Restoration of cognitive abilities of 100 patients (translation of the article by Dale Bredesen)

Hi, Habr! I present to you the translation of the original article by Dale Bredesen, Director of the Department of Neurodegenerative Diseases, Faculty of Medicine, University of California at Los Angeles (UCLA), author of "The End Program Alzheimer's: Prevention Program for Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline and restore cognitive functions). If you have a relative or friend with Alzheimer's disease, the protocol described here may be able to help.

Short review

In two previous studies, we obtained the first results of cognitive function recovery in Alzheimer's disease and pre-dementia states, such as MCI (Mild Cognitive Impairment - Moderate Cognitive Impairment) and SCI (Subjective Cognitive Impairment - Subjective Cognitive Impairment). A total of 19 patients showed sustained subjective and objective improvement in cognitive functions. This was achieved with a systemic, personalized treatment protocol. The protocol includes the identification of factors that could potentially contribute to the development of dementia, such as inflammation caused by pathogenic microorganisms or increased intestinal permeability, a decrease in atrophic or hormonal support, the effect of specific toxins, etc. Having assessed the individual disease profile for each patient, all potential factors contributing to cognitive decline are subject to correction. This comprehensive, personalized treatment protocol was originally called MEND (Metabolic Enhancement of Neurodegeneration - Metabolic Strengthening for Neurodegenerative Diseases), and is now called ReCode (Reversal of Cognitive Decline - Restoration of Cognitive Functions).

The obvious disadvantage of previous studies is a small sample of patients. Therefore, in this study, we described 100 patients who received treatment from several doctors, with documented recovery of cognitive functions. This study may serve as the basis for a future randomized controlled clinical trial protocol.

Introduction

Today, Alzheimer's disease is the third leading cause of death in the United States [1-6], and the development of effective treatment and prevention is a major public health task. However, all clinical trials of candidate Alzheimer's drugs have almost completely failed. There are several reasons for this succession of failures: (1) given the long pre-symptomatic period, treatment usually begins in the late stages of the pathophysiological process; (2) what is called Alzheimer's disease is not a single disease, but rather has several different subtypes [3,4]; (3) as well as for other complex chronic diseases, such as cardiovascular diseases, there may be many potential factors contributing to the development of Alzheimer's disease, such as inflammation, various chronic infections, reduced hormone production, insulin resistance, vascular insufficiency, trauma, or exposure to certain toxins. Consequently, a monotherapeutic, monophasic approach is likely to be suboptimal, and personalized, multi-phase protocols based on the genetics and biochemistry of each patient individually may be preferred. This protocol can also help testing monotherapeutic drugs, if tested against the background of appropriate therapy. (4) The Alzheimer's disease model on which drug targets are based (eg, amyloid-β-peptide) may be an inaccurate or incomplete model of the disease. Thus, it was shown that the Aβ peptide functions as an antimicrobial peptide [11]. This suggests

We advocate a fundamentally different view of Alzheimer's disease [1,2,5,7], in which the amyloid precursor protein APP (Amyloid Precursor Protein) functions as a molecular switch due to its activity as an integrating receptor of dependence [8-10], t . if it receives the optimal amount of atrophic factors, the APP is cleaved at the alpha site, which results in the production of two synaptoblast peptides, sAPPα and αCTF. In contrast, in the absence of an optimal amount of atrophic factors, APP is cleaved at sites beta, gamma and caspase, which leads to the production of four synaptoclast peptides, sAPPβ, Aβ, Jcasp and C31. In this model, inflammation has an anthrophic effect on APP, partly through the induction of beta-secretase BACE (Beta-site APP-cleaving enzyme) and gamma secretase by nuclear factor NF-κB. Similarly, toxins, such as divalent metals (for example, mercury), have an anthrophic effect on APP, since they lead to an increase in the production of the toxin-binding peptide Aβ. This model is consistent with the discovery that the Aβ peptide functions as an antimicrobial peptide [11], indicating that Alzheimer's disease may be a protective response to several types of adverse factors: pathogens / inflammation, toxins, nutritional deficiencies, hormones or atrophic factors [5].

This model suggests that the development of Alzheimer's disease depends on the ratio of synaptoclastic and synaptoblastic activity [5]. This concept implies a treatment regimen in which many factors of synaptoblastic and synaptoclastic activity are detected for each patient, after which an individual program is created aimed at each factor, increasing synaptoblastic and reducing synaptoblastic activity. Some examples are: (1) the identification and treatment of pathogenic microorganisms, for example, Borrelia, Babesia or Herpes viruses; (2) identification and treatment of increased intestinal penetrability, correction of the microbiome; (3) detection of insulin resistance and increased glycation, increased insulin sensitivity and reduced glycation; (4) identification and correction of non-optimal nutrient, hormonal or trophic support (including vascular); (5) identification of toxins (metallotoxins and other inorganic substances, organic toxins or biotoxins), reduction of exposure to toxins and detoxification. Because each patient has a different combination of many factors, the treatment approach is targeted and personalized.

Below, we describe 100 patients who received therapy on the basis of this systemic, personalized approach, and showed the recovery of cognitive functions.

Description of clinical cases

Patient 1

The 68-year-old woman began to notice paraphasic errors in her speech, serious enough for others to notice. She developed depression and was receiving antidepressant medication. She began to experience difficulties with everyday activities, such as shopping, cooking and working at the computer, communicating with her granddaughter. She mixed up the minute and hour hands on the clock. She had difficulty spelling. Her symptoms progressed and she began to forget her daily schedule. She was very worried when she forgot to pick up her grandchildren at school twice in a two-week period.

She had an ApoE heterozygous genotype (3/4). Had amyloid, PET scan (floor betapyr) was positive. On MRI, a decrease in the volume of the hippocampus to the 14th percentile for its age. Highly sensitive C-reactive protein (hs-CRP) was 1.1 mg / l, fasting insulin 5.6 mIU / l, hemoglobin A1c 5.5%, homocysteine ​​8.4 micromol / L, vitamin B12 471 pg / ml, free triiodothyronine (free T3) 2.57 pg / ml, thyroid stimulating hormone (TSH) 0.21 mIU / l, albumin 3.7 g / dl, globulin 2.7 g / dl, total cholesterol 130 mg / dl, triglycerides 29 mg / dl, serum zinc 49 µg / dl, complement factor 4a (C4a) 7990 ng / ml, transforming growth factor beta-1 (TGF-β1) 4460 pg / ml and matrix metalloproteinase-9 497 ng / ml.

She was diagnosed with Mild Cognitive Impairment (MCI), and she took part in the clinical trials of an anti-amyloid antibody. However, with each administration of the test drug, its cognitive functions worsened for 3-5 days, and then returned to its original state. After four treatment sessions, she stopped participating in the study.

She began treatment using the systems approach described here earlier [1]. The MoCA cognitive ability test results increased from 24 to 30 for 17 months and remained stable for 18 months. The volume of the hippocampus increased from the 14th percentile to the 28th. The symptoms improved markedly: the spelling difficulties went away, her speech improved, and her ability to go shopping, cook, and work at the computer — everything improved and remained stable with further observation.

Patient 2

A 73-year-old female doctor complained about memory problems and the choice of words that began about 20 years ago, but worsened over the past year, which led her close friend to describe her memory as "catastrophic." She could not recall recent conversations, plays she had seen, or books she read, confused the names of people and pets. She found it difficult to navigate, it is even difficult to find a way to the table in the restaurant after visiting the toilet.

Fluorodeoxyglucose positron emission tomography (FDG-PET) showed a decrease in glucose utilization in the parietal and temporal regions. An MRI scan revealed a decrease in the volume of the hippocampus (16th percentile by age). Cognitive testing put her on the 9th percentile for her age. ApoE genotype was 3/3, fasting glucose 90 mg / dl, hemoglobin A1c 5.3%, fasting insulin 1.6 mIU / l, homocysteine ​​14.1 micromol / L, TSH 4.1 mIU / ml, free T3 2, 6 pg / ml, reverse T3 22.6 ng / dl, vitamin B12 202 pg / ml, vitamin D 27.4 ng / ml, total cholesterol 226 mg / dl, LDL 121 mg / dl, HDL 92 mg / dl and mercury 7 ng / ml.

After 12 months, as a result of treatment using the system approach described earlier [1], testing of its cognitive functions improved from the 9th to the 97th percentile. Her close friend noted that her memory improved from a state of "catastrophic" to "just lousy" and, finally, to "normal." She remains on the therapeutic program and continues to observe improvements.

Patient 3

A 62-year-old woman suffered from cognitive decline, fatigue, poor sleep and depression. She lost the ability to memorize names, keep accounts, which she did earlier, and run her business.

The body mass index was 24, with a predominance of abdominal fat. MOSA was 20. She was ApoE4 heterozygous (3/4). Fasting serum glucose level 101 mg / dl, hemoglobin A1c 6.1%, fasting insulin 14 mIU / l, hs-CRP 1.7 mg / l, 25-hydroxycholecalciferol 24 ng / ml, TSH 2.4 mIU / l, free T3 is 2.9 pg / ml, reverse T3 is 19 ng / dl, estradiol is <6 pg / ml and pregnenolone is 38 ng / dl. Pathogen testing was negative for borrelia, tick-borne infections, and the Herpes family of viruses. Testing for toxins revealed no signs of mercury or lead toxicity.

She was treated with the complex program described earlier [1], which in her case included hormone replacement therapy, restoration of insulin sensitivity with the help of a ketogenic and plant-rich diet, regular exercise and stress reduction; microbiome correction with probiotics and prebiotics; reduction of systemic inflammation with omega-3 fats; increased vitamin D and K2; regulation of methylation by methyl-cobalamin and methyl tetrahydrofolate; brain training.

Over the next 12 months, she improved her metabolic status: her BMI dropped to 21.8, fasting glucose 87 mg / dl, hemoglobin A1c 5.2%, fasting insulin 5.5 mIU / l, hs-CRP 0.5 mg / l, free T3 3.2 pg / ml TSH 2.1 mIU / l, estradiol 51 pg / ml. Her cognitive symptoms improved, she was able to resume her business, and her MoCA score increased from 20 to 28. The improvement was steady.

In table 1100 patients are listed with cognitive impairment caused by Alzheimer's disease and pre-dementia conditions such as MCI (mild cognitive impairment) or SCI (subjective cognitive impairment), as well as cognitive impairment without clear diagnosis. All patients demonstrated a documented improvement using the same targeted, multi-component approach that was used for the three patients described above.

Discussion

Alzheimer's disease is a major public health problem, and the inability to develop effective treatment and prevention has dire consequences at the national and global levels. Therefore, the development of effective treatments is a top priority for translational biomedicine and public health programs around the world. However, the field of neurodegenerative diseases is probably the area of ​​greatest failure. There is still no effective treatment for Alzheimer's disease, Parkinson's and Levy's disease, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear paresis, macular degeneration and other neurodegenerative diseases.

There can be several reasons for continuing failures in the treatment of neurodegenerative diseases: trying to treat all patients in the same way, without identifying their individual factors, may be one of them. Assuming a single cause, attempting to treat with monotherapy can lead to suboptimal and ineffective therapeutic approaches. In addition, targeting mediators (eg, Aβ peptides) instead of underlying causes (eg, pathogens, toxins and insulin resistance) may be another reason for the lack of success to date.

On the contrary, we used a completely different approach, evaluating and influencing many potential factors contributing to a decrease in cognitive abilities, individually for each patient. This has led to an unprecedented improvement in cognitive function. Most importantly, the improvement is usually sustainable, provided that the protocol does not stop. Even the first patients who received treatment in 2012 still show steady improvement. This effect suggests that the cause is at the root of the degenerative process. The sustained effect of the system protocol is a major advantage over monotherapeutic approaches.

This study extends the results reported previously for 19 patients [1,2]. 100 patients are now described with cognitive decline and documented improvement. Most patients had Alzheimer's disease or a condition preceding Alzheimer's disease: MCI or SCI. Patients with cognitive decline without a clear diagnosis may or may not have Alzheimer's disease. Assessment of their condition did not provide conclusive evidence of BA, nor did it provide conclusive evidence of any other specific degenerative disease. Also among the patients who showed an improvement were those whose laboratory indicators indicated each of the main subtypes of BA [3,5]: inflammatory, atrophic, glycotoxic (insulin resistant) and toxic.

The results presented here were obtained by several doctors in several clinics, which suggests that this approach should be scalable and feasible for many doctors. These results can also serve as the basis for future randomized, controlled, prospective clinical trials. However, obtaining recognition of such tests can be difficult, since they are bound to be multicomponent and heterogeneous (i.e., personalized). In addition, it is highly unlikely that the therapeutic response will act as a linear system, and, therefore, the effect of the program as a whole is unlikely to be equal to the sum of the effects of each component, which makes it difficult to analyze each component of the protocol separately. However, alternative approaches

Of the 100 patients, 72 were evaluated using MoCA, MMSE or SLUMS before and after treatment. The average improvement was 4.9 points, with a standard deviation of 2.6 and a range of 1-12. Since dementia is usually only a decline, this result should be considered in the context of an additional response to cognitive impairment. Of course, these numbers must be corrected by cases of failure and resistance to therapy, so it is important to revise them in the context of a randomized controlled clinical trial.

This protocol may also help test monotherapeutic drugs. Perhaps the reason for the lack of improvement in the overwhelming majority of monotherapeutic approaches today is that solving only one problem does not allow overcoming the threshold needed to measure improvements. In addition, the positive effects described here can put patients in a dynamic range at which small, both positive and negative effects of a monotherapeutic approach can be detected.

As an increasing number of patients receive treatment under this protocol, new patterns are likely to manifest themselves: conditions for improvement or lack of improvement, terms, which functions usually improve and which do not, and the associated new ideas and approaches. Although this was not emphasized in the cases described here, some observations were made. For example, close patients noted that they were “more involved” and more responsive to treatment in this particular test. Face recognition, navigation, and memory often improved, while calculations and aphasia improved less frequently. For those with specific pathogens or toxins, improvement did not occur until they were eliminated. Those patients who had a lesser decline to the start of treatment responded more readily and more fully than those who was at a later stage of the disease, which is not surprising. However, there were examples of improvement, even with MoCA scores of zero.

Thus, a targeted, personalized approach to the problem, which takes into account the many potential factors contributing to a decrease in cognitive functions in each patient individually, is promising for the treatment of Alzheimer's disease and its precursors: MCI and SCI. The improvements documented in the 100 patients described here can serve as the basis for a prospective, randomized controlled clinical trial, especially given the lack of effective alternative treatment for this common and severe disease to date.

Thanks

We are grateful to many doctors who analyze and treat patients with cognitive impairment using this complex protocol. We are especially grateful to Dr. Mary Kay Ross, Hilary Shafto and Margaret Conger for visiting some of the patients reported here, Dr. Christine Lokken, Dr. Jonathan Kanik and Dr. Kathayun Shahroh Walters for neuropsychological testing of some patients, Amanda Williams and Cytoplan Ltd. for providing some supplements for some patients, to James and Phyllis Easton for their invaluable support in the study, and to the Evanthea Foundation for support in preparing a clinical trial.

The authors

Dale E Bredesen ¹ *, Kenneth Sharlin ² , David Jenkins ³ , Miki Okuno ³ , Wes Youngberg ⁴ , Sharon Hausman Cohen ⁵ , Anne Stefani ⁵ , Ronald L Brown ⁶ , Seth Conger ⁶ , Craig Tanio ⁷ , Ann Hathaway ⁸ , Mikhail Kogan ⁹ , David Hagedorn ¹⁰ , Edwin Amos ¹¹ , Amylee Amos ¹² , Nathaniel Bergman ¹³ , Carol Diamond ¹⁴ , Jean Lawrence ¹⁵ , Ilene Naomi Rusk ¹⁶ , Patricia Henry ¹⁶and Mary Braud <sup>16

1</sup> Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
² Sharlin Health and Neurology / Functional Medicine, Ozark, MO, USA
3NeuroHub, Sydney, Australia
⁴ Youngberg Lifestyle Medicine Clinic, Temecula, CA, USA
⁵ Resilient Health, Austin, TX, USA
⁶ Carolina Healthspan Institute, Charlotte, NC, USA
⁷ Rezilir Health, Hollywood, FL, USA
⁸ Integrative Functional Medicine, San Rafael, CA, USA
⁹ GW Center for Integrative Medicine, George Washington University, Washington, DC, USA
¹⁰Coastal Integrative Medicine, Jacksonville, NC, USA
¹¹ Department of Neurology, University of California, Los Angeles, CA, USA
¹² Amos Institute, Los Angeles, CA, USA
¹³ Center for Functional Medicine, Cleveland Clinic, Cleveland, OH, USA
¹⁴ Mount Sinai Hospital, New York, NY, USA
¹⁵ Lawrence Health & Wellness, Toccoa, GA, USA
¹⁶ Brain and Behavior Clinic, Boulder, CO, USA

* Corresponding author: Dale E Bredesen, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA, Tel: +014152541041, Email: dbredesen@buckinstitute.org


Original article:

Bredesen DE, Sharlin K, Jenkins D, Okuno M, Youngberg W, et al. (2018) Reversal of Cognitive Decline: 100 Patients. J Alzheimers Dis Parkinsonism 8: 450. DOI: 10.4172 / 2161-0460.1000450