Alzheimer's disease (AD), one of the most common causes of dementia in Singapore and the developed world, is a neurodegenerative disorder with high socioeconomic impact. Accumulation of neurotoxic proteins (ie. amyloid, tau) are purported to lead to neuroinflammation, synaptic dysfunction and cognitive decline. The available pharmacotherapy provide limited symptomatic control, modest effect on disease progression with significant risk of side effects. Patients with AD eventually run out of effective pharmacotherapy and deteriorate.
Recent evidence implicated the glymphatic system, meningeal lymphatics of the brain, and downstream drainage to the cervical lymphatic system in the accumulation of neurotoxic proteins in AD. This presented the opportunity for extra-cranial intervention, and has since been demonstrated in preclinical models. Based on these development, Xie and colleagues pioneered the deep cervical lymph node to venous bypass (DCLNV-BP) procedure with very promising early outcomes. The observed improvement had been attributed to enhanced clearance of the neurotoxic proteins. Knowledge gap and clinical equipoise remain, and clinical trials are required to understand the safety, mechanism of action, patient selection, and long-term outcomes.
In this proof of concept study, the investigators aim to assess safety and preliminary efficacy of DCLNV-BP in AD. An approach using objective clinical assessments, biomarkers and neuroimaging, to assess safety, evaluate preliminary efficacy and elucidate the possible mechanism underlying the observed effects, is undertaken. Since there are limited effective treatment for AD, this procedure is potentially ground breaking if it proves to halt progression or even improve patients' cognition, function and behaviour. Indirectly, this will have enormous health economic benefit for Singapore and the developed world that is facing the silver tsunami. Findings from this pilot study will lay the groundwork for future trials and research collaboration in AD and other neurodegenerative diseases.
Diagnosis of mild-moderate Alzheimer's disease (based on NIA-AA criteria);
Mini-Mental State Examination (MMSE) score 10-22;
Both participants and caregiver are able to understand English or Mandarin
Ability to provide informed consent or have a legally authorised representative to provide informed consent;
Cognitive decline due to prior infection or autoimmune diseases;
History of major cerebrovascular events or significant cardiovascular diseases;
Inability to have the head turned passively by at least 40 degrees;
Previous neck lymph node surgery or irradiation;
Single group
Deep cervical lymph node to venous bypass (DCLNV-BP)
Procedure/SurgeryParticipants will under bilateral deep cervical lymph node to venous bypass procedure under general anaesthesia.
Safety: Number of treatment-related adverse events
Treatment related adverse events and postoperative side effects eg. anaesthetic complications, infection, seroma, nerve or vascular injuries, wound healing issues, death.
Mini Mental State Examination
Quick assessment of the cognitive domain. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 3; (3) PO day 7; (4) PO day 14; (5) PO 6 week; (6) PO 3 months; (7) PO 6 months; (8) PO 1 year; (9) PO 2 years.
Montreal Cognitive Assessment
Brief assessment of the cognitive domains, especially in mild cognitive impairment, for memory, visuospatial skills, executive function. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.
Clinical Dementia Rating (CDR)
Assessment administered to the participant and caregiver to test various cognitive domains (ie. orientation, attention and working memory, memory, visuospatial, language, executive function) and activities of daily living. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.
Fluid biomarkers
Blood plasma and cerebrospinal fluids will be analysed for biomarkers related to Alzheimer's disease, neurodegeneration and lymphatic dysfunction. Blood plasma will be sampled at (1) Operative day; (2) Postoperative(PO) day 3; (3) PO day 7; (4) PO day 14; (5) PO 6 weeks; (6) PO 3 months; (7) PO 6 months; (8) PO 1 year. CSF will be sampled at (1) Operative day; (2) PO day 7; (3) PO 6 weeks \[Optional\]; (4) PO 3 months \[Optional\].
Magnetic Resonance Imaging (MRI) of the Brain
Participants will undergo pre- and post-intervention MRI of the brain for evaluation of neuroanatomical pathology and surrogate markers of glymphatic function (eg. DTI-ALPS). The scans will be performed at (1) Baseline, (2) Postoperative Day 7, (3) Postoperative 3 months.
Positron Emission Tomography (PET) of the brain
Participants will undergo pre- and post-intervention PET fluorodeoxyglucose (FDG) brain scan to provide functional spatial information on changes before and after the surgery (at 3 months).
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Vincent Tay Khwee Soon
Lead sponsor
Changi General Hospital
Sponsor institution
Changi General Hospital
Collaborator
Singapore General Hospital
Collaborator
National Neuroscience Institute
Collaborator
