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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
10
Participants will under bilateral deep cervical lymph node to venous bypass procedure under general anaesthesia.
Changi General Hospital
Singapore, Singapore
RECRUITINGSafety: 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.
Time frame: Over 2 years
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.
Time frame: Over 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.
Time frame: Over 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.
Time frame: Over 2 years
Neuropsychiatric Inventory (NPI)
A comprehensive assessment of neuropsychiatric symptoms in patients with dementia, specifically behavioral changes, and administered to the main caregiver over about 5 minutes. 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.
Time frame: Over 2 years
Geriatric Depression Scale-Short Form (GDS-SF)
This assessment will take 5-7 minutes and will be administered to the participant to measure depressive symptoms. 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.
Time frame: Over 2 years
Quality of Life - Alzheimer's Disease (QoL-AD)
This assessment will take 5-10 minutes and will be administered to the participant to measure Quality of Life measures in AD. 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.
Time frame: Over 2 years
Zarit Burden Score
This assessment will take take 5-10 minutes and will be administered to the main caregiver to ascertain changes in caregiver burden.. 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.
Time frame: Over 2 years
Basic and instrumental Activities of Daily Living
This evaluation checklist will take under 5 minutes to assess participant's function status. 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.
Time frame: Over 2 years
Basic Gait Assessment
Basic gait assessment will be performed including (A) Gait Speed, (B) Timed up and go test, (C) 5X sit to stand test. 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.
Time frame: Over 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 \[Optional\].
Time frame: Over 1 year
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.
Time frame: Over 1 year
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).
Time frame: Over 3 months
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