Distinct metabolomic signature in cerebrospinal fluid in early parkinson's disease.

OBJECTIVE: The purpose of this study was to profile cerebrospinal fluid (CSF) from early-stage PD patients for disease-related metabolic changes and to determine a robust biomarker signature for early-stage PD diagnosis. METHODS: By applying a non-targeted and mass spectrometry-driven approach, we investigated the CSF metabolome of 44 early-stage sporadic PD patients yet without treatment (DeNoPa cohort). We compared all detected metabolite levels with those measured in CSF of 43 age- and gender-matched healthy controls. After this analysis, we validated the results in an independent PD study cohort (Tübingen cohort). RESULTS: We identified that dehydroascorbic acid levels were significantly lower and fructose, mannose, and threonic acid levels were significantly higher (P < .05) in PD patients when compared with healthy controls. These changes reflect pathological oxidative stress responses, as well as protein glycation/glycosylation reactions in PD. Using a machine learning approach based on logistic regression, we successfully predicted the origin (PD patients vs healthy controls) in a second (n = 18) as well as in a third and completely independent validation set (n = 36). The biomarker signature is composed of the three markers-mannose, threonic acid, and fructose-and allows for sample classification with a sensitivity of 0.790 and a specificity of 0.800. CONCLUSION: We identified PD-specific metabolic changes in CSF that were associated with antioxidative stress response, glycation, and inflammation. Our results disentangle the complexity of the CSF metabolome to unravel metabolome changes related to early-stage PD. The detected biomarkers help understanding PD pathogenesis and can be applied as biomarkers to increase clinical diagnosis accuracy and patient care in early-stage PD. © 2017 International Parkinson and Movement Disorder Society.

Coexisting variants in OSTM1 and MANEAL cause a complex neurodegenerative disorder with NBIA-like brain abnormalities.

Coexistence of different hereditary diseases is a known phenomenon in populations with a high consanguinity rate. The resulting clinical phenotypes are extremely challenging for physicians involved in the care of these patients. Here we describe a 6-year-old boy with co-occurrence of a homozygous splice defect in OSTM1, causing infantile malignant osteopetrosis, and a loss-of-function variant in MANEAL, which has not been associated with human disease so far. The child suffered from severe infantile-onset neurodegeneration that could not be stopped by bone marrow transplantation. Magnetic resonance imaging demonstrated global brain atrophy and showed hypointensities of globus pallidus, corpora mamillaria, and cerebral peduncles, which were comparable to findings in neurodegeneration with brain iron accumulation disorders. LC-MS/MS analysis of urine and cerebrospinal fluid samples revealed a distinct metabolic profile with accumulation of mannose tetrasaccharide molecules, suggestive of an oligosaccharide storage disease. Our results demonstrate that exome sequencing is a very effective tool in dissecting complex neurological diseases. Moreover, we suggest that MANEAL is an interesting candidate gene that should be considered in the context of neurological disorders with brain iron accumulation and/or indications of an oligosaccharide storage disease.

[Gas chromatography in express diagnosis of candidiasis and monitoring of antifungal therapy efficacy by D-arabinitol and mannose levels in pediatric patients]. / Gazokhromatograficheskaia ékspress diagnostika kandidoza i monitoring éffektivnosti protivogribkovoi terapii po urovniu D-arabinitola i mannozy u detei.

Seventy three children (40 blood and 43 liquor specimens) were examined with the use of gas chromatography (GC) to detect background concentrations of Candida metabolites. The criterium of the children enrollment to the control group was the absence of the clinical and laboratory signs of the fungal infection. The normal contents of the fungus metabolites were considered to be 0.51 +/- 0.28 microgram/ml for D-arabinitol and 17.7 +/- 10.4 micrograms/ml for mannose in the serum and 7.24 +/- 3.04 micrograms/ml for D-arabinitol and 67.1 +/- 47.4 micrograms/ml for mannose in the liquor. Fifty four children at the age of 1 month to 12 years with the signs of the fungal infection requiring systemic antifungal therapy were also examined. Prior to the use of antifungal drugs the routine microbiological tests and GC detection of the fungus metabolites were performed. The fungus was isolated with the cultural method from the blood in 2 patients (6.3 per cent), from the mucosa in 25 (71.4 per cent) out of 32 patients with fungal complications at the background of cytostatic therapy and neutropenia, from the liquor in 3 (21.4 per cent) out of 14 patients with meningitis and from the urine in 8 (100 per cent) out of 8 patients with urinary infection. The GC examination revealed increased levels of the Candida metabolites in 96 per cent of the children. A favourable time course of the infection at the background of amphotericin B or fluconasol use was recorded by the clinical indices which correlated with a reliable decrease of the contents of D-arabinitol and mannose to the normal. The use of GC is recommended in express diagnosis of candidiasis especially when the results of the cultural tests are negative as well as in monitoring of the fungal therapy efficacy.

Mannose in body fluids as an indicator of invasive candidiasis.

Using gas-liquid chromatography, we measured five mannose in the serum of six nondiabetic patients with autopsy-proven invasive candidiasis. In all patients serum mannose concentrations were higher than mannose levels found in serum from normal adults and children or from patients with catheter-associated candidemia, mucosal candidiasis, and other mycoses. Spinal fluid from two patients with Candida meningitis showed increased free mannose as compared to seven non-inflammatory spinal fluid samples. However, free mannose in the serum of poorly controlled diabetics (blood glucose of greater than or equal to 300 mg/dl) did overlap concentrations in patients with invasive candidiasis. In vitro culture of Candida albicans demonstrated increasing concentrations of mannose associated with growth of the organism. We conclude that physical and chemical assay for mannose in body fluids may be a useful technique to assist in the diagnosis in invasive candidiasis.