Hyperbaric Oxygen Therapy for Cognition in Diabetic Elderly at High Dementia Risk
Phase: NA
Conditions: Diabetes Mellitus
Sponsor: Icahn School of Medicine at Mount Sinai

Hyperbaric Oxygen Therapy for Cognition in Diabetic Elderly at High Dementia Risk 
PI: Michal Beeri, MD
NCT03036254
Document Date: 5/21/2020

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This is a resubmission of an application responding to “PAR-16-365-Pilot Clinical Trials for the Spectrum 
of Alzheimer’s Disease and Age-related Cognitive Decline (R01)”. It examines the efficacy of hyperbaric oxygen 
therapy (HBOT) in improving cognition in cognitively impaired elderly with type 2 diabetes (T2D), who have high 
dementia risk. It is a collaboration of the Icahn School of Medicine at Mount Sinai, NY, the University of 
Wisconsin, Madison WI, the Sagol Center for Hyperbaric Medicine and Research at Asaf Harofeh Medical 
Center, Israel—one of the largest hyperbaric units worldwide, treating over 100 patients daily—and the Sheba 
Medical Center, Israel (8 miles from Asaf Harofeh).  
HBOT is a treatment in which oxygen-enriched air (up to 100%) is administered to patients in a chamber 
at a pressure above one atmosphere absolute (1ATA), the ambient atmospheric pressure. The combined action 
of hyperoxia and hyperbaric pressure leads to significant improvements in tissue oxygenation, resulting in 
benefits to the cebrovascular milieu, with improvements in ischemic damage and cerebral blood flow (CBF). 
Recently, our group published compelling evidence from clinical trials indicating HBOT neurotherapeutic effects 
in stroke, with improved cognitive function and elevated brain activity in SPECT. Additionally, our preliminary 
data showing better cognitive performance and brain activity in T2D subjects with mild cognitive impairment 
(MCI) suggests potential HBOT neurotherapeutic effects,.  
Elderly with T2D have higher risk of developing dementia, MCI, and cognitive decline. T2D is a vascular 
disease culminating in tissue hypoxia, so cerebrovascular disease is the primary contributor to this increased 
risk. Impairment of cerebrovascular integrity in T2D may lead to reduced CBF on the vessel level, and reduced 
glucose metabolism on the neuronal level, which may be rectified with HBOT by cerebral vascular repair 
processes. We thus propose a randomized controlled trial (RCT) of the beneficial effects of HBOT on cognition 
and on ischemic injury (through assessment of CBF using MRI, and of glucose metabolism using FDG-PET). 
We focus on T2D elderly with MCI, who are enriched in cerebrovascular disease and are in the prodromal phase 
of the dementia process, an ideal opportunity for HBOT to protect and enhance cognition by reversing, 
preventing, or delaying neuropathologic processes that cause cognitive decline. We will test the extent to which 
60 sessions of 90 minutes of 100% oxygen at 2 ATA—compared with a sham condition—improve cognitive 
performance in the short term (immediately after treatment) and a longer term (12 months after treatment). 
Subjects will be recruited through talks in the community, advertisements, and companies which have large lists 
of elderly interested in receiving emails about health related topics.  In addition, we have a large-scale project in 
Israel (NIA R01AG034087), where 1200 T2D elderly are followed for cognitive decline providing an additional 
large recruitment source.  
We hypothesize that HBOT compared to a sham condition (n=77 in each group) improves cognitive function and 
favorably alters cerebrovascular pathology (increasing CBF and glucose utilization) in T2D patients with MCI, 
focusing on the following outcomes: 
Aim 1. Cognitive functioning: Aim 1a: The primary outcome will be a composite measure of cognitive function 
balancing tests of both executive and memory function. Domain-specific measures of cognition (executive 
function and episodic memory) will be secondary outcomes.  

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Aim 2. Ischemic Injury: CBF at the level of capillaries in gray matter measured by MRI arterial spin labeling, 
and in macrovessels, measured by a novel 4D Flow MRI technology developed by our group. 
Aim 3. Neuronal function: [F18]FDG-PET measuring cerebral glucose utilization. 
Aim 4. Mediation by brain biomarkers. To examine whether CBF and glucose utilization mediate HBOT effects 
on cognitive function. Hypothesis: inclusion of the biomarkers in a mediation model will attenuate the effect of 
HBOT on cognition, suggesting them as underlying mechanisms.  
 
We propose an RCT examining the short and long-term efficacy of HBOT, a therapy with strong biological 
plausibility for affecting beneficially impaired cognition through vascular mechanisms, in elderly with T2D-related 
MCI, who are enriched in cerebrovascular disease and are at high dementia risk. We focus on both cognitive 
and biomarker outcomes, providing context for identifying relevant mechanisms, and explore factors associated 
with HBOT efficacy, suggesting subgroups who may most benefit from the therapy. The study will be performed 
in Israel, with 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. With 
the current lack of effective treatments for dementia while the proportion of elderly increases, the accelerating 
prevalence of T2D and dementia amplify this application’s public health impact. 
 
B. SIGNIFICANCE 
B1. The urgent need for therapies for dementia- An urgent need exists to identify effective interventions to arrest 
or reverse dementia at its earliest stages. Mild cognitive disturbances and pathophysiologic changes associated 
with dementia can precede clinical symptoms by more than a decade. Mild cognitive impairment (MCI), 
characterized by mild memory loss and/or mild executive dysfunction, is the presumed prodrome of clinical 
dementia. The greatest risk factor for cognitive impairment is age; currently 13% of the US population is over 65, 
but they are projected to increase by 115% in 40 years1. This group has the largest health care expenditures. 
Recent estimates of MCI prevalence are 10% in 70 year-olds, 20% in 80 year-olds, and as high as 40% in 85 
year-olds2. Enhancing or preserving cognition in elderly at high risk of cognitive decline and dementia would 
have enormous benefits for the affected individuals, and their support systems that bear the social and financial 
burdens of long-term care. However, studies of pharmaceutical interventions to prevent or arrest cognitive 
decline in MCI—such as cholinesterase inhibitors, vitamins, anti-inflammatories, anti-hypertensives, and 
statins—have been largely negative3-7. A major challenge in understanding and treating cognitive decline and 
dementia is the lack of a firm relationship between cognitive outcomes and targeted neurobiological 
mechanisms. For example, clinical trials with amyloid-reducing agents have succeeded at target engagement, 
but failed to cause clinical benefit for Alzheimer’s disease (AD). Thus, novel disease modifying strategies—such 
as hyperbaric oxygen therapy (HBOT)—with strong biological plausibility to benefit cognition in aging, must be 
investigated. 

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B2. The primary underlying mechanism for HBOT benefits on cognition is cerebrovascular- HBOT is a treatment 
in which oxygen-enriched air (up to 100%) is administered to patients in a chamber at a pressure above one 
atmosphere absolute (1ATA), which is the ambient atmospheric pressure. For the peripheral vasculature, a well-
accepted indication of HBOT is hypoxia-induced foot ulcers; there is broad evidence suggesting significant 
improvements through stimulation of vessel repair processes and angiogenesis8, 9.  Similarly, in the brain, based 
on current evidence in 1) animals, 2) small clinical trials in humans, and 3) our own stroke clinical trial (see D1a), 
the combined action of hyperoxia and hyperbaric pressure of HBOT improves hypoxia/ischemic injury and 
consequently cerebral blood flow (CBF) leading to cognitive improvements10, 11. Angiogenesis is induced by 
HBOT through downregulation of hypoxia-inducible factor-1α (HIF-1α)12, 13 including in the hippocampus14, 15. 
HBOT also increases vascular density in the hippocampus, improves spatial learning in rodents16, reduces 
cortical infarct area17 and  improves CBF in the piriform cortex of adult rats with vascular dementia18. Small HBOT 
studies performed on humans also support our hypotheses19 and proposed mechanism of action. In a 
randomized clinical trial (RCT), HBOT treatment as an adjuvant to donepezil showed improved cognitive 
performance compared with donepezil alone in vascular dementia patients20. Similarly, HBOT had positive 
effects compared to hyperbaric air on neurological and cognitive outcomes in a small (n=26) controlled trial of 
patients with cerebrovascular disease (patients, but not investigators, were blind to the study condition)21. More 
recently, HBOT—compared with normobaric oxygen—was associated with increased CBF in frontal and 
temporal regions in healthy subjects22. Finally, our clinical trial on post-stroke patients showed enhanced CBF 
and cognition following HBOT. On the neuronal level, it is well established that glucose utilization is impaired in 
ischemic cortical regions23-25. In animal models there is growing evidence for improved neuronal hypometabolism 
with HBOT26-28, suggesting that intracellular bioavailability of oxygen attenuates the deleterious effects of 
ischemia on neuronal glucose utilization29. The evidence thus supports investigation of CBF (using MRI) and 
glucose utilization (using FDG-PET) as biomarker outcomes of HBOT in T2D patients, who are enriched in 
cerebrovascular disease.   
 
B3. Type 2 diabetes (T2D) patients are at high risk for cognitive compromise- T2D is consistently associated 
with risk for cognitive decline30, MCI31, and dementia32-34. Its average onset at 5535, 15-35 years before dementia 
onset, provides a window of opportunity for prevention. T2D is diagnosed in 26% of those above age 65 in the 
US; over half have T2D or “pre-T2D”36, an enormous number at high risk for cognitive compromise. T2D affects 
multiple domains of cognitive function, primarily executive functions37 and episodic memory38. The primary 
outcome of the proposed RCT is a summary measure of these cognitive domains, with the executive function 
and episodic memory domains as secondary outcomes. 
 
 
 
 

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B3a. T2D affects cognition primarily through cerebrovascular mechanisms- Increased risk for vascular pathology 
in T2D39 gives strong biological plausibility to involvement of cerebrovascular pathology in the association of T2D 
with dementia. Brain MRI shows cerebrovascular abnormalities in T2D patients:  stroke40, lacunar infarcts41, 
microbleeds42, white matter hyperintensities43, reduced CBF44, 45 and cerebrovascular reactivity46. The negative 
effect of T2D on cognition was largely mediated by cerebrovascular disease in the AGES-Reykjavik Study47. 
Consistent with this, we have shown that both metabolic syndrome and insulin resistance are associated with a 
significant reduction of CBF. On ASL perfusion MRI, this effect was observed robustly in prefrontal and temporo-
parietal areas, and lower CBF mediated the negative effect of metabolic syndrome on memory48, 49. Consistent 
with compromised cerebrovasculature, T2D and elevated HbA1c levels have been associated with brain 
hypometabolism as measured by [F18]FDG-PET49—a proxy for neuronal activity50—and our group has found 
significant and widespread reductions in glucose metabolism with higher levels of insulin resistance among late-
middle-aged individuals (see Figure 5).  
 
B3b. T2D patients have smaller brain volume but not more amyloid pathology: Elderly subjects with T2D have 
smaller total brain51-53 and gray matter volume51, 53, 54, as well as larger CSF volume46, 55. Smaller hippocampi 
were found in both middle-aged56-58 and older T2D patients59, 60. In pre-T2D subjects, smaller hippocampi were 
associated with impaired glucose tolerance61, insulin resistance62  or higher fasting glucose levels63. Our group 
has also shown insulin resistance associated with smaller medial temporal lobes volume64, and volume mediated 
the its association with cognition, in a group of largely pre-T2D middle- and older-aged adults. In contrast, 
evidence for a role of amyloid in T2D dementia risk is equivocal, given that T2D has not been associated with 
amyloid neuropathology in many postmortem studies65-68 and in recent amyloid PET studies49. Overall, the data 
point toward a primary role of cerebrovascular disease in T2D cognitive compromise. Thus, the proposed study 
will focus on the biological outcomes with the highest relevance to the potential HBOT beneficial effects to T2D, 
CBF in small vessels (measured by MRI ASL), and neuronal hypometabolism (measured by FDG-PET).   
 
B4. Rationale for use of HBOT in T2D-related MCI- As described above, current evidence strongly supports a 
vascular pathology mechanism underlying cognitive compromise in T2D. While the bulk of the evidence fails to 
support more AD neuropathology in T2D than in non-T2D, AD neuropathology is present in T2D. This is important 
since HBOT benefits on the brain are primarily through a vascular mechanism and improvement in vascular 
function may have downstream beneficial effects on tau and amyloid69, 70. We focus on T2D patients, who are 
enriched in cerebrovascular pathology, and thus may be strong candidates for improvements by HBOT. The 
enriched levels of neuropathology71nand the long prodromal period of MCI provide an ideal opportunity for HBOT 
to protect or enhance cognition by reversing, preventing, or delaying neuropathologic processes that cause 
cognitive decline. Importantly, this application responds to the National Plan to Address Alzheimer’s Disease 
(NAPA) 2015 update that specifically urges acceleration of treatments for non-AD dementia72, and may have 
implications for AD per se. 

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C. INNOVATION 
As the US prevalence above age 65 increases by 2050 to an alarming 28%36 for T2D and 20% for dementia73,  
finding therapies to prevent or delay the development of dementia due to T2D is imperative.  
C1. First study of HBOT in MCI at high risk due to T2D-This is the first RCT of HBOT in MCI patients with 
particularly high dementia risk due to comorbid T2D. In contrast to many unsuccessful pharmacologic 
approaches, it innovates by examining a relatively safe, non-pharmacologic therapy with strong biological 
plausibility, and solid preliminary data for positive effects on clinical symptoms, and on vascular markers. The 
design includes short-term (immediately post-treatment) and longer-term (12 months post-treatment) outcomes, 
to investigate the legacy effects of HBOT over time.  
 
C2. Innovative design and cognitive outcomes- In the context of cognitive impairment, this will be the first HBOT 
RCT with a parallel sham condition, rather than a cross-over design (which does not permit  evaluating long-
term effects of HBOT), or HBOT as an adjuvant to donepezil20 (without a sham condition). The sham control 
creates identical conditions to the HBOT treatment (noises, mask on face, nurse in the chamber, etc.), except 
for hyperbaric pressure. The overall cognition primary outcome includes a balanced combination of four tests of 
executive functions and four tests of episodic memory, cognitive domains characterizing T2D-related cognitive 
compromise. Both domains have benefitted from HBOT74, 75 and will be secondary outcomes. We will also 
expand the secondary outcomes with executive functions assessments using innovative and sensitive computer-
administered tests. Although this is not an ADCS trial, the innovative strategies for cognitive assessment may 
inform future MCI RCTs, consistent with a key ADCS aim. 
 
C3. Innovative integration of cognitive and biomarker outcomes relevant to T2D and to HBOT beneficial effects- 
Objective biomarkers can detect progression of dementia pathology long before frank cognitive impairment76. 
Focusing on both cognitive and biomarker outcomes provides the context for identifying underlying mechanisms. 
We will examine HBOT effects on small and large vessel CBF using MRI, and on cerebral glucose uptake using 
FDG-PET77. Both the cognitive and biomarker outcomes are relevant to T2D-related cognitive impairment. 
Moreover, there is robust biological plausibility for HBOT beneficial effects on these biomarkers since they are 
linked to vascular integrity, as shown in our preliminary data. 
 
C4. A unique opportunity to explore contributing factors- The Israeli HMOs have well computerized medical 
charts. Thus, upon participant’s approval, we will request historical information on diagnoses, blood tests, and 
medications. Exploring factors (e.g. T2D microvascular complications) potentially associated with HBOT efficacy 
(see D6) is valuable in a pilot RCT, to identify groups that benefit most, refining the design for a large-scale multi-
center RCT.  
 

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D. APPROACH 
D1. Preliminary Studies 
Overall- This study will examine the short and long-term effects of HBOT on overall cognition, CBF, and glucose 
metabolism, in T2D patients with MCI, who are enriched with cerebrovascular pathology and have high dementia 
risk, making them an optimal population for the potential beneficial effects of HBOT. Our preliminary data show 
beneficial effects of HBOT on cognition and CBF in post-stroke patients and in a small sample of T2D-MCI 
patients, feasibility and rationale for the use of FDG-PET as a biomarker outcome in this study, clinical and 
neuroimaging capabilities at the Sheba Medical Center, available 
infrastructure of the Israel Diabetes and Cognitive Decline study, and a 
summary of the study team’s expertise and well-coordinated long-term 
collaboration, fully supporting the successful execution of the proposed 
RCT.  
 
D1a. HBOT induces neuroplasticity in post stroke patients- Randomized 
prospective trial78- Patients 6-36 months after stroke (n=74) were randomly 
assigned to a “treated” or “crossed” group. Brain activity (by SPECT 
imaging), neurologic functions (by the NIH stroke scale), activities of daily 
living and quality of life were assessed at baseline and after HBOT (40 90-
minute sessions, 5 days/week, 100% oxygen at 2ATA). Patients in the 
crossed group were also assessed after an initial two months control period 
of no treatment.  Neurological functions, ADL, and quality of life improved 
significantly following HBOT sessions, but with no improvement after the crossed group control period. Elevated 
brain activity was detected mostly in regions of live cells (as confirmed by CT) with low activity (based on SPECT) 
(Figure 1). This highlights the advantage of our design, examining MCI subjects, who may have compromised 
neuronal and vascular function due to their T2D but are not demented yet, suggesting substantial brain tissue 
has the potential to recover. 
 
Figure 1- A patient in the treated group with left 
hemiparesis due to ischemic stroke from 26 
months prior to the study. Brain perfusion maps 
(upper 2 images) show the infarcted brain (deep 
blue color) involving right antero-postero-lateral 
frontal, right superior-parietal and right parieto-
occipital regions. Curved sagittal view in CT MIP 
reconstruction shows the anatomical stroke area 
(left lower image, V= posterior horn of right 
ventricle). The peri-infarct region show improved 
perfusion after HBOT (right upper image). Right 
lower image: Quantitation of cerebral blood flow 
change (delta between baseline and HBOT). 

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D1b. Improvement of memory in post stroke by HBOT 75- This study addressed HBOT effects on memory 
impairment after stroke at late chronic stages in a retrospective analysis of 91 stroke patients 18 years or older 
(mean 60 years) who had either ischemic or hemorrhagic stroke 3–180 months (M  30–35 months) before HBOT 
(40 to 60 90-minute sessions, 5 days/week, 100% oxygen 
at 2ATA). Memory tests before and after HBOT therapy 
used the NeuroTrax computerized testing battery (verbal or 
nonverbal, immediate or delayed memory). In all tests there 
was a statistically significant improvement after HBOT (all 
p-values <.0005, effect sizes medium to large), largest in 
immediate (28% improvement) and delayed (27%) verbal 
memory, respectively (Figure 2). SPECT before and after 
HBOT (n=56) showed several regions had significantly 
higher relative change in activation, particularly in temporal 
lobe (entorhinal cortex, inferior and middle temporal gyri). 
These results support strongly the potential of HBOT to improve cognition and brain activation even years after 
the acute event. Of note, Drs. Efrati and Beeri co-authored this paper, illustrating their productive collaboration.  
 
D1c. Improvement of cognitive impairment in MCI by HBOT- 
In a pilot study for proof of concept, two T2D MCI patients 
were treated using the proposed HBOT protocol. The overall 
cognition measure improved by 32.6% (from 0.99 to 1.47) 
and 30.0% (from 0.81 to 1.15) for subject 1 and 2, 
respectively; 
SPECT 
results 
showed 
substantial 
improvements in CBF in broad cortical regions (see Figure 
3, subject 1). The provocative results of this very small pilot 
study support both the cognitive and biomarker hypotheses. 
 
D1d. Low cerebral blood flow is associated with lower memory function 
in metabolic syndrome48- Dr. Bendlin, our neuroimaging collaborator, 
compared CBF using arterial spin labeling perfusion MRI (ASL-MRI) 
in middle-aged adults (n=69; mean age=60.4) with and without the 
metabolic syndrome (a pre-T2D condition). Mean gray matter CBF 
was 15% lower in the metabolic syndrome group (Figure 4).  Voxel-wise image 
analysis indicated that this decrease pertained to a large portion of the cortical 
surface. The poorer memory in the metabolic syndrome group was partially 
mediated by CBF. These findings demonstrate feasibility of the proposed ASL-MRI and its sensitivity to the pre-
Figure 4- Controlling for age and gender, 
participants with metabolic syndrome had lower 
cerebral blood flow (an index of neural function) in 
parietal, frontal, and temporal lobes (shown in orange 
overlay, FWEcorrected, p < 0.05). Left panel: medial 
surface of left hemisphere; Right panel: left lateral 
cortex.). 
Figure 3- SPECT of a subject with MCI before (lower panel) and 
after HBOT, showing extensive increases in brain activity by SPECT 
Figure 2- Memory scores (mean+SE) before and after 
HBOT. All improvements are significant at a level of p<0.0005. 

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T2D metabolic syndrome supporting Aim 2a. 
 
 
 
 
 
 
 
 
D1e. Insulin resistance is associated 
with poorer brain glucose uptake- Dr. 
Bendlin’s 
group 
examined 
the 
association of insulin resistance (using 
HOMA-IR) with global and regional 
FDG-PET uptake in 150 middle-aged 
adults. Higher insulin resistance (a pre-
T2D condition) was associated with 
lower FDG-PET uptake (Figure 5); uptake 
in regions more strongly associated with 
insulin resistance (such as medial temporal 
lobe) was associated with cognitive 
function (Figure 6). These results show 
relationships of a T2D characteristic 
(insulin resistance) with regional glucose uptake supporting its use as a biological outcome in the proposed 
study. 
 
D1f. The Israel Diabetes and Cognitive Decline Study (IDCD)80-85- This prospective population-based longitudinal 
study, to identify T2D-related characteristics linked with cognitive decline, has cognitive, functional, demographic, 
psychiatric, DNA, and inflammatory marker assessments every 18 months. T2D subjects from Maccabi (n=1200) 
were initially cognitively normal, 65+, averaging 73 years old at baseline, 13 years of education, and 10 years of 
T2D in the Diabetes Registry; 42% were women. All subjects approved, through their informed consent, to be 
approached for other relevant studies, providing an opportunity to approach them for this RCT. The IDCD rate 
of cognitive decline is used to calculate statistical power. 
 
D1g. Neuroimaging at Sheba- We recently received an R21 (AG043878) using MRI in IDCD subjects. 
Demonstrating willingness to participate, all the 18-months follow up subjects signed the informed consent 
Figure 5- The association between
higher HOMA-IR and lower regional
FDG-PET uptake in 150 late
middle-aged adults (p<.05 FWE).
Uptake values were adjusted for
age, sex, family history status,
APOE4, and glucose metabolism in
the reference region. The color bar
depicts 
t-values. 
Brains 
are
oriented in neurological space.
FWE= family-wise error corrected. 
Figure 6- (A-B) Higher FDG-PET in left
medial temporal lobe predicted better
performance 
on 
verbal 
learning 
and
immediate memory. (C-D) Left medial
temporal uptake was not associated with
working memory, but was associated with
the speed and flexibility factor. Signal was
adjusted by the FDG reference region, age, 
sex, APOE4, and family history status, and 
HOMA-IR.*=p<.05; **=p<.001.JAMA Neuro 

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amended to include neuroimaging. The Sheba Helsinki Committee requires that all scanned subjects receive a 
clinical report from a neuroradiologist, providing a great incentive. In the last 10 months, we scanned 150 IDCD 
subjects using the ASL methods described in D2k; Dr. Bendlin confirmed superb quality. Sheba performs over 
4,500 PET-CT exams per year, about 450 in brain, 15% of them for research (see letters from Drs. Ben Chaim 
and Konen, chairs of Sheba’s Nuclear Medicine and Radiology Departments, describing this infrastructure). 
 
 
 
D1h. A multidisciplinary team of integrated and productive investigators covering all the necessary expertise for 
successful implementation of this RCT: Dr. Beeri (PI) is an expert in the neuropsychology of cognitive aging and 
dementia, with a main focus on the contribution of T2D; Dr. Sano (joint PI) is a neuropsychologist who is a 
national leader in clinical trials for MCI and dementia; Dr. Efrati (PI Asaf Harofeh) is a world renowned expert of 
HBOT; Dr. Bendlin (PI: U Wisconsin site) is an expert in neuroimaging of dementia and focuses on metabolic 
disorders’ effects on the brain; Dr. Ravona (PI: Sheba site) is a geriatric psychiatrist, a young, rising physician-
investigator; Dr. Leroith is an internationally recognized expert in mechanisms underlying complications of T2D; 
Dr. Ashery’s recent research focuses on the 
biological mechanisms of HBOT. Dr. Bagiella is a 
biostatistician 
with 
expertise 
in 
complex 
longitudinal analyses of clinical trials. Dr. Beeri has 
published with all the PIs and has other joint grants 
with them. Thus, despite the distance, the team is 
well integrated, with expertise to ensure successful 
implementation of all components, analyses, and 
interpretation of results. 
D2. Methods: 
D2a. Participants- Elderly patients (n=250) with 
T2D and MCI (amnestic or non-amnestic) will be 
enrolled to examine potential HBOT therapeutic 
effects on the brain preceding dementia, when neuropathologic processes causing decline still have potential for 
prevention or delay. MMSE>24 and clinical dementia rating [CDR] = 0.5 will be required. An informant must be 
available for supplemental information throughout the trial. 
  Candidates will complete a cognitive assessment, physical and neurological examinations, and a clinical 
interview with an informant present. Cholinesterase inhibitors are an exclusion since their interaction with HBOT 
is not known. Subjects with an indication for HBOT (such as diabetic foot) will be excluded, to avoid 
randomization to the control arm. Israel is a country of immigration, so Hebrew fluency is required for valid 
neuropsychological testing84. Table 1 summarizes eligibility criteria. Subjects will be preferably from central Israel 
Table 1: Eligibility criteria 
Inclusion Criteria 
Exclusion Criteria 
1. Diagnosis of T2D 
2. Diagnosis of MCI 
3. > the age of 65 
4. Hebrew fluency 
5. An informant 
1. Brain disease that affects cognition (e.g. 
Parkinson’s disease, schizophrenia). 
2. Stroke 
3. Epilepsy 
4. Chest pathology incompatible with HBOT 
5. Inner ear disease 
6. Claustrophobia 
7. Cholinesterase inhibitors 
8. Subjects with an indication for HBOT 
9. Individuals with previous HBOT treatments. 
10.  Individuals with cancer and other medical 
illnesses requiring intensive therapy. 
11.  Individuals with proliferative retinopathy. 

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since the HBOT treatment will be performed in Asaf Harofeh, located in central Israel. The treatment is very time 
consuming and far away participants may have a hard time complying to the treatment protocol. 
D2b. Recruitment- Subjects will 
be recruited through talks in the 
community, advertisements, and 
companies which have large lists 
of elderly interested in receiving 
emails 
about 
health 
related 
topics. IDCD subjects diagnosed 
at follow up with MCI (21% at the 
36-months follow up) will be 
offered 
participation 
in 
the 
proposed trial. Although the 
IDCD study participation was far 
less 
demanding 
than 
the 
proposed RCT, recruiting 1200 
subjects within 2 years reinforces 
our confidence in recruiting 154 
subjects for this RCT—including 
many already in the IDCD—in 3 
1/2 years. Additional recruitment 
will be performed through clinics 
(e.g. diabetes and executive 
clinics). 
D2c. Procedures- Table 2 presents study procedures for each subject. HBOT sessions will take place in Asaf 
Harofeh Medical Center; informed consent and all other assessments, including cognitive, functional, MRI, and 
FDG-PET will be performed at the Sheba Medical Center. Adverse event monitoring is done at every HBOT and 
sham session, by a nurse in the chamber throughout the session and a physician always present. Physical 
exams and blood collection for safety monitoring will occur before randomization, and at 12 weeks. Medication 
review will occur before randomization, before and after the intervention, and 6 and 12 months later, with 
cognitive testing at these times except before randomization. The T2D-related biomarkers (Blood test, MRI ASL 
and FDG-PET) will be assessed before and after the intervention, and 12 months later. After intervention, a 
questionnaire will examine whether blindness was maintained. At the end of the participant's 12 months' 
participation in the trial, the participant can choose to receive HBOT treatment for which the costs will be covered 
by the study team. At the end of the second HBOT treatment course, an additional neuropsychological 
assessment will be administered to the participants. 
Table 2- Summary of study procedures 
 
Screen 
Baseline/ 
beginning of 
intervention 
12 weeks /end 
of intervention  
6 
months 
12 
months 
Informed consent 
X 
 
 
 
 
History, cognitive assessment (for 
MCI classification), clinical 
evaluation 
X 
 
 
 
 
Medication review 
X 
X 
X 
X 
X 
Physical exam 
X 
 
X 
 
 
Blood test 
 
X 
X 
 
X 
Follow up information  
 
X 
X 
X 
X 
Adverse event monitoring* 
 
 
X* 
 
 
Group assignment: review 
program and expectations at time 
of randomization 
 
X 
 
 
 
Cognitive testing (ADAS 
COG13+executive functions tests) 
 
X 
X 
X 
X 
Functional assessment (CDR)  
X 
 
X 
X 
X 
ADL, IADL 
 
X 
X 
X 
X 
Depression questionnaire 
X 
 
X 
X 
X 
MRI ASL 
 
X 
X 
 
X 
FDG-PET 
 
X 
X 
 
X 
Blindness testing 
 
 
X 
 
 
The intervention will begin within three weeks after the Baseline assessments and end at 12 
weeks after 60 HBOT/Sham treatments.  A physician is always present during the HBOT sessions, 
and a nurse is in the chamber throughout the whole treatment, so adverse events will be de facto 
closely monitored at each session up to the end of the intervention. 

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D2d. Randomization and Blinding of Intervention-Eligible candidates will be randomized with equal probability to 
the HBOT and sham interventions. When a cluster of at least 3 subjects from one of the interventions is filled, 
the intervention for that cluster will begin (77 subjects will be recruited for each treatment). Clusters will be a 
random effect in the analyses (see D6). Three study technicians who activate HBOT or sham protocol sessions 
will be the only unblinded staff who have the key for the subjects’ group assignments. All subjects and other 
clinic staff will remain blinded to group assignment. Study nurses will monitor AEs during all sessions and a 
physician will be present during each session. Importantly, staff from Sheba, who assesses outcomes, will not 
be exposed to the subjects during their intervention and vice-versa. 
Procedures before enrollment will maximize participant adherence to the intervention. Only volunteers 
who fully understand the expectations regarding consistent participation in the treatment and completion of 
assessments will be enrolled. The judgment of field site staff will be essential to determine eligibility based on 
anticipated adherence. During initial telephone screening and again prior to the baseline visit, subjects will be 
asked to confirm their willingness to be assigned to either intervention. Dr. Efrati’s group has long experience 
with RCTs using HBOT conditions, ensuring subject satisfaction and continued commitment to the program. 
 
D2e. HBOT intervention- The multiplace HBOT unit at Asaf Harofeh is state of the art, the most advanced 
available in the market. The inside looks like an airplane, with comfortable chairs for 11 subjects and the nurse 
who stays throughout the session (a significant advantage compared to the monoplace chamber). The HBOT 
protocol is 90 minutes, 5 times/week, 60 sessions, 100% oxygen at 2 ATA with 5 minute air breaks every 30 
minutes. This safe protocol is used worldwide for treatment of ischemic non-healing wounds (diabetic foot or 
post radiation injury), was used in our stroke clinical trial78, and in our MCI preliminary data, indicating favorable 
cognitive outcomes. It improves on a prior study on memory-impaired elderly89 that was too short to reduce 
ischemic injury or for angiogenic processes to occur, even in peripheral tissue90-92.  
The team members present at all times during the HBOT/sham sessions are a physician, two nurses 
(one inside the chamber and one outside), and at least one of the three unblinded technicians. Only study 
subjects—not clinical patients—are in the chamber during research hours. When subjects arrive at the 
Hyperbaric Unit, one of the nurses signs them in; measures their glucose, blood pressure, heart beat, and 
temperature; and asks about any change in their medical condition. Subjects with signs of any infectious disease 
(such as upper respiratory tract infection), or arriving with systolic blood pressure >170mmHg or <90mmHg, or 
glucose <75mg/dl do not enter until it improves. While in the chamber, subjects may drink, read, write, sleep, 
hear music with headphones, or watch TV. Video games, laptops, phones, or other electronic devices are not 
allowed in the chamber. Subjects have their own masks. The atmospheric pressure goes up to 2.0 ATA during 
the first five minutes of the session, with a noise of circulating air. Subjects will feel pressure in their ears; the 
nurse will advise releasing the pressure by pumping the ears (closing their nose with their fingers and pushing 
air). In the last five minutes of the session, the pressure is slowly decreased to 1ATA.  

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D2f. Sham intervention- 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.  
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.). In contrast to 2 ATA 
for the HBOT, the sham condition pressure goes up to 1.1 ATA during the five first minutes of the session with 
noise of circulating air. This provides a minimal pressure sensation in the ears, with the same nurse advice on 
pumping the ears. Pressure then decreases very slowly during the next half hour; in the last 5 minutes of the 
session, the air is circulated again with its related noise. Sham and HBOT sessions will never be adjacent, so 
subjects from the two groups cannot meet and compare sessions. This sham model makes the two conditions 
very comparable, except for the hyperbaric effect, to minimize breaking the subjects’ blindness.  
Consideration of alternative sham and HBOT conditions: The two clinical trials described in the 
preliminary data section had a treatment group and a crossover group (assessed at baseline, after two months 
with no intervention, and again after HBOT intervention). A more effective design is a sham condition that is very 
similar to the HBOT condition but without known treatment effects (and also permitting the assessment of the 
long-term effect of HBOT). We considered a sham condition using a slightly higher 1.3 ATA level, but this 
hyperbaric condition has an increase in tissue oxygenation greater than 50%92, which may have substantial 
physiological effects, so 1.1 ATA for sham is preferable. We considered 100% oxygen with 2.5 ATA in the HBOT 
condition, but in our experience, this protocol induced more adverse events. 
 
D2g.Optimizing adherence to the intervention. One challenge in a study that requires high commitment is 
achieving high rates of intervention adherence for the duration of the trial, especially in the elderly due to 
restrictive life events such as illness, caregiving responsibilities, environmental barriers, and disabilities. 
Nonetheless, several studies indicate that the elderly with cognitive impairment can successfully adhere to 
intensive programs and benefit from the experience, particularly when these programs provide adequate 
structure and support to the participant93, 94. Our HBOT studies had relatively low dropout rates of 5% (stroke 
study) to 20% (mTBI study). The great expertise and experience of the team, and the liberty to pass the time in 
the chamber reading, watching TV, listening to music, etc. facilitate high compliance. At screening, and again at 
randomization, Drs. Ravona and Efrati will discuss with each subject what is expected, and the importance of 
strong commitment. We will attempt to assess for outcomes subjects who withdraw from the intervention.  
 
D2h. Outcomes.  Primary cognitive outcome. The primary cognitive outcome is a balanced composite sum of 
z-scores of four executive function tests (Trails B, Mazes, Digit-Symbol, and Category Fluency), and four episodic 
memory tests (immediate and delayed recall of the word list from the ADAS-Cog, and immediate and delayed 

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recall of Logical Memory Story I from the Wechsler Memory Scale-III). These functions are affected by T2D37 
and commonly administered in other MCI trials95 96, 97. Z-scores are reversed if necessary so that a positive value 
refers to good cognition. We have published Hebrew norms for T2D elderly subjects for all the executive functions 
(except Mazes, which is not language dependent), and the episodic memory tests. 84 
For Trails B, subjects draw lines connecting alternating numbers and letters (1, A, 2, B, etc.); for Mazes, 
subjects draw lines from start to finish in mazes of increasing complexity, without back-tracking or crossing a 
boundary; 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. 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.  We will use 
the 1st story for immediate recall and for delayed recall, 15 minutes later.  
Secondary cognitive outcomes. These will be the domain-specific composites, i.e. the 4 tests each for 
executive function and episodic memory, both affected by T2D37, 38, and benefitted by HBOT74, 75. Since there is 
especially broad evidence for impairment of executive functions in T2D12, 98, another  secondary outcome will 
sum z-scores for 3 computer-based tests (not language dependent), developed through NIH initiatives for new 
sensitive instruments that will ultimately be public domain (NIH Toolbox assessing multiple domains: 
http://www.nihtoolbox.org; EXAMINER assessing executive abilities: http://examiner.ucsf.edu). For Flanker, 
subjects make a speeded response—whether the central arrow is pointing left or right, between flanker arrows 
pointing in the same or opposite direction; for Set-Shifting, subjects match figures by either color or shape 
depending on a cue on the screen; and for Dot-Counting, subjects count out loud the number of targets displayed 
among distractors, and recall the number of targets when queried, 1 to 4 screens later.  
Secondary functional outcomes- Three measures will be the CDR-SB, which summarizes impairment 
in 6 domains (memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal 
care)99 based on subject and informant interviews, and the ADL100 and IADL101 questionnaires. 
Primary imaging outcomes. Given our robust preliminary data in T2D and pre-T2D showing reduced 
CBF and glucose metabolism, and supported by others45, 49, 102, and the evidence of effects of HBOT on CBF 
and glucose metabolism (see B2), our imaging outcomes are CBF (Arterial Spin Labeling MRI for small vessels)  
and [F18]FDG-PET.  
D2i. Maintenance of participant blinding- Effectiveness of blinding will be evaluated at the end of the study in two 
ways: 1) we will ask whether participants received the “real” intervention. A post-intervention questionnaire 
(CSRQ-64103), which typically takes 5-10 minutes, will explore reasons for their answer: in 64 statements on 8 
cognitive abilities, (e.g., “Did you improve, remain the same, or worsen, specifically because of being in the 
study?”), 2) We will compare participants’ rates of voluntary withdrawal. A difference between groups’ 
percentages over 15% will be interpreted as perception of, or lack of confidence in, the intervention.  

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D2j. Neuroimaging- Participants will undergo a full protocol to acquire CBF and ancillary data on a 3 Tesla (3T) 
GE x750 scanner with echo planar and asset capability using an 8-channel head radio frequency (RF) coil 
(General Electric, Milwaukee, WI). The MRI protocol will include: ASL-MRI, T2FLAIR, and T1-weighted imaging. 
ASL-MRI- ASL-MRI will be acquired to assess CBF at baseline, 12 weeks (immediately after treatment) and 12 
months after treatment. The sequence will be acquired using background-suppressed pseudo-continuous ASL 
(pcASL), featuring a 3D fast spin echo spiral sequence (TR = 6000 ms; TE = 21 ms; FOV = 240 x 240 x 160 
mm; slice thickness = 4 mm no gap; matrix size=128 x 128; NEX=3; and labeling RF amplitude=0.24 mG, with 
a post-labeling delay of 2025 ms. 3D T2FLAIR will be acquired to assess WMH burden (TR 6000, TE 120, TI 
1870, 256 x 256 matrix, FOV 256 mm acquired over 88 2mm thick slices, no gap, with final voxel resolution 1mm 
x 1mm x 2mm; 2). 3D T1-weighted imaging will be acquired to use for registration, atrophy correction, and 
regional volumes (inversion-recovery prepared fast spin echo, TR 8.2, TE 4.0, TI 450, matrix 256 x 256, FOV 
256 mm, acquired over 156 1mm thick, no gap,  axial slices with isotropic 1mm voxel resolution) .  Participants 
will be asked to refrain from caffeine  and nicotine for 4 hours prior to the study. The pcASL sequence includes 
3 averages (NEX=3). The sequence also includes a fluid-suppressed proton density (PD) acquisition, with the 
same imaging sequence/image slab location as the pcASL but without the RF labeling preparation, for CBF 
quantitation and image registration. The entire pcASL sequence—all 3 excitations plus PD scan—is acquired in 
4.5 minutes and can be inspected for quality on the scanner and repeated if necessary. We have previously 
reported excellent test-retest reliability (intraclass correlation coefficient >.95) of this pcASL procedure104.  
MRI Quality Control: The quality control of the scanner is done by Sheba Department of Radiology in 
conjunction with GE field engineers. This is augmented by administration of a MAGPHAN Quantitative Imaging 
phantom which has been consistently scanned at least monthly since April 2009; the scanner has been highly 
stable over time. Based on our experience, we anticipate technical problems <2%. There is sufficient time in the 
session for rescanning if motion or other artifacts are observed. Trained and certified MR technologists operate 
the console; scans are prescribed in a standardized fashion and assessed at the scanner for acceptable quality. 
Scans are downloaded to the imaging lab server immediately after the session and the post-processing 
procedures are implemented including an additional quality check by the study team. If baseline re-imaging is 
necessary, study intervention will be delayed until satisfactory images are obtained.  
MRI Data Backup: Multiple backups are performed to prevent technical loss of data. At the scan console, 
the exam is backed up to DVD and kept at the MR facility. The exam is also uploaded to a PACs server and 
permanently archived. A complete copy is downloaded to a 40TB RAID6 server and weekly backups (to a 
separately located server) are made of processed and incremental data.  
MRI Image Processing: Images will be pre-processed prior to statistical analysis using well established tools 
and pipelines including SPM12 and FSL. The pipelines are scripted and extendable such that improved methods 
developed in the software or locally can easily be applied to all data in batch. The pipeline steps include: 1) 
Conversion of images to NIFTI file format for broad compatibility between software packages; 2) Insertion of the 

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exam into the imaging SQL database (so Drs. Beeri, Livny-Ezer, and Bendlin can view the data online via web 
tools); 3) coregistration of each ASL CBF map to the baseline map which is in turn coregistered to the T1-
weighted 3D SPGR volume at baseline; coregistration uses a mutual information algorithm and linear least 
squares minimization in SPM12; 4) transformation into MNI canonical atlas space using the ICBM 152 template 
in SPM12. Finally, data are smoothed with a Gaussian kernel of 8mm FWHM to accommodate individual 
variability and comply with assumptions of random field theory necessary for statistical analysis of the images. 
T2FLAIR images will be segmented according to methods previously used by our group106. WMH will be used 
as covariates in the second-level analysis.   FDG-PET: Dr. Simona Ben Chaim, Chair of the Nuclear Medicine 
Department at Sheba, will oversee acquisition of [F18]FDG on a Philips Gemini GXL + PET scanner in 3D mode. 
[F18]FDG-PET Acquisition: Participants will be studied after a minimum 4 hour fast (water allowed). Because 
participants with glucoregulatory dysfunction are being imaged, blood glucose will be closely monitored prior to 
the injection of [F18]FDG. Blood glucose prior to [F18]FDG administration must be ≤ 180 mg/dL for [F18]FDG to 
be injected. Following injection with 5.0 ± 0.5 mCi of [18F][F18]FDG participants will remain awake but relaxed 
in a quiet room. Imaging will begin 45 min. post injection, and the scan acquired as six 5-min. frames. A 5-min. 
transmission scan will be acquired following the emission scan. The dynamic PET data will be reconstructed 
using ECAT v7.2.2 software. A filtered back projection algorithm (DIFT) will be used with brain mode sinogram 
trimming, zoom = 2.8, and a 4mm Gaussian filter to a reconstructed image of 128 x 128 x 63 voxel matrix (voxel 
size = 1.84mm x 1.84mm x 2.43mm). The PET data will be corrected for the attenuation of annihilation radiation 
(using segmented attenuation maps), scanner normalization, and scatter radiation. [F18]FDG image processing: 
Data will be transferred to the ADRC imaging lab at the UW-Madison using a secure protocol our group has in 
place. The reconstructed images will be used for comparison of regional differences of [F18]FDG uptake in the 
targeted areas of the brain. The dynamic [F18]FDG will first be corrected for frame to frame motion using SPM12 
software. Any frames with excessive motion will be discarded from further processing. The data will then be 
summed to create a single image representing [F18]FDG uptake in the brain from the period of 45–75 minutes. 
This image will then be scaled so the mean whole brain activity will be equal for all subject scans. Images will 
be corrected for atrophy based on the three-compartment approach (includes GM, WM and CSF) based on the 
method published by Meltzer et al.107, 108. In brief, the MR T1 image is segmented in SPM12 to provide GM, WM 
& CSF maps. The partial volume corrected gray matter tissue tracer concentration will be used for the second 
level group analysis, extracted from regions of interest (dorsolateral prefrontal, medial temporal, and lateral 
parietal cortices). These regions have been selected based on their vulnerability to T2D and AD. Data will be 
extracted bilaterally using the Automated Anatomical Labeling (AAL) atlas implemented in WFU PickAtlas, and 
averaged across hemispheres prior to being entered into statistical models. Secondary analyses will include 
exploratory whole-brain analyses conducted on a voxel-wise basis.  
D2K. Inflammatory and diabetes and dementia related markers - Morning bloods will be obtained after a 10-
hour fast, then centrifuged. Bloods will be stored at -70C until determination in Sheba Medical center. 

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We will analyze the bloods to determine the diabetes and dementia related biomarkers in several well established 
methods, like:  
High sensitivity C-reactive protein- CRP levels will be measured with a sandwich-type ELISA in which 
polyclonal rabbit anti-CRP antibodies are used as catching antibodies and a biotinylated mAb against CRP 
(CLB anti-CRP-2) is used as the detecting antibody. The inter- and intra-assay coefficients of variation are 
expected to be less than 5%. 
Interleukin-6- IL-6 will be measured using a commercial solid phase immulite (Diagnostic Products Corporation 
[DPC], Los Angeles, CA, USA). Reported inter-assay coefficient of variation is 6% and intra-assay 4%, with a 
detection limit of 1.0 pg/ml. 
Haptoglobin- Haptoglobin will be typed (Hp 1-1, Hp 2-2 or Hp 2-1) by Dr. Andy Levy, at the Technion Israel 
Institute of Technology by polyacrylamide gel electrophoresis from 10 ul of plasma according to established 
methods. Dr. Levy’s lab processes about 20 thousand blood draws per year for haptoglobin typing. The 
haptoglobin gene on chromosome 16 exists as two allelic variants, producing distinct set of polymeric 
haptoglobin molecules. Distinct signature patterns of polymeric species which are detected by gel 
electrophoresis are obtained from individuals homozygous for the Hp 1 or Hp 2  alleles (Hp 1-1 or Hp 2-2 
respectively), or who are heterozygous (Hp 2-1). Polyacrylamide electrophoresis is the most common method 
for typing haptoglobin with 100% concordance with genotyping. 
Diabetes related markers e.g. Advanced Glycation End products (AGEs) (Hemoglobin A1c, LDL etc.) 
Dementia related markers e.g. Plasma Amyloid Beta and Tau- Amyloid Beta and Tau proteins will be analyzed 
via Immunoprecipitation–mass spectrometry (IP–MS) assay. If in the future new dementia and diabetes related 
biomarkers will be discovered, we request the IRB’s approval to analyze those markers as well. 
 
 
D2I. Performing the study at the pilot stage in Israel is optimal - Dr. Shai Efrati, the Asaf Harofeh site PI , is the 
chairman of the Israeli Society for Hyperbaric & Diving Medicine and an internationally renowned leader in HBOT. 
The Asaf Harofeh Hyperbaric Unit is one of the largest, most active worldwide with about 100 patients treated 
per day, in a variety of FDA approved indications (e.g. non-healing ischemic wounds, post radiation injury, 
chronic osteomyelitis). There is widespread accessibility of HBOT chambers in the US (please see letter of 
support from Dr. Peters, the American Undersea & Hyperbaric Medical Society Executive Director describing 
~1400 US HBOT chambers, with an estimated annual growth of 8-10%). This suggests that finding collaborative 
HBOT facilities in the US would not be a problem in a large-scale multi-center RCT for cognitively impaired T2D 
patients based on this pilot study. Importantly, the typical US cost of HBOT treatment is significantly higher than 
in Israel, making the proposed pilot study sample size feasible within the current funding mechanism. The Sheba 
Medical Center is the largest hospital in the Middle East, and is home for the NIH funded IDCD study, so it has 
all the necessary infrastructure, personnel, experience, and expertise in recruitment of elderly subjects with T2D, 
and of assessment of the cognitive and biological outcome measures of the proposed study. It is only 8 miles 
from Asaf Harofeh, facilitating visits by subjects who will be primarily from the Tel-Aviv area encompassing both 
hospitals. The professional staff is of superb quality but at significantly lower cost than in the US. Finally, subjects 
will be recruited through talks in the community, advertisements, and companies which have large lists of elderly 
interested in receiving emails about health related topics. Medical information will be given us by the subject. 

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This data is very valuable, enabling a pilot study to refine the design for a future large-scale multi-center RCT, 
by exploring T2D-related characteristics, such as severity of disease, which may identify groups of subjects with 
more benefit from HBOT. Finally, generalizability of results to Americans is crucial. Americans and Israelis are 
similar in prevalence of several cardiovascular risk factors and diseases, specifically T2D. The prevalence of 
T2D in both the US and in Israel is about 25% for individuals above the age of 65109, 110, and the mortality rate 
associated with diabetes is essentially identical in both countries, slightly below 40 per 100,000111, 112. The 
distribution of type of medication used (none, oral, or insulin) is also very similar in the US110 and Israel80. 
 
D2J. Pitfalls and solutions- Potentially larger sham dropout rates- The sham group will feel less ear pressure 
than the HBOT group. Since the intervention is time consuming, there may be more dropouts among those who 
think they are in the control group. In the majority of RCTs of behavioral interventions, there are no differences 
in the dropout rates of control groupse.g.113-117. All subjects will be told that they will be randomized to high or low 
hyperbaric pressure, and that it is unknown yet if either works. At the end of the participant's 12 months 
participation in the trial, the participant can choose to receive HBOT treatment for which the costs will be covered 
by the study team. At the end of the second HBOT treatment course, an additional neuropsychological 
assessment will be administered to participants. The nurse might perceive the difference between HBOT and 
sham but will be instructed not to discuss this with participants. No non-T2D control arms- inclusion of non-T2D 
parallel HBOT and sham arms would show whether efficacy is specific to T2D, or generalizes to all MCI patients. 
However, for this pilot funding mechanism, the aim is proof of concept that HBOT improves cognition, focusing 
on T2D-MCI patients, who are enriched in cerebrovascular disease—the main target of HBOT—and at high risk 
for decline, improving statistical power. With ½ of the US elderly suffering from T2D or pre-T2D, this study has 
potential for broad public health impact. Collecting AD neuropathology data- Despite associations of insulin with 
amyloid118-120 and of T2D with tau pathology121, we decided against measuring them in CSF, due to a focus on 
vascular mechanisms, incomplete scientific evidence supporting AD neuropathology as an HBOT mechanistic 
target in a T2D context, and minimizing participants’ burden.  
 
D3. Logistics and communication among the international investigators- Dr. Beeri has collaborated for 
many years with all investigators and has numerous joint publications demonstrating her capability to effectively 
lead international studies with complex logistics. Drs. Beeri and Sano will lead 2 biweekly conference calls. One, 
with the Sheba and the Asaf Harofeh teams, will discuss day-to-day aspects of the trial (recruitment, refusals 
and ways to overcome them, data entry and missing data, staffing and coordination, and adverse events). The 
other, with the senior investigators, Drs. Bendlin, Ravona, Efrati, Ashery, and Leroith, will monitor overall 
progress toward the trial’s goals. Both meetings will have minutes that will be sent to the meeting participants 
and action items will be reviewed in each meeting. Drs. Bendlin and Livni communicate very often on the 
neuroimaging aspects of other collaborative studies facilitating continuous communication on the proposed 
study. Images upload to the warehouse is done at the scan day and Dr. Bendlin has access to them (see D5). 

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Funds are allocated for Drs. Beeri and Sano travel to Israel for close study supervision of progress, and for the 
annual AAIC conference where the senior investigators will meet face-to-face. 
 
D4. Study Timelines- The first three months will be devoted to obtaining IRB approvals from all sites and training 
study physicians, neuropsychologists, and nurses for data collection. Screening and enrollment will occur from 
month 4 of the study and until the middle of year 4 (~47 subjects/year); data collection and cleaning will extend 
for another year. Analyses and preparation of the primary manuscript will be in the final 6 months. 
 
D5. Data handling and transmission- The Mount Sinai Department of Psychiatry data management 
infrastructure is a web based data warehouse including all its cognition and AD projects. A region specifically 
designed for the proposed study includes MRI and PET scan data. The original study materials, including the 
MRI and PET scans, will be transmitted via a secure FTP. Data entry is through a web portal by a double entry 
system. The warehouse files have built-in range and logical checks to flag or prevent impossible values. Each 
study team member has identification to download data files via a secure web portal, so analyses do not affect 
warehoused data. Data transmission has been successful in the IDCD and our other international projects. 
 
D6. Statistical Analysis Plan- Efficacy analyses will be performed for the intent-to-treat (ITT) population, our 
primary analysis, and for fully and partially compliant per-protocol (PP) populations. The ITT population will 
include all participants in the group to which they were randomized, regardless of any protocol deviation including 
non-compliance, adverse events, or loss of follow-up. The PP populations will include participants in the group 
according to the intervention actually received, but a separate analysis will be performed for those who were fully 
compliant (at least 80% of sessions completed) and for those who were partially compliant (at least one session 
completed). A complier-average causal effect (CACE) analysis using a latent class modeling approach will also 
be performed on both fully and partially compliant populations. Patients missing a baseline value of a continuous 
efficacy outcome measure will be excluded from all analyses and maximum likelihood estimation methods will 
be used to handle missing data arising from an unobserved follow-up visit122.  
Aims 1a and 1b: The primary (overall cognition) and secondary (executive functions, episodic memory 
domains, and computer-based tests) cognitive outcome measures (all summaries of z-scores), will each be 
analyzed using a mixed model analysis of covariance (ANCOVA) with time of assessment (baseline or 12 weeks) 
as the within-subjects factor, treatment group (HBOT vs. sham) as the between-subjects factor and baseline 
value of the outcome measure as the covariate. Both, subject and ‘cluster’ (the variable used to identify to which 
group of at least 3 subjects each individual is assigned) will be modeled as random effects to account for the 
correlation among repeated measurements made over time within a subject as well as potential ‘cluster effects’ 
arising from blocks of at least 3 patients receiving treatment at a particular time after randomization. An 
interaction term between time of assessment and treatment group will be included in each model allowing for 
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in change scores between groups. A test of parallel treatment effects across the range of baseline values will be 
conducted by including a three-way interaction term among time of assessment, treatment group and baseline 
value of the outcome variable as well as all lower order two-way interaction terms. If the three-way interaction 
term is statistically significant it will be retained in the final model and estimates of the difference in mean change 
scores between treatment groups will be evaluated at selected percentiles of the baseline distribution. Secondary 
mixed model ANCOVA analyses will be performed for cognitive assessments at 6 and 12 months following 
treatment. As an exploratory analysis, linear mixed effects models will assess the relationship between treatment 
group (fixed effect) and the longitudinal trend (random intercept and slope for each subject) in the primary and 
secondary cognitive outcome measures, assessed at 12-weeks, 6 months and 12 months following treatment. 
The primary hypothesis will be tested by assessing the interaction between treatment group and time of cognitive 
follow-up assessment, with a significant interaction indicating a difference in longitudinal cognitive trends 
between treatment groups. Potential confounders (age, gender, education, duration of T2D, HbA1c, diabetes 
medications [insulin vs. no medications and oral agents vs. no medication], levels of atrophy and white matter 
hyperintensities) will be included as covariates if there is imbalance at baseline (p<0.1) or association between 
the covariate and the response (p<0.15).  
To explore whether specific dichotomized T2D characteristics (such as the last HbA1c level 
(dichotomized at 7) in the Diabetes Registry, the number of T2D complications, and the number of severe 
hypoglycemic episodes in the year preceding randomization) are associated with greater improvements following 
treatment with HBOT, mixed effects ANCOVA models similar to those for Aims 1 and 2 will add a main effect for 
the specific T2D characteristic and an interaction term between treatment group and the characteristic. Using 
the MHS dataset, we will also explore associations of dosage of the most prevalently used medications with 
cognitive outcomes. When potential confounders are associated with cognitive outcomes, this also may identify 
subgroups for which HBOT is particularly effective. 
  
Aims 2a and 2b: CBF and cerebral glucose utilization will be analyzed with a similar strategy to Aims 1a 
and 1b except that there will be no 6 month assessment. Mixed effects ANCOVA models will be used to compare 
changes in these outcome measures from baseline to 12 weeks following treatment, and, as exploratory 
analyses, linear mixed effects models will be used to assess relationships between treatment group (fixed effect) 
and the longitudinal trend (random intercept and slope for each subject) in MRI-ASL and FDG-PET outcome 
measures, assessed at 12-weeks and 12 months following treatment. Vascular effects of HBOT vs. Sham: Since 
CBF derived from ASL perfusion may represent combined effects of neural metabolism and vascular effects, a 
secondary mixed effects ANCOVA model (similar to Aim 2b) of vascular changes from baseline to 12 weeks as 
measured by ASL CBF will adjust for neural metabolism derived from FDG-PET. 
Aim 3: Outcome measures (changes in CBF and cerebral glucose utilization) identified as having 
significant associations with treatment group in Aims 2a and 2b will be further explored as mediators of the 
relationship between treatment group and the change in cognition. To ensure that measurement of mediator 

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variables precedes measurement of cognition, we will define the outcome as the change in cognition from 
baseline to 12 months, and the mediators as changes in CBF and cerebral glucose utilization, from baseline to 
12 weeks. The product of coefficients approach will be used within a multiple mediator modeling framework to 
provide point estimates of both the specific indirect effect (i.e. the effect of treatment group on the change in 
cognition from baseline to 12 months via a mediator among other mediators in the model) and the total indirect 
effect (i.e. the sum of specific indirect effects for all mediators in the model). The bootstrapping method93 will be 
used in each multiple mediator model to compute bias-corrected standard errors (and 95% confidence intervals) 
for the specific and total indirect effect point estimates. 
 
 
D7. Power Analysis and sample size justification 
Aim 1. Power is presented for detecting the difference in mean 
change (from baseline to 12 weeks) in overall cognition z-
scores between the sham and HBOT treatment groups. Power 
calculations are based on two-sample t-tests and are 
conducted with a 2-sided 5% significance level (Table 3). A 2-
sample t-test provides a more conservative power estimate 
than the proposed mixed model approach, which is expected 
to explain more variability and thus have more power to detect 
the same effect size with the same sample size.  
The predicted mean change in the sham group from 
baseline to 12 weeks is -0.02 (based on the IDCD 12-week 
change in overall cognition). Assuming an SD of 0.50 in both the sham and HBOT groups, with a minimum 
sample size of 67 patients per arm, we have 80% power to detect an improvement in the HBOT group of 0.224, 
a “medium” effect size of 0.49. To account for an anticipated dropout rate of 13% (a reasonable estimate 
compared to the 5% dropout rate in our stroke study), we plan to enroll 77 patients per group for a total of 154 
patients. Our HBOT trial years after mild traumatic brain injury74 had an effect size of 0.47 for information speed 
processing which is clinically comparable to our primary outcome measure of overall cognition, and our HBOT 
trial on stroke patients78 showed an effect size of 0.49 for the National Institutes of Health stroke scale, 
suggesting our detectable effect size of 0.49 is feasible.   
Aim 2: As for Aim 1, power is presented for detecting the difference in the mean changes in CBF velocity 
and cerebral glucose utilization between the Sham and HBOT groups.  Assuming a mean change in CBF velocity 
of -0.45 in the Sham group and an SD of 5.6 in both groups, with a minimum sample size of 67 patients per arm 
we have 80% power to detect an improvement in the HBOT group of 2.28, an effect size of 0.49. To account for 
an anticipated dropout rate of 13%, we plan to enroll 77 patients per group for a total of 154 patients. For cerebral 
glucose utilization, assuming a mean change in the sham group of -0.08 and an SD of 4.40 in both groups, with 
Table 3: Two group t-test of equal means, equal n's)* 
Outcome 
Overall 
Cognition 
z-score 
CBFV† 
CGU‡ 
 
Sham Mean Change, D1 
-0.020 
-0.450 
-0.08 
HBOT Mean Change, D2 
0.224 
2.28 
2.065 
Difference in means, D1–D2 
-0.244 
-2.73 
-2.145 
HBOT SD 
0.50 
5.60 
4.40 
Minimum N per group 
67 
67 
67 
Enrollment N per group** 
77 
77 
77 
* Test of significance level=0.05; **assuming a 13% drop-out 
rate; Two-sided test; Power=80%; Effect size=0.49; †  CBF= 
CBF; ‡ CGU = cerebral glucose utilization 

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67 patients per group we are powered to detect an improvement in the HBOT group of 2.065, an effect size of 
0.49. According to literature sources48, 123 these are observable effect sizes.  
 
D8. Future directions: If this pilot study is successful, we will pursue a multi-center large-scale clinical trial to 
provide definitive evidence for the benefits of HBOT to cognition in T2D patients at high risk for dementia, taking 
advantage of the new knowledge acquired in this pilot study regarding effect sizes, design, recruitment 
strategies, attrition, cognitive outcomes, biomarkers, and subgroups benefitting most. Since HBOT is widely 
available and well tolerated, the proposed trial’s success may suggest testing HBOT efficacy in non-T2D elderly 
with MCI as well. 
 
 E. 
 HUMAN SUBJECTS RESEARCH 
1. 
Risks to the Subjects - Human Subject Involvement and Characteristics. 
 
a. Involvement and Characteristics: 
Involvement.  The T2D subjects involved in this RCT will participate in neuropsychological assessments involving 
a clinical/diagnostic interview and paper and pencil tests.  In addition, they will be interviewed in a risk factor 
inventory in which basic demographic, some medical information, and past behaviors (e.g. smoking, physical 
activity) will be assessed. In addition, subjects will go through an MRI examination and a PET scan. Subjects 
will be also asked about their activities of daily living and instrumental activities of daily living. Only subjects who 
have a diagnosis of T2D and a diagnosis of MCI will participate in the study. Subjects will be randomized to 
HBOT or sham. Both groups will be treated in the oxygen chamber for 60 sessions, 5 times/week, 90 minutes 
each session and will receive 100% oxygen. The HBOT group will have 2.0 ATA during the treatment while the 
sham group will receive 1.1 ATA during the first and last five minutes of the 90-minute sessions. All other 
conditions and assessments will be identical for the two groups. All assessments will be performed at baseline 
(before treatment), at 12 weeks (immediately after treatment) and at 12 months (to assess maintenance of HBOT 
effects in the long term). At 6 months, only the cognitive assessments will be assessed. Upon informed consent, 
subjects’ long term diabetes characteristics (such as HbA1C, duration of disease, anti-diabetic medication status, 
and hypertension status) will be given by the subject who will provide the investigating team with the 
computerized medical chart from the HMO.  
Characteristics.  Eligibility criteria are summarized in Table 1, section D2a of the application. This study will 
consist of 154 elderly subjects (>65 years of age) who have T2D and a diagnosis of MCI (both amnestic and 
non-amnestic). Subjects must have at least one informant and must speak fluent Hebrew for the 
neuropsychological assessment. Subjects may not have a brain disease that might affect cognition such as 
schizophrenia or Parkinson’s disease, they may not have epilepsy, inner ear disease, or claustrophobia. Subjects 
cannot be receiving cholinesterase inhibitors and cannot have an indication for HBOT, such as diabetic foot, 
since then they cannot be randomized to the sham group. There are no inclusion or exclusion criteria on the 
basis of sex, race, ethnicity, religion, or any other minority affiliations. Within the elderly, Israel is primarily a 

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country of immigrants and subjects may come from over 60 countries, from all continents.  
 
b. Sources of Material.  The sources of the research material will be obtained from individually identified 
living human subjects in the form of digitalized brain scan images, computerized medical records, and interview 
data and medical examination. This material will be obtained specifically for research purposes and only research 
staff will be able to access it.   
 
c. Potential Risks.  The potential risks are small.  The assessments, tests, and questionnaires are 
innocuous, though the subjects may experience some boredom in the course of the interviews. It is possible that 
the perception of a poor performance in the cognitive assessment may lead to some anxiety but not more than 
is experienced in everyday life. Lying down in an MRI for 60 minutes may cause some discomfort and 
claustrophobia. The MRI machine is dangerous to approach when carrying metallic or magnetic objects or if 
subjects have surgical clips, magnetic prostheses, shrapnel or other metallic substances in their body. A study 
doctor will assess each subject just prior to the procedure to ensure that subjects are free of such materials. In 
addition to the MRI technicians, a member of the study team will accompany subjects to reassure participants 
and aid in relaxing them. When subjects finish all MRI procedures, they will lie down for a few minutes; they will 
be seated for another few minutes, until they feel comfortable and secure to stand up and leave. The FDG-PET 
exam will take about 50 minutes and will be performed on a separate day from the MRI so not to over-burden 
the subjects. The HBOT protocol will include 60 sessions, five times/week, for 90 minutes each session, at 2.0 
ATA and 100% oxygen. The sham group will receive exactly the same protocol but with 1.1ATA at the first five 
and last five minutes of the 90-minute sessions. Description of the HBOT, MRI, and FDG-PET risks and the 
measures the study team will take to minimize them are described in the “Adequacy of Protection Against Risks” 
below. 
 
 
2. Adequacy of Protection Against Risks 
a. Recruitment and Informed Consent.  Recruitment will be done through talks in the community, 
advertisements, and companies which have large lists of elderly interested in receiving emails about health 
related topics. All IDCD subjects have signed through the IDCD informed consent that they agree to be 
approached for other research projects. Subjects will have MCI but frank dementia is an exclusion criteria so 
they will have capacity to understand the informed consent (even mild to moderate cases with frank dementia 
typically have capacity to sign consent). Dr. Ravona-Springer, the PI of the Sheba site, is a senior geriatric 
psychiatrist and will perform the diagnostic process to confirm MCI. Cognitive assessments, MRI, and PET scans 
will be performed in Sheba. The HBOT and sham interventions will be performed at the oxygen multiplace 
chamber at Asaf Harofeh. 
Consent will be obtained from the patient. The IRB-approved consent document will explain the purpose 
of the study, procedures to be followed, potential risks and benefits to be expected, costs, treatment alternatives, 
confidentiality statement, an offer to answer questions, a statement regarding the right to refuse to participate or 
withdraw, and a statement on rights and obligations if injury occurs during the course of the trial. 

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Subjects will be told that all identifying information will be maintained solely by the research staff and kept 
strictly confidential. The project will be required to be approved by all three sites IRB committees. The consent 
form informs the subjects upfront that this is a joint study of the Icahn School of Medicine at Mount Sinai, Asaf 
Harofeh, Sheba Medical Center, and University of Wisconsin. Informed consent will be obtained by Dr. Ravona, 
Dr. Efrati, or the other study physicians. All subjects are required to have an informant and the study is fully 
explained to the subjects before the initial assessment is performed. Dr. Efrati will again explain the study and 
the commitment required before entering the oxygen chamber for the first time. Signed and witnessed consents 
are kept in a locked file, in a locked room, with other patient data.  
MRI: For the MRI component of the renewal, subjects will be asked to come to the Sheba Medical Center 
Department of Radiology where the MRI machines are located. Subjects will respond to a detailed questionnaire 
regarding the presence of body metals and only then entered into the magnet. It will be explained to subjects 
that lying down in the MRI may provoke claustrophobia and discomfort, because their head will be in a relatively 
narrow tube and the MRI makes loud sounds. Subjects will be told that the whole MRI session will take 
approximately 60 minutes; afterwards they will rest for a few minutes and sit for a few more minutes, and can 
leave when they feel comfortable.  
FDG-PET- PET imaging involves exposure to small amounts of ionizing radiation, which has no expected harmful 
effects. No adverse effects from radiopharmaceuticals used in this study have been reported. However, the 
possibility exists for a rare reaction to any of the substances or procedures to which the subject is exposed and 
for that reason a physician will be present at all times in the PET-CT area when participants are in the scanner. 
The radiation dose received by the subjects from the [F-18]FDG scan will be below the limits established in 
21CFR §361.1 for whole body (50 mSv), active blood forming organs, lens of eye and gonads (5 rad) and target 
organ (15 rad). The effective human radiation dose for a subject undergoing FDG-PET will be less than 15 mSv, 
based upon the published dosimetry data for FDG. FDG is a commonly used radioligand with no known side-
effects. All radioligand samples will meet strict sterility and quality requirements and are closely monitored. 
HBOT- Hyperbaric oxygen therapy is generally safe and well tolerated. Most side effects are mild and reversible, 
although severe consequences can occur in rare cases89. Middle ear barotrauma is the most common side effect 
of hyperbaric oxygen, with an incidence of less than 2%89. Middle ear effusions (which may be hemorrhagic) and 
tympanic membrane rupture occur in less than 1% of patients. Middle ear symptoms may be alleviated by 
teaching the patient autoinflation techniques which will be done before subjects enter the chamber. Sinus 
barotrauma (sinus squeeze) is the second most common complication of hyperbaric oxygen and is usually seen 
in patients with upper respiratory tract infections. Subjects with such conditions will not be allowed to continue 
the intervention until symptoms are over. Seizures due to central nervous system oxygen toxicity are a rare but 
a possible dramatic consequence of HBOT; estimates of incidence range from 1 in about 3000 to 2.4 per 100,000 
treatments90, 91. The risk is increased by HBOT exposure greater than 120 minutes and by pressures greater 
than 2.8 ATA. In our study, patients will be treated for 90 minutes and at 2.0 ATA. Patients receiving 
glucocorticoids, insulin, thyroid replacement, and sympathomimetic medications may be at higher risk of central 

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nervous system oxygen toxicity. HBOT has been associated with hypoglycemia in some patients with diabetes, 
and hypoglycemia should therefore be considered in the differential diagnosis of HBOT-associated seizures92. 
Seizures due to oxygen toxicity do not typically result in permanent structural brain damage89. In the unlikely 
case of a seizure in this trial, it will be managed acutely by reducing the inspired oxygen concentration to that of 
air (FIO2 = 0.21), administering anticonvulsant therapy, and terminating hyperbaric treatment. Importantly, a 
nurse from the Hyperbaric Unit team will be at all times with the subjects inside the chamber, and a physician 
will be at all times in the Unit providing immediate medical response if any of the adverse events arises. All other 
potential adverse effects (reversible myopia, pulmonary oxygen toxicity) are very rare and reversible.  
 
b. Protection Against Risk.  The overall risks of this proposal are small. Potential risks will be minimized 
by enrolling only participants who meet eligibility requirements and have undergone screening medical 
assessment, including laboratory tests, to ensure health status, warning subjects and their caregivers of potential 
study risks, inquiring about potential adverse reactions at regular intervals and performing screening laboratory 
tests at regular intervals to help ensure continuing good health. Professional treatment will not be altered or 
modified for research purposes. Subjects are informed that they may terminate testing at any time should they 
find any aspect objectionable. The interviewers and research assistants will be clinically trained and sensitive to 
signs of stress, anxiety and/or fatigue. In the event that study participation results in injury or illness requiring 
emergency medical treatment, appropriate acute medical care will be provided at no cost to the subject. A Data 
Safety and Monitoring Board will be established to monitor adverse events and other safety concerns. 
Protection of patient confidentiality and privacy will be rigorously guarded through several measures: 1) by the 
assignment of coded numbers to each file in the computer database; 2) storage of written information in locked 
filing cabinets at all times; 3) storage of electronic information in databases accessible only through a password 
that is not available to anyone outside of the study staff; and 4) no use of names or other identifying information 
in publications or other publicly available documents. However, subjects will be told that should confidential 
information be accidentally disclosed to the wrong party, it could have adverse consequences for the subject in 
terms of liability in legal proceedings, or discrimination in obtaining life or private health insurance.  Again, we 
note that Israelis have the right for complete health coverage. 
 
3. Potential Benefits of the Proposed Research to the Subjects and Others 
 
Risks of this project to the subjects are judged to be small, the discomfort of having an MRI and a PET-
scan, and the potential ear pressure during the HBOT sessions. Potential benefits include improved symptoms 
of cognitive function or slower rate of progression of dementia symptoms. Improved symptoms would be 
expected to improve patient quality of life. These potential benefits exceed the potential harm by HBOT to study 
participants. Additional possible direct benefits are those that might arise from a comprehensive cognitive and 
neuroimaging examination. Such assessments may provide clinically relevant information and lead to referrals 
for otherwise unrecognized cognitive or brain abnormalities that may require treatment. For this reason, the 
relatively small risks to subjects are reasonable in relation to the anticipated benefits to subjects and others. 

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4. Importance of the Knowledge to be Gained. 
 
The overriding aim of this project is to examine the potential beneficial effect of HBOT on cognitive 
function in diabetic elderly who are at high risk of developing dementia since they already have mild cognitive 
impairment. The study will also examine whether HBOT affects beneficially the brain through improved cerebral 
blood flow and glucose uptake. Cognitive decline and dementia are major public health concerns today and will 
only become even greater concern in the future as longevity increases and the age structure of the population 
shifts toward increasingly older ages. Currently, approved treatment for dementia is only modestly effective, and 
it would be an important advance if HBOT will show effectiveness. In relation to this potential benefit, potential 
risks are reasonable. 
 
5. Data Safety and Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will consist of four members, with expertise in the four areas 
relevant to this RCT: type 2 diabetes, cognitive aging, HBOT, and neuroimaging. No investigator involved in the 
trial is a member of the DSMB. The initial task of the DSMB will be to review the protocol, procedures and consent 
form to identify any necessary modifications. If modifications are necessary, revisions will be reviewed by the 
DSMB prior to its recommendation on initiation of the project. The modifications will be submitted and approved 
by the IRBs before study initiation. Throughout the study, any changes to the protocol will be submitted to the 
DSMB. The DSMB will identify the data parameters and format of the information to be regularly reported. The 
DSMB will be informed of the occurrence of any serious adverse events and immediately notified of fatal or life-
threatening events. The DSMB may at any time request additional information from the PI. The DSMB will initially 
be provided with data blinded to treatment status, but they may request an unblinding if there is a safety concern. 
Based on the review of safety data, the DSMB will make recommendations regarding the conduct of the study. 
These may include amending safety-monitoring procedures, modifying the protocol or consent, terminating the 
study or continuing the study as designed. The discussions and decisions of the DSMB will be summarized in 
written reports and provided to the PIs. All DSMB reports will be shared with the Mount Sinai IRB, which is the 
supervisory IRB for this study and which will transfer these reports to the other 2 IRBs involved (Asaf Harfeh, 
Sheba) and will become part of the study regulatory binder. The DSMB will meet in person or by conference call 
on a quarterly basis. The DSMB will also provide advice regarding any discrepancies found by the data auditing 
system or other sources. 
 
6. Data and Safety Monitoring Plan. 
 
a. Data Quality The quality of the data will be monitored by the PIs. The following elements will be 
monitored: recruitment proceeding as expected; subjects fully match the inclusion/exclusion criteria; deviations 

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from the protocol; timeliness, accuracy, and confidentiality of all information both in study documents and 
database.   
 
We are cognizant that overseeing a project that takes place in a geographically distant place and in 
another country poses challenges with respect to data quality and protocol adherence. The successful 
implementation of the IDCD study clearly demonstrates the feasibility of this international collaboration. In 
addition, we will conduct bi-weekly conference calls, one with the data collection team, and one with the senior 
investigators.  Prior to each meeting, Dr. Beeri sends an email compiling the issues that should be discussed. 
The investigators of the study have maintained, literally, email and phone contact on a daily basis. Drs. Beeri 
and Sano work closely for over a decade. Dr. Beeri has international collaborations with all other study 
investigators involving other projects in Israel (IDCD study, IRAP study) and travels every other month to Israel, 
for face to face meetings and review of data and procedures on site. The PIs of the Asaf Harofeh (Dr. Efrati) and 
Sheba (Dr. Ravona) sites are both physician scientists. Thus, the investigators have all the necessary expertise 
relevant for this RCT, have continuous contact, and are well integrated around this (and other) joint dementia-
related projects. 
 
b. Safety Monitoring  Safety monitoring for adverse events (AEs) will be conducted in real time by the 
Drs. Beeri and Sano together with Drs. Efrati and Ravona, both of whom are MDs, the Project Director, Research 
Coordinators, and the IRBs at Mount Sinai, Asaf Harofeh and Sheba and reported to the Data Safety and 
Monitoring Board. They will determine the severity of the event, will assign attribution to the event, and will 
monitor the event until its resolution. All adverse events will be indicated on the source documentation for the 
study, and on the specific adverse event report form. The following information about adverse events will be 
collected: 1) the onset and resolution of the AE, 2) an assessment of the severity or intensity (use existing grading 
scales whenever possible), 3) an assessment of the relationship of the event to the study (definitely, probably, 
possibly or not related), and 4) action taken (e.g., none, referral to MD, start or adjust concomitant medication). 
All serious adverse events (SAEs) will be reported to the three sites’ IRBs within 24 hours of the investigative 
team learning about them. The initial report will be conducted by phone, email or fax. This initial contact will later 
be followed by a written report to the IRB (using their SAE reporting form). All serious adverse events (SAEs) 
will be reported to the DSMB within 48 hours. 
 
F. INCLUSION OF WOMEN AND MINORITIES- Since in Israel about half of those above the age of 65 who 
have type 2 diabetes are women, we anticipate a similar proportion of women in the RCT. A large proportion of 
the Israeli elderly are immigrants from approximately 60 countries and there is no exclusion criteria for any 
country of origin, ethnic group or religion.  
 
G. INCLUSION OF CHILDREN- Children will not participate in this study since it investigates the elderly.  
 
CLINICALTRIALS.GOV REQUIREMENT- This project includes a trial which requires registration in 

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ClinicalTrials.gov. The project will be registered with ClinicalTrials.gov. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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