Overview
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clinical_trials_neuro_immune_i["Neuro-immune Interactome in Parkinsons Disease"]
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clinical_trials_neur_0["Scientific Objectives"]
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clinical_trials_neur_1["Primary Objective"]
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clinical_trials_neur_2["Secondary Objectives"]
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clinical_trials_neur_3["Study Hypothesis"]
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clinical_trials_neur_4["Study Design"]
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clinical_trials_neur_5["Study Procedures"]
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...Overview
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NCT07026929 is an observational case-control longitudinal study conducted by Yale University investigating the role of T cell-mediated autoimmunity and neuro-immune interactions in Parkinson's disease pathogenesis. The trial aims to determine whether autoimmune processes initiated by alpha-synuclein-specific T cell activation, potentially triggered by gut microbiome dysbiosis, represent the initiating mechanism of neurodegeneration["@clinicaltrialsgov"].
Key Details:
- Sponsor: Yale University
- Collaborator: Michael J. Fox Foundation for Parkinson's Research
- Principal Investigator: Jesse Cedarbaum, MD
- Status: Active, not recruiting
- Enrollment: 94 subjects (actual)
- Study Period: May 2021 – June 2024 (primary completion), estimated completion June 2031
- Location: Yale New Haven Hospital, New Haven, Connecticut
- Study Type: Observational, case-control, longitudinal
Scientific Objectives
Primary Objective
The primary objective of this study is to determine whether
T cell-mediated autoimmunity initiates the neurodegenerative process in PD, and whether these early immunological processes converge on classic archetypes of neurodegeneration.
Secondary Objectives
Gut Origin Hypothesis: Determine to what extent the T cell-mediated autoimmune process initiates in the gut microbiome
Genetic Factors: Determine whether different PD-related genes or HLA types are associated with the presence of T cell-mediated autoimmunityStudy Hypothesis
The investigators hypothesize that progression of Parkinson's disease pathology is initiated and/or abetted by an autoimmune process involving:
Alpha-synuclein-specific T cell activation triggered by gut microbiome dysbiosis
Neuro-immune interactions that establish PD in the brainThe study proposes to address this hypothesis by integrating neuroimmunology, single cell genomics, mouse models, and microbiome approaches.
Study Design
This is an observational prospective case-control longitudinal cohort study with the following characteristics:
- Cohort Type: Prospective
- Time Perspective: Longitudinal (follow-up over several years)
- Study Population: Subjects with idiopathic REM behavior disorder (RBD), Parkinson's disease with RBD, and healthy controls
- Assessments: Clinical (cognitive, sensory, motor), dopamine transporter scanning, smell testing, biological samples
Study Procedures
All subjects undergo:
Sleep study (polysomnography) to determine eligibility
Baseline clinical assessments: cognitive, sensory, and motor clinical assessment
Dopamine transporter scanning (DaT Scan)
Smell testing (olfactory assessment)
Biological sample collection:
- Phlebotomy (blood)
- Lumbar puncture (cerebrospinal fluid)
- Stool collection
- Saliva collection
6.
Genome-wide association scansFollow-up Assessments
Eligible subjects return annually for:
- Sensory and motor clinical assessment
- Monitoring for phenoconversion to neurodegenerative disease
Study Arms
The study enrolls subjects into five distinct cohorts:
| Arm | Description | PD Risk Status |
|-----|-------------|-----------------|
| RBD without motor or cognitive dysfunction | RBD participants with normal DaT Scan, no constipation, normosmic | No or remote risk |
| RBD and at-risk | RBD with asymmetric findings, reduced DaT scan, symptomatic constipation, or hyposmia with/without minor motor signs | At-risk |
| RBD with PD | RBD with PD for less than 10 years | Established PD |
| PD without RBD | PD patients without RBD | Established PD |
| Healthy controls | No RBD, no PD | No risk |
Outcomes
Primary Outcomes
| Measure | Description | Timeframe |
|---------|-------------|------------|
|
Characterization of T cells | Number and types of T cells which autoreact to alpha-synuclein in blood and CSF | 2 months |
Secondary Outcomes
| Measure | Description | Timeframe |
|---------|-------------|------------|
|
T cell clonality | Presence of increased clonality of T cells reflecting immune cell activation in PBMCs and CSF nucleated cells | 2 months |
|
Microbial cross-reactivity | Presence of cross-reactivity of anti-alpha-synuclein T cells with microbial agents from gut stool samples | 2 months |
Eligibility Criteria
Inclusion Criteria
General:
- English speaking
- Able and willing to provide informed consent
REM Behavior Disorder:
- Repeated episodes of sleep-related vocalization and/or complex motor behaviors documented by polysomnography
- Polysomnographic recording demonstrates REM sleep without atonia (RWA)
- disturbance not better explained by another sleep disorder, mental disorder, medication, or substance abuse
Parkinson's Disease:
- Meets Movement Disorders Society criteria for Clinically Probable Parkinson's disease
- Disease duration < 10 years
Healthy Controls:
- No clinical evidence of Parkinson's disease or RBD
- Normosmic (normal smell function)
Exclusion Criteria
General:
- Known immune deficiency disorder
- Personal history of neurological disorder (MS, Alzheimer's disease, MSA, PSP, ALS, repeated head trauma)
- Solid or hematological malignancy (unless no active disease and no treatment within 12 months)
- Known blood clotting disorder
- Short Bowel Syndrome, Ileostomy, or colostomy
- History of vagotomy
- Taking anticoagulant or antiplatelet medication
- Receiving chemotherapy or radiation therapy (within 12 months)
- Receiving potent immunosuppressant agents (anti-TNF, IL-6 antibodies, JAK/STAT inhibitors)
- Treatment with experimental agent within 3 months
- Pregnancy or actively breastfeeding
- Thyroid disease treated with radioactive iodine
- Lidocaine allergy
Additional for PD Subjects: Meets any MDS exclusionary criteria for PD diagnosis
Additional for RBD Subjects: Identified secondary cause of RBD; neurodegenerative disease; secondary RBD from antidepressants; narcolepsy
Additional for Healthy Controls: History of Parkinson's disease in first-degree blood relative
Mechanistic Significance
This trial represents a critical investigation into the autoimmune hypothesis of Parkinson's disease, focusing on:
Alpha-Synuclein-Specific T Cells
- The study examines whether T cells specifically reactive to alpha-synuclein are present in blood and CSF
- These autoreactive T cells may attack dopaminergic neurons expressing alpha-synuclein
- The presence and activity of these cells may correlate with disease progression
Immune Cell Clonality
- Increased T cell clonality suggests clonal expansion of antigen-specific T cells
- This indicates an ongoing immune response against a specific target (alpha-synuclein)
- Clonal analysis can reveal the diversity and specificity of the immune response
Gut-Brain Axis
The study investigates the
gut-origin hypothesis of PD:
- Stool sample analysis examines gut microbiome composition
- Cross-reactivity testing determines if anti-alpha-synuclein T cells recognize microbial antigens
- This would support the hypothesis that gut dysbiosis triggers autoimmune responses that spread to the brain
Neuro-immune Interactions
The trial examines how peripheral immune processes interact with the central nervous system:
Blood-CSF Interface: How do peripheral immune cells or signals cross into the CNS?
Neuroinflammation: What is the relationship between peripheral autoimmunity and CNS neuroinflammation?
Disease Propagation: Can peripheral immune responses accelerate or trigger central neurodegeneration?Phenoconversion Studies
The longitudinal design allows investigation of:
- Which biological markers predict conversion from RBD to PD
- The timeline of immune changes relative to motor symptom development
- Whether immune markers correlate with disease severity or progression rate
Translational Implications
Diagnostic Biomarkers
If T cell autoreactivity to alpha-synuclein is validated:
- Could serve as a diagnostic biomarker for early PD
- May identify patients in prodromal stages (RBD) before motor symptoms
- Could differentiate PD subtypes based on immune profiles
Therapeutic Targets
Understanding the immune mechanisms could lead to:
- Immunomodulatory therapies targeting alpha-synuclein-specific T cells
- Gut microbiome interventions to reduce triggers of autoimmunity
- Peripheral immune tolerance approaches to reduce neuronal attack
Disease Modification
If autoimmunity is confirmed as a trigger:
- Interventions in prodromal RBD could prevent or delay PD onset
- Early immunomodulation might slow or halt disease progression
- Combination approaches targeting both immune and neurodegenerative processes
Cross-Linking to NeuroWiki Content
This trial relates to multiple established NeuroWiki pages:
- [alpha-synuclein](/proteins/alpha-synuclein) — The target of T cell autoimmunity
- [Neuroinflammation in PD](/mechanisms/neuroinflammation-pd) — CNS inflammatory response
- [Peripheral Immune System in Parkinson's](/mechanisms/peripheral-immune-system-parkinsons) — Peripheral immune involvement
- [Adaptive Immunity in Neurodegeneration](/mechanisms/adaptive-immunity) — T cell-mediated immunity
- [Parkinson's Disease](/diseases/parkinsons-disease) — Target disease
- [REM Sleep Behavior Disorder](/diseases/rem-sleep-behavior-disorder) — Prodromal condition being studied
- [T Lymphocytes in CNS](/cell-types/t-lymphocytes-cns) — Key immune cells being characterized
- [Enteric Glia](/cell-types/enteric-glia-parkinson-v2) — Gut-brain axis component
- [Gut-Brain Axis](/mechanisms/gut-brain-axis) — Proposed pathway for immune trigger
- [Exenatide Parkinson's Trial](/clinical-trials/exenatide-parkinsons) — GLP-1 trial with anti-inflammatory mechanisms
- [Inosine Sure PD3](/clinical-trials/inosine-sure-pd3) — Urate elevation neuroprotection
- [Bacillus subtilis PD](/clinical-trials/bacillus-subtilis-pd) — Microbiome intervention
References
[ClinicalTrials.gov: NCT07026929 — Neuro-immune Interactome in Parkinson's Disease](https://clinicaltrials.gov/study/NCT07026929)Pathway Diagram
The following diagram shows the key molecular relationships involving Neuro-immune Interactome in Parkinson's Disease (NCT07026929) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)