An Exploratory Study to Confirm Efficacy of Modified Deep Cervical Lymphovenous Anastomosis (LVA) in Alzheimer's Disease/ Parkinson's Disease

NCT06852352 | Recruiting DMC

• 1 other identifier: KY2025008
• Study Type: interventional
• Target: 160
• Locations: 1 country
• Sites: 1

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.

Conditions

Alzheimer Disease; Parkinson Disease

Keywords

LVA

Outcome Measures

Primary Outcomes (7)

• Alzheimer's disease: Change in Clinical Dementia Rating Scale sum of the boxes (CDR-SB)

  The Clinical Dementia Rating Scale sum of the boxes (CDR-SB) will be used to evaluate the general cognitive function. CDR-SB ranges from 0 to 18, and higher value represents a worse outcome.

  up to 2 years

• Alzheimer's disease: Change in Mini-mental State Examination (MMSE)

  The Mini-mental State Examination (MMSE) will be used to evaluate the general cognitive function. MMSE ranges from 0 to 30, and higher value represents a better outcome.

  up to 2 years

• Alzheimer's disease: Change in Montreal Cognitive Assessment (MoCA)

  The Montreal Cognitive Assessment (MoCA) will be used to evaluate the general cognitive function. MoCA ranges from 0 to 30, and higher value represents a better outcome.

  up to 2 years

• Alzheimer's disease: Change in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Severe Version) (ADCS-ADL-SEV)

  The ADCS-ADL-SEV consists of 19 items. Ratings reflect caregiver observations about the patient's actual functioning over the previous month and provide an assessment of change in the functional state of the participant over time. The total score ranges from 0 to 54, with lower values over time reflecting functional deterioration.

  up to 2 years

• Parkinson's disease：Change in Unified Parkinson's Disease Rating Scale (UPDRS)

  The scale assesses the functional status of patients with parksinon´s disease, including the independency of daily activities, mood, secondary effects of medications and motor complications. The total UPDRS score ranges from 0 to 199 points, with higher scores indicating more severe symptoms.

  up to 2 years

• Parkinson's disease：Change in The Hoehn and Yahr Scale

  The Hoehn and Yahr (H\&Y) scale is the most widely used and universally accepted staging system for overall functional disability in Parkinson's disease. The H\&Y Scale categorizes Parkinson's disease progression into 7 stages. Each stage reflects worsening motor function and loss of independence.

  up to 2 years

• Parkinson's disease：Change in Parkinson's Disease Questionnaire-39 (PDQ-39)

  The Parkinson's Disease Questionnaire-39 (PDQ-39) is a vital tool for assessing the quality of life in Parkinson's disease patients. The total score ranges from 0 to 100 points, with higher scores indicating worse quality of life.

  up to 2 years

Secondary Outcomes (10)

• Alzheimer's disease: Change in amyloid deposit in brain

  baseline, 1year, 2 years

• Alzheimer's disease: Change in brain Tau deposition in a subset of participants

  baseline, 1year, 2 years

• Alzheimer's disease: Change in fluid biomarker

  up to 2 years

• Alzheimer's disease: Change in Neuropsychiatric Inventory (NPI-Q) Total Severity Score

  up to 2 years

• Alzheimer's disease: Change in Clinical Global Impression

  up to 2 years

Study Arms (1)

The clinically diagnosed patients with MCI or mild-moderate dementia caused by AD/PD

EXPERIMENTAL

Procedure: Modified deep cervical Lymphatic-Venous Anastomosis

Interventions

Modified deep cervical Lymphatic-Venous Anastomosis PROCEDURE

Deep cervical lymph-vein anastomosis surgery, connecting deep cervical lymph input vein vessels to enhance glymphatic-mediated protein clearance

The clinically diagnosed patients with MCI or mild-moderate dementia caused by AD/PD

Eligibility Criteria

• Age: 50 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Alzheimer's disease:
• Male or female, the age ranged from 50 to 75 years old
• Informed consent signed and dated by patient or legal representative
• Patients diagnosed principally with mild cognitive impairment or dementia caused by Alzheimer's disease
• Positive result of Amyloid PET imaging (Centiloids ≥37)
• HAMD score ≤17
• Hachinski score ≤4 Patients who meet ASA (American Society of Anesthesiologists) grade I-III criteria
• Parkinson's disease:
• Male or female, the age ranged from 50 to 80 years old
• Informed consent signed and dated by patient or legal representative
• 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
• Stage I-IV patients according to Hoehn and Yahr Scale
• 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

You may not qualify if:

• Contraindications for MRI, ICG angiography, or PET scanning
• Contraindications for lumbar puncture
• 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
• MRI results suggesting intracranial active/acute pathologies, including infections, space-occupying lesions, major hemorrhages, or ≥4 lobar microhemorrhages;
• Conditions predisposing to increased intracranial hemorrhage risk, such as hematological disorders, hemorrhagic/coagulation disorders;
• Poorly controlled thyroid dysfunction;
• Cerebrovascular or systemic vasculopathy;
• Severe cardiac disease or hemodynamic instability;
• Uncontrolled severe hypertension;
• Substance use disorders (including illicit drugs, anesthetics, and alcohol dependence);
• Active severe infections, including HIV positivity and acute critical infections;
• Severe psychiatric disorders or significant suicide risk;
• Chronic hypnotic use (more than twice weekly for over one month);
• History of untreated/uncured malignancies;
• Participation in other interventional clinical trials within preceding 3 months;

Sponsors & Collaborators

• Zhejiang Provincial People's Hospital: lead
• Zybio Inc.: collaborator

Study Sites (1)

Zhejiang Provincial People's Hospital

Hangzhou, Zhejiang, 310014, China

RECRUITING

Related Publications (11)

• Li Y, Wang L, Zhong J, Xu H, Han Y; Alzheimer's Disease Neuroimaging Initiative; Zuo C, Jiang J. Impaired glymphatic function as a biomarker for subjective cognitive decline: An exploratory dual cohort study. Alzheimers Dement. 2024 Sep;20(9):6542-6555. doi: 10.1002/alz.14149. Epub 2024 Aug 6.

  PMID: 39107995 BACKGROUND

• Huang SY, Zhang YR, Guo Y, Du J, Ren P, Wu BS, Feng JF; Alzheimer's Disease Neuroimaging Initiative; Cheng W, Yu JT. Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease. Alzheimers Dement. 2024 May;20(5):3251-3269. doi: 10.1002/alz.13789. Epub 2024 Mar 19.

  PMID: 38501315 BACKGROUND

• Pappolla M, Sambamurti K, Vidal R, Pacheco-Quinto J, Poeggeler B, Matsubara E. Evidence for lymphatic Abeta clearance in Alzheimer's transgenic mice. Neurobiol Dis. 2014 Nov;71:215-9. doi: 10.1016/j.nbd.2014.07.012. Epub 2014 Aug 4.

  PMID: 25102344 BACKGROUND

• Nedergaard M, Goldman SA. Glymphatic failure as a final common pathway to dementia. Science. 2020 Oct 2;370(6512):50-56. doi: 10.1126/science.abb8739.

  PMID: 33004510 BACKGROUND

• Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012 Aug 15;4(147):147ra111. doi: 10.1126/scitranslmed.3003748.

  PMID: 22896675 BACKGROUND

• Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015 Jun 29;212(7):991-9. doi: 10.1084/jem.20142290. Epub 2015 Jun 15.

  PMID: 26077718 BACKGROUND

• Chen F, Xie X, Wang L. Research Progress on Intracranial Lymphatic Circulation and Its Involvement in Disorders. Front Neurol. 2022 Mar 14;13:865714. doi: 10.3389/fneur.2022.865714. eCollection 2022.

  PMID: 35359624 BACKGROUND

• Zhao H, Sun M, Zhang Y, Kong W, Fan L, Wang K, Xu Q, Chen B, Dong J, Shi Y, Wang Z, Wang S, Zhuang X, Li Q, Lin F, Yao X, Zhang W, Kong C, Zhang R, Feng D, Zhao X. Connecting the Dots: The Cerebral Lymphatic System as a Bridge Between the Central Nervous System and Peripheral System in Health and Disease. Aging Dis. 2024 Feb 1;15(1):115-152. doi: 10.14336/AD.2023.0516.

  PMID: 37307828 BACKGROUND

• Vera Quesada CL, Rao SB, Torp R, Eide PK. Immunohistochemical visualization of lymphatic vessels in human dura mater: methodological perspectives. Fluids Barriers CNS. 2023 Mar 28;20(1):23. doi: 10.1186/s12987-023-00426-3.

  PMID: 36978127 BACKGROUND

• Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jul 16;523(7560):337-41. doi: 10.1038/nature14432. Epub 2015 Jun 1.

  PMID: 26030524 BACKGROUND

• Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S, Farber E, Raper D, Viar KE, Powell RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature. 2018 Aug;560(7717):185-191. doi: 10.1038/s41586-018-0368-8. Epub 2018 Jul 25.

  PMID: 30046111 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease; Parkinson Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies

Central Study Contacts

Youmao Zheng

CONTACT

+86-571-85335800; Zhengym6228@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Lymphatic and Microsurgical Reconstructive Surgery

Study Record Dates

• First Submitted: February 18, 2025
• First Posted: February 28, 2025
• Study Start: February 28, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): January 31, 2028
• Last Updated: March 11, 2025

Record last verified: 2025-02

Locations

CN (1)