Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. In Alzheimer's disease, levels of increased CSF tau protein and decreased levels of β-amyloid 1-42 (Aβ42) have been shown to correlate with brain plaque formation and tangle pathology. Intracellular Lewy inclusions containing aggregated α-synuclein (α-syn) represent a pathological hallmark of Parkinson's disease (PD). In most - but not all - studies published to date total CSF α-syn concentrations have been found to be decreased in disorders related to α-syn pathology, that is, PD, dementia with Lewy bodies and multiple system atrophy. However, these reports show extensive signal overlap among tested individuals, thereby diminishing its potential for routine use in clinical practice. To investigate potential biological (i.e., non-technical) confounders of reported CSF levels for α-syn, Aβ42, and tau in PD and related disorders, we carried out a methodical review of known factors that underlie signal variability and speculate on those that have not yet been tested. We discuss several biological factors, such as neuropathology, demographics, clinical phenotype, progression and duration of disease, concomitant illnesses and, last but not least, pharmacotherapy, which in isolation or combination can substantially alter values for CSF proteins of interest. Enhanced implementation of standardized clinical protocols, streamlined operating procedures, and further progress in the development of validated assays for CSF proteins have the potential to (i) inform us as to the pathogenesis of disease, (ii) support the laboratory-based diagnosis for symptomatic subjects in the future, and (iii) facilitate breakthrough therapies to alter the course of neurodegenerative disorders, such as PD and Alzheimer's disease. Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. To investigate potential biological confounders of reported CSF levels for α-synuclein (α-Syn), amyloid-β 1-42(Aβ42) and tau protein in Parkinson's disease and related disorders, we reviewed the current literature for known factors that underlie signal variability and speculate on those that have not yet been tested. This article is part of a special issue on Parkinson disease.

Applied Neuroscience Group CEITEC MU Masaryk University Brno Czech Republic

Centre for Age Related Medicine Stavanger University Hospital Stavanger Norway

Centro Disturbi della Memoria Unità Valutativa Alzheimer Clinica Neurologica Università di Perugia Perugia Italy

Department for Clinical Neuroscience Karolinska Institute Stockholm Sweden

Department of Neurology Department of Laboratory Medicine Donders Institute for Brain Cognition and Behaviour Radboud University Medical Centre Nijmegen The Netherlands

Department of Neurology University Medical Center Ljubljana Ljubljana Slovenia

Division for Neurogeriatrics Department of NVS Karolinska Institutet Center for Alzheimer Research Stockholm Sweden

Institute of Clinical Medicine Neurology University of Eastern Finland Kuopio Finland

Paracelsus Elena Klinik Kassel Germany

Program in Neuroscience and Division of Neurology The Ottawa Hospital University of Ottawa Brain and Mind Research Institute Ottawa Ontario Canada

University Medical Center Georg August University Goettingen Goettingen Germany

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