Wednesday, December 17, 2014

Memory loss associated with Alzheimer's can be reversed on early stages

In the first, small study of a novel, personalized and comprehensive program to reverse memory loss, conducted by University of California, Los Angeles (UCLA), nine of 10 participants displayed subjective or objective improvement in their memories beginning within three to six months after the program’s start.

Novel approach to Alzheimer’s treatment

Patient one had two years of progressive memory loss. She was considering quitting her job, which involved analyzing data and writing reports, she got disoriented driving, and mixed up the names of her pets.

Patient two kept forgetting once familiar faces at work, forgot his gym locker combination, and had to have his assistants constantly remind him of his work schedule.

Patient three's memory was so bad she used an iPad to record everything, then forgot her password. Her children noticed she commonly lost her train of thought in mid-sentence, and often asked them if they had carried out the tasks that she mistakenly thought she had asked them to do.

Since its first description over 100 years ago, Alzheimer's disease has been without effective treatment. That may finally be about to change: in the first, small study of a novel, personalized and comprehensive program to reverse memory loss, nine of 10 participants, including the ones above, displayed subjective or objective improvement in their memories beginning within three to six months after the program's start. Of the six patients who had to discontinue working or were struggling with their jobs at the time they joined the study, all were able to return to work or continue working with improved performance. Improvements have been sustained, and as of this writing the longest patient follow-up is two and one-half years from initial treatment. These first ten included patients with memory loss associated with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI; when a patient reports cognitive problems). One patient, diagnosed with late stage Alzheimer's, did not improve.

The study, which comes jointly from the UCLA Mary S. Easton Center for Alzheimer's Disease Research and the Buck Institute for Research on Aging, is the first to suggest that memory loss in patients may be reversed, and improvement sustained, using a complex, 36-point therapeutic program that involves comprehensive changes in diet, brain stimulation, exercise, optimization of sleep, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry.

The findings, published in the current online edition of the journal Aging, "are very encouraging. However, at the current time the results are anecdotal, and therefore a more extensive, controlled clinical trial is warranted," said Dale Bredesen, the Augustus Rose Professor of Neurology and Director of the Easton Center at UCLA, a professor at the Buck Institute, and the author of the paper.

In the case of Alzheimer's disease, Bredesen notes, there is not one drug that has been developed that stops or even slows the disease's progression, and drugs have only had modest effects on symptoms. "In the past decade alone, hundreds of clinical trials have been conducted for Alzheimer's at an aggregate cost of over a billion dollars, without success," he said.

Other chronic illnesses such as cardiovascular disease, cancer, and HIV, have been improved through the use of combination therapies, he noted. Yet in the case of Alzheimer's and other memory disorders, comprehensive combination therapies have not been explored. Yet over the past few decades, genetic and biochemical research has revealed an extensive network of molecular interactions involved in AD pathogenesis. "That suggested that a broader-based therapeutics approach, rather than a single drug that aims at a single target, may be feasible and potentially more effective for the treatment of cognitive decline due to Alzheimer's," said Bredesen.

While extensive preclinical studies from numerous laboratories have identified single pathogenetic targets for potential intervention, in human studies, such single target therapeutic approaches have not borne out. But, said Bredesen, it's possible addressing multiple targets within the network underlying AD may be successful even when each target is affected in a relatively modest way. "In other words," he said, "the effects of the various targets may be additive, or even synergistic."

The uniform failure of drug trials in Alzheimer's influenced Bredesen's research to get a better understanding of the fundamental nature of the disease. His laboratory has found evidence that Alzheimer's disease stems from an imbalance in nerve cell signaling: in the normal brain, specific signals foster nerve connections and memory making, while balancing signals support memory loss, allowing irrelevant information to be forgotten. But in Alzheimer's disease, the balance of these opposing signals is disturbed, nerve connections are suppressed, and memories are lost.

The model of multiple targets and an imbalance in signaling runs contrary to the popular dogma that Alzheimer's is a disease of toxicity, caused by the accumulation of sticky plaques in the brain. Bredesen believes the amyloid beta peptide, the source of the plaques, has a normal function in the brain -- as part of a larger set of molecules that promotes signals that cause nerve connections to lapse. Thus, the increase in the peptide that occurs in Alzheimer's disease shifts the memory-making vs. memory-breaking balance in favor of memory loss.

Given all this, Bredesen thought that rather than a single targeted agent, the solution might be a systems type approach, the kind that is in line with the approach taken with other chronic illnesses -- a multiple-component system.

"The existing Alzheimer's drugs affect a single target, but Alzheimer's disease is more complex. Imagine having a roof with 36 holes in it, and your drug patched one hole very well -- the drug may have worked, a single "hole" may have been fixed, but you still have 35 other leaks, and so the underlying process may not be affected much."

Bredesen's approach is personalized to the patient, based on extensive testing to determine what is affecting the plasticity signaling network of the brain.

Case Studies

Patient one

A 67-year-old woman presented with two years of progressive memory loss. She held a demanding job that involved preparing analytical reports and traveling widely, but found herself no longer able to analyze data or prepare the reports, and therefore was forced to consider quitting her job. She noted that when she would read, by the time she reached the bottom of a page she would have to start at the top once again, since she was unable to remember the material she had just read. She was no longer able to remember numbers, and had to write down even 4-digit numbers to remember them. She also began to have trouble navigating on the road: even on familiar roads, she would become lost trying to figure out where to enter or exit the road. She also noticed that she would mix up the names of her pets, and forget where the light switches were in her home of years.

Her mother had developed similar progressive cognitive decline beginning in her early 60s, had become severely demented, entered a nursing home, and died at approximately 80 years of age. When the patient consulted her physician about her problems, she was told that she had the same problem her mother had had, and that there was nothing he could do about it. He wrote "memory problems" in her chart, and therefore the patient was turned down in her application for long-term care.

After being informed that she had the same problem as her mother had had, she recalled the many years of her mother's decline in a nursing home. Knowing that there was still no effective treatment and subsequently losing the ability to purchase long-term care, she decided to commit suicide. She called a friend to commiserate, who suggested that she get on a plane and visit, and then referred her for evaluation.

She began System, and was able to adhere to some but not all of the protocol components. Nonetheless, after three months she noted that all of her symptoms had abated: she was able to navigate without problems, remember telephone numbers without difficulty, prepare reports and do all of her work without difficulty, read and retain information, and, overall, she became asymptomatic. She noted that her memory was now better than it had been in many years. On one occasion, she developed an acute viral illness, discontinued the program, and noticed a decline, which reversed when she reinstated the program. Two and one-half years later, now age 70, she remains asymptomatic and continues to work full-time.

The patient with the demanding job who was forgetting her way home, her therapeutic program consisted of some, but not all of the components involved with Bredesen's therapeutic program, and included:
(1) eliminating all simple carbohydrates, leading to a weight loss of 20 pounds;
(2) eliminating gluten and processed food from her diet, with increased vegetables, fruits, and non-farmed fish;
(3) to reduce stress, she began yoga;
(4) as a second measure to reduce the stress of her job, she began to meditate for 20 minutes twice per day;
(5) she took melatonin each night;
(6) she increased her sleep from 4-5 hours per night to 7-8 hours per night;
(7) she took methylcobalamin each day;
(8) she took vitamin D3 each day;
(9) fish oil each day;
(10) CoQ10 each day;
(11) she optimized her oral hygiene using an electric flosser and electric toothbrush;
(12) following discussion with her primary care provider, she reinstated hormone replacement therapy that had been discontinued;
(13) she fasted for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime;
(14) she exercised for a minimum of 30 minutes, 4-6 days per week.

Patient two

A 69-year-old entrepreneur and professional man presented with 11 years of slowly progressive memory loss, which had accelerated over the past one or two years. In 2002, at the age of 58, he had been unable to recall the combination of the lock on his locker, and he felt that this was out of the ordinary for him. In 2003, he had FDG-PET (fluoro-deoxyglucose positron emission tomography), which was read as showing a pattern typical for early Alzheimer's disease, with reduced glucose utilization in the parietotemporal cortices bilaterally and left > right temporal lobes, but preserved utilization in the frontal lobes, occipital cortices, and basal ganglia. In 2003, 2007, and 2013, he had quantitative neuropsychological testing, which showed a reduction in CVLT (California Verbal Learning Test) from 84% to 1%, a Stroop color test at 16%, and auditory delayed memory at 13%. In 2013, he was found to be heterozygous for ApoE4 (3/4). He noted that he had progressive difficulty recognizing the faces at work (prosopagnosia), and had to have his assistants prompt him with the daily schedule. He also recalled an event during which he was several chapters into a book before he finally realized that it was a book he had read previously. In addition, he lost an ability he had had for most of his life: the ability to add columns of numbers rapidly in his head.

He began on the therapeutic program, and after six months, his wife, co-workers, and he all noted improvement. He lost 10 pounds. He was able to recognize faces at work unlike before, was able to remember his daily schedule, and was able to function at work without difficulty. He was also noted to be quicker with his responses. His life-long ability to add columns of numbers rapidly in his head, which he had lost during his progressive cognitive decline, returned. His wife pointed out that, although he had clearly shown improvement, the more striking effect was that he had been accelerating in his decline over the prior year or two, and this had been completely halted.

The patient began on the following parts of the overall therapeutic system:
(1) he fasted for a minimum of three hours between dinner and bedtime, and for a minimum of 12 hours between dinner and breakfast;
(2) he eliminated simple carbohydrates and processed foods from his diet;
(3) he increased consumption of vegetables and fruits, and limited consumption of fish to non-farmed, and meat to occasional grass-fed beef or organic chicken;
(4) he took probiotics;
(5) he took coconut oil i tsp bid;
(6) he exercised strenuously, swimming 3-4 times per week, cycling twice per week, and running once per week;
(7) he took melatonin 0.5mg po qhs, and tried to sleep as close to 8 hours per night as his schedule would allow;
(8) he took herbs Bacopa monniera 250mg, Ashwagandha 500mg, and turmeric 400mg each day;
(9) he took methylcobalamin 1mg, methyltetrahydrofolate 0.8mg, and pyridoxine-5-phosphate 50mg each day;
(10) he took citicoline 500mg po bid;
(11) he took vitamin C 1g per day, vitamin D3 5000IU per day, vitamin E 400IU per day, CoQ10 200mg per day, Zn picolinate 50mg per day, and α-lipoic acid 100mg per day;
(12) he took DHA (docosahexaenoic acid) 320mg and EPA (eicosapentaenoic acid) 180mg per day.

Patient three

A 55-year-old attorney suffered progressively severe memory loss for four years. She accidentally left the stove on when she left her home on multiple occasions, and then returned, horrified to see that she had left it on once again. She would forget meetings, and agree to multiple meetings at the same time. Because of an inability to remember anything after a delay, she would record conversations, and she carried an iPad on which she took copious notes (but then forgot the password to unlock her iPad). She had been trying to learn Spanish as part of her job, but was unable to remember virtually anything new. She was unable to perform her job, and she sat her children down to explain to them that they could no longer take advantage of her poor memory, that instead they must understand that her memory loss was a serious problem. Her children noted that she frequently became lost in mid-sentence, that she was slow with responses, and that she frequently asked if they had followed up on something she thought she had asked them to do, when in fact she had never asked them to do the tasks to which she referred.

After five months on the therapeutic program, she noted that she no longer needed her iPad for notes, and no longer needed to record conversations. She was able to work once again, was able to learn Spanish, and began to learn a new legal specialty. Her children noted that she no longer became lost in mid-sentence, no longer thought she had asked them to do something that she had not asked, and answered their questions with normal rapidity and memory.

She began on the following parts of the therapeutic system:
(1) she fasted for a minimum of three hours between dinner and bedtime, and for a minimum of 12 hours between dinner and breakfast;
(2) she eliminated simple carbohydrates and processed foods from her diet;
 (3) she increased consumption of vegetables and fruits, limited consumption of fish to non-farmed, and did not eat meat;
(4) she exercised 4-5 times per week;
(5) she took melatonin 0.5mg po qhs, and tried to sleep as close to 8 hours per night as her schedule would allow;
(6) she tried to reduce stress in her life with meditation and relaxation;
(7) she took methylcobalamin 1mg 4x/wk and pyridoxine-5-phosphate 20mg each day;
(8) she took citicoline 200mg each day;
(9) she took vitamin D3 2000IU per day and CoQ10 200mg per day;
(10) she took DHA 700mg and EPA 500mg bid;
(11) her primary care provider prescribed bioidentical estradiol with estriol (BIEST), and progesterone; (12) her primary care provider worked with her to reduce her bupropion from 150mg per day to 150mg 3x/wk.

General Approach

While the therapeutic programs were designed for each individual, a general theme included the following:

* Supplement with high quality Omega 3s (like KO3+ Krill), and D3 (D3-10,000)
* Exercise 30-40 minutes 5-6 days per week
* Fast for 3 hours before bedtime and 12 hours between dinner and breakfast
* Eliminate simple carbohydrate from the diet
* Increase consumption of vegetables and fruits


The results for nine of the 10 patients reported in the paper suggest that memory loss may be reversed, and improvement sustained with this therapeutic program, said Bredesen. "This is the first successful demonstration," he noted, but he cautioned that the results are anecdotal, and therefore a more extensive, controlled clinical trial is needed.

The downside to this program is its complexity. It is not easy to follow, with the burden falling on the patients and caregivers, and none of the patients were able to stick to the entire protocol. The significant diet and lifestyle changes, and multiple pills required each day, were the two most common complaints. The good news, though, said Bredesen, are the side effects: "It is noteworthy that the major side effect of this therapeutic system is improved health and an optimal body mass index, a stark contrast to the side effects of many drugs."

The results for nine of the 10 patients reported in the paper suggest that memory loss may be reversed, and improvement sustained with this therapeutic program, said Bredesen. "This is the first successful demonstration," he noted, but he cautioned that the results need to be replicated. "The current, anecdotal results require a larger trial, not only to confirm or refute the results reported here, but also to address key questions raised, such as the degree of improvement that can be achieved routinely, how late in the course of cognitive decline reversal can be effected, whether such an approach may be effective in patients with familial Alzheimer's disease, and last, how long improvement can be sustained," he said.

Cognitive decline is a major concern of the aging population. Already, Alzheimer's disease affects approximately 5.4 million Americans and 30 million people globally. Without effective prevention and treatment, the prospects for the future are bleak. By 2050, it is estimated that 160 million people globally will have the disease, including 13 million Americans, leading to potential bankruptcy of the Medicare system. Unlike several other chronic illnesses, Alzheimer's disease is on the rise--recent estimates suggest that AD has become the third leading cause of death in the United States behind cardiovascular disease and cancer.

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