Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: a translational study from chronic life stress to brain injury.

Circulating autoantibodies (AB) of different immunoglobulin classes (IgM, IgA, and IgG), directed against the obligatory N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB), belong to the mammalian autoimmune repertoire, and appear with age-dependently high seroprevalence across health and disease. Upon access to the brain, they can exert NMDAR-antagonistic/ketamine-like actions. Still unanswered key questions, addressed here, are conditions of NMDAR1-AB formation/boosting, intraindividual persistence/course in serum over time, and (patho)physiological significance of NMDAR1-AB in modulating neuropsychiatric phenotypes. We demonstrate in a translational fashion from mouse to human that (1) serum NMDAR1-AB fluctuate upon long-term observation, independent of blood-brain barrier (BBB) perturbation; (2) a standardized small brain lesion in juvenile mice leads to increased NMDAR1-AB seroprevalence (IgM + IgG), together with enhanced Ig-class diversity; (3) CTLA4 (immune-checkpoint) genotypes, previously found associated with autoimmune disease, predispose to serum NMDAR1-AB in humans; (4) finally, pursuing our prior findings of an early increase in NMDAR1-AB seroprevalence in human migrants, which implicated chronic life stress as inducer, we independently replicate these results with prospectively recruited refugee minors. Most importantly, we here provide the first experimental evidence in mice of chronic life stress promoting serum NMDAR1-AB (IgA). Strikingly, stress-induced depressive-like behavior in mice and depression/anxiety in humans are reduced in NMDAR1-AB carriers with compromised BBB where NMDAR1-AB can readily reach the brain. To conclude, NMDAR1-AB may have a role as endogenous NMDAR antagonists, formed or boosted under various circumstances, ranging from genetic predisposition to, e.g., tumors, infection, brain injury, and stress, altogether increasing over lifetime, and exerting a spectrum of possible effects, also including beneficial functions.

Circulating damage marker profiles support a neuroprotective effect of erythropoietin in ischemic stroke patients.

The German Multicenter EPO Stroke Trial, which investigated safety and efficacy of erythropoietin (EPO) treatment in ischemic stroke, was formally declared a negative study. Exploratory subgroup analysis, however, revealed that patients not receiving thrombolysis most likely benefited from EPO during clinical recovery, a result demonstrated in the findings of the Göttingen EPO Stroke Study. The present work investigated whether the positive signal on clinical outcome in this patient subgroup was mirrored by respective poststroke biomarker profiles. All patients of the German Multicenter EPO Stroke Trial nonqualifying for thrombolysis were included if they (a) were treated per protocol and (b) had at least two of the five follow-up blood samples for circulating damage markers drawn (n = 163). The glial markers S100B and glial fibrillary acid protein (GFAP) and the neuronal marker ubiquitin C-terminal hydrolase (UCH-L1) were measured by enzyme-linked immunosorbent assay in serum on d 1, 2, 3, 4 and 7 poststroke. All biomarkers increased poststroke. Overall, EPO-treated patients had significantly lower concentrations (area under the curve) over 7 d of observation, as reflected by the composite score of all three markers (Cronbach α = 0.811) and by UCH-L1. S100B and GFAP showed a similar tendency. To conclude, serum biomarker profiles, as an outcome measure of brain damage, corroborate an advantageous effect of EPO in ischemic stroke. In particular, reduction in the neuronal damage marker UCH-L1 may reflect neuroprotection by EPO.

Increased Lipoprotein (a) concentrations in patients with chronic venous leg ulcers: a study on patients with or without postthrombotic syndrome.

Chronic venous leg ulcers are common and cause considerable burden of disease for affected patients with significant costs for health care systems worldwide. The complex pathophysiology of chronic venous leg ulcers is still not entirely understood. In addition, reliable pathogenic and/or prognostic parameters are not known. Published data suggest that patients with chronic venous leg ulcers reveal congenital or acquired thrombophilia. We examined the serum Lipoprotein (a) [Lp(a)] level, a proatherogenic and prothrombotic risk factor, in patients with chronic venous leg ulcers (n=210, stratified into patients with postthrombotic syndrome or without) and in a healthy control group (n=341). Forty-two percent of all patients, compared with 20% of healthy controls, revealed significantly increased Lp(a) serum concentrations above 0.3 g/L. Furthermore, 49% without postthrombotic syndrome but only 35% with postthrombotic syndrome showed increased Lp(a) levels. The increase of Lp(a) level was significantly different between all three groups (p<0.001). There was no correlation of Lp(a) levels and CRP values in all groups. Based on these data, it is conceivable that Lp(a) plasma level is a novel pathogenic parameter for chronic venous leg ulcers. Elevated concentrations may contribute to the pathogenesis through induction of thrombogenic microcirculatory dysregulations, impaired extravascular fibrinolysis, or other mechanisms like proinflammatory effects.

Clinical features of rapidly progressive Alzheimer's disease.

OBJECTIVE: To characterize clinical features, CSF biomarkers and genetic polymorphisms of patients suffering from a rapidly progressing subtype of Alzheimer's dementia (rpAD). METHODS: Retrospective analyses of 32 neuropathologically confirmed cases differentially diagnosed as AD out of a group with rapidly progressive dementia. CSF biomarkers (14-3-3, tau, beta-amyloid 1-42) and genetic markers (PRNP codon 129, apolipoprotein E, ApoE, polymorphism) were determined. RESULTS: Median survival was 26 months, age at onset 73 years. Biomarkers: mean beta-amyloid 1-42: 266 pg/ml, median tau: 491 pg/ml, 14-3-3 positive: 31%. Genetic polymorphisms showed a predominance of methionine homozygosity at PRNP codon 129 and a low frequency of ApoE4 (38%, no homozygous patients). Thirty-five symptoms were studied. Frequent symptoms were myoclonus (75%), disturbed gait (66%) and rigidity (50%). DISCUSSION: rpAD is associated with a diversity of neurological signs even able to mimic Creutzfeldt-Jakob disease. Biomarkers and genetic profile differ from those seen in classical AD. The findings on biomarkers, symptomatology and genetics may aid the differential diagnostic process.

C677T variant in the methylentetrahydrofolate reductase gene is a genetic risk factor for primary open-angle glaucoma.

PURPOSE: To estimate the prevalence of C677T single nucleotide polymorphism in the 5,10-methylentetrahydrofolate reductase (MTHFR) gene in primary open-angle glaucoma (POAG) and pseudoexfoliation open-angle glaucoma (PEXG). DESIGN: Case-control study METHODS: MTHFR was assessed in 147 patients (76 POAG, 71 PEXG) and 71 control subjects with cataract. Associations of genotypes were assessed by Armitage's trend test and the corresponding odds ratio (OR) for allele positivity with 95% confidence interval (CI). RESULTS: We observed significant evidence of a higher prevalence of C677T in POAG (9% homozygote, 49% heterozygote, 42% wildtype, P = .01, OR = 2.38, 95% CI 1.23-4.62), but not in PEXG (9% homozygote, 41% heterozygote, 50% wildtype, P = .09, OR = 1.78, 95% CI 0.91-3.50) compared with the controls (3% homozygote, 34% heterozygote, 63% wildtype). CONCLUSIONS: The MTHFR C677T variant leading to moderate hyperhomocysteinemia may play a role in the pathogenesis of POAG acting as a genetic risk factor.

Lack of efficacy of mitoxantrone in primary progressive Multiple Sclerosis irrespective of pharmacogenetic factors: a multi-center, retrospective analysis.

BACKGROUND: Mitoxantrone is used on an off-label basis in primary progressive MS (PPMS). ABC-transporter-genotypes are associated with therapeutic response in relapsing/secondary progressive MS (RP/SPMS). OBJECTIVE: To evaluate potential pharmacogenetic response markers for mitoxantrone in PPMS. METHODS: 41 mitoxantrone-treated PPMS-patients, 155 mitoxantrone-treated RP/SPMS-patients and 43 PPMS-controls were retrospectively assessed for clinical therapy-response and in correlation with four single-nucleotide-polymorphisms in ABCB1- and ABCG2-genes. RESULTS: 53.7% PPMS-patients were mitoxantrone-responders, in comparison to 78.1% of RP/SPMS-patients (p=0.039). There was no association between genotype and treatment response. CONCLUSION: Our data discourages the use of mitoxantrone in PPMS regardless of pharmacogenetic response markers previously described in RP/SPMS.

A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain.

Central nervous and hematopoietic systems share developmental features. We report that thrombopoietin (TPO), a stimulator of platelet formation, acts in the brain as a counterpart of erythropoietin (EPO), a hematopoietic growth factor with neuroprotective properties. TPO is most prominent in postnatal brain, whereas EPO is abundant in embryonic brain and decreases postnatally. Upon hypoxia, EPO and its receptor are rapidly reexpressed, whereas neuronal TPO and its receptor are down-regulated. Unexpectedly, TPO is strongly proapoptotic in the brain, causing death of newly generated neurons through the Ras-extracellular signal-regulated kinase 1/2 pathway. This effect is not only inhibited by EPO but also by neurotrophins. We suggest that the proapoptotic function of TPO helps to select for neurons that have acquired target-derived neurotrophic support.