Brain-targeting autoantibodies in patients with dementia

Abstract

Autoantibodies against proteins in the brain are increasingly considered as a potential cause of cognitive decline, not only in subacute autoimmune encephalopathies but also in slowly progressing impairment of memory in patients with classical neurodegenerative dementias. In this retrospective cohort study of 161 well-characterized patients with different forms of dementia and 34 controls, we determined the prevalence of immunoglobulin (Ig) G and IgA autoantibodies to brain proteins using unbiased immunofluorescence staining of unfixed murine brain sections. Autoantibodies were detected in 21.1% of dementia patients and in 2.9% of gender-matched controls, with higher frequencies in vascular dementia (42%), Alzheimer's disease (30%), dementia of unknown cause (25%), and subjective cognitive impairment (16.7%). Underlying antigens involved glial fibrillary acidic protein (GFAP), glycine receptor, and Rho GTPase activating protein 26 (ARHGAP26), but also a range of yet undetermined epitopes on neurons, myelinated fiber tracts, choroid plexus, glial cells, and blood vessels. Antibody-positive patients were younger than antibody-negative patients but did not differ in the extent of cognitive impairment, epidemiological and clinical factors, or comorbidities. Further research is needed to understand the potential contribution to disease progression and symptomatology, and to determine the antigenic targets of dementia-associated autoantibodies.

Keywords: CSF; autoantibodies; autoimmunity; cognitive impairment; neurodegenerative dementia.

Figure 1

Recruitment of patients and controls into the study.

Figure 2

Prevalence of autoantibody-positive patients among different diagnostic groups. The percentage of positive patients within the diagnostic group is given for serum and for CSF, respectively. Lewy body dementia, mixed dementia, and amyloid angiopathy. AD, Alzheimer’s disease; MCI, Mild cognitive impairment; FTD, Frontotemporal dementia; VaD, Vascular dementia; SCI, Subjective cognitive impairment; CG, Control group; and CSF, Cerebrospinal fluid.

Figure 3

Immunofluorescence staining patterns on unfixed mouse brain with serum/CSF of different patients. (A) Staining of astrocytes in the hippocampal region (blue: co-staining of the nuclei with DAPI) with serum of an AD patient. (B) Distinct labeling of Bergmann glia cells in the cerebellum with serum of an AD patient. (C) Intense myelin staining in the deep white matter of the cerebellum with CSF of an AD patient. (D) Survey micrograph showing ubiquitous ANA staining in the cerebellum using serum of an AD patient. (E) Distinct staining of the ependymal layering of brain ventricles with serum of an AD patient. (F) Net-like staining in the choroid plexus with serum of an AD patient. (G) Intense ANA staining of rings and rod-like structures in hippocampus and cortex using CSF of an AD patient. (H) Reticular labeling of choroid plexus cells resembling a tight junction pattern, in addition staining of nucleoli, using serum of an MCI patient. (I) Finely speckled, granular ANA staining in the cerebellum with serum of an SCI patient (blue: co-staining of the nuclei with DAPI).