Alzheimer's disease affects nearly seven million Americans over the age of 65, or 1 in 9 people in this age group, according to the Alzheimer's Association. Symptoms such as memory loss, trouble concentrating and performing familiar tasks, and personality changes start slowly and progress. Researchers have come a long way in understanding Alzheimer's disease and Alzheimer's Disease Related Dementias (AD/ADRD). A new consensus study report, "Preventing and Treating Dementia: Research Priorities to Accelerate Progress," identifies prevention and treatment strategies for the next decade.  

"We need cutting-edge treatments to help improve the lives of patients who are suffering from debilitating symptoms of dementia and prevention for those at risk," says Nilüfer Ertekin-Taner, M.D., Ph.D., chair of the Department of Neuroscience at Mayo Clinic and leader of the Genetics of Alzheimer's Disease and Endophenotypes Laboratory at Mayo Clinic's campus in Florida. "Neurodegenerative diseases not only affect patients but also the friends and family who care for them."

Dr. Ertekin-Taner served on the select ad hoc committee of the National Academies of Sciences, Engineering, and Medicine (NASEM) which conducted a study assessing the state of research on AD/ADRD and outlined critical research priorities for treatment and prevention, as well as potential barriers to progress. The National Institutes of Health, National Institute on Aging, and National Institute of Neurological Disorders and Stroke asked NASEM to form the committee in response to a request from the U.S. Congress to accelerate research into these diseases.

Researchers looked broadly at the field, including basic to translational to clinical research; lifestyle interventions aimed at preventing and treating AD/ADRD; barriers to advancing progress in the field; and the most promising areas of research. The study looked at Alzheimer's disease, frontotemporal dementia, Lewy body dementia and other vascular causes of cognitive impairment and dementia.

The report identified 11 research priorities for further NIH-funded biomedical research, including:

• Developing better tools, including novel biomarker tests and digital assessment technologies, to monitor brain health across the life course and to screen, predict and diagnose AD/ADRD at scale.

• Implementing advances in clinical research methods and tools to generate data from real-world clinical practice settings that can inform future research.

• Identifying factors driving AD/ADRD risk in diverse populations, particularly understudied and disproportionately affected groups, to better understand disease heterogeneity — including molecular subtypes and disparities in environmental exposures — and to identify prevention opportunities and advance health research equity.

• Characterizing the exposome and gene-environment interactions across the life course to gain insights into biological mechanisms and identify opportunities to reduce AD/ADRD risk and increase resilience.

• Integrating innovative approaches and novel tools into the planning, design and execution of studies to accelerate the identification of effective interventions.

• Advancing the development and evaluation of combination therapies (including pharmacological and nonpharmacological approaches) to better address the multifactorial nature of AD/ADRD.

• Evaluating precision medicine approaches for the prevention and treatment of AD/ADRD to better identify interventions likely to benefit specific groups of individuals.

The report calls for breaking down silos for more collaborative, multidisciplinary research; fostering inclusive research to eliminate health disparities; developing innovative funding strategies; and increasing innovation in research through the expansion of public-private partnerships, among others.

"The past decade of research investments in AD/ADRD has led to significant progress in our understanding of these diseases, bringing us closer to treatments," Dr. Taner said. "In the next decade, we must maintain the momentum of research and innovation to translate these advances to cures for millions of patients and caregivers affected by the dementia epidemic."

Note: Dr. Ertekin-Taner will participate in a webinar on Jan. 15 with other committee members to discuss the report.

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Most patients with Alzheimer's disease and Alzheimer's Disease Related Dementias (ADRD) experience the gradual onset and progression of cognitive symptoms, leading to decline over years or decades. However, in a small subset of patients, symptoms begin rapidly, leading to dementia within one year and complete incapacitation within two years of symptom onset. A new study at Mayo Clinic aims to determine why patients with Alzheimer’s disease and ADRD develop this rapidly progressive dementia (RPD).

"The factors that give rise to extreme, rapidly progressive clinical traits are unknown," says Gregg Day, M.D., a neurologist and clinical researcher at Mayo Clinic in Florida. "These cases are challenging to treat in practice because there are many possible causes and diseases to consider, many tests that can be done and a clear need to coordinate evaluations rapidly."

Dr. Day will lead a team of researchers from Mayo Clinic in Florida and Rochester, Minnesota, to study the biology of RPD through a project funded by the National Institute on Aging of the National Institutes of Health (NIA/NIH).

Specifically, the research team and collaborators aim to:

• Determine the factors that make patients with Alzheimer's disease and ADRD susceptible to RPD.
• Study the contributions of amyloid and tau toxic proteins and vascular changes in the brain to rates of progression in patients with Alzheimer's disease and ADRD.
• Identify cellular pathways that contribute to rapid declines in patients with Alzheimer's disease and ADRD.

The researchers plan to collect clinical and genomic information from 120 diverse patients with rapid progressive Alzheimer's disease and ADRD over the next three years. Findings in patients with RPD, identified through Alzheimer's Disease Research Centers studies nationally, will be compared with data from participants with typical progressive Alzheimer's disease and ADRD enrolled in studies at the Alzheimer's Disease Research Center at Mayo Clinic.  

The team hopes to learn how factors such as age, sex, medical history, structural and social determinants of health, genetic variants and other brain changes may make some patients more susceptible to rapid decline. Findings will be validated through expansive protein analyses in cerebrospinal fluid from an independent group of patients with autopsy-confirmed rapid progressive Alzheimer's disease and ADRD. Results will be extended to identify biomarkers and disease-modifying targets that may improve diagnosis and treatment of patients with Alzheimer's disease and ADRD.

"This project represents a substantial investment from NIH to study patients with RPD," says Dr. Day. "We hope the results of our research will inform new approaches, diagnostic tests and treatment targets that will improve outcomes in patients with AD/ADRD. The ultimate goal is to slow down the pathologic progression of disease in these patients, independent of their rate of decline."

The research will combine Mayo Clinic's expertise in digital innovation and telemedicine to engage patients across the United States. This study will also leverage Mayo's Clinical Trials Beyond Walls program, which allows patients to complete some, if not all assessments from the comfort of their own homes or local community facilities. The decentralized clinical trials initiative is designed to remove barriers to clinical trial participation by providing digital solutions and remote services to reimagine the trial experience for all involved, including participants, investigators, study teams and clinical care providers. Decentralized research ― studies conducted outside the walls of traditional research facilities ― may use a wide range of technologies and services such as telehealth, remote monitoring, mobile phlebotomy, retail pharmacy and home healthcare.

Other Mayo Clinic researchers working on this project include:

• Christian Lachner, M.D.
• Neill Graff-Radford, M.D.
• Leonard Petrucelli, M.D., Ph.D.
• Tania Gendron, Ph.D.
• Manoj Jain, M.D.
• Owen Ross, Ph.D.
• Nilufer Ertekin-Taner, M.D., Ph.D.
• Dennis Dickson, Ph.D.
• Melissa Murray, Ph.D.
• Vijay Ramanan, M.D., Ph.D.
• David T. Jones, M.D.
• Prashanthi Vemuri, Ph.D.
• Alicia Algeciras-Schimnich, Ph.D.
• John R. Mills, Ph.D.
• Rickey Carter, Ph.D.
• Lauren Haydu, Ph.D.

The research will be made possible through NIH grant award number R01 AG089380.

Related:

Researchers identify new criteria to detect rapidly progressive dementia

Researchers find other diseases may mimic rare brain disorder linked to dementia

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The bloodstream is teeming with plasma proteins that can increase and decrease depending on what is happening in the body. As a result, these proteins can serve as valuable biomarkers for health.

Mayo Clinic researchers have found that a specific plasma protein, called IL-23R, increases with age. The finding reveals a connection between a cellular aging process, called senescence, and specific plasma proteins in the blood that increase with age and decrease in response to therapeutics targeting senescent cells. This new discovery is published in Nature Aging.

"Our research is the first to show that IL-23R is an aging biomarker linked to senescence. Since IL-23R influences many inflammatory conditions that can increase with age, our discovery opens new lines of investigation as to how circulating IL-23R may influence disease processes with age," says senior author Marissa Schafer, Ph.D.

IL-23R is known to alert immune cells to help fight infections through inflammation, the body's defense mechanism. However, when IL-23R is overactive, it can lead to tissue damage and drive the persistent inflammation that underlies conditions such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis.

The research team measured IL-23R levels in donated blood samples of 40 men and 40 women ranging in age from 20 to 90 years old. They found that IL-23R increased in blood circulation with age among the participants. Using a preclinical model, they showed that IL-23R is linked to markers of senescence in aged organs, particularly the kidneys.

Additionally, the researchers tested five different senotherapeutics, drugs specially designed to eliminate senescent cells. All of these drugs targeted genes or proteins that are highly expressed in senescent cells. They found the senotherapeutics reduced the amount of plasma proteins including IL-23R.

"By targeting and reducing senescent cells, we can influence the systemic landscape by decreasing inflammatory mediators that are secreted in tissues and into circulation, such as IL-23R. This suggests that IL-23R is an important aging biomarker in senescence, inflammation and organ 'cross talk' that may be useful in clinical research and practice," explains lead author Chase Carver, Ph.D.

Next steps and implications

The researchers are continuing to study how circulating IL-23R is produced, how it affects inflammatory signaling throughout the body and how it drives disease states.

They are also collaborating with others to assess if other senotherapeutic approaches or exercise reduce circulating IL-23R levels in humans.

Review the study for a complete list of authors, disclosures and funding.

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ROCHESTER, Minn. — How long a person can stand — on one leg — is a more telltale measure of aging than changes in strength or gait, according to new Mayo Clinic research. The study appears today in the journal PLOS ONE.

Good balance, muscle strength and an efficient gait contribute to people's independence and well-being as they age. How these factors change, and at what rate, can help clinicians develop programs to ensure healthy aging. Individually, people can train their balance without special equipment and work on maintaining it over time.

In this study, 40 healthy, independent people over 50 underwent walking, balance, grip strength and knee strength tests. Half of the participants were under 65; the other half were 65 and older.

In the balance tests, participants stood on force plates in different situations: on both feet with eyes open, on both feet with eyes closed, on the non-dominant leg with eyes open, and on the dominant leg with eyes open. In the one-legged tests, participants could hold the leg they weren't standing on where they wanted. The tests were 30 seconds each.

Standing on one leg — specifically the nondominant leg — showed the highest rate of decline with age.

"Balance is an important measure because, in addition to muscle strength, it requires input from vision, the vestibular system and the somatosensory systems," says Kenton Kaufman, Ph.D., senior author of the study and director of the Motion Analysis Laboratory at Mayo Clinic. "Changes in balance are noteworthy. If you have poor balance, you're at risk of falling, whether or not you're moving. Falls are a severe health risk with serious consequences."

Unintentional falls are the leading cause of injuries among adults who are 65 and older. Most falls among older adults result from a loss of balance.

In the other tests:

• Researchers used a custom-made device to measure participants' grip. For the knee strength test, participants were in a seated position and instructed to extend their knee as forcefully as possible. Both the grip and knee strength tests were on the dominant side. Grip and knee strength showed significant declines by decade but not as much as balance. Grip strength decreased at a faster rate than knee strength, making it better at predicting aging than other strength measures.
• For the gait test, participants walked back and forth on an 8-meter, level walkway at their own pace and speed. Gait parameters didn't change with age. This was not a surprising result since participants were walking at their normal pace, not their maximum pace, Dr. Kaufman says.
• There were no age-related declines in the strength tests that were specific to sex. This indicates that participants' grip and knee strength declined at a similar rate. Researchers did not identify sex differences in the gait and balance tests, which suggests that male and female subjects were equally affected by age.

Dr. Kaufman says people can take steps to train their balance. For example, by standing on one leg, you can train yourself to coordinate your muscle and vestibular responses to maintain correct balance. If you can stand on one leg for 30 seconds, you are doing well, he says.

"If you don't use it, you lose it. If you use it, you maintain it," Dr. Kaufman says. "It's easy to do. It doesn't require special equipment, and you can do it every day."

Funding for this study includes the Robert and Arlene Kogod Professorship in Geriatric Medicine and W. Hall Wendel Jr. Musculoskeletal Professorship.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

• Rhoda Madson, Mayo Clinic Communications, newsbureau@mayo.edu

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The Mayo Clinic Brain Bank is home to more than 11,000 brain tissue samples used for research studies worldwide. About 3,000 of those donated brains come from patients across the state of Florida. Now, a new grant will help fund community outreach and computer technology programs that make it easier for researchers to access the brain bank and share discoveries in neurodegenerative diseases.  

The Alzheimer's Association Florida Gulf Coast Chapter has awarded the grant to Melissa Murray, Ph.D., a professor of neuroscience and co-director of the Mayo Clinic Brain Bank. Dr. Murray is also director of the Translational Neuropathology Laboratory at Mayo Clinic in Florida, which has a mission to prevent Alzheimer's disease and related dementias. The funds are designated to the Florida Autopsied Multi-Ethnic (FLAME) Cohort within the brain bank, which focuses on the diversity of abnormal proteins found in brains and seeks to ensure the inclusion of Hispanic and Black American brain donors. 

The risk of developing dementia is 1.5 times greater in Hispanic Americans and twice as high in Black Americans compared with non-Hispanic white Americans, according to Mayo Clinic researchers.

"Brain banking is built around a compassion for families and care partners to provide closure through diagnostic evaluation of the brain. The scientific goal of brain banks is to characterize, store and share tissue with qualified researchers to accelerate therapeutic discoveries by uncovering a deeper understanding of how disease affects these patients," says Dr. Murray.

"Brain banking is a costly endeavor that is difficult to obtain funding for and, with an ever-increasing demand for tissue sharing, we need to find ways to enhance workflow," she says. "This grant will help us develop technology that can be used to support documentation of important information critical for scientific discoveries. Perhaps even more importantly, this grant will fund efforts to share knowledge with, and learn from, Hispanic and Black communities affected by Alzheimer's disease and related dementias."

Specifically, the funding will support outreach and education efforts, as well as preliminary support for the development of a website that can connect with a database system for the brain bank. Erica Engelberg-Cook, Ph.D., the Mayo Clinic Brain Bank community and scientific liaison, will work with researchers to identify their research needs, which can be used to design an online system for tissue requests.

The Mayo Clinic Brain Bank was established in 1991 on the Mayo Clinic in Florida campus and led by Dennis Dickson, M.D., since 1998. The donated brains are shared with researchers at Mayo and academic medical centers around the world to advance studies on the pathology of diseases and conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Lewy body dementia, progressive supranuclear palsy and stroke.

The brain bank receives donations from across the nation through programs such as the Alzheimer's Disease Research Center and from across the state through the Florida Alzheimer's Disease Initiative.

The brains are obtained at autopsy after patients' consent and are sent to the brain bank for diagnostic evaluation and research studies. The brain bank also collects non-diseased brain tissue to establish control groups for studies.

"Through the sharing of human tissue, researchers at Mayo Clinic and around the world are one step closer to directly improving patient care," says Dr. Murray. "There is also a great need for people unaffected by disease to donate their brains to allow us to understand the aging process. Even more important is the need to enhance brain donations from underrepresented groups through the sharing of knowledge and learning from communities."

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Mayo Clinic researchers have found that senescent cells — non-dividing "zombie" cells — accumulate in the skin as people age and may influence aging in other parts of the body. Their recent study revealed that transplanting senescent skin cells into a preclinical model revealed that they not only caused that senescence to spread to other tissues but also accelerated physical decline, impaired muscle function and adversely affected brain health. This discovery indicates that senescent cells in the skin could drive broader, systemic aging.

"This discovery is significant because it suggests that senescent cells in the skin — an organ not typically associated with aging, beyond wrinkles — might be driving broader, systemic aging processes. These findings could also help explain the link between skin conditions and cognitive decline, offering potential new pathways for addressing both physical and mental deterioration as we age," says Mayo Clinic researcher João Passos, Ph.D., who is one of the lead authors on the study, published recently in Aging Cell.

This research also offers support for anti-aging strategies that aim to keep both the body and mind healthier for longer.

"This study suggests that skin senescence may accelerate aging in other organs, highlighting the importance of preventing factors like sun exposure, smoking, alcohol and poor diet that contribute to premature skin aging," says Ana Catarina Franco, the study's first author and Mayo Clinic visiting graduate student.

The researchers aim to investigate whether senolytic drugs, originally developed at Mayo Clinic and shown to eliminate senescent cells among people with a high number of senescent cells, can improve overall health when applied topically to the skin. They also plan to do more research to try to understand the mechanisms by which senescent cells may spread from the skin to other organs.

Review the study for a complete list of authors, disclosures and funding.

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Lewy body dementia (LBD) is a progressive neurodegenerative disease that shares traits with both Parkinson's disease and Alzheimer's disease but can be more difficult to diagnose. Symptoms can include hallucinations, movement disorders, cognitive issues, sleep problems and depression.

To better understand how the disease develops, Mayo Clinic scientists created mini brain models in a dish that closely match key features seen in the brains of patients with Lewy body dementia. Mini brains, also known as brain organoids, are lab-grown clusters of cells that mimic the human brain structure. The team also identified four potential drug compounds that may offer promising approaches to treating the disease. Their findings are published in Science Advances.

There is no cure for LBD, and scientists say there are few accurate preclinical models available to study it. A hallmark of the disease is a protein called alpha-synuclein, which is encoded by the SNCA gene. This protein is found in nerve cells of the brain and can build up into masses called Lewy bodies, which may contribute to symptoms of dementia.

To better understand the pathology of the disease, a Mayo Clinic research team led by neuroscientist and senior author Na Zhao, M.D., Ph.D., developed preclinical mini-brain models using stem cells from LBD patients who had extra copies of the SNCA gene, which may have caused their condition. The patients donated their skin cells upon diagnosis while they were still alive. Scientists then converted the skin cells to stem cells and used them for research.

Using advanced genomic techniques such as single-cell RNA sequencing, which examines genetic material in individual cells, the researchers showed that their mini-brain models mirrored changes seen in the human brains of LBD patients who had donated their brains to the Mayo Clinic Brain Bank, making the models valuable tools for studying how the disease develops.

The researchers used their novel model system to screen nearly 1,300 Food and Drug Administration-approved drugs, identifying four candidates that may help prevent the buildup of alpha-synuclein in neurons.

"This study suggests that these mini-brain models can effectively mimic disease development, providing a potential platform for testing individualized treatments for patients," says Dr. Zhao. "The four identified drug candidates, which have the potential to inhibit alpha-synuclein and restore the energy production in neurons derived from LBD patients, could be further refined or modified to develop new treatments for LBD and associated dementias in the future."

Researchers say additional studies could introduce additional cell types to better mimic the complexity of the human brain. Researchers could then use these enhanced models to further investigate disease mechanisms, such as exploring how high-risk genes influence the development of LBD.

For a complete list of authors, funding and disclosures, see the paper.

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A recent Mayo Clinic study has linked frailty to poor outcomes for patients suffering from pulmonary embolism, a blood clot that blocks and stops blood flow to an artery in the lung. Frailty is a condition that often accompanies aging and is characterized by a reduced ability to cope with acute stressors, such as illnesses or injuries.

The findings underscore the importance of managing chronic health conditions among older people and countering those and other factors that contribute to frailty, when possible, the researchers say.

Researchers applied an assessment tool known as the Hospital Frailty Risk Score (HFRS) to sort patients into low, medium and high-risk groups. The study included 288,070 patients 65 years or older with a primary diagnosis of pulmonary embolism.

"We discovered that patients with higher frailty risk, as indicated by their HFRS, experienced significantly higher all-cause in-hospital mortality rates compared to those with lower frailty risk," says Pablo Moreno Franco, M.D., senior author of the study. He and his research team also learned that frailer patients needed more aggressive treatments.

Dr. Moreno Franco is chair of Critical Care Medicine at Mayo Clinic in Florida, and has a joint appointment in Transplantation Medicine. He chairs Mayo Clinic Quality in Florida and regularly collaborates with the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, on research like the current study to improve or transform the practice of medicine.

Findings allow for improved, individualized care

"Working with our Acute Care Research Consortium M.D. trainees during their time at Mayo on this retrospective analysis was a pleasure," says Terri Menser, Ph.D., a Florida-based collaborative scientist in the Kern Center for the Science of Health Care Delivery and expert in mixed methods studies.

"By utilizing the National Inpatient Sample, the largest publicly available U.S. inpatient, all payer database, we were able to capture a much broader sample that yielded more generalizable findings."

The findings revealed that patients with high frailty risk were more likely to be older and female, with a higher frequency of comorbidities such as heart attack, congestive heart failure, cerebrovascular disease, dementia, diabetes and kidney diseases compared with those with medium and low frailty scores, the researchers say.

The investigators also discovered that frailty was associated with increased odds of needing invasive interventions for pulmonary embolism, such as thrombolysis, thrombectomy and mechanical ventilation, as well as a higher likelihood of complications like acute kidney injury and cardiogenic shock.

"These findings underscore the importance of considering frailty in the management and treatment of older patients with pulmonary embolism, as it can be a crucial predictor of adverse outcomes," says Dr. Moreno Franco.

The response, he says, should both include raising awareness in patients of the risks of frailty and encouraging them to make proactive changes to counter it where possible. Regular check-ups to monitor and manage comorbidities like heart disease, diabetes and kidney issues can help, he says.

"Preventative measures to counteract frailty include maintaining a balanced diet, engaging in regular physical activity and staying socially active," says Dr. Moreno Franco.

People also can do strength and balance exercises that can help improve resilience and reduce the risk of falls and other complications.

"It's all about taking proactive steps to maintain overall health and well-being," he says.

The study's authors further emphasize that by recognizing frailty early, healthcare teams can implement targeted interventions, such as more frequent monitoring, personalized treatment plans and proactive management of comorbidities, which ultimately leads to better patient outcomes.

Dr. Moreno Franco says that the collaborative efforts of the Kern Center and Mayo's Florida-based Acute Care Research Consortium team were invaluable to the success of the study.

Review the study for a complete list of authors, disclosures and funding.

About Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery

The Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery collaborates with clinical areas across Mayo to create and evaluate data-driven solutions to transform the experience of health and healthcare for patients, staff and communities. It drives continuous improvement of Mayo Clinic as a learning health system, enabling safe, evidence-based, high-quality care.

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Already the most aggressive form of brain cancer, glioblastoma can become even more deadly when it arises near the brain's C-shaped, fluid-filled cavities called the lateral ventricles. 

What makes this type of tumor so aggressive? In a new study published in Science Advances, Mayo Clinic researchers set out to answer this question.

First, the scientists developed a preclinical model in which they fluorescently labeled proteins produced by neural stem cells. With the help of the fluorescence, which colorfully highlights different parts of cells, the scientists could see that glioblastoma-induced senescence, or premature aging, of neural stem cells located in the lateral ventricles, could promote tumor growth.

Next, they looked at glioblastoma cell cultures and discovered that these cells produce elevated amounts of a tumor-promoting protein called cathepsin b (CTSB), which is associated with a worse prognosis for patients.

Through a battery of experiments, the team found that the CTSB protein contributes to increased glioblastoma malignancy. They observed this consistently in cell cultures, animal models and tumor tissue samples — particularly in lateral ventricle-associated tumors — from patients who donated to the Mayo Clinic Neurosurgery BRIDGE Biobank and The Cancer Genome Atlas.

The team hypothesizes that "crosstalk," or communication between neural stem cells and glioblastoma tumors, leads to CTSB protein expression.

"Our findings give us better insight into the biology of glioblastoma, which is essential to finding a treatment or cure for this deadly disease," says senior author Hugo Guerrero Cazares, M.D., Ph.D., associate professor of neurosurgery, cancer biology and neuroscience and leader of the Neurogenesis and Brain Tumors Lab at Mayo Clinic in Florida. Dr. Guerrero Cazares also is vice chair of research in the Neurosurgery Department.

The scientists next plan to build on their findings in two ways: First is identifying proteins or other molecules released by lateral ventricle cells that cause glioblastoma tumors to express CTSB. Second is conducting preclinical studies to target CTSB with pharmaceutical compounds.

Preoperative radiotherapy for glioblastoma enhances survival in a preclinical model

Preoperative radiotherapy is commonly used to treat different cancers that have spread to the brain but has never been used in primary glioblastoma, or cancer that originates in the brain.

Since 2005, the standard of care for glioblastoma has been surgical removal of the tumor, followed by radiation and chemotherapy. Even with this aggressive treatment approach, survival is poor — on average, just under 15 months. This poor outcome is often due to incomplete elimination of the cancer cells, cancer recurrence and the tumor's acquired resistance to therapies. In many patients with newly diagnosed glioblastoma, brain tumors recur immediately after surgery and before chemotherapy is administered.

In a study published in the Journal of Neuro-Oncology, Mayo Clinic researchers found that using a radiation boost before surgery increased survival in a preclinical glioblastoma model, compared to postoperative radiation. The study also sheds light on how this approach impacts the tumor microenvironment—the cellular environment in which a tumor exists—specifically highlighting changes in cell senescence and the movement of cancer-attacking cells to the tumor. The researchers say these insights not only advance the understanding of glioblastoma biology but also propose a pioneering therapeutic approach that could one day benefit patients facing this challenging cancer.

"Our research challenges the conventional treatment sequence and suggests a potentially more effective strategy for managing glioblastoma," says senior study author Paula Schiapparelli, Ph.D., a neurosurgery researcher at Mayo Clinic.

First author Beatriz Fernandez-Gil, Ph.D., says additional laboratory studies and clinical trials are needed to confirm the team's results. Scientists plan to study stereotactic radiosurgery before tumor removal, followed by standard-of-care radiotherapy.

Genetic mutations identified globally for rare disorder causing cognitive decline

A rare cause of hereditary cognitive decline known as CSF1R-Related Disorder (CSF1R-RD) gets its name from mutations in the CSF1R gene. Memory loss occurs as the condition advances, while early symptoms include personality changes, anxiety, depression and loss of inhibition. Genetic testing has become more widely available, but there is no cure for the disorder.

In a new study published in Neurology: Genetics, Mayo Clinic researchers identified eight novel genetic mutations in patients with CSF1R-Related Disorder worldwide. This highlights the prevalence of the disease and paves the way for future individualized treatment. The discovery also suggests that genetic and environmental factors may influence the disease. For example, steroids used to treat inflammation and immune responses can reduce neuroinflammation and prevent symptom occurrence in asymptomatic carriers of CSF1R gene mutations, according to the research team.

Researchers analyzed a range of data — demographics, genotype, family history, clinical status — collected from 14 families from the Americas, Asia, Australia and Europe. They found 15 CSF1R mutations, including eight not reported previously. There are nearly 200 known mutations associated with this disease.

"This study contributes to the overall understanding of the inheritance and global prevalence of rare neurodegenerative conditions in people with and without familial history of the disease," says senior study author Zbigniew Wszolek, M.D., a neurologist and clinical neurophysiologist at Mayo Clinic. "The discovery will allow scientists to target disease-modifying treatments specific to these mutations of the CSF1R gene."

According to Dr. Wszolek, genetic variations can complicate the diagnosis of CSF1R-RD because symptoms can mimic other conditions. He says an accurate diagnosis and medical management of the disease require updated diagnostic criteria and treatment options.

The research team says more studies are needed to look at asymptomatic and symptomatic carriers of the CSF1R gene mutations to better understand the disease. They note that knowledge gleaned from that research will enhance genetic counseling, guide the development of treatment interventions and improve risk prediction for disease onset.

Dr. Wszolek and his research team discovered the CSF1R gene in 2011. One of the team's previous studies on CSF1R-Related Disorder, also known as CSF1R-related leukoencephalopathy, examined a disease-modifying treatment.

Related: Read about other recent neuroscience research breakthroughs at Mayo Clinic.

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ROCHESTER, Minn. — Researchers at Mayo Clinic have established new criteria for a memory-loss syndrome in older adults that specifically impacts the brain's limbic system. It can often be mistaken for Alzheimer's disease. The good news: Limbic-predominant Amnestic Neurodegenerative Syndrome, or LANS, progresses more slowly and has a better prognosis, and is now more clearly defined for doctors working to find answers for memory loss patients.

Prior to the researchers developing clinical criteria published in the journal Brain Communications, the hallmarks of the syndrome could be confirmed only by examining brain tissue after a person's death. The proposed criteria provide a framework for neurologists and other experts to classify the condition in patients living with symptoms, offering a more precise diagnosis and potential treatments. They consider factors such as age, severity of memory impairment, brain scans, and biomarkers indicating the deposits of specific proteins in the brain.

The criteria were developed and validated using data from more than 200 participants in databases for the Mayo Clinic Alzheimer's Disease Research Center, the Mayo Clinic Study of Aging and the Alzheimer's Disease Neuroimaging Initiative.

Understanding the condition will lead to better management of symptoms and more tailored therapies for patients suffering from this type of cognitive decline, distinct from Alzheimer's disease, says David T. Jones, M.D., a Mayo Clinic neurologist and senior author of the study.

"In our clinical work, we see patients whose memory symptoms appear to mimic Alzheimer's disease, but when you look at their brain imaging or biomarkers, it's clear they don’t have Alzheimer's. Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers," Jones says. "This research creates a precise framework that other medical professionals can use to care for their patients. It has major implications for treatment decisions, including amyloid-lowering drugs and new clinical trials, and counseling on their prognosis, genetics and other factors."

Decades of work to understand and classify different types of dementia is ongoing, says Nick Corriveau-Lecavalier, Ph.D., the paper's first author. These findings build upon scientists' continued efforts to untangle neurological conditions that often have similar symptoms or can occur simultaneously, but can have drastically different treatments and prognoses.

"Historically, you might see someone in their 80s with memory problems and think they may have Alzheimer's disease, and that is often how it's being thought of today," Corriveau-Lecavalier says. "With this paper, we are describing a different syndrome that happens much later in life. Often, the symptoms are restricted to memory and will not progress to impact other cognitive domains, so the prognosis is better than with Alzheimer's disease."

Without signs of Alzheimer's disease, the researchers looked at the involvement of one possible culprit – a buildup of a protein called TDP-43 in the limbic system that scientists have found in the autopsied brain tissue of older adults. Researchers have classified the build-up of these protein deposits as limbic-predominant age-related TDP-43 encephalopathy, or LATE. These protein deposits could be associated with the newly defined memory loss syndrome, but there are also other likely causes and more research is needed, the authors say.

With clinical criteria established by Jones, Corriveau-Lecavalier and co-authors, practitioners could soon diagnose LANS in patients so those living with memory loss might better understand options for treatment and potential progression of the disease, opening doors for research to further illuminate the characteristics of the disease.

The research was funded in part by National Institutes of Health grants P30 AG062677, P50 AG016574, U01 AG006786, R37 AG011378 and R01 AG041851 and by the Robert Wood Johnson Foundation, the Elsie and Marvin Dekelboum Family Foundation, the Liston Family Foundation, the J. Orin Edson Foundation, the GHR Foundation and the Foundation Dr. Corinne Schuler.

Drs. Jones and Corriveau-Lecavalier reported no conflicts of interest. A complete list of co-authors and financial disclosures is available in the manuscript.

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• Samiha Khanna, Mayo Clinic Communications, newsbureau@mayo.edu

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