer patients can result in autoimmune disease as serious adverse event [43][44][45][46]. CTLA4 is an important regulator of the immune response, exerting its influence on reactivity to both foreign and self-antigens.…”

“…Since treatment of cancer patients with checkpointinhibitors (anti-CTLA4) has led to autoimmune diseases as serious adverse events [43][44][45][46], we next treated healthy female WT mice with CTLA4-AB, starting at age 11 weeks ( Fig. 2e).…”

Health-related quality of life of long-term advanced melanoma survivors treated with anti-CTLA-4 immune checkpoint inhibition compared to matched controls

“…However, cancer-related cognitive impairment (CRCI) is frequently reported and seems to be associated with cancer and all components of cancer treatment [41]. Despite the fact that there is limited research describing the effects of ICI on the brain, given the highly regulated immune response in the brain, it is expected that all the treatment modalities and cancer itself might be associated with CRCI [42][43][44].…”

Serum anti-NMDA-receptor antibodies and cognitive function after ischemic stroke (PROSCIS-B)

“…Cumulative evidence from disease cohorts other than stroke patients link serum presentation particularly with cognitive outcomes: for example was NMDAR1-abs IgA and IgM seropositivity associated with cognitive impairment in melanoma patients, and others found serum IgA to be associated with different types of slowly progressive cognitive impairment. (3)(4)(5) In stroke, however, NMDAR1-abs seropositivity was foremost linked with beneficial effects on infarct volumes, which was explained by presumed effects of NMDAR1-abs on NMDA-receptor mediated excitotoxicity. (7,8,21) In line with other studies mentioned earlier, (3)(4)(5) in our study of firstever stroke patients high titers were associated with decreased cognitive function, challenging previous hypotheses of beneficial effects of these antibodies in stroke pathology.…”

“…(3)(4)(5) In stroke, however, NMDAR1-abs seropositivity was foremost linked with beneficial effects on infarct volumes, which was explained by presumed effects of NMDAR1-abs on NMDA-receptor mediated excitotoxicity. (7,8,21) In line with other studies mentioned earlier, (3)(4)(5) in our study of firstever stroke patients high titers were associated with decreased cognitive function, challenging previous hypotheses of beneficial effects of these antibodies in stroke pathology. (7,8) This current observation further coincides with our observation regarding NMDAR1-abs and other outcomes in the PROSCIS study, i.e.…”