Neuro-immune Interactome in Parkinson's Disease (NCT07026929)

Overview

Overview

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

Secondary Objectives

Study Hypothesis

The 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

• Phlebotomy (blood)
• Lumbar puncture (cerebrospinal fluid)
• Stool collection
• Saliva collection

Follow-up Assessments

• 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

Secondary Outcomes

Eligibility Criteria

Inclusion Criteria

General:

• English speaking
• Able and willing to provide informed consent

• 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

• Meets Movement Disorders Society criteria for Clinically Probable Parkinson's disease
• Disease duration < 10 years

• 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 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

T Cell-Mediated Autoimmunity in PD

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

• 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:

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

• 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

• 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

• 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:

Related Mechanisms

• [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

Related Diseases and Conditions

• [Parkinson's Disease](/diseases/parkinsons-disease) — Target disease
• [REM Sleep Behavior Disorder](/diseases/rem-sleep-behavior-disorder) — Prodromal condition being studied

Related Cell Types and Pathways

• [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

Related Clinical Trials

• [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

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: