Dataset Information

Alterations in Self-Aggregating Neuropeptides in Cerebrospinal Fluid of Patients with Parkinsonian Disorders.

ABSTRACT:

Background

Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) present with similar movement disorder symptoms but distinct protein aggregates upon pathological examination.

Objective

Discovery and validation of candidate biomarkers in parkinsonian disorders for differential diagnosis of subgroup molecular etiologies.

Methods

Untargeted liquid chromatography (LC)-mass spectrometry (MS) proteomics was used for discovery profiling in cerebral spinal fluid (CSF) followed by LC-MS/MS based multiple reaction monitoring for validation of candidates. We compared clinical variation within the parkinsonian cohort including PD subgroups exhibiting tremor dominance (TD) or postural instability gait disturbance and those with detectable leukocytes in CSF.

Results

We have identified candidate peptide biomarkers and validated related proteins with targeted quantitative multiplexed assays. Dopamine-drug naïve patients at first diagnosis exhibit reduced levels of signaling neuropeptides, chaperones, and processing proteases for packaging of self-aggregating peptides into dense core vesicles. Distinct patterns of biomarkers were detected in the parkinsonian disorders but were not robust enough to offer a differential diagnosis. Different biomarker changes were detected in male and female patients with PD. Subgroup specific candidate biomarkers were identified for TD PD and PD patients with leukocytes detected in CSF.

Conclusion

PD, MSA, and PSP exhibit overlapping as well as distinct protein biomarkers that suggest specific molecular etiologies. This indicates common sensitivity of certain populations of selectively vulnerable neurons in the brain, and distinct therapeutic targets for PD subgroups. Our report validates a decrease in CSF levels of self-aggregating neuropeptides in parkinsonian disorders and supports the role of native amyloidogenic proteins in etiologies of neurodegenerative diseases.

SUBMITTER: Zhu S

PROVIDER: S-EPMC9198747 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Alterations in Self-Aggregating Neuropeptides in Cerebrospinal Fluid of Patients with Parkinsonian Disorders.

Zhu Shaochun S Bäckström David D Forsgren Lars L Trupp Miles M

Journal of Parkinson's disease 20220101 4

<h4>Background</h4>Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) present with similar movement disorder symptoms but distinct protein aggregates upon pathological examination.<h4>Objective</h4>Discovery and validation of candidate biomarkers in parkinsonian disorders for differential diagnosis of subgroup molecular etiologies.<h4>Methods</h4>Untargeted liquid chromatography (LC)-mass spectrometry (MS) proteomics was used for discovery profiling ...[more]

PMID: 35253777

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Project description:BackgroundPatients presenting with parkinsonian syndromes share many clinical features, which can make diagnosis difficult. This is important as atypical parkinsonian syndromes (APSs) such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS) carry a poor prognosis, compared with patients with Parkinson's disease (PD). In addition, there is overlap between APS and dementia diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD).ObjectiveTo use a panel of cerebrospinal fluid (CSF) biomarkers to differentiate patients with APS from PD and dementia.MethodsA prospective cohort of 160 patients and 30 control participants were recruited from a single specialist centre. Patients were clinically diagnosed according to current consensus criteria. CSF samples were obtained from patients with clinical diagnoses of PD (n=31), PSP (n=33), CBS (n=14), MSA (n=31), AD (n=26) and FTD (n=16). Healthy, elderly participants (n=30) were included as controls. Total τ (t-τ), phosphorylated τ (p-τ), β-amyloid 1-42 (Aβ42), neurofilament light chain (NFL), α-synuclein (α-syn), amyloid precursor protein soluble metabolites α and β (soluble amyloid precursor protein (sAPP)α, sAPPβ) and two neuroinflammatory markers (monocyte chemoattractant protein-1 and YKL-40) were measured in CSF. A reverse stepwise regression analysis and the false discovery rate procedure were used.ResultsCSF NFL (p<0.001), sAPPα (p<0.001) and a-syn (p=0.003) independently predicted diagnosis of PD versus APS. Together, these nine biomarkers could differentiate patients with PD from APS with an area under the curve of 0.95 and subtypes of APS from one another. There was good discriminatory power between parkinsonian groups, dementia disorders and healthy controls.ConclusionsA panel of nine CSF biomarkers was able to differentiate APS from patients with PD and dementia. This may have important clinical utility in improving diagnostic accuracy, allowing better prognostication and earlier access to potential disease-modifying therapies.

Project description:BackgroundClinical diagnosis of parkinsonian syndromes like Parkinson's disease (PD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is hampered by overlapping symptomatology and lack of diagnostic biomarkers, and definitive diagnosis is only possible post-mortem.ObjectiveSince impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that profiles of select lysosomal network proteins in cerebrospinal fluid could be differentially expressed in these parkinsonian syndromes.MethodsCerebrospinal fluid samples were collected from PD patients (n = 18), clinically diagnosed 4-repeat tauopathy patients; corticobasal syndrome (CBS) (n = 3) and PSP (n = 8); and pathologically diagnosed PSP (n = 8) and CBD patients (n = 7). Each patient set was compared to its appropriate control group consisting of age and gender matched individuals. Select lysosomal network protein levels were detected via Western blotting. Factor analysis was used to test the diagnostic sensitivity, specificity and accuracy of the select lysosomal network protein expression profiles.ResultsPD, CBD and PSP were markedly different in their cerebrospinal fluid lysosomal network protein profiles. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in PD; early endosomal antigen 1 was decreased and lysozyme increased in PSP; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in CBD. A panel of lysosomal-associated membrane protein 2, lysozyme and microtubule-associated protein 1 light chain discriminated between controls, PD and 4-repeat tauopathies.ConclusionsThis study offers proof of concept that select lysosomal network proteins are differentially expressed in cerebrospinal fluid of Parkinson's disease, corticobasal syndrome and progressive supranuclear palsy. Lysosomal network protein analysis could be further developed as a diagnostic fluid biomarker in parkinsonian syndromes.

Dataset Information

Alterations in Self-Aggregating Neuropeptides in Cerebrospinal Fluid of Patients with Parkinsonian Disorders.

Background

Objective

Methods

Results

Conclusion

Publications

Alterations in Self-Aggregating Neuropeptides in Cerebrospinal Fluid of Patients with Parkinsonian Disorders.

Similar Datasets

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