Abstract
A female patient born in 1931 suffered mental decline for about 1 year. She could no longer conduct her usual activities and home chores and could not hear without a hearing aid. Brain magnetic resonance imaging (MRI) performed in February, 2008, revealed degenerative changes. Treatment consisted of repeated sessions of intermittent hypoxic training (IHT), and individualized vitamins, amino acids, microelements, supplementation, and nutritional adjustment. Until April, 2009, the patient had completed four cycles of IHT and 8 months of the supplementation program. The patient gradually recovered her healthy mental state; she resumed shopping and cooking and began playing piano again, which she was not capable of doing last year. An MRI of her brain performed during April, 2009, showed no degenerative changes.
Background
Diagnostics
A female patient, Mrs. K.G, who was born in 1931, came to my clinic with complaints about declining memory, low energy, low-quality sleep, and loss of interests and motivations. She had a past medical history of moderate hypertension. The patient had a normal weight and did not smoke, consumed alcohol very little, and did not have a family history of neurological conditions. Her medication regimen included the hypotensive Nitrendipin (5 mg), calcium, and vitamin D supplementation.
An examination, including blood analysis, revealed no obvious pathology. However, detailed investigation exposed that during the last year Mrs. K.G. suffered a progressive mental deterioration in spite of her physically active lifestyle; she had swum regularly in the sea until the end of November. She was suffering from declining memory; she could no longer drive a car, cook, or go shopping because she became disorientated and lost directions. She became apathetic; she was losing her hearing and was unable to hear without a hearing aid device. A progressive hearing impairment is known to accompany the onset and development of Alzheimer-type dementia. 1
Brain magnetic resonance imaging (MRI) from February, 2008, showed degenerative changes (hippocampal and cortical atrophy, enlarged volume of ventricles) typical for Alzheimer-type dementia. The neurologist in charge concluded that hardly anything could be done to improve or stabilize the mental deterioration of Mrs. K.G.
Intervention
The regenerative treatment program for this patient included sessions of intermittent hypoxic training (IHT) three to four times a week and an individualized protocol of vitamins, amino acids, microelements, and supplementation, as well as nutritional adjustments. After each cycle of 15 IHT sessions, we paused for 1 month and then repeated the whole cycle again. By April, 2009, the patient had completed four cycles of IHT and 8 months of the supplementation program.
Technically, an IHT session consists of 6–10 repeated, 2- to 6-minute duration intervals of normobaric hypoxic (9–12% O2) air inhalation, interspersed with 3- to 5-minute inhalations of normoxic or hyperoxic air. IHT sessions are repeated 3–6 days a week. Throughout each session, the patient undergoes multiple controlled physiological hypoxia–reoxygenation episodes that in the course of 2–4 weeks of treatment gradually induce a systemic, long-term hypoxia adaptation (hypoxic preconditioning).
During a hypoxic interval, patients experience deep relaxation and a meditative state. While patients comfortably relax in a recliner, their cells and mitochondria go through multiple oscillations of pO2, which are similar, but more deep, compared to those found under intensive physical load. However, in contrast to various physical training regiments, IHT causes no physical stress and poses no risk of injury, whereas its beneficial cellular and systemic effects are significantly more pronounced.
Contraindications to IHT include acute infections, intoxications, exacerbations of chronic inflammatory diseases, fever, acute somatic conditions and trauma (shock syndrome, myocardial infarction, stroke, asthma attack, etc.), and severely decompensated chronic diseases.
Supplementation program
Vitamins, amino acid, and microelement supplementation consisted of two formulas of Dr. Rath's program: Vitacor Plus, 3 tablets a day; Epican Forte, 3 × 2 capsules a day.
Nutritional adjustment
The patient was advised to eat a low-glycemic-index, low-carbohydrate, ketogenic diet, enriched with animal proteins and omega-3 fatty acids. Additionally, Mrs. K.G. was advised to undertake an individualized fasting protocol. Earlier we have found that outpatients could be more conveniently treated with a partial (early daytime) fasting regime that was dubbed extended morning fasting (EMF). The protocol suggests the first meal should be taken not earlier than at 13:00 and the second one not later than at 19:00–20:00. This approach extends physiological night fasting time from usual 12 hours up to 18 h.
Results
The improvement in the mood and vitality of the patient was noticeable after the first five IHT sessions. Gradually, the mental and cognitive state of Mrs. K.G. recovered. She reported increased energy and activity, better memory and cognition, a slight weight loss, improved sleep, and better mood. The patient gradually recovered her previous healthy mental state; she started reading, resumed cooking, and began shopping again. Moreover, she began playing piano, which she would not have been capable of doing last year. Now she only needed the hearing aid for a few hours every day, compared to the whole-day use several months before.
An MRI of her brain was performed in mid April, 2009. According to the conclusion of the neurologist in charge, the volume of ventricles and hippocampus returned to normal. No degenerative changes in the cortex could be noticed.
Discussion
Currently, there is no specific treatment of Alzheimer-type dementia. Data on preventive medications, such as antiinflammatories, Ginkgo biloba, and vitamin E, as well as on experimental medications, are still controversial. According to Stewart, 2 “The best number of medications to use is zero (or sometimes one). When in doubt, get rid of medications!”
Terry 3 summarizes the pathogenetic mechanisms of Alzheimer-type dementia: “Synapse loss causes dementia, not tangles and plaques! Cholinergic loss is a major contributor especially in memory decline. Hyperphosphorylation of Tau causes instability of microtubules, so axoplasmic transport is reduced resulting in loss of synapses. Most of the shrunken neurons in normal aging and most of the lost neurons in AD are glutamatergic. Microglia are activated throughout the cortex, perhaps in response to degeneration of synapses, which is also diffuse. Synapse loss can cause neuron loss because trophic factors get to perikaryon via the synapse and retrograde through the axon.”
The following mechanisms may explain potent effect of described integrative treatment: intermittent oxygen restriction (IOR) is a universal stimulus rapidly triggering multiple compensatory strategies that support genome integrity. 4,5,6 IOR elicits upregulation of cytoglobins (myoglobin and neuroglobin), which function as intracellular O2 buffer and provide protection against reactive nitrogen species (RNS). 7,8 IOR stimulates insulin-independent glucose transport and accumulation of glycogen in the oxygen-sensitive cells, including cardiomyocytes and neurons, thus increasing instantly available intracellular energy reserves. 9 IOR is more efficient than chronic hypoxia in stimulating activator protein-1 and hypoxia-inducible factor-1 (HIF-1), the master proteins responsible for numerous nonspecific protective and adaptational pathways. 8,10 IOR efficiently stimulates erythropoetin (EPO) production. EPO is not only the main regulator of erythropoesis, but also provides multiple adaptogenic and neuroprotective effects. 11,12
Stress-inducible Hsp70, one of the major proteins in the chaperone family, is upregulated by IOR. 13 It was demonstrated recently that overexpression of Hsp70 in skeletal muscle and brain provides protection against injury and facilitates recovery after damage in old animals. 14 The IOR treatement has been shown to stimulate growth hormone and insulin-like growth factor-1 (IGF-1) release, whereas chronic hypoxia suppresses both. 15 In addition, IOR increases production of endogenous antioxidative enzymes, 8 modulates humoral and cellular immunity, 16 and stimulates brain-derived growth factor (BDGF) and glial cells-derived growth factor (GDNF) that provide neuronal protection and regeneration. 17
Physiological hypoxia stimulates proliferation, release, and homing of mesenchimal stem cells (MSCs). 18 At least in some instances, MSCs donate wild-type mitochondrial DNA (mtDNA) by fusion with damaged cells without actually transforming into them. 19 IOR opens an opportunity for enhanced MSC-dependent mitochondrial rejuvenation of alternated, energy-deficient nonreplaceable cells (myocytes, cardiomyocytes, neurons, hormone-producing cells). IHT is the most “engineered” mitochondria-targeting intervention among IOR protocols. 20 IHT purifies mitochondrial populations from mutated mitochondria and prevents mtDNA deletions and mitochondrial structure damage in ischemia–reperfusion in vivo. 8
Under ketogenic diet-induced hypoglycemia, mitochondria switch to metabolizing fat-derived ketones for energy production. Ketone bodies (KBs), consisting of acetoacetate and β-hydroxybutyrate are derived from fat in the liver, and their concentration in blood is inversely related to that of glucose. KBs are more energetically efficient than either pyruvate or fatty acids because they are more reduced (greater hydrogen/carbon ratio) than pyruvate and do not uncouple the mitochondrial proton gradient as occurs with fatty acid metabolism. The amount of acetyl-coenzyme A (CoA) formed from KB metabolism is also greater than that formed from glucose metabolism, which increases adenosine triphosphate (ATP) production. Remarkably, the KB-induced boost in the ATP production is accomplished using less oxygen. 21 In addition, KB metabolism also lessens the production of free radicals, which diminishes tissue inflammation caused by reactive oxygen species (ROS). It is noteworthy that compared to oxidation of fat acids and ketones, glucose oxidation in mitochondria results in significantly higher ROS production. 22 Thus, fat-derived KB are more efficient metabolic fuel than glucose and they also suppress inflammation.
Conclusion
The integrative program of regenerative treatments described here has resulted in recovery of functional neurocognitive status and morphological structure in the brain of a senior female patient suffering from progressive, Alzheimer-type dementia. This positive clinical experience justifies initiation of a pilot study with dementia patients.