Efficacy of Lymphatic-Venous Anastomosis Plus Donepezil Versus Donepezil Alone for Alzheimer's Disease

A Multicenter Randomized Controlled Trial on the Efficacy and Safety of Cervical Lymph Vessel/Node-venous Anastomosis Combined With Donepezil Versus Donepezil Alone in the Treatment of Alzheimer's Disease

This study employed a multicenter, randomized controlled trial (RCT) design to evaluate the efficacy and safety of deep cervical lymphatic/lymph node-venous anastomosis combined with oral donepezil compared to donepezil monotherapy in patients with Alzheimer's disease and moderate dementia. Participants were randomized using a central randomization system with stratified block design, with the study center and age group (50-64 years, 65-80 years) as stratification factors. While study participants and surgical investigators could not be blinded due to the nature of the intervention, efficacy assessors and imaging specialists remained blinded to ensure the objectivity and reliability of the findings. The intervention group received deep cervical lymphatic/lymph node-venous anastomosis (detailed surgical procedure is specified in the protocol) in combination with oral donepezil (5-10 mg/day), while the control group received oral donepezil alone. The total treatment and follow-up period was 18 months, with assessments conducted at baseline, 1 week, 1, 3, 6, 12, and 18 months post-operation. These included neuropsychological evaluations (MMSE, MoCA, CDR, BADL, IADL, NPI, AES), neuroimaging (MRI, PET, ultrasound), fluid biomarker analyses (CSF and blood levels of Aβ, Tau, neuroinflammatory factors, etc.), and safety monitoring. The primary efficacy endpoint was the change in CDR-SB score at 12 months post-treatment. Secondary endpoints included changes in multiple cognitive scales, neuroimaging metrics, and biomarkers at 18 months. Safety indicators encompassed adverse event recording, vital signs, and laboratory tests.

Study Overview

• Status: Not yet recruiting
• Conditions: Alzheimer s Disease
• Intervention / Treatment: Procedure: Cervical lymph vessel/node-venous anastomosis surgery combined with oral donepezil; Drug: Oral treatment with donepezil

• Study Type: Interventional
• Enrollment (Estimated): 216
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ke Li
• Study Contact Backup: Name: Yixin Zhang; Phone Number: +86 13061775858; Email: zhangyixin6688@163.com

Study Locations

• China
  • Huangpu
    • Shanghai, Huangpu, China, 200011
      • Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University
      • Contact: Yixin Zhang, MD.; Phone Number: 5576 +86-21-23271699; Email: shjyiec@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. The patient or guardian signs the informed consent form;
2. Age 50-80 years (≥50 years, ≤80 years), male or female;
3. The first diagnosis is Alzheimer's disease with dementia;
4. MMSE score ≤24;
5. Positive β-amyloid protein PET imaging findings;
6. HAMD score ≤17;
7. Hachinski score ≤7;
8. No AD-related drug treatment has been received within the past 1 month;
9. ASA grade 1-3 (≥ grade 1, ≤ grade 3).
10. CDR-SB score of 9.5-15.5

Exclusion Criteria

1. Presence of contraindications to MRI, ICG angiography, or PET scan;
2. Presence of contraindications to lumbar puncture;
3. Severe heart disease or unstable hemodynamic status;
4. Severe lung disease, including severe obstructive, restrictive, or mixed ventilatory dysfunction, or acute inflammation within 3 months;
5. Hepatic insufficiency, AST or ALT >3 times the upper limit of normal;
6. Renal insufficiency, GFR <60 mL/min or need for blood purification treatment;
7. MRI indicates active or acute intracranial lesions, including intracranial infection, space-occupying lesions, major hemorrhage, and ≥4 lobar microbleeds, etc.;
8. History of cerebral hemorrhage or cerebral infarction with severe residual neurological dysfunction;
9. Blood diseases, bleeding/coagulation disorders, coagulation dysfunction;
10. Abnormal thyroid function;
11. Moderate or severe stenosis of intracranial or cervical vessels with severe residual neurological dysfunction;
12. Severe hypertension not effectively controlled, systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg;
13. The disease requires systemic use of steroids;
14. Drug addiction (including alcohol, narcotics, and alcohol dependence);
15. Severe infectious diseases, including HIV positivity, severe infection, etc.;
16. Severe psychiatric disease or potential suicide risk;
17. Within 3 years after radical surgery for malignant tumor;
18. Participation in other interventional clinical trials within the past three months;
19. In the physician's judgment, poor compliance, inability to complete, or unwillingness to cooperate with regular postoperative follow-up;
20. Other circumstances that the physician considers unsuitable for this clinical trial.
21. Anti-Aβ monoclonal antibody treatment has been received within half a year

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cervical lymph vessel/node-venous anastomosis surgery combined with oral donepezil group	Procedure: Cervical lymph vessel/node-venous anastomosis surgery combined with oral donepezil; Under total intravenous anesthesia, the patient is placed supine with the head turned and shoulders elevated. A transverse neck incision is made, the platysma is opened, and the external jugular vein and great auricular nerve are exposed and protected. Dissection proceeds along the sternocleidomastoid muscle and carotid sheath to create two lymphatic composite flaps: a lateral IIB/III flap rich in deep cervical lymph nodes and lymphatic vessels, and a medial IIA flap containing the angular lymph node. Both flaps are prepared to ensure continuous lymphatic fluid outflow. Revascularization is then performed by end-to-end anastomosis of the IIA flap to a branch of the common facial vein or external jugular vein, and end-to-side anastomosis of the IIB/III flap to the internal or external jugular vein. After the anastomosis is completed, the incision is sutured layer by layer for cosmetic purposes.; Drug: Oral treatment with donepezil; After randomly assigned into the group, the study participants were given donepezil orally (the cervical lymph vessel/node-venous anastomosis surgery combined with oral donepezil group began to take donepezil orally on the first day after operation, and the oral donepezil group began to take donepezil after completing the baseline examination), once a day, before sleep, starting at 5 mg/day, and adjusted to 10 mg/day after 6 weeks; if not tolerated, it will be maintained at 5 mg/day, continued for 6 weeks, and then 10 mg/day will be attempted again, with continuous administration for 18 months. If research participants still cannot tolerate the high dose, they may be maintained at 5 mg/day for 18 months.
Active Comparator: Oral donepezil group	Drug: Oral treatment with donepezil; After randomly assigned into the group, the study participants were given donepezil orally (the cervical lymph vessel/node-venous anastomosis surgery combined with oral donepezil group began to take donepezil orally on the first day after operation, and the oral donepezil group began to take donepezil after completing the baseline examination), once a day, before sleep, starting at 5 mg/day, and adjusted to 10 mg/day after 6 weeks; if not tolerated, it will be maintained at 5 mg/day, continued for 6 weeks, and then 10 mg/day will be attempted again, with continuous administration for 18 months. If research participants still cannot tolerate the high dose, they may be maintained at 5 mg/day for 18 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Clinical Dementia Rating-Sum of Boxes Score at Month 12	The Clinical Dementia Rating-Sum of Boxes is a clinician-rated measure of dementia severity. The score ranges from 0 to 18, with higher scores indicating greater impairment and more severe dementia. The outcome measure is the change from baseline to Month 12. The scale will be administered face to face by trained evaluators blinded to treatment assignment, and results will be reviewed by an independent endpoint adjudication committee.	Baseline and Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Clinical Dementia Rating-Sum of Boxes Score at Month 18	The Clinical Dementia Rating-Sum of Boxes score ranges from 0 to 18, with higher scores indicating greater dementia severity. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Mini-Mental State Examination Score at Month 18	The Mini-Mental State Examination assesses global cognitive function. The score ranges from 0 to 30, with higher scores indicating better cognitive function. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Montreal Cognitive Assessment Score at Month 18	The Montreal Cognitive Assessment assesses cognitive function. The score ranges from 0 to 30, with higher scores indicating better cognitive function. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in 18-item Apathy Evaluation Scale Score at Month 18	The 18-item Apathy Evaluation Scale assesses apathy symptoms. The total score ranges from 18 to 72, with higher scores indicating more severe apathy. The outcome measure is the change from baseline to Month 18. Assessments will be performed by trained evaluators blinded to treatment assignment.	Baseline and Month 18
Change From Baseline in Neuropsychiatric Inventory Total Score at Month 18	The 12-item Neuropsychiatric Inventory assesses behavioral and psychological symptoms in dementia. For each domain, the domain score is calculated as frequency multiplied by severity. The total score ranges from 0 to 144, with higher scores indicating more severe neuropsychiatric symptoms. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Basic Activities of Daily Living Score at Month 18	The Basic Activities of Daily Living score is derived from six items of the Activities of Daily Living scale, including walking, eating, dressing, grooming, bathing, and toileting. Each item is scored from 1 to 4, and the total score ranges from 6 to 24, with higher scores indicating greater impairment in basic self-care ability. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Instrumental Activities of Daily Living Score at Month 18	The Instrumental Activities of Daily Living score is derived from eight items of the Activities of Daily Living scale, including using public transportation, cooking, doing housework, taking medication, doing laundry, shopping, using the telephone, and handling personal finances. Each item is scored from 1 to 4, and the total score ranges from 8 to 32, with higher scores indicating greater impairment in complex daily living ability. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in PET Imaging Measures at Month 18	Positron emission tomography (PET) will be used to assess cerebral amyloid and tau burden: Amyloid PET: Cerebral amyloid deposition will be quantified using the unitless standardized uptake value ratio (SUVR) and the standardized Centiloid scale. Higher SUVR and Centiloid values indicate greater amyloid deposition. Tau PET: Cerebral tau deposition will be quantified using the unitless standardized uptake value ratio (SUVR). Higher SUVR values indicate greater tau deposition.	Baseline and Month 18
Change From Baseline in Brain Volumetric MRI Measures at Month 18	Structural brain MRI will be used to measure gray matter volume (GMV), white matter volume (WMV), cerebrospinal fluid volume (CSFV), intracranial volume (ICV), white matter hyperintensity volume (WMHV), hippocampal volume (HippV), and frontal lobe volume (FronV). All volumes will be reported in milliliters (mL). The outcome measures are the changes in these MRI-derived volumes from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Glymphatic System-Related MRI Measures at Month 18	MRI will be used to assess glymphatic system-related measures: perivascular space volume fraction in the whole brain, white matter, and basal ganglia (PVSVF-ALL, PVSVF-WM, and PVSVF-BG); free-water fraction in the whole brain, white matter, and basal ganglia (FW-ALL, FW-WM, and FW-BG); and diffusion tensor imaging analysis along the perivascular space indices for the left hemisphere, right hemisphere, and overall brain (ALPS-L, ALPS-R, and ALPS-ALL). PVSVF and FW are reported as unitless numerical fractions, and the ALPS indices are dimensionless. The outcome measures are the changes in these MRI-derived values from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Internal Jugular Vein Diameter on Ultrasound at Month 18	Ultrasound will be used to measure the diameter of the internal jugular vein in the operative area. The diameter will be reported in millimeters. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in External Jugular Vein Diameter on Ultrasound at Month 18	Ultrasound will be used to measure the diameter of the external jugular vein in the operative area. The diameter will be reported in millimeters. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Maximum Jugular Vein Flow Velocity on Ultrasound at Month 18	Ultrasound will be used to measure the maximum flow velocity of the internal or external jugular vein in the operative area. Flow velocity will be reported in centimeters per second. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Histopathological Findings in Intraoperatively Collected Lymph Node Tissue	Histopathological findings in lymph node tissue collected intraoperatively, when available, will be assessed using routine histopathological staining.	During surgery
Concentration of Phosphorylated Tau 217 in Intraoperatively Collected Lymphatic Fluid	The concentration of phosphorylated tau 217 (P-tau217) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Amyloid-Beta 42 in Intraoperatively Collected Lymphatic Fluid	The concentration of amyloid-beta 42 (Aβ42) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Phosphorylated Tau 181 in Intraoperatively Collected Lymphatic Fluid	The concentration of phosphorylated tau 181 (P-tau181) in lymphatic fluid collected intraoperatively, when available, will be measured （pg/ml).	During surgery
Concentration of Amyloid-Beta 40 in Intraoperatively Collected Lymphatic Fluid	The concentration of amyloid-beta 40 (Aβ40) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Neurofilament Light Chain in Intraoperatively Collected Lymphatic Fluid	The concentration of neurofilament light chain (NfL) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Glial Fibrillary Acidic Protein in Intraoperatively Collected Lymphatic Fluid	The concentration of glial fibrillary acidic protein (GFAP) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Interleukin-1 Alpha in Intraoperatively Collected Lymphatic Fluid	The concentration of interleukin-1 alpha (IL-1α) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Interleukin-1 Beta in Intraoperatively Collected Lymphatic Fluid	The concentration of interleukin-1 beta (IL-1β) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Interleukin-8 in Intraoperatively Collected Lymphatic Fluid	The concentration of interleukin-8 (IL-8) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Tumor Necrosis Factor Alpha in Intraoperatively Collected Lymphatic Fluid	The concentration of tumor necrosis factor alpha (TNF-α) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Interleukin-12 in Intraoperatively Collected Lymphatic Fluid	The concentration of interleukin-12 (IL-12) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Interleukin-6 in Intraoperatively Collected Lymphatic Fluid	The concentration of interleukin-6 (IL-6) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Interferon Gamma in Intraoperatively Collected Lymphatic Fluid	The concentration of interferon gamma (IFN-γ) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Interleukin-17A in Intraoperatively Collected Lymphatic Fluid	The concentration of interleukin-17A (IL-17A) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Interleukin-4 in Intraoperatively Collected Lymphatic Fluid	The concentration of interleukin-4 (IL-4) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Interleukin-10 in Intraoperatively Collected Lymphatic Fluid	The concentration of interleukin-10 (IL-10) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Interleukin-1 Receptor Antagonist in Intraoperatively Collected Lymphatic Fluid	The concentration of interleukin-1 receptor antagonist (IL-1ra) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Concentration of Transforming Growth Factor Beta in Intraoperatively Collected Lymphatic Fluid	The concentration of transforming growth factor beta (TGF-β) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).	During surgery
Change From Baseline in Cerebrospinal Fluid P-tau181 Level at Month 18	The concentration of phosphorylated tau 181 (P-tau181) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid Total Tau Level at Month 18	The concentration of total tau (T-tau) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid Aβ42 Level at Month 18	The concentration of amyloid-beta 42 (Aβ42) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid Aβ40 Level at Month 18	The concentration of amyloid-beta 40 (Aβ40) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid Aβ42/Aβ40 Ratio at Month 18	The ratio of amyloid-beta 42 to amyloid-beta 40 (Aβ42/Aβ40) in cerebrospinal fluid will be reported as a unitless ratio. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid BD-tau Level at Month 18	The concentration of brain-derived tau (BD-tau) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid GFAP Level at Month 18	The concentration of glial fibrillary acidic protein (GFAP) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid NfL Level at Month 18	The concentration of neurofilament light chain (NfL) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid pTau217 Level at Month 18	The concentration of phosphorylated tau 217 (pTau217) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-1α Level at Month 18	The concentration of interleukin-1 alpha (IL-1α) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-1β Level at Month 18	The concentration of interleukin-1 beta (IL-1β) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-8 Level at Month 18	The concentration of interleukin-8 (IL-8) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid TNF-α Level at Month 18	The concentration of tumor necrosis factor alpha (TNF-α) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-12 Level at Month 18	The concentration of interleukin-12 (IL-12) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-6 Level at Month 18	The concentration of interleukin-6 (IL-6) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IFN-γ Level at Month 18	The concentration of interferon gamma (IFN-γ) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-17A Level at Month 18	The concentration of interleukin-17A (IL-17A) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-4 Level at Month 18	The concentration of interleukin-4 (IL-4) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-10 Level at Month 18	The concentration of interleukin-10 (IL-10) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-1ra Level at Month 18	The concentration of interleukin-1 receptor antagonist (IL-1ra) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid TGF-β Level at Month 18	The concentration of transforming growth factor beta (TGF-β) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma P-tau181 Level at Month 18	The concentration of phosphorylated tau 181 (P-tau181) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma Total Tau Level at Month 18	The concentration of total tau (T-tau) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma Aβ42 Level at Month 18	The concentration of amyloid-beta 42 (Aβ42) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma Aβ40 Level at Month 18	The concentration of amyloid-beta 40 (Aβ40) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma Aβ42/Aβ40 Ratio at Month 18	The ratio of amyloid-beta 42 to amyloid-beta 40 (Aβ42/Aβ40) in plasma will be reported as a unitless ratio. The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma BD-tau Level at Month 18	The concentration of brain-derived tau (BD-tau) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma GFAP Level at Month 18	The concentration of glial fibrillary acidic protein (GFAP) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma NfL Level at Month 18	The concentration of neurofilament light chain (NfL) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma pTau217 Level at Month 18	The concentration of phosphorylated tau 217 (pTau217) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma IL-1α Level at Month 18	The concentration of interleukin-1 alpha (IL-1α) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma IL-1β Level at Month 18	The concentration of interleukin-1 beta (IL-1β) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma IL-8 Level at Month 18	The concentration of interleukin-8 (IL-8) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma TNF-α Level at Month 18	The concentration of tumor necrosis factor alpha (TNF-α) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma IL-12 Level at Month 18	The concentration of interleukin-12 (IL-12) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma IL-6 Level at Month 18	The concentration of interleukin-6 (IL-6) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma IFN-γ Level at Month 18	The concentration of interferon gamma (IFN-γ) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma IL-17A Level at Month 18	The concentration of interleukin-17A (IL-17A) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma IL-4 Level at Month 18	The concentration of interleukin-4 (IL-4) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma IL-10 Level at Month 18	The concentration of interleukin-10 (IL-10) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma IL-1ra Level at Month 18	The concentration of interleukin-1 receptor antagonist (IL-1ra) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18
Change From Baseline in Plasma TGF-β Level at Month 18	The concentration of transforming growth factor beta (TGF-β) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.	Baseline and Month 18

Collaborators and Investigators

• Sponsor: Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University

Publications and helpful links

General Publications

• Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature. 2016 Sep 1;537(7618):50-6. doi: 10.1038/nature19323.
• van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Jan 5;388(1):9-21. doi: 10.1056/NEJMoa2212948. Epub 2022 Nov 29.
• Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chetelat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimer's disease. Lancet. 2021 Apr 24;397(10284):1577-1590. doi: 10.1016/S0140-6736(20)32205-4. Epub 2021 Mar 2.
• Jia J, Wei C, Chen S, Li F, Tang Y, Qin W, Zhao L, Jin H, Xu H, Wang F, Zhou A, Zuo X, Wu L, Han Y, Han Y, Huang L, Wang Q, Li D, Chu C, Shi L, Gong M, Du Y, Zhang J, Zhang J, Zhou C, Lv J, Lv Y, Xie H, Ji Y, Li F, Yu E, Luo B, Wang Y, Yang S, Qu Q, Guo Q, Liang F, Zhang J, Tan L, Shen L, Zhang K, Zhang J, Peng D, Tang M, Lv P, Fang B, Chu L, Jia L, Gauthier S. The cost of Alzheimer's disease in China and re-estimation of costs worldwide. Alzheimers Dement. 2018 Apr;14(4):483-491. doi: 10.1016/j.jalz.2017.12.006. Epub 2018 Feb 9.
• Jia L, Du Y, Chu L, Zhang Z, Li F, Lyu D, Li Y, Li Y, Zhu M, Jiao H, Song Y, Shi Y, Zhang H, Gong M, Wei C, Tang Y, Fang B, Guo D, Wang F, Zhou A, Chu C, Zuo X, Yu Y, Yuan Q, Wang W, Li F, Shi S, Yang H, Zhou C, Liao Z, Lv Y, Li Y, Kan M, Zhao H, Wang S, Yang S, Li H, Liu Z, Wang Q, Qin W, Jia J; COAST Group. Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study. Lancet Public Health. 2020 Dec;5(12):e661-e671. doi: 10.1016/S2468-2667(20)30185-7.
• Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, Wessels AM, Shcherbinin S, Wang H, Monkul Nery ES, Collins EC, Solomon P, Salloway S, Apostolova LG, Hansson O, Ritchie C, Brooks DA, Mintun M, Skovronsky DM; TRAILBLAZER-ALZ 2 Investigators. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023 Aug 8;330(6):512-527. doi: 10.1001/jama.2023.13239.
• Louveau A, Plog BA, Antila S, Alitalo K, Nedergaard M, Kipnis J. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest. 2017 Sep 1;127(9):3210-3219. doi: 10.1172/JCI90603. Epub 2017 Sep 1.
• Zhang XX, Tian Y, Wang ZT, Ma YH, Tan L, Yu JT. The Epidemiology of Alzheimer's Disease Modifiable Risk Factors and Prevention. J Prev Alzheimers Dis. 2021;8(3):313-321. doi: 10.14283/jpad.2021.15.
• Jack CR Jr, Andrews JS, Beach TG, Buracchio T, Dunn B, Graf A, Hansson O, Ho C, Jagust W, McDade E, Molinuevo JL, Okonkwo OC, Pani L, Rafii MS, Scheltens P, Siemers E, Snyder HM, Sperling R, Teunissen CE, Carrillo MC. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024 Aug;20(8):5143-5169. doi: 10.1002/alz.13859. Epub 2024 Jun 27.
• 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.
• Kukreja-Pandey S, Al-Malak M, Ku Y, Duarte-Bateman D, Chen WF. D40. Effects of Lymphaticovenular Anastomosis in Contralateral Leg in Patients with Acquired Bilateral Leg Lymphedema. Plast Reconstr Surg Glob Open.2023;11(4S):81-82.
• 卢鸿瑞,谭云飞,谢庆平. 3D脱目镜下行颈深淋巴管-静脉引流术治疗老年认知障碍患者一例疗效初步观察. 中华显微外科杂志,2022,45(5):570-574.
• Zhang S, Qiu Q, Qian S, Lin X, Yan F, Sun L, Xiao S, Wang J, Fang Y, Li X. Determining Appropriate Screening Tools and Cutoffs for Cognitive Impairment in the Chinese Elderly. Front Psychiatry. 2021 Dec 2;12:773281. doi: 10.3389/fpsyt.2021.773281. eCollection 2021.
• Xie Q, Louveau A, Pandey S, Zeng W, Chen WF. Rewiring the Brain: The Next Frontier in Supermicrosurgery. Plast Reconstr Surg. 2024 Feb 1;153(2):494e-495e. doi: 10.1097/PRS.0000000000010933. Epub 2023 Jul 18. No abstract available.
• Da Mesquita S, Papadopoulos Z, Dykstra T, Brase L, Farias FG, Wall M, Jiang H, Kodira CD, de Lima KA, Herz J, Louveau A, Goldman DH, Salvador AF, Onengut-Gumuscu S, Farber E, Dabhi N, Kennedy T, Milam MG, Baker W, Smirnov I, Rich SS; Dominantly Inherited Alzheimer Network; Benitez BA, Karch CM, Perrin RJ, Farlow M, Chhatwal JP, Holtzman DM, Cruchaga C, Harari O, Kipnis J. Meningeal lymphatics affect microglia responses and anti-Abeta immunotherapy. Nature. 2021 May;593(7858):255-260. doi: 10.1038/s41586-021-03489-0. Epub 2021 Apr 28.
• 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.
• Winblad B, Amouyel P, Andrieu S, Ballard C, Brayne C, Brodaty H, Cedazo-Minguez A, Dubois B, Edvardsson D, Feldman H, Fratiglioni L, Frisoni GB, Gauthier S, Georges J, Graff C, Iqbal K, Jessen F, Johansson G, Jonsson L, Kivipelto M, Knapp M, Mangialasche F, Melis R, Nordberg A, Rikkert MO, Qiu C, Sakmar TP, Scheltens P, Schneider LS, Sperling R, Tjernberg LO, Waldemar G, Wimo A, Zetterberg H. Defeating Alzheimer's disease and other dementias: a priority for European science and society. Lancet Neurol. 2016 Apr;15(5):455-532. doi: 10.1016/S1474-4422(16)00062-4. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): July 15, 2026
• Primary Completion (Estimated): September 30, 2028
• Study Completion (Estimated): March 31, 2029

Study Registration Dates

• First Submitted: June 7, 2026
• First Submitted That Met QC Criteria: June 25, 2026
• First Posted (Actual): July 2, 2026

Study Record Updates

• Last Update Posted (Actual): July 2, 2026
• Last Update Submitted That Met QC Criteria: June 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Alzheimer; LVA; cervical lymph vessel/node-venous anastomosis
• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrocarbons; Hydrocarbons, Cyclic; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Piperidines; Indans; Indenes; Donepezil; Therapeutics
• Other Study ID Numbers: SH9H-2025-T549

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No