Dysfunction of the blood-cerebrospinal fluid-barrier and N-methyl-d-aspartate glutamate receptor antibodies in dementias

Abstract

N-Methyl-D-aspartate glutamate receptor (NMDA-R) antibodies (Abs) could play a role in neurodegenerative disorders. Since, in these diseases, NMDA-R Abs were detected in serum, but only sporadic in cerebrospinal fluid (CSF), the origin and impact of the Abs are still unresolved. We examined the presence of NMDA-R Abs in serum and CSF using a cell-based immunofluorescence assay as well as the function of the blood-CSF-barrier (B-CSF-B) by determination of Q albumin (ratio of albumin in CSF and serum) in patients with mild cognitive impairment (MCI; N = 59) and different types of dementia, Alzheimer's disease (AD; N = 156), subcortical ischemic vascular dementia (SIVD; N = 61), and frontotemporal dementia (FTD; N = 34). Serum IgA/IgM NMDA-R Abs and/or a disturbed B-CSF-B were sporadically present in all investigated patients' groups. In AD, these Abs often developed during the disease course. Patients with either no hippocampal atrophy and/or no AD-related characteristic changes in CSF, referred to "non-classical" AD, were characterized by seropositivity at diagnosis and loss of function of the B-CSF-B showed a progressive decline in cognitive functions and a poor prognosis. Our data indicate that NMDA-R Abs are present in different types of dementia and elderly healthy individuals. In combination with disturbed B-CSF-B integrity, they seem to promote their pathological potential on cognitive decline, and thus, a subgroup of dementia patients with these unique characteristics might inform clinicians.

Blood-brain barrier regulation in psychiatric disorders

“…BBB dysfunction was represented as increased serum albumin levels with BBB dysfunction being the only sign of dysfunction in 24% of cases [91]. A dysfunctional blood-CSF barrier has also been reported in patients with several forms of dementia including Alzheimer's disease and frontotemporal dementia with elevated QAlb [92]. However, analysis of QAlb has its limitations as increased QAlb can result from other factors including low rates of CSF production, increased subarachnoid flow resistance or blocking of arachnoid villi causing reduced outflow into venous.…”

Neuronal surface autoantibodies in dementia: a systematic review and meta-analysis

“…Eight studies met the inclusion criteria [9,19,[28][29][30][31][32][33]. However, one study [9] was subsequently excluded due to having an overlapping sample with a larger study [30].…”

“…A second study examined α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibodies only [28] and so was excluded from the meta-analyses. Six remaining studies examined NMDAR antibodies and were included in the meta-analysis [19,[29][30][31][32][33].…”

“…All studies recruited patients with clinical diagnoses of dementia; four of these confirmed diagnoses with clinical testing, including neuropsychological assessments and MRI [29][30][31]33]. Three studies excluded patients with possibly confounding co-morbidities (e.g., infection, autoimmune disease, and cancer) [29][30][31]. One study recorded the prevalence of autoimmune disease and cancer in their cohort, but did not exclude these patients from the typical dementia group [32].…”

Biomarkers for Alzheimer’s disease: from pathogenesis to drug development

“…NMDAR antibodies play a role in neurodegenerative disorders [2]. In this issue, Busse et al [3] measured the presence of NMDAR antibodies in serum and cerebrospinal fluid (CSF) in patients with mild cognitive impairment (n = 59) and different types of dementia, AD (n = 156), subcortical ischemic vascular dementia (SIVD: n = 61), and frontotemporal dementia (FTD: n = 34). Serum IgA/IgM NMDAR antibodies and/or a disturbed blood-CSF barrier were sporadically present in all of the investigated patient groups.…”