Association of cerebrospinal fluid brain-binding autoantibodies with cognitive impairment in post-COVID-19 syndrome

Abstract

Background: Neurological symptoms, in particular cognitive deficits, are common in post-COVID-19 syndrome (PCS). There is no approved therapy available, and the underlying disease mechanisms are largely unknown. Besides others, autoimmune processes may play a key role.

Design: We here present data of a prospective study conducted between September 2020 and December 2021 and performed at two German University hospitals with specialized Neurology outpatient clinics. Fifty patients with self-reported cognitive deficits as main complaint of PCS and available serum and CSF samples were included. Cell-based assays and indirect immunofluorescence on murine brain sections were used to detect autoantibodies against intracellular and surface antigens in serum and CSF and analyzed for associations with cognitive screening assessment.

Results: Clearly abnormal cognitive status (MoCA ≤ 25/30 points) was only seen in 18/50 patients with self-reported cognitive deficits. Most patients (46/50) had normal routine CSF parameters. anti-neuronal autoantibodies were found in 52 % of all patients: n = 9 in serum only, n = 3 in CSF only and n = 14 in both, including those against myelin, Yo, Ma2/Ta, GAD65 and NMDA receptor, but also a variety of undetermined epitopes on brain sections. These included cerebral vessel endothelium, Purkinje neurons, granule cells, axon initial segments, astrocytic proteins and neuropil of basal ganglia or hippocampus as well as a formerly unknown perinuclear rim pattern. Pathological MoCA results were associated with the presence of anti-neuronal antibodies in CSF (p = 0.0004).

Conclusions: Autoantibodies targeting brain epitopes are common in PCS patients and strongly associate with pathological cognitive screening tests, in particular when found in CSF. Several underlying autoantigens still await experimental identification. Further research is needed to inform on the clinical relevance of these autoantibodies, including controlled studies that explore the potential efficacy of antibody-depleting immunotherapy in PCS.

Keywords: Autoantibody; CSF; Neurocognitive disorder; Neurology; Post-COVID-19.

Fig. 1

CSF of patients with neurocognitive disorders in post-COVID-19 syndrome frequently shows autoreactivity on unfixed mouse brain sections. Representative images of indirect immunofluorescence using undiluted CSF with incubation overnight at 4 °C demonstrate autoantibody binding following nine major patterns including anti-nuclear antibodies (A, from patient #8), vessel endothelium (B), large neurons (C, from patient #2), perinuclear rim pattern (D, from patient #13), Purkinje neurons (E, from patient #12), cerebellar granule cells (F, from patient #5), astrocytic proteins (G, from patient #7), axon initial segments (H, from patient #10) and neuropil of basal ganglia (I, from patient #5) or hippocampus.

Fig. 2

Results of the cognitive screening for PCS patient groups with any anti-neuronal autoantibodies found in CSF (left) or in serum only (middle) or antibody-negative patients (right).