Archives for November 2016

Science Behind the Headlines: Brain Training

(Alzheimers Society, UK) Brain training includes a wide variety of activities that are designed to challenge the brain, ranging from crosswords and Sudoku puzzles to bespoke computer games. Many people engage in brain training in the hope that keeping their brains active will maintain or improve their cognitive abilities as they get older.

The Theory Behind Brain Training

The idea of brain training is based on the concept of ‘use it or lose it’. The popular theory goes that the more you regularly challenge your brain the less likely you are to experience cognitive impairment (a reduction in someone’s ability to remember or learn things) or dementia in your later years. The theory is based on an observation made by some that people who have complex jobs or who regularly participate in activities such as crosswords, puzzles or learning new hobbies throughout life appear to have lower rates of dementia.

Computer-based brain training games have been developed that challenge brain functions such as memory, problem solving and reasoning, abilities that can slow down or worsen with age.

What Research Has Been Done?

Observational and interventional studies have looked at the role of brain training activities in older people. Observational studies collect data about a group of people and look for an association between two or more factors. The results from several observational studies have indicated that people who do cognitively stimulating activities may have a lower risk of cognitive decline and dementia. This has been reported for people who do the activities in both middle age and in later life. However, this type of study cannot tell us that brain training activities are directly responsible for lower rates of dementia.

Interventional studies, sometimes called clinical trials, ask groups of people to start doing a new activity and follow them over time to see what effect it has on their brain function. There have not been any interventional studies looking at the effects of crosswords or Sudoku on cognition and dementia risk in older people but a number of studies of this type have tested computer brain training games.

Most of these studies have been small or have only followed participants over a short time frame so there is a lack of robust evidence to show that brain training games can bring long term cognitive benefits in older people over several years.

A recent study analysed the results of 51 interventional studies. The review indicated that brain training could lead to a small improvement in thinking and memory in older people during the duration of the study. However, the analysis also found that thinking and memory was not improved in older people who used the brain training unsupervised.

The largest study conducted to date testing computer brain training was funded by Alzheimer’s Society and involved almost 7,000 people over the age of 50. The brain training package tested in this study challenged people’s reasoning and problem solving skills. The results showed that using this brain training package resulted in improvements in reasoning and remembering words after six months. The more the exercises were completed, the more likely participants were to see improvements in these brain functions.

The study was a randomised controlled trial. This means that some people in the study acted as ‘controls’,  taking cognitive tests but not trying out the brain training games. This type of study is considered rigorous because the researchers can compare the results of those who did brain training with those who didn’t to discover whether the brain training was having an effect.

People over 60 who participated in this study reported that using the brain training packages also improved their ability to get on with their daily activities such as managing a household budget, preparing meals, shopping and navigating public transport.

Can Brain Training Prevent Dementia?

Some studies have found that cognitive training can improve some aspects of memory and thinking, particularly for people who are middle-aged or older. So far, no studies have shown that brain training prevents dementia. However, this is a relatively new area of research and most studies have been too small and too short to test any effect of brain training on the development of cognitive decline or dementia.

Evidence suggests that brain training may help older people to manage their daily tasks better, but longer term studies are needed to understand what effect, if any, these activities may have on a person’s likelihood of developing dementia.

Commercial Brain Training Games

There are a large number of commercial brain training games or products on the market, some of which have been tested in research studies but the majority have not. It is not possible to apply the results of studies that test a particular training package to all brain training games because they may be designed to challenge a different kind of brain function.

People should be cautious if they find commercial packages that claim they can prevent or delay cognitive decline as the evidence for this is currently lacking. Recently, one of the leading providers of commercial brain training games was fined for making false claims about the benefits of their product.

Can I Try Brain Training?

Alzheimer’s Society is funding the researchers at King’s College London to continue to study the effects of brain training in people over 50. This study will test how well people can continue to do the exercises over a long period of time. It will also take genetic information into account by using mouth swabs donated by the volunteers.

If you are aged 50 or over and interested in participating in our brain training study, you can sign up online by visiting the Protect study’s homepage.

People of any age can try a demonstration of one of the reasoning tasks here; however this is not part of the brain training trial and your information will not be used by the researchers.

Citation

https://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=2211&categoryID=200424&pageNumber=12

All content © 2016 Alzheimer’s Society.

 

Understanding Palliative Care: What Every Caregiver Should Know

(Family Caregiver Alliance) Palliative care, also increasingly known as Supportive Care, may be one of the most misunder­stood terms in healthcare. Many people believe it’s the same as hospice care and it means the end of life. But palliative care is different from hospice, and when put in place, palliative care can bring hope, control, and a chance at a better quality of life for seriously ill patients and their caregivers.

This Fact Sheet will summarize key features of pal­liative care, describe how it differs from hospice, and clarify some of the misconceptions that prevent people from considering palliative care for them­selves or for loved ones.

What is Palliative Care and How Can My Family Member Benefit?

For individuals living with serious illness, and for their caregiving family and friends, palliative care offers medical and related treatment towards living as well and as fully as possible. Healthcare professionals embrace a patients’ values, goals, and wishes when considering disease management and burden relief from pain, anxiety, fear, and other symptoms. The patients’ plans and wishes are shared with family and friends who provide care, and support is provided to help relieve burdens.

Most importantly, this patient/family-centered care is appropriate at any age and at any stage in a serious or chronic illness. For example, a person with cancer may be treated for unrelenting pain and appetite loss concurrent with curative treatment; a person living with Alzheimer’s disease may be treated for anxiety and sleeplessness. Care may be offered in the hospital, long-term care facility, at home, or in outpatient clinics.

First used in the 15th century, the term palliative today means to remedy or lessen without curing. Although in the past palliative care and hospice care were bound together, now they can be con­sidered two related approaches that respond to serious illness, depending on the patient’s condition and wishes. They share similar philosophies, and a person in palliative care may transition to hospice care if they are approaching the end of life.

Looking deeper into the concept, the National Consensus Project on Palliative Care describes it this way: “Palliative care is both a philosophy of care and an organized, highly structured system for delivering care. The goal of palliative care is to prevent and relieve suffering and to support the best possible quality of life for patients and their families, regardless of the stage of the disease or the need for other therapies. Palliative care expands traditional disease-model medical treatments to include the goals of enhancing quality of life for patients and family members, helping with deci­sion making, and providing opportunities for per­sonal growth. Palliative care can be rendered along with life-prolonging treatment or as the main focus of care.”

What is the “organized, highly structured system,” and how did it come to be so widespread now in healthcare? First, palliative care takes a collabora­tive, interdisciplinary team (IDT) approach. In addition to the patient and family, the specially trained team can consist of: doctors, registered nurses, social workers, chaplains, dieticians, phar­macists, licensed mental health professionals, phys­ical and occupational therapists, music therapists, massage therapists, and others.

The most common health conditions addressed in palliative care include:

  • Cancer
  • Congestive heart failure (CHF)
  • Kidney failure
  • Liver failure
  • Chronic obstructive pulmonary disease (COPD) or other lung diseases
  • HIV/AIDS
  • Spinal cord injuries
  • Brain diseases such as stroke, ALS, or Parkinson’s
  • Multiple sclerosis (MS)
  • Alzheimer’s and other dementias

When patients choose to begin palliative care, they receive a formal assessment of their health early in the process. Symptoms most commonly addressed include:

  • Pain or discomfort
  • Shortness of breath
  • Fatigue
  • Anxiety
  • Depression
  • Lack of appetite
  • Nausea
  • Constipation
  • Adjusting to and living with the diagnosis of a serious health condition
  • Sleep problems

There will be discussions about the need for an Advance Directive and preferences about with­holding or withdrawing life-sustaining treatments (POLST). (See Making End-of-Life Decisions: What Are Your Important Papers?)

The palliative approach focuses not just on difficult symptoms of an illness, but on the overall benefits and/or side effects of potential treatments, and the emotional, physical, and financial stresses for someone dealing with a serious, perhaps life-threat­ening, disease. Ensuring patients’ dignity, coordi­nating care, and shared decision-making are critical components.

Palliative care is more likely to be suggested when there are:

  • Frequent emergency room visits
  • Three or more admissions to the hospital with the same symptoms within a year
  • Serious side effects from treatments like chemotherapy
  • Eating problems caused by serious illness

This is a dramatically different approach to health­care from the fragmented care we sometimes see in standard medical practice, where treatment is not always well coordinated among primary doc­tors and specialists, and where time limitations and funding don’t allow for an in-depth look at patients.

Physicians are trained to focus on fixing a problem(s) and charging specific fees for specific ser­vices, not necessarily offering comfort measures to patients or treating the whole person, including his or her emotional issues. Additionally, unlike a pallia­tive program, healthcare practices too often neglect to recognize the family as part of the team, even though the family is, of course, greatly impacted by a loved one’s chronic or serious illness, and is usually providing significant amounts of care.

History

The philosophy of palliative care in the US has evolved over time. It began in the hospice move­ment, in which a more patient-centered approach was offered when death was imminent, and where comfort, peace, pain relief, and dignity were the goals, and cure not a possibility.

Although palliative care is a natural practice in many cultures worldwide, the advancement of life-sustaining technology had charted a more cure-focused path in the United States. Life-prolonging measures such as a pacemaker early on in a condition, or a feeding tube or respirator as a disease progresses, are often assumed to be part of the treatment plan of care. Patients and their caregiver(s) can question these assumptions, opting for a plan of care that recognizes and acts on their preferences.

Palliative care became a recognized medical sub-­specialty in the US fairly recently, in 2006. As with other medical specialties, physicians can become board certified in palliative care, and there is training and certification for other healthcare staff as well. Now about 80% of large US hospitals offer palliative care programs. The palliative philosophy of support, comfort, peace, and dignity is offered at any stage—even early in the diagnosis—of a chronic or serious illness that ultimately may or may not be life-threatening.

Medical professionals who practice palliative care are committed to communication, to compassion, to seeing the “whole” person, and to including the family as part of the healthcare team. Studies have indicated the benefits of palliative care:

  • Better quality of life for patient and caregivers
  • Help getting through difficult medical treatments
  • Reductions in hospitalizations and readmissions
  • At times faster recovery and longer survival rates

It’s easy to understand, for example, that patients are better able to function when their pain is well managed and substantially reduced. But not all patients have access to palliative care. Hospital staff may not have the right training. A doctor may feel it would not be beneficial in a specific case. Or, because it is more time-consuming than standard medical care, facilities may have concerns about reimbursement of costs.

Paying for Palliative Care and Hospice Care

Most insurance will cover palliative services as it covers other healthcare procedures and medi­cations, although there may be co-payments. Medicare and Medicaid (Medi-Cal in California) will likewise cover many of the costs. If questions about coverage remain, a social worker or con­sultant from the health care team may be able to clarify pay provisions for the service.

Comprehensive hospice coverage is available for patients with Medicare Part A. This benefit is broader than the coverage for palliative care: most services are free. This may include medical equip­ment such as wheelchairs and hospital beds, medi­cations, professional fees, counseling, and more. Most private insurance programs pay for hospice programs, and state Medicaid programs cover costs as well.

How are Palliative Care and Hospice Care Different?

Hospice is a specific kind of palliative care for patients approaching the end of life and focuses on death with dignity, not on seeking cure. While both palliative and hospice care deal with serious disease and offer a team approach, hospice becomes an option when there are no further treatments available, or the treatments’ side effects, pain, and suffering are overwhelming and will not contribute to a cure. In contrast, palliative care can start at any stage of a serious disease, and curative treatments can continue.

With Advance Directives in place, families and healthcare professionals know that when someone is in hospice care, painful or intrusive treatments, admission to intensive care units, or frightening ambulance trips to emergency rooms, for example, may not be wanted or accepted. In fact, if a patient has a medical emergency, families or caregivers are instructed to call the hospice provider rather than 911.

Patients become eligible for hospice care when doc­tors have determined that they are likely to have six months or less to live. Hospice is always a voluntary program, and patients may continue in hospice if they survive longer, may be discharged from hos­pice if their condition improves, or may withdraw. Hospice staff are available for consultation 24 hours a day. In hospice, as in palliative care, the focus is on comfort and dignity, and spiritual concerns are addressed. Hospice also offers grief therapy and sup­port for families, even after the death of a loved one.

How Can Patients Access Palliative and Hospice Care?

If it hasn’t been offered, ask for it. Not all hospitals provide the services, but most do. The patient’s pri­mary physician should be able to refer families, or check the directory at https://getpalliativecare.org/(link is external). There are different types of local hospice organizations—large and small, and nonprofit and for-profit. Care can be provided in the home, in assisted living or nursing home, hospital, or in a special hospice residence.

In both palliative and hospice care, patients and families are gently supported as they are asked to do deep soul-searching about their values and beliefs during a very challenging time. There is no ques­tion that the decisions are complicated and can be wrenching. Yet while most doctors are trained to do everything possible to prevent death even if treat­ment is painful or futile, with palliative and hospice services in place, patients have the final say.

Resources

Family Caregiver Alliance
National Center on Caregiving

785 Market Street, Suite 750
San Francisco, CA 94103
(415) 434-3388
(800) 445-8106
Website: www.caregiver.org
E-mail: info@caregiver.org(link sends e-mail)
Family Care Navigator: www.caregiver.org/family-care-navigator

Family Caregiver Alliance (FCA) seeks to improve the quality of life for caregivers through education, services, research, and advocacy.

Through its National Center on Caregiving, FCA offers information on current social, public policy, and caregiving issues and provides assistance in the development of public and private programs for caregivers.

For residents of the greater San Francisco Bay Area, FCA provides direct support services for caregivers of those with Alzheimer’s disease, stroke, traumatic brain injury, Parkinson’s, and other debilitating health conditions that strike adults.

FCA Fact Sheets

All FCA Fact Sheets are available online at www.caregiver.org/fact-sheets. Print versions are avail­able to purchase online by visiting www.caregiver.org/fca-publication-order-form.

  • Advance Health Care Directives and POLST
  • Making End-of-Life Decisions: What Are Your Important Papers?

Palliative Care and Hospice Organizations

Center to Advance Palliative Care (CAPC)
https://www.capc.org/(link is external)
Sponsors the website https://getpalliativecare.org/(link is external) with consumer information and provider directory.

National Hospice and Palliative Care Organization
http://www.nhpco.org/(link is external)
Offers information for families and caregivers through the website caringinfo.org, including downloadable Advance Directives for every state

Compassion & Choices
https://www.compassionandchoices.org/(link is external)
Works to protect and expand end-of-life options — and to ensure healthcare providers honor and enable patients’ decisions about their care.

Hospice Foundation of America
https://hospicefoundation.org/(link is external)
(800) 854-3402

Medicare and Medicaid
https://www.cms.gov/(link is external)
(800) MEDICARE

United Hospital Fund
Sponsors http://nextstepincare.org/(link is external). See For Family Caregivers > Hospice and Palliative Care.

Citation

https://www.caregiver.org/understanding-palliativesupportive-care-what-every-caregiver-should-know

Prepared by Family Caregiver Alliance. Reviewed by Helene Martel, MA, Director, Elder Care and Palliative Care, Care Management Institute, Kaiser Permanente. Funded by California Department of Health Care Services. © 2016 Family Caregiver Alliance. All rights reserved.

Copyright © 1996–2016 Family Caregiver Alliance. All rights reserved.

 

New Imaging Technique Measures Toxicity of Proteins Associated with Alzheimer’s and Parkinson’s Diseases

(University of Cambridge) Researchers have developed a new imaging technique that makes it possible to study why proteins associated with Alzheimer’s and Parkinson’s diseases may go from harmless to toxic. The technique uses a technology called multi-dimensional super-resolution imaging that makes it possible to observe changes in the surfaces of individual protein molecules as they clump together. The tool may allow researchers to pinpoint how proteins misfold and eventually become toxic to nerve cells in the brain, which could aid in the development of treatments for these devastating diseases.

crop_17

A new super-resolution imaging technique allows researchers to track how surface changes in proteins are related to neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases.

The researchers, from the University of Cambridge, have studied how a phenomenon called hydrophobicity (lack of affinity for water) in the proteins amyloid-beta and alpha synuclein – which are associated with Alzheimer’s and Parkinson’s respectively – changes as they stick together. It had been hypothesised that there was a link between the hydrophobicity and toxicity of these proteins, but this is the first time it has been possible to image hydrophobicity at such high resolution. Details are reported in the journal Nature Communications.

“These proteins start out in a relatively harmless form, but when they clump together, something important changes,” said Dr Steven Lee from Cambridge’s Department of Chemistry, the study’s senior author.

“But using conventional imaging techniques, it hasn’t been possible to see what’s going on at the molecular level.”

In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, naturally-occurring proteins fold into the wrong shape and clump together into filament-like structures known as amyloid fibrils and smaller, highly toxic clusters known as oligomers which are thought to damage or kill neurons, however the exact mechanism remains unknown.

For the past two decades, researchers have been attempting to develop treatments which stop the proliferation of these clusters in the brain, but before any such treatment can be developed, there first needs to be a precise understanding of how oligomers form and why.

“There’s something special about oligomers, and we want to know what it is,” said Lee.

“We’ve developed new tools that will help us answer these questions.”

When using conventional microscopy techniques, physics makes it impossible to zoom in past a certain point. Essentially, there is an innate blurriness to light, so anything below a certain size will appear as a blurry blob when viewed through an optical microscope, simply because light waves spread when they are focused on such a tiny spot. Amyloid fibrils and oligomers are smaller than this limit so it’s very difficult to directly visualise what is going on.

However, new super-resolution techniques, which are 10 to 20 times better than optical microscopes, have allowed researchers to get around these limitations and view biological and chemical processes at the nanoscale.

Lee and his colleagues have taken super-resolution techniques one step further, and are now able to not only determine the location of a molecule, but also the environmental properties of single molecules simultaneously.

Using their technique, known as sPAINT (spectrally-resolved points accumulation for imaging in nanoscale topography), the researchers used a dye molecule to map the hydrophobicity of amyloid fibrils and oligomers implicated in neurodegenerative diseases. The sPAINT technique is easy to implement, only requiring the addition of a single transmission diffraction gradient onto a super-resolution microscope. According to the researchers, the ability to map hydrophobicity at the nanoscale could be used to understand other biological processes in future.

The research was supported by the Medical Research Council, the Engineering and Physical Sciences Research Council, the Royal Society and the Augustus Newman Foundation.

Citation

http://www.neuroscience.cam.ac.uk/news/article.php?permalink=ccb7babf10

Journal Reference:

Marie N. Bongiovanni et al. Multi-dimensional super-resolution imaging enables surface hydrophobicity mapping. Nature Communications, 2016 DOI: 10.1038/ncomms13544

© 2016 University of Cambridge

 

Comparing Gait Parameters Can Predict Decline in Memory and Thinking

(Mayo Clinic) Walking is a milestone in development for toddlers, but it’s actually only one part of the complex cognitive task known as gait that includes everything from a person’s stride length to the accompanying swing of each arm. A Mayo Clinic study recently published in the Journal of Alzheimer’s Disease found that problems associated with gait can predict a significant decline in memory and thinking.

Using the Rochester Epidemiology Project, Mayo Clinic researchers examined medical records of Olmsted County, Minnesota, residents, who were between ages 70 to 89 as of Oct. 1, 2004. The analysis included 3,426 cognitively normal participants enrolled in the Mayo Clinic Study of Aging who had a complete gait and neuropsychological assessment.

Using computerized analyses, researchers measured gait parameters, such as:

  • Stride length
  • Ambulatory time
  • Gait speed
  • Step count
  • Cadence
  • Stance time
  • Arm swing

Alterations in several gait parameters were associated with decline in memory, thinking and language skills, and visual perception of the spatial relationship of objects. The study results also supported the role of computerized analysis because the computer tool detected modifications before impairment was detected with a standard neuropsychological test.

“The presence of gait disturbances increases with advancing age and affects the independence of daily living, especially in the elderly,” says neurologist Rodolfo Savica, M.D., lead author on the study.

“Computerized gait analysis is a simple, noninvasive test that potentially could be used to identify patients at high risk for cognitive decline and to target appropriate therapies.”

Citation

http://newsnetwork.mayoclinic.org/discussion/comparing-gait-parameters-can-predict-decline-in-memory-and-thinking/?_ga=1.28234811.641625560.1480463271

By Susan Barber Lindquist

Journal Reference:

Rodolfo Savica, Alexandra M.V. Wennberg, Clinton Hagen, Kelly Edwards, Rosebud O. Roberts, John H. Hollman, David S. Knopman, Bradley F. Boeve, Mary M. Machulda, Ronald C. Petersen, Michelle M. Mielke. Comparison of Gait Parameters for Predicting Cognitive Decline: The Mayo Clinic Study of Aging. Journal of Alzheimer’s Disease, 2016; 55 (2): 559 DOI: 10.3233/JAD-160697

© Copyright 2016. Mayo Clinic. All Rights Reserved

 

Use of Prescription Pain Medicines Different Between Persons with With and Without Alzheimer’s Disease

(University of Eastern Finland) Approximately one third of persons with Alzheimer’s disease use prescription medicines for pain after their diagnosis, reports a recent study conducted at the University of Eastern Finland. The use of analgesics was as common among persons with Alzheimer’s disease as it was among those of the same age without the disease, but there were significant differences in the types of medicines used. The results were published in European Journal of Pain.

The researchers found out that 35% of those with Alzheimer’s disease and 34% of those without used a prescription analgesic in the first six months after the disease diagnosis. Paracetamol was the most common medicine in both groups, but it was significantly more frequently used by persons with Alzheimer’s disease.

Persons with Alzheimer’s disease also used less anti-inflammatory medicines, such as ibuprofen, and mild opioids for their pain.. During a six-year follow-up, the use of paracetamol and opioids increased significantly, while the use of anti-inflammatory drugs became less common..

Pain is a common symptom among older adults, but its treatment with medicines demands careful weighing of benefits and risks. According to this study, persons with Alzheimer’s disease are commonly treated with paracetamol, which is the preferred first-line analgesic for older people. The treatment of pain among older adults and persons with cognitive disorders requires regular assessment of pain and the benefits and risks of used analgesics.

The study is part of the MEDALZ cohort, which included 67,215 persons with Alzheimer’s disease diagnosed during 2005-2011 and comparison persons with the same age, gender and region of residence without the disease. Data for the study were derived from Finnish nationwide registers.

Citation

http://www.uef.fi/-/alzheimerin-tautia-sairastavien-kipua-hoidetaan-eri-laakkein-kuin-muilla-iakkailla

Journal Reference:

A. Hamina, H. Taipale, A. Tanskanen, A.-M. Tolppanen, J. Tiihonen, S. Hartikainen. Differences in analgesic use in community-dwelling persons with and without Alzheimer’s disease. European Journal of Pain, 2016; DOI: 10.1002/ejp.969

© University of Eastern Finland

Turning Back the Aging Clock

(California Institute of Technology) Researchers from Caltech and UCLA have developed a new approach to removing cellular damage that accumulates with age. The technique can potentially help slow or reverse an important cause of aging.

Led by Nikolay Kandul, senior postdoctoral scholar in biology and biological engineering in the laboratory of Professor of Biology Bruce Hay, the team developed a technique to remove mutated DNA from mitochondria, the small organelles that produce most of the chemical energy within a cell. A paper describing the research appears in the November 14 issue of Nature Communications.

There are hundreds to thousands of mitochondria per cell, each of which carries its own small circular DNA genome, called mtDNA, the products of which are required for energy production. Because mtDNA has limited repair abilities, normal and mutant versions of mtDNA are often found in the same cell, a condition known as heteroplasmy. Most people start off life with some level of heteroplasmy, and the levels of mutant mtDNA increase throughout life. When a critical threshold level of mutant mtDNA is passed, cells become nonfunctional or die.
bhay_turningbackagingclock-news-web
Mitochondrial DNA is the small circular chromosome found inside mitochondria. The mitochondria are organelles found in cells that are the sites of energy production. Credit: http://www.genome.gov/ (CC0)

The accumulation of mutant mtDNA over a lifetime is thought to contribute to aging and degenerative diseases of aging such as Alzheimer’s, Parkinson’s, and sarcopenia—age-related muscle loss and frailty. Inherited defects in mtDNA are also linked to a number of conditions found in children, including autism.

“We know that increased rates of mtDNA mutation cause premature aging,” says Hay, Caltech professor of biology and biological engineering.

“This, coupled with the fact that mutant mtDNA accumulates in key tissues such as neurons and muscle that lose function as we age, suggests that if we could reduce the amount of mutant mtDNA, we could slow or reverse important aspects of aging.”

The team—in collaboration with Ming Guo, the P. Gene and Elaine Smith Chair in Alzheimer’s Disease Research and professor of neurology and pharmacology at UCLA, and UCLA graduate student Ting Zhang—genetically engineered Drosophila, the common fruit fly, so that about 75 percent of the mtDNA in muscles required for flight, one of the most energy demanding tissues in the animal kingdom, underwent mutation in early adulthood.

This model recapitulates aging in young animals. Drosophila grow quickly and most human disease genes have counterparts in the fly, making it an important model in which to study human disease-related processes. The researchers chose to focus on muscle because this tissue undergoes age-dependent decline in all animals, including humans, and it is easy to see the consequences of loss of function.

Unlike mutations in the DNA in the nucleus, which can be corrected through cellular repair mechanisms, mutations in mtDNA are often not repaired. However, cells can break down and remove dysfunctional mitochondria through a process called mitophagy, a form of cellular quality control. What was unclear prior to this work was whether this process could also promote the selective elimination of mutant mtDNA.

The team found that when they artificially increased the activity of genes that promote mitophagy, including that of several genes implicated in familial forms of Parkinson’s disease, the fraction of mutated mtDNA in the fly muscle cells was dramatically reduced. For example, overexpressing the gene parkin, which is known to specifically promote the removal of dysfunctional mitochondria and is mutated in familial forms of Parkinson’s disease, reduced the fraction of mutant mtDNA from 76 percent to 5 percent, while the overexpression of the gene Atg1 reduced the fraction to 4 percent.

“Such a decrease would completely eliminate any metabolic defects in these cells, essentially restoring them to a more youthful, energy-producing state,” notes Hay.

“The experiments serve as a clear demonstration that the level of mutant mtDNA can be reduced in cells by gently tweaking normal cellular processes.”

“Now that we know mtDNA quality control exists and can be enhanced, our goal is to work with Dr. Guo’s lab to search for drugs that can achieve the same effects,” Hay adds.

“Our goal is to create a future in which we can periodically undergo a cellular housecleaning to remove damaged mtDNA from the brain, muscle, and other tissues. This will help us maintain our intellectual abilities, mobility, and support healthy aging more generally.”

Citation

http://www.caltech.edu/news/turning-back-aging-clock-53030

Journal Reference:

Nikolay P. Kandul, Ting Zhang, Bruce A. Hay, Ming Guo. Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila. Nature Communications, 2016; 7: 13100 DOI: 10.1038/ncomms13100

Written by Lori Dajose

Copyright © 2016 California Institute of Technology

 

Among Antidementia Drugs, Memantine Associated with Highest Risk of Pneumonia

(University of Eastern Finland)  A recent study from the University of Eastern Finland shows that among users of antidementia drugs, persons using memantine have the highest risk of pneumonia. The use of rivastigmine patches is associated with an increased risk as well.

The study found that persons using donepezil or galantamine had the lowest risk of pneumonia. However, persons using memantine or rivastigmine patches had a 1.6 and 1.15 times higher risk of pneumonia, respectively, but no elevated risk was observed among patients using rivastigmine in capsule form. The real risk increase may be even higher, as only cases of pneumonia leading to hospitalisation or death were taken into account.

The study is the first to compare the risk of pneumonia associated with different antidementia drugs and drug forms. The results are not likely to be explained by differences between drug molecules, as rivastigmine was associated with an increased risk of pneumonia in patch form only. The increased pneumonia risk among persons using memantine or rivastigmine patches may be explained at least partly by the fact that these medications are often used in more advanced states of dementia. However, all participants were home-dwelling persons.

The study is based on data from a nationwide register-based study (MEDALZ) conducted at the University of Eastern Finland. The risk of pneumonia was compared among users of different antidementia drugs. The study population consisted of 65,481 persons diagnosed with Alzheimer’s disease during 2005-2011 in Finland.

No cure for Alzheimer’s diseases currently exists, but the progression of the disease can be slowed down by antidementia drugs, such as memantine and acetylcholinesterase inhibitors such as donepezil, galantamine, and rivastigmine. Persons with Alzheimer’s disease have an elevated risk of pneumonia, and it is one of the most common causes of hospitalisation among persons with Alzheimer’s disease. Pneumonia is also a common cause of death in this population.

The findings published in the Annals of Medicine. In addition to researchers from the University of Eastern Finland, also researchers from the University of Turku and Karolinska Institutet participated in the study.

Citation
https://www.uef.fi/-/dementialaakkeista-memantiinin-kayttoon-liittyy-suurin-keuhkokuumeen-riski?inheritRedirect=true&redirect=%2Fen%2Fetusivu

Research article:

Lampela P, Tolppanen AM, Tanskanen A, Tiihonen J, Lavikainen P, Hartikainen S, Taipale H. Use of antidementia drugs and risk of pneumonia in older persons with Alzheimer’s disease. Annals of Medicine, published online October 27, 2016, http://dx.doi.org/10.1080/07853890.2016.1254349

© University of Eastern Finland

Eli Lilly’s Experimental Alzheimer’s Drug Fails in Large Trial

(NYTimes) An experimental Alzheimer’s drug that had previously appeared to show promise in slowing the deterioration of thinking and memory has failed in a large Eli Lilly clinical trial, dealing a significant disappointment to patients hoping for a treatment that would alleviate their symptoms.

The failure of the drug, solanezumab, underscores the difficulty of treating people who show even mild dementia, and supports the idea that by that time, the damage in their brains may already be too extensive. And because the drug attacked the amyloid plaques that are the hallmark of Alzheimer’s, the trial results renew questions about a leading theory of the disease, which contends that it is largely caused by amyloid buildup.

No drug so far has been able to demonstrate that removing or preventing the accumulation of amyloid translates into a result that matters for patients: stalling or blocking some of the symptoms of dementia.

“It’s not going to be disease-modifying therapy for mild patients, so that’s heartbreaking,” said Dave Ricks, the incoming president and chief executive of Eli Lilly.

There are clinical trials underway with several similar drugs made by other companies, and two large trials with solanezumab are in the works. Experts said on Wednesday that they still held out hope for those studies, noting that many involve people who are at high risk for Alzheimer’s but do not display symptoms.

Some Alzheimer’s experts not involved in trials testing anti-amyloid drugs said they were not surprised by Lilly’s results, saying they reflect an emerging scientific understanding of Alzheimer’s as a disease with a multipronged cascade of causes, including amyloid buildup.

“We’re much more really appreciative of how complex this disease is,” said Dr. Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California.

“There’s so much going on, and as the brain is failing or dying, it is dying on all levels.”

It has also become clear that Alzheimer’s pathology begins damaging the brain years before symptoms emerge, leading many experts to think a drug given to people with even mild dementia may have little chance of success.

“Once you see amyloid on a scan, it’s probably been there for decades,” said Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai Hospital.

“I’m worried and have been worried that that’s just too late,” he said. “I think it has a better chance of working much earlier.”

But, he said, testing a drug before people have begun showing symptoms is challenging and costly. Such trials need to involve even larger numbers of patients to produce a useful result, and because the patients are healthy, without symptoms, the drugs cannot have side effects that might make them feel sick.

Solanezumab had previously failed in two large clinical trials involving patients with mild or moderate Alzheimer’s disease. But when Lilly reported the results of those trials in 2012, the company said the drug did have an effect in a subset of patients with mild symptoms. So it started another trial with 2,100 patients with mild dementia caused by Alzheimer’s.

In a news release on Wednesday, the company said that although some of the effects looked promising, “patients treated with solanezumab did not experience a statistically significant slowing in cognitive decline compared to patients treated with placebo.”

The company said it would evaluate future plans for solanezumab, but no longer planned to seek regulatory approval for use of the drug in treating symptomatic patients. Eli Lilly stock initially dropped after the news.

“This is very disappointing,” said Dr. Reisa Sperling, a neurologist who is recruiting patients for a trial testing whether solanezumab can help people with amyloid buildup who are about 10 years away from having symptoms.

“But I have to be honest that I’ve always thought we needed to treat much earlier, because by the time people have mild dementia, they already have a lot of irreversible damage,” she said.

The trial she is leading, called Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4), which has funding from Lilly and the federal government, had hoped to reach its goal of about 1,150 patients by the middle of next year, said Dr. Sperling, who directs the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and Massachusetts General Hospital.

“I have several patients within my practice who were hoping to take this drug,” she said. But she said it was at least encouraging that patients taking solanezumab in Lilly’s trial did show improvement, just not enough to be statistically significant, and she plans to evaluate the data to see if changes should be made to the design of the A4 trial.

“What does that mean for an earlier population?” Dr. Sperling said. “Do we need more people? Do we need a longer time? I just want to get a clear result.”

The other major solanezumab trial, the Dominantly Inherited Alzheimer Network Trials Unit, is also testing a Roche drug, gantenerumab, and is funded by industry, the federal government and the Alzheimer’s Association. It involves people who have not yet shown symptoms, but have a very high risk of an early-onset version of the disease because they have a genetic mutation that causes a small subset of cases.

Other trials are using anti-amyloid drugs that work in different ways, experts said. Solanezumab is a monoclonal antibody that removes amyloid by attaching itself to free-floating amyloid protein before the protein forms into plaques, while several other antibody drugs also attack amyloid fibrils that are part of the plaques.

Another class of anti-amyloid drugs are called BACE inhibitors, which block an enzyme that makes a protein needed for amyloid production.

“You can’t really say that the solanezumab results predict that a drug with a different mechanism will fail,” Dr. Schneider said.

Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute, is leading a prevention trial involving members of a large extended family in Colombia who do not have symptoms but have a genetic mutation that causes early Alzheimer’s. They are taking Genentech’s crenezumab.

Dr. Reiman said Wednesday’s results raised questions about whether Lilly’s dose was high enough, whether the researchers were “attacking the right form of amyloid,” and whether they were they treating patients too late in the disease process. The results may also support theories that the ultimate answer will be combinations of drugs addressing different aspects of Alzheimer’s.

He and other experts continue to believe that “the accumulation of amyloid serves as the kindling for other events” that ignite the fire of Alzheimer’s disease, he said, and “it would be a grave mistake to throw out the baby with the bathwater and not give the amyloid hypothesis its best real test.”

Still, “a win for Lilly would have been a win for the entire field,” Dr. Reiman said, and “would have opened up new opportunities for patients.”

Citation

http://www.nytimes.com/2016/11/23/health/
eli-lillys-experimental-alzheimers-drug-failed-in-large-trial.html?_r=0

By PAM BELLUCK

© 2016 The New York Times Company