Prospective Single-Arm Safety Study of Cervical LVA in AD Patients

Phase 1Not Yet RecruitingNCT07458620

Chang Gung Memorial Hospital35 enrolled

Overview

Official Title Prospective Single-Arm Safety Study of Cervical Lymphaticovenular Anastomosis (LVA) in Patients with Alzheimer's Disease Purpose of the Study Researchers are conducting this study to see if a minimally invasive microsurgery, called Cervical Lymphaticovenular Anastomosis (LVA), is safe for people with Alzheimer's Disease. How the Surgery Works Alzheimer's Disease is linked to the buildup of metabolic waste products (certain proteins) in the brain. Recent medical discoveries show that these wastes normally drain through small channels in the neck into the blood system. In this study, surgeons will use high-powered microscopes to connect these drainage channels (lymphatic vessels) in the neck directly to small nearby veins. The goal is to create a "detour" that helps the brain clear out these harmful proteins more effectively. What to Expect Safety First: The main goal is to find out if the surgery is safe and well-tolerated by patients. The Procedure: The surgery is performed under general anesthesia and typically takes 4 to 6 hours. It involves small (about 5 cm) incisions on both sides of the neck. Follow-up: Participants will be monitored for at least 12 months. Researchers will use memory tests, brain scans (MRI and PET), and blood tests to see if the surgery helps with daily activities or slows down memory loss.

Official Title Prospective Single-Arm Safety Study of Cervical Lymphaticovenular Anastomosis (LVA) in Patients with Alzheimer's Disease Scientific Rationale Neurodegenerative diseases like Alzheimer's (AD) are characterized by the misfolding and accumulation of proteins such as Amyloid-beta and Tau. The glymphatic and meningeal lymphatic systems serve as the primary pathways for clearing these metabolic wastes from the central nervous system into the deep cervical lymph nodes. This study investigates whether enhancing this drainage via supermicrosurgical lymphaticovenular anastomosis (LVA) can reduce intracranial protein burden and systemic oxidative stress. Study Design and Intervention This is a prospective, single-arm safety study. Participants undergo bilateral cervical LVA. Using Indocyanine Green (ICG) fluorescence lymphography for navigation, lymphatic vessels in the neck are identified and anastomosed to adjacent small veins to facilitate lymph drainage into the venous circulation. Safety Monitoring and Data Integrity Primary Safety Endpoint: The study defines safety as a Serious Adverse Event (SAE) rate of ≤10% within the first month post-operation. Events are graded using CTCAE v5.0. Independent Oversight: To ensure objectivity, cognitive and behavioral assessments (including MMSE, CDR, and CASI) are conducted by clinical psychologists who are not members of the core research team. External Auditing: An independent Clinical Research Organization (CRO) has been contracted to perform four periodic audits to verify data accuracy and GCP compliance. Exploratory Objectives The study will track longitudinal changes in: Fluid Biomarkers: Plasma levels of Amyloid-beta 40/42, p-Tau 217, GFAP, and Nf-L at baseline, 1, 6, and 12 months. Neuroimaging: Amyloid-PET and FDG-PET scans at baseline and 12 months to evaluate protein deposition and metabolic activity. Clinical Outcomes: Changes in cognitive scores (CDR, MMSE, CASI, NPI) from baseline to 6 months post-surgery.

Interventions

Supermicrosurgical Lymphaticovenular Anastomosis (LVA)PROCEDURE

This intervention is uniquely distinguished by its use of supermicrosurgery to perform bilateral cervical Lymphaticovenular Anastomosis (LVA) as a direct physiological treatment for Alzheimer's Disease. Unlike traditional pharmacological trials that target protein production or aggregation, this surgical approach focuses on the mechanical clearance of metabolic waste. A key technical differentiator is the specific targeting of neck lymph nodes using Indocyanine Green (ICG) fluorescence to map the drainage pathway of cerebrospinal fluid. This allows for a precise, "super-microsurgical" bypass (connecting vessels often \<0.8mm) in the neck. This method aims to bypass potential blockages in the aging dCLNs (deep cervical lymph nodes), directly enhancing the outflow of Amyloid-beta and Taufrom the glymphatic and meningeal systems into the venous circulation.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of Alzheimer's Disease: Participants must have a confirmed diagnosis of Alzheimer's Disease as evaluated by a neurologist and a psychiatrist at the hospital. * Positive Amyloid-PET Scan: The result of a \[18F\] Florbetapir (Amyloid-PET) scan must be positive, indicating the presence of amyloid plaques in the brain. * Willingness to Consent: Participants or their legal representatives must be willing to sign a written informed consent form. * Participants must be adults aged 18 years or older Exclusion Criteria: * Lack of Informed Consent: Potential participants are excluded if they are unable to exercise autonomy and informed consent cannot be obtained from a legal representative or authorized person. * Prior Surgical History: Individuals who have previously undergone neck lymphatic dissection, nasopharyngeal surgery, or intracranial surgery are excluded. * Concurrent Medical Conditions: The trial excludes persons with thyroid disease or chronic heart failure. * Specific Allergies: Candidates with a history of allergies to shellfish or iodine are excluded due to the use of Indocyanine Green (ICG) during the procedure. * Unresolved Concerns: Anyone who has doubts about the trial and cannot receive satisfactory answers is excluded. * Anesthesia Risks: Individuals deemed medically unfit for general anesthesia-for example, those with severe cardiopulmonary insufficiency or a history of specific anesthetic drug allergies-are ineligible.

Outcomes

Primary Outcomes

Incidence of Treatment-Emergent Adverse Events (Safety and Feasibility)

Assessment of the safety and feasibility of bilateral cervical supermicrosurgical lymphaticovenular anastomosis (LVA). Safety is evaluated by the frequency and severity of adverse events (AEs) and serious adverse events (SAEs) occurring from the start of the surgical procedure through the 1-month post-operative follow-up period. Events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Time frame: From the start of surgery up to 1 month post-operation.

Secondary Outcomes

Change from Baseline in Mini-Mental State Examination (MMSE) Score

A 30-point questionnaire used to measure cognitive impairment. Lower scores indicate greater impairment.

Time frame: Baseline and 6 months post-operation

Change from Baseline in Clinical Dementia Rating (CDR)

A scale used to characterize the level of cognitive and functional performance.

Time frame: Baseline and 6 months post-operation.

Changes from Baseline in Cognitive Abilities Screening Instrument (CASI)

The CASI is a comprehensive tool used to assess multiple cognitive domains, including attention, concentration, orientation, short-term memory, long-term memory, language abilities, visual construction, list-generating fluency, and abstraction. It provides a more detailed assessment than the MMSE, with a total score ranging from 0 to 100. Higher scores indicate better cognitive performance, while lower scores represent greater impairment.

Time frame: Baseline and 6 months post-operation.

Change in Brain Amyloid-beta Deposition via PET Scan

Assessment of the change in brain amyloid plaque density using \[18F\] Florbetapir (Amyloid-PET) imaging. This measures whether the surgical intervention has facilitated the clearance of pathological proteins.

Time frame: Baseline and post-operation.

Change in Plasma Neurodegenerative Biomarker Levels

Quantification of plasma levels for GFAP and NfL. These markers are used to track neuroaxonal damage and protein clearance efficiency.