Restoring Cervical Lymphatic Drainage in Alzheimer's Disease

NCT07854327 | Recruiting DMC

• 1 other identifier: LymphDAD
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with the accumulation of abnormal proteins, including amyloid-beta and tau, in the brain. Recent evidence suggests that the glymphatic and meningeal lymphatic systems, which contribute to the removal of waste products from the brain, may play a role in AD. In particular, impaired drainage through the deep cervical lymphatic system may contribute to the accumulation of disease-related proteins. The LymphDAD study is a prospective, single-center pilot study designed to explore whether surgically improving cervical lymphatic drainage may be associated with changes in biological markers, brain imaging, and cognitive and clinical measures in selected patients with AD who are not eligible for currently available disease-modifying treatments. Five participants with AD will undergo a minimally invasive microsurgical procedure called lymphovenous anastomosis (LVA), in which small cervical lymphatic vessels are connected to nearby small veins to facilitate lymphatic drainage. During the procedure, a small sample of lymphatic fluid will also be collected for exploratory analysis of amyloid-beta and tau proteins. Participants will undergo clinical and neuropsychological assessments, blood sampling, magnetic resonance imaging (MRI), and amyloid positron emission tomography (PET) before the procedure and during follow-up. Follow-up assessments will be performed at 1, 3, 6, and 12 months after surgery. The study is exploratory and is not designed to demonstrate a definitive clinical benefit. Its primary purpose is to obtain preliminary information on the feasibility, safety, and possible biological and clinical effects of cervical LVA in AD, which may support the design of future controlled studies.

Conditions

Alzheimer; Alzheimer Dementia (AD)

Keywords

Alzheimer Disease; Alzheimer Dementia; Lymphovenous Anastomosis; Cervical Lymphatic Drainage; Deep Cervical Lymphatic System; Glymphatic System; Meningeal Lymphatics; Lymphovenous Bypass; Amyloid Beta; Tau

Outcome Measures

Primary Outcomes (3)

• Change from baseline in plasma amyloid-beta concentrations

  Change from baseline in plasma amyloid-beta 42 (Aβ42) and amyloid-beta 40 (Aβ40) concentrations following cervical lymphovenous anastomosis (LVA).

  Baseline, 1 month, and 6 months after LVA

• Change from baseline in plasma phosphorylated tau concentrations

  Change from baseline in plasma phosphorylated tau 181 (p-tau181) and phosphorylated tau 217 (p-tau217) concentrations following cervical LVA.

  Baseline, 1 month, and 6 months after LVA

• Change from baseline in plasma NfL and GFAP concentrations

  Change from baseline in plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) concentrations following cervical LVA.

  Baseline, 1 month, and 6 months after LVA

Secondary Outcomes (5)

• Change from baseline in Mini-Mental State Examination score

  Baseline to 3, 6, and 12 months after LVA

• Change from baseline in Montreal Cognitive Assessment score

  Baseline to 3, 6, and 12 months after LVA

• Change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale score

  Baseline to 3, 6, and 12 months after LVA

• Change from baseline in Neuropsychiatric Inventory score

  Baseline to 3, 6, and 12 months after LVA

• Change from baseline in Clinical Dementia Rating score

  Baseline to 3, 6, and 12 months after LVA

Other Outcomes (6)

• Change from baseline in hippocampal volume on magnetic resonance imaging

  Baseline and 6 months after LVA

• Change from baseline in cortical gray-matter volume on magnetic resonance imaging

  Baseline and 6 months after LVA

• Change from baseline in amyloid PET standardized uptake value ratio

  Baseline and 6 months after LVA

Study Arms (1)

Cervical Lymphovenous Anastomosis (LVA)

EXPERIMENTAL

Participants in this single-arm pilot study will undergo cervical lymphovenous anastomosis (LVA), a minimally invasive supermicrosurgical procedure intended to enhance cervical lymphatic drainage. Patent cervical lymphatic vessels will be connected to small-caliber cervical venous branches under high magnification, with indocyanine green (ICG) fluorescence lymphography used to identify lymphatic vessels and assess anastomotic flow. A small sample of lymphatic fluid will be collected intraoperatively for exploratory analysis of amyloid-beta and tau biomarkers. Participants will continue standard-of-care treatment for Alzheimer's disease and other comorbidities throughout the study.

Procedure: Cervical lymphovenous anastomosis (LVA)

Interventions

Cervical lymphovenous anastomosis (LVA) PROCEDURE

Microsurgical restoration of cervical lymphatic drainage by connecting patent lymphatic channels to small-caliber cervical venous branches. The procedure is performed along the posterior edge of the sternocleidomastoid muscle using supermicrosurgical techniques. Indocyanine green (ICG) fluorescence lymphography is used to identify lymphatic vessels and assess anastomotic flow. A small sample of lymphatic fluid is collected intraoperatively from a lymphatic channel already exposed during the procedure for exploratory analysis of amyloid-beta and tau biomarkers.

Cervical Lymphovenous Anastomosis (LVA)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of Alzheimer's disease according to NIA-AA 2024 criteria.
• Not eligible for other disease-modifying therapies.
• Ability to personally provide written informed consent after clinical evaluation -of decisional capacity.

You may not qualify if:

• Coagulopathy or active infection of the head and neck region.
• Prior extensive cervical lymph node dissection or radiotherapy.
• Uncontrolled systemic disease or contraindication to general anesthesia.
• Participation in another interventional trial within the previous 3 months.
• Known hypersensitivity or allergy to indocyanine green.
• Evidence of alternative or concomitant causes of cognitive decline other than Alzheimer's disease, such as subdural hematoma, primary or metastatic brain malignancy, or normal-pressure hydrocephalus.
• Current or recent treatment with immunosuppressive or immunomodulatory therapy within the previous 3 months.
• Clinically significant infectious disease within the previous 6 months.
• Severe psychiatric disorder that could interfere with cognitive assessment or study participation.
• Pregnancy or breastfeeding.
• End-stage malignant disease with an estimated life expectancy of less than 6 months.
• History indicative of systemic autoimmune disease.
• Inability to personally provide valid informed consent.

Sponsors & Collaborators

• University of Siena: lead

Study Sites (1)

Azienda Ospedaliera Universitaria Le Scotte

Siena, Tuscany, 53100, Italy

RECRUITING

Related Publications (1)

• Imholz C, Schaller C, Watson JA, Zurfluh CE, Grigorean A, Lindenblatt N. Robotic-assisted lymphovenous anastomosis to treat periorbital lymphedema and systematic review of lymphatic reconstruction of face and neck lymphedema. J Robot Surg. 2025 Jul 12;19(1):380. doi: 10.1007/s11701-025-02552-6. Xie Q, Pak CJ, Kwon J, Chao SC, Hong JP . Potential Role of Lymphovenous Bypass in Mitigating Alzheimer's Disease Dementia. Arch Plast Surg. 2025 Jul 23;52(4):247-252. doi: 10.1055/a-2627-9243. Chen JY, Zhao DW, Yin Y, Gui L, Chen X, Wang XM, Wang PB, Zuo CH, Lai ZP , Li C, Wang R, Xian JS, Chen Z, Feng H, Hu R. Deep cervical lymphovenous anastomosis (LVA) for Alzheimer's disease: microsurgical procedure in a prospective cohort study. Int J Surg. 2025 Jul 1;111(7):4211-4221. doi: 10.1097/JS9.0000000000002490. Ma X, Wang F, Wang G, Zhao M, Zheng Y, Guo Y, Wu J, Liu Y, Liu Y, He G, Ren L, Gong Z, Wang J, Chen L, Hu S, Chu Q, Li Z, Wu J, Li R, Zhang X, Shi Q, Lian H, Ye J. A surgical therapy for Alzheimer's disease with lymphaticovenular anastomosis. J Alzheimers Dis Rep. 2025 Oct 3;9:25424823251384244. doi: 10.1177/25424823251384244. Tang C, Zheng X, Li H, Wang B, Zheng Y, Song W, Wu A, Xin L, Zhang D, Yang R, Du S, He P , Li Y, Wu L, Wang X, Shi Q, Bernardes GJL. Deep cervical lymphatic-venous anastomosis in dementia: a clinical and mechanistic evaluation. Int J Surg. 2025 Dec 17. doi: 10.1097/JS9.0000000000004561. Wu C, Yuan J, Tian Y, Wang Y, He X, Zhao K, Huang J, Jiang R. Tauopathy after long-term cervical lymphadenectomy. Alzheimers Dement. 2025 Apr;21(4):e70136. doi: 10.1002/alz.70136. Jessup M, Iglesias NJ, Tadisina KK, Xu K, Mella-Catinchi J, Pinchuk L, Singh D, Tse DT, Nayak VV, Coelho PG. The emerging role of biomaterial applications in cerebral lymphatic surgical interventions: A narrative review. Biomater Biosyst. 2025 Aug 9;19:100117. doi: 10.1016/j.bbiosy.2025.100117. Hong JP , Chen WF, Nguyen DH, Xie Q. A Proposed Role for Lymphatic Supermicrosurgery in the Mana

  BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease; Plaque, Amyloid; Pick Disease of the Brain

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Frontotemporal Dementia; Frontotemporal Lobar Degeneration

Study Officials

• Paolo Gennaro, Professor

  University of Siena, Department of Biotechnology

  STUDY CHAIR

• Domenico Plantone, Professor

  University of Siena, Department of Neurology

  PRINCIPAL INVESTIGATOR

• Federica Orsini, MD

  University of Siena, Department of Nuclear Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andrea Frosolini, MD

CONTACT

3939447318; andreafrosolini@gmail.com

Carlo Manco, MD

CONTACT

3460221117; carlooo95.CM@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: Professor

Study Record Dates

• First Submitted: August 19, 2026
• First Posted: October 2, 2026
• Study Start: July 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): December 31, 2028
• Last Updated: October 2, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)