Memory loss associated with Alzheimer’s reversed for first time

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 3-to-6 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. As one example, in the case of 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.

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’s 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.

(Image: Corbis)

Can Your Blood Type Affect Your Memory?

People with blood type AB may be more likely to develop memory loss in later years than people with other blood types, according to a study published in the September 10, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology.

AB is the least common blood type, found in about 4 percent of the U.S. population. The study found that people with AB blood were 82 percent more likely to develop the thinking and memory problems that can lead to dementia than people with other blood types. Previous studies have shown that people with type O blood have a lower risk of heart disease and stroke, factors that can increase the risk of memory loss and dementia.

The study was part of a larger study (the REasons for Geographic And Racial Differences in Stroke, or REGARDS Study) of more than 30,000 people followed for an average of 3.4 years. In those who had no memory or thinking problems at the beginning, the study identified 495 participants who developed thinking and memory problems, or cognitive impairment, during the study. They were compared to 587 people with no cognitive problems.

People with AB blood type made up 6 percent of the group who developed cognitive impairment, which is higher than the 4 percent found in the population.

“Our study looks at blood type and risk of cognitive impairment, but several studies have shown that factors such as high blood pressure, high cholesterol and diabetes increase the risk of cognitive impairment and dementia,” said study author Mary Cushman, MD, MSc, of the University of Vermont College of Medicine in Burlington. “Blood type is also related to other vascular conditions like stroke, so the findings highlight the connections between vascular issues and brain health. More research is needed to confirm these results.”

Researchers also looked at blood levels of factor VIII, a protein that helps blood to clot. High levels of factor VIII are related to higher risk of cognitive impairment and dementia. People in this study with higher levels of factor VIII were 24 percent more likely to develop thinking and memory problems than people with lower levels of the protein. People with AB blood had a higher average level of factor VIII than people with other blood types.

(Image credit)

Rigid connections: Molecular basis of age-related memory loss explained

From telephone numbers to foreign vocabulary, our brains hold a seemingly endless supply of information. However, as we are getting older, our ability to learn and remember new things declines. A team of scientists around Associate Prof Dr Antonio Del Sol Mesa from the Luxembourg Centre for Systems Biomedicine of the University of Luxembourg and Dr Ronald van Kesteren of the VU University Amsterdam have identified the molecular mechanisms of this cognitive decline using latest high-throughput proteomics and statistical methods.

The results were published this week in the prestigious scientific journal “Molecular and Cellular Proteomics”.

Brain cells undergo chemical and structural changes, when information is written into our memory or recalled afterwards. Particularly, the number and the strength of connections between nerve cells, the so-called synapses, changes. To investigate why learning becomes more difficult even during healthy ageing, the scientists looked at the molecular composition of brain connections in healthy mice of 20 to 100 weeks of age. This corresponds to a period from puberty until retirement in humans. “Amazingly, there was only one group of four proteins of the so-called extracellular matrix which increased strongly with age. The rest stayed more or less the same,” says Prof Dr Antonio del Sol Mesa from the Luxembourg Centre for Systems Biomedicine.

The extracellular matrix is a mesh right at the connections between brain cells. A healthy amount of these proteins ensures a balance between stability and flexibility of synapses and is vital for learning and memory. “An increase of these proteins with age makes the connections between brain cells more rigid which lowers their ability to adapt to new situations. Learning gets difficult, memory slows down,” Dr Ronald van Kesteren of the VU University Amsterdam elaborates.

In addition, the researchers not only looked at the individual molecules but also analysed the whole picture using a systems biology approach. Here they described the interplay between molecules as networks that together tightly control the amount of individual molecules and their interactions. “A healthy network keeps all molecules in the right level for proper functioning. In older mice we found, however, that the overall molecular composition is more variable compared to younger animals. This shows that the network is losing its control and can be more easily disturbed when we age,” Prof Dr Antonio del Sol Mesa explains. According to the researchers this makes the brain more susceptible to diseases.

Hence, this insight into the normal aging process could also help in the future to better understand complex neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Chemical compounds that modulate the extracellular matrix might be promising new treatments for learning disorders and memory loss.

Restoring Active Memory Program Poised to Launch

Teams will develop and test implantable therapeutic devices for memory restoration in patients with memory deficits caused by disease or trauma

DARPA has selected two universities to initially lead the agency’s Restoring Active Memory (RAM) program, which aims to develop and test wireless, implantable “neuroprosthetics” that can help servicemembers, veterans, and others overcome memory deficits incurred as a result of traumatic brain injury (TBI) or disease.

The University of California, Los Angeles (UCLA), and the University of Pennsylvania (Penn) will each head a multidisciplinary team to develop and test electronic interfaces that can sense memory deficits caused by injury and attempt to restore normal function. Under the terms of separate cooperative agreements with DARPA, UCLA will receive up to $15 million and Penn will receive up to $22.5 million over four years, with full funding contingent on the performer teams successfully meeting a series of technical milestones. DARPA also has a cooperative agreement worth up to $2.5 million in place with Lawrence Livermore National Laboratory to develop an implantable neural device for the UCLA-led effort.

“The start of the Restoring Active Memory program marks an exciting opportunity to reveal many new aspects of human memory and learn about the brain in ways that were never before possible,” said DARPA Program Manager Justin Sanchez. “Anyone who has witnessed the effects of memory loss in another person knows its toll and how few options are available to treat it. We’re going to apply the knowledge and understanding gained in RAM to develop new options for treatment through technology.”

TBI is a serious cause of disability in the United States. Diagnosed in more than 270,000 military servicemembers since 2000 and affecting an estimated 1.7 million U.S. civilians each year, TBI frequently results in an impaired ability to retrieve memories formed prior to injury and a reduced capacity to form or retain new memories following injury. Despite the scale of the problem, no effective therapies currently exist to mitigate the long-term consequences of TBI on memory. Through the RAM program, DARPA seeks to accelerate the development of technology needed to address this public health challenge and help servicemembers and others overcome memory deficits by developing new neuroprosthetics to bridge gaps in the injured brain.

“We owe it to our service members to accelerate research that can minimize the long-term impacts of their injuries,” Sanchez said. “Despite increasingly aggressive prevention efforts, traumatic brain injury remains a serious problem in military and civilian sectors. Through the Restoring Active Memory program, DARPA aims to better understand the underlying neurological basis of memory loss and speed the development of innovative therapies.”

Specifically, RAM performers aim to develop and test wireless, fully implantable neural-interface medical devices that can serve as “neuroprosthetics”—technology that can effectively bridge the gaps that interfere with an individual’s ability to encode new memories or retrieve old ones.

To start, DARPA will support the development of multi-scale computational models with high spatial and temporal resolution that describe how neurons code declarative memories—those well-defined parcels of knowledge that can be consciously recalled and described in words, such as events, times, and places. Researchers will also explore new methods for analysis and decoding of neural signals to understand how targeted stimulation might be applied to help the brain reestablish an ability to encode new memories following brain injury. “Encoding” refers to the process by which newly learned information is attended to and processed by the brain when first encountered.

Building on this foundational work, researchers will attempt to integrate the computational models developed under RAM into new, implantable, closed-loop systems able to deliver targeted neural stimulation that may ultimately help restore memory function. These studies will involve volunteers living with deficits in the encoding and/or retrieval of declarative memories and/or volunteers undergoing neurosurgery for other neurological conditions.

Unique to the UCLA team’s approach is a focus on the portion of the brain known as the entorhinal area. UCLA researchers previously demonstrated that human memory could be facilitated by stimulating that region, which is known to be involved in learning and memory. Considered the entrance to the hippocampus—which helps form and store memories—the entorhinal area plays a crucial role in transforming daily experience into lasting memories. Data collected during the first year of the project from patients already implanted with brain electrodes as part of their treatment for epilepsy will be used to develop a computational model of the hippocampal-entorhinal system that can then be used to test memory restoration in patients.

After developing an advanced, new wireless neuromodulation device—featuring ten-times smaller size and much higher spatial resolution than existing devices—the UCLA team will implant such devices into the entorhinal area and hippocampus of patients with traumatic brain injury.

The Penn team’s approach is based on an understanding that memory is the result of complex interactions among widespread brain regions. Researchers will study neurosurgical patients who have electrodes implanted in multiple areas of their brains for the treatment of various neurological conditions. By recording neural activity from these electrodes as patients play computer-based memory games, the researchers will measure “biomarkers” of successful memory function—patterns of activity that accompany the successful formation of new memories and the successful retrieval of old ones. Researchers could then use those models and a novel neural stimulation and monitoring system—being developed in partnership with Medtronic—to restore brain memory function. The investigational system will simultaneously monitor and stimulate a number of brain sites, which may lead to better understandings of the brain and how brain stimulation therapy can potentially restore normal brain function following injury or the onset of neuropsychological illness.

In addition to human clinical efforts, RAM will support animal studies to advance the state-of-the-art of quantitative models that account for the encoding and retrieval of complex memories and memory attributes, including their hierarchical associations with one another. This work will also seek to identify any characteristic neural and behavioral correlates of memories facilitated by therapeutic devices.

Fight Memory Loss with a Smile (or Chuckle)

Too much stress can take its toll on the body, mood, and mind. As we age it can contribute to a number of health problems, including high blood pressure, diabetes, and heart disease. Recent research has shown that the stress hormone cortisol damages certain neurons in the brain and can negatively affect memory and learning ability in the elderly. Researchers at Loma Linda University have delved deeper into cortisol’s relationship to memory and whether humor and laughter—a well-known stress reliever—can help lessen the damage that cortisol can cause. Their findings were presented on Sunday, April 27, at the Experimental Biology meeting.

Gurinder Singh Bains et al. showed a 20-minute laugh-inducing funny video to a group of healthy elderly individuals and a group of elderly people with diabetes. The groups where then asked to complete a memory assessment that measured their learning, recall, and sight recognition. Their performance was compared to a control group of elderly people who also completed the memory assessment, but were not shown a funny video. Cortisol concentrations for both groups were also recorded at the beginning and end of the experiment.

The research team found a significant decrease in cortisol concentrations among both groups who watched the video. Video-watchers also showed greater improvement in all areas of the memory assessment when compared to controls, with the diabetic group seeing the most dramatic benefit in cortisol level changes and the healthy elderly seeing the most significant changes in memory test scores.

From the authors: “Our research findings offer potential clinical and rehabilitative benefits that can be applied to wellness programs for the elderly,” Dr. Bains said. “The cognitive components—learning ability and delayed recall—become more challenging as we age and are essential to older adults for an improved quality of life: mind, body, and spirit. Although older adults have age-related memory deficits, complimentary, enjoyable, and beneficial humor therapies need to be implemented for these individuals.”

Study co-author and long-time psychoneuroimmunology humor researcher, Dr. Lee Berk, added, “It’s simple, the less stress you have the better your memory. Humor reduces detrimental stress hormones like cortisol that decrease memory hippocampal neurons, lowers your blood pressure, and increases blood flow and your mood state. The act of laughter—or simply enjoying some humor—increases the release of endorphins and dopamine in the brain, which provides a sense of pleasure and reward. These positive and beneficial neurochemical changes, in turn, make the immune system function better. There are even changes in brain wave activity towards what’s called the “gamma wave band frequency”, which also amp up memory and recall. So, indeed, laughter is turning out to be not only a good medicine, but also a memory enhancer adding to our quality of life.”

Brain Implants Hold Promise Restoring Combat Memory Loss

The Pentagon is exploring the development of implantable probes that may one day help reverse some memory loss caused by brain injury.

The goal of the project, still in early stages, is to treat some of the more than 280,000 troops who have suffered brain injuries since 2000, including in combat in Iraq and Afghanistan.

The Defense Advanced Research Projects Agency is focused on wounded veterans, though some research may benefit others such as seniors with dementia or athletes with brain injuries, said Geoff Ling, a physician and deputy director of Darpa’s Defense Sciences office. It’s still far from certain that such work will result in an anti-memory-loss device. Still, word of the project is creating excitement after more than a decade of failed attempts to develop drugs to treat brain injury and memory loss.

“The way human memory works is one of the great unsolved mysteries,” said Andres Lozano, chairman of neurosurgery at the University of Toronto. “This has tremendous value from a basic science aspect. It may have huge implications for patients with disorders affecting memory, including those with dementia and Alzheimer’s disease.”

At least 1.7 million people in the U.S. are diagnosed with memory loss each year, costing the nation’s economy more than $76 billion annually, according to the most recent federal health data. The Department of Veterans Affairs estimates it will spend $4.2 billion to care for former troops with brain injuries between fiscal 2013 and 2022.

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Researchers find ECT can rid the mind of selected memory

A team of researchers working in the Netherlands has found that partial selective memory deletion can be achieved using Electroconvulsive Therapy (ECT). In their paper published in the journal Nature Neuroscience, the team describes a memory experiment they conducted with the assistance of severely depressed people who had already consented to undergoing ECT and found that such treatment could be used to at least partially erase memories of a specified event.

Scientists have known since 1968 (thanks to experiments conducted by psychologist Donald Lewis) that applying a shock to the brain of a rat can cause it to forget something unpleasant it had remembered. Subsequent experiments have found that memories can be blunted using repetitive type therapies or by injecting drugs such as propranolol into the brain. The one element all such findings have in common is that they must be applied during a time when a person is attempting to recall a certain event. Scientists hope that such research may lead to new ways to treat PTSD and other memory related mental ailments. In this new effort the researchers explored the idea of erasing specific memories using ECT.

Currently, people with severe depression who don’t respond to any other type of treatment are offered ECT as a last resort. It has a remarkably good success rate (approximately 86 percent rate of remission) but causes some degree of memory loss. In the Netherlands study, the team enlisted the assistance of 39 such patients who had already agreed to undergo ECT. Instead of receiving just the standard treatment, however, the volunteers were asked to watch two slide shows (along with narration) —both of which contained unsettling content. A week later the participants were divided into three groups—two to get the shock treatment and one to serve as a control group—all were asked to remember and describe one of the traumatic events described in the slide shows. Afterwards, one of the groups was given ECT and then the next day was asked to recount both stores. The other non-control group was given ECT and then were asked right afterwards to recount the unpleasant stories. The control group was asked to try to recount both stories as well.

In comparing the results between the groups, the researchers found that the first group that had been quizzed a day after receiving ECT had difficulty recalling the first story, which they had recounted prior to ECT, but remembered most of second. The second group that received ECT were able to recall both stories equally well, and the third—the control group—were able to remember both stories better than either of the groups that had received ECT.

The experiment suggests that it is possible to selectively erase short term memory in a controlled environment. Much more research will have to be conducted to determine if it would work in real world situations.