Conservative Care May Be a Reasonable Option for Elderly Kidney Failure Patients

Dialysis may not prolong patients’ survival

Among kidney failure patients aged ≥80 years, there was no statistically significant survival advantage for those who chose dialysis over conservative management.'

Half or more of all patients on dialysis are aged ≥65 years in some countries.

Newswise, March 18, 2016— A new study found no significant survival advantage among elderly kidney failure patients who chose dialysis over conservative management. The findings, which appear in an upcoming issue of the Clinical Journal of the American Society of Nephrology (CJASN), indicate that conservative care may be a reasonable choice for selected older patients.

Worldwide, increasing numbers of older patients are developing kidney failure, or end-stage renal disease (ESRD), that can be treated with renal replacement therapy such as kidney transplantation or dialysis.

Some experts have questioned whether older patients, who often have other medical conditions, are likely to benefit from these treatment options and should instead opt to be treated conservatively, with care that includes control of fluid and electrolyte balance, correcting anemia, and providing appropriate palliative and end of life care.

To look at the issue, a team in the country where hemodialysis was originally invented compared survival in older patients with ESRD who chose either dialysis (204 patients) or conservative management (107 patients) between 2004 and 2014. In this single-center observational study, investigators led by Wouter Verberne, MD and Willem Jan Bos, MD,PhD (St. Antonius Hospital, Nieuwegein, in The Netherlands) found no statistically significant survival advantage among patients aged ≥80 years old who chose dialysis over conservative management. In general, patients with additional medical illnesses died sooner than patients without comorbidities.

“We do not conclude that dialysis treatment should not be given to anybody ≥80 years or with severe comorbidity, but we show that the treatment is on average of little advantage regarding survival,” said Dr. Verberne.

“Our next task is to predict who benefits and who does not. Until we are able to give a better prediction of the results of dialysis treatment at high age, we can merely suggest that conservative management is an option which should honestly be discussed when ESRD is approaching.” Dr. Verberne added that more research is needed to determine how different treatment options affect patients’ other outcomes, such as quality of life and severity of symptoms.

In an accompanying editorial, Helen Tam-Tham, MSc and Chandra Thomas, MSc, MD (University of Calgary, in Canada) noted that conservative management programs can vary considerably from place to place. “Further research is necessary for enhancing and evaluating the multiple components necessary for a comprehensive conservative management program,” they wrote.

Study co-authors include A.B.M. Tom Geers, MD, PhD, Wilbert Jellema, MD, PhD, Hieronymus Vincent, MD, PhD, and Johannes van Delden, MD, PhD.

Disclosures: This research was made possible thanks to an unrestricted grant from Roche (Woerden, The Netherlands) to the St. Antonius Research Fund.

The Brain May Show Signs of Aging Earlier Than Old Age

Newswise, March 18, 2016--A new study published in Physiological Genomics suggests that the brain shows signs of aging earlier than old age. The study found that the microglia cells—the immune cells of the brain—in middle-aged mice already showed altered activity seen in microglia from older mice.

Parkinson’s, Alzheimer’s and other aging-related neurodegenerative disorders are associated with excessive inflammation in the brain. Scientists believe that overactive microglia cells contribute to the excess inflammation. Normally, microglia protect the brain from infection and ensure the brain functions properly. Their immune response is tightly controlled.

Microglia produce pro-inflammatory molecules to turn the inflammation process on, followed by anti-inflammatory molecules to turn inflammation off. With aging, microglial cells can overreact, and their immune activity can become less controlled—they turn inflammation on too quickly or turn it off too slowly. The prolonged or constant inflammation that results can damage the brain.

While it is known that microglia immune activity changes with aging, which response is affected first—the pro-inflammatory or the anti-inflammatory—or, more importantly, when microglial aging begins is not clear, says Jyoti Watters of the University of Wisconsin-Madison and lead investigator of the study. “We show in a mouse model that it may begin earlier than we thought,” Watters says.

The research team at the University of Wisconsin-Madison studied the microglia activity of young (two months old) and middle-aged (nine to 10 months old) mice. The researchers injected the mice with lipopolysaccharide, a molecule found in bacteria that strongly activates the immune system and causes inflammation. The mice were injected twice to assess the microglia’s ability to reset their immune activity and respond to another bout of inflammation.

The researchers found that middle-aged mice displayed exaggerated pro-inflammatory responses after the first injection. However, anti-inflammatory responses were normal. After the second injection, both pro-inflammatory and anti-inflammatory responses were normal.

The data suggest that at middle age, the microglia already showed signs of an altered immune response. But not everything is impaired: The microglia of the middle-aged mice still responded normally to the second injection.

“At this time, age-related alterations may only be beginning since other critical capacities have not begun to deteriorate yet,” according to Watters. “Of course, it is not known when aging-associated changes in microglial activities begin in the human brain, but these results in mice suggest that it may be earlier than we had previously appreciated,” Watters says.

The article “Age-dependent differences in microglial responses to systemic inflammation are evident as early as middle age” is published ahead-of-print in Physiological Genomics.

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About the American Physiological Society
Physiology is the study of how molecules, cells, tissues and organs function in health and disease. Established in 1887, the American Physiological Society (APS) was the first U.S. society in the biomedical sciences field. The Society represents more than 10,000 members and publishes 15 peer-reviewed journals with a worldwide readership. 

Women May Keep Verbal Memory Skills Longer than Men in the Early Stages of Alzheimer’s

Newswise, March 18, 2016 – Women may have a better memory for words than men despite evidence of similar levels of shrinkage in areas of the brain that show the earliest signs of Alzheimer’s disease, according to a study published in the March 16, 2016, online issue of Neurology®, the medical journal of the American Academy of Neurology

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According to study author Erin E. Sundermann, PhD, of Albert Einstein College of Medicine in Bronx, NY, “One way to interpret the results is that because women have better verbal memory skills than men throughout life, women have a buffer of protection against loss of verbal memory before the effects of Alzheimer’s disease kick in.

Because verbal memory tests are used to diagnose people with Alzheimer’s disease and its precursor, mild cognitive impairment, these tests may fail to detect mild cognitive impairment and Alzheimer’s disease in women until they are further along in the disease.”

The study included participants from the Alzheimer’s Disease Neuroimaging Initiative: 235 people with Alzheimer’s disease, 694 people with mild cognitive impairment that included memory problems, and 379 people with no memory or thinking problems. The groups’ performance on a test of verbal memory was compared to the size of the hippocampal area of the brain, which is responsible for verbal memory and affected in the early stages of Alzheimer’s disease.

Women performed better than men on the tests of both immediate recall and delayed recall among those showing evidence of minimal to moderate amounts of hippocampal shrinkage.

At the high level of hippocampal shrinkage, there was no difference in the scores of men and women. At the score that indicates the start of verbal memory impairment, or 37 on a scale of zero to 75 for immediate recall, women showed greater evidence of hippocampal shrinkage (ratio of hippocampal volume to total brain volume multiplied by 103 was 5 compared to 6 for men).

Mary Sano, PhD, of Icahn School of Medicine at Mount Sinai in New York, NY, and a member of the American Academy of Neurology, said in a corresponding editorial, “At a public policy level, the potential health care cost for under-detection or delayed diagnosis of women with Alzheimer’s disease or its early stages is staggering and should motivate funding in this area.”

“If these results are confirmed, then we may need to adjust memory tests to account for the difference between men and women in order to improve our accuracy in diagnosis,” said Sundermann.

The Alzheimer’s Disease Neuroimaging Initiative was supported by the National Institute on Aging, National Institute of Biomedical Imaging and Bioengineering, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, U.S. Food and Drug Administration, Abbott, Amorfix Life Sciences, AstraZeneca, Bayer HealthCare, BioClinica, Biogen Idec, Bristol-Myers Squibb, Eisai, Elan Pharmaceuticals, Eli Lilly, F. Hoffmann-La Roche and Genentech, GE Healthcare, Innogenetics, IXICO, Janssen Alzheimer Immunotherapy Research and Development, Johnson and Johnson Pharmaceutical Research and Development, Medpace, Merck, Meso Scale Diagnostics, Novartis Pharmaceuticals; Pfizer, Servier, Synarc and Takeda Pharmaceutical.

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

The American Academy of Neurology, an 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.

Alzheimer’s Plaques Found in Middle-Aged People with Brain Injuries

Newswise, March 18, 2016 —  A new study suggests that people with brain injuries following head trauma may have buildup of the plaques related to Alzheimer’s disease in their brains. The research is published in the  online issue of Neurology®, the medical journal of the American Academy of Neurology.

A corresponding editorial states that over the past decade the rate of emergency department visits related to traumatic brain injury (TBI) has increased by 70 percent. The editorial also says an estimated three to five million Americans live with a TBI-related disability.

“The study is small and the findings preliminary, however, we did find an increased buildup of amyloid plaques in people who had previously sustained a traumatic brain injury,” said study author Professor David Sharp, MD, of Imperial College London, in the United Kingdom.

 “The areas of the brain affected by plaques overlapped those areas affected in Alzheimer’s disease, but other areas were involved. People after a head injury are more likely to develop dementia, but it isn’t clear why. Our findings suggest TBI leads to the development of the plaques which are a well-known feature of Alzheimer’s disease.”

For the study, nine people with an average age of 44 who had a single moderate to severe TBI had PET and MRI brain scans. The brain injuries occurred between 11 months and up to 17 years before the start of the study. The participants were compared to 10 people with Alzheimer’s disease and nine healthy participants.

The PET scans used a marker that detects plaques in the brain. The MRI scans used diffusion tensor imaging to detect damage to brain cells that occurs after TBI. Both the people with brain injuries and the people with Alzheimer’s disease had plaques in the posterior cingulate cortex, which is affected early in Alzheimer’s, but only those with brain injuries had plaques in the cerebellum. The researchers also found that plaques were increased in patients with more damage to the brain’s white matter.

“It suggests that plaques are triggered by a different mechanism after a traumatic brain injury,” Sharp said. “The damage to the brain’s white matter at the time of the injury may act as a trigger for plaque production.”

“If a link between brain injury and later Alzheimer’s disease is confirmed in larger studies, neurologists may be able to find prevention and treatment strategies to stave off the disease earlier,” said Sharp.

The study was supported by the Imperial College Healthcare Trust Biomedical Research
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To learn more about Alzheimer’s disease, please visit www.aan.com/patients.

The American Academy of Neurology, an 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.

Combining Two Techniques to 'Rewire' the Brain May Improve Arm and Hand Movement for Stroke Survivors

Newswise, March 18, 2016-- Used in combination, two innovative rehabilitation approaches can promote better long-term recovery of arm and hand movement function in stroke survivors, suggests a paper in the American Journal of Physical Medicine & Rehabilitation, the official journal of the Association of Academic Physiatrists. The journal is published by Wolters Kluwer.

Adding peripheral nerve stimulation (PNS) to "constraint-based" therapy enhances recovery of movement in the affected arm and hand—even more than one year after a stroke, according to the study by Dr. Lumy Sawaki and colleagues of University of Kentucky, Lexington.

Adding Nerve Stimulation Improves Results of Constraint-Based Therapy

The preliminary study evaluated the effects of combining two emerging approaches to post-stroke rehabilitation of partial paralysis (hemiparesis). Constraint-induced therapy (CIT) is an approach that forces "intensive, task-oriented use" of the affected hand. This is done by limiting movement of the less-affected hand, forcing the patient to use the partially paralyzed limb.

Peripheral nerve stimulation consists of non-invasive, low-level electrical stimulation applied to the nerves in the paralyzed arm muscles, which in turn increases activity in the brain area that controls the arm. Both CIT and PNS take advantage of the brain's potential for "neuroplasticity"—the ability to reorganize or "rewire" itself after injury.

The study included 19 stroke survivors who were left with mild to moderate hemiparesis of one upper limb, at least one year after a stroke. All received a modified CIT approach, including wearing a padded mitt on the less-affected hand during therapy sessions. Subjects were also asked to wear the mitt for 90 percent of waking hours during their daily lives.

In addition, subjects received either active or "sham" (inactive) PNS, delivered through electrodes placed on the affected arm. At each session, PNS was applied for two hours, followed by four hours of CIT.

After ten sessions, arm and hand function improved for both groups. But on most measures, improvement was significantly greater for patients who received active PNS added to CIT. Grip strength was the only measure to show no significant added advantage with active PNS.

Significant differences between groups persisted to one-month follow-up. "Compared with the sham PNS group, the active PNS group may have made more extensive use of the affected upper extremity in settings outside the lab, such as in activities of daily living," Dr. Sawaki and coauthors write. However, they caution that further studies are needed to provide conclusive evidence in this regard.

There's a crucial need for treatments to enhance long-term recovery of function after a stroke—particularly after the first year, when most spontaneous improvement occurs. Both CIT and PNS can enhance movement function after stroke. The new study is the first to suggest that combining these two techniques can lead to further improvement in arm and hand movement in stroke survivors with mild-to-moderate chronic hemiparesis.

"It appears that PNS has enormous promise as a clinical intervention to enhance outcomes of motor training for stroke survivors with mild to moderate hemiparesis," Dr. Sawaki and colleagues conclude. They emphasize the need for further research to maximize the benefits of combined PNS and other rehabilitation techniques—including studies to optimize the PNS sites and settings and the other approaches used.

‘Broken’ Heart Breakthrough: Researchers Reprogram Cells to Better Battle Heart Failure

UNC School of Medicine scientists overcame a significant barrier to convert scar-making fibroblasts into living, beating cardiomyocytes

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Newswise, March 18, 2016--Patients with heart failure often have a buildup of scar tissue that leads to a gradual loss of heart function. In a new study published today in the journal Cell Stem Cell, researchers from the University of North Carolina School of Medicine report significant progress toward a novel approach that could shrink the amount of heart scar tissue while replenishing the supply of healthy heart muscle.

“Our past work brought hope that we could one day improve heart function in people with heart failure by converting scar tissue into beating heart muscle,” said Li Qian, PhD, assistant professor of pathology and laboratory medicine and the study’s senior author.

“But that was more of a proof-of-principle study, and the conversion rate was quite low. Now we have found the barrier to conversion, and by removing it, we have been able to significantly increase the yield of muscle-like cells.”

Heart failure has no cure and currently affects an estimated 5.7 million people in the United States. Common symptoms include shortness of breath, fatigue, and swelling, all of which often worsen as the heart weakens over time.

“Our hope is that this approach could extend the lives of people with heart failure and markedly improve their quality of life in the future,” said Qian, who is also a member of the McAllister Heart Institute at UNC.

In 2012, Qian and her colleagues created a “cocktail” of proteins capable of converting fibroblasts, which create scar tissue, into cardiomyocytes – heart muscle cells that beat on their own exactly the way regular heart muscle cells do.

Notably, the team’s approach did not require converting fibroblasts into stem cells, which is typical of other tissue regeneration techniques. Qian’s approach lowered the likelihood of uncontrolled cell growth and tumor formation.

In experiments using mice, the cocktail proved successful at shrinking the size of scar tissue and improving heart function. But the process had remained disappointingly slow – until now.

“We wanted to have a better yield and shorten the conversion time so in the future this process could be fast, easy, and efficient for disease modeling or for treatment,” Qian said.

The new breakthrough came when the team discovered that a gene called Bmi1 interfered with the expression of other key genes needed to convert fibroblasts into heart muscle cells. Bmi1 previously had been investigated for its role in neural stem cells and cancer cells, but this is the first study to pinpoint a role in its interaction with cardiogenic genes.

When the team depleted Bmi1, the conversion rate sped up markedly; the percentage of fibroblasts that transformed into heart muscle cells increased 10-fold. Repressing Bmi1 also allowed Qian’s team to simplify the cocktail by reducing the number of different proteins in it.

The ultimate goal, Qian said, is to refine the cocktail into a pill that could safely be given to patients during a heart attack or after the heart has already become damaged, thus reducing the long-term loss of functional heart tissue and helping people live longer, healthier lives. If further experiments using larger animal models bear out, Qian estimates such a pill could be developed within a decade.

The technique also holds potential for improving personalized medicine. Currently, there are a number of therapeutics doctors can prescribe to help improve a patient’s heart function, but there is often trial and error involved to find the most effective drug with the fewest side effects. Qian’s protein cocktail could help avoid this.

For instance, if Qian’s technique could convert a patient’s skin cells into heart muscle cells in a lab dish, then lab technicians could use the resulting cell culture to quickly screen existing drugs and find the one most likely to help a specific patient.

In addition, the team’s approach and platform built to study barriers to cardiac reprogramming could help to increase yields for studies focused on reprogramming other cells, such as neurons, pancreas cells, and liver cells for regenerative purposes.

“Hopefully these findings and our approach can be leveraged so that other researchers can identify the barriers to regenerating other types of target tissues more efficiently,” Qian said.

Link Between Gum Disease and Cognitive Decline in Alzheimer’s

Newswise, March 14, 2016 — A new study, jointly led by the University of Southampton and King’s College London, has found a link between gum disease and greater rates of cognitive decline in people with early stages of Alzheimer’s Disease.

Periodontitis or gum disease is common in older people and may become more common in Alzheimer’s disease because of a reduced ability to take care of oral hygiene as the disease progresses. 

Higher levels of antibodies to periodontal bacteria are associated with an increase in levels of inflammatory molecules elsewhere in the body, which in turn has been linked to greater rates of cognitive decline in Alzheimer’s disease in previous studies.

The latest study, published in the journal PLOS ONE, set out to determine whether periodontitis or gum disease is associated with increased dementia severity and subsequent greater progression of cognitive decline in people with Alzheimer’s disease.

In the observational study, 59 participants with mild to moderate Alzheimer’s Disease were cognitively assessed and a blood sample was taken to measure inflammatory markers in their blood. 

Participants’ dental health was assessed by a dental hygienist who was blind to cognitive outcomes. The majority of participants (52) were followed-up at six months when all assessments were repeated.

The presence of gum disease at baseline was associated with a six-fold increase in the rate of cognitive decline in participants over the six-month follow-up period of the study. Periodontitis at baseline was also associated with a relative increase in the pro-inflammatory state over the six-month follow-up period. The authors conclude that gum disease is associated with an increase in cognitive decline in Alzheimer’s Disease, possibly via mechanisms linked to the body’s inflammatory response.

Limitations of the study included the small number of participants; the authors advise that the study should be replicated ideally with a larger cohort. The precise mechanisms by which gum disease may be linked to cognitive decline are not fully clear and other factors might also play a part in the decline seen in participants’ cognition alongside their oral health.

However, growing evidence from a number of studies links the body’s inflammatory response to increased rates of cognitive decline, suggesting that it would be worth exploring whether the treatment of gum disease might also benefit the treatment of dementia and Alzheimer’s Disease.

Professor Clive Holmes, senior author from the University of Southampton, says: “These are very interesting results which build on previous work we have done that shows that chronic inflammatory conditions have a detrimental effect on disease progression in people with Alzheimer’s disease. 

"Our study was small and lasted for six months so further trials need to be carried out to develop these results. However, if there is a direct relationship between periodontitis and cognitive decline, as this current study suggests, then treatment of gum disease might be a possible treatment option for Alzheimer’s.”

Dr Mark Ide, first author from the Dental Institute at King’s College London says: “Gum disease is widespread in the UK and US, and in older age groups is thought to be a major cause of tooth loss. In the UK in 2009, around 80% of adults over 55 had evidence of gum disease, whilst 40% of adults aged over 65-74 (and 60% of those aged over 75) had less than 21 of their original 32 teeth, with half of them reporting gum disease before they lost teeth.

“A number of studies have shown that having few teeth, possibly as a consequence of earlier gum disease, is associated with a greater risk of developing dementia. 

"We also believe, based on various research findings, that the presence of teeth with active gum disease results in higher body-wide levels of the sorts of inflammatory molecules which have also been associated with an elevated risk of other outcomes such as cognitive decline or cardiovascular disease. Research has suggested that effective gum treatment can reduce the levels of these molecules closer to that seen in a healthy state.

“Previous studies have also shown that patients with Alzheimer’s Disease have poorer dental health than others of similar age and that the more severe the dementia the worse the dental health, most likely reflecting greater difficulties with taking care of oneself as dementia becomes more severe.”