Detection of A-synuclein Aggregate as Biomarker in Diagnosing Parkinson's Disease at Early Stage by Using Protein Misfolding Cyclic Amplification (PMCA)

NCT ID: NCT04536857

Last Updated: 2025-03-19

Basic Information

• Recruitment Status: WITHDRAWN
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-10-01
• Study Completion Date: 2025-12-30

Brief Summary

The study will investigate the biomarker of a-synuclein aggregate in CSF detected by protein misfolding cyclic amplification (PMCA) and its sensitivity and specificity in diagnosing Parkinson's disease at H-Y stage I and disease duration less than 1 year, compared with that from age-matched controls without neurodegeneration, those with Multiple System Atrophy (MSA) as a disease control with a-synucleinopathy, and those with Progressive Supranuclear Palsy (PSP) as a control with non-a-synucleinopathy neurodegeneration.

Detailed Description

This will be an observational study aiming to develop the protein misfolding cyclic amplification (PMCA) technology that detects minute amounts of αSyn aggregates circulating in cerebrospinal fluid (CSF) as a novel assay with high sensitivity and specificity for the early diagnosis of PD. To achieve this goal, we will apply the PMCA to detect the αSyn aggregates in the CSF samples acquired from a discovery cohort that consist of well-characterized early PD patients (disease duration ≤1 year and Hoehn and Yahr Stage I, and DAT-PET and FDG-PET meet the imaging features of PD, n=75) and gender, age-matched healthy controls (n=38). Furthermore, we will confirm the findings in a separate confirmatory cohort with well-characterized early PD patients (disease duration ≤1 year and Hoehn and Yahr Stage I, and DAT-PET and FDG-PET meet the imaging features of PD, n=75), early multiple system atrophy (MSA) patients (disease duration ≤1 year, n=38), early progressive supranuclear palsy (PSP) patients (disease duration ≤1 year, n=38) and age-matched healthy controls (n=38). The sensitivity, specificity, positive predictive value, negative predictive value, and area under curve of the PMCA for the early diagnosis of PD will be calculated in the discovery cohort and be confirmed in the confirmatory cohort, respectively. In addition, the clinical characteristics, including motor and nonmotor symptoms of early PD, MSA and PSP patients in the two cohort will be comprehensively assessed at baseline and during followed-up. To assess the value of the PMCA technology in the evaluation of the disease severity and progress, we will perform the partial correlation analysis between clinical features of early PD patients and the PMCA T50 defined as the time needed to reach 50% of the maximum aggregation.

Misfolded αSyn aggregates have the potential to serve as a biomarker for early PD. The PMCA technology could detect small quantities of misfolded αSyn aggregates by taking advantage of their ability to nucleate further aggregation, enabling a very high amplification of the signal. This study examines the effectiveness of using the PMCA as a novel technique for discriminating early PD from gender, age-matched healthy controls and other early parkinsonian disorders (MSA, PSP) by detecting small misfolded αSyn aggregates in CSF.

Conditions

Parkinson's Disease

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

Parkinson's Disease

Subjects who have a PD diagnosis

Biomarker assay

Intervention Type: OTHER

Biomarker assay will be used to quantify levels of misfolded alpha-synuclein aggregates in cerebrospinal fluid from patients with Parkinson's disease, multiple system atrophy, progressive superanuclear palsy and controls.

Multiple System Atrophy

Subjects who have an MSA diagnosis

Biomarker assay

Intervention Type: OTHER

Biomarker assay will be used to quantify levels of misfolded alpha-synuclein aggregates in cerebrospinal fluid from patients with Parkinson's disease, multiple system atrophy, progressive superanuclear palsy and controls.

Progressive Superanuclear Palsy

Subjects who have a PSP diagnosis

Biomarker assay

Intervention Type: OTHER

Biomarker assay will be used to quantify levels of misfolded alpha-synuclein aggregates in cerebrospinal fluid from patients with Parkinson's disease, multiple system atrophy, progressive superanuclear palsy and controls.

Age-matched controls

Subjects who do not have a diagnosed neurological disorder

Biomarker assay

Intervention Type: OTHER

Biomarker assay will be used to quantify levels of misfolded alpha-synuclein aggregates in cerebrospinal fluid from patients with Parkinson's disease, multiple system atrophy, progressive superanuclear palsy and controls.

Interventions

Biomarker assay

Biomarker assay will be used to quantify levels of misfolded alpha-synuclein aggregates in cerebrospinal fluid from patients with Parkinson's disease, multiple system atrophy, progressive superanuclear palsy and controls.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Clinical diagnosis of "probable PD" by two neurologists specializing in movement disorders according to the International Parkinson and Movement Disorder Society (MDS) Clinical Diagnostic Criteria for PD (2015);
• Age 50-75, disease duration is less than 1 year, and Hoehn & Yahr Stage I;
• the dopamine reuptake transporter (DAT) is significantly reduced in striatum on PET imaging;
• Metabolic brain network detected by fluorine-18-labelled-fluorodeoxyglucose-PET(18F-FDG PET) is consistent with Parkinson's disease-related pattern (PDRP), with FDG hypermetabolism being in basal ganglia and cerebellum;
• Good response to anti-PD medications;
• Ability of completing questionnaires;
• Ability of providing informed consent;
• Willingness of being assessed by neurologists during off-medication state defined as discontinuing anti-PD medications for at least 12 hours before assessment.

• Clinical diagnosis of "probable MSA" by two neurologists specializing in movement disorders according to the International Parkinson and Movement Disorder Society (MDS) second consensus criteria for MSA (2019);
• Age 50-75, and disease duration is less than 1 year;
• Metabolic brain network detected by fluorine-18-labelled-fluorodeoxyglucose-PET(18F-FDG PET) is consistent with MSA related pattern;
• Ability of completing questionnaires;
• Ability of providing informed consent;
• Willingness of being assessed by neurologists during off-medication state defined as discontinuing anti-PD medications for at least 12 hours before assessment.

• Clinical diagnosis of "probable PSP" by two neurologists specializing in movement disorders according to MDS Clinical Diagnostic Criteria for PSP (2017);
• Age 50-75, disease duration is less than 1 year;
• Metabolic brain network detected by fluorine-18-labelled-fluorodeoxyglucose-PET(18F-FDG PET) is consistent with PSP related pattern;
• Ability of completing questionnaires;
• Ability of providing informed consent;
• Willingness of being assessed by neurologists during off-medication state defined as discontinuing anti-PD medications for at least 12 hours before assessment.

• Age 50-75;
• No history of neurodegenerative disease of the central nervous system;
• No history of infective disease of the central system;
• Ability of completing questionnaires;
• Ability of providing informed consent.

Exclusion Criteria

• Secondary parkinsonism (ie. drug induced);
• Atypical parkinsonisms like MSA or PSP etc;
• Presence of any item in 10 red flags of the MDS Clinical Diagnostic Criteria for PD (2015) in the comprehensive assessments during follow-up;
• History of being diagnosed as any cancer within 5 years;
• Presence of any condition risking the procedure of performing lumbar puncture (LP);
• Pregnancy;
• Inability to comply with study procedures.

For early MSA patients

• Secondary parkinsonism (ie. drug induced);
• History of being diagnosed as any cancer within 5 years;
• Presence of any condition risking the procedure of performing lumbar puncture (LP);
• Pregnancy;
• Inability to comply with study procedures.

For PSP patients

• Secondary parkinsonism (ie. drug induced);
• History of being diagnosed as any cancer within 5 years;
• Presence of any condition risking the procedure of performing lumbar puncture (LP);
• Pregnancy;
• Inability to comply with study procedures.

For controls without diagnosis of neurodegenerative disorders

• With prodromal symptoms of PD, such as rapid eye movement sleep behavior disorder (RBD);
• History of being diagnosed as any cancer within 5 years;
• Presence of any condition increasing the risk of the procedure of performing lumbar puncture (LP);
• Pregnancy;
• Inability to comply with study procedures.

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Huashan Hospital

OTHER

Sponsor Role: lead

Responsible Party

Jian Wang

Professor & Deputy Director, Department of Neurology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jian Wang, MD

Role: PRINCIPAL_INVESTIGATOR

Huashan Hospital

Locations

Huashan Hospital Affiliated to Fudan University

Shanghai, Shanghai Municipality, China

Countries

China

Other Identifiers

2020 Provisional Audit No.1004

Identifier Type: -

Identifier Source: org_study_id