Hyperbaric Oxygen Therapy for Cognition in Diabetic Elderly at High Dementia Risk

Study Overview
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Brief Summary
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An urgent need exists to identify effective interventions to arrest or reverse dementia and cognitive loss at its earliest stages. The proposed pilot randomized clinical trial will investigate the short and long-term effects of hyperbaric oxygen therapy on cognitive functioning, cerebral blood flow, and glucose uptake in diabetic elderly with mild cognitive impairment. and provide the basis for a large-scale multi-center study of hyperbaric oxygen therapy effects on cognition in diabetes. The potential to preserve, or even enhance, cognition in elderly at high risk of cognitive decline and dementia has major implications for the affected individuals and their support systems that bear the social and financial burdens of long-term caregiving.

Detailed Description
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This resubmission responds to PAR-16-365-Pilot Clinical Trials for the Spectrum of Alzheimer's Disease and Age-related Cognitive Decline (R01). It will examine the efficacy of hyperbaric oxygen therapy (HBOT) in improving cognitive functioning in cognitively impaired elderly with diabetes (T2D), who have high risk for dementia. It is a collaboration of the Icahn School of Medicine at Mount Sinai, NY, the University of Wisconsin, the Sagol Center for Hyperbaric Medicine and Research at Asaf Harofeh Medical Center, Israel-one of the world's largest and busiest hyperbaric units-and the Sheba Medical Center, Israel. HBOT is a treatment in which oxygen-enriched air (up to 100%) is administered to patients at a pressure above the ambient atmosphere. The combined action of hyperoxia and hyperbaric pressure leads to significant improvements in tissue oxygenation, resulting in cerebrovascular benefits with improved ischemic damage and cerebral blood flow. Recently, the researchers of this group published compelling evidence from clinical trials indicating HBOT neurotherapeutic effects in stroke, with better cognitive function and elevated brain activity in SPECT. New preliminary data suggests potential neurotherapeutic effects of HBOT on T2D elderly with mild cognitive impairment (MCI), showing better cognitive performance and brain activity. The researchers propose a randomized controlled clinical trial examining the short (12 weeks) and long-term (12 months) efficacy of HBOT. The researchers will test hypotheses that HBOT compared to a sham condition improves cognitive function and increases cerebral blood flow and glucose utilization in MCI patients with T2D. Such patients are at high dementia risk and enriched in cerebrovascular disease, and thus have high potential for benefitting from HBOT. Aim 1 examines the potential beneficial effects of HBOT on cognition (with a primary composite measure of executive functions and episodic memory, both affected by T2D). Aim 2 examines effects of HBOT on ischemic injury which will be measured by CBF at the level of capillaries in gray matter (by MRI arterial spin labeling), and in macrovessels (by a novel 4D Flow MRI technology developed by the researchers of this group). Aim 3 focuses on effects of HBOT on cerebral glucose utilization using [F18]FDG-PET. Finally, Aim 4 investigates mediation by the biomarkers, i.e. whether their inclusion in a mediation model will attenuate the effect of HBOT on cognition, suggesting them as underlying mechanisms. This study will be performed in Israel, where there is optimal infrastructure and expertise for all the study components at significantly lower costs. HBOT can be widely deployed in the US so if successful, this pilot study will provide the basis for a multi-center large-scale clinical trial for definitive evidence of its benefits to cognition in T2D patients at high dementia risk. Despite advances in the understanding of risk factors and the pathologic basis for dementia, treatments are of very limited effects. As the proportion of elderly increases, the accelerating prevalence of T2D and dementia amplifies this application's public health impact.

Official Title
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Hyperbaric Oxygen Therapy for Cognition in Diabetic Elderly at High Dementia Risk

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Device: HBOT intervention
* Device: Sham intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of T2D Diagnosis of MCI > the age of 65 Hebrew fluency An informant Exclusion Criteria: Brain disease that affects cognition (e.g. Parkinson's disease, schizophrenia). Stroke Epilepsy Chest pathology incompatible with HBOT Inner ear disease Claustrophobia Cholinesterase inhibitors Subjects with an indication for HBOT Counter-indication for MRI or PET Individuals with severe cataracts must have cataract operations before enrolling in the study

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HBOT intervention<br>The multiplace HBOT unit at Asaf Harofeh. The inside looks like an airplane, with comfortable chairs for 11 subjects and the nurse who stays throughout the session. The HBOT protocol is 90 minutes, 5 times/week, 60 sessions, 100% oxygen at 2 ATA with 5 minute air breaks every 30 minutes. | Device: HBOT intervention<br>* HBOT is a treatment in which oxygen-enriched air (up to 100%) is administered to patients at a pressure. HBOT intervention arm - 3 months of HBOT treatment, 9 months observation all participants receive HBOT treatment for 3 months at year 2<br>* Other names: Hyperbaric oxygen therapy;|
| Sham Comparator: Sham intervention<br>Except for pressure, all the conditions of the HBOT intervention are provided in the sham intervention (nurse measures vitals and asks about health before entering the chamber, time in the chamber, number of sessions per week and overall, nurse in the chamber at all times, mask on the face, etc.). | Device: HBOT intervention<br>* HBOT is a treatment in which oxygen-enriched air (up to 100%) is administered to patients at a pressure. HBOT intervention arm - 3 months of HBOT treatment, 9 months observation all participants receive HBOT treatment for 3 months at year 2<br>* Other names: Hyperbaric oxygen therapy;Device: Sham intervention<br>* Sham was selected as the control condition rather than usual care to equate intervention groups with respect to other variables that could influence cognition and functional status, such as a new challenge (completing an activity program), peer socialization, and attention from staff.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cognitive outcome | A balanced composite sum of z-scores of 4 executive function tests: (For Trails B, subjects draw lines connecting alternating numbers and letters; for Mazes, subjects draw lines from start to finish in mazes of increasing complexity; for Digit-Symbol, numbers and abstract symbols are paired in a legend, and subjects fill in the symbols for a series of numbers; and Category Fluency totals words for two categories, animals, and for fruit and vegetables. ) And 4 episodic memory tests (immediate and delayed recall - ADAS word list- Subjects read aloud 10 unrelated words on printed cards, and are asked to immediately recall as many as possible, in three learning trials. Delayed recall tests recall of the 10 words, after 15 minutes. Logical Memory subtest of the Wechsler Memory Scale-III is a paragraph recall test. The 1st story for immediate recall and for delayed recall, 15 minutes later will be used.) | baseline and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in secondary cognitive outcomes | The sum z-scores for 3 computer-based tests (not language dependent), developed through NIH; EXAMINER assessing executive abilities: http://examiner.ucsf.edu). | baseline and 12 months | 
| CDR-SB | Clinical Dementia Rating-Sum of Boxes (CDR-SB), which summarizes impairment in 6 domains (memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care) based on subject and informant interviews. Scores in each of these are combined to obtain a composite score ranging from 0 (no symptoms of dementia) through 3 (severe symptoms of dementia). | baseline and 12 months | 
| ADL questionnaire | The Barthel scale or Barthel ADL index used to measure performance in ADL with scoring from 0-20. A higher number is associated with a greater likelihood of being able to live at home with a degree of independence following discharge from hospital. | baseline and 12 months | 
| IADL questionnaire | The Lawton instrumental activities of daily living scale contains 8 items, with a summary score from 0 (low function) to 8 (high function). | baseline and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Cognition