N-methyl-d-aspartate glutamate receptor (NMDA-R) antibodies in mild cognitive impairment and dementias

Busse, Stefan; Brix, Britta; Kunschmann, Ralf; Bogerts, Bernhard; Stoecker, Winfried; Busse, Mandy

doi:10.1016/j.neures.2014.06.002

Cited by 33 publications

(26 citation statements)

References 74 publications

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“…They range from the absence of IgG-positive cases in >8000 controls with various disorders25 to the absence in more than 500 healthy control subjects,23,26–29 to the presence of IgG and further isotypes in 7% of controls, none of them solely tested against the NR1 subunit of the NMDAR 30. Another study found NMDAR IgM (but not IgA and IgG) in two of 21 healthy controls 31. A large recent study used blood donors as controls and found a ~10% seroprevalence of NMDAR antibodies, mostly IgM and IgA subtypes 32.…”

Section: Discussionmentioning

confidence: 99%

High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types

Doss

Wandinger

Hyman³

et al. 2014

Ann Clin Transl Neurol

116

107

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ObjectiveTo retrospectively determine the frequency of N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia.MethodsClinical characterization of 660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age-matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients.ResultsSerum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with “unclassified dementia” followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson’s disease-related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA-associated cognitive decline.InterpretationSerum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy.

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Section: Discussionmentioning

confidence: 99%

High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types

Doss

Wandinger

Hyman³

et al. 2014

Ann Clin Transl Neurol

116

107

View full text Add to dashboard Cite

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“…The use of protein, peptides, and even peptoid arrays has led to the identification of autoantibodies specific to patients with AD. Autoantibodies against targets involved in synaptic activity, including neurotransmitters and receptors, are associated with cognitive decline, suggesting their use as signals of brain malfunction [262][263][264][265][266][267][268][269][270][271] (Table 1). With respect to inflammation, the relationship between neurodegeneration and autoimmunity was recently genetically confirmed in an epidemiological study where specific single-nucleotide polymorphisms in TREM2 (triggering receptor expressed on myeloid cells 2) and complement factors were shown to overlap between AD and immune diseases [272].…”

Section: Circulating Autoantibodies As Biomarkersmentioning

confidence: 99%

Biomarkers for the Early Detection and Progression of Alzheimer's Disease

et al. 2017

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The recent failures of potential disease-modifying drugs for Alzheimer's disease (AD) may reflect the fact that the enrolled participants in clinical trials are already too advanced to derive a clinical benefit. Thus, well-validated biomarkers for the early detection and accurate diagnosis of the preclinical stages of AD will be crucial for therapeutic advancement. The combinatorial use of biomarkers derived from biological fluids, such as cerebrospinal fluid (CSF), with advanced molecular imaging and neuropsychological testing may eventually achieve the diagnostic sensitivity and specificity necessary to identify people in the earliest stages of the disease when drug modification is most likely possible. In this regard, positive amyloid or tau tracer retention on positron emission tomography imaging, low CSF concentrations of the amyloid-β 1-42 peptide, high CSF concentrations in total tau and phospho-tau, mesial temporal lobe atrophy on magnetic resonance imaging, and temporoparietal/precuneus hypometabolism or hypoperfusion on 18F-fluorodeoxyglucose positron emission tomography have all emerged as biomarkers for the progression to AD. However, the ultimate AD biomarker panel will likely involve the inclusion of novel CSF and blood biomarkers more precisely associated with confirmed pathophysiologic mechanisms to improve its reliability for detecting preclinical AD. This review highlights advancements in biological fluid and imaging biomarkers that are moving the field towards achieving the goal of a preclinical detection of AD.

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“…These are neurotoxic and are associated with cognitive impairment. Patients with autoantibodies to NMDA have dystonia, seizures, and mild cognitive impairment . On the brighter side, the gabapentinoids, pregabalin and gabapentin, bind to α 2 δ subunit of voltage‐gated Ca ++ channel and inhibit the entry of Ca 2+ to the presynaptic afferents (Fig.…”

Section: Intractable Vocs With Persistent Pain In Between Episodesmentioning

confidence: 99%

Pathophysiology and principles of management of the many faces of the acute vaso‐occlusive crisis in patients with sickle cell disease

Ballas

2014

European J of Haematology

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Effective management of sickle cell pain entails a thorough understanding of its pathophysiology and the pharmacogenomics of the opioids used to manage it. In recent years, there has been significant progress along these two lines. At the pathophysiologic level, there is evidence that the severity and frequency of painful stimuli modulate their transmission at the level of the dorsal horn of the spinal cord. This modulation is achieved via two channels: the a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors. Initially, the AMPA channel controls the transmission of stimuli of mild-moderate severity. Once the AMPA channel reaches its limit of membrane depolarization, the NMDA channel is activated and facilitates the transmission of painful stimuli in a progressive fashion leading to central sensitization and glial activation. At the level of pharmacogenomics, the metabolism of each opioid is patient-specific. Glucuronidation is unique for the metabolism of morphine, hydromorphone, and oxymorphone. The metabolism of all other opioids requires specific Cytochrome P450 (CYP) isoenzymes. The activity of each isoenzyme and the activity of the metabolites of each opioid vary among patients depending on their genetic makeup and coexistent environmental factors such as the use of other medications that may enhance or inhibit the CYP isoenzyme activity. The clinical picture of sickle cell disease (SCD) in general and sickle cell anemia (SS) in particular has evolved significantly over the years. In the 1950s, 1960s, and 1970s, many patients died during childhood or young adulthood (1-3) and the knowledge of healthcare providers about sickle cell pain and its management were suboptimal. Since then, things have improved significantly but not totally. With the advent of newborn screening, penicillin/antibiotic prophylaxis, better vaccines, better antibiotics, safer blood transfusion, iron chelation therapy and hydroxyurea survival and the quality of life of patients with SCD improved (4, 5), and it is not unusual nowadays to have occasional patients with SCD who are 50-70 yr old. With increased longevity, however, a host of new phenomena appeared and the incidence of new complications of SCD became apparent and previously milder complications became more severe and more common. The acute vaso-occlusive crisis (VOC), for example, is no more characterized by the intermittent sudden onset and sudden offset only with pain-free periods in between recurrent VOCs; chronic pain syndromes have become more common and more severe requiring special treatments and interventions, neuropathic pain has been well documented in transgenic sickle cell mice, and most importantly numerous comorbidities emerged that complicate the already complex disease. There are at least 23 comorbid conditions reported in SCD (6). Despite these advances, management of acute sickle cell pain did not change much; it is still fixed at the level of type, amount, frequency, and

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N-methyl-d-aspartate glutamate receptor (NMDA-R) antibodies in mild cognitive impairment and dementias

Cited by 33 publications

References 74 publications

High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types

High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types

Biomarkers for the Early Detection and Progression of Alzheimer's Disease

Pathophysiology and principles of management of the many faces of the acute vaso‐occlusive crisis in patients with sickle cell disease

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