Novel Protein Biomarkers of Monoamine Metabolism Defects Correlate with Disease Severity.

BACKGROUND: Genetic defects of monoamine neurotransmitters are rare neurological diseases amenable to treatment with variable response. They are major causes of early parkinsonism and other spectrum of movement disorders including dopa-responsive dystonia. OBJECTIVES: The objective of this study was to conduct proteomic studies in cerebrospinal fluid (CSF) samples of patients with monoamine defects to detect biomarkers involved in pathophysiology, clinical phenotypes, and treatment response. METHODS: A total of 90 patients from diverse centers of the International Working Group on Neurotransmitter Related Disorders were included in the study (37 untreated before CSF collection, 48 treated and 5 unknown at the collection time). Clinical and molecular metadata were related to the protein abundances in the CSF. RESULTS: Concentrations of 4 proteins were significantly altered, detected by mass spectrometry, and confirmed by immunoassays. First, decreased levels of apolipoprotein D were found in severe cases of aromatic L-amino acid decarboxylase deficiency. Second, low levels of apolipoprotein H were observed in patients with the severe phenotype of tyrosine hydroxylase deficiency, whereas increased concentrations of oligodendrocyte myelin glycoprotein were found in the same subset of patients with tyrosine hydroxylase deficiency. Third, decreased levels of collagen6A3 were observed in treated patients with tetrahydrobiopterin deficiency. CONCLUSION: This study with the largest cohort of patients with monoamine defects studied so far reports the proteomic characterization of CSF and identifies 4 novel biomarkers that bring new insights into the consequences of early dopaminergic deprivation in the developing brain. They open new possibilities to understand their role in the pathophysiology of these disorders, and they may serve as potential predictors of disease severity and therapies. © 2020 International Parkinson and Movement Disorder Society.

CSF and Blood Levels of GFAP in Alexander Disease

Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region of GFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect the levels of GFAP in brain parenchyma, we have assayed GFAP levels in two body fluids in humans that are readily accessible as biopsy sites: CSF and blood. We find that GFAP levels are consistently elevated in the CSF of patients with Alexander disease, but only occasionally and modestly elevated in blood. These results provide the foundation for future studies that will explore whether GFAP levels can serve as a convenient means to monitor the progression of disease and the response to treatment.

Jugular venous oxygen saturation or arteriovenous difference of lactate content and outcome in children with severe traumatic brain injury.

OBJECTIVE: To assess the association between neurologic out-come and the alterations of jugular venous oxygen saturation (SjvO2) or the increase in arteriovenous difference of lactate content (AVDL) in children with severe traumatic brain injury. DESIGN: Observational prospective cohort study. SETTING: Multidisciplinary pediatric intensive care unit of a university hospital. PATIENTS: A total of 27 pediatric patients with severe traumatic brain injury, with a Glasgow Coma Scale after resuscitation of <9, who were admitted to the pediatric intensive care unit within 36 hrs after injury. INTERVENTIONS: Intermittent measurement of SjvO2 and AVDL. MEASUREMENTS AND MAIN RESULTS: SjvO2 and AVDL were assessed simultaneously every 6 hrs. The primary dependent variable measured was assessed independently 3 months after trauma according to the Pediatric Cerebral Performance Category. Patients were classified into two groups: group 1 (favorable outcome, Pediatric Cerebral Performance Category 1-3) and group 2 (unfavorable outcome, Pediatric Cerebral Performance Category 4-6); 81% were included in group 1 and 19% in group 2. A total of 354 measurements of SjvO2 and AVDL were made, with a mean of 13.1 +/- 7.9 per patient. The number of abnormal measurements of SjvO2 and increased AVDL used to predict the neurologic outcome was selected according to the area under the receiver operating characteristic curve. Mortality was 15% (four patients). The strongest association was found between a poor neurologic outcome and two or more pathologic AVDL measurements (higher than -0.37 mmol/L; relative risk, 17.6; 95% confidence interval, 2.5-112.5; p = .001). The presence of two or more measurements of SjvO2 of < or = 55% was significantly associated with a poor neurologic outcome (relative risk, 6.6; 95% confidence interval, 1.5-29.7; p = .003). The frequency of measurements of SjvO2 of > or = 75% was not different between groups 1 and 2. CONCLUSION: In children with severe traumatic brain injury, two or more measurements of SjvO2 of < or = 55% or two or more pathologic AVDL measurements were associated with a poor neurologic outcome. Further studies are needed to recommend the use of these variables as a guideline to optimize treatment.