CSF and blood biomarkers for Parkinson's disease

Parnetti, Lucilla; Gaetani, Lorenzo; Eusebi, Paolo; Paciotti, Silvia; Hansson, Oskar; El‐Agnaf, Omar M. A.; Mollenhauer, Brit; Blennow, Kaj; Calabresi, Paolo

doi:10.1016/s1474-4422(19)30024-9

Cited by 487 publications

(442 citation statements)

References 98 publications

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“…The presence of αSyn in CSF can be measured biochemically, and many efforts have been directed at developing assays for detection of CSF-originated αSyn as a biomarker [93][94][95] . It is important to emphasize that our system provides extra information by detecting hαSyn forms that are able to get into the cytosol of cells.…”

Section: Discussionmentioning

confidence: 99%

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A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol

Gerdes

Waal

Offner

et al. 2019

Preprint

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Aggregation and spreading of α-Synuclein (αSyn) are hallmarks of several neurodegenerative diseases, thus monitoring human αSyn (hαSyn) in animal models or cell cultures is vital for the field. However, the detection of native hαSyn in such systems is challenging. We found that the nanobody NbSyn87, previously-described to bind hαSyn, also shows cross-reactivity for the proteasomal subunit Rpn10. As such, when the NbSyn87 is expressed in the absence of hαSyn, it is continuously degraded by the proteasome, while it is stabilized when it binds to hαSyn. Here, we exploited this feature to design a new Fluorescent Reporter for hαSyn (FluoReSyn) by coupling NbSyn87 to fluorescent proteins, which results in fluorescence signal fluctuations depending on the presence and amounts of intracellular hαSyn. We characterized this biosensor in cells and tissues, and finally, revealed the presence of transmittable αSyn in human cerebrospinal fluid demonstrating the potential of FluoReSyn for clinical research and diagnostics.

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Section: Discussionmentioning

confidence: 99%

“…This is particularly relevant in the light of emerging evidence which suggests that particular species of αSyn (e.g. oligomers, aggregates) that are associated with toxicity can serve as far-better biomarkers than total αSyn in CSF 94 .…”

Section: Discussionmentioning

confidence: 99%

A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol

Gerdes

Waal

Offner

et al. 2019

Preprint

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“…In addition to total CSF α-synuclein, levels of the CSF oligomeric and phosphorylated α-synuclein have both been reported to be elevated in PD compared to controls, which requires further validation [78].…”

Section: Csf α-Synucleinmentioning

confidence: 99%

“…The protein is widely expressed in multiple fluids outside of the CNS, with red blood cells being a major source of α-synuclein in the blood and a source of potential contamination [70,79]. Trials measuring αsynuclein in whole blood, plasma and serum of PD patients yielded conflicting results, limiting its utility as a diagnostic biomarker [78]. However, similarly to CSF, studies measuring oligomeric or phosphorylated forms of the protein in the serum and in red blood cells have shown to be consistently elevated in PD patients in comparison to controls [78,80].…”

Section: Blood α-Synucleinmentioning

confidence: 99%

“…Trials measuring αsynuclein in whole blood, plasma and serum of PD patients yielded conflicting results, limiting its utility as a diagnostic biomarker [78]. However, similarly to CSF, studies measuring oligomeric or phosphorylated forms of the protein in the serum and in red blood cells have shown to be consistently elevated in PD patients in comparison to controls [78,80].…”

Section: Blood α-Synucleinmentioning

confidence: 99%

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Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course—a joint PhD student course at University College London and University of Gothenburg

et al. 2020

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Until relatively recently, a diagnosis of probable Alzheimer's disease (AD) and other neurodegenerative disorders was principally based on clinical presentation, with post-mortem examination remaining a gold standard for disease confirmation. This is in sharp contrast to other areas of medicine, where fluid biomarkers, such as troponin levels in myocardial infarction, form an integral part of the diagnostic and treatment criteria. There is a pressing need for such quantifiable and easily accessible tools in neurodegenerative diseases. In this paper, based on lectures given at the 2019 Biomarkers in Neurodegenerative Diseases Course, we provide an overview of a range of cerebrospinal fluid (CSF) and blood biomarkers in neurodegenerative disorders, including the 'core' AD biomarkers amyloid β (Aβ) and tau, as well as other disease-specific and general markers of neuroaxonal injury. We then highlight the main challenges in the field, and how those could be overcome with the aid of new methodological advances, such as assay automation, mass spectrometry and ultrasensitive immunoassays. As we hopefully move towards an era of disease-modifying treatments, reliable biomarkers will be essential to increase diagnostic accuracy, allow for earlier diagnosis, better participant selection and disease activity and treatment effect monitoring.

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Association of Cerebrospinal Fluid Neurofilament Heavy Protein Levels With Clinical Progression in Patients With Parkinson Disease

et al. 2022

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IMPORTANCENeurofilament light in biofluids has been associated with progression of Parkinson disease (PD), but the association between neurofilament heavy (NfH) and progression of PD has not been investigated. OBJECTIVE To evaluate the associations of cerebrospinal fluid (CSF) NfH (cNfH) levels and motor and cognitive progression in PD. DESIGN, SETTING, AND PARTICIPANTS This cohort study used data from the Parkinson Progression Marker Initiative ranging from June 2010 to November 2018. Participants were recruited from 24 participating sites worldwide (United States, Europe, and Australia). Data were analyzed from October 20 to December 18, 2021. EXPOSURES Concentrations of NfH in CSF. MAIN OUTCOMES AND MEASURES The primary outcomes were Movement Disorder Societysponsored revisions of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part III; scores range from 0 to 132, with higher scores indicating worse motor function, and Montreal Cognitive Assessment (MoCA); scores range from 0 to 30, with higher scores indicating better cognitive function. The associations of cNfH levels and longitudinal change in MDS-UPDRS-Part-III and MoCA were examined using linear mixed-effects models with PD duration as the time scale. Partial correlation analysis was conducted to examine the associations of cNfH levels and α-synuclein, amyloid-β 1-42 (Aβ 42) , phosphorylated tau at threonine 181 position (P-tau), and total tau (T-tau) levels in CSF. RESULTS A total of 404 patients with PD (mean [SD] age, 61.7 [9.7] years; 263 were men [65.1%];within 2 years of diagnosis; Hoehn and Yahr <3) were included. Higher baseline cNfH levels were associated with greater increases in MDS-UPDRS Part-III (β = 0.39; 95% CI, 0.12-0.66; P = .003) and faster decreases in MoCA (β = −0.18; CI, −0.24 to −0.11; P < .001). Levels of cNfH were correlated with CSF levels of α-synuclein (Spearman r = 0.25; 95% CI, 0.15-0.34; P < .001), Aβ 42 (Spearman r = 0.18; 95% CI, 0.08-0.27; P < .001), P-tau (Spearman r = 0.25; 95% CI, 0.15-0.35; P < .001), and T-tau (Spearman r = 0.31; 95% CI, 0.21-0.40; P < .001) at baseline. CONCLUSIONS AND RELEVANCEHigher baseline cNfH levels were associated with faster motor and cognitive progression. This finding suggests that cNfH may be of some value for stratifying patients with PD who have different progression rates.

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CSF and blood biomarkers for Parkinson's disease

Cited by 487 publications

References 98 publications

A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol

A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol

Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course—a joint PhD student course at University College London and University of Gothenburg

Association of Cerebrospinal Fluid Neurofilament Heavy Protein Levels With Clinical Progression in Patients With Parkinson Disease

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