Assessing the Polygenic Burden of Rare Disruptive Mutations in Parkinson's Disease

Assessing the Polygenic Burden of Rare Disruptive Mutations in Parkinson's Disease: a Novel Diagnostic Test to Predict Parkinson's Disease Risk

The project intends to assess the polygenic burden of rare disruptive mutations in Parkinson's disease (PD) and how they influence the phenotype/pathological heterogeneity of disease.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: Diagnostic test: targeted resequencing

Detailed Description

The investigators intend to extend the genetic analysis to a cohort of 300 PD cases and 300 healthy subjects (wife / husband of the patients) that will be recruited at Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Neuromed.

After signed informed consent patients will be assessed for disease progression (Hoehn and Yahr stadium, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS), Montreal Cognitive Assessment (MoCA) test, no motor symptoms, therapy and levodopa induced Dyskinesia (LID) occurrence). Each patient and control will be subjected to peripheral blood sampling for the isolation of DNA, RNA, plasma and serum. The investigators will use a disease-specific gene panel including about 100 genes related to Parkinson's Disease, autophagy and levodopa induced Dyskinesia (LID).

Bioinformatics analysis will allow to catalog in a database the identified variants/mutations according to their frequency and characteristics.

The investigators will specifically assess if the inheritance of multiple rare deleterious variants in Parkinson's Disease genes is predictive of disease risk.

The presence of one or more variants will be tested for association with phenotypic manifestation of Parkinson's Disease (motor, non-motor, and cognitive signs, as well as age at onset, LID and neuroimaging changes) to assess the variant burden effect on progression, and prognosis of the disease.

• Study Type: Observational
• Enrollment (Anticipated): 600

Contacts and Locations

Study Locations

• Italy
  • Pozzilli, Italy, 86077
    • Recruiting
    • IRCCS Neuromed
    • Contact: Teresa Esposito, PhD; Phone Number: 0865915249; Email: teresa.esposito@igb.cnr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The study includes 300 PD patients and 300 age/gender-matched controls. All PD patients will be diagnosed at the IRCCS Neuromed and followed-up (at least for 3 years) for disease progression.

Description

Inclusion Criteria:

• Presence of at least two out the following cardinal signs: resting tremor, cogwheel rigidity, bradykinesia, asymmetrical onset of symptoms and symptomatic response to L-dopa (levodopa).

Exclusion Criteria:

• Previous thalamotomy on the implanted sides;
• Significant brain atrophy or structural damage seen on CT or MRI;
• Marked cognitive dysfunction;
• Active psychiatric symptoms;
• Concurrent neurological disorders;
• Other uncontrolled medical disorders.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cases; Participants will be assessed for disease progression: Hoehn and Yahr stadium, MDS-UPDRS part III, MoCA test, no motor symptoms, therapy and LID occurrence. Participants will be subjected to peripheral blood sampling for the purification of DNA, RNA, plasma and serum. DNA of each participant will be analysed by targeted resequencing of a disease-specific gene panel including about 100 genes related to Parkinson's Disease, autophagy and levodopa induced Dyskinesia (LID).	Diagnostic test: targeted resequencing; The investigators will use a disease-specific gene panel including about 100 genes related to Parkinson's Disease, autophagy and levodopa induced Dyskinesia (LID).
controls; Participants will be assessed for the presence of disease. Participants will be subjected to peripheral blood sampling for the purification of DNA, RNA, plasma and serum. DNA of each participant will be analysed by targeted resequencing of a disease-specific gene panel including about 100 genes related to Parkinson's Disease, autophagy and levodopa induced Dyskinesia (LID).	Diagnostic test: targeted resequencing; The investigators will use a disease-specific gene panel including about 100 genes related to Parkinson's Disease, autophagy and levodopa induced Dyskinesia (LID).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clinical evaluation of PD patients and controls	disease progression (Hoehn and Yahr stadium, MDS-UPDRS part III, MoCA test, no motor symptoms, therapy and LID occurrence	three years
identification of variants/mutations	assessing if the inheritance of multiple rare deleterious variants in PD genes is predictive of PD risk.	two years
association with phenotypic manifestation of PD	The presence of one or more variants will be tested for association with phenotypic manifestation of PD (motor, non-motor, and cognitive signs, as well as age at onset, LID and neuroimaging changes) to assess the variant burden effect on progression, and prognosis of the disease.	three years

Collaborators and Investigators

• Sponsor: Neuromed IRCCS
• Investigators: Principal Investigator: Teresa Esposito, PhD, Head of CNR Unit

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2021
• Primary Completion (Anticipated): September 30, 2023
• Study Completion (Anticipated): May 17, 2024

Study Registration Dates

• First Submitted: November 3, 2020
• First Submitted That Met QC Criteria: November 3, 2020
• First Posted (Actual): November 9, 2020

Study Record Updates

• Last Update Posted (Actual): September 28, 2022
• Last Update Submitted That Met QC Criteria: September 27, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: RF-2019-12370224

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: genetics data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No