Clinical trial NCT06852352: An Exploratory Study to Confirm Efficacy of Modified Deep Cervical Lymphovenous Anastomosis (LVA) in Alzheimer's Disease/ Parkinson's Disease
Official title: A Prospective, Single-center, Single-arm, Exploratory, 24-Month Study to Confirm Efficacy of Modified Deep Cervical Lymphovenous Anastomosis (LVA) in Subjects with Alzheimer's Disease/ Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Alzheimer Disease
Parkinson Disease
Keywords: LVA
Lead sponsor: Zhejiang Provincial People's Hospital
Sponsor class: OTHER
Collaborators: name: Zybio Inc.
First posted: 2025-02-28
Enrollment: 160
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by pathological protein accumulation in the brain-Aβ/tau in AD and α-synuclein in PD. Recent studies have indicated that age-related lymphatic vessel atrophy compromises the metabolic clearance capacity of meningeal lymphatic vessels, potentially disrupting the equilibrium between production and clearance of Aβ/α-synuclein, ultimately leading to pathological accumulation of these proteins within the brain. Deep cervical lymphovenous anastomosis (LVA), a surgical technique proven effective in restoring lymphatic drainage in lymphedema, may enhance clearance of neurotoxic proteins by improving cervical lymphatic outflow. This project aims to evaluate the efficacy of modified deep cervical LVA in treating AD and PD, establishing a novel therapeutic strategy to modify disease progression and improve quality of life in neurodegenerative disorders, additionally offering the pathogenic mechanisms underlying neurodegenerative disorders.

Detailed description: Alzheimer's disease (AD) and Parkinson's disease (PD) are progressive neurodegenerative disorders characterized by pathological protein aggregation-Aβ plaques and tau tangles in AD, and α-synuclein Lewy bodies in PD. Emerging evidence implicates that the glymphatic-meningeal lymphatic system and deep cervical lymph nodes constitute the central pathway for metabolite clearance of cerebral macromolecules. Aging-associated lymphatic vessel atrophy disrupts the equilibrium between protein production and clearance, exacerbating neurotoxicity. Deep cervical lymphovenous anastomosis (LVA), a surgical technique validated in lymphedema management, aims to restore cervical lymphatic drainage and enhance glymphatic-mediated protein clearance. This study investigates the therapeutic potential of modified deep cervical LVA in AD and PD. A prospective cohort will undergo modified deep cervical LVA with longitudinal assessments, including cerebrospinal fluid (CSF) and plasma biomarkers (Aβ42, p-tau181, p-tau217, GFAP, NfL, α-synuclein), neuroimaging (MRI and PET-CT), and clinical endpoints (CDR, MMSE, MoCA, BADL and IADL for AD, UPDRS and PDQ-39 for PD). Mechanistically, we hypothesize that modified deep cervical LVA will reduce intracranial pressure gradients, augment meningeal lymph flow, and accelerate interstitial waste drainage, thereby mitigating neuroinflammation and neuronal damage. This trial aims to verify the efficacy of modified deep cervical LVA to modify disease progression in AD and PD, providing a surgically scalable approach to delay progression of neurodegenerative disorders and improve patient quality of life.

Eligibility criteria: Inclusion Criteria:

Alzheimer's disease:

1. Male or female, the age ranged from 50 to 75 years old
2. Informed consent signed and dated by patient or legal representative
3. Patients diagnosed principally with mild cognitive impairment or dementia caused by Alzheimer's disease
4. Positive result of Amyloid PET imaging (Centiloids ≥37)
5. HAMD score ≤17
6. Hachinski score ≤4 Patients who meet ASA (American Society of Anesthesiologists) grade I-III criteria

Parkinson's disease:

1. Male or female, the age ranged from 50 to 80 years old
2. Informed consent signed and dated by patient or legal representative
3. Patients diagnosed with Parkinson's disease or probable Parkinson's disease according to the Clinical Diagnostic Criteria for Parkinson's Disease in China (2016) or MDS
4. Stage I-IV patients according to Hoehn and Yahr Scale
5. Patients documented history of Parkinson's disease for more than 2-5 years to ensure clinical stability of symptoms and exclude the possibility of early misdiagnosis of other conditions

Exclusion Criteria:

1. Contraindications for MRI, ICG angiography, or PET scanning
2. Contraindications for lumbar puncture
3. Functional impairment of vital organs (cardiac, pulmonary, renal, hepatic), including reduced left ventricular ejection fraction, prolonged QT interval, severe pulmonary diseases, and severe hepatic/renal insufficiency
4. MRI results suggesting intracranial active/acute pathologies, including infections, space-occupying lesions, major hemorrhages, or ≥4 lobar microhemorrhages;
5. Conditions predisposing to increased intracranial hemorrhage risk, such as hematological disorders, hemorrhagic/coagulation disorders;
6. Poorly controlled thyroid dysfunction;
7. Cerebrovascular or systemic vasculopathy;
8. Severe cardiac disease or hemodynamic instability;
9. Uncontrolled severe hypertension;
10. Substance use disorders (including illicit drugs, anesthetics, and alcohol dependence);
11. Active severe infections, including HIV positivity and acute critical infections;
12. Severe psychiatric disorders or significant suicide risk;
13. Chronic hypnotic use (more than twice weekly for over one month);
14. History of untreated/uncured malignancies;
15. Participation in other interventional clinical trials within preceding 3 months;
16. Poor compliance with inability/unwillingness to complete scheduled postoperative follow-ups;
17. Other investigator-determined contraindications for trial participation.

Primary outcomes:
measure: Alzheimer's disease: Change in Clinical Dementia Rating Scale sum of the boxes (CDR-SB)
timeFrame: up to 2 years
measure: Alzheimer's disease: Change in Mini-mental State Examination (MMSE)
timeFrame: up to 2 years
measure: Alzheimer's disease: Change in Montreal Cognitive Assessment (MoCA)
timeFrame: up to 2 years
measure: Alzheimer's disease: Change in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Severe Version) (ADCS-ADL-SEV)
timeFrame: up to 2 years
measure: Parkinson's disease：Change in Unified Parkinson's Disease Rating Scale (UPDRS)
timeFrame: up to 2 years
measure: Parkinson's disease：Change in The Hoehn and Yahr Scale
timeFrame: up to 2 years
measure: Parkinson's disease：Change in Parkinson's Disease Questionnaire-39 (PDQ-39)
timeFrame: up to 2 years
Secondary outcomes:
measure: Alzheimer's disease: Change in amyloid deposit in brain
timeFrame: baseline, 1year, 2 years
measure: Alzheimer's disease: Change in brain Tau deposition in a subset of participants
timeFrame: baseline, 1year, 2 years
measure: Alzheimer's disease: Change in fluid biomarker
timeFrame: up to 2 years
measure: Alzheimer's disease: Change in Neuropsychiatric Inventory (NPI-Q) Total Severity Score
timeFrame: up to 2 years
measure: Alzheimer's disease: Change in Clinical Global Impression
timeFrame: up to 2 years
measure: Alzheimer's disease: Changes in the functional connectivity in brain in a subset of participants
timeFrame: baseline, 1year, 2 years
measure: Parkinson's disease: Change in fluid biomarker
timeFrame: up to 2 years
measure: Changes in the hippocampal volume
timeFrame: baseline, 1year, 2 years
measure: Changes in the cortical thickness
timeFrame: baseline, 1year, 2 years
measure: Changes in the water diffusion characteristics in brain
timeFrame: baseline, 1year, 2 years
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: Zhejiang Provincial People's Hospital
state: Zhejiang
Study officials:
References:
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