ABSTRACT
BACKGROUND: Aggregation of α-synuclein is central to the pathophysiology of PD. Biomarkers related to α-synuclein may be informative for PD diagnosis/progression. OBJECTIVES: To analyze α-synuclein in CSF in drug-naïve PD, healthy controls, and prodromal PD in the Parkinson's Progression Markers Initiative. METHODS: Over up to 36-month follow-up, CSF total α-synuclein and its association with MDS-UPDRS motor scores, cognitive assessments, and dopamine transporter imaging were assessed. RESULTS: The inception cohort included PD (n = 376; age [mean {standard deviation} years]: 61.7 [9.62]), healthy controls (n = 173; age, 60.9 [11.3]), hyposmics (n = 16; age, 68.3 [6.15]), and idiopathic rapid eye movement sleep behavior disorder (n = 32; age, 69.3 [4.83]). Baseline CSF α-synuclein was lower in manifest and prodromal PD versus healthy controls. Longitudinal α-synuclein decreased significantly in PD at 24 and 36 months, did not change in prodromal PD over 12 months, and trended toward an increase in healthy controls. The decrease in PD was not shown when CSF samples with high hemoglobin concentration were removed from the analysis. CSF α-synuclein changes did not correlate with longitudinal MDS-UPDRS motor scores or dopamine transporter scan. CONCLUSIONS: CSF α-synuclein decreases early in the disease, preceding motor PD. CSF α-synuclein does not correlate with progression and therefore does not reflect ongoing dopaminergic neurodegeneration. Decreased CSF α-synuclein may be an indirect index of changes in the balance between α-synuclein secretion, solubility, or aggregation in the brain, reflecting its overall turnover. Additional biomarkers more directly related to α-synuclein pathophysiology and disease progression and other markers to be identified by, for example, proteomics and metabolomics are needed. © 2019 International Parkinson and Movement Disorder Society.
Subject(s)
Parkinson Disease/cerebrospinal fluid , Prodromal Symptoms , alpha-Synuclein/cerebrospinal fluid , Adult , Age of Onset , Aged , Aged, 80 and over , Biomarkers/cerebrospinal fluid , Cohort Studies , Female , Genetic Variation , Humans , Longitudinal Studies , Male , Middle Aged , Negative Results , Olfaction Disorders/etiology , Parkinson Disease/diagnostic imaging , Parkinson Disease/psychology , Prospective Studies , Psychiatric Status Rating Scales , REM Sleep Behavior Disorder/etiology , Tomography, Emission-Computed, Single-PhotonABSTRACT
OBJECTIVE: To analyze longitudinal levels of CSF biomarkers in drug-naive patients with Parkinson disease (PD) and healthy controls (HC), examine the extent to which these biomarker changes relate to clinical measures of PD, and identify what may influence them. METHODS: CSF α-synuclein (α-syn), total and phosphorylated tau (t- and p-tau), and ß-amyloid 1-42 (Aß42) were measured at baseline and 6 and 12 months in 173 patients with PD and 112 matched HC in the international multicenter Parkinson's Progression Marker Initiative. Baseline clinical and demographic variables, PD medications, neuroimaging, and genetic variables were evaluated as potential predictors of CSF biomarker changes. RESULTS: CSF biomarkers were stable over 6 and 12 months, and there was a small but significant increase in CSF Aß42 in both patients with patients with PD and HC from baseline to 12 months. The t-tau remained stable. The p-tau increased marginally more in patients with PD than in HC. α-syn remained relatively stable in patients with PD and HC. Ratios of p-tau/t-tau increased, while t-tau/Aß42 decreased over 12 months in patients with PD. CSF biomarker changes did not correlate with changes in Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale motor scores or dopamine imaging. CSF α-syn levels at 12 months were lower in patients with PD treated with dopamine replacement therapy, especially dopamine agonists. CONCLUSIONS: These core CSF biomarkers remained stable over 6 and 12 months in patients with early PD and HC. PD medication use may influence CSF α-syn. Novel biomarkers are needed to better profile progressive neurodegeneration in PD.
Subject(s)
Amyloid beta-Peptides/cerebrospinal fluid , Parkinson Disease/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Aged , Apolipoproteins E/genetics , Case-Control Studies , Dopamine/metabolism , Female , Humans , Longitudinal Studies , Male , Middle Aged , Parkinson Disease/diagnostic imaging , Parkinson Disease/genetics , Polymorphism, Single Nucleotide/genetics , Retrospective Studies , Severity of Illness Index , Time Factors , Tomography, Emission-Computed, Single-PhotonSubject(s)
3' Untranslated Regions/genetics , Collagen Type IV/genetics , Dementia, Multi-Infarct/genetics , Family Health , Genetic Predisposition to Disease/genetics , Mutation/genetics , Dementia, Multi-Infarct/physiopathology , Female , Genetic Association Studies , HEK293 Cells , Humans , Male , MicroRNAs/genetics , MicroRNAs/metabolism , Sweden , TransfectionABSTRACT
A GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. There is suggestion that these expansions may be a rare cause of parkinsonian disorders such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD). Screening the C9orf72 gene in 37 patients with features of corticobasal syndrome (CBS) detected an expansion in 3 patients, confirmed by Southern blotting. In a series of 22 patients with clinically diagnosed PSP, we found 1 patient with an intermediate repeat length. We also screened for the C9orf72 expansion in a large series of neuropathologically confirmed samples with MSA (n = 96), PSP (n = 177), and CBD (n = 18). Patients were found with no more than 22 GGGGCC repeats. Although these results still need to be confirmed in a larger cohort of CBS and/or CBD patients, these data suggest that in the presence of a family history and/or motor neuron disease features, patients with CBS or clinical PSP should be screened for the C9orf72 repeat expansion. In addition, we confirm that the C9orf72 expansions are not associated with pathologically confirmed MSA, PSP, or CBD in a large series of cases.
Subject(s)
DNA Repeat Expansion , Parkinsonian Disorders/genetics , Proteins/genetics , Adult , Aged , Basal Ganglia/pathology , Basal Ganglia Diseases/genetics , C9orf72 Protein , Female , Humans , Male , Middle Aged , Multiple System Atrophy/genetics , Neurodegenerative Diseases/genetics , Supranuclear Palsy, Progressive/genetics , SyndromeABSTRACT
TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.
