SuperAger brains shrink more slowly than peers’ brains

Donald Tenbrunsel is 89 years old, but he is just as likely to talk to you about Chance the Rapper as reminisce about Frank Sinatra.

The highly engaged and delightful conversationalist, who reads, volunteers and routinely researches questions on the Internet, is part of a new path-breaking Northwestern Medicine study that shows that SuperAgers’ brains shrink much slower than their age-matched peers, resulting in a greater resistance to “typical” memory loss and dementia.

Over the course of the 18-month study, normal agers lost volume in the cortex twice as fast as SuperAgers, a rare group of people aged 80 and above whose memories are as sharp as those of healthy persons decades younger.

“Increasing age is often accompanied by ‘typical’ cognitive decline or, in some cases, more severe cognitive decline called dementia,” said first author Amanda Cook, a clinical neuropsychology doctoral student in the laboratory of Emily Rogalski and Sandra Weintraub. “SuperAgers suggest that age-related cognitive decline is not inevitable.”

The study was published in JAMA. Senior author Emily Rogalski will present the findings at the 2017 Cognitive Aging Summit in Bethesda, Maryland, April 6.

SuperAger Tenbrunsel, who lives with his daughter’s family, is intent on being a good conversationalist with his three grandchildren.

“I have to adapt to that kind of life,” Tenbrunsel said. “They don’t know much about Frank Sinatra or Franklin Delano Roosevelt, so I have to keep saying, ‘Is the Chance the Rapper coming this week or is it Taylor Swift?'”

The researchers already knew SuperAgers’ brains tended to retain more brain volume and typically don’t show the same wear-and-tear as normal agers.

“For this study we explored whether SuperAgers’ brains were on a different trajectory of decline,” said Rogalski, associate professor at the Cognitive Neurology and Alzheimer’s Disease Center (CNADC) at Northwestern University Feinberg School of Medicine. “We found that SuperAgers are resistant to the normal rate of decline that we see in average elderly, and they’re managing to strike a balance between life span and health span, really living well and enjoying their later years of life.”

Using magnetic resonance imaging (MRI), the scientists measured the thickness of the cortex in 24 SuperAgers and 12 same-age, educationally and cognitive average peers (control group) to determine the approximate health of the brain over 18 months. The annual percent decline in thickness between the first and second visit for the SuperAgers was 1.06 and 2.24 for the control group.

Previous research showed that SuperAgers have a thicker cortex than those who age normally. By studying what makes SuperAgers unique, the scientists said they hope to undercover biological factors, such as the reduced cortical brain atrophy demonstrated here, that might contribute to the maintenance of memory ability in advanced age.

SuperAger research at Northwestern is flipping the traditional approach to Alzheimer’s research of focusing on brains that are underperforming to instead focusing on outperforming brains.

“Sometimes it’s useful to turn a complex problem on its head and look from a different vantage point,” Rogalski said. “The SuperAging program studies people at the opposite end of the spectrum: those with unexpectedly high memory performance for their age.”

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Materials provided by Northwestern University. Original written by Kristin Samuelson. Note: Content may be edited for style and length.

US burden of neurological disease is nearly $800 billion/year

The most common neurological diseases cost the United States $789 billion in 2014, and this figure is projected to grow as the elderly population doubles between 2011 and 2050, according to a new study published in the April issue of the Annals of Neurology. The research shows the price tag of this serious, annual financial burden for the nation, and comes at a time when the new administration has proposed significant budget cuts for federally-funded research.

Based on this demographic trend, the American Neurological Association (ANA) commissioned a study led by former ANA marketing committee and public advocacy committee chair Clifton L. Gooch, MD, currently professor and chair of the Department of Neurology at the University of South Florida’s Morsani College of Medicine in Tampa. The study, The Burden of Neurological Disease in the United States: A Summary Report and Call to Action, details the annual cost of nine key neurological diseases and disorders, including Alzheimer’s disease and other dementias; low back pain; stroke; traumatic brain injury; migraine; epilepsy; multiple sclerosis; spinal cord injury; and Parkinson’s disease. Neurological diseases impact an estimated 100 million Americans every year, with the costs of dementia and stroke alone projected to total more than $600 billion by 2030.

A “Moonshot” for Neurology:

The huge and sustained capital investments made in cardiovascular and cancer research starting in the 1970s have increased lifespan. Ironically, these gains have increased the number of elderly who are most susceptible to neurological disease, creating a growing epidemic.

“Neurological research, like cancer, needs its own ‘Moonshot’ to focus substantial research investment on the neurological diseases that are impacting the mortality and quality of life of more and more Americans every year,” said Gooch, referring to the $1.8 billion in funding for cancer research authorized by Congress in 2016. “We hope the findings of this report will serve as a wake-up call to

Congress to increase much needed basic and clinical research funding required to discover treatments which can mitigate, and ultimately cure, the major neurological diseases which have such profound effects in our patients and for the national economy.”

“The future of funding for neurological research was a concern in 2012 when the ANA voted to support this investigation,” said ANA President Barbara G. Vickrey, MD, MPH. “With the cuts currently proposed to the NIH budget by the President of the United States, it is of even greater concern today. As representatives of the scholars working to eradicate these diseases, we feel we must raise our collective voices, armed with the facts.”

Researchers compiled the report through a detailed review of the world literature of the most costly and most prevalent neurological diseases in the United States. To be conservative, researchers focused on the prevalence and cost estimates they considered most comprehensive and accurate, excluding disorders like depression and chronic pain, which often have mixed etiologies beyond primary nervous system injury.

A conservative estimate:

“A full accounting of all neurological disorders, would of course, push cost estimates substantially higher,” the authors wrote. Direct and indirect costs for each of the major diseases were estimated based on care norms for each disease and are detailed in the report.

Alzheimer’s and other dementias accounted for $243 billion of the $789 billion total, while chronic low back pain represented $177 billion; and stroke, $110 billion.

Dollar figures were converted to 2014 values using the all-items consumer price index for non-medical (indirect) costs. Direct costs were converted using the medical price index.

In addition to documenting the financial costs of neurological disease, Gooch and his USF colleagues recommend an action plan for reducing the burden through infrastructure investment in neurological research and enhanced clinical management of neurological disorders. Specifics include:

  • Acceleration of translational research in preventative and disease-modifying therapy;
  • Enhanced outcome and comparative effectiveness research;
  • Comprehensive databasing and tracking of neurological disease; and
  • Taking advocacy to the next level, coordinating efforts at the individual, neurology association, and local, state and federal government levels to make funding these initiatives a priority.

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Stem cells help explain varied genetics behind rare neurologic disease

Researchers at Case Western Reserve University School of Medicine have successfully grown stem cells from children with a devastating neurological disease to help explain how different genetic backgrounds can cause common symptoms. The work sheds light on how certain brain disorders develop, and provides a framework for developing and testing new therapeutics. Medications that appear promising when exposed to the new cells could be precisely tailored to individual patients based on their genetic background.

In the new study, published in The American Journal of Human Genetics, researchers used stem cells in their laboratory to simultaneously model different genetic scenarios that underlie neurologic disease. They identified individual and shared defects in the cells that could inform treatment efforts.

The researchers developed programmable stem cells, called induced pluripotent stem cells, from 12 children with various forms of Pelizaeus-Merzbacher Disease, or PMD. The rare but often fatal genetic disease can be caused by one of hundreds of mutations in a gene critical to the proper production of nerve cell insulation, or myelin. Some children with PMD have missing, partial, duplicate, or even triplicate copies of this gene, while others have only a small mutation. With so many potential causes, researchers have been in desperate need of a way to accurately and efficiently model genetic diseases like PMD in human cells.

By recapitulating multiple stages of the disease in their laboratory, the researchers established a broad platform for testing new therapeutics at the molecular and cellular level. They were also able to link defects in brain cell function to patient genetics.

“Stem cell technology allowed us to grow cells that make myelin in the laboratory directly from individual PMD patients. By studying a wide spectrum of patients, we found that there are distinct patient subgroups.

This suggests that individual PMD patients may require different clinical treatment approaches,” said Paul Tesar, PhD, study lead, Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics, and Associate Professor of Genetics and Genome Sciences at Case Western Reserve University School of Medicine.

The researchers watched in real-time as the patients’ stem cells matured in the laboratory. “We leveraged the ability to access patient-specific brain cells to understand why these cells are dysfunctional. We found that a subset of patients exhibited an overt dysfunction in certain cellular stress pathways,” said Zachary Nevin, first author of the study and MD/PhD student at Case Western Reserve University School of Medicine. “We used the cells to create a screening platform that can test medications for the ability to restore cell function and myelin. Encouragingly, we identified molecules that could reverse some of the deficits.” The promising finding provides proof-of-concept that medications that mend a patient’s cells in the laboratory could be advanced to clinical testing in the future.

The stem cell platform could also help other researchers study and classify genetic diseases with varied causes, particularly other neurologic disorders. Said Tesar, “Neurological conditions present a unique challenge, since the disease-causing cells are locked away in patients’ brains and inaccessible to study. With these new patient-derived stem cells, we can now model disease symptoms in the laboratory and begin to understand ways to reverse them.”

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Graphene-based neural probes probe brain activity in high resolution

Measuring brain activity with precision is essential to developing further understanding of diseases such as epilepsy and disorders that affect brain function and motor control. Neural probes with high spatial resolution are needed for both recording and stimulating specific functional areas of the brain. Now, researchers from the Graphene Flagship have developed a new device for recording brain activity in high resolution while maintaining excellent signal to noise ratio (SNR). Based on graphene field-effect transistors, the flexible devices open up new possibilities for the development of functional implants and interfaces.

The research, published in 2D Materials, was a collaborative effort involving Flagship partners Technical University of Munich (TU Munich; Germany), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS; Spain), Spanish National Research Council (CSIC; Spain), The Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN; Spain) and the Catalan Institute of Nanoscience and Nanotechnology (ICN2; Spain).

The devices were used to record the large signals generated by pre-epileptic activity in rats, as well as the smaller levels of brain activity during sleep and in response to visual light stimulation. These types of activities lead to much smaller electrical signals, and are at the level of typical brain activity. Neural activity is detected through the highly localised electric fields generated when neurons fire, so densely packed, ultra-small measuring devices is important for accurate brain readings.

The neural probes are placed directly on the surface of the brain, so safety is of paramount importance for the development of graphene-based neural implant devices. Importantly, the researchers determined that the graphene-based probes are non-toxic, and did not induce any significant inflammation.

Devices implanted in the brain as neural prosthesis for therapeutic brain stimulation technologies and interfaces for sensory and motor devices, such as artificial limbs, are an important goal for improving quality of life for patients. This work represents a first step towards the use of graphene in research as well as clinical neural devices, showing that graphene-based technologies can deliver the high resolution and high SNR needed for these applications.

First author Benno Blaschke (TU Munich) said “Graphene is one of the few materials that allows recording in a transistor configuration and simultaneously complies with all other requirements for neural probes such as flexibility, biocompability and chemical stability. Although graphene is ideally suited for flexible electronics, it was a great challenge to transfer our fabrication process from rigid substrates to flexible ones. The next step is to optimize the wafer-scale fabrication process and improve device flexibility and stability.”

Jose Antonio Garrido (ICN2), led the research. He said “Mechanical compliance is an important requirement for safe neural probes and interfaces. Currently, the focus is on ultra-soft materials that can adapt conformally to the brain surface. Graphene neural interfaces have shown already great potential, but we have to improve on the yield and homogeneity of the device production in order to advance towards a real technology. Once we have demonstrated the proof of concept in animal studies, the next goal will be to work towards the first human clinical trial with graphene devices during intraoperative mapping of the brain. This means addressing all regulatory issues associated to medical devices such as safety, biocompatibility, etc.”

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