FDA-approved Drugs Slow or Reverse Alzheimer’s

A research team at Washington University School of Medicine in St. Louis has identified potential new treatment targets for Alzheimer’s disease, as well as existing drugs that have therapeutic potential against these targets.

The potential targets are defective proteins that lead to the buildup of amyloid in the brain, contributing to the onset of problems with memory and thinking that are the hallmark of Alzheimer’s. The 15 existing drugs identified by the researchers have been approved by the Food and Drug Administration (FDA) for other purposes, providing the possibility of clinical trials that could begin sooner than is typical, according to the researchers.

In addition, the experiments yielded seven drugs that may be useful for treating faulty proteins linked to Parkinson’s disease, six for stroke and one for amyotrophic lateral sclerosis (ALS).

Scientists have worked for decades to develop treatments for Alzheimer’s by targeting genes rooted in the disease process but have had little success. That approach has led to several dead ends because many of those genes don’t fundamentally alter proteins at work in the brain. The new study takes a different approach, by focusing on proteins in the brain, and other tissues, whose function has been altered.

In this study, we used human samples and the latest technologies to better understand the biology of Alzheimer’s disease,” said principal investigator Carlos Cruchaga, the Reuben Morriss III Professor of Neurology and a professor of psychiatry. “Using Alzheimer’s disease samples, we’ve been able to identify new genes, druggable targets and FDA-approved compounds that interact with those targets to potentially slow or reverse the progress of Alzheimer’s.”

The scientists focused on protein levels in the brain, cerebrospinal fluid (CSF) and blood plasma of people with and without Alzheimer’s disease. Some of the proteins were made by genes previously linked to Alzheimer’s risk, while others were made by genes not previously connected to the disease. After identifying the proteins, the researchers compared their results to several databases of existing drugs that affect those proteins.

The new study, funded by the National Institute on Aging of the National Institutes of Health (NIH), is published in the journal Nature Neuroscience.

Source: https://source.wustl.edu/

What is the Human Cortex?

The cerebral cortex is the thin surface layer of the brain found in vertebrate animals that has evolved most recently, showing the greatest variation in size among different mammals (it is especially large in humans). Each part of the cerebral cortex is six layered (e.g., L2), with different kinds of nerve cells (e.g., spiny stellate) in each layer. The cerebral cortex plays a crucial role in most higher level cognitive functions, such as thinking, memory, planning, perception, language, and attention. Although there has been some progress in understanding the macroscopic organization of this very complicated tissue, its organization at the level of individual nerve cells and their interconnecting synapses is largely unknown.

Petabyte connectomic reconstruction of a volume of human neocortex. Left: Small subvolume of the dataset. Right: A subgraph of 5000 neurons and excitatory (green) and inhibitory (red) connections in the dataset. The full graph (connectome) would be far too dense to visualize.

Mapping the structure of the brain at the resolution of individual synapses requires high-resolution microscopy techniques that can image biochemically stabilized (fixed) tissue. We collaborated with brain surgeons at Massachusetts General Hospital in Boston (MGH) who sometimes remove pieces of normal human cerebral cortex when performing a surgery to cure epilepsy in order to gain access to a site in the deeper brain where an epileptic seizure is being initiated. Patients anonymously donated this tissue, which is normally discarded, to our colleagues in the Lichtman lab. The Harvard researchers cut the tissue into ~5300 individual 30 nanometer sections using an automated tape collecting ultra-microtome, mounted those sections onto silicon wafers, and then imaged the brain tissue at 4 nm resolution in a customized 61-beam parallelized scanning electron microscope for rapid image acquisition.

Imaging the ~5300 physical sections produced 225 million individual 2D images. The team then computationally stitched and aligned this data to produce a single 3D volume. While the quality of the data was generally excellent, these alignment pipelines had to robustly handle a number of challenges, including imaging artifacts, missing sections, variation in microscope parameters, and physical stretching and compression of the tissue. Once aligned, a multiscale flood-filling network pipeline was applied (using thousands of Google Cloud TPUs) to produce a 3D segmentation of each individual cell in the tissue. Additional machine learning pipelines were applied to identify and characterize 130 million synapses, classify each 3D fragment into various “subcompartments” (e.g., axon, dendrite, or cell body), and identify other structures of interest such as myelin and cilia. Automated reconstruction results were imperfect, so manual efforts were used to “proofread” roughly one hundred cells in the data. Over time, the scientists expect to add additional cells to this verified set through additional manual efforts and further advances in automation.

Source: https://ai.googleblog.com/

Neuralink Wants to Implant Human Brain Chips Within a Year

Tesla CEO Elon Musk released a video showing how his company Neuralink – a brain-computer-interface company – had advanced its technology to the point that the chip could allow a monkey to play video games with its mind.

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Neuralink could transition from operating on monkeys to human trials within the year, if the startup meets a previous prediction from Musk. In February, he said the company planned to launch human trials by the end of the year after first mentioning his work with the monkey implants.

At the time, the CEO gave the timeline in response to another user’s request to join human trials for the product, which is designed to implant artificial intelligence into human brains as well as potentially cure neurological diseases like Alzheimer’s and Parkinson’s.

Musk has made similar statements in the past about his project, which was launched in 2016. He said in 2019 that it would be testing on humans by the end of 2020.

There has been a recent flurry of information on the project. Prior to the recent video release on Twitter, Musk had made an appearance on the social media site, Clubhouse, and provided some additional updates on Neuralink back in February.

During his Clubhouse visit, Musk detailed how the company had implanted the chip in the monkey’s brain and talked about how it could play video games using only its mind.

Source: https://www.sciencealert.com/

Intravenous Immunoglobulins Could Stop Thrombosis after Astrazeneca Vaccination

Some people have developed dangerous blood clots in the brain after receiving the corona vaccination with the AstraZeneca preparation The University Medical Center Greifswald in Germany has now broken down the likely cause of the blood clots. According to Andreas Greinacher, he and his team found special antibodies in the blood of those affected, which are directed against the body’s own blood platelets. These cells play an important role in blood clotting. The antibodies activate the platelets: they clump together, as they normally do to close a wound, and thus form blood clots. The basic problem is therefore an autoimmune reaction.

In Germany, 13 cases of sinus vein thrombosis were reported shortly after an AstraZeneca vaccination, all of which were associated with a lack of blood platelets, i.e. a so-called thrombocytopenia. Around 1.6 million people in Germany were vaccinated. According to Greinacher, the problems that arose shortly after the vaccination are similar to a long-known complication with the administration of another agent, heparin-induced thrombocytopenia, or HIT for short. There, too, antibodies activate platelets so that clots form. In both cases the symptoms appear within 5 to 14 days after administration of the preparation. Greinacher therefore emphasized that the flu-like symptoms that often occur on the day after the vaccination are not a warning signal that a blood clot is developing. But anyone who has a painful leg about five days after the vaccination – as a sign of a deep vein thrombosis – or a severe headache should see a doctor immediately.

The Society for Thrombosis and Hemostasis Research has already published recommendations for doctors based on the Greifswald findings. She assumes that the formation of clots in people with sinus vein thrombosis and thrombocytopenia can be stopped by giving high doses of intravenous immunoglobulins. Greinacher could not answer how reliably this therapy helps those affected. That is not his area of expertise, he said.

Source: https://www.uni-greifswald.de/
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https://www.quora.com/

Immunotherapy Drug for Advanced Lung Cancer

Lung cancer spreads to the brain in about one-quarter of patients with an advanced form of the disease. To date, radiation has been the only treatment option, but it comes with toxic side effects. Researchers at Yale Cancer Center (YCC) have found that use of the checkpoint inhibitor pembrolizumab in place of radiation can extend life with very few side effects in this patient population.

The findings, published in The Lancet Oncology, found that patient response depended on the level of the biomarker (PD-L1) expressed in their tumors. Of those that did respond, overall survival at one year was 40% and 34% at two years.

Pembrolizumab monoclonal antibody drug protein.

Survival in this cohort of patients exceeds the historically documented survival for patients with brain metastasis from non-small cell lung cancer or NSCLC, which is a two-year survival of about 14%,” said the study’s lead investigator Sarah B. Goldberg, M.D., M.P.H., associate professor of medicine (medical oncology) at YCC.

This is the first study to specifically test the benefit of the treatment in a prospective clinical trial of lung cancer patients who had not yet been treated for brain metastasis or whose tumors recurred after radiation. Before this, most clinical trials of a checkpoint immunotherapy drug did not include patients with brain metastasis, but the few that did provided hints of benefit when retrospectively analyzed.

Source: https://news.yale.edu/

Blocking Enzymes Reverse Alzheimer’s Memory Loss

Inhibiting certain enzymes involved in abnormal gene transcription may offer a way to restore memory loss associated with Alzheimer’s disease, a new study in mice suggests.

The findings could pave the way toward new treatments for Alzheimer’s disease (AD).

“By treating AD mouse models with a compound to inhibit these enzymes, we were able to normalize gene expression, restore neuronal function, and ameliorate cognitive impairment,” says senior author Zhen Yan, a professor in the department of physiology and biophysics in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo.

Alzheimer’s disease alters the expression of genes in the prefrontal cortex, a key region of the brain controlling cognitive processes and executive functions.

When they focused on gene changes caused by epigenetic processes (those not related to changes in DNA sequences) such as aging, the researchers could reverse elevated levels of harmful genes that cause memory deficits in AD.

The current research extends the work the team reported in 2019 in the journal Brain, in which they reversed the loss or downregulation of genes beneficial to cognitive function in AD.

In the new paper in Science Advances, the team reports they reversed the upregulation of genes involved in impairing cognitive function.

http://www.buffalo.edu/

Nanoparticle Drug-Delivery To Treat Brain Disorders

In the past few decades, researchers have identified biological pathways leading to neurodegenerative diseases and developed promising molecular agents to target them. However, the translation of these findings into clinically approved treatments has progressed at a much slower rate, in part because of the challenges scientists face in delivering therapeutics across the blood-brain barrier (BBB) and into the brain.

To facilitate successful delivery of therapeutic agents to the brain, a team of bioengineers, physicians, and collaborators at Brigham and Women’s Hospital and Boston Children’s Hospital created a nanoparticle platform, which can facilitate therapeutically effective delivery of encapsulated agents in mice with a physically breached or intact BBB. In a mouse model of traumatic brain injury (TBI), they observed that the delivery system showed three times more accumulation in brain than conventional methods of delivery and was therapeutically effective as well, which could open possibilities for the treatment of numerous neurological disorders.

It’s very difficult to get both small and large molecule therapeutic agents delivered across the BBB,” said corresponding author Nitin Joshi, PhD, an associate bioengineer at the Center for Nanomedicine in the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine. “Our solution was to encapsulate therapeutic agents into biocompatible nanoparticles with precisely engineered surface properties that would enable their therapeutically effective transport into the brain, independent of the state of the BBB.”

The technology could enable physicians to treat secondary injuries associated with TBI that can lead to Alzheimer’s, Parkinson’s, and other neurodegenerative diseases, which can develop during ensuing months and years once the BBB has healed.

To be able to deliver agents across the BBB in the absence of inflammation has been somewhat of a holy grail in the field,” said co-senior author Jeff Karp, PhD, of the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine. “Our radically simple approach is applicable to many neurological disorders where delivery of therapeutic agents to the brain is desired.”

Findings were published in Science Advances.

https://www.eurekalert.org/

General Cognitive Assessment Of The Brain In Seven Minutes

React Neuro, a startup founded three years ago by veterans of Harvard Medical School (HMS) and Massachusetts General Hospital (MGH), wants to analyze how healthy your brain is.

Rudy Tanzi, a well-known Alzheimer’s disease researcher and professor of neurology at HMS and MGH, started the company in 2017 with Brian Nahed, a neurosurgical oncologist specializing in brain tumors and associate program director of neurosurgery at MGH and HMS. The two had worked with the NFL for years — Tanzi as a brain-health advisor to the New England Patriots, Nahed as a neurotrauma consultant for the league — and wanted to focus on the issue of concussions in football players. Specifically, they wanted to take a scientific approach to figuring out when a player could safely return to the sport following a concussion. The startup has evolved since then to take a holistic look at brain health through AI software and a VR headset.

From a consumer health standpoint, the idea is essentially [that by] using software, we can assess people’s brain health and provide feedback on what’s working and what’s not working,” said React Neuro CEO Shahid Azim, who joined the company in early 2019. “What really got me interested was not so much the concussion use case, but the more fundamental question that the team was looking to ask, which was, ‘Is there a better way to measure your brain health?’”

React Neuro answers that question with digital exams administered through a custom VR headset, which is developed by Pico Interactive in San Francisco. Designed based on the tools, techniques and exams traditionally used to assess neurological conditions, the tests return results that the startup’s AI software turns into actionable insights for physicians.

Azim, a 2009 MIT Sloan School of Management grad, calls the brain assessments via headsetdigital exams,” or “experiences on screen.” The exams, he said, can last anywhere from two and a half minutes to 10 minutes, depending on the use case. A general cognitive assessment typically lasts seven minutes.

We’re using eye tracking and voice analysis [for the exams],” Azim said. “In some cases, they’re voice-based, so you’re asked to repeat something that you see on the screen.

Source: https://reactneuro.com/
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https://www.bizjournals.com/

Human Brain Cells Gene-edited To reduce The Risk Of Developing Alzheimer’s Disease

Cells in the human brain could one day be edited by scientists to prevent the development of Alzheimer’s disease, a new study suggests. The causes of Alzheimer’s are still not well understood, but a leading theory is that it is triggered by the build-up of a protein called beta-amyloid outside the brain cells. Researchers from Laval University in Canada have been investigating how a key gene in human nerve cells could reduce the formation of this protein. Many variants of this gene increases beta-amyloid production, but one variant, called A673T, instead reduces it.

A673T was first discovered in 2012, and is only active in one in 150 people in Scandinavia, but those that have it are four times less likely to get Alzheimer’s. The researchers believe that switching on this gene variant in brain cells could reduce the production of beta-amyloid and thereby reduce Alzheimer’s risk. As the A673T variant doesn’t become relevant until later in life, it isn’t selected for by evolution, according to the study authors. It differs from other variants of the gene by a single DNA letter. Researchers showed that, by editing this one DNA letter, they were able to activate the A673T variant in brain cells growing in a culture dish. Jacques Tremblay and colleagues say this is the first step to proving that engineering the variant into brains could have the same benefits as inheriting it.

The team are still refining the technique before they try it on animals. The researchers initially used a CRISPR technique called base editing, which allows the direct, irreversible conversion of a DNA base into another, targeted base. However, they have now switched to a relatively new method called prime editing – a ‘search and replace‘ technique for editing genomes that directly writes new genetic information into a targeted DNA site using a fusion protein.  Working with cells in a dish they managed to edit about 40 per cent of the cells, but they think a higher proportion might be needed for it to work in a human brain.

The researchers  worked with a process known as base editing, a relatively new method that allows the direct, irreversible conversion of a DNA base into another, targeted base
Source: https://www.dailymail.co.uk/

Bringing drugs to the brain to treat neurodegenerative diseases

The blood-brain barrier is the main obstacle in treating neurodegenerative diseases such as Alzheimer and Parkinson. According to a recent study conducted by Jean-Michel Rabanel, a postdoctoral researcher under the supervision of Professor Charles Ramassamy, nanoparticles with specific properties could cross this barrier and be captured by neuronal cells. Researchers are confident that these results will open important prospects for releasing drugs directly to the brain. This breakthrough finding would enable improved treatment for neurodegenerative diseases affecting more than 565,000 Canadians, including 141,000 Quebecers.

The blood-brain barrier filters out harmful substances to prevent them from freely reaching the brain. But this same barrier also blocks the passage of drugs,” explains the pharmacologist Charles Ramassamy. Typically, high doses are required to get a small amount of the drug into the brain. What remains in the bloodstream has significant side effects. Often, this discomfort leads the patient to stop the treatment.  The use of nanoparticles, which encapsulate the drugs, would result in fewer collateral side effects while increasing brain efficiency.

To prove the effectiveness of this method, the research team first tested it on cultured cells, then on zebrafish. “This species offers several advantages. Its blood-brain barrier is similar to that of humans and its transparent skin makes it possible to see nanoparticles’ distribution almost in real time,” says Professor Ramassamy, Chairholder of the Louise and André Charron Research Chair on Alzheimer’s disease, from the Fondation Armand-Frappier.

Using in vivo tests, researchers were able to observe the crossing of the blood-brain barrier. They also confirmed the absence of toxicity in the library of selected nanoparticles. “We made the particles with polylactic acid (PLA), a biocompatible material that is easily eliminated by the body. A layer of polyethylene glycol (PEG) covers these nanoparticles and makes them invisible to the immune system, so they can longer circulate in the bloodstream,” he explains.

The findings have been published in the Journal of Controlled Release.

http://www.inrs.ca