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

Not Applicable

Completed

Conditions: Diabetes Mellitus

Registration Number: NCT03036254

Lead Sponsor: Icahn School of Medicine at Mount Sinai

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 155

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Change in Global Cognition Score	baseline, 12, weeks, 6 months and 12 months	This analysis involves 11 cognitive performance variables, each measuring a specific aspect of cognition. In general, higher scores indicate better performance (Digit Symbol measures processing speed, Semantic Fluency measures verbal fluency, Word Recall Task measures immediate verbal memory, Delayed Word Recall Test measures delayed verbal memory, and Recall Unit measures immediate and delayed story recall), except for two variables (Trail Making Test Part A measures processing speed, Trail Making Test Part B measures cognitive flexibility) that measure time (where higher values indicate worse performance). These variables are standardized using Z-scores, which allow for combining and comparing values across different scales. The standardized values (Z-scores) of all 11 measures are averaged to create the composite score. Full range of composite score is -1 to 1. Higher composite Z-score reflects better cognitive performance and more favorable outcomes.
Cerebral Blood Flow	baseline, 3 months, and 12 months	Cerebral blood flow (CBF) via arterial spin labeling magnetic resonance imaging (ASL-MRI). CBF is defined as the blood volume that flows per unit mass per unit time in brain tissue.
Whole Brain SUVr (FDG-PET)	Baseline, 12 weeks, 12 months	Measures how actively the brain uses glucose, highlighting areas with abnormal activity that may signal diseases like Alzheimer's. Dimmer areas suggest reduced activity seen in disorders like dementia.

Secondary Outcome Measures

Name	Time	Method
NIH Computerized Cognitive Test	Baseline, 12 weeks, 6 months, 12 months	The sum z-scores for 3 computer-based tests (not language dependent), developed through NIH; EXAMINER assessing executive abilities: http://examiner.ucsf.edu). Early in the study, it became clear that participants-older adults with significant frailty, multiple chronic conditions (average \>4 per participant), and high medication burden (mean \>5 medications)-were finding the assessment protocol burdensome. The protocol already required repeated cognitive testing, MRI, FDG-PET imaging, and other assessments, leading many participants to report fatigue and difficulty concentrating. To prioritize participant well-being, decision made not to add the NIH computerized cognitive tests. The existing paper-and-pencil battery was well-established, sensitive to cognitive changes, and adequately covered executive function and episodic memory. The NIH computerized cognitive test was never administered, and no data was collected at any time.
Alzheimer's Disease Cooperative Study-Activities of Daily Living - Prevention Questionnaire (ADL-PI)	baseline, 12 weeks, 6 months, and 12 months	ADL questionnaire Participant The ADL-PI was developed, comprising 15 ADL (e.g. managing medications, managing finances) and 5 physical function (e.g. shopping and meal preparation) questions. All responses relate to the 3 months prior to the time of rating. Total range 0-30, higher scores indicate greater impairment.
Clinical Dementia Rating-Sum of Boxes (CDR-SB)	baseline, 12, weeks, 6 months and 12 months	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). Total scale from 0-18. Higher scores indicating worse cognitive status.
Beck Depression Inventory (BDI)	baseline, 12 weeks, 6 months and 12 months	This is a 21-item, self-report questionnaire that measures attitudes and symptoms of depression during the last week (i.e. mood, feelings of hopelessness, failure, guilt, self-esteem, etc.). Each question has a set of at least four possible responses, ranging in intensity. Total scale 0-63. Higher scores indicate more severe symptoms of depression.
Total Mini-Mental State Examination (MMSE)	Baseline, 12 weeks, 6 months, and 12 months	Total range 0-30, higher scores indicate better cognitive function.
Alzheimer's Disease Cooperative Study-Activities of Daily Living - Mild Cognitive Impairment (ADCS-ADL MCI)	Baseline, 12 weeks, 6 months, and 12 months	ADL Informant This tool is based on caregiver's report to assess participants' abilities to perform basic and instrumental activities of daily living (ADLs) like bathing, walking and self-grooming. All responses should relate to the 4 weeks prior to the time of rating. Full Scale range from 0-53, higher score indicates more impairment for the participant.

Trial Locations

Locations (4): Icahn School of Medicine at Mount Sinai
🇺🇸
New York, New York, United States
University of Wisconsin
🇺🇸
Madison, Wisconsin, United States
Sheba Medical Center
🇮🇱
Ramat Gan, Israel
Assaf HaRofeh Medical Center
🇮🇱
Tzrifin, Israel
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States