New connection between Alzheimer’s dementia and Dlgap2

A gene known for helping facilitate communication between neurons in the nervous system has been discovered to be connected with Alzheimer’s dementia and cognitive decline, according to a national research team led by The Jackson Laboratory and University of Maine.

Catherine Kaczorowski, associate professor and Evnin family chair in Alzheimer’s research at The Jackson Laboratory (JAX), and adjunct professor with the UMaine Graduate School of Biomedical Science and Engineering (GSBSE), spearheaded a study to pinpoint the genetic mechanisms that affect resistance or vulnerability to weakening cognition and dementias, such as Alzheimer’s.

Andrew Ouellette, a Ph.D student at JAX and a GSBSE NIH T32 predoctoral awardee, led the project, along with his mentor Kaczorowski and scientists from across the U.S.

By studying the memory and brain tissue from a large group of genetically diverse mice, the team found that the expression of the gene Dlgap2 is associated with the degree of memory loss in mice and risk for Alzheimer’s dementia in humans. Further research will ascertain how the gene influences dementia and mental function.

Dlgap2, located in the synapses of neurons, serves to anchor critical receptors for signals between neurons required for learning and memory. When studying post-mortem human brain tissue, the team discovered low levels of Dlgap2 in people experiencing “poorer cognitive health” and “faster cognitive decline” prior to death, according to researchers.

The team’s findings were published in the journal Cell Reports.

“The reason why this is so important is because a lot of research around cognitive aging and Alzheimer’s has been hyper-focused on well-known risk genes like APOE and brain pathologies,” Kaczorowski says. “We wanted to give ourselves the option of looking at new things people keep ignoring because they’ve never heard about a gene before.”

Researchers found that Dlgap2 influences the formation of dendritic spines on neurons, which can affect cognitive function. Longer, thinner spines shaped like mushrooms demonstrate higher mental performance than stubbier spines in mice, Ouellette says, and decreased cognition correlates with a loss in dendritic spines.

The study serves as a springboard for additional research into Dlgap2. Ouellette will explore how it influences cognition and how it can be used in therapeutic treatment for memory loss, in part by manipulating the gene with the editing tool CRISPR. Other members of the Kaczorowski lab are studying how to regulate Dlgap2 with pharmaceuticals to help prevent cognitive decline with age.

Scientists relied on Diversity Outbred mice, a population from eight parents created by The Jackson Laboratory to better reflect genetic diversity in humans. The Dlgap2 study involved 437 mice, each one either six, 12 or 18 months old.

“It’s great because you can harness the best parts of a mouse study and human society,” Ouellette says. “Historically, research has been done with inbred mice with similar genetic makeups; same, similar genetic models. But clinically, humans don’t work like that because they’re not genetically identical.”

The team performed quantitative trait loci mapping on the mouse population, examining entire genome sequences to identify genes responsible for varying cognitive function and where they occurred in the sequences. After pinpointing the connection between Dlgap2 and memory decline in mice, researchers evaluated its significance in human mental functionality using genomewide association studies for Alzheimer’s dementia and studying samples of post-mortem brain tissue using imaging, microscopy and other methods.

Kaczorowski says the project relied on information and expertise from all 25 co-authors. For example, Gary Churchill, professor and Karl Gunnar Johansson chair at JAX, Elissa Chesler, professor at JAX, and postdoctoral fellow Niran Hadad provided their expertise in utilizing diversity outbred models and cross-species genomic data integration to the project. Their efforts, she says, emphasizes the importance of teamwork in advancing medical research.

“We’re going to be able to contribute a lot more to human health with team science,” she says.

The GSBSE and The Jackson Laboratory partner to provide cooperative Ph.D. programs that include on-site training at the laboratory in Bar Harbor. The school also partners with other academic and research institutions to provide similar learning experiences. UMaine grants the degrees for these programs.

Kaczorowski says the GSBSE’s biomedical science Ph.D. program gives students hands-on learning opportunities that, like with Ouellette, can help them realize their passion and talents. Researching Dlgap2 with Kaczorowski influenced Ouellette’s Ph.D. dissertation further exploring how the Dlgap2 influences cognition in animals.

“I really like this study because it’s very interdisciplinary,” Ouellette says, adding that it harmonizes biological and computational science. “This study set me on a path that makes me want to be a more interdisciplinary scientist.”

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U.S. should look at how other high-income countries regulate health care costs, experts urge

Structuring negotiations between insurers and providers, standardizing fee-for-service payments and negotiating prices can lower the United States’ health care spending by slowing the rate at which healthcare prices increase, according to a Rutgers study.

The study, published in the journal Health Affairs, examined how other high-income countries that use a fee-for-service model regulate health care costs.

Although the United States has the highest health care prices in the world, the specific mechanisms commonly used by other countries to set and update prices are often overlooked. In most countries with universal health insurance, physicians are paid on a fee-for-service basis, yet health care prices there are lower than in the U.S. To lower health care spending, American policymakers have focused on eliminating fee-for-service reimbursement, which provides an incentive for performing additional services rather than setting up price negotiations to address the main factor that drives health care spending.

U.S. policy makers emphasize the need to reduce the volume of care that the system provides, but prior research shows that U.S. health care expenditures are higher than in other countries because of the price, not the volume, of services.

The researchers compared policies in France, Germany and Japan where payers and physicians engage in structured fee negotiations and standardized prices in systems where fee-for-service is the main model of outpatient physician reimbursement. They interviewed 37 stakeholders and health policy experts in those three countries to understand the process for creating physician fee schedules and updates, to learn about recent policy changes in physician payment and to identify the remaining challenges in the use of fee-for-service payment to physicians.

“The parties involved, the frequency of fee schedule updates and the scope of the negotiations vary, but all three countries attempt to balance the interests of payers with those of physician associations,” said lead author Michael K. Gusmano, lead study author and a professor at the Rutgers School of Public Health and research scholar at The Hastings Center.

Expanding public insurance and creating universal health care coverage for U.S. residents have been popular — even more so during the COVID-19 pandemic. However, addressing the price of health care is crucial for making universal coverage affordable.

The use of fee-for-service physician payment does create issues, but marking fee-for-service as the major cause of high health care spending in the United States is problematic, especially as countries with lower prices and expenditures use fee-for-service systems, while also providing universal health care to its residents. France, Germany and Japan limit the incomes of physicians by standardizing and adjusting the fees they are paid while using a variety of approaches to limit the volume of services provided.

According to Gusmano — who is also a member of the Rutgers Institute for Health, Health Care Policy and Aging Research and Rutgers Global Health Institute — regardless of whether the United States will pursue fundamental policy changes such as Medicare for All or incremental expansion of the Affordable Care Act, both would require that policy makers address health care prices.

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Materials provided by Rutgers University. Original written by Michelle Edelstein. Note: Content may be edited for style and length.

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Zebra finches amazing at unmasking the bird behind the song

If songbirds could appear on “The Masked Singer” reality TV competition, zebra finches would likely steal the show. That’s because they can rapidly memorize the signature sounds of at least 50 different members of their flock, according to new research from the University of California, Berkeley.

In findings recently published in the journal Science Advances, these boisterous, red-beaked songbirds, known as zebra finches, have been shown to pick one another out of a crowd (or flock) based on a particular peer’s distinct song or contact call.

Like humans who can instantly tell which friend or relative is calling by the timbre of the person’s voice, zebra finches have a near-human capacity for language mapping. Moreover, they can remember each other’s unique vocalizations for months and perhaps longer, the findings suggest.

“The amazing auditory memory of zebra finches shows that birds’ brains are highly adapted for sophisticated social communication,” said study lead author Frederic Theunissen, a UC Berkeley professor of psychology, integrative biology and neuroscience.

Theunissen and fellow researchers sought to gauge the scope and magnitude of zebra finches’ ability to identify their feathered peers based purely on their unique sounds. As a result, they found that the birds, which mate for life, performed even better than anticipated.

“For animals, the ability to recognize the source and meaning of a cohort member’s call requires complex mapping skills, and this is something zebra finches have clearly mastered,” Theunissen said.

A pioneer in the study of bird and human auditory communication for at least two decades, Theunissen acquired a fascination and admiration for the communication skills of zebra finches through his collaboration with UC Berkeley postdoctoral fellow Julie Elie, a neuroethologist who has studied zebra finches in the forests of their native Australia. Their teamwork yielded groundbreaking findings about the communication skills of zebra finches.

Zebra finches usually travel around in colonies of 50 to 100 birds, flying apart and then coming back together. Their songs are typically mating calls, while their distance or contact calls are used to identify where they are, or to locate one another.

“They have what we call a ‘fusion fission’ society, where they split up and then come back together,” Theunissen said. “They don’t want to separate from the flock, and so, if one of them gets lost, they might call out ‘Hey, Ted, we’re right here.’ Or, if one of them is sitting in a nest while the other is foraging, one might call out to ask if it’s safe to return to the nest.”

These days, Theunissen keeps a few dozen zebra finches in aviaries on and around campus, 20 of which were used in this latest experiment.

In a two-part experiment, 20 captive zebra finches were trained to distinguish between different birds and their vocalizations. At first, half the birds were tested on memorizing songs, while the other half were assessed on distance or contact calls. They then switched those tasks.

Next, the zebra finches were placed, one at a time, inside a chamber and listened to sounds as part of a reward system. The goal was to train them to respond to particular zebra finches by hearing several different renditions of those birds’ distinct vocalizations and memorizing them.

By pecking a key inside the chamber, the bird subjects triggered an audio recording of a zebra finch vocalization. If they waited until the six-second recording ended, and it was part of the reward group, they received birdseed. If they pecked before the recording was finished, they moved to the next recording. Over several trials, they learned which vocalizations would yield birdseed, and which ones to skip.

Next, the zebra finches were introduced to more audio recordings from new zebra finches, to teach them to distinguish which vocalizations belonged to which bird. They soon learned to differentiate between 16 different zebra finches.

In fact, the zebra finches, both male and female, performed so well in the tests that four of them were given the more challenging task of distinguishing between 56 different zebra finches. On average, they succeeded in recognizing 42 different zebra finches, based on their signature sounds. Plus, they were still able to identify the birds based on their unique sounds a month later.

“I am really impressed by the spectacular memory abilities that zebra finches possess in order to interpret communication calls,” Theunissen said. “Previous research shows that songbirds are capable of using simple syntax to generate complex meanings and that, in many bird species, a song is learned by imitation. It is now clear that the songbird brain is wired for vocal communication.”

In addition to Theunissen, co-authors of the study are Kevin Yu and Willam Wood at UC Berkeley.

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Hyperbaric oxygen treatment: Clinical trial reverses two biological processes associated with aging in human cells

A new study from Tel Aviv University (TAU) and the Shamir Medical Center in Israel indicates that hyperbaric oxygen treatments (HBOT) in healthy aging adults can stop the aging of blood cells and reverse the aging process. In the biological sense, the adults’ blood cells actually grow younger as the treatments progress.

The researchers found that a unique protocol of treatments with high-pressure oxygen in a pressure chamber can reverse two major processes associated with aging and its illnesses: the shortening of telomeres (protective regions located at both ends of every chromosome) and the accumulation of old and malfunctioning cells in the body. Focusing on immune cells containing DNA obtained from the participants’ blood, the study discovered a lengthening of up to 38% of the telomeres, as well as a decrease of up to 37% in the presence of senescent cells.

The study was led by Professor Shai Efrati of the Sackler School of Medicine and the Sagol School of Neuroscience at TAU and Founder and Director of the Sagol Center of Hyperbaric Medicine at the Shamir Medical Center; and Dr. Amir Hadanny, Chief Medical Research Officer of the Sagol Center for Hyperbaric Medicine and Research at the Shamir Medical Center. The clinical trial was conducted as part of a comprehensive Israeli research program that targets aging as a reversible condition.

The paper was published in Aging on November 18, 2020.

“For many years our team has been engaged in hyperbaric research and therapy — treatments based on protocols of exposure to high-pressure oxygen at various concentrations inside a pressure chamber,” Professor Efrati explains. “Our achievements over the years included the improvement of brain functions damaged by age, stroke or brain injury.

“In the current study we wished to examine the impact of HBOT on healthy and independent aging adults, and to discover whether such treatments can slow down, stop or even reverse the normal aging process at the cellular level.”

The researchers exposed 35 healthy individuals aged 64 or over to a series of 60 hyperbaric sessions over a period of 90 days. Each participant provided blood samples before, during and at the end of the treatments as well as some time after the series of treatments concluded. The researchers then analyzed various immune cells in the blood and compared the results.

The findings indicated that the treatments actually reversed the aging process in two of its major aspects: The telomeres at the ends of the chromosomes grew longer instead of shorter, at a rate of 20%-38% for the different cell types; and the percentage of senescent cells in the overall cell population was reduced significantly — by 11%-37% depending on cell type.

“Today telomere shortening is considered the ‘Holy Grail’ of the biology of aging,” Professor Efrati says. “Researchers around the world are trying to develop pharmacological and environmental interventions that enable telomere elongation. Our HBOT protocol was able to achieve this, proving that the aging process can in fact be reversed at the basic cellular-molecular level.”

“Until now, interventions such as lifestyle modifications and intense exercise were shown to have some inhibiting effect on telomere shortening,” Dr. Hadanny adds. “But in our study, only three months of HBOT were able to elongate telomeres at rates far beyond any currently available interventions or lifestyle modifications. With this pioneering study, we have opened a door for further research on the cellular impact of HBOT and its potential for reversing the aging process.”

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Materials provided by American Friends of Tel Aviv University. Note: Content may be edited for style and length.

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Age is no barrier to successful weight loss

Obese patients over the age of 60 can lose an equivalent amount of weight as younger people using only lifestyle changes, according to a new study from the University of Warwick and University Hospitals Coventry and Warwickshire (UHCW) NHS Trust that demonstrates that age is no barrier to losing weight.

The researchers hope that their findings will help to correct prevailing societal misconceptions about the effectiveness of weight loss programmes in older people, as well dispel myths about the potential benefits of older people trying to reduce their weight.

The findings are based on analysis of patient records from a hospital-based obesity service and are reported in the journal Clinical Endocrinology.

This retrospective study was conducted at the Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) at UHCW. The researchers randomly selected 242 patients who attended the WISDEM-based obesity service between 2005 and 2016, and compared two groups (those aged under 60 years and those aged between 60 and 78 years) for the weight loss that they achieved during their time within the service.

All patients had their body weight measured both before and after lifestyle interventions administered and coordinated within the WISDEM-based obesity service, and the percentage reduction in body weight calculated across both groups. When compared, the two groups were equivalent statistically, with those aged 60 years and over on average reducing their body weight by 7.3% compared with a body weight reduction of 6.9% in those aged under 60 years. Both groups spent a similar amount of time within the obesity service, on average 33.6 months for those 60 years and over, and 41.5 months for those younger than 60 years.

The hospital-based programme used only lifestyle-based changes tailored to each individual patient, focusing on dietary changes, psychological support and encouragement of physical activity. Most of the patients referred to the obesity service were morbidly obese with BMIs typically over 40Kgm-2.

There are more than fifty co-morbidities of obesity that can be lessened as we lose weight, including diabetes, psychiatric conditions such as depression and anxiety, osteoarthritis and other mechanical problems. Obesity is also linked to increased mortality and poor wellbeing.

Lead author Dr Thomas Barber of Warwick Medical School at the University of Warwick said: “Weight loss is important at any age, but as we get older we’re more likely to develop the weight-related co-morbidities of obesity. Many of these are similar to the effects of aging, so you could argue that the relevance of weight loss becomes heightened as we get older, and this is something that we should embrace.

“There are a number of reasons why people may discount weight loss in older people. These include an ‘ageist’ perspective that weight-loss is not relevant to older people and misconceptions of reduced ability of older people to lose weight through dietary modification and increased exercise. Older people may feel that hospital-based obesity services are not for them. Service providers and policymakers should appreciate the importance of weight loss in older people with obesity, for the maintenance of health and wellbeing, and the facilitation of healthy ageing. Furthermore, age per se should not contribute towards clinical decisions regarding the implementation of lifestyle management of older people.

“Age should be no barrier to lifestyle management of obesity. Rather than putting up barriers to older people accessing weight loss programmes, we should be proactively facilitating that process. To do otherwise would risk further and unnecessary neglect of older people through societal ageist misconceptions.”

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

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