GBA Brain Molecular Imaging and Blood Biomarkers for Precision Medicine in PD (NCT06167603)
Overview
NCT06167603 is an observational prospective cohort study led by [IRCCS San Raffaele](https://www.hsr.it) (Milan, Italy) in collaboration with the [IRCCS National Neurological Institute "C. Mondino" Foundation](https://www.mondino.it) (Pavia, Italy). The study investigates the role of [glucocerebrosidase](/genes/gba) (GBA) mutations in accelerating alpha-synuclein and synaptic pathologies in [Parkinson's disease](/diseases/parkinson-disease) through combined neuroimaging (FDG-PET), biochemical, and clinical features[@gba2024a].
The goal is to illuminate the pathophysiology underlying GBA mutations in PD, identify biomarkers for the malignant GBA-PD phenotype, and define a prognostic algorithm for predicting faster disease progression and monitoring disease trajectories in unaffected GBA mutation carriers[@gba2024b].
Key Facts
| Field | Value |
|---|---|
| NCT ID | NCT06167603 |
| Status | RECRUITING |
| Study Type | Observational (Cohort, Prospective) |
| Start Date | April 30, 2023 (Actual) |
| Primary Completion | December 12, 2024 (Estimated) |
| Final Completion | April 1, 2026 |
| Enrollment | 140 participants (Estimated) |
| Study Design | Cohort study, three groups: GBA-PD, idiopathic PD (iPD), asymptomatic GBA carriers |
| Sponsor | IRCCS San Raffaele |
| Lead PI | Chiti Arturo, Professor in Diagnostic Imaging and Radiotherapy, Vita-Salute San Raffaele University |
Study Groups
...GBA Brain Molecular Imaging and Blood Biomarkers for Precision Medicine in PD (NCT06167603)
Overview
NCT06167603 is an observational prospective cohort study led by [IRCCS San Raffaele](https://www.hsr.it) (Milan, Italy) in collaboration with the [IRCCS National Neurological Institute "C. Mondino" Foundation](https://www.mondino.it) (Pavia, Italy). The study investigates the role of [glucocerebrosidase](/genes/gba) (GBA) mutations in accelerating alpha-synuclein and synaptic pathologies in [Parkinson's disease](/diseases/parkinson-disease) through combined neuroimaging (FDG-PET), biochemical, and clinical features[@gba2024a].
The goal is to illuminate the pathophysiology underlying GBA mutations in PD, identify biomarkers for the malignant GBA-PD phenotype, and define a prognostic algorithm for predicting faster disease progression and monitoring disease trajectories in unaffected GBA mutation carriers[@gba2024b].
Key Facts
| Field | Value |
|---|---|
| NCT ID | NCT06167603 |
| Status | RECRUITING |
| Study Type | Observational (Cohort, Prospective) |
| Start Date | April 30, 2023 (Actual) |
| Primary Completion | December 12, 2024 (Estimated) |
| Final Completion | April 1, 2026 |
| Enrollment | 140 participants (Estimated) |
| Study Design | Cohort study, three groups: GBA-PD, idiopathic PD (iPD), asymptomatic GBA carriers |
| Sponsor | IRCCS San Raffaele |
| Lead PI | Chiti Arturo, Professor in Diagnostic Imaging and Radiotherapy, Vita-Salute San Raffaele University |
Study Groups
The study recruits three distinct populations[@gba2024c]:
GBA-PD: Patients with [Parkinson's disease](/diseases/parkinson-disease) carrying heterozygous GBA mutations — representing the high-risk GBA-PD phenotype with more malignant clinical trajectories
Idiopathic PD (iPD): Patients with Parkinson's disease who do not carry GBA mutations — serving as the control/comparison group
Asymptomatic GBA Carriers: Relatives of GBA-PD patients carrying GBA mutations but without PD diagnosis — enabling study of prodromal/preclinical phasesThis three-group design allows direct comparison of disease mechanisms and progression patterns between GBA-mediated and sporadic forms of PD[@gba2024b].
Interventions and Assessments
Primary Intervention: FDG-PET
Fluorodeoxyglucose positron emission tomography (FDG-PET) is the primary neuroimaging tool[@fdgpet2020]. FDG-PET represents a unique tool to study early metabolic alterations associated with neurodegeneration, both at group and individual subject levels:
- Metabolic patterns: Detects regional cerebral glucose metabolism changes characteristic of PD and GBA-PD subtypes
- Network analysis: Identifies patterns such as the PD-related spatial covariance pattern (PDRP) that may differ between GBA-PD and iPD
- Individual assessment: Enables subject-level metabolic profiling beyond group averages
Secondary Assessments: Blood Tests and Clinical Examination
Blood sampling and standardized clinical assessments performed at three timepoints:
- Baseline (enrollment)
- 12-month follow-up
- 24-month follow-up
Clinical assessments likely include:
- MDS-UPDRS (Movement Disorder Society-Unified Parkinson's Disease Rating Scale)
- Cognitive testing (MDS-MCI, neuropsychological batteries)
- Non-motor symptoms assessment (sleep, autonomic, psychiatric)
- Motor examination
Eligibility Criteria
Inclusion Criteria
- PD diagnosis according to MDS-PD criteria
- For the GBA-PD group: presence of heterozygous GBA mutations
- Disease duration between 3–7 years
Exclusion Criteria
- Other neurological or systemic diseases
- Presence of mutations in another PD-related gene (e.g., [LRRK2](/genes/lrrk2), [SNCA](/genes/snca), [PARKIN](/genes/parkin))
- Inability or unwillingness to undergo FDG-PET imaging
Population Characteristics
- Minimum age: 18 years
- Sex: ALL (male and female)
- Healthy volunteers: No
- Sampling method: Probability sample
Outcomes
Primary Outcome
FDG-PET cerebral metabolism comparison: Measures cerebral metabolism differences between Parkinson's subjects with a mutation in the [GBA](/genes/gba) gene (GBA-PD group) compared to patients with idiopathic Parkinson's[@fdgpet2020].
- Measure: Differences in expression levels of posterior cerebral metabolism between GBA-PD and iPD patients
- Time Frame: 3 years
- Significance: Identification of metabolic signatures unique to GBA-PD that could serve as biomarkers for the malignant phenotype
Expected Secondary Outcomes
While full secondary outcomes were not detailed in the available protocol data, the study description suggests these endpoints:
- Blood biomarker profiles comparing GBA-PD, iPD, and asymptomatic GBA carriers
- Longitudinal clinical progression rates across groups
- Prognostic algorithm development for disease trajectory prediction
- Biomarkers for monitoring disease progression in prodromal GBA carriers
Scientific Rationale
GBA-PD as a Distinct Entity
GBA mutations are the most common genetic risk factor for [Parkinson's disease](/diseases/parkinson-disease), with carriers showing a more malignant phenotype characterized by[@gba2024a; @gba2024b]:
- Earlier age of onset
- Faster motor progression
- Higher prevalence of cognitive impairment
- Greater burden of non-motor symptoms
- More severe alpha-synuclein pathology
The GBA-Alpha-Synuclein Bidirectional Relationship
The study is grounded in the well-established bidirectional relationship between glucocerebrosidase activity and alpha-synuclein aggregation[@gcase2023]:
- GCase deficiency → reduced lysosomal function → impaired alpha-synuclein clearance → accumulation of toxic oligomers
- Alpha-synuclein accumulation → further inhibits GCase activity → creates a vicious cycle of neurodegeneration
FDG-PET provides a window into the downstream metabolic consequences of this pathogenic loop, potentially revealing imaging biomarkers that precede clinical manifestations.
Precision Medicine Approach
The study explicitly aims to move toward precision medicine for PD by:
Stratifying patients based on genetic and molecular profiles rather than clinical phenotype alone
Identifying prognostic biomarkers that predict faster progression in GBA-PD
Monitoring disease trajectories in unaffected GBA carriers to enable early intervention
Informing therapeutic development for GBA-targeted approaches (e.g., GCase enhancers such as ambroxol)Primary Site
Neurological Institute Foundation Casimiro Mondino
- Location: Pavia, Italy
- Status: RECRUITING
- Coordinates: 45.19205, 9.15917
| Name | Role | Phone | Email |
|---|---|---|---|
| Micol Avenali | Principal Investigator / Contact | 0382.380221 | micol.avenali@mondino.it |
| Cinzia Fattore | Contact | 0382.380221 | cinzia.fattore@mondino.it |
| Arturo Chiti | Sub-Investigator | — | — |
| Silvia Paola Caminiti | Sub-Investigator | — | — |
Collaborating Sites
- IRCCS San Raffaele (Milan) — Lead sponsor and imaging expertise
- IRCCS National Neurological Institute "C. Mondino" Foundation (Pavia) — Lead clinical site
Relationship to Other GBA-PD Trials
This observational study complements several interventional trials targeting GBA in PD:
- [Ambroxol to Slow Progression in Parkinson Disease (NCT05778617)](/clinical-trials/ambroxol-parkinson-progression-nct05778617) — Phase IIIa pharmacological chaperone trial of ambroxol to enhance GCase activity
- AAV-GBA gene therapy approaches for atypical parkinsonism (PSP, MSA)[@gba2024a]
NCT06167603 provides mechanistic imaging data that could inform patient selection and outcome measures for these interventional approaches.
Data Sharing
The study does not include individual participant data (IPD) sharing. No results are currently posted on ClinicalTrials.gov.
References
[GBA1-associated Parkinson's Disease Is a Distinct Entity (Ann Neurol, 2024)](https://pubmed.ncbi.nlm.nih.gov/39000225/)
[Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson's disease (Transl Neurodegener, 2024)](https://pubmed.ncbi.nlm.nih.gov/39267121/)
[Glucocerebrosidase and alpha-synuclein: A bidirectional relationship (JPD, 2023)](https://doi.org/10.3233/JPD-230123)
[Brain glucose metabolism in Parkinson's disease with and without GBA mutations (Neurobiol Aging, 2020)](https://pubmed.ncbi.nlm.nih.gov/31604809/)
[GBA1 Mutations and Parkinson's Disease: From Genetics to Disease Phenotype (J Neurol, 2024)](https://pubmed.ncbi.nlm.nih.gov/39598607/)