Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression

Abstract

Background There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ-1 and/or α-synuclein in the cerebrospinal fluid (CSF) is a potential index for PD diagnosis, but not for PD severity. Methods Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (Aβ1-42), Flt3 ligand and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these five markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ-1 and α-synuclein. The major results were further validated in an independent cohort of cross-sectional PD patients as well as in PD cases with CSF samples collected longitudinally. Findings The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/Aβ1-42 that positively correlated with PD severity in cross-sectional samples as well as with PD progression in longitudinal samples. Interpretation We have demonstrated that this panel of seven CSF proteins could aid in PD diagnosis, differential diagnosis, and correlation with disease severity and progression.

Alpha‐synuclein RT‐QuIC in the CSF of patients with alpha‐synucleinopathies

“…The measurement of a‐syn concentrations in CSF by ELISAs has been proposed as a biomarker for a‐syn‐related disorders. However, despite many studies showing a reduction in CSF a‐syn levels in PD and in DLB,4, 6 overall results are not consistent 7. Even in those studies where a reduction in CSF a‐syn has been demonstrated, the differences are small8 and there is considerable overlap within patient groups and between patient and control groups.…”

CFS Biomarkers in Parkinson’s Disease

“…Moreover, these changes are not disease specific, being shared by many neurodegenerative diseases. A recent study, carried out in a large cohort including PD (n. 126), MSA (n. 32), AD (n. 50), and controls (n. 137), showed significantly lower CSF levels of the cytokine Flt3 ligand in MSA patients as compared to PD subjects (Shi et al, 2011).…”

“…These findings have lead to a revision of the National Institute of Neurological Disorders and Stroke-Alzheimer Disease and Related Disorders (NINCDS-ADRDA) criteria for the diagnosis of AD including CSF biomarkers (Dubois et al, 2007). Studies report normal CSF levels of tau and phosphorylated tau in PD (Blennow et al, 1995;Parnetti et al, 2008;Alves et al, 2010;, whereas unchanged or slightly decreased levels of A 1-42 have been reported (Sjögren et al, 2002;Mollenhauer et al, 2006;Bibl et al, 2006;Parnetti et al, 2008;Compta et al, 2009;Alves et al, 2010;Siderowf et al, 2010;Montine et al, 2010;Leverenz et al, 2011;Shi et al, 2011). More recently, several studies have been published reporting a possible association between low A 1-42 levels and cognitive impairment in PD (Compta et al, 2009;Alves et al, 2010;Siderowf et al, 2010;Montine et al, 2010;Leverenz et al, 2011).…”

Recent advances in biomarkers for Parkinson’s disease focusing on biochemicals, omics and neuroimaging

“…Shi and coworkers measured total tau, phosphorylated tau, Aβ peptide 1-42 [Aβ (1-42)], Flt3 ligand, and fractalkine levels in CSF in a large cohort of PD patients at different stages, as well as in healthy and diseased controls, and found that the ratio of phosphorylated-tau/tau can be used to distinguish PD from MSA (a disease that overlaps with PD clinically). Moreover, with the CSF Flt3 ligand, PD could be clearly differentiated from MSA with an excellent sensitivity (99%) and specificity (95%) [26]. Furthermore, the authors identified CSF fractalkine/Aβ (1-42) as positively correlated with PD severity in cross-sectional samples, as well as with PD progression in longitudinal samples [26].…”

“…Correlated with PD severity [14] [9] α-Synuclein↓ [7,22] 71% sensitivity and 53% specificity patients with PD vs. controls, DLB, and MSA [22] Phosphorylated α-synuclein↑ [21,23] No correlation between the α-synuclein level and PD severity [7,19,22,24] Antibody towards monomeric α-synuclein↑ [25] Tau Total tau↓ [26] Distinguish Patients with low UA levels in serum may be more prone to developing PD, and an inverse relationship between UA and severity of PD was robust for men but weak for women [11]. Another study in the Chinese population reported similar results, which suggests that the serum UA level could be a useful biomarker of PD diagnosis and disease progression [12].…”