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

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.

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