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Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin‐3 gene. Although no curative therapy is yet available, preclinical gene‐silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. Objective: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ‐expanded ataxin‐3 in plasma and cerebrospinal fluid (CSF). Methods: Using the novel single molecule counting ataxin‐3 immunoassay, we analyzed cross‐sectional and longitudinal patient biomaterials. Results: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ‐expanded ataxin‐3 during conversion from the pre‐ataxic to the ataxic phases. Conclusions: The novel immunoassay is able to quantify polyQ‐expanded ataxin‐3 in plasma and CSF, whereas ataxin‐3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ‐expanded ataxin‐3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

We investigated whether cerebrospinal fluid (CSF) analysis discriminates between idiopathic Parkinson's disease (PD; n = 35) and multiple system atrophy (MSA; n = 30). The median CSF concentration of the neurotransmitter metabolites 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) was reduced significantly (49-70%) in MSA compared to PD. In contrast, several brain-specific proteins (tau, neuron-specific enolase, myelin basic protein) were elevated (130-230%) in MSA compared with those in PD. A combination of CSF tau and MHPG discriminated PD from MSA (adjusted odds ratios: tau, 27.2; MHPG, 0.14). Our data suggest that the more progressive and widespread neurodegenerative nature of MSA, as compared with PD, is reflected in the composition of CSF. We propose that CSF analysis may become part of the diagnostic work-up of patients with parkinsonian syndromes. [ABSTRACT FROM AUTHOR]