A double‐blind placebo‐controlled clinical trial testing the effect of hyperbaric oxygen therapy on brain and cognitive outcomes of mildly cognitively impaired elderly with type 2 diabetes: Study design

Type 2 diabetes (T2D) is a risk factor for dementia. Ischemia due to vascular pathology is hypothesized to be an underlying mechanism for this association. Hyperbaric oxygen therapy (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. HBOT is approved for the treatment of T2D ischemic non‐healing wounds. Evidence from animal studies and small clinical trials suggests that HBOT improves hypoxic/ischemic brain injuries, consequently inducing brain angiogensis, leading to cognitive improvement.

[1]  J. Bamfo,et al.  Spontaneous , 2020, Definitions.

[2]  Yuwu Zhao,et al.  Protective Effect of Hyperbaric Oxygen Therapy on Cognitive Function in Patients with Vascular Dementia , 2019, Cell transplantation.

[3]  R. Choudhury.  Hypoxia and hyperbaric oxygen therapy: a review , 2018, International journal of general medicine.

[4]  Joseph K. W. Lim,et al.  Regional White Matter Hyperintensity Influences Grey Matter Atrophy in Mild Cognitive Impairment. , 2018, Journal of Alzheimer's disease : JAD.

[5]  Miia Kivipelto,et al.  Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease , 2018, Nature Reviews Neurology.

[6]  J. de Bresser,et al.  Cognitive functioning and structural brain abnormalities in people with Type 2 diabetes mellitus , 2018, Diabetic medicine : a journal of the British Diabetic Association.

[7]  M. Bondi,et al.  Reduced Regional Cerebral Blood Flow Relates to Poorer Cognition in Older Adults With Type 2 Diabetes , 2018, Front. Aging Neurosci..

[8]  G. Biessels,et al.  Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications , 2018, Nature Reviews Endocrinology.

[9]  Christoforos Hadjichrysanthou,et al.  Why do so many clinical trials of therapies for Alzheimer's disease fail? , 2017, The Lancet.

[10]  Shao-da Lin,et al.  Efficacy and Safety of Hyperbaric Oxygen Therapy Used in Patients With Diabetic Foot: A Meta-analysis of Randomized Clinical Trials. , 2017, Clinical therapeutics.

[11]  D. Mathieu,et al.  Correction to Mathieu D, Marroni A, Kot J: Tenth European Consensus Conference on Hyperbaric Medicine: recommendations for accepted and non-accepted clinical indications and practice of hyperbaric oxygen treatment. Diving Hyperb Med. 2017 Mar;47(1):24-32. , 2017, Diving and hyperbaric medicine.

[12]  S. Dohgu,et al.  Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model , 2017, PloS one.

[13]  Alessandro Marroni,et al.  Tenth European Consensus Conference on Hyperbaric Medicine: recommendations for accepted and non-accepted clinical indications and practice of hyperbaric oxygen treatment. , 2017, Diving and hyperbaric medicine.

[14]  R. Swerdlow,et al.  Antioxidants Rescue Mitochondrial Transport in Differentiated Alzheimer's Disease Trans-Mitochondrial Cybrid Cells. , 2016, Journal of Alzheimer's disease : JAD.

[15]  Wei Li,et al.  An Update on Type 2 Diabetes Mellitus as a Risk Factor for Dementia. , 2016, Journal of Alzheimer's disease : JAD.

[16]  M. M. Rahman,et al.  Worldwide trends in diabetes since 1980 : pooled analysis of 751 population-based measurement studies with over 4 . 4 million participants , 2016 .

[17]  M. Prince,et al.  World Alzheimer Report 2015 - The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends , 2015 .

[18]  E. Ben-Jacob,et al.  Improvement of memory impairments in poststroke patients by hyperbaric oxygen therapy. , 2015, Neuropsychology.

[19]  C. Lyketsos,et al.  Modifiable predictors of dementia in mild cognitive impairment: a systematic review and meta-analysis. , 2015, The American journal of psychiatry.

[20]  M. Assadi,et al.  99mTc-ECD brain perfusion SPECT imaging for the assessment of brain perfusion in cerebral palsy (CP) patients with evaluation of the effect of hyperbaric oxygen therapy. , 2015, International journal of clinical and experimental medicine.

[21]  A. Hatzitolios,et al.  Type 2 diabetes is associated with a worse functional outcome of ischemic stroke. , 2014, World journal of diabetes.

[22]  A. Scholey,et al.  Assessing Premorbid Cognitive Ability in Adults With Type 2 Diabetes Mellitus—a Review With Implications for Future Intervention Studies , 2014, Current Diabetes Reports.

[23]  Kristine Yaffe,et al.  Potential for primary prevention of Alzheimer's disease: an analysis of population-based data , 2014, The Lancet Neurology.

[24]  A. Venn,et al.  Type 2 Diabetes, Skin Autofluorescence, and Brain Atrophy , 2014, Diabetes.

[25]  C. Jack,et al.  Diabetes and Elevated Hemoglobin A1c Levels Are Associated with Brain Hypometabolism but Not Amyloid Accumulation , 2014, The Journal of Nuclear Medicine.

[26]  Yongming Zhang,et al.  Hyperbaric Oxygen Therapy Ameliorates Local Brain Metabolism, Brain Edema and Inflammatory Response in a Blast-Induced Traumatic Brain Injury Model in Rabbits , 2014, Neurochemical Research.

[27]  G. Biessels,et al.  Magnitude of Cognitive Dysfunction in Adults with Type 2 Diabetes: A Meta-analysis of Six Cognitive Domains and the Most Frequently Reported Neuropsychological Tests Within Domains , 2014, Journal of the International Neuropsychological Society.

[28]  E. Ben-Jacob,et al.  Reflections on the neurotherapeutic effects of hyperbaric oxygen , 2014, Expert review of neurotherapeutics.

[29]  Vilmundur Gudnason,et al.  Diabetes, markers of brain pathology and cognitive function , 2014, Annals of neurology.

[30]  E. Ben-Jacob,et al.  Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury - Randomized Prospective Trial , 2013, PloS one.

[31]  A. Venn,et al.  Brain Atrophy in Type 2 Diabetes , 2013, Diabetes Care.

[32]  Christina I. Petlura,et al.  Molecular mechanisms linking diabetes to the accelerated development of atherosclerosis. , 2013, Canadian journal of diabetes.

[33]  Costantino Balestra,et al.  The "normobaric oxygen paradox": a new tool for the anesthetist? , 2013, Minerva anestesiologica.

[34]  A. Micarelli,et al.  Neurobiological insight into hyperbaric hyperoxia , 2013, Acta physiologica.

[35]  S. Kuroda,et al.  Validity of Dual MRI and 18F-FDG PET Imaging in Predicting Vulnerable and Inflamed Carotid Plaque , 2013, Cerebrovascular Diseases.

[36]  J. Brade,et al.  Impact of blood glucose, diabetes, insulin, and obesity on standardized uptake values in tumors and healthy organs on 18F-FDG PET/CT. , 2013, Nuclear medicine and biology.

[37]  Sterling C. Johnson,et al.  Insulin Resistance, Brain Atrophy, and Cognitive Performance in Late Middle–Aged Adults , 2013, Diabetes Care.

[38]  E. Ben-Jacob,et al.  Hyperbaric Oxygen Induces Late Neuroplasticity in Post Stroke Patients - Randomized, Prospective Trial , 2013, PloS one.

[39]  Jennifer G. Robinson,et al.  Influence of Type 2 Diabetes on Brain Volumes and Changes in Brain Volumes , 2012, Diabetes Care.

[40]  Sterling C. Johnson,et al.  Low cerebral blood flow is associated with lower memory function in metabolic syndrome , 2012, Obesity.

[41]  G. Biessels,et al.  An update on type 2 diabetes, vascular dementia and Alzheimer's disease , 2012, Experimental Gerontology.

[42]  P. Sachdev,et al.  Higher normal fasting plasma glucose is associated with hippocampal atrophy , 2012, Neurology.

[43]  Reisa A. Sperling,et al.  Executive function and instrumental activities of daily living in mild cognitive impairment and Alzheimer's disease , 2011, Alzheimer's & Dementia.

[44]  M. Viergever,et al.  Microvascular Determinants of Cognitive Decline and Brain Volume Change in Elderly Patients with Type 2 Diabetes , 2010, Dementia and Geriatric Cognitive Disorders.

[45]  Shui-ping Wang,et al.  Hyperbaric oxygen combined with donepezil in the treatment of vascular dementia , 2009 .

[46]  A. Convit,et al.  A blunted cortisol awakening response and hippocampal atrophy in type 2 diabetes mellitus , 2009, Psychoneuroendocrinology.

[47]  Vilmundur Gudnason,et al.  Glycemic Status and Brain Injury in Older Individuals , 2009, Diabetes Care.

[48]  S. Thom,et al.  Physiology and Medicine of Hyperbaric Oxygen Therapy , 2008 .

[49]  R. Petersen,et al.  Mild Cognitive Impairment: An Overview , 2008, CNS Spectrums.

[50]  J. Wardlaw,et al.  Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. , 2007, Brain : a journal of neurology.

[51]  Richard Mayeux,et al.  Relation of diabetes to mild cognitive impairment. , 2007, Archives of neurology.

[52]  P. Scheltens,et al.  Cognitive impairment and MRI correlates in the elderly patients with type 2 diabetes mellitus. , 2007, Age and ageing.

[53]  A. Convit,et al.  Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes , 2007, Diabetologia.

[54]  P. Scheltens,et al.  Brain Lesions on MRI in Elderly Patients with Type 2 Diabetes Mellitus , 2006, European Neurology.

[55]  D. Bennett,et al.  Diabetes is related to cerebral infarction but not to AD pathology in older persons , 2006, Neurology.

[56]  P. Scheltens,et al.  Brain Aging in Very Old Men With Type 2 Diabetes , 2006, Diabetes Care.

[57]  J. Pisarello,et al.  Improvement in motor and cognitive impairment after hyperbaric oxygen therapy in a selected group of patients with cerebrovascular disease: a prospective single-blind controlled trial. , 2005, Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc.

[58]  K. Davis,et al.  Type 2 diabetes is negatively associated with Alzheimer's disease neuropathology. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[59]  J. Schmeidler,et al.  Diabetes mellitus in midlife and the risk of dementia three decades later , 2004, Neurology.

[60]  C. Jack,et al.  Mild cognitive impairment – beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment , 2004, Journal of internal medicine.

[61]  S. Salloway,et al.  Efficacy of donepezil in mild cognitive impairment , 2004, Neurology.

[62]  P. J. Koudstaal,et al.  Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI , 2003, Diabetologia.

[63]  S. Grundy,et al.  The metabolic syndrome , 2003, The Lancet.

[64]  A. Convit,et al.  Reduced glucose tolerance is associated with poor memory performance and hippocampal atrophy among normal elderly , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[65]  N. Sadato,et al.  Neurotoxicity after hypoxia/during ischemia due to glutamate with/without free radicals as revealed by dynamic changes in glucose metabolism , 2000, Brain Research.

[66]  Zhao-Jun Liu,et al.  Hyperbaric oxygen therapy activates hypoxia‐inducible factor 1 (HIF‐1), which contributes to improved wound healing in diabetic mice , 2015, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[67]  M. Assadi,et al.  99 mTc-ECD brain perfusion SPECT imaging for the assessment of brain perfusion in cerebral palsy ( CP ) patients with evaluation of the effect of hyperbaric oxygen therapy , 2015 .

[68]  Graham Dunn,et al.  Complier-Average Causal Effect (CACE) Estimation , 2011, International Encyclopedia of Statistical Science.

[69]  D. Bennett,et al.  The neuropathology of older persons with and without dementia from community versus clinic cohorts. , 2009, Journal of Alzheimer's disease : JAD.

[70]  S. Ferris,et al.  The effects of hyperbaric and normobaric oxygen on cognitive impairment in the elderly. , 1978, Archives of general psychiatry.

[71]  A. Heyman,et al.  Effects of hyperbaric oxygen on behavioral and physiological measures in elderly demented patients. , 1976, Journal of gerontology.