Prosthetic memory system successful in humans

April 02, 2018

Scientists at Wake Forest Baptist Medical Center and the University of Southern California (USC) have demonstrated the successful implementation of a prosthetic system that uses a person’s own memory patterns to facilitate the brain’s ability to encode and recall memory.

In the pilot study, published in today’s Journal of Neural Engineering, participants’ short-term memory performance showed a 35 to 37 percent improvement over baseline measurements.

“This is the first time scientists have been able to identify a patient’s own brain cell code or pattern for memory and, in essence, ‘write in’ that code to make existing memory work better, an important first step in potentially restoring memory loss,” said the study’s lead author Robert Hampson, Ph.D., professor of physiology/pharmacology and neurology at Wake Forest Baptist.

The study focused on improving episodic memory, which is the most common type of memory loss in people with Alzheimer’s disease, stroke and head injury. Episodic memory is information that is new and useful for a short period of time, such as where you parked your car on any given day. Reference memory is information that is held and used for a long time, such as what is learned in school.

The researchers enrolled epilepsy patients at Wake Forest Baptist who were participating in a diagnostic brain-mapping procedure that used surgically implanted electrodes placed in various parts of the brain to pinpoint the origin of the patients’ seizures. Using the team’s electronic prosthetic system based on a multi-input multi-output (MIMO) nonlinear mathematical model, the researchers influenced the firing patterns of multiple neurons in the hippocampus, a part of the brain involved in making new memories in eight of those patients.

First, they recorded the neural patterns or ‘codes’ while the study participants were performing a computerized memory task. The patients were shown a simple image, such as a color block, and after a brief delay where the screen was blanked, were then asked to identify the initial image out of four or five on the screen.

The USC team led by biomedical engineers Theodore Berger, Ph.D., and Dong Song, Ph.D., analyzed the recordings from the correct responses and synthesized a MIMO-based code for correct memory performance. The Wake Forest Baptist team played back that code to the patients while they performed the image recall task. In this test, the patients’ episodic memory performance showed a 37 percent improvement over baseline.

In a second test, participants were shown a highly distinctive photographic image, followed by a short delay, and asked to identify the first photo out of four or five others on the screen. The memory trials were repeated with different images while the neural patterns were recorded during the testing process to identify and deliver correct-answer codes.

After another longer delay, Hampson’s team showed the participants sets of three pictures at a time with both an original and new photos included in the sets, and asked the patients to identify the original photos, which had been seen up to 75 minutes earlier. When stimulated with the correct-answer codes, study participants showed a 35 percent improvement in memory over baseline.

“We showed that we could tap into a patient’s own memory content, reinforce it and feed it back to the patient,” Hampson said. “Even when a person’s memory is impaired, it is possible to identify the neural firing patterns that indicate correct memory formation and separate them from the patterns that are incorrect. We can then feed in the correct patterns to assist the patient’s brain in accurately forming new memories, not as a replacement for innate memory function, but as a boost to it.

“To date we’ve been trying to determine whether we can improve the memory skill people still have. In the future, we hope to be able to help people hold onto specific memories, such as where they live or what their grandkids look like, when their overall memory begins to fail.”

The current study is built on more than 20 years of preclinical research on memory codes led by Sam Deadwyler, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist, along with Hampson, Berger and Song. The preclinical work applied the same type of stimulation to restore and facilitate memory in animal models using the MIMO system, which was developed at USC.

The research was funded by the U.S. Defense Advanced Research Projects Agency (DARPA).

Story Source:

Materials provided by Wake Forest Baptist Medical Center. Note: Content may be edited for style and length.

This article was originally published by:
https://www.sciencedaily.com/releases/2018/03/180327194350.htm

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Pre and post testing show reversal of memory loss from Alzheimer’s disease in 10 patients

June 28, 2016

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Results from quantitative MRI and neuropsychological testing show unprecedented improvements in ten patients with early Alzheimer’s disease (AD) or its precursors following treatment with a programmatic and personalized therapy. Results from an approach dubbed metabolic enhancement for neurodegeneration are now available online in the journal Aging.

The study, which comes jointly from the Buck Institute for Research on Aging and the UCLA Easton Laboratories for Neurodegenerative Disease Research, is the first to objectively show that memory loss in patients can be reversed, and improvement sustained, using a complex, 36-point therapeutic personalized 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.

“All of these patients had either well-defined mild cognitive impairment (MCI), subjective cognitive impairment (SCI) or had been diagnosed with AD before beginning the program,” said author Dale Bredesen, MD, a professor at the Buck Institute and professor at the Easton Laboratories for Neurodegenerative Disease Research at UCLA, who noted that patients who had had to discontinue work were able to return to work and those struggling at their jobs were able to improve their performance. “Follow up testing showed some of the patients going from abnormal to normal.”

One of the more striking cases involved a 66-year old professional man whose neuropsychological testing was compatible with a diagnoses of MCI and whose PET scan showed reduced glucose utilization indicative of AD. An MRI showed hippocampal volume at only the 17th percentile for his age. After 10 months on the protocol a follow-up MRI showed a dramatic increase of his hippocampal volume to the 75th percentile, with an associated absolute increase in volume of nearly 12 percent.

In another instance, a 69-year old professional man and entrepreneur, who was in the process of shutting down his business, went on the protocol after 11 years of progressive memory loss. After six months, his wife, co-workers and he noted improvement in memory. A life-long ability to add columns of numbers rapidly in his head returned and he reported an ability to remember his schedule and recognize faces at work. After 22 months on the protocol he returned for follow-up quantitative neuropsychological testing; results showed marked improvements in all categories with his long-term recall increasing from the 3rd to 84th percentile. He is expanding his business.

Another patient, a 49-year old woman who noted progressive difficulty with word finding and facial recognition went on the protocol after undergoing quantitative neuropsychological testing at a major university. She had been told she was in the early stages of cognitive decline and was therefore ineligible for an Alzheimer’s prevention program. After several months on the protocol she noted a clear improvement in recall, reading, navigating, vocabulary, mental clarity and facial recognition. Her foreign language ability had returned. Nine months after beginning the program she did a repeat of the neuropsychological testing at the same university site. She no longer showed evidence of cognitive decline.

All but one of the ten patients included in the study are at genetic risk for AD, carrying at least one copy of the APOE4 allele. Five of the patients carry two copies of APOE4 which gives them a 10-12 fold increased risk of developing AD. “We’re entering a new era,” said Bredesen. “The old advice was to avoid testing for APOE because there was nothing that could be done about it. Now we’re recommending that people find out their genetic status as early as possible so they can go on prevention.” Sixty-five percent of the Alzheimer’s cases in this country involve APOE4; with seven million people carrying two copies of the ApoE4 allele.

Bredesen’ s systems-based approach to reverse memory loss follows the abject failure of monotherapies designed to treat AD and the success of combination therapies to treat other chronic illnesses such as cardiovascular disease, cancer and HIV. Bredesen says decades of biomedical research, both in his and other labs, has revealed that an extensive network of molecular interactions is involved in AD pathogenesis, suggesting that a broader-based therapeutic approach may be more effective. “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 said. “We think addressing multiple targets within the molecular network may be additive, or even synergistic, and that such a combinatorial approach may enhance drug candidate performance, as well.”

While encouraged by the results of the study, Bredesen admits more needs to be done. “The magnitude of improvement in these ten patients is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective,” Bredesen said. “Even though we see the far-reaching implications of this success, we also realize that this is a very small study that needs to be replicated in larger numbers at various sites.” Plans for larger studies are underway.

Cognitive decline is often listed as the major concern of older adults. 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.

Story Source:

The above post is reprinted from materials provided by Buck Institute for Research on Aging. Note: Materials may be edited for content and length.


Journal Reference:

  1. Dale E. Bredesen et al. Reversal of cognitive decline in Alzheimer’s disease. Aging, June 2016 [link]

https://www.sciencedaily.com/releases/2016/06/160616071933.htm

New protein structure could help treat Alzheimer’s, related diseases

July 29, 2014

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There is no cure for Alzheimer’s disease and other forms of dementia, but the research community is one step closer to finding treatment.

University of Washington bioengineers have a designed a peptide structure that can stop the harmful changes of the body’s normal proteins into a state that’s linked to widespread diseases such as Alzheimer’s, Parkinson’s, heart disease, Type 2 diabetes and Lou Gehrig’s disease. The synthetic molecule blocks these proteins as they shift from their normal state into an abnormally folded form by targeting a toxic intermediate phase.

The discovery of a protein blocker could lead to ways to diagnose and even treat a large swath of diseases that are hard to pin down and rarely have a cure.

“If you can truly catch and neutralize the toxic version of these proteins, then you hopefully never get any further damage in the body,” said senior author Valerie Daggett, a UW professor of bioengineering. “What’s critical with this and what has never been done before is that a single peptide sequence will work against the toxic versions of a number of different amyloid proteins and peptides, regardless of their amino acid sequence or the normal 3-D structures.”

The findings were published online this month in the journal eLife.

More than 40 illnesses known as amyloid diseases — Alzheimer’s, Parkinson’s and rheumatoid arthritis are a few — are linked to the buildup of proteins after they have transformed from their normally folded, biologically active forms to abnormally folded, grouped deposits called fibrils or plaques. This happens naturally as we age, to a certain extent — our bodies don’t break down proteins as quickly as they should, causing higher concentrations in some parts of the body.

Each amyloid disease has a unique, abnormally folded protein or peptide structure, but often such diseases are misdiagnosed because symptoms can be similar and pinpointing which protein is present usually isn’t done until after death, in an autopsy.

As a result, many dementias are broadly diagnosed as Alzheimer’s disease without definitive proof, and other diseases can go undiagnosed and untreated.

The molecular structure of an amyloid protein can be only slightly different from a normal protein and can transform to a toxic state fairly easily, which is why amyloid diseases are so prevalent. The researchers built a protein structure, called “alpha sheet,” that complements the toxic structure of amyloid proteins that they discovered in computer simulations. The alpha sheet effectively attacks the toxic middle state the protein goes through as it transitions from normal to abnormal.

The structures could be tailored even further to bind specifically with the proteins in certain diseases, which could be useful for specific therapies.

The researchers hope their designed compounds could be used as diagnostics for amyloid diseases and as drugs to treat the diseases or at least slow progression.

“For example, patients could have a broad first-pass test done to see if they have an amyloid disease and then drill down further to determine which proteins are present to identify the specific disease,” Daggett said.

The research team includes Gene Hopping, Jackson Kellock and James Bryers of UW bioengineering; Gabriele Varani and Ravi Pratap Barnwal of UW chemistry; Peter Law, a former UW graduate student; and Byron Caughey of the National Institutes of Health’s Rocky Mountain Laboratories.

Working with the UW’s Center for Commercialization, they have a patent on one compound and have submitted an application to patent the entire class of related compounds.

This research began a decade ago in Daggett’s lab when a former graduate student, Roger Armen, first discovered this new secondary structure through computer simulations. Daggett’s team was able to prove its validity in recent years by designing stable compounds and testing their ability to bind toxic versions of different amyloid proteins in the lab.

The research was funded by the National Institutes of Health (General Medicine Sciences), the National Science Foundation, the Wallace H. Coulter Foundation and Coins for Alzheimer’s Research Trust.


Story Source:

The above story is based on materials provided by University of Washington. The original article was written by Michelle Ma. Note: Materials may be edited for content and length.

‘Chaperone’ compounds offer new approach to Alzheimer’s treatment

April 21, 2014

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“Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,” said Scott Small, MD, the Boris and Rose Katz Professor of Neurology.  “This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins.”

A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer’s disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer’s.

Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.

“Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,” said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer’s Disease Research Center in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC, and a senior author of the paper. “This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins.”

In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer’s disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer’s-like symptoms. Retromer abnormalities have also been observed in Parkinson’s disease.

In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. “The idea that it would be beneficial to protect a protein’s structure is one that nature figured out a long time ago,” said Dr. Petsko. “We’re just learning how to do that pharmacologically.”

Other researchers had already determined retromer’s three-dimensional structure. “Our challenge was to find small molecules—or pharmacologic chaperones—that could bind to retromer’s weak point and stabilize the whole protein complex,” said Dr. Ringe.

This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.

The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. “One concern was that this compound would be toxic,” said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. “But R55 was found to be relatively non-toxic in mouse neurons in cell culture.”

More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer’s. The researchers are currently testing the clinical effects of R55 in the actual mouse model .

“The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,” said Dr. Petsko. “While we’re testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”


Story Source:

The above story is based on materials provided by Columbia University Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Vincent J Mecozzi, Diego E Berman, Sabrina Simoes, Chris Vetanovetz, Mehraj R Awal, Vivek M Patel, Remy T Schneider, Gregory A Petsko, Dagmar Ringe, Scott A Small. Pharmacological chaperones stabilize retromer to limit APP processing. Nature Chemical Biology, 2014; DOI: 10.1038/nchembio.1508

http://www.sciencedaily.com/releases/2014/04/140420131519.htm