Older Women in the United States Not Receiving Recommended Bone Density Testing Before Starting Cancer Treatment, Study Finds

A Medical College of Wisconsin study published in the July issue of JNCCN found that older women are not receiving recommended bone density assessment prior to adjuvant therapy with aromatase inhibitors, possibly making them more vulnerable to bone fracture and comorbidity as a result of injury.

Newswise, July 29, 2016— Aromatase inhibitors (AIs)—drugs that stop the production of estrogen in women—are standard adjuvant therapy for post-menopausal women with hormone-receptor positive breast cancer.

AIs are an effective treatment for this population, but have the major side effect of bone density loss, which can lead to increased fractures and long-term injury.

To ensure patient safety, the National Comprehensive Cancer Network® (NCCN®) recommends that patients undergo bone mineral density (BMD) testing before starting treatment with AIs, and that women at increased risk for osteoporosis consider antiresorptive therapy, such as bisphosphonates, which slow or stop bone density loss.[1]

Researchers at Medical College of Wisconsin, led by John Alan Charlson, MD, Associate Professor of Medicine, Division of Hematology and Oncology, studied women ages 67 and older to assess when and if they were undergoing the recommended bone density testing.

According to the findings, as women aged—increasing their odds of osteoporosis and bone fracture—they were less likely to receive NCCN-recommended baseline testing.

The study, Bone Mineral Density Testing Disparities among Breast Cancer Patients Prescribed Aromatase Inhibitors (AIs), is featured in the July issue of JNCCN – Journal of the National Comprehensive Cancer Network.

“This study highlights sub-optimal U.S. compliance with guideline recommendations for baseline BMD testing when starting AI therapy,” said Dr. Charlson.

“Older women, at higher risk for fractures in general, are least likely to get testing, and the slight increase in empiric treatment in no way closes the gap.”

Looking at Medicare Part A, B, and D claims from 2006 through 2012, Dr. Charlson and fellow investigators found that approximately two-thirds of patients received recommended baseline BMD testing.

Lower rates of baseline testing correlated to several factors, including race and income, but the most substantial correlation, the investigators found, was older age—86 years and older. In the study population, baseline BMD test rates fell progressively from 73 percent in women ages 67-70 to 51 percent in women over the age of 85.

“The oldest patients are most likely to be vulnerable to bone density loss, so BMD testing results may be especially important in this age group for analysis of risks and benefits of treatment, as well as to determine whom should be treated with bone-modifying agents,” said Dr. Charlson.

Older women are at higher risk of osteoporosis and bone fracture. Hip fracture rates, according to the study, are seven times higher in women ages 70 and older than in other populations and higher comorbidity is also linked to these fractures.

Although the oldest women in the study were least likely to receive BMD assessment, they did receive slightly higher rates of bisphosphonates as empiric therapy.

“While a larger number of older patients did receive bisphosphonates, this does not explain the disparities in bone density findings, or even substantially change our finding that attending to BMD was higher in lower risk younger women,” said Dr. Charlson.

“These findings may be even more important in light of recent data from additional studies suggesting bone fracture rates may be even higher than previously recognized for women using adjuvant aromatase inhibitors,” said Steven J. Isakoff, MD, PhD, Massachusetts General Hospital Cancer Center, Member of the NCCN Guidelines Panel for Breast Cancer. “In addition, many women may now be using aromatase inhibitors beyond five years, which may further increase the risk of fractures.

This study highlights that, as a breast cancer community, we need to do a better job screening for bone health because with proper screening and treatment, many of these fractures can be prevented, particularly in the older patients at highest risk for fractures but who have the lowest rates of bone health screening.”

Complimentary access to this research is available until September 30, 2016 at  JNCCN.org.

Alzheimer’s Gene May Show Effects on Brain Starting in Childhood

Newswise, July 29, 2016– A gene associated with Alzheimer’s disease and recovery after brain injury may show its effects on the brain and thinking skills as early as childhood, according to a study published in the July 13, 2016, online issue of Neurology®, the medical journal of the American Academy of Neurology.

Prior studies showed that people with the epsilon(ε)4 variant of the apolipoprotein-E gene are more likely to develop Alzheimer’s disease than people with the other two variants of the gene, ε2 and ε3.

“Studying these genes in young children may ultimately give us early indications of who may be at risk for dementia in the future and possibly even help us develop ways to prevent the disease from occurring or to delay the start of the disease,” said study author Linda Chang, MD, of the University of Hawaii in Honolulu and a Fellow of the American Academy of Neurology.

For the study, 1,187 children ages three to 20 years had genetic tests and brain scans and took tests of thinking and memory skills. The children had no brain disorders or other problems that would affect their brain development, such as prenatal drug exposure.

Each person receives one copy of the gene (ε2, ε3 or ε4) from each parent, so there are six possible gene variants: ε2ε2, ε3ε3, ε4ε4, ε2ε3, ε2ε4 and ε3ε4.

The study found that children with any form of the ε4 gene had differences in their brain development compared to children with ε2 and ε3 forms of the gene. The differences were seen in areas of the brain that are often affected by Alzheimer’s disease.

In children with the ε2ε4 genotype, the size of the hippocampus, a brain region that plays a role in memory, was approximately 5 percent smaller than the hippocampi in the children with the most common genotype (ε3ε3).

Children younger than 8 and with the ε4ε4 genotype typically had lower measures on a brain scan that shows the structural integrity of the hippocampus.

“These findings mirror the smaller volumes and steeper decline of the hippocampus volume in the elderly who have the ε4 gene,” Chang said.

In addition, some of the children with ε4ε4 or ε4ε2 genotype also had lower scores on some of the tests of memory and thinking skills.

Specifically, the youngest ε4ε4 children had up to 50 percent lower scores on tests of executive function and working memory, while some of the youngest ε2ε4 children had up to 50 percent lower scores on tests of attention.

However, children older than 8 with these two genotypes had similar and normal test scores compared to the other children.

Limitations of the study include that it was cross-sectional, meaning that the information is from one point in time for each child, and that some of the rarer gene variants, such as ε4ε4 and ε2ε4, and age groups did not include many children.

The study was supported by the National Institutes of Health, including the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute on Child Health and Human Development.

To learn more about brain health, please visit http://www.aan.com/patients.

The American Academy of Neurology, the world’s largest association of 30,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care.

A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson’s disease and epilepsy.

For more information about the American Academy of Neurology, visit http://www.aan.com or find us on Facebook, Twitter, Google+ and YouTube.

How the Brain Improves Motor Control

Error signals in motor cortices drive adaptation in reaching

Newswise, July 29, 2016--Adaptation in reaching -- gradual improvement of motor control in response to a perturbation -- is a central issue in motor neuroscience.However, even the cortical origin of errors that drive adaptation has remained elusive. In a new paper published in Neuron, Inoue, Uchimura and Kitazawa have shown that error signals encoded by motor cortical neurons drive adaptation in reaching.

• The premotor and primary motor cortices encoded visual error in reaching.
• Stimulation to the motor cortices induced trial-by-trial increases in reach errors.
• The error increased opposite to the preferred direction of errors at each location.
• The after-effect of stimulation subsided gradually as in ordinary adaptation.

The neural mechanisms of motor learning and adaptation constitute a central issue in both basic and clinical neuroscience.

However, it is surprising that very little is known about the neural mechanisms underlying the motor learning and adaptation of voluntary arm movements. For example, the origin of cortical error signals that drive adaptation in reaching remains an unanswered question.

A major theory in motor learning (feedback error learning) proposed by Kawato and Gomi (1992) hypothesized that error signals are provided by premotor circuits, including the motor cortical circuits.

However, neuroimaging studies to date have not indicated whether motor cortices encode error signals. Preceding human imaging studies unanimously implicated parietal regions, such as areas 2, 5 and 7, in representing reaching errors.

In the current study, Inoue and colleagues were successful for the first time in inducing trial-by-trial "adaptation" in voluntary arm movements by artificial electrical stimulation of the premotor cortex (PM) or the primary motor cortex (M1).

When the stimulation was terminated, the error (after-effect) did not decrease at once but recovered with practice, as observed after typical adaptation.

The direction of the increase in the error was opposite to the "preferred" error direction of the neuron recorded in the stimulation site. The results clearly show that the motor cortices submit error signals that drive adaptation in voluntary arm movements, as predicted by the feedback error learning scheme.

The novel technique to artificially "improve" a motor skill by a small amount of stimulation would be applicable to performance enhancement in athletes as well as for restoring motor control in neurological patients.

Life Preserver: Exercise May Be the Simple Solution for Rescuing Seniors’ Lost and Injured Muscle

Newswise, July 22, 2016 — Exercise may have some surprising benefits for seniors who experience rapid muscle loss and muscle injury and loss as they age. Researchers at McMaster University have found that physical activity can help retain, even repair and regenerate damaged muscle in the elderly.

The findings challenge what is generally seen as an inevitable fact of life: that muscle atrophy and damage cannot be completely repaired in old age and in some cases lost altogether.

Researchers compared and analyzed the capacity for muscle repair performance ofin a group of young mice, a group of old sedentary mice and a group of old exercise-trained mice. three groups of young and old mice, some of which had experienced muscle injury, some of which had been exercise trained, and others which had not.

“The world’s older population is rapidly growing and preventing muscle loss and promoting muscle repair is paramount to preserve health,” says Gianni Parise, lead author of the study and an associate professor in the Department of Kinesiology at McMaster.

“These findings suggest that age-related compromised muscle repair can be rescued with regular exercise,” he says.

After eight weeks of exercise, researchers found the old mice were able to repair and rebuild muscle more quickly following injury when compared to the old mice which had not exercised.

And after a period of 28 days, muscle repair was comparable to that of young mice. Old mice that had not exercised did not fully recover.

The findings suggest that exercise can be used as a preventative measure in older adults who lose muscle rapidly when their activity levels fall, which can happen for a variety of reasons, including illness or extended hospital stays.

“Quite simply, this demonstrates the importance of remaining active throughout life,” says Parise. “Regular exercise can preserve basic processes that govern muscle health.” 

The research was published in the FASEB Journal.

Link Found Between Traumatic Brain Injury and Late-Life Parkinson’s, but Not Alzheimer’s Disease

Newswise, July 22, 2016--Traumatic brain , (TBI) with a loss of consciousness (LOC) may be associated with later development of Parkinson’s disease but not Alzheimer’s disease or incident dementia, according to a study conducted at the Icahn School of Medicine at Mount Sinai and the University of Washington School of Medicine.

The research, published today in JAMA Neurology, contradicts common assumptions about the relationship between TBI and Alzheimer’s disease as found in other high-profile studies.

There is great interest in the late effects of TBI and the widespread public health implications. The Centers for Disease Control and Prevention estimates that more than 1.3 million Americans visit an emergency department each year because of a TBI-related injury.

The research team studied head injury data from 7,130 older adults – the largest study ever on this topic – as part of three prospective cohort studies that performed annual or biennial cognitive and clinical testing. Of this group, 865 people had suffered TBI with LOC at some point before the study began.

Of the 865, 142 had been unconscious for more than one hour. 

The researchers evaluated associations between TBI and late-life clinical outcomes, such as dementia, Alzheimer’s disease, mild cognitive impairment, Parkinson’s disease and change in parkinsonian signs. Roughly 23 percent of the study group had brain autopsies, and in that group researchers searched for any link between TBI and neuropathological findings. 

Neuropathology is considered the gold standard for diagnosing neurodegenerative disease.

No statistically significant relationship between TBI with LOC and dementia risk was discovered when the group with TBI with LOC was compared with the 1,537 patients who developed dementia during the study. Results for Alzheimer’s disease (diagnosed in 1,322 study participants) were similar. However, regression data showed a strong association between TBI with LOC greater than an hour and Parkinson’s disease (117 cases during the study). 

Neuropathological findings at autopsy (1,652 autopsy cases) showed no association between TBI with LOC and beta amyloid plaques or neurofibrillary tangles, the hallmark indicators of Alzheimer’s disease. 

However, the autopsies found an increased risk for Lewy bodies (abnormal aggregates of protein) in TBI with LOC less than an hour and an increased risk of cerebral microinfarcts (microscopic stroke) in TBI with LOC more than an hour.

“The results of this study suggest that some individuals with a history of TBI are at risk for late-life neurodegeneration but not Alzheimer’s disease,” says Kristen Dams-O’Connor, PhD, Co-Director of the Brian Injury Research Center and Associate Professor in the Department of Rehabilitative Medicine at the Icahn School of Medicine at Mount Sinai.

“We want to identify and treat post-TBI neurodegeneration while people are still alive, but to do this, we need to first understand the disease. Prospective TBI brain donation studies can help us characterize post-TBI neurodegeneration, identify risk factors, and develop effective treatments.”

These findings suggest that clinicians may be misdiagnosing late-life TBI-related neurodegeneration as Alzheimer’s disease, and therefore treatment targeting Alzheimer’s would be ineffective in helping late-life decline among patients who experienced TBI. Further work is needed to characterize post-TBI neurodegeneration.

The lead investigator for this study is Paul Crane, MD, MPH, Professor in the Department of Medicine at the University of Washington School of Medicine. Cleveland Clinic, University of Utah, Rush University Medical Center and Group Health Research Institute also contributed to this research.

The National Institutes of Health and the Paul Allen Family Foundation provided funding for the study.

Use It or Lose It: Visual Activity Regenerates Neural Connections Between Eye and Brain

NIH-funded mouse study is the first to show that visual stimulation helps re-wire the visual system and partially restores sight

Newswise, July 22, 2016 — A study in mice funded by the National Institutes of Health (NIH) shows for the first time that high-contrast visual stimulation can help damaged retinal neurons regrow optic nerve fibers, otherwise known as retinal ganglion cell axons.

In combination with chemically induced neural stimulation, axons grew further than in strategies tried previously. Treated mice partially regained visual function. The study also demonstrates that adult regenerated central nervous system (CNS) axons are capable of navigating to correct targets in the brain.

The research was funded through the National Eye Institute (NEI), a part of NIH.

“Reconnecting neurons in the visual system is one of the biggest challenges to developing regenerative therapies for blinding eye diseases like glaucoma,” said NEI Director Paul A. Sieving, M.D., Ph.D.

“This research shows that mammals have a greater capacity for central nervous system regeneration than previously known.”

The optic nerve is the eye’s data cable, carrying visual information from the light-sensing neurons of the retina to the brain. Like a bundle of wires, it consists of about a million axons that each extend from an individual retinal ganglion cell.

A variety of optic neuropathies, such as glaucoma, cause vision loss when they destroy or damage these axons. In adults, retinal ganglion cell axons fail to regrow on their own, which is why vision loss from optic neuropathies is usually permanent.

The researchers induced optic nerve damage in mice using forceps to crush the optic nerve of one eye just behind the eyeball. The mice were then placed in a chamber several hours a day for three weeks where they viewed high-contrast images—essentially changing patterns of black lines.

The mice had modest but significant axonal regrowth compared to control mice that did not receive the high-contrast visual stimulation.

Prior work by the scientists showed that increasing activity of protein called mTOR promoted optic nerve regeneration.

And so they wondered if combining visual stimulation with increased mTOR activity might have a synergistic effect. Two weeks prior to nerve crush, the scientists used gene therapy to cause the retinal ganglion cells to overexpress mTOR.

Optic nerve crush was performed and mice were exposed to high-contrast visual stimulation daily.

After three weeks, the scientists saw more extensive regeneration, with axons growing through the optic nerve as far as the optic chiasm, a distance from the eye of about 6 millimeters.

Encouraged by these results, the researchers again increased mTOR activity but then forced mice to use the treated eye during visual stimulation by suturing shut the good eye.

This combined approach of increasing mTOR activity with intense visual stimulation promoted regeneration down the full length of the optic nerve and into various visual centers of the brain.

“We saw the most remarkable growth when we closed the good eye, forcing the mice to look through the injured eye,” said Andrew Huberman, Ph.D., associate professor, Stanford University School of Medicine’s department of neurobiology, and lead author of the report, published online today in Nature Neuroscience. In three weeks, the axons grew as much as 12 millimeters, a rate about 500 times faster than untreated CNS axons.

The regenerating axons also navigated to the correct brain regions, a finding that Huberman said sheds light on a pivotal question in regenerative medicine: “If a nerve cell can regenerate, does it wander or does it recapitulate its developmental program and find its way back to the correct brain areas?”

Using transgenic mouse lines designed to express fluorescent proteins only in specific retinal ganglion cell subtypes (about 30 exist), the investigators traced where regenerating axons went.

“The two types of retinal ganglion cells that we looked at—α-cells and melanopsin cells—seemed fully capable of navigating back to correct locations in the brain, plugging in and forming synapses,” said Huberman.

“And just as interesting, they didn’t go to the wrong places.” Fluorescent axons appeared in brain regions where α-cells and melanopsin cells would be expected but were absent in other regions.

Visual function was partially restored in animals that received visual/mTOR combination therapy. The investigators used four tests to assess four types of visual perception: ability to track moving objects, pupillary reflex, depth perception, and ability to detect an overhead predator—a stimulus that normally causes mice to freeze or flee for cover. Mice treated with combination therapy performed significantly better than untreated mice in two of the four tests

.

“This study’s striking finding that activity promotes nerve regrowth holds great promise for therapies aimed at degenerative retinal diseases,” noted Thomas Greenwell, NEI program director for retinal neuroscience research. Greenwell said the research has great relevance to the NEI Audacious Goals Initiative (AGI), a sustained effort to develop regenerative medicine for retinal diseases.

For future therapies that preserve optic nerve axons, Huberman envisions the development of filters for virtual reality video games, television programs, or eyeglasses designed to deliver regeneration-inducing visual stimulation.

A drawback of the optic nerve crush model is that it does not mimic typical blinding diseases or injuries. The investigators are therefore currently examining the effect of intense visual stimulation in a mouse glaucoma model. Going forward, they are homing in on the specific qualities of visual stimulation that drive retinal regeneration.

This research was funded by NIH grant EY026100 and the Glaucoma Research Foundation.

For more information about glaucoma, visit www.nei.nih.gov/health/glaucoma .

The NEI AGI is an effort to push the boundaries of vision science. By facilitating cross-disciplinary research, the AGI is tackling the most devastating and difficult-to-treat eye diseases. Learn more about the NEI AGI at www.nei.nih.gov/audacious.

Alzheimer’s Detected Before Symptoms via New Eye Technology

Human clinical trials scheduled

Newswise, July 22, 2016. — Scientists may have overcome a major roadblock in the development of Alzheimer’s therapies by creating a new technology to observe ― in the back of the eye ― progression of the disease before the onset of symptoms. Clinical trials are to start in July to test the technology in humans according to a paper recently published in Investigative Ophthalmology & Visual Science (IOVS). 

The paper, titled Early detection of amyloidopathy in Alzheimer’s mice by hyperspectral endoscopy, builds upon previous work in cells by detecting changes in the retina of mice predisposed to develop Alzheimer’s.

Early detection of Alzheimer’s is critical for two reasons. “First, effective treatments need to be administered well before patients show actual neurological signs,” said author Robert Vince, PhD, of the Center for Drug Design at the University of Minnesota (UMN).

“Second, since there are no available early detection techniques, drugs currently cannot be tested to determine if they are effective against early Alzheimer’s disease. An early diagnostic tool like ours could help the development of drugs as well.”

Looking through the eye to see the brain is a key advantage of the new technology. “The retina of the eye is not just ‘connected’ to the brain — it is part of the central nervous system,” said author Swati More, PhD, also of the Center for Drug Design at UMN. While the brain and retina undergo similar changes due to Alzheimer’s disease, “unlike the brain, the retina is easily accessible to us, making changes in the retina easier to observe.” 

“We saw changes in the retinas of Alzheimer’s mice before the typical age at which neurological signs are observed,” said More. “The results are close to our best-case scenario for outcomes of this project.”

For more information on participating in the clinical trial, please visit the trial website.

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The ARVO peer-reviewed open access journal Investigative Ophthalmology & Visual Science (IOVS) publishes results from original hypothesis-based clinical and laboratory research studies, as well as Reviews,Perspectives, and special issues. IOVSranks No. 1 among 58 ophthalmology journals for number of citations and its 2015 Impact Factor places it at No. 6. The journal is online-only (iovs.arvojournals.org) and articles are published daily. ARVO, an organization of nearly 12,000 researchers from over 75 countries, advances research worldwide into understanding the visual system and preventing, treating and curing its disorders. In addition to IOVS, ARVO publishes the Journal of Vision and Translational Vision Science & Technology.

Gut Bacteria Can Cause, Predict and Prevent Rheumatoid Arthritis

  

Newswise, July 22, 2016— The bacteria in your gut do more than break down your food. They also can predict susceptibility to rheumatoid arthritis, suggests Veena Taneja, Ph.D., an immunologist at Mayo Clinic’s Center for Individualized Medicine. Dr. Taneja recently published two studies — one in Genome Medicine and one in Arthritis and Rheumatology — connecting the dots between gut microbiota and rheumatoid arthritis.

More than 1.5 million Americans have rheumatoid arthritis, a disorder that causes painful swelling in the joints. Scientists have a limited understanding of the processes that trigger the disease. Dr. Taneja and her team identified intestinal bacteria as a possible cause; their studies indicate that testing for specific microbiota in the gut can help physicians predict and prevent the onset of rheumatoid arthritis.

“These are exciting discoveries that we may be able to use to personalize treatment for patients,” Dr. Taneja says.

The paper published in Genome Medicine summarizes a study of rheumatoid arthritis patients, their relatives and a healthy control group. The study aimed to find a biomarker — or a substance that indicates a disease, condition or phenomena — that predicts susceptibility to rheumatoid arthritis. They noted that an abundance of certain rare bacterial lineages causes a microbial imbalance that is found in rheumatoid arthritis patients.

“Using genomic sequencing technology, we were able to pin down some gut microbes that were normally rare and of low abundance in healthy individuals, but expanded in patients with rheumatoid arthritis,” Dr. Taneja says.

Implications for predicting and preventing rheumatoid arthritis

After further research in mice and, eventually, humans, intestinal microbiota and metabolic signatures could help scientists build a predictive profile for who is likely to develop rheumatoid arthritis and the course the disease will take, Dr. Taneja says.

Based on mouse studies, researchers found an association between the gut microbe Collinsella and the arthritis phenotype. The presence of these bacteria may lead to new ways to diagnose patients and to reduce the imbalance that causes rheumatoid arthritis before or in its early stages, according to John Davis III, M.D., and Eric Matteson, M.D., Mayo Clinic rheumatologists and study co-authors. Continued research could lead to preventive treatments.

Possibility for more effective treatment with fewer side effects

The second paper, published in Arthritis and Rheumatology, explored another facet of gut bacteria. Dr. Taneja treated one group of arthritis-susceptible mice with a bacterium, Prevotella histicola, and compared that to a group that had no treatment. The study found that mice treated with the bacterium had decreased symptom frequency and severity, and fewer inflammatory conditions associated with rheumatoid arthritis. The treatment produced fewer side effects, such as weight gain and villous atrophy — a condition that prevents the gut from absorbing nutrients — that may be linked with other, more traditional treatments.

While human trials have not yet taken place, the mice’s immune systems and arthritis mimic humans, and shows promise for similar, positive effects. Since this bacterium is a part of healthy human gut, treatment is less likely to have side effects, says study co-author Joseph Murray, M.D., a Mayo Clinic gastroenterologist.

Rheumatoid arthritis is an autoimmune disorder; it occurs when the body mistakenly attacks itself. The body breaks down tissues around joints, causing swelling that can erode bone and deform the joints. The disease can damage other parts of the body, including the skin, eyes, heart, lung and blood vessels.

The study was funded by the Mayo Clinic Center for Individualized Medicine, which supports research that aims to find treatments compatible with a patient’s unique genetic structure. It also supports the transformation of research discoveries into practical applications for patient care.

Sac to the Future: Cellular Vessels Predict Likelihood of Developing Dementia

 Blood-based neuronally-derived exosomes carry tell-tale proteins that could help forecast transition from mild cognitive impairment to Alzheimer’s

disease

Newswise, July 8, 2016 — Researchers at University of California San Diego School of Medicine say tiny micro-vesicle structures used by neurons and other cells to transport materials internally or dispose of them externally carry tell-tale proteins that may help to predict the likelihood of mild cognitive impairment (MCI) developing into full-blown Alzheimer’s disease (AD).

The findings, published online this week in the journal Alzheimer’s & Dementia, represent a quicker and less invasive way to identify impending cognitive decline and begin treatment before progression to established, irreversible dementia.

“MCI is often a transitional stage between normal aging and dementia,” said senior author Robert A. Rissman, PhD, associate professor in the Department of Neurosciences at UC San Diego School of Medicine, director of the Biomarker Core for the Alzheimer’s Disease Cooperative Study (ADCS) and director of the Neuropathology Core and Brain Bank for the UC San Diego Shiley-Marcos Alzheimer’s Disease Research Center.

“It’s associated with more minor cognitive impairment and carries an increased risk of developing Alzheimer’s dementia.”

MCI patients progress to AD at rates as high as 10 to 15 percent per year, prompting an increased emphasis upon diagnosing MCI early and developing treatments that can delay or prevent conversion to AD.

The need is underscored, write the authors, by the fact that clinical trials of treatments for established AD have thus far failed.

While clinically distinguishable from normal aging and AD, MCI remains nonetheless a complex condition with many and varied causes.

“That has prompted great interest in pinpointing underlying biomarkers that can predict the conversion from MCI to AD dementia,” said Rissman.

“Finding such biomarkers would also identify persons most likely to be responsive to preventive treatments.”

Currently, the accepted methods for diagnosing preclinical AD patients is to detect protein biomarkers found in cerebrospinal fluid (CSF), in combination with advanced neuroimaging and neuropsychological testing.

But CSF sampling involves an invasive, often painful, process. Neuroimaging is expensive. Neuropsychological testing is time-consuming and can often vary from visit to visit.

The new method described in the Alzheimer’s & Dementia study evaluated the potential of exosomes – extremely small vesicles or sacs found in most cell types, including neurons. Exosomes are thought to move materials inside cells and are used to dump cellular trash into the bloodstream for disposal.

In the case of disease, Rissman’s group predicted that neuronal derived exosomes (NDEs) would carry damaged or excess proteins and metabolites out of brain cells, among them amyloid and tau biomarker proteins that are strongly associated with AD.

The researchers harvested NDEs from human blood plasma of 60 patients who participated in an 18-month ADCS clinical trial that enrolled MCI patients only.

Some of these MCI patients converted to AD over the course of the study and some did not. Rissman’s lab also gathered samples from control patients and samples from known AD patients.

They enriched the NDE content of those originating from neurons. The samples represented patients with normal cognitive function, diagnoses of stable MCI and stable AD and patients who had recently transitioned from MCI to AD.

After characterizing NDEs by size, shape and concentration, the researchers compared that data with the different patient cohorts.

They found that NDEs carried targeted biomarker proteins, which have previously been found to predict development of AD up to 10 years before onset of clinical symptoms, and correctly distinguished 100 percent of patients with AD from normal cohorts.

Moreover, the researchers showed for the first time that plasma NDEs from AD and MCI patients may propagate tau tangles in the brains of normal mice similar to what is seen in human AD brains.

The fact that these NDEs could induce pathological-like structures in “naïve” mice (animals not previously subjected to experiments) suggests that the contents of NDEs are bioactive, said Rissman. It also suggests that released NDEs can be taken up by cells, raising the possibility of NDEs potential for drug delivery.

The development of blood-based biomarkers for AD (and other neurodegenerative diseases) diagnostics could significantly improve the effectiveness and reliability of patient care and future research, said the authors, who encouraged further studies to refine and validate the approach.

Co-authors include Charisse N. Winston, Bob C. Carter, Edward M. Rockenstein, Douglas Galasko and Eliezer Masliah, all at UC San Diego; and Edward J. Goetz and Johnny C. Akers, UC San Francisco.

Funding for this research came, in part, from the National Institutes of Health (grants AG04484, BX003040, AG0051839), the Alzheimer’s Association and the Alzheimer’s Art Quilt Initiative.

Genetic Risk Factors for Alzheimer’s Disease May Be Detectable Even in Young Adults

Newswise, July 8, 2016 – New research shows that a genetic risk score may detect those at higher risk for Alzheimer’s disease long before symptoms appear—even possibly in healthy young adults, according to a study published in the July 6, 2016, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“The stage of Alzheimer’s before symptoms show up is thought to last over a decade,” said Elizabeth C. Mormino, PhD, with Massachusetts General Hospital in Charlestown, Mass.

“Given that current clinical trials are testing whether therapies can slow memory and thinking decline among people at risk for the disease, it is critical to understand the influence of risk factors before symptoms are present.”

For the study, researchers calculated a polygenic risk score, or a numeric score based on whether or not a person has several high-risk gene variants, in 166 people with dementia and 1,026 without dementia.

Participants had an average age of 75. Scientists also looked for specific markers of Alzheimer’s disease. The markers included memory and thinking decline, clinical progression of the disease and the volume of the hippocampus (the memory center of the brain). 

Researchers also looked at links between the risk score and hippocampus volume in 1,322 healthy, younger participants between the ages of 18 and 35.

The study found that within older people free of dementia, a higher polygenic risk score was associated with worse memory and smaller hippocampus at the start of the study, accounting for 2.3 percent of the total variance in memory and 2.0 percent of the variance in hippocampus volume.

Over the three years of the study, a higher score was also linked to greater longitudinal memory and executive function decline and clinical progression of the disease.

Finally, the risk score was associated with overall disease progression, with 15 of 194 participants that were cognitively normal at the start of the study developing mild cognitive impairment or Alzheimer’s disease, and 143 of 332 with mild cognitive impairment at the start of the study developing Alzheimer’s disease after three years. Each standard deviation increase in polygenic risk was associated with a 1.6 times increase in risk of clinical progression.

Within the younger group, a higher risk score was tied to smaller hippocampus volume. For the younger group, the risk score accounted for 0.2 percent of the difference in hippocampus volume between those with high and low risk scores.

“Our study was small and larger numbers of participants will need to be studied to confirm our findings,” said Mormino. “The goal of this type of research is to help physicians better identify those at high risk of dementia so that future preventative treatments may be used as early as possible.”

The study was supported by the National Institutes of Health.

To learn more about Alzheimer’s disease, please visit http://www.aan.com/patients.

The American Academy of Neurology, the world’s largest association of 30,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson’s disease and epilepsy.

For more information about the American Academy of Neurology, visit http://www.aan.com or find us on Facebook, Twitter, Google+ and YouTube.

Does Chronic Pain Run in Families?

 Genetics, Parenting, and Stress May All Play a Role

Newswise, July 8, 2016– Can an increased risk of chronic pain be transmitted from parents to children? Several factors may contribute, including genetics, effects on early development, social learning, and more according to a report in the journal PAIN®, the official publication of the International Association for the Study of Pain (IASP). The journal is published by Wolters Kluwer.

Amanda L. Stone of Vanderbilt University, in Nashville, Tenn., and Anna C. Wilson of Oregon Health & Science University, in Portland, Ore., present a conceptual model of transmission of chronic pain, including potential mechanisms and moderating factors.

The researchers write, "Such a framework highlights chronic pain as inherently familial and intergenerational, opening up avenues for new models of intervention and prevention that can be family-centered and include at-risk children."

Proposed Explanations for Familial Transmission of Chronic Pain Risk
Knowing that offspring of parents with chronic pain are at increased risk of developing chronic pain, as well as the adverse mental and physical health outcomes associated with chronic pain, Drs. Stone and Wilson developed an "integrative conceptual model" to explore possible explanations for this risk.

The researchers identify five "plausible mechanisms" to explain the transmission of chronic disease risk from parent to child:

• Genetics. Children of parents with chronic pain might be at increased genetic risk for sensory as well as psychological components of pain. Research suggests that genetic factors may account for roughly half of the risk of chronic pain in adults.

• Early Neurobiological Development. Having a parent with chronic pain may affect the features and functioning of the nervous system during critical periods in early development. For example, a baby's development might be affected by the mother's stress level or health behaviors during and after pregnancy.

• Pain-Specific Social Learning. Children may learn "maladaptive pain behaviors" from their parents, who may act in ways that reinforce those behaviors. Catastrophizing—exaggerated responses and worries about pain—might be one key factor.

• General Parenting and Health Habits. Chronic pain risk could be affected by parenting behaviors linked to adverse child outcomes—for example, permissive parenting or lack of consistency and warmth. The parents' physical activity level and other health habits might also play a role.

• Exposure to Stressful Environment. There may be adverse effects from growing up in stressful circumstances related to chronic pain—for example, financial problems or parents' inability to perform daily tasks.

The model also identifies some "moderators" that might explain when and under what circumstances children are at highest risk of developing chronic pain. These include chronic pain in the other parent; the timing, course, and location of the parent's pain; and the children's characteristics, including their personal temperament.

"The outlined mechanisms, moderators, and vulnerabilities likely interact over time to influence the development of chronic pain and related outcomes in offspring of parents with chronic pain," Drs. Stone and Wilson note.

They hope their model will provide a framework to guide future research—toward the goal of developing effective prevention and treatment approaches for children of parents with chronic pain.

Click here to read “Transmission of risk from parents with chronic pain to offspring: an integrative conceptual model.”

Role of Gender, Aging in Heart Failure Focus of Study

Newswise, July 8, 2016 — Why do women have lower rates of heart failure than men for most of their lives?

University of Guelph researchers have uncovered a possible clue – an actin binding protein called “CapZ” that also protects against heart attacks.

Now they’ll be studying how its levels are affected by gender and aging, backed by a prestigious Catalyst Grant from the Canadian Institutes of Health Research (CIHR).

Their research may lead to new therapeutic treatments for reducing heart problems and extending lives of both men and women.

“Age continues to be the largest independent risk factor for the development of heart failure,” said Glen Pyle, a professor in the Department of Biomedical Sciences in the Ontario Veterinary College and member of U of G’s Centre for Cardiovascular Investigations.

“With people living longer throughout the world, it’s expected that the rates of heart failure will rise dramatically.”

Pre-menopausal women are relatively protected against heart failure compared to men, Pyle said. But the gap starts to close after menopause; by age 80, women and men are at equal risk. No one knows exactly why.

It’s been speculated that estrogen plays a role, “but what are the hormonal changes doing to the cells in the heart? That is where we don’t know very much,” Pyle said.

“Once we figure it out, we can identify what is happening after menopause to make females more vulnerable to heart failure, and why they are protected earlier in life.”

Previously, Pyle found that hearts of aged male mice contain higher levels of CapZ than female mice of the same age. The males show signs of declining heart performance, but the females have normal function.

Pyle’s group has discovered that female mice somehow decrease CapZ levels to protect against cardiac dysfunction, while male mice are unable to do so.

Pyle and his research team genetically engineered male mice with decreased CapZ levels, and found it prevented heart failure.

“Even a small decrease – 20 per cent – offered protection,” he said.

“These results suggest that CapZ may be a viable target to protect hearts against the process of aging.”

He now plans to assess the impact of sex and aging on CapZ levels in the heart.

“We’ll be looking at how and when protein levels naturally change over time in both female and male mice,” said Pyle, who has studied CapZ for nearly 20 years.

They will need to study mice much older than those typically used in research – two and three years of age, the equivalent of 70 and 90 years in humans.

Nurturing lab mice to that age takes time and resources. That is why the $150,000 CIHR Catalyst Grant is critical, Pyle said. The funding comes from CIHR’s Institute of Cancer Research, Institute of Genetics, Institute of Infection and Immunity, and Institute of Gender and Health.

“We plan to age the female mice longer, to three years — the equivalent of 90 years in humans — to see when they get to the point where they lose the CapZ protection,” he said.

This is important because menopause duration varies in women, and it takes time for the heart to change. “We often do not see an effect in women until they are in their 60s or 70s,” Pyle said.

Pyle will work with postdoctoral researcher Ilka Lorenzen-Schmidt on the project, which he called “unique research and in an under-examined field.”

“The relative lack of research using female subjects is finally being recognized as a significant issue in medicine, and aging populations worldwide are creating the potential for a heart failure epidemic,” he said.

“This work will advance our understanding of the influence of both gender and aging on heart function, and tackle two emerging problems at the same time.”

The GW Cancer Center Joins Nearly 1,000 Local and National Organizations to Increase Colorectal Cancer Screening Rates Nationwide

Newswise, July 8, 2016 —George Washington University (GW) Cancer Center has joined with nearly 1,000 local and national organizations to support the 80% by 2018 initiative, led by the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), and the National Colorectal Cancer Roundtable (NCCRT), an organization co-founded by ACS and CDC. The 80% by 2018 initiative represents a shared goal to have 80 percent of adults age 50 and over regularly screened for colorectal cancer by 2018.

Colorectal cancer is the nation’s second-leading cause of cancer-related deaths when men and women are combined; however, it is one of only a few cancers that can be prevented. Through proper colorectal cancer screening, doctors can find and remove hidden growths (called “polyps”) in the colon before they become cancerous. Removing polyps can prevent cancer altogether.

“Our support of the 80% by 2018 initiative represents a continuation and recognition of our work in comprehensive cancer control,” said Mandi Pratt-Chapman, associate center director for patient-centered initiatives and health equity for the GW Cancer Center. “We are committed to spreading the word about the importance of regular colorectal cancer screening and supporting the great work of the NCCRT.”

The GW Cancer Center is committed to increasing colorectal cancer screening and has expertise in colorectal cancer information and research.

The GW Cancer Center contributed to the ACS Colorectal Cancer Survivorship Care Guidelines and recently launched a new colorectal cancer survivorship module in its popular e-learning series for primary care providers.

In addition to its provider education work, the GW Cancer Center created a social media toolkit to promote colorectal cancer screening in tandem with the launch of the “80% by 2018 Communications Guidebook: Effective Messaging to Reach the Unscreened.” GW Cancer Center staff have also presented about evaluating colorectal cancer social media campaigns as part of ongoing technical assistance efforts to cancer control professionals. The Center is also an active member of the Comprehensive Cancer Control National Partnership’s Colorectal Cancer Screening Workgroup.

Part of the 80% by 2018 goal is to leverage the energy of multiple and diverse partners to empower communities, patients and providers to increase screening rates.

The 80% by 2018 initiative consists of health care providers, health systems, communities, businesses, community health centers, government, non-profit organizations and patient advocacy groups who are committed to getting more people screened for colorectal cancer to prevent more cancers and save lives.

For more information or to learn about the 80% by 2018 pledge, visit http://nccrt.org/tools/80-percent-by-2018/.