Blood levels of 'free range' DNA may signal early detection of dementia and frailty

 In a long-term prospective study of more than 600 older participants, Johns Hopkins Medicine researchers say they have evidence that higher levels of cell-free DNA circulating in the blood may signal increased risk of chronic inflammation associated with early signs of frailty and dementia.

The findings, published Oct. 11 in the Journal of Alzheimer's Disease, could advance the search for relatively simple blood tests that detect risk of Alzheimer's disease and other forms of cognitive decline.

Circulating cell-free genomic DNA, (ccf-gDNA) is a long identified product of natural cell death in the body. As cells die via apoptosis (programed cell death), the cells shrink, degrade their plasma membrane, and ultimately rupture and release their contents into the body, including DNA fragments. These fragments end up as free-range DNA in the bloodstream.

"These ccf-gDNA fragments may trigger long-term chronic inflammatory reactions that have previously been linked to the premature destruction and aging of tissues and organs, including the brain," says Peter Abadir, M.D., associate professor of geriatric medicine and gerontology at the Johns Hopkins University School of Medicine. "The body sees these ccf-gDNA fragments as something that needs to be removed, therefore the body's immune system is running at a higher rate than it should. Such immune system overdrive may be a factor in identifying the onset of dementia."

For the new study, the researchers tested the blood of 631 people with the average age of 79 who showed no cognitive impairment when the study began. Participants received yearly physical and cognitive testing, at the time of each blood draw. Researchers found that during the eight-year study period, higher levels of ccf-gDNA in the blood were associated with increased cognitive decline and worsening frailty.

Alzheimer's disease affects an estimated 6.5 million people in the United States, according to the Alzheimer's Association, and there are no known cures or effective therapies. However, the potential of a blood test to identify those most at risk or in early stages could lead to supportive services and other interventions to plan for, compensate for or slow down worsening symptoms.

"Our world population is aging quickly. We have so many advances that have helped extend our life span, so the goal now is to live healthier as we age," says Lolita Nidadavolu, M.D., Ph.D., assistant professor of geriatric medicine and gerontology at the Johns Hopkins University School of Medicine. "Dementia and frailty are increasing in frequency. Many people know someone affected by these conditions. With a single blood draw, we may have the potential to identify people who can benefit from early interventions."

Moving forward, researchers say they hope to learn more about the cellular origins of ccf-gDNA fragments. If researchers can identify that a large amount of these fragments are coming from a specific type of cell, it is hoped that they can advance the search for drugs that target the aging and dementia process.

Other scientists who contributed to this research are Danielle Feger, Yuqiong Wu, Alden Gross, Jeremy Walston and Esther Oh of Johns Hopkins, and David Bennett and Francine Grodstein of Rush University.

This research was funded by the BrightFocus Foundation, the Johns Hopkins University Claude D. Pepper Older Americans Independence Center (which is funded by the National Institute on Aging of the National Institutes of Health), the Nathan W. and Margaret T. Shock Aging Research Foundation and the Nathan Shock Scholar in Aging Research Award. This study was also supported by the National Institute on Aging's translational aging research training program and the institute's epidemiology and biostatistics of aging program.

The authors have no conflict of interest to report.

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Story Source:

Materials provided by Johns Hopkins Medicine. Note: Content may be edited for style and length.

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Journal Reference:

1. Lolita S. Nidadavolu, Danielle Feger, Yuqiong Wu, Francine Grodstein, Alden L. Gross, David A. Bennett, Jeremy D. Walston, Esther S. Oh, Peter M. Abadir. Circulating Cell-Free Genomic DNA Is Associated with an Increased Risk of Dementia and with Change in Cognitive and Physical Function. Journal of Alzheimer's Disease, 2022; 89 (4): 1233 DOI: 10.3233/JAD-220301

https://www.sciencedaily.com/releases/2022/10/221011105802.htm

Therapeutic games and brain stimulation mitigates cognitive decline in older adults

 Older people may be able to boost their working memory with a new approach that couples online therapeutic games with a non-invasive brain stimulation technique.

Working memory is critical for people to function well in everyday life. This volatile form of memory holds and manipulates a finite amount of information over a short time interval, enabling people to interact with their environment in an effective and efficient manner. Working memory typically declines with age, with the decline in its capacity causing daily difficulties in people with Parkinson's disease, dementia, and stroke.

Scientists and clinicians from the University of Birmingham, UK, Dalhousie University in Nova Scotia, Canada, and the University of Trento, Italy have devised a new technology to mitigate this decline.

The investigators refer to the technology as cognitive needs and skills training, or COGNISANT, and research published in Frontiers in Ageing Neuroscience shows it can provide particular benefit for older people who have low working memory capacity (WMC).

The online therapeutic exercises, developed to improve working memory, attention and vigilance, are packaged in the type of engaging interface that will be familiar to online game or App users. Brain stimulation was administered via a mobile wireless device that delivers a small (2milliAmpère) transcranial direct current stimulation (tDCS) during training.

The study involved healthy people aged 55 to 76 years old, who were split into two groups. Both groups did the online games for 20 minutes day, over a five-day period. While one group also received tDCS, the other group wore the tDCS device, which resembles a swimming cap, but did not receive tDCS.

The researchers measured baseline working memory capacity (WMC) before the study, and two days after completion. They found that WMC improved significantly in all participants, regardless of age or whether they received tDCS.

Importantly, the combination of training games and tDCS showed particular benefit in older people with lower initial working memory. This subset included people aged 69.5 to 76 years, the advantage was evident from the first day of training and became statistically significant by the end of training.

The paper was senior authored by biomedical engineer Dr Sara Assecondi, formerly at Birmingham but now at Trento's Centre for Mind/Brain Sciences (CIMeC), who worked on developing the technology with cognitive neuroscientist Professor Kim Shapiro from Birmingham's School of Psychology and Centre for Human Brain Health, using online therapeutic games developed by neuropsychologist Professor Gail Eskes from Dalhousie's departments of Psychology & Neuroscience, and Psychiatry, whose clinical practice focusses on training to improve and repair cognitive function.

The researchers are now working with technology transfer offices from the University of Birmingham and Dalhousie University, who are seeking commercial partners who wish to collaborate in developing technology using this approach and taking it to market.

Dr Sara Assecondi said: "Approaches used for hospital rehabilitation are difficult to translate to the home setting, but our approach uses online tools, and delivers brain stimulation via a device that can be used anywhere, with the dose determined remotely by the physician."

Professor Eskes' clinical research, which focusses on training to improve and repair cognitive functions, designed the brain exercises. She said: "Intensive exercises at just the right difficulty are important for increasing brain capacity or efficiency. And the game-like aspects increase motivation and make it easier to stick with the challenging sessions."

Professor Shapiro, whose research focusses on attention and memory, said: "Although cognitive decline in the elderly is an inevitability, approaches such as COGNISANT, in combination with regular physical exercise, can stem this decline and provide individuals with a higher quality of life."

The researchers have already shown in a previous study that coupling tDCS with strategy on how to do tasks requiring working memory can help young people with low WMC improve their performance, by helping them put in place strategies that they would not otherwise be able to come up with.

Dr Assecondi added: "The effects seen in both studies were strong, with the first study indicating that the combination of stimulation and strategy instruction can improve WM performance in younger adults, and the second study showing that strategy use may be facilitated by stimulation in older participants."

The researchers are planning further studies to examine other means of brain stimulation that may be even more effective and are currently concluding a study evaluating the benefits of COGNISANT in post-stroke patients with publication expected shortly.

Story Source:

Materials provided by University of Birmingham. Note: Content may be edited for style and length.

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Journal Reference:

1. Sara Assecondi, Rong Hu, Jacob Kroeker, Gail Eskes, Kim Shapiro. Older adults with lower working memory capacity benefit from transcranial direct current stimulation when combined with working memory training: A preliminary study. Frontiers in Aging Neuroscience, 2022; 14 DOI: 10.3389/fnagi.2022.1009262

https://www.sciencedaily.com/releases/2022/10/221012103127.htm

Enzyme that tamps down inflammation holds promise for protecting eyes in diabetes, premature birth

 An enzyme under study to treat certain cancers is also showing promise in reducing the significant vision damage that can result from diabetes and premature birth, scientists report.

Inflammation is considered a hallmark of cancer. It's pervasive as well in both of these potentially blinding eye conditions, in which inadequate oxygen to the eyes prompts growth of new blood vessels to better deliver oxygen, but which instead often obstruct the vision pathway and become leaky, which causes swelling, further hindering vision.

Scientists at the Medical College of Georgia report in newly published studies in the journals Cell Death and Disease and Cells, increasing evidence that making more of the enzyme arginase 1, or A1, available helps alleviate these unhealthy responses and interrupt a natural body response that promotes destructive ongoing, high levels of inflammation in both diabetic retinopathy and retinopathy of prematurity.

Key to the process is making less of the amino acid L-arginine available. With diabetes, for example, high blood sugar and lipid levels as well as oxidative stress increase expression of inducible nitric oxide synthase, or iNOS, which uses the L-arginine to help produce even more inflammation and promote disease progression. The way it's supposed to work is iNOS goes up in response to an infection then high-expressing A1 cells move in to turn iNOS off and inflammation down.

That's because A1 competes with iNOS for L-arginine. They theorized that more A1, which actually breaks down L-arginine into two products, would make less L-arginine available to "feed this (unhealthy) iNOS explosion," and help tamp down the vicious cycle of inflammation and related damage, says Dr. William Caldwell, pharmacologist and chair emeritus of the MCG Department of Pharmacology and Toxicology.

"If you reduce L-arginine levels, iNOS cannot work. This will make things better," Caldwell says.

As a great example about how everything in the body is about balance, the powerful blood vessel dilator NO, or nitric oxide, which iNOS makes, is good for blood vessels and blood pressure when it is produced at low levels by the endothelial cells that line blood vessels. This NO has the added benefit of being anti-inflammatory. But the "toxic" high levels produced by iNOS result in production of more reactive oxygen species, which feeds inflammation, which basically "rusts" whatever tissue it touches, Caldwell says.

They found that when a diabetic, obese mouse that eats constantly and develops a condition similar to early stage diabetic retinopathy is given A1 three times a week for two weeks, it improves their visual acuity and enables the rodents to better distinguish degrees of darkness, like shades of grey.

The mice had less oxidative stress and inflammation in the retina, restoration of the protective blood retinal barrier to help avoid leakage of tiny capillaries and the swelling and damage that would follow, and reduced progression of diabetic retinopathy, says Dr. Ruth B. Caldwell, cell biologist in the MCG Vascular Biology Center.

Conversely, they have shown that mice which express only half the usual amount of A1 have more abnormal blood vessel growth and retinal injury, they write. William Caldwell notes that when A1 is completely eliminated, mice and people will die of ammonia poisoning because another important ongoing job of A1 is constantly working in the liver to help eliminate ammonia, which is produced when proteins, a basic building block of the body, are broken down.

That's how A1 occupies so much L-arginine, which it cleaves or cuts to form urea, a form of ammonia which can be eliminated in the urine, and l-ornithine, which is important to normal physiological functions like cell proliferation and collagen formation.

The MCG scientists also have shown that A1 is naturally present in the immune cells and retinal cells of mice with oxygen-induced retinopathy, a common model for the destructive blood vessel growth that occurs in retinopathy of prematurity. The model also is used to mimic some aspects of diabetic retinopathy because diabetic mice don't live long enough to develop full blown eye disease. They've also found A1 present in the retinas of humans with diabetic retinopathy and in blood samples of young patients with retinopathy of prematurity.

AI's anti-inflammatory power is exhibited in the way it can keep those immune cells, called macrophages, which can both promote and reduce inflammation, from becoming too proinflammatory, Ruth Caldwell says.

She notes that numerous antioxidants and other anti-inflammatory agents have been tried and failed to help patients with these conditions. "What we think is happening is this pegylated A1 is reducing within these immune cells the ability to make inducible nitric oxide synthase in big amounts. We think that is the deal."

A1 normally breaks down in a matter of minutes, so like with studies in cancer, which also cannot grow and survive without L-arginine, they used a humanmade pegylated, or stable, form that instead stays around for days.

New, accessible therapies are needed to help avoid the vision consequence of both type 1 and 2 diabetes as well as retinopathy of prematurity, the Caldwells say. Their studies indicate that in diseases where the blood retinal barrier is broken, A1 can penetrate the eye making shots directly into the eye unnecessary, which should make treatment much more accessible, the scientists say. Anti-VEGF (vascular endothelial growth factor) therapy, for example, used to also combat the growth of abnormal and leaky blood vessels, requires injections into the back of the eye.

The Caldwells are co-corresponding authors on the two new papers. Dr. Abdelrahman Y. Fouda, Ruth Caldwell's former postdoctoral fellow who is now on the faculty of the University of Arkansas for Medical Sciences College of Medicine, is first author on the Cell Death and Disease paper. Dr. Ammar A. Abdelrahman, a postdoc in William Caldwell's lab, is first author on the Cells paper.

The scientific team has already shown that administering pegylated A1 improves protection in ischemia/reperfusion injury, when oxygen supply is lost for a limited time, like with a knife injury, then the blood supply gets restored; in major optic nerve trauma; and following an ischemic stroke, by far the most common stroke type where a clot typically cuts off the blood and oxygen supply to a part of the brain.

The research projects were supported by the National Eye Institute, the James and Jean Culver Vision Discovery Institute at Augusta University and the Department of Veterans Affairs.

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Story Source:

Materials provided by Medical College of Georgia at Augusta University. Original written by Toni Baker. Note: Content may be edited for style and length.

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Journal References:

1. Ammar A. Abdelrahman, Katharine L. Bunch, Porsche V. Sandow, Paul N-M Cheng, Ruth B. Caldwell, R. William Caldwell. Systemic Administration of Pegylated Arginase-1 Attenuates the Progression of Diabetic Retinopathy. Cells, 2022; 11 (18): 2890 DOI: 10.3390/cells11182890
2. Abdelrahman Y. Fouda, Zhimin Xu, Jutamas Suwanpradid, Modesto Rojas, Esraa Shosha, Tahira Lemtalsi, Chintan Patel, Ji Xing, Syed A. Zaidi, Wenbo Zhi, Brain K. Stansfield, Paul Ning-Man Cheng, S. Priya Narayanan, R. William Caldwell, Ruth B. Caldwell. Targeting proliferative retinopathy: Arginase 1 limits vitreoretinal neovascularization and promotes angiogenic repair. Cell Death & Disease, 2022; 13 (8) DOI: 10.1038/s41419-022-05196-8

https://www.sciencedaily.com/releases/2022/10/221012103148.htm

Links between people taking multiple medications and dementia diagnosis?

 People with dementia are likely to have taken more than three medications for other health conditions in the five years directly before their diagnosis, according to new research.

The study is the first to provide an in-depth exploration of the links between evolving polypharmacy -- which involves a patient being prescribed more than one drug at any given time -- and a dementia diagnosis.

Published in the Aging and Disease journal, it is based on an analysis of the records of more than 33,000 dementia patients in Wales between 1990 to 2015.

Experts in e-health used machine learning techniques to identify potentially damaging patterns in a patient's medicine usage, and how these patterns evolve in the run-up to diagnosis.

They found that in the 20 years leading up to them being diagnosed, the proportion of patients taking three or more medications rose from 5.5% (for the period 16 to 20 years prior to diagnosis) to 82.16% among those less than five years from a diagnosis.

Researchers also found that as the development towards dementia progressed, the patterns of polypharmacy shifted from being clearly distinct to being more closely associated with particular medical conditions.

And of those closest to their diagnosis, almost two-thirds (66.55%) were found to be taking multiple medicines for a combination of respiratory or urinary infections, arthropathies and rheumatism, and cardio-vascular disease. A further 22% of patients were found to be taking medicines for infections, arthropathies and rheumatism, cardio-metabolic disease and depression.

The study was supported by the Health Data Research UK and conducted by an international team of researchers from the University of Plymouth, Aptuit (an Evotec company), Swansea University Medical School, and the University of Oxford.

Shangming Zhou, Professor of e-Health at the University of Plymouth, led the study. He said: "Given the rise in dementia cases internationally, the need to understand how patterns of polypharmacy evolve before and after a dementia diagnosis are important for devising a safe treatment programme for each patient. Our aim in this study was to help doctors find ways to prescribe multiple items of dementia medication safely and without reducing their effectiveness. The use of machine learning has been vital in helping us understand how these patterns develop, and our hope is we can now use this knowledge to treat patients."

It has previously been established that when multiple types of preventative medication are being prescribed, the benefits of the drugs may be reduced and the chances of harm from drug interaction and side effects increased.

Those requiring hospital treatment who are taking multiple medications are also known to have a higher likelihood of re-admission within three months after being discharged.

With the number of people with dementia in the UK projected to rise to 1.6 million by 2040, researchers hope this new study will inform safe prescribing practices and encourage doctors to prescribe medicine combinations developed with a view to minimising cognitive impairments.

Story Source:

Materials provided by University of Plymouth. Original written by Alan Williams. Note: Content may be edited for style and length.

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Journal Reference:

1. Elisabetta Longo, Bruce Burnett, Sarah Bauermeister, Shang-Ming Zhou. Identifying Dynamic Patterns of Polypharmacy for Patients with Dementia from Primary Care Electronic Health Records: A Machine Learning Driven Longitudinal Study. Aging and Disease, 2022 DOI: 10.14336/AD.2022.0829

https://www.sciencedaily.com/releases/2022/10/221012103131.htm

Coherus: Corporate presentation

 

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FDA Accepts BioMarin's Biologics License Application (BLA) for Hemophilia A Med

 If Approved, Would Be 1st Gene Therapy in U.S. for Treatment of Severe Hemophilia A

PDUFA Target Action Date is March 31, 2023

https://finance.yahoo.com/news/fda-accepts-biomarins-biologics-license-200500695.html

Media malfeasance: Rolling Stone laughs off fentanyl crisis it once feared

 The warning about fentanyl from the 55-year-old magazine was stark: 

“The super-potent drug has been the leading killer of the opioid epidemic — now it’s finding its way into illegal stimulants, and the death toll is rising. …The combination is killing people: In New York City, for example, 37 percent of cocaine-related overdose deaths reported in 2016 involved fentanyl.” 

That was Rolling Stone magazine responsibly sounding the alarm about a new opioid called fentanyl emerging on the U.S. illegal drug market in 2018. As the piece, titled “How Fentanyl Is Contaminating America’s Cocaine Supply,” noted, the synthetic opioid is up to 50 times more potent than heroin. 

Fast forward to October 2022. Here’s what Rolling Stone has to say about fentanyl after several Republican lawmakers sounded their own alarm on opioid overdoses driven by fentanyl, the biggest killer of adults aged 18-49.

“No Treats, Only Tricks: Republicans Try to Ruin Halloween With Fake Rainbow Fentanyl Threat.”

The piece reads, in part:

“Halloween this year falls exactly 8 days before the November midterms, and what better way is there to drive home your tough-on-crime, war on drugs-electoral messaging than to convince parents that the cartels are in the house down the block and are handing out synthetic opioids to your kid?”

Rolling Stone’s snark and mockery was prompted by a public service announcement featuring several Republican senators warning parents of fentanyl disguised as candy being found in communities across the country. 

In New York City, for example, one person was arrested and approximately 15,000 fentanyl pills were seized, according to the Drug Enforcement Administration (DEA). The seizure was the largest to date. 

“Rainbow fentanyl – fentanyl pills and powder that come in a variety of bright colors, shapes, and sizes – is a deliberate effort by drug traffickers to drive addiction amongst kids and young adults,” said DEA Administrator Anne Milgram. To that end, the DEA recently announced that it had seized 36 million lethal doses nationally during a DEA operation spanning just 15 weeks. 

Rolling Stone is dismissing all this as hype. One must wonder whether this kind of tone would be applied if the president or members of the Democratic Party had aired similar warnings. 

“The PSA ended by instructing parents to implement (surprise!) the measures most parents already take when planning trick-or-treating excursions: getting candy from trusted neighbors, family, and friends, setting a curfew, trick-or-treating in groups, and checking your kid’s candy when they come home, usually just to steal the best pieces for themselves. Regardless, the only thing kids should expect in their Halloween haul is a well-deserved sugar high,” the piece concludes. 

It’s interesting that Rolling Stone doesn’t bother to mention bipartisan legislation recently introduced by Sen. Chuck Grassley (R-Iowa) called the Stop Pills That Kill Act. The bill ensures “that existing penalties for possessing paraphernalia used to manufacture methamphetamine would also apply to possessing paraphernalia used to make counterfeit pills that contain methamphetamine, fentanyl and fentanyl analogues,” according to a statement released by one of the bill’s supporters, Sen. Maggie Hassan (D-N.H.). 

For its part, the Biden administration has been almost completely silent on the fentanyl crisis. And it is a crisis, because when an average of 300 Americans are dying every day of opioid overdoses driven by fentanyl, that deserves ample attention from leaders and the media alike.

The White House has earmarked $11 billion for national drug programs and agencies in its 2022 budget, which looks good on paper before considering that the overall budget is $5.8 trillion, making that $11 billion investment just 0.0018 percent of the total money spent.

The president has painted MAGA-Republicans as the biggest threat to this country. But the biggest threat to this country is fentanyl. Not just because so many people are dying from it, but because families and communities are being torn apart by the demons of addiction.

But given that fentanyl is manufactured in China and sent to Mexico before crossing over the U.S. southern border and into communities across the country, don’t expect Biden to rush down to the border to do a primetime speech (or any speech) to address something this urgent.  

Rolling Stone was once a highly respected publication full of outstanding journalism. In recently years, it has become not only extremely partisan, but also plagued by scandal.

Rolling Stone wasn’t in the business of endorsing presidential candidates until relatively recently. But in 2020, it endorsed Joe Biden for president, arguing that his platform offered “progressive solutions to every major problem facing the country.” 

Apparently “every major problem facing the country” doesn’t include the weapon of mass destruction that is fentanyl, all because a few Republican lawmakers decided to warn parents about the rainbow candy-looking version of it ahead of Halloween. 

https://thehill.com/opinion/healthcare/3682850-media-malfeasance-rolling-stone-laughs-off-fentanyl-crisis-it-once-feared/