Parkinson's disease (PD) is the most common neurodegenerative movement disorder, afflicting more than 10 million people worldwide and more than one million Americans. While there is no cure for PD, current therapies focus on treating motor symptoms and fail to reverse, or even address, the underlying neurological damage. In a new study, researchers at the Medical University of South Carolina (MUSC) have identified a novel role for the regulatory protein Bach1 in PD. Their results, published on Oct. 25 in the Proceedings of the National Academy of Sciences, showed that levels of Bach1 were increased in postmortem PD-affected brains, and that cells without Bach1 were protected from the damages that accumulate in PD. In collaboration with vTv Therapeutics, they identified a potent inhibitor of Bach1, called HPPE, that protected cells from inflammation and the buildup of toxic oxidative stress when administered either before or after the onset of disease symptoms.
"This is the first evidence that Bach1 is dysregulated in Parkinson's disease," said Bobby Thomas, Ph.D., professor of Pediatrics in the College of Medicine and the SmartState COEE Endowed Chair in Pediatric Neurotherapeutics.
In PD, brain cells that produce the chemical messenger dopamine begin to die as the disease progresses, resulting in tremors and other disruptions to motor function. Additionally, as we age, neurons accumulate damage through inflammation and the buildup of toxic oxidative stress.
Dementia—a condition involving the extreme loss of cognitive function—is caused by a variety of disorders, including Alzheimer's disease. According to World Health Organization estimates, approximately 10 million individuals worldwide develop dementia every year, indicating the high psychological and social impact of this condition. Dementia mainly affects older people, and so far, simple and effective strategies for preventing this condition have remained elusive.
In a recent study published in Science Advances, Japanese researchers showed that a low protein diet can accelerate brain degeneration in mouse models of Alzheimer's disease. More importantly, they found that Amino LP7—a supplement containing seven specific amino acids—can slow down brain degeneration and dementia development in these animals. Their work expands on previous studies, which have demonstrated the effectiveness of Amino LP7 in improving cognitive function.
Dr. Makoto Higuchi from the National Institutes for Quantum Sciences and Technology, one of the lead scientists on the study, explains, "In older individuals, low protein diets are linked to poor maintenance of brain function. Amino acids are the building blocks of proteins. So, we wanted to understand whether supplementation with essential amino acids can protect the brains of older people from dementia, and if yes, what mechanisms would contribute to this protective effect."
First, the researchers studied how a low protein diet affects the brain in mouse models of Alzheimer's disease, which generally demonstrate neurodegeneration and abnormal protein aggregates called "Tau" aggregates in the brain. They found that mice consuming a low protein diet not only showed accelerated brain degeneration but also had signs of poor neuronal connectivity. Interestingly, these effects were reversed after supplementation with Amino LP7, indicating that the combination of seven specific amino acids could inhibit brain damage.
For the first time, researchers have used human data to quantify the speed of different processes that lead to Alzheimer's disease and found that it develops in a very different way than previously thought. Their results could have important implications for the development of potential treatments.
The international team, led by the University of Cambridge, found that instead of starting from a single point in the brain and initiating a chain reaction which leads to the death of brain cells, Alzheimer's disease reaches different regions of the brain early. How quickly the disease kills cells in these regions, through the production of toxic protein clusters, limits how quickly the disease progresses overall.
The researchers used post-mortem brain samples from Alzheimer's patients, as well as PET scans from living patients, who ranged from those with mild cognitive impairment to those with full-blown Alzheimer's disease, to track the aggregation of tau, one of two key proteins implicated in the condition.
When immune cells move throughout the brain, they act as the first line of defense against viruses, toxic materials and damaged neurons, rushing over to clear out them.
Researchers at Indiana University School of Medicine have been investigating how these immune cells in the brain—microglia—relate to a gene mutation recently found in Alzheimer's disease patients. They published their findings today in Science Advances.
The study, led by Hande Karahan, Ph.D., postdoctoral fellow in medical and molecular genetics, and Jungsu Kim, Ph.D., the P. Michael Conneally Professor of Medical and Molecular Genetics, found that deleting the gene—called ABI3—significantly increased amyloid-beta plaque accumulation in the brain and decreased the amount of microglia around the plaques.
"This study can provide further insight into understanding the key functions of microglia contributing to the disease and help identify new therapeutic targets," Karahan said.Karahan based her research on a human genetics study of more than 85,000 people—fewer than half were Alzheimer's patients—that identified the mutation in the ABI3 gene. Researchers concluded this mutation increased the risk of late-onset Alzheimer's.
In an unexpected discovery, Georgetown University Medical Center researchers have identified what appears to be a significant vascular defect in patients with moderately severe Parkinson's disease. The finding could help explain an earlier outcome of the same study, in which the drug nilotinib was able to halt motor and non-motor (cognition and quality of life) decline in the long term.
The researchers say their finding, detailed in a study published November 12, 2021, in Neurology Genetics, suggests that blood vessel walls called the blood brain barrier, which normally act as a crucial filter to protect the brain against toxins as well as allow passage of nutrients to nourish it, doesn't work correctly in some Parkinson's patients: It prohibits toxins from leaving the brain and inhibits nutrients such as glucose from entering. Perhaps even more damaging, the dysfunctional barrier allows inflammatory cells and molecules from the body to enter and damage the brain.
The research, the first longitudinal study to use such advanced genomics, now provides investigators with a new target for therapeutic intervention in Parkinson's disease, says the study's senior author, Charbel Moussa, MBBS, Ph.D., director of the Medical Center's Translational Neurotherapeutics Program.
Huntington's disease is a progressively debilitating brain disease that causes uncontrolled movements, psychological problems, and loss of cognition. Huntington's is caused by a mutation in the gene that encodes huntingtin, a protein that normally plays important roles in keeping brain cells healthy and active. But the mutation gives huntingtin an abnormally long tail of glutamine amino acids, which cause huntingtin to aggregate inside neurons and eventually kill them.
These aggregates, or inclusion bodies, of huntingtin have been the subject of a lot of research efforts in the attempt to find a way to understand and treat Huntington's. What has been missing, though, is a deep analysis of the inclusions' ultrastructure—a term that describes the level of structure that lies beyond the capacity of a conventional microscope to observe.
A study of large-scale functional brain network organization and educational history, led by researchers at the Center for Vital Longevity (CVL), has identified a new biomarker of Alzheimer's disease. The findings, published online this week in Nature Aging, describe how declines in a measure of brain network organization precede cognitive impairment in older adults. Researchers also found that brain network declines are greater among individuals without a college education, suggesting that there are aspects of an individual's environment that may accelerate brain aging.
"What's exciting about this study is that we've identified a measure of brain function that seems to be sensitive to an individual's past and present environmental exposures during adulthood. That brain network organization is also uniquely related to the prognosis of dementia, which opens up the possibility of incorporating the measure with other markers of Alzheimer's disease risk and pathology in a clinical setting," says Dr. Gagan Wig, director of the Wig Neuroimaging Lab at the CVL and associate professor at The University of Texas at Dallas.
A gene mutation linked to Alzheimer's disease alters a signaling pathway in certain immune cells of individuals with the disease, according to a new study by scientists at Weill Cornell Medicine. The team also found that blocking the pathway—with a drug that's currently being tested in cancer clinical trials—protects against many features of the condition in a preclinical model. The results could lead to new strategies to block the development of Alzheimer's disease or slow its progression.
The study, published Dec. 1 in Science Translational Medicine, focused on microglia, immune cells of the central nervous system that are the first to respond when something goes wrong in the brain. Studies have identified many genetic variants linked to Alzheimer's disease that are highly expressed in microglia, providing compelling evidence that alterations within these cells may play a role in the disease's onset and progression.
"Microglia are guardians of the brain under healthy conditions, but can turn detrimental in disease conditions. Our goal is to identify how they become toxic and contribute to Alzheimer's disease pathogenesis and whether we can identify immune modulators to reverse the toxicity without diminishing their normal protective function," said senior author Dr. Li Gan, director of the Helen and Robert Appel Alzheimer's Disease Research Institute and the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.
A new study from Texas Biomedical Research Institute (Texas Biomed) and collaborators has identified a promising drug candidate to minimize uncontrolled, erratic muscle movements, called dyskinesia, associated with Parkinson's disease.
The small molecule, called PD13R, reduced dyskinesia by more than 85% in the marmoset animal model of Parkinson's disease. Additionally, the animals got much better sleep taking this compound compared to another drug often prescribed for dyskinesia. The results were published in the journal Experimental Neurology.
Dyskinesia is a common side effect in patients with Parkinson's disease. It is not a symptom of the disease itself, but typically emerges about five years into taking levodopa, the leading medication used to restore balance, reduce shaking and manage other motor control issues patients experience.
"Levodopa is amazing, it works like magic, but it has side effects. If we can eliminate these side effects, it could change the life of patients with Parkinson's," says Marcel Daadi, Ph.D., an associate professor at Texas Biomed and lead paper author.
What changes occur in parts of the brain affected by neurodegenerative disease? How does the structure of the neurons change? Some pathological changes in the tissue are easy to identify using standard microscopy. For example, the protein deposits known as "plaques," which occur in Alzheimer's disease, can be seen with staining techniques. However, pathological changes can also be of a more subtle nature and easily missed unless there is a complete digitilisation and analysis of the three-dimensional structure. Researchers at the University of Göttingen and University Medical Center Göttingen have now found a new technique to measure and quantify neuronal tissue architecture in three dimensions and at high resolution, which enabled them to identify changes in neurons in Alzheimer's. The results were published in the Proceedings of the National Academy of Sciences (PNAS).
The team developed a special X-ray imaging method that enabled them to detect a previously unknown transition in neuronal cell nuclei in tissue samples from the hippocampus of Alzheimer's patients. The changes indicate altered activity of neurons. The scientists examined neuronal tissue from the hippocampus, a brain region where memories are transferred from short-term to long-term memory. Chemically fixed tissue samples just a few millimeters wide were first X-rayed using phase-contrast tomography. The researchers used a special phase-contrast tomograph, which the team, led by Professor Tim Salditt from the Institute of X-ray Physics at the University of Göttingen, has set up at the PETRA III storage ring at the German Electron Synchrotron (DESY). The tomograph can be used to image tissue that only weakly absorbs X-rays, or not at all. This meant that large volumes of tissue could be recorded in their entirety, without damaging the samples and without time-consuming preparation.
Research at Nottingham Trent University and Queen Mary University of London investigated the role of trimethylamine N-oxide (TMAO) a molecule which is present in people's diets and produced by the body during digestion of fish.
Alzheimer's Research UK funded the study, which adds to a growing body of work aiming to understand and demonstrate how bacteria in the gut and the molecules they interact with influence human health and disease.
As foods containing TMAO are ingested, the molecule is broken down by bacteria in the gut. The breakdown product is taken up into the bloodstream and converted back to TMAO, which interacts with organs throughout the body.
Importantly, the brain's circulatory and vascular system is exposed to TMAO, which interacts directly with the 'blood-brain barrier." This barrier works to prevent potentially harmful toxins in the body from reaching the brain.
Researchers have developed the first detachable head-mounted photoacoustic microscope for imaging brain activity in freely moving mice. Because the device can be removed after imaging, it enables long-term studies that could reveal important new insights into neurodegenerative diseases and other neurological disorders.
"Epilepsy, Alzheimer's disease and Parkinson's disease can all seriously interrupt neurovascular coupling—the link between neural activity and subsequent changes in cerebral blood flow," said research team leader Lei Xi from the Southern University of Science and Technology in China. "Our new probe is ideal for studying neurovascular coupling because it has the potential to capture the dynamics of both neuron and vascular networks simultaneously."
The new microscope probe weighs just 1.8 grams and is based on optical resolution photoacoustic microscopy (ORPAM), which can capture anatomical and functional dynamics of the brain without requiring the use of fluorescent tags or labels. In the Optica Publishing Group journal Optics Letters, Xi and colleagues describe how they optimized the design of the new probe to make it light enough for use in freely moving mice.
"Head-mounted microscopes that use multi-photon or fluorescence imaging primarily capture the activities of single neurons," said Xi. "Our ORPAM probe can capture cerebral vascular network and hemodynamics of large portions of the cerebral cortex with capillary-level resolution without requiring any labels."
Miniaturizing a microscope
The new work builds on a wearable ORPAM probe the researchers previously built for freely moving rats. Although it performed well, it had to be permanently fixed on the rat and was too large and heavy to be carried around by mice, which are the preferred animal models for many brain studies.
A molecule that shows promise in preventing Parkinson's disease has been refined by scientists at the University of Bath in the UK, and has the potential to be developed into a drug to treat the deadly neurodegenerative disease.
Professor Jody Mason, who led the research from the Department of Biology and Biochemistry at Bath, said: "A lot of work still needs to happen, but this molecule has the potential to be a pre-cursor to a drug. Today there are only medicines to treat the symptoms of Parkinson's—we hope to develop a drug that can return people to good health even before symptoms develop."
Parkinson's Disease is characterized by a specific protein in human cells 'misfolding', where it becomes aggregated and malfunctions. The protein—alpha-synuclein (αS) – is abundant in all human brains. After misfolding, it accumulates in large masses, known as Lewy bodies. These masses consist of αS aggregates that are toxic to dopamine-producing brain cells, causing them to die. It is this drop in dopamine signaling that triggers the symptoms of Parkinson's Disease, as the signals transmitting from the brain to the body become noisy, leading to the distinctive tremors seen in sufferers.
As our brains age, small lesions begin to pop up in the bundles of white matter that carry messages between our neurons. The lesions can damage this white matter and lead to cognitive deficits. Now, researchers at Stevens Institute of Technology and colleagues not only provide an explanation for the location of these lesions but also how they develop in the first place.
The work, led by Johannes Weickenmeier, an assistant professor of mechanical engineering at Stevens, highlights the importance of viewing the brain as more than neural circuitry that underpins how thoughts are formed, and memories created. It's also a physical object that's prone to glitches and mechanical failures. "The brain is susceptible to wear and tear in vulnerable areas," Weickenmeier said. "Especially in an aging brain, we need to look at its biomechanical properties to better understand how things can start to go wrong.'
These lesions—known as deep and periventricular white matter hyperintensities because they show up as bright white patches on MRI scans—are poorly understood. But they are not uncommon: most people have some by the time they reach their 60s, and changes only increase with age. The more lesions that accumulate and the faster they grow, the more prone we become to cognitive impairments ranging from memory problems to motor disorders.
Using MRI scans from eight healthy subjects, Weickenmeier worked with Valery Visser, now a doctorate student at the University of Zurich, and Henry Rusinek, a radiologist at NYU Grossman School of Medicine, to develop an individualized computer model of each subject's brain. The team mapped the strain placed on ventricular walls, the linings of fluid-filled chambers deep in the brain, as waves of pressure pulse through the subject's cerebral spinal fluid, or CSF. They found that hyperintensities tend to occur near areas that must stretch more to accommodate pressure changes of the circulating CSF because, as such areas wear thin, CSF can leak into the brain and cause lesions.
The question of genetic vs environmental influences plays a major role in research into brain aging, with researchers from UNSW Sydney's Centre for Healthy Brain Aging (CHeBA) revealing new insights into one of the hallmarks of Alzheimer's disease—amyloid plaques—by looking at the brains of identical and non-identical twins.
The world first study, led by Dr. Rebecca Koncz and published in the Journal of Neurology, Neurosurgery & Psychiatry, used a special type of imaging called amyloid PET, or 'position emission tomography' to determine what proportion of amyloid accumulation is determined by genes, and what proportion is determined by environmental, or modifiable risk factors such as high blood pressure and high cholesterol.
"Amyloid is a protein that accumulates in the brain very early in the development of Alzheimer's disease," said Dr. Koncz. "It is a hallmark feature of the condition that starts to accumulate decades before memory problems become apparent."
According to Professor Perminder Sachdev, co-director of CHeBA and leader of the Older Australian Twins Study, twins provide a unique opportunity to investigate the relative importance of genetic and lifestyle factors for Alzheimer's disease, because monozygotic twins share 100 percent of their genetic material, and dizygotic twins share an estimated 50 percent. Australia has one of the world's leading twin registries—Twin Research Australia—members of which participated in the study. The amyloid PET imaging was done in collaboration with the Department of Molecular Imaging and Therapy, Austin Hospital, Melbourne, and the Department of Nuclear Medicine and PET at Prince of Wales Hospital in Sydney.
Biogen Quickly Cuts Alzheimer's Drug Cost After Payer Pushback
Source: Bloomberg
(Bloomberg) -- Biogen Inc. said it would cut the list price of its Alzheimer’s disease drug Aduhelm in half in the U.S., a move that comes after the treatment’s high cost spurred concerns that it could strain Medicare and health insurers.
The company said in a statement on Monday that it would reduce the annual list price of the treatment to $28,200 to lower out-of-pocket costs for patients and reduce “the potential financial implications for the U.S. health-care system.”
It is unusual for pharmaceutical companies to drastically reduce the cost of a medication soon after it is approved. Aduhelm won backing from the Food and Drug Administration in June, becoming the first new drug for Alzheimer’s in nearly 20 years. The memory-wasting disease affects some 6 million Americans, most of them elderly.
However, the treatment has faced skepticism from doctors and medical experts who aren’t certain that it works and from payers who viewed its $56,000-a-year cost as prohibitive. Private insurers say they need more evidence that Aduhelm actually slows the rate at which Alzheimer’s patients deteriorate. Last month, none of the 25 large insurers that responded to a Bloomberg News survey said that they found the drug to be “medically necessary.”
The brain has a natural protective mechanism against Alzheimer's disease, and researchers at Baylor College of Medicine, Texas Children's Hospital and collaborating institutions have discovered that gene variants associated with risk of developing the disease disturb the protective mechanism in ways that can lead to neurodegeneration. The researchers also showed in a fruit fly model of the condition that a chemical known as ABCA1 agonist can restore certain alterations of the brain protective mechanism.
The team reveals evidence supporting reactive oxygen species (ROS), natural byproducts of cellular metabolism linked to inflammation and other processes, as key players in events leading to the disruption of the neuroprotective mechanism. In addition, the researchers found that ROS, together with amyloid-beta, the main component in the plaques found in the brains of people with Alzheimer's disease, accelerated disease development in animal models. Altogether, the findings provide new mechanistic insight into factors involved in Alzheimer's disease development, supporting the idea that multiple alterations at the genetic and other cellular levels combine to induce the disease. The study appears in the Proceedings of the National Academy of Sciences.
An international team led by Case Western Reserve University's School of Medicine has made a significant breakthrough in understanding why Alzheimer's disease progresses so rapidly in some people that they die within three years.
The researchers found a link between strains of misshapen and fast-replicating tau protein and accelerated cognitive decline—a critical result that illuminates the variations in Alzheimer's disease and could help lead to more precise diagnoses and targeted therapies.
Such work could lead to changes in Alzheimer's care, possibly giving patients and families more accurate prognoses.
"For the first time, we established the link between the behavior of tau protein in the test tube and the clinical duration of the disease in patients," said Jiri Safar, a professor in the departments of pathology, neurology, and neurosciences at the Case Western Reserve School of Medicine. "What the research says in general is that Alzheimer's is not a single disease. There is a spectrum, and different cases have distinct biological drivers of the progression—and they should be handled as separate diseases."
People with Parkinson's disease who eat more flavonoids—compounds found in richly colored foods like berries, cocoa and red wine—may have a lower mortality risk than those who don't, according to a new study.
Specifically, the researchers found that when people who had already been diagnosed with Parkinson's disease (PD) ate more flavonoids, they had a lower chance of dying during the 34-year study period than those who did not consume as many flavonoids.
Additionally, they found that eating more flavonoids before being diagnosed with PD was associated with a lower risk of dying in men, but not in women.
A research team affiliated with the Faculty of Dentistry at the University of Montreal has shed new light on a human protein with potential benefits beyond oral and dental health.
Recent studies have shown that a protein present in the gingival epithelium (the part of the gums that surrounds the teeth) may have antimicrobial properties, in particular against the bacterium Porphyromonas gingivalis (P. gingivalis). In addition to playing a significant role in periodontal disease, this bacterium may also be linked to neurodegenerative diseases such as Alzheimer's.
The findings of the study led by Antonio Nanci, a researcher and professor in the Department of Stomatology at the University of Montreal, and postdoctoral researcher Charline Mary, in collaboration with colleagues from Université Laval and McGill University, were recently published in the journal Scientific Reports.
The study sheds new light on secretory calcium-binding phosphoprotein proline-glutamine rich 1 (SCPPPQ1), a protein expressed by the cells of the junctional epithelium. The findings suggest that this protein has antibacterial potential and identify its active portions.