{'fraction_non_alphanumeric': 0.02821770238765174, 'fraction_numerical': 0.01310394726264169, 'mean_word_length': 5.353421859039837, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Hyperbaric oxygen ameliorates cognitive impairment in patients with Alzheimer's disease and amnestic mild cognitive impairment

Abstract Introduction It has been reported that environmental factors such as hypoxia could contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutics like hyperbaric oxygen treatment, which improves tissue oxygen supply and ameliorates hypoxic conditions in the brain, may be an alternative therapy for AD and amnestic mild cognitive impairment (aMCI). The present work aims to investigate the potential therapeutic effect of hyperbaric oxygen treatment for AD and aMCI. Methods We recruited 42 AD, 11 aMCI, and 30 control AD patients in this study. AD and aMCI patients were treated with 40 minutes of hyperbaric oxygen once a day for 20 days and assessed by neuropsychiatric assessments including Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Activities of Daily Living (ADL) scale before and at 1‐, 3‐, and 6‐month follow‐up after treatment. Control AD patients who were not given hyperbaric oxygen treatment had similar clinical profile as hyperbaric oxygen treated AD. We examined 10 of the AD/aMCI patients with fluorodeoxyglucose positron emission tomography. Results In self‐comparison study, one course of hyperbaric oxygen treatment significantly improved the cognitive function assessed by MMSE and MoCA in AD patients after 1‐month follow‐up; such treatment also significantly improved MMSE score at 3‐month follow‐up and MoCA score at 1‐ and 3‐month follow‐up in aMCI patients. The ADL scale was significantly improved in AD patients after 1‐ and 3‐month follow‐up. Compared to the control AD patients, the MMSE and MoCA in hyperbaric oxygen treated AD patients were significantly improved after 1‐month follow‐up. Hyperbaric oxygen treatment also ameliorated the reduced brain glucose metabolism in some of the AD and aMCI patients. Conclusion Based on previous studies and our recent findings, we propose that hyperbaric oxygen treatment may be a promising alternative therapy for AD and aMCI.


INTRODUCTION
Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is generally considered that AD arises through the interactions between genetic and non-genetic factors. 1 Genic factors are dominantly inherited mutations in amyloid beta (A ) precursor protein, presenilin 1, and presenilin 2; and there are several risk genes, including apolipoprotein E, which may contribute to the disease pathogenesis. 2 Non-genetic factors such as brain trauma, cerebrovascular diseases, type 2 diabetes, intellectual activity, sleep disorders, and hypoxia are thought to play an important role in sporadic AD. 3,4 Results from animal studies have indicated that hypoxia affects many aspects of AD-associated pathophysiology including A and tau neuropathy, neuroinflammation, autophagy dysfunction, oxidative stress, and mitochondrial abnormality. [5][6][7][8] In AD patients, comorbidities such as stroke, cardiovascular diseases, obstructive sleep apnea syndrome, and chronic obstructive pulmonary disease (COPD) may cause acute and chronic hypoxic conditions. [8][9][10] A prospective study showed that women with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia. 11 Several studies have reported that high-altitude hypoxia exposure may cause deleterious effects on cognitive performance. 12,13 High altitude decreases brain oxygen saturation, reduces neural activity, induces immune response, and impairs cognitive functions. 14 These evidences imply that hypoxia may be an important culprit for cognitive decline. B hypoxia contributes to the pathogenesis of AD, anti-hypoxia treatment may be helpful to ameliorate the disease. Hyperbaric oxygen treatment is a well-established therapy used to treat neurological conditions by enhancing oxygen delivery to brain tissues and protect neurons. 15,16 According to the epidemiological data in 2005, 24.2 million people worldwide suffer from dementia with 4.6 million new cases per year. By 2040, there will be >81 million people suffering from dementia, 70% of which are AD patients. 17,18 As the population ages, AD will undoubtedly bring significant social and economic burdens to the world. However, there is still no cure or effective treatment to reverse the pathological process of AD. Currently there are only a few anti-AD drugs in clinical use, such as cholinesterase inhibitors (ChEIs; donepezil, rivastigmine, and galantamine), and N-Methyl-Daspartic acid (NMDA) receptor antagonist (memantine). These drugs have a limited therapeutic effect on symptoms and poorly affect the progression of the disease. 19 Despite great efforts to develop new anti-AD drugs aiming to stop the progression of AD, the therapeutic interventions predominantly targeting A pathology have lim-ited success. 20 Other novel therapeutics, including anti-tau and antiinflammation interventions have not successfully yielded any good results. 19,21 Recent studies have indicated that dementia and stroke share some of the pathological risk factors resulting from small vessel degeneration; and dementia could be reduced through stroke prevention by using anticoagulation of atrial fibrillation and quit of smoking. 22,23 Microvascular flow impairment leading to tissue hypoxia has been demonstrated in AD and amnestic mild cognitive impairment (aMCI), and the degree of hypoxia correlates with the extent of cognitive decline. 23 Moreover, the hypoxia condition may cause energy failure resulting in dyshomeostasis of cytosol calcium ion concentration. The breakdown of the calcium ion signaling system is one of the common mechanisms of neurodegeneration. 23 Thus, hyperbaric oxygen treatment, which improves tissue oxygen supply and ameliorates hypoxic conditions, may be a potential therapeutic strategy for AD and aMCI.
In the present study, we recruited 42 AD and 11 aMCI patients for hyperbaric oxygen treatment and 30 AD patients without hyperbaric oxygen treatment as control. All the participants were tested with a battery of neuropsychiatric assessments before and at 1-, 3-, and 6-month follow-up after treatment. We aimed to investigate the potential therapeutic effect of hyperbaric oxygen treatment in patients with AD and aMCI.

Neuropsychiatric assessments
Neuropsychiatric assessments used in the study were MMSE, MoCA, and Activities of Daily Living (ADL) scale. [29][30][31][32] After the clinical history collection, physical examination, laboratory tests, and neuroimaging, the patients were examined with the neuropsychiatric assessments before the hyperbaric oxygen treatment and re-examined at 1-, 3-, and

Fluorodeoxyglucose positron emission tomography
Six of the AD patients and four of the aMCI patients underwent fluorodeoxyglucose positron emission tomography (FDG-P) before and at

Data analysis
Data were analyzed by SPSS 21.0 software (IBM Corporation, Armonk, NY, USA) and GraphPad Prism 8 (GraphPad Software Inc., La Jolla, CA, USA). The results were considered to be statistically significant when P value was <0.05.

MMSE score before and after treatment
Compared to the baseline level, the MMSE score was significantly improved at 1-month follow-up in AD patients (Table 1) and at 3month follow-up in aMCI patients after hyperbaric oxygen treatment (Table 1). Compared to control AD, the hyperbaric oxygen treated AD patients got significant improvement in MMSE score at 1-month follow-up.

MoCA score before and after treatment
The MoCA score was improved significantly at 1-month follow-up in AD patients and at 1-month and 6-month follow-up in aMCI patients after hyperbaric oxygen treatment compared to the baseline level ( Table 2). The six subitems of MoCA scores are summarized in Table 2.
The visuospatial abilities and executive functions were significantly improved at 1-month follow-up and the language and abstract reasoning were significantly improved at 1-, 3-, and 6-month follow-up in AD patients after hyperbaric oxygen treatment compared to baseline level (Table 2). In aMCI patients, the language and abstract reasoning were improved at 1-month follow-up after hyperbaric oxygen treatment.
TA B L E 2 Self-comparison of MoCA scores in AD and aMCI patients before and after hyperbaric oxygen treatment   (Table 2). Compared to control AD, the hyperbaric oxygen treated AD patients got significantly higher MoCA score at 1-month follow-up ( Figure 1).

ADL in AD and aMCI patients before and after hyperbaric oxygen treatment
Compared to the baseline level, the daily living activities of AD patients were significantly improved at 1-month and 3-month follow-up after hyperbaric oxygen treatment (Table 3). There were no significant differences in ADL scores of aMCI patients after the hyperbaric oxygen treatment (Table 3).

MMSE, MoCA, and ADL scores in different stages, medications, and sexes in AD patients after hyperbaric oxygen treatment
The difference of MMSE, MoCA, and ADL scores in disease stages, medications, and sexes AD patients was further analyzed. As shown in   Table S4 in supporting information. The MMSE and MoCA scores were improved significantly at 1-month follow-up after hyperbaric oxygen treatment in both sexes. And the ADL score was increased significantly at 1-and 3-month follow-up after hyperbaric oxygen treatment in female AD patients.

Fluorodeoxyglucose positron emission tomography imaging before and after hyperbaric oxygen treatment
The representative images of AD and aMCI patients are shown in Figure 2. Compared to the images at the baseline, as the disease,

DISCUSSION
Increasing evidence has shown that non-pharmacological interventions have promising roles in the treatment of AD. 33  A and tau pathologies are the two main hypotheses in AD onset and progression. Our previous study reported that chronic hypoxia can increase A deposition and cause learning and memory deficits in AD mice. 5 Moreover, we found that chronic hypoxia can enhance the -secretase activity to promote A production through the downregulation of the DNA methyltransferase 3b to reduce the methylation at CpG sites in promoter region of genes of -secretase components, indicating that chronic hypoxia can aggravate AD pathology through epigenetic modifications. 5 On the other hand, chronic hypoxia may upregulate protein kinases, including GSK-3 and CDK5, and suppress phosphatase, PP2A, leading to an enhanced tau phosphorylation. 48,49 Because hypoxia is involved in AD pathogenesis, hyperbaric oxygen treatment targeting hypoxia may be helpful to delay or ameliorate the progression of AD. Studies have shown that hyperbaric oxygen treatment can improve cognitive behavioral performance, reduce A load and tau hyperphosphorylation, and alleviate neuroinflammation in AD mouse models. 50 Studies have also shown that hyperbaric oxygen decreased lipid peroxidation, inhibited leucocyte activation, and restored the functional blood-brain barrier. 16 Hyperbaric oxygen treatment might be a multi-targeted non-pharmacological intervention for AD. The underlying mechanisms need further investigation.
Hyperbaric oxygen treatment was occasionally studied in vascular dementia, showing that such therapy could improve the cognitive function and enhance the activities of daily living assessed by MMSE and ADL, respectively. 51,52 There was only a case report that hyperbaric oxygen treatment could reverse the patient's symptomatic decline and increase global brain metabolism assessed by. 53 In the present study, considering the ethic issue, approved drug treatment was maintained in hyperbaric oxygen treated AD and control AD. It is not known if the therapeutic effect of hyperbaric oxygen treatment is directly acting on brain functions or indirectly influencing the efficacy of the medications undertaken by AD patients. Multiplecenter studies with larger numbers of participants with or without medications, multiple courses of treatments, and longer time follow-up, should be applied in the future study. Moreover, more measurements of AD progression in addition to neuropsychiatric assessments, such as A levels and neuroimaging, should be performed. Furthermore, earlier application of hyperbaric oxygen treatment in aMCI or in the early stage AD is mostly needed to validate if the procedure can block the conversion from aMCI to AD and reduce the cognitive decline in AD.