Dementia is reversible
Recovery of cognitive abilities of 100 patients
Bredesen et al., Reversal of Cognitive Decline: 100 Patients
Journal of Alzheimers Disease & Parkinsonism, 2018
Abbreviated translation: antontryam, Habr
For a list of references, see the original article.
I present to your attention a translation of an article by Dale Bredesen, director of the Department of Neurodegenerative Diseases at the UCLA School of Medicine, author of "The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline" (The End of Alzheimer's disease: The first program for the prevention and restoration of cognitive functions). If you have a relative or friend suffering from Alzheimer's disease, then the protocol described here may be able to help.
A brief overview
In two previous studies, we obtained the first results of the restoration of cognitive functions in Alzheimer's disease and pre-dementia conditions, 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 the help of a systematic, personalized treatment protocol. The protocol includes the identification of factors that can potentially contribute to the development of dementia, such as inflammation caused by pathogenic microorganisms or increased intestinal permeability, decreased atrophic or hormonal support, exposure to specific toxins, etc. Having assessed the individual profile of the disease for each patient, all potential factors contributing to cognitive decline are corrected. This comprehensive, personalized treatment protocol was originally called MEND (Metabolic Enhancement of Neurodegeneration – metabolic strengthening in neurodegenerative diseases), and now it is called ReCode (Reversal of Cognitive Decline – restoration of cognitive functions).
The obvious drawback 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 of the 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. Nevertheless, all clinical trials of candidate drugs for the treatment of Alzheimer's disease have almost completely failed. There may be several reasons for such a series of failures:
(1) given the long pre-symptomatic period, treatment is usually initiated at 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) just 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, decreased hormone production, insulin resistance, vascular insufficiency, trauma or exposure to certain toxins.
Therefore, a monotherapeutic, monophasic approach is likely to be suboptimal, and personalized, multiphase protocols based on the genetics and biochemistry of each patient individually may be preferable. This protocol can also help the testing of monotherapy drugs if they are tested against the background of appropriate therapy. (4) The Alzheimer's disease model on which drug targets are based (e.g., amyloid-β-peptide) may be an inaccurate or incomplete model of the disease. Thus, it has been shown that the Aß peptide functions as an antimicrobial peptide [11]. This suggests that Alzheimer's disease may be a network-downsizing protective reaction to certain types of adverse factors: pathogens/inflammation, toxins, nutritional deficiencies, hormones or atrophic factors [5].
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 dependence receptor [8-10], i.e. if it receives the optimal amount of atrophic factors, APP is cleaved in the alpha site, which leads to to the production of two synaptoblastic peptides, sAPPa and aCTF. On the contrary, in the absence of an optimal number of atrophic factors, APP is cleaved at beta, gamma and caspase sites, which leads to the production of four synaptoclastic peptides, sAPPß, Aß, Jcasp and C31. In this model, inflammation has an antitrophic effect on APP, partly through the induction of beta-secretase BACE (Beta-site APP-cleaving enzyme) and gamma-secretase by nuclear factor NF-kB. Similarly, toxins such as divalent metals (e.g. mercury) have an antitrophic effect on APP, as they lead to an increase in the production of the toxin-binding peptide Aß. This model is consistent with the discovery that the Aß peptide functions as an antimicrobial peptide [11], which indicates that Alzheimer's disease may be a protective reaction to certain 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 identified for each patient, after which an individual program is created aimed at each factor, increasing synaptoblastic and decreasing synaptoclastic activity. Some examples: (1) detection and treatment of pathogenic microorganisms, for example, viruses of the Borrelia, Babesia or Herpes family; (2) detection and treatment of increased intestinal permeability, microbiome correction; (3) identification of insulin resistance and increased glycation, increased insulin sensitivity and decreased glycation; (4) identification and correction of suboptimal nutritional, hormonal or trophic support (including vascular); (5) detection of toxins (metallotoxins and other inorganic substances, organic toxins or biotoxins), reduction of exposure to toxins and detoxification. Since each patient has a different combination of many factors, the treatment approach is targeted and personalized.
Below we describe 100 patients who received therapy based on this systematic, personalized approach, and showed recovery of cognitive functions.
Description of clinical cases
Patient 1
A 68-year-old woman began to notice paraphasic errors in her speech, serious enough that others began to notice it. She developed depression and was receiving antidepressant treatment. She began to experience difficulties with everyday activities, such as shopping, cooking and working at the computer, communicating with her granddaughter. She confused the minute and hour hands on the clock. She had difficulties with 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 a heterozygous genotype according to ApoE (3/4). Had amyloid, PET scan (florbetapir) was positive. On MRI, the hippocampal volume decreased to the 14th percentile for her age. Highly sensitive C-reactive protein (hs-CRP) was 1.1 mg/l, fasting insulin 5.6 mMU/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 mMU/l, albumin 3.7 g/dl, globulin 2.7 g/dl, total cholesterol 130 mg/dl, triglycerides 29 mg/dl, serum zinc 49 mcg/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 took part in a clinical trial of an anti-amyloid antibody. However, with each administration of the tested drug, her cognitive functions deteriorated for 3-5 days, and then returned to their original state. After four sessions of treatment, she stopped participating in the study.
She started treatment using the systematic approach described here earlier [1]. The results of the MoCA cognitive ability test 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. Symptoms have improved markedly: spelling difficulties went away, her speech improved, and her ability to shop, cook and work at the computer – everything improved and remained stable under further observation.
Patient 2
A 73-year-old female doctor complained of problems with memory and word selection that began about 20 years ago, but worsened over the past year, which led to her close friend describing her memory as "catastrophic." She couldn't remember recent conversations, plays she'd seen, or books she'd read, confused the names of people and pets. It was difficult for her to navigate, even difficult to find her way to a table in a restaurant after visiting the toilet.
Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed a decrease in glucose utilization in the parietal and temporal regions. MRI revealed a decrease in the volume of the hippocampus (16th percentile by age). Cognitive testing put her in the 9th percentile for her age. The ApoE genotype was 3/3, fasting glucose 90 mg/dl, hemoglobin A1c 5.3%, fasting insulin 1.6 mMU/L, homocysteine 14.1 micromol/L, TSH 4.1 mMU/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 systematic approach described earlier [1], testing of her 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 therapy program and continues to see improvements.
Patient 3
The 62-year-old woman suffered from cognitive decline, fatigue, poor sleep and depression. She lost the ability to remember names, keep accounting records, which she had done before, and run her own 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 101 mg/dl, hemoglobin A1c 6.1%, fasting insulin 14 mMU/l, hs-CRP 1.7 mg/L, 25-hydroxycholecalciferol 24 ng/ml, TSH 2.4 mMU/l, free T3 2.9 pg/ml, reverse T3 19 ng/dl, estradiol <6 pg/ml and pregnenolone 38 ng/dl. Testing for pathogens was negative for borrelia, tick-borne infections and viruses of the Herpes family. Toxin testing revealed no signs of mercury or lead toxicity.
She was treated according to the comprehensive program described earlier [1], which in her case included hormone replacement therapy, restoration of insulin sensitivity using a ketogenic and plant-rich diet, regular exercise and stress reduction; correction of the microbiome with probiotics and prebiotics; reduction of systemic inflammation with omega-3 fats; increase in 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 decreased to 21.8, fasting glucose 87 mg/dl, hemoglobin A1c 5.2%, fasting insulin 5.5 mMU/L, hs-CRP 0.5 mg/l, free T3 3.2 pg/ml. TSH 2.1 mMU/l, estradiol 51 pg/lml. Her cognitive symptoms improved, she was able to resume her business, and her MoCA score rose from 20 to 28. The improvement was steady.
In table 1 (see the original article) 100 patients with cognitive impairments caused by Alzheimer's disease and pre-dementia conditions, such as MCI (moderate cognitive impairment) or SCI (subjective cognitive impairment), as well as cognitive decline without a clear diagnosis, are listed. All patients demonstrated 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 failure to develop effective treatment and prevention has severe consequences at the national and global levels. Therefore, the development of effective treatment methods is a top priority for translational biomedicine and public health programs around the world. However, the field of neurodegenerative diseases is arguably 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 may be several reasons for incessant failures in the treatment of neurodegenerative diseases: an attempt to treat all patients equally, without identifying their individual factors, may be one of them. Assuming a single cause, an attempt to treat with monotherapy may lead to suboptimal and ineffective therapeutic approaches. In addition, targeting mediators (e.g. Aß peptides) instead of underlying causes (e.g. 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, assessing and influencing many potential factors contributing to cognitive decline, individually for each patient. This has led to an unprecedented improvement in cognitive functions. Most importantly, the improvement is usually sustainable, provided that the protocol is not terminated. Even the first patients who received treatment in 2012 still show steady improvement. This effect suggests that the underlying cause of the degenerative process is affected. The sustained effect of the system protocol is the main advantage over monotherapy approaches.
This study extends the results previously reported for 19 patients [1,2]. Currently, 100 patients with cognitive decline and documented improvement have been described. Most patients were diagnosed with 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. The assessment of their condition did not provide convincing evidence of AD, nor did it provide convincing evidence of any other specific degenerative disease. Also among the patients who showed improvement were those whose laboratory indicators indicated each of the main subtypes of AD [3,5]: inflammatory, atrophic, glycotoxic (insulin resistant) and toxic. This suggests that the effectiveness of the system protocol is not limited to just one subtype of Alzheimer's disease.
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 a basis for future randomized, controlled, prospective clinical trials. However, obtaining recognition of such tests may be difficult, since they will necessarily 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 equal the sum of the effects of each component, which makes it difficult to analyze each component of the protocol separately. However, alternative approaches, such as step-by-step removal of individual components from the protocol or comparing a large number of protocols that differ in just a few components, can give some idea of the most and least important components (although, of course, they may vary from patient to patient).
Out of 100 patients, 72 were evaluated with 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 usually only a decline is observed in dementia, this result should be considered in the context of additional counteraction to the deterioration of cognitive functions. Of course, these figures need to be adjusted by cases of failures and resistance to therapy, so it is important to review them in the context of a randomized controlled clinical trial.
This protocol can also help the testing of monotherapy drugs. Perhaps the reason for the lack of improvements in the vast majority of monotherapy approaches today is that solving only one problem does not allow you to overcome the threshold required to measure improvements. In addition, the positive effects described here can place patients in a dynamic range at which small both positive and negative effects of the monotherapy approach can be detected.
As more and more patients receive treatment under this protocol, new patterns are likely to emerge: conditions for improvement or lack of improvement, timing, which functions are usually improved and which are not, and related new ideas and approaches. Although this was not emphasized in the cases described here, some observations were still made. For example, relatives of patients noted that they were "more involved" and more responsive to treatment in this particular trial. Facial recognition, navigation, and memory were often improved, while computing and aphasia improved less frequently. For those with specific pathogens or toxins identified, no improvement occurred until they were eliminated. Those patients who had less decline at the beginning of treatment responded more readily and more fully than those who were at a later stage of the disease, which is not surprising. However, there have been examples of improvement even with MoCA scores equal to zero.
Thus, a targeted, personalized approach to the problem, which takes into account many potential factors contributing to cognitive decline 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 may serve as the basis for a prospective randomized controlled clinical trial, especially given the current lack of effective alternative treatment for this common and severe disease.
Thanks
We are grateful to the many doctors who analyze and treat patients with cognitive impairments using this comprehensive protocol. We are especially grateful to Dr. Mary Kay Ross, Hilary Shaftoe and Margaret Conger for visiting some of the patients reported here, Dr. Kristina Lokken, Dr. Jonathan Kanik and Dr. Katayun Shahrokh Walters for neuropsychological testing of some patients, Amanda Williams and Cytoplan Ltd. for providing some supplements for some patients, James and Phyllis Easton for invaluable support in the study, as well as to the Evanthea Foundation for support in the preparation of the clinical trial.
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