Correlates of cerebrospinal fluid levels of oligomeric- and total-α-synuclein in premotor, motor and dementia stages of Parkinson’s disease

Compta, Yaroslau; Valente, Tony; Saura, Josep; Segura, Bàrbara; Iranzo, Álex; Serradell, Mónica; Junqué, Carme; Tolosa, Eduard; Valldeoriola, Francesc; Muñoz, Esteban; Santamaría, Joan; Cámara, Ana; Fernández, Manel; Fortea, Juan; Buongiorno, Maríateresa; Molinuevo, José Luís; Bargalló, Núria; Martı́, Marı́a José

doi:10.1007/s00415-014-7560-z

Cited by 89 publications

(102 citation statements)

References 48 publications

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“…To date, inconsistent results in this respect have been related to different disease stages [11,12]. Our results suggest that SNCA polymorphisms also alter the toxicity of α-synuclein and tau even in early stages, increasing the complexity of the association between α-synuclein, tau, and neurodegeneration in PD.…”

Section: Discussionmentioning

confidence: 68%

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Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson’s Disease Is Modified by the SNCA rs356181 Polymorphism

et al. 2018

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The role of cerebrospinal fluid (CSF) biomarkers such as CSF α-synuclein and CSF tau in predicting cognitive decline in Parkinson’s disease (PD) continues to be inconsistent. Here, using a cohort of de novo PD patients with preserved cognition from the Parkinson’s Progression Markers Initiative (PPMI), we show that the SNCA rs356181 single nucleotide polymorphism (SNP) modulates the effect of these CSF biomarkers on cortical thinning. Depending on this SNP’s genotype, cortical atrophy was associated with either higher or lower CSF biomarker levels. Additionally, this SNP modified age-related atrophy. Importantly, the integrity of the brain regions where this phenomenon was observed correlated with cognitive measures. These results suggest that this genetic variation of the gene encoding the α-synuclein protein, known to be involved in the development of PD, also interferes in its subsequent neurodegeneration. Overall, our findings could shed light on the so far incongruent association of common CSF biomarkers with cognitive decline in PD.

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Section: Discussionmentioning

confidence: 68%

“…Notably, both high and low CSF α-synuclein levels were related to cognitive decline, and most studies found no association between CSF tau or ptau and cognitive decline [9][10][11]. Furthermore, atrophic patterns associated with these biomarkers were also inconsistent in structural neuroimaging studies [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson’s Disease Is Modified by the SNCA rs356181 Polymorphism

et al. 2018

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“…The relationship between CSF α -synuclein levels and longitudinal atrophy has been relatively understudied (Campbell et al., 2015, Compta et al., 2014, Mattsson et al., 2013). In our present study, CSF α -synuclein was not associated with whole-brain atrophy or with ventricular enlargement.…”

Section: Discussionmentioning

confidence: 99%

“…In our present study, CSF α -synuclein was not associated with whole-brain atrophy or with ventricular enlargement. This runs counter to previous studies, where reductions in CSF α -synuclein have been shown to correlate with functional deficits in motor networks (Campbell et al., 2015) and frontal atrophy in nondemented PD (Compta et al., 2014). Interestingly, Compta et al.…”

Section: Discussionmentioning

confidence: 99%

“…observed a reverse relationship in the PD-D group, where increased CSF α -synuclein was associated with atrophy in the parahippocampal gyrus and precuneus, both of which are commonly implicated in preclinical and established stages of dementia (Mak et al., 2017, Villemagne and Chételat, 2016). However, the correlations did not persist after adjusting for CSF tau, suggesting that any effects of CSF α -synuclein may be mediated through tau (Compta et al., 2014). In agreement with our study, a previous analysis involving the ADNI cohort also found that baseline levels of CSF α -synuclein were not correlated to atrophy brain rates across the spectrum of normal aging, MCI, and AD (Mattsson et al., 2013).…”

Section: Discussionmentioning

confidence: 99%

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Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease

Mak

Williams

et al. 2017

Neurobiology of Aging

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We investigated whole-brain atrophy and ventricular enlargement over 18 months in nondemented Parkinson's disease (PD) and examined their associations with clinical measures and baseline CSF markers. PD subjects (n = 100) were classified at baseline into those with mild cognitive impairment (MCI; PD-MCI, n = 36) and no cognitive impairment (PD-NC, n = 64). Percentage of whole-brain volume change (PBVC) and ventricular expansion over 18 months were assessed with FSL-SIENA and ventricular enlargement (VIENA) respectively. PD-MCI showed increased global atrophy (−1.1% ± 0.8%) and ventricular enlargement (6.9 % ± 5.2%) compared with both PD-NC (PBVC: −0.4 ± 0.5, p < 0.01; VIENA: 2.1% ± 4.3%, p < 0.01) and healthy controls. In a subset of 35 PD subjects, CSF levels of tau, and Aβ42/Aβ40 ratio were correlated with PBVC and ventricular enlargement respectively. The sample size required to demonstrate a 20% reduction in PBVC and VIENA was approximately 1/15th of that required to detect equivalent changes in cognitive decline. These findings suggest that longitudinal MRI measurements have potential to serve as surrogate markers to complement clinical assessments for future disease-modifying trials in PD.

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Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid

Shahnawaz¹,

et al. 2017

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IMPORTANCE Parkinson disease (PD) is a highly prevalent and incurable neurodegenerative disease associated with the accumulation of misfolded α-synuclein (αSyn) aggregates. An important problem in this disease is the lack of a sensitive, specific, and noninvasive biochemical diagnosis to help in clinical evaluation, monitoring of disease progression, and early differential diagnosis from related neurodegenerative diseases. OBJECTIVE To develop a novel assay with high sensitivity and specificity to detect small quantities of αSyn aggregates circulating in cerebrospinal fluid (CSF) of patients affected by PD and related synucleinopathies. DESIGN, SETTING, AND PARTICIPANTS The strategy evaluated in this proof-of-concept study uses the protein misfolding cyclic amplification (PMCA) technology that detects minute amounts of misfolded oligomers by taking advantage of their ability to nucleate further aggregation, enabling a very high amplification of the signal. The technology was first adapted with synthetic αSyn oligomers prepared in vitro and used to screen in 2 blinded cohorts of CSF samples from German and Japanese patients with PD (n = 76) and individuals serving as controls affected by other neurologic disorders (n = 65), neurodegenerative diseases (n = 18), and Alzheimer disease (n = 14). The kinetics of αSyn aggregation were measured by αSyn-PMCA in the presence of CSF samples from the participants to detect αSyn oligomeric seeds present in this biological fluid. The assays were conducted from November 15, 2013, to August 28, 2015. MAIN OUTCOMES AND MEASURES Kinetic parameters correlated with disease severity at the time of sample collection, measured by the Hoehn and Yahr scale, with the lowest grade indicating unilateral involvement with minimal or no functional impairment, and the highest grade defining patients with complete confinement to wheelchair or bed. RESULTS Studies with synthetic αSyn aggregates showed that αSyn-PMCA enabled to detect as little as 0.1 pg/mL of αSyn oligomers. The αSyn-PMCA signal was directly proportional to the amount of αSyn oligomers added to the reaction. A blinded study of CSF samples correctly identified patients affected by PD with an overall sensitivity of 88.5% (95% CI, 79.2%-94.6%) and specificity of 96.9% (95% CI, 89.3%-99.6%). The αSyn-PMCA results for different patients correlated with the severity of the clinical symptoms of PD (Japanese cohort: r s = −0.54, P = .006; German cohort: r s = −0.36, P = .02). CONCLUSIONS AND RELEVANCE The findings suggest that detection of αSyn oligomers by αSyn-PMCA in the CSF of patients affected by PD may offer a good opportunity for a sensitive and specific biochemical diagnosis of the disease. Further studies are needed to investigate the usefulness of αSyn-PMCA to monitor disease progression and for preclinical identification of patients who may develop PD.

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Correlates of cerebrospinal fluid levels of oligomeric- and total-α-synuclein in premotor, motor and dementia stages of Parkinson’s disease

Cited by 89 publications

References 48 publications

Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson’s Disease Is Modified by the SNCA rs356181 Polymorphism

Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson’s Disease Is Modified by the SNCA rs356181 Polymorphism

Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease

Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid

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