GBA Brain Molecular Imaging and Blood Biomarkers for Precision Medicine in PD (NCT06167603)

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]:

This 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

• 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

Precision Medicine Approach

The study explicitly aims to move toward precision medicine for PD by:

Locations and Contacts

Primary Site

Neurological Institute Foundation Casimiro Mondino

• Location: Pavia, Italy
• Status: RECRUITING
• Coordinates: 45.19205, 9.15917

Contact Information

| 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]

Data Sharing

The study does not include individual participant data (IPD) sharing. No results are currently posted on ClinicalTrials.gov.

References