Striatal and Extra-Striatal Cholinergic Terminal Density in LRRK2-PD Mutation (LRRK2)

This study explores how a specific genetic mutation of leucine-rich repeat kinase 2 (LRRK2) affects individuals with Parkinson's disease (PD), comparing those with the mutation to others with Parkinson's disease and without the mutation (iPD). Participants will complete positron emission tomography (PET) and magnetic resonance imaging (MRI) brain imaging, cognitive tests, motor tests, sensory tests, and questionnaires. The aims of this study are to compare brain chemicals in LRRK2 PD patients with iPD patients and to correlate brain chemicals with motor and cognitive tests in LRRK2 PD and iPD patients.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease

Detailed Description

LRRK2 mutations are among the most common genetic risk factors for Parkinson's Disease (PD), accounting for ~1% to 36% of familial cases depending on the ancestry, and a significant fraction of sporadic cases. These mutations are not fully penetrant, with 17-85% of carriers eventually developing PD. Among LRRK2-PD patients, clinical features manifest differently compared to idiopathic PD (iPD). LRRK2-PD patients often experience milder progression, with fewer non-motor symptoms and relatively preserved cognition, but higher likelihood of postural instability and gait difficulties (PIGD). This complex profile likely reflects the pleiotropic nature of LRRK2 effects, with mutations causing pathological increases in kinase activity and hyperphosphorylation of downstream targets. A comprehensive understanding of the protective and harmful changes induced by LRRK2 mutations remains a significant research gap.

While PD has traditionally been viewed as primarily a dopaminergic disorder, it is increasingly recognized as a multi-system condition involving other neuromodulatory systems, particularly cholinergic systems. Loss of cholinergic systems integrity is linked to dopamine-refractory symptoms, including morbid gait and cognitive impairments. Recent studies, however, demonstrate that subsets of both newly diagnosed and established PD patients exhibit upregulation of the vesicular acetylcholine transporter (VAChT), associated with preserved cognitive function, in both cross-sectional and longitudinal analyses.

A comprehensive, whole-brain investigation using the specific 18F-fluoroethoxybenzovesamicol ([18F]FEOBV) radioligand will help us better understand the nuanced whole-brain system changes in cholinergic nerve terminal integrity in LRRK2-PD compared to iPD. Our primary recruitment efforts will focus on the University of Michigan's Movement Disorder clinics, allowing us to connect with individuals diagnosed with PD who have the LRRK2 mutation. Additionally, we will work closely with PDGENEration and their sites such as Cleveland and Columbus. This collaboration will provide access to a larger pool of individuals with LRRK2 mutations, improving our ability to recruit participants for our study and ensuring a thorough investigation. We will identify regional cholinergic system alterations in PD with LRRK2 mutations. This would facilitate research on understanding the pathogenic basis for cholinergic activity alterations in iPD as well. Cholinergic systems offer multiple potential targets for pharmacologic and non-invasive neurostimulation interventions. Identification of distinctive cholinergic systems abnormalities in LRRK2-PD would provide new targets for potential therapies, initiating new approaches to experimental therapeutics in PD with LRRK2 mutations and informed by novel insights into PD pathomechanisms.

Aim 1a: To assess in vivo comprehensive, whole-brain expression and activity of cholinergic nerve terminals of LRRK2-PD patients relative to iPD patients using the [18F]FEOBV vesicular acetylcholine transporter (VAChT) radioligand.

Aim 1b: To correlate in vivo striatal and extra-striatal [18F]FEOBV regional binding with cognitive and motor assessments (esp. PIGD symptoms) in LRRK2-PD and iPD.

Aim 2a: To examine differences in striatal and extra-striatal dopamine terminal density between LRRK2-PD and iPD using the complementary PET tracer N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methyl-phenyl)nortropane ([¹¹C]PE2i).

Aim 2b: To investigate the association between dopaminergic function, cognition, and PIGD symptoms

• Study Type: Observational
• Enrollment (Estimated): 15

Contacts and Locations

• Study Contact: Name: Nathan Alexander, BSc; Phone Number: 734-998-6894; Email: natealex@med.umich.edu

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Recruiting
      • University of Michigan
      • Principal Investigator: Prabesh Kanel, PhD
      • Contact: Nathan Alexander, BSc; Phone Number: 734-998-6894; Email: natealex@med.umich.edu
      • Contact: Gerianne Que, BSc; Phone Number: 734-998-4790; Email: queg@med.umich.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Individuals with Parkinson's disease and the LRRK2 genetic mutation.

Description

Inclusion Criteria:

1. Male or Female, age 45 years and over.
2. Diagnosis of PD based on the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Research Criteria (Hughes et al., 1992).
3. Presence of LRRK2 mutation as confirmed by referral from UM Movement Disorders clinic, medical record review, or participation in the PDGENEration study.

Exclusion Criteria:

1. Evidence of atypical parkinsonism.
2. Contra-indications to MR imaging including but not limited to pacemakers, aneurysm clips, intraocular metal, cochlear implant, or severe claustrophobia.
3. Evidence of large vessel stroke or mass lesion on MRI.
4. Regular use of typical anti-cholinergic drugs or cholinesterase inhibitors.
5. History of deep brain stimulation surgery.
6. Pregnant or nursing.
7. Suicidal ideation, as indicated by a response of 2 or 3 on question 9 of the Beck Depression Inventory.
8. Cognitive impairment that results in the inability to give consent, as demonstrated by the Decision Making Capacity Tool.
9. Any other condition or criterion that would preclude safe and meaningful participation in the study.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
LRRK2; Individuals with PD and LRRK2 genetic mutation.
iPD; Individuals with PD and without LRRK2 genetic mutation (Pre-existing cohorts, not recruiting).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cholinergic Differences Between leucine-rich repeat kinase 2 (LRRK2) Parkinson's disease (PD) and Idiopathic/non-LRRK2 PD (iPD)	The cholinergic system changes for people with PD. It is anticipated that LRRK2-PD will demonstrate different cholinergic expression compared to iPD. 18F-fluoroethoxybenzovesamicol ([18F]FEOBV) PET scans will be used to measure Vesicular acetylcholine transporter (VAChT). Higher levels of VAChT binding indicate higher levels of acetylcholine in the brain. Lower levels of VAChT binding indicate lower levels of acetylcholine in the brain. VAChT levels will be compared across brain regions for LRRK2 vs iPD.	Baseline
Dopaminergic Differences Between LRRK2-PD and iPD	The dopaminergic system changes for people with PD. It is anticipated that LRRK2-PD will demonstrate different dopaminergic expression compared to iPD. N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methyl-phenyl)nortropane ([¹¹C]PE2i) PET scans will be used to measure dopamine transporter (DAT). Higher levels of DAT binding indicate higher levels of dopamine in the brain. Lower levels of DAT binding indicate lower levels of dopamine in the brain. DAT levels will be compared across brain regions for LRRK2 vs iPD.	Baseline
Association of Cholinergic Data With Cognition in LRRK2-PD	Association of the global average cholinergic uptake (represented by VAChT uptake) with the global average cognitive z-score of individuals with LRRK2-PD.	Baseline
Association of Cholinergic Data With Postural Instability and Gait Difficulties (PIGD) in LRRK2-PD	Association of the global average cholinergic uptake (represented by VAChT uptake) with the global average PIGD score of individuals with LRRK2-PD.	Baseline
Association of Dopaminergic Data With Cognition in LRRK2-PD	Association of the global average dopaminergic uptake (represented by DAT uptake) with the global average cognitive z-score of individuals with LRRK2-PD.	Baseline
Association of Dopaminergic Data With PIGD in LRRK2-PD	Association of the global average dopaminergic uptake (represented by DAT uptake) with the global average PIGD score of individuals with LRRK2-PD.	Baseline

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: Michael J. Fox Foundation for Parkinson's Research
• Investigators: Principal Investigator: Prabesh Kanel, PhD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2025
• Primary Completion (Estimated): September 17, 2026
• Study Completion (Estimated): September 17, 2026

Study Registration Dates

• First Submitted: May 13, 2026
• First Submitted That Met QC Criteria: June 8, 2026
• First Posted (Actual): June 11, 2026

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 8, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Parkinson's Disease; functional neuroimaging; LRRK2; LRRK
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Parkinson Disease
• Other Study ID Numbers: HUM00276006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (imaging data, clinical assessments, and neuropsychological test results) may be shared with other researchers. Data will be shared with the study sponsor (Michael J. Fox Foundation) for the purposes of contributing to Parkinson's Progression Markers Initiative (PPMI) repository. Data will be available through PPMI on a case-by-case basis upon reasonable request after the completion of the study.
• IPD Sharing Time Frame: Data will be made available within 12 months of primary study completion (by September 2027) and will remain available for a minimum of 5 years.
• IPD Sharing Access Criteria: Researchers seeking access to de-identified data must submit a brief research proposal to the principal investigator and execute a data use agreement in accordance with University of Michigan institutional policies or request access to the data via PPMI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

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