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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Процедура Modified deep cervical Lymphatic-Venous Anastomosis
  Deep cervical lymph-vein anastomosis surgery, connecting deep cervical lymph input vein vessels to enhance glymphatic-mediated protein clearance

Первичные конечные точки

• Alzheimer's disease: Change in Clinical Dementia Rating Scale sum of the boxes (CDR-SB) [Срок оценки: up to 2 years]
• Alzheimer's disease: Change in Mini-mental State Examination (MMSE) [Срок оценки: up to 2 years]
• Alzheimer's disease: Change in Montreal Cognitive Assessment (MoCA) [Срок оценки: up to 2 years]
• Alzheimer's disease: Change in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Severe Version) (ADCS-ADL-SEV) [Срок оценки: up to 2 years]
• Parkinson's disease：Change in Unified Parkinson's Disease Rating Scale (UPDRS) [Срок оценки: up to 2 years]
• Parkinson's disease：Change in The Hoehn and Yahr Scale [Срок оценки: up to 2 years]
• Parkinson's disease：Change in Parkinson's Disease Questionnaire-39 (PDQ-39) [Срок оценки: up to 2 years]

Вторичные конечные точки (10)

• Alzheimer's disease: Change in amyloid deposit in brain [Срок оценки: baseline, 1year, 2 years]
• Alzheimer's disease: Change in brain Tau deposition in a subset of participants [Срок оценки: baseline, 1year, 2 years]
• Alzheimer's disease: Change in fluid biomarker [Срок оценки: up to 2 years]
• Alzheimer's disease: Change in Neuropsychiatric Inventory (NPI-Q) Total Severity Score [Срок оценки: up to 2 years]
• Alzheimer's disease: Change in Clinical Global Impression [Срок оценки: up to 2 years]
• Alzheimer's disease: Changes in the functional connectivity in brain in a subset of participants [Срок оценки: baseline, 1year, 2 years]
• Parkinson's disease: Change in fluid biomarker [Срок оценки: up to 2 years]
• Changes in the hippocampal volume [Срок оценки: baseline, 1year, 2 years]
• Changes in the cortical thickness [Срок оценки: baseline, 1year, 2 years]
• Changes in the water diffusion characteristics in brain [Срок оценки: baseline, 1year, 2 years]

Критерии участия

Критерии включения

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

Критерии исключения

• 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;
• Poor compliance with inability/unwillingness to complete scheduled postoperative follow-ups;
• Other investigator-determined contraindications for trial participation.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Zhejiang Provincial People's Hospital — Ханчжоу

Публикации

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Идентификаторы

NCT: NCT06852352 · KY2025008

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗