Understanding Alpha-Synuclein Spread in Parkinson's Disease Through Blood Biomarkers and Neuroimaging

Official title

From Genes to Virtual Brain: Defining the Pathogenic Mechanisms Promoting Alfa-synuclein Seeding and Spreading in Parkinson's Disease.

Overview

The project aims to investigate how abnormal accumulation of alpha synuclein and its interaction with tau influence brain function across the Parkinson's disease (PD) spectrum, with particular focus on individuals carrying GBA1 mutations. This interventional, monocentric, cross sectional study includes patients with PD, individuals with idiopathic REM sleep behavior disorder, and participants without PD. All enrolled subjects will undergo clinical and neuropsychological assessments, blood based biomarker analyses related to neurodegeneration, synaptic and mitochondrial function, and multimodal brain MRI to evaluate brain structure, white matter integrity, and functional connectivity. The study aims to: * characterize the relationship between alpha synuclein/tau pathology and synaptic mitochondrial dysfunction; * identify biomarker and connectivity signatures across disease stages and genetic backgrounds; * integrate preclinical, clinical, biological, and imaging data to support the development of mechanistic models of alpha synuclein propagation. In parallel, preclinical studies in GBA PD mouse models and wild type mice will be used to investigate how changes in PD-related pathology (alpha-synuclein and tau) relates to behavior, brain imaging alterations and mitochondrial, axonal and synaptic damage. Animal model will also aid the validation of a new PET tracer that targets alpha synuclein (i.e., \[¹⁸F\]Syntacasyn). Together, human and preclinical studies are designed to provide a translational framework integrating molecular changes with brain network alterations and clinical heterogeneity in PD.

Detailed description

Parkinson's disease (PD) is characterized by pathological aggregation and propagation of alpha synuclein, leading to synaptic and mitochondrial dysfunction. Heterozygous mutations in the GBA1 gene represent the strongest genetic risk factor for PD and are associated with earlier onset, faster progression, and increased burden of misfolded alpha synuclein. Experimental evidence suggests that alpha synuclein toxicity may be amplified by its interaction with tau, promoting synergistic neurodegenerative mechanisms; however, in vivo human data on these processes remain limited.

This study aims to define, through a personalized and multimodal approach, how alpha synuclein accumulation and its interaction with tau influence synaptic and mitochondrial dysfunction and brain connectivity across the PD spectrum, from periclinal stages to established disease, with particular focus on the impact of GBA1 mutations. The study includes patients with PD, individuals with idiopathic REM sleep behavior disorder (iRBD), and subjects without PD, both carriers and non carriers of GBA1 mutations.

All participants will undergo comprehensive clinical and neuropsychological assessments to characterize motor, non motor, and cognitive manifestations across disease stages. Blood samples will be collected to define a fluid biomarker profile, including alpha synuclein, tau, markers of synaptic integrity, mitochondrial function, and neurodegeneration. In addition, all participants will undergo multimodal brain MRI, including structural, diffusion weighted, and resting state functional sequences, to evaluate brain structure, white matter integrity, and functional connectivity.

In a subset of participants, a skin biopsy will be performed to generate patient specific induced pluripotent stem cell (hiPSC) derived dopaminergic neurons. These cellular models will be used to investigate neuronal and synaptic function in relation to individual biomarker profiles and genetic background. In parallel, preclinical studies will be conducted in GBA-PD mouse models and wild type mice injected with saline, alpha synuclein or combined alpha synuclein/tau fibrils. Mice will undergo behavioral, in vivo MRI and PET imaging and post mortem assessment of synaptic, axonal and mitochondrial pathology. In addition, a novel alpha synuclein PET tracer, \[¹⁸F\]Syntacasyn, will undergo preclinical validation.

Multimodal human and animal data will be integrated using advanced statistical and computational approaches to identify vulnerable network hubs and generate subject specific "virtual brain" models of alpha synuclein pathology propagation.

The study is designed to provide a translational framework linking molecular pathology, brain network dysfunction and clinical heterogeneity in PD, supporting biomarker development and precision medicine strategies across the prodromal and clinical spectrum, with particular focus on genetically defined populations such as GBA1 mutation carriers.

Interventions

• Diagnostic test brain imaging
  Participants will undergo a single brain MRI acquisition, including structural, diffusion-weighted, and resting-state functional MRI.
• Procedure blood draw
  Collection of a venous blood sample for biochemical analyses
• Procedure Skin biopsy
  A small punch skin biopsy (about 3-4 mm) will be performed under local anesthesia on a small sample of enrolled participants (n=10)

Primary outcome measures

• Concentration of alpha-synuclein levels in plasma [Time frame: Baseline visit]
• Concentration of tau levels in plasma [Time frame: Baseline visit]
• Investigation of glucocerebrosidase activity in Peripheral Blood Mononuclear Cells [Time frame: Baseline visit]

Secondary outcome measures (6)

• Assessment of mitochondrial damage in plasma [Time frame: Baseline visit]
• Plasma synaptic protein concentration [Time frame: Baseline visit]
• Brain network connectivity in Parkinson's disease [Time frame: Baseline visit]
• In vitro neuronal responses in hiPSC-derived dopaminergic neurons [Time frame: Baseline visit]
• Estimation of synaptic damage in Neuronal extracellular vesicle [Time frame: Baseline visit]
• Concentration of neurofilament light chain [Time frame: Baseline visit]

Eligibility criteria

Inclusion criteria for Parkinson's disease cohorts (GBA-PD and nonGBA-PD):

• Diagnosis of PD according to MDS-PD criteria and, for the GBA-PD group, presence of heterozygous GBA mutations (with a balanced distribution of severe, risk, mild, and complex variants);
• Disease duration between 3 and 7 years;
• Disease stage according to Hoehn \& Yahr ≤ 3;
• Absence of mutations in other known genes associated with PD susceptibility;
• Age > 18 Years;
• Ability to understand and voluntarily sign informed consent and to comply with study procedures.

Exclusion criteria for Parkinson's disease cohorts:

• Diagnosis of atypical and/or secondary parkinsonism;
• Diagnosis of dementia according to DSM-5 criteria;
• Presence of other neurological disorders and/or essential tremor;
• Presence of systemic inflammatory or infectious diseases, autoimmune diseases, or malignant tumors at the time of enrollment.

Inclusion criteria for unaffected subjects (GBA-nonPD and nonGBA-nonPD):

• Age > 18 Years;
• Ability to understand and voluntarily sign informed consent and to comply with study procedures;
• No diagnosis of PD or other neurological disorders;
• Presence of a heterozygous GBA mutation for the GBA-nonPD group and absence of such mutation for control subjects (nonGBA-nonPD);
• Absence of mutations in other known genes associated with PD susceptibility.

Exclusion criteria for unaffected subjects (GBA-nonPD and nonGBA-nonPD):

• Presence of systemic inflammatory or infectious diseases, autoimmune diseases, or malignant tumors at the time of enrollment;
• Diagnosis of atypical and/or secondary parkinsonism;
• Diagnosis of dementia according to DSM-5 criteria.

Inclusion criteria for subjects with idiopathic REM Sleep Behavior Disorder (GBA-iRBD and nonGBA-iRBD):

• Diagnosis of idiopathic REM Sleep Behavior Disorder according to ICSD-3;
• Age > 18 Years;
• Ability to understand and voluntarily sign informed consent and to comply with study procedures;
• No diagnosis of PD or other neurological disorders;
• Presence of a heterozygous GBA mutation for the GBA-iRBD group and absence of such mutation for the nonGBA-iRBD group;
• Absence of mutations in other known genes associated with PD susceptibility.

Exclusion criteria for subjects with idiopathic REM Sleep Behavior Disorder (GBA-iRBD and nonGBA-iRBD):

• Presence of systemic inflammatory or infectious diseases, autoimmune diseases, or malignant tumors at the time of enrollment;
• Diagnosis of atypical and/or secondary parkinsonism;
• Diagnosis of dementia according to DSM-5 criteria.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

Italy · 2 centers

• Neurological Institute Foundation Casimiro Mondino — Pavia
• University of Pavia — Pavia

Publications

• Baden P, Perez MJ, Raji H, Bertoli F, Kalb S, Illescas M, Spanos F, Giuliano C, Calogero AM, Oldrati M, Hebestreit H, Cappelletti G, Brockmann K, Gasser T, Schapira AHV, Ugalde C, Deleidi M. Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism. Nat Commun. 2023 Apr 6;14(1):1930. doi: 10.1038/s41467-023-37454-4. PMID 37024507
• Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009 Jul;132(Pt 7):1783-94. doi: 10.1093/brain/awp044. Epub 2009 Mar 13. PMID 19286695
• Vogel JW, Corriveau-Lecavalier N, Franzmeier N, Pereira JB, Brown JA, Maass A, Botha H, Seeley WW, Bassett DS, Jones DT, Ewers M. Connectome-based modelling of neurodegenerative diseases: towards precision medicine and mechanistic insight. Nat Rev Neurosci. 2023 Oct;24(10):620-639. doi: 10.1038/s41583-023-00731-8. Epub 2023 Aug 24. PMID 37620599
• Pan L, Li C, Meng L, Tian Y, He M, Yuan X, Zhang G, Zhang Z, Xiong J, Chen G, Zhang Z. Tau accelerates alpha-synuclein aggregation and spreading in Parkinson's disease. Brain. 2022 Oct 21;145(10):3454-3471. doi: 10.1093/brain/awac171. PMID 35552614
• Guo M, Wang J, Zhao Y, Feng Y, Han S, Dong Q, Cui M, Tieu K. Microglial exosomes facilitate alpha-synuclein transmission in Parkinson's disease. Brain. 2020 May 1;143(5):1476-1497. doi: 10.1093/brain/awaa090. PMID 32355963
• Recasens A, Dehay B. Alpha-synuclein spreading in Parkinson's disease. Front Neuroanat. 2014 Dec 18;8:159. doi: 10.3389/fnana.2014.00159. eCollection 2014. PMID 25565982

Identifiers

NCT: NCT07474779 · FIS-2023-00979

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗