Alzheimer's Disease, Alzheimer's Disease (AD), Alzheimer Disease, Dementia Alzheimer's Type, Dementia Alzheimer Type
Conditions
Keywords
Alzheimer's Disease, Dementia, lymphatic surgery, lymphaticovenous anastomosis, lymphaticovenous bypass, cervical lymph node, meningeal lymphatic system, glymphatic system
Brief summary
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.
Interventions
PROCEDUREDeep cervical lymph node to venous bypass (DCLNV-BP)
Participants will under bilateral deep cervical lymph node to venous bypass procedure under general anaesthesia.
Sponsors
Changi General Hospital
Singapore General Hospital
National Neuroscience Institute
Vincent Tay Khwee Soon
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* 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; * Good family support for post-treatment care and rehabilitation; * Fit for general anaesthesia/deep sedation and surgery (ASA 1-2; excluding the diagnosis of Alzheimer's Disease).
Exclusion criteria
* 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; * Active infection or malignancy; * Any contraindications to surgery or lumbar puncture * Any contraindication to MRI/PET scan (eg. metallic implant that are not MRI-safe, known radiotracer allergy) * Experimental Alzheimer's Disease treatment within the past 6 months. • Current use of monoclonal antibodies treatment (eg. lecanemab/donanemab)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Basic Gait Assessment | Over 2 years | 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. |
| Quality of Life - Alzheimer's Disease (QoL-AD) | Over 2 years | 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. |
| Zarit Burden Score | Over 2 years | 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. |
| Basic and instrumental Activities of Daily Living | Over 2 years | 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. |
| Mini Mental State Examination | Over 2 years | 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. |
| Safety: Number of treatment-related adverse events | Over 2 years | Treatment related adverse events and postoperative side effects eg. anaesthetic complications, infection, seroma, nerve or vascular injuries, wound healing issues, death. |
| Montreal Cognitive Assessment | Over 2 years | 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) | Over 2 years | 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. |
| Neuropsychiatric Inventory (NPI) | Over 2 years | 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. |
| Geriatric Depression Scale-Short Form (GDS-SF) | Over 2 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Magnetic Resonance Imaging (MRI) of the Brain | Over 1 year | 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 | Over 3 months | 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). |
| Fluid biomarkers | Over 1 year | 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 \[Optional\]. |
Countries
Singapore
Contacts
Primary ContactVincent KS Tay, MD, FAMS
Backup ContactJeremy MF Sun, MBBS, FAMS
Outcome results
None listed