Reversal of Cognitive Decline: 100 Patients

The first examples of reversal of cognitive decline in Alzheimer’s disease and the pre-Alzheimer’s disease conditions MCI (Mild Cognitive Impairment) and SCI (Subjective Cognitive Impairment) have recently been published. These two publications described a total of 19 patients showing sustained subjective and objective improvement in cognition, using a comprehensive, precision medicine approach that involves determining the potential contributors to the cognitive decline (e.g., activation of the innate immune system by pathogens or intestinal permeability, reduction in trophic or hormonal support, specific toxin exposure, or other contributors), using a computer-based algorithm to determine subtype and then addressing each contributor using a personalized, targeted, multi-factorial approach dubbed ReCODE for reversal of cognitive decline. An obvious criticism of the initial studies is the small number of patients reported. Therefore, we report here 100 patients, treated by several different physicians, with documented improvement in cognition, in some cases with documentation of improvement in electrophysiology or imaging, as well. This additional report provides further support for a randomized, controlled clinical trial of the protocol and the overall approach. Citation: 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


Introduction
Alzheimer's disease is now the third leading cause of death in the United States [1][2][3][4][5][6], and the development of effective treatment and prevention is a major healthcare goal. However, clinical trials of drug candidates for Alzheimer's disease treatment have been almost uniformly unsuccessful. There may be several reasons for such repeated failure: (1) given the long pre-symptomatic period, treatment is typically initiated late in the pathophysiological process; (2) what is referred to as Alzheimer's disease is not a single disease, but rather exhibits several different subtypes [3,4]; (3) just as for other complex chronic illnesses such as cardiovascular disease, there may be many potential contributors to Alzheimer's disease, such as inflammation, various chronic pathogens, trophic withdrawal, insulin resistance, vascular compromise, trauma, and exposure to specific toxins. Therefore, a monotherapeutic, monophasic approach is likely to be suboptimal, and personalized, multiphasic programs based on each individual's genetics and biochemistry may be preferable. Indeed, such personalized programs may offer advantages in future clinical trials of drug candidates. (4) The model of Alzheimer's disease on which the drug targets (e.g., amyloid-β peptide) have been based may be an inaccurate or incomplete model of the disease. model is compatible with the finding that the Aβ peptide functions as an antimicrobial peptide [11], together suggesting that what is referred to as Alzheimer's disease is a protective, network-downsizing response to several classes of insults: pathogens/inflammation, toxins, and withdrawal of nutrients, hormones, or trophic factors [5].
This model suggests that the probability of developing Alzheimer's disease is proportional to the ratio of synaptoclastic signaling to synaptoblastic signaling [5]. This notion has led to a treatment regimen in which the dozens of contributors to synaptoblastic and synaptoclastic signaling are measured for each patient, and a personalized program is generated to target each contributor, thus increasing synaptoblastic signals and reducing identified synaptoclastic signals. Some examples include: (1) identifying and treating pathogens such as Borrelia, Babesia, or Herpes family viruses; (2) identifying gastrointestinal hyperpermeability, repairing the gut, and enhancing the microbiome; (3) identifying insulin resistance and protein glycation, and returning insulin sensitivity and reduced protein glycation; (4) identifying and correcting suboptimal nutrient, hormone, or trophic support (including vascular support); (5) identifying toxins (metallotoxins and other inorganics, organic toxins, or biotoxins), reducing toxin exposure, and detoxifying. Since each patient has a different combination of the many potential contributors to cognitive decline, the approach to treatment is targeted and personalized.
Here we describe 100 patients with cognitive decline treated with this multi-component, precision medicine approach, and showing documented improvement.

Patient 1
A 68-year-old professional woman began to note paraphasic errors in her speech, severe enough that it created confusion in her listeners. She also developed depression, and was treated with an antidepressant. She began to have difficulty with everyday work such as shopping, cooking, and working at the computer. She struggled to complete a gingerbread man with her granddaughter, even though she had done this without difficulty many times before. She confused the minute hand and hour hand on a clock. She had difficulty with spelling. Her symptoms progressed, and she began to forget daily tasks. She became very concerned when she forgot to pick up her grandchildren at school twice in a two-week period.
She was found to be heterozygous for the ε4 allele of apolipoprotein E (ApoE 3/4). An amyloid PET scan (florbetapir) was positive. MRI demonstrated a hippocampal volume of 14 th percentile for her age. High-sensitivity C-reactive protein (hs-CRP) was 1.1 mg/L, fasting insulin 5.6 mIU/L, hemoglobin A1c 5.5%, homocysteine 8.4 micromolar, 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 mcg/dL, complement factor 4a (C4a) 7990 ng/mL, transforming growth factor beta-1 (TGF-β1) 4460 pg/ml, and matrix metalloprotease-9 497 ng/mL. A diagnosis of Mild Cognitive Impairment (MCI) was made, and she was placed on a trial of an anti-amyloid antibody. However, with each administration, her cognition became worse for 3-5 days, then returned toward her previous MCI status. After she had become worse with each of the first four treatments, she discontinued her participation in the study.
She began treatment with the programmatic approach described previously [1]. Her MoCA increased from 24 to 30 over 17 months, and has remained stable for 18 months. Hippocampal volume increased from 14 th percentile to 28 th . Her symptoms improved markedly: her ability to spell returned, her speech improved, and her ability to shop, cook, and work at the computer all improved and have remained stable on follow-up.

Patient 2
A 73-year-old female physician presented with a history of memory decline and word-finding problems that had begun insidiously nearly 20 years previously, but had accelerated over the past year, leading her significant other to describe her memory as "disastrous. " She could not remember recent conversations, plays she had seen, or books she had read, and mixed up the names of people and pets. She had trouble navigating, even difficulty finding her way back to her restaurant table after using the restroom.
Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) scan revealed a decrease in glucose utilization in the anterior superior precuneus bilaterally, as well as the anterolateral left temporal lobe. MRI revealed mild biparietal atrophy, with decreased hippocampal volume (16 th percentile for age). On-line cognitive testing placed her at the 9 th 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 micromolar, 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. She was treated with the programmatic approach described previously [1], and over 12 months, her on-line cognitive assessment improved from the 9 th percentile to the 97 th percentile. Her significant other noted that her memory had improved from "disastrous" to "just plain lousy" and finally to "normal. " She remains on the therapeutic program, and has sustained her improvement.

Patient 3
A 62-year-old woman presented with cognitive decline, fatigue, poor sleep, and depression. She had lost the ability to remember names, do the accounting she had done previously, and run her business.
She was treated with the personalized program described previously [1], which in her case included bio-identical hormone replacement, restoring insulin sensitivity with a mildly ketogenic, plant-rich diet, regular exercise, and stress reduction; enhancing her microbiome with probiotics and prebiotics; reducing systemic inflammation with omega-3 fats; enhancing vitamin D and vitamin K2; enhancing methylation with methyl-cobalamin and methyl-tetrahydrofolate; and 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 symptoms resolved, she was able to reopen her business, and her follow-up MoCA score had risen from 20 to 28. Her improvement has been sustained.

Discussion
Alzheimer's disease represents a major healthcare problem, and the failure to develop effective treatment and prevention for Alzheimer's would have dire consequences nationally and globally, the bankruptcy of Medicare being among them. Therefore, the development of effective treatments is a high priority for translational biomedicine and public health programs throughout the world. However, the area of neurodegenerative diseases is arguably the area of greatest biomedical therapeutic failure from Alzheimer's to Parkinson's to Lewy body disease to amyotrophic lateral sclerosis to frontotemporal dementia to progressive supranuclear paralysis to macular degeneration and other neurodegenerative diseases, there has been no effective treatment with a sustainable, disease-modifying effect.
There may be several reasons for such uniform failure: attempting to treat without identifying the cause(s) and contributors for each patient may be one reason. Assuming a single cause, attempting to treat with a monotherapy, uniform and monophasic, may all contribute to previous suboptimal and ineffective approaches. Furthermore, targeting the mediators (e.g., Aβ peptides) instead of the root causes (e.g., pathogens, toxins, and insulin resistance) may be yet another reason for the lack of success to date.
Here we have taken a very different approach, evaluating and addressing the many potential contributors to cognitive decline for each patient. This has led to unprecedented improvements in cognition. Most importantly, the improvement is typically sustained unless the protocol is discontinued, and even the initial patients treated in 2012 have demonstrated sustained improvement. This effect implies that the root cause(s) of the degenerative process are being targeted, and thus the process itself is impacted, rather than circumventing the process with a monotherapeutic that does not affect the pathophysiology. Therefore, the sustained effect of the protocol represents a major advantage over monotherapeutics.
The current study expands on results reported earlier for 19 patients [1,2], here describing 100 patients with cognitive decline and documented improvement. Most of these patients were shown to have Alzheimer's disease or a pre-Alzheimer's condition, MCI or SCI; the remainder may or may not have had Alzheimer's disease, since the evaluations in those cases did not provide definitive evidence of Alzheimer's, nor did they provide definitive evidence of any other specific degenerative condition. The patients shown to improve included some whose laboratory values suggested each of the major subtypes [3,5] Inflammatory, atrophic, glycotoxic (insulin resistant), and toxic suggesting that the efficacy of this general approach is not restricted to a single subtype of Alzheimer's disease.
The results presented here were obtained by multiple physicians at multiple sites, suggesting that the approach should be scalable and practicable for many physicians. These results should also provide background to support randomized, controlled, prospective clinical trials. Gaining approval for such trials may be difficult, however, since they will necessarily be multi-variable and non-uniform (i.e., personalized). Furthermore, it is highly unlikely that the therapeutic response will act as a linear system, and thus the effect of the program as a whole is unlikely to equal the sum of the effects of each component, making the dissection of the protocol components difficult. However, alternative approaches, such as the removal of single components systematically, or the comparison of large numbers of program effects differing by a few components, may offer some insight into the most and least important components (although of course these may vary from patient to patient).
In the current set of 100 patients, for those evaluated by MoCA, MMSE, or SLUMS pre-and post-treatment (72 of the 100), there was a mean improvement of 4.9 points, with a standard deviation of 2.6 and a range of 1-12. Since the natural history is one of decline, the improvements that were documented must be considered as additional to the prevention of decline that would otherwise have occurred. Of course these numbers must be tempered with any failures that occur, so that it will be important to revise these in the context of a randomized, controlled clinical trial.
One of the benefits of the protocol used here is that it may enhance pharmaceutical testing and clinical trials: given the lack of improvement in the vast majority of monotherapeutic trials to date, it is possible that one problem results from a floor effect, i.e., there may be a threshold In summary, a targeted, personalized, precision medicine approach that addresses the multiple potential contributors to cognitive decline for each patient shows promise for the treatment of Alzheimer's disease and its harbingers, MCI and SCI. The improvements documented in the 100 patients reported here provide support for the performance of a prospective, randomized, controlled clinical trial, especially given the current lack of effective treatment for this common and otherwise terminal illness.