Seroprevalence of n-methyl-d-aspartate glutamate receptor (NMDA-R) autoantibodies in aging subjects without neuropsychiatric disorders and in dementia patients

Abstract

N-methyl-D-aspartate glutamate receptors (NMDA-R) play a key role in learning and memory. Therefore, they may be involved in the pathophysiology of dementia. NMDA-R autoantibodies directed against the NR1a subunit of the NMDA-R, which were first identified as a specific marker for a severe form of encephalitis, cause a decrease in NMDA-Rs, resulting in cognitive impairment and psychosis. We examined the prevalence of NR1a NMDA-R autoantibodies in the serum and cerebrospinal fluid (CSF) of 24 patients with Alzheimer's disease (AD), 20 patients with subcortical ischemic vascular dementia (SIVD), and 274 volunteers without neuropsychiatric disorder. The latter cases showed an association of seropositivity with age. Notably, the overall seroprevalence was not statistically different between dementia patients and matched controls. Further analysis of the patient samples showed that four patients with AD and three patients with SIVD had positive NMDA-R IgM, IgG, and/or IgA autoantibody titers in serum. These patients suffered from psychosis (with the exception of one case). CSF samples were negative for NMDA-R autoantibodies. We conclude that the seroprevalence of NMDA-R-directed autoantibodies is age-related. It has to be clarified by larger studies whether NMDA-R autoantibodies in peripheral blood may predispose patients with AD and SIVD to susceptibility for psychotic episodes if disturbances of blood-brain-barrier integrity occur.

All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class

“…5 Rendering the situation more complex, a high age-dependent seroprevalence of NMDAR1-AB has been recognized recently. [9][10][11][12][13][14] According to these findings in meanwhile 45000 subjects, any 40-year-old person has an~10%, any 80-year-old person an~20% chance of displaying NMDAR1-AB seropositivity. 11 Disease groups, ranging from schizophrenia and major depression, over multiple sclerosis, Parkinson's and Alzheimer's disease, to hypertension, diabetes and stroke, as well as healthy individuals, share not only similar NMDAR1-AB seroprevalence but also immunoglobulin (Ig) class distribution (IgM, IgA and IgG) and titer range.…”

Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke

“…11,12 Corresponding results were confirmed by others. [13][14][15] Importantly, immunoglobulin isotypes, titers, and functionality of NMdAR1-AB are comparable in health and disease. 11,12,16 Moreover, we provided experimental evidence that neuropsychiatric syndrome relevance of circulating NMdAR1-AB requires a compromised blood-brain barrier (BBB).…”

Autoimmune encephalitis in psychiatric institutions: current perspectives

“…Although the presence of IgG is found in most cases, other immunoglobulin subtypes can also be found 30. The distinction between IgG, IgA and IgM immunoglobulins subtypes is essential as the prevalence,24,31 the physiopathology,32 and the clinical presentation33 are different. Anti-NMDAR encephalitis is a primary antibody-mediated disease, and the treatment is based on immunotherapy and tumor removal (if present).…”