High prevalence of neuronal surface autoantibodies associated with cognitive deficits in cancer patients

Abstract

The recent discovery of neuronal cell-surface antibodies profoundly expanded the clinical spectrum of paraneoplastic neurological syndromes. Many of these syndromes are associated with impaired cognitive function, a clinical symptom that is of increasing concern in cancer patients. However, the frequency of these antibodies in cancer patients and their relation to clinical syndromes is currently unknown. Here, we investigated the prevalence of neuronal cell-surface antibodies and associated paraneoplastic neurological syndromes in 323 patients with different cancer types and in 105 controls. Cerebrospinal fluid and serum samples were analysed for a large panel of anti-neuronal antibodies and all patients were screened for cognitive deficits. Blood-brain barrier integrity was assessed using the age-normalized albumin cerebrospinal fluid/serum ratio. Anti-neuronal autoantibodies were observed in 24.5% of cancer patients (in contrast to 3.1% in neurological control patients without cancer and 2.5% in healthy controls) and were almost exclusively detected in serum. The majority of antibodies were directed against cell-surface antigens (75.9%), most frequently IgA/IgM isotypes targeting the N-methyl-D-aspartate (NMDA) receptor. Cognitive deficits and cerebellar syndromes were significantly more prevalent in antibody-positive in comparison with antibody-negative patients (21 vs. 7%, p = 2.7 × 10; 11 vs. 2%, p = 3.0 × 10). Antibody-positive patients with cognitive deficits had a significantly increased albumin cerebrospinal fluid/serum ratio in comparison with antibody-positive patients with other neurological deficits, indicating blood-brain barrier dysfunction (49.1 × 10 vs. 12.0 × 10; p = 0.036). Our results show that anti-neuronal antibodies have a high prevalence in a wide range of different tumour types and are associated with distinct neurological deficits. Specifically, the results suggest a so far undefined cognitive paraneoplastic syndrome in patients with antibodies targeting neuronal surface antigens and concurrent blood-brain barrier dysfunction. Anti-neuronal antibodies might thus serve as a biomarker for potentially treatment-responsive cognitive impairments in cancer patients.

Serum Systemic Autoantibodies in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

“…Positive systemic autoantibodies were detected in the CSF in neuropsychiatric lupus patients, which played important role in the disruption of blood brain barrier (BBB) (25)(26)(27). Recent studies have suggested the integrity of BBB was impaired in anti-NMDAR antibody positive patients (28,29). Although systemic autoantibodies were not tested in the CSF in our study, it is thus tempting to speculate that serum systemic autoantibodies play a role in the damages of neurons by interacting with anti-NMDAR antibody against neuronal surface antigens, where they can access the brain because of BBB disruption.…”

Autoantibodies against N-methyl-d-aspartate receptor 1 in health and disease

“…Many reports, including recent ones, describing either higher seroprevalence in certain disorders and/or absence/scarcity in a particular disease/health group are based on much too small numbers of subjects for a firm conclusion to be drawn (e.g. [ 31 ▪ , 32 ▪ ]). Among them are case reports, often without mentioning immunoglobulin classes, titers, or whether serum or cerebrospinal fluid (CSF) was analyzed.…”

“…In a heterogeneous group of 323 cancer patients, the seroprevalence of neuronal surface AB (IgA, IgM) was reported to be high [ 32 ▪ ], but is actually in the expected range of the investigated age (NMDAR1-AB 16.7%; mean age 62 years) [ 18 , 27 , 28 ]. The number of controls in this study ( N = 65 neurological disease controls and N = 40 healthy blood donors) is too low for solid comparative conclusions.…”

The pathological hallmarks of Alzheimer’s disease derive from compensatory responses to NMDA receptor insufficiency

“…(i) Autoimmune antibodies. Anti-NMDA receptor autoantibodies are frequent (seroprevalence 10-20%, rising with age) (Zerche et al, 2015), act anti-excitatory in vitro (Pruss et al, 2012;Castillo-Gomez et al, 2016) and appear to be broadly associated with cognitive deficits and dementia (Pruss et al, 2012;Doss et al, 2014;Finke et al, 2017). Notably, their association with outcome in clinical stroke depends on the ApoE genotype (Zerche et al, 2015).…”