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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
216
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.
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.
Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University
Shanghai, Huangpu, China
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.
Time frame: Baseline and Month 12
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: During surgery
Concentration of Interleukin-2 in Intraoperatively Collected Lymphatic Fluid
The concentration of interleukin-2 (IL-2) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).
Time frame: 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).
Time frame: 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).
Time frame: During surgery
Concentration of Interleukin-12 p70 in Intraoperatively Collected Lymphatic Fluid
The concentration of interleukin-12 p70 (IL-12p70) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).
Time frame: 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).
Time frame: 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).
Time frame: During surgery
Concentration of Interleukin-17 in Intraoperatively Collected Lymphatic Fluid
The concentration of interleukin-17 (IL-17) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).
Time frame: 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).
Time frame: 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).
Time frame: During surgery
Concentration of Interleukin-5 in Intraoperatively Collected Lymphatic Fluid
The concentration of interleukin-5 (IL-5) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).
Time frame: During surgery
Concentration of Interferon Alpha in Intraoperatively Collected Lymphatic Fluid
The concentration of interferon alpha (IFN-α) in lymphatic fluid collected intraoperatively, when available, will be measured (pg/mL).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-2 Level at Month 18
The concentration of interleukin-2 (IL-2) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-12p70 Level at Month 18
The concentration of interleukin-12 p70 (IL-12p70) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-17 Level at Month 18
The concentration of interleukin-17 (IL-17) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid IL-5 Level at Month 18
The concentration of interleukin-5 (IL-5) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.
Time frame: Baseline and Month 18
Change From Baseline in Cerebrospinal Fluid Interferon Alpha Level at Month 18
The concentration of interferon alpha (IFN-α) in cerebrospinal fluid will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Month 18
Change From Baseline in Plasma IL-2 Level at Month 18
The concentration of interleukin-2 (IL-2) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Month 18
Change From Baseline in Plasma IL-12p70 Level at Month 18
The concentration of interleukin-12 p70 (IL-12p70) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Month 18
Change From Baseline in Plasma IL-17 Level at Month 18
The concentration of interleukin-17 (IL-17) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Month 18
Change From Baseline in Plasma IL-5 Level at Month 18
The concentration of interleukin-5 (IL-5) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.
Time frame: Baseline and Month 18
Change From Baseline in Plasma Interferon Alpha Level at Month 18
The concentration of interferon alpha (IFN-α) in plasma will be measured in picograms per milliliter (pg/mL). The outcome measure is the change from baseline to Month 18.
Time frame: Baseline and Month 18
Ke Li
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