Hyperbaric Oxygen Therapy for Prodromal Alzheimer´s Disease With Cerebrovascular Disease

Hyperbaric Oxygen Therapy for Prodromal Alzheimer´s Disease With Cerebrovascular Disease: A Prospective, Randomized, Double Blind Study

Alzheimer´s disease is a devastating illness that effects the patients as well as their family members. Its prevalence increases exponentially and the burden on the healthcare system is enormous. AD neuropathology begins 15-20 years before the occurrence of cognitive symptoms, which ranges from preclinical stage to mild cognitive impairment (MCI) to dementia. Prodromal AD is an early stage of the disease which is characterized by positive biomarkers and MCI. To this day, there is no medication that can cure or halt the progression of the disease and most studies focus on finding reversible risk factors and changing their influence. Several aetiologies have been proposed, like the deposition of amyloid and tau proteins, neuroinflammation and cerebral ischemia due to cerebrovascular factors. The Amyloid deposition, which serves as the biological marker of AD, was originally thought to be the main cause of the disease, however, recent data suggests that it is not the cause and that it might actually has a protective role. On the other hand, it is known today that vascular changes with related tissue ischemia and neuroinflammation have a crucial role in the development of AD in many patients. These pathologies, ischemia & neuroinflammation, can be improved by the use of hyperbaric oxygen therapy (HBOT). The goal of this study is to explore the potential beneficial effect of HBOT on prodromal AD.

Study Overview

• Status: Recruiting
• Conditions: Mild Cognitive Impairment; Prodromal Alzheimer's Disease; Vascular Cognitive Impairment; Cerebral Vascular Disorder
• Intervention / Treatment: Device: Sham; Device: Hyperbaric oxygen therapy

Detailed Description

Alzheimer disease is characterised by cognitive, mental and functional disability that is expected to progress until the patient is fully dependent on others for activities of daily living. The pathology begins many years until the cognitive symptoms appear. Prodromal Alzheimer's disease is a state where a person has mild cognitive impairment and Amyloid deposition, which is seen on brain Amyloid PET or in lumbar puncture.

To date, there has been neither a cure nor a therapy that can significantly halt or relieve symptoms for most patients.

This study offers a new biological therapeutic approach aimed to induce neuroplasticity and improve neurological and cognitive functions. Pre -clinical as well as clinical data indicate that HBOT can be beneficial for those patients who suffer from MCI due to Alzheimer's disease and also to patients with cerebral vascular disease.

HBOT is a well-known treatment used in clinical practice for other indications and is considered to be safe with relative rare mild and reversible side effect .The study is designed as a prospective, randomized, sham controlled double blinded study.

Subjects will be enrolled up to a total of 100 subjects, age 60-85, diagnosed with MCI and positive Amyloid PET and vascular changes on brain MRI.

Eligible patients will be randomized to the two study groups at a ratio of 6:6 (in clusters of 6 patients). The HBOT/sham treatment includes 60 daily sessions of 90 minutes each, five days per week. After the treatment period, there will be a maintenance period of HBOT/sham sessions twice a week for 6 months. All assessments with be done on baseline, after the treatment period and after the maintenance period.

The primary endpoint includes improvement in cognitive scores in neurocognitive evaluations (Neurotrax). Secondary and tertiary endpoints include changes in cognitive, physiological, physical, imaging, lab tests and self report questionaires.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Karin Elman Shina, MD; Phone Number: 0097289778061; Email: karine@shamir.gov.il

Study Locations

• Israel
  • Zerifin, Israel, 70300
    • Recruiting
    • Shamir Medical Center (Assaf Harofeh)
    • Contact: Karin Elman Shina, MD; Email: karine@shamir.gov.il

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of Mild cognitive impairment (MCI) due to AD or mixed AD and vascular dementia pathology
2. MMSE score of 20 and above
3. Stable psychological and pharmacological treatment for more than three months prior to inclusion.
4. Caregiver that is seeing the patient at least twice per week and is willing to participate and accompany the patient and fill questionnaires
5. Subject willing and able to read, understand and sign an informed consent

Exclusion Criteria:

1. Inability to attend scheduled clinic visits and/or comply with the study protocol
2. History of traumatic brain injury, brain tumors, brain surgery, chronic subdural haemorrhages, Epilepsy
3. Active malignancy
4. Substance use at baseline, except for prescribed cannabis if vaporized or taken PO as tincture
5. History of other neurodegenerative diseases including Parkinson's disease (PD), Lewy body dementia (LBD), Frontotemporal dementia (FTD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Creutzfeld Jacob disease (CJD), Multisystem atrophy (MSA), Pseudobulbar palsy (PSP), Corticobasal degeneration (CBD), Wernicke Korsakoff syndrome
6. Chronic use of medications that may compromise cognitive function and cannot be stopped: Anticonvulsants, Anticholinergics, antiparkinsonian, corticosteroids, Benzodiazepines
7. Moderate to severe sleep apnea with no use of CPAP
8. Diagnosis of a psychiatric disorder including: major depression, schizophrenia, bipolar disorder
9. Serious suicidal ideation
10. Renal or liver insufficiency, electrolyte imbalances
11. Chronic heart failure with ejection fraction of 35 or less
12. HBOT for any reason prior to study enrolment
13. Chest pathology incompatible with pressure changes (including active asthma or COPD)
14. Ear or Sinus pathology incompatible with pressure changes (above 3 otolaryngologist visits a year)
15. An inability to perform an awake brain MRI or Amyloid PET
16. An inability to perform computerized cognitive tests (Neurotrax)
17. MMSE score below 20
18. No evidence of amyloid in the brain PET
19. No evidence of vascular related lesions in the brain MRI
20. Active smoking
21. Participation in another study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hyperbaric Oxygen Therapy active arm; The protocol comprises of 60 consecutive hyperbaric oxygen treatment (HBOT) sessions, 5 sessions per week within a three months' period. Then there will be a maintenance period for 6 months in which the participants will receive HBOT twice a week.	Device: Hyperbaric oxygen therapy; Each session will include exposure of 90 minutes to 100% at 2 ATA, with 5 minutes air breaks every 20 minutes
Sham Comparator: Sham active arm; The protocol comprises of 60 consecutive Sham sessions, 5 sessions per week within a three months' period. Then there will be a maintenance period for 6 months in which the participants will receive Shan sessions twice a week.	Device: Sham; Each session will include exposure of 90 minutes to 21% at 1.2 ATA during the first five minutes of the session with the noise of circulating air, and then decrease slowly during the next five minutes to 1.03 ATA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline of neurocognitive functions evaluation by Mindstreams cognitive battery test (Neurotrax)	Memory, attention and information process will be evaluated using the NeuroTrax computerized cognitive evaluation battery.	At baseline, 3 months
Change from baseline of neurocognitive functions evaluation by Mindstreams cognitive battery test (Neurotrax)	Memory, attention and information process will be evaluated using the NeuroTrax computerized cognitive evaluation battery.	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain amyloid PET using Flumetamol (Vizamyl) tracer	Brain amyloid assessment using PET scan with Flumetamol (Vizamyl) tracer will be used to assess change in amyloid burden	At baseline, 3 months, 9 months
Whole-brain quantitative perfusion imaging	Whole-brain quantitative perfusion imaging will be performed using Dynamic susceptibility contrast (DSC)-MRI technique	At baseline, 3 months, 9 months
Brain microstructure MRI evaluation	Fractional anisotropy (FA) and Mean diffusivity (MD) will be evaluated using diffusion tensor imaging (DTI) MRI protocol	At baseline, 3 months, 9 months
Brain volume MRI evaluation	Gray matter and hippocampal volumetric measurement using high-resolution MP-RAGE 3D MRI	At baseline, 3 months, 9 months
Brain functional connectivity imaging	Resting state functional MRI	At baseline ,3 months, 9 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life SF-36 questionnaire	Self reported SF-36 quality of life questionnaire	At baseline, 3 months, 9 months
The Pittsburgh Sleep Quality Index (PSQI) questionnaire	Self reported quality of sleep questionnaire	At baseline, 3 months, 9 months
The Depression, Anxiety and Stress Scale-21 (DASS-21)	Self reported questionnaire of depression, anxiety and stress	At baseline, 3 months, 9 months
Advanced Activities of Daily Function (a-ADL)	Questionnaire of activities of daily living for the patient and the informant	At baseline, 3 months, 9 months
Clinical Dementia Rating (CDR) scale - sum of boxes	Cognitive assessment of 6 cognitive and functional domains, based on an interview of the patient and a reliable informant	At baseline, 3 months, 9 months
Montreal Cognitive Assessment (MOCA)	Neurocognitive assessment	At baseline, 3 months, 9 months
Mini Mental State Exam (MMSE)	Neurocognitive assessment	At baseline, 3 months, 9 months
Serum inflammatory markers	Serum inflammatory markers include: IL-1, IL-6, tumor necrosis factor-alpha, hsCRP	At baseline, 3 months, 9 months
Alzheimer's disease (AD) biomarkers: Abeta 42/40	Plasma will be tested for Abeta 42/40	At baseline, 3 months, 9 months
Alzheimer's disease (AD) biomarkers: P-tau181	Plasma will be tested for P-tau181	At baseline, 3 months, 9 months
Alzheimer's disease (AD) biomarkers: P-tau231	Plasma will be tested for P-tau 231	At baseline, 3 months, 9 months
Alzheimer's disease (AD) biomarkers: neurofilament light (NfL)	Plasma will be tested for neurofilament light (NfL)	At baseline, 3 months, 9 months
Alzheimer's disease (AD) biomarkers: plasma glial fibrillary acidic protein (GFAP)	Plasma will be tested for plasma glial fibrillary acidic protein (GFAP)	At baseline, 3 months, 9 months
Vascular biomarker- Vascular endothelial growth factor (VEGF)	Serum will be tested for VEGF	At baseline, 3 months, 9 months
Passive behavioral monitoring using BHQ smartphone application	An application will be installed on the participants' smartphones for continuous passive monitoring of human behavior	Through study completion, up to one year
Cardiopulmonary exercise test (CPET)	CPET determines the anaerobic threshold that is expected to change through the intervention	At baseline, 3 months, 9 months
Neuro-physical evaluation - Static balance	Static balance will be assessed by the Balance Error Scoring System (BESS)	At baseline, 3 months, 9 months
Neuro-physical evaluation- Timed Up and Go test	Dynamic balance and risk of falling will be assessed by the Timed Up and Go test (TUG)	At baseline, 3 months, 9 months
Neuro-physical evaluation - 10 meter walk	Dynamic balance and risk of falling will be assessed by 10-meter walk (10MW).	At baseline, 3 months, 9 months
Neuro-physical evaluation - Sit to Stand test	Muscle function will be assessed by the sit to stand (STS) test for the leg strength and endurance	At baseline, 3 months, 9 months
Neuro-physical evaluation - Hand held dynamometery	Muscle function will be assessed by the hand-held dynamometry (HHD) for the isometric grip strength.	At baseline, 3 months, 9 months
Neuro-physical evaluation - 6 minute walk	The sub-maximal aerobic capacity and endurance will be assessed by the 6-minute walk test (6MWT).	At baseline, 3 months, 9 months
Event-related synchronization (ERS) change - EEG	The EEG will include a three-level visual N-back task, and go-no-go task	At baseline, 3 months, 9 months
Event-related desynchronization (ERD) change - EEG	The EEG will include a three-level visual N-back task, and go-no-go task	At baseline, 3 months, 9 months
Grand average P300 ERP change - EEG	The EEG will include a three-level visual N-back task, and go-no-go task	At baseline, 3 months, 9 months
Alpha band power change - EEG	The EEG will include a three-level visual N-back task, and go-no-go task	At baseline, 3 months, 9 months
Beta band power change - EEG	The EEG will include a three-level visual N-back task, and go-no-go task	At baseline, 3 months, 9 months
Gamma band power change - EEG	The EEG will include a three-level visual N-back task, and go-no-go task	At baseline, 3 months, 9 months
Delta band power change - EEG	The EEG will include a three-level visual N-back task, and go-no-go task	At baseline, 3 months, 9 months
Theta to alpha bands power ratio change - EEG	The EEG will include a three-level visual N-back task, and go-no-go task	At baseline, 3 months, 9 months
N-back match/no match percentage change - EEG	The EEG will include a three-level visual N-back task, and go-no-go task	At baseline, 3 months, 9 months

Collaborators and Investigators

• Sponsor: Assaf-Harofeh Medical Center
• Investigators: Principal Investigator: Karin Elman Shina, MD, Senior Neurologist and director of the neuropsychology and physiology unit

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2022
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: March 21, 2022
• First Submitted That Met QC Criteria: April 24, 2022
• First Posted (Actual): April 27, 2022

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Cardiovascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Vascular Diseases; Alzheimer Disease; Cognitive Dysfunction; Cerebrovascular Disorders
• Other Study ID Numbers: 254-21-ASF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No