Archives for February 2015

Denial Challenges Families in Alzheimer’s Caregiving

(Mayo Clinic with Angela Lunde) A couple months back I read a comment from one of you that stuck with me.  It was from a woman (I’ll call her Norma) whose mother has mild Alzheimer’s. Here’s some of what she said:

“My brother insists that we not fix our mother’s meals and we let her do it (she is struggling) … he says she only has very mild short term memory loss (and therefore believes she will figure it out) … I feel my family is in denial about mom’s condition & looking for yet another reason to stay uninvolved.”

The theme of family members in denial comes up frequently on this blog. In previous posts, I’ve addressed why denial is so common, the role it serves and the detrimental consequences of getting stuck in denial. Yet, putting the notion of denial aside for a moment, most of us caring for someone in the early stages of a dementia go through this sort of dance where we waver between promoting independence and offering help.

We see things changing and notice the person losing the ability to do what they once could. Often we’re reluctant to step in and take over as it may feel like we’re giving up on the person or crushing their dignity. Yet, it can be heart wrenching to watch them struggle. We want desperately for things to stay static and for the person (and us) to maintain independence.

And it gets even more blurred, this dance of knowing when to push independence and when to step in and help (or take over) because it’s not always simply a problem of memory or forgetfulness. Sometimes it’s a decline in processing.

For example, it might seem logical that Norma’s brother think that his mom should be able to remember how to fix her own meals. After all, she’s been doing it for 50 years. And longer term memories that have been over learned are generally better preserved.

Here’s the deal though — most persons diagnosed with Alzheimer’s lose some ability early on to sequence or plan out an activity, to organize, initiate and monitor actions. This is called executive functioning.

Think about the steps involved in fixing a meal: deciding what to make, identifying ingredients, putting the items or recipe together in a particular order, concentrating and often multitasking. Preparing a meal or following a recipe that includes several steps is difficult and sometimes unachievable even in early dementia due to changes in the brain that are responsible for processing.

I think we’d all agree that people with Alzheimer’s aren’t choosing to give up skills of daily living such as fixing meals, managing finances, or driving. They wouldn’t choose to forgo their independence, and they aren’t lazy or unmotivated. The truth is, people with Alzheimer’s can’t “just try harder” and it’s not realistic to expect them to do all they used to do.

I realize though that some family members will still not get it.  Quite possibly they’re in denial. From time to time, we’re all in denial about various aspects of our life. It’s how we cope — denial masks emotions of grief, loss, fear and uncertainty. I ask you to do your best to be kind, gentle, and calm in approaching a family member in denial. Anger will only cause them to dig their heels in deeper. And when we resist, blame, or reject, we stay trapped in our own anger.

I don’t mean that you can’t actively work to make things better with family members — I simply suggest that you make peace with the way things (and others) are today. Choosing to operate from a place of acceptance is a form of self-care.

“If he could, he would.”
– a wife and caregiver

Citation

Angela Lunde

http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/expert-blog/alzheimers-denial/bgp-20055897/?utm_source=newsletter&utm_medium=email&utm_campaign=alzheimers-caregiving

© 1998-2015 Mayo Foundation for Medical Education and Research. All rights reserved.

 

Nicotine Affects Learning, Memory

(Medical College of Georgia at Georgia Regents University via ScienceDaily) Nicotine’s primary metabolite supports learning and memory by amplifying the action of a primary chemical messenger involved in both, researchers report.

“This is the first hint of what the mechanism of the metabolite cotinine might be,” said Dr. Alvin V. Terry, Chairman of the Department of Pharmacology and Toxicology at the Medical College of Georgia at Georgia Regents University and corresponding author of the study in the Journal of Pharmacology and Experimental Therapeutics.

While the findings show therapeutic promise for a metabolite once thought to be inactive, cotinine’s benefits don’t hold up across all learning and memory systems so Terry is already looking at analogues that would be even more broadly effective and equally safe.

The new findings indicate cotinine makes brain receptors more sensitive to lower levels of the messenger acetylcholine, which are typical in Alzheimer’s, and may boost effectiveness, at least for a time, of existing therapies for Alzheimer’s and possibly other memory and psychiatric disorders.

The neurotransmitter acetylcholine is produced by cholinergic neurons, a target in diseases such as Alzheimer’s. The first sign of damage is these brain cells start pulling back the axons that connect them, then they die, Terry said. Most Alzheimer’s drugs, including the widely used Aricept, or donepezil, help patients maintain higher levels of acetylcholine longer by blocking an enzyme that breaks it down. “This could be an extra boost,” Terry said.

Nicotine has long been known to aid learning and memory, but it’s also highly addictive with a host of side effects from nausea and vomiting to increasing blood pressure and heart rate. The side effects reflect nicotinic receptors’ presence in other areas of the brain and body and explain why its therapeutic use has essentially been limited to helping smokers quit, Terry said.

The body doesn’t make nicotine or cotinine but when the body is exposed to nicotine, from smoking, chewing tobacco or gum, or wearing slow-release patches, the liver converts it to less noxious metabolites, primarily cotinine, that can be easily eliminated in the urine. In fact, insurance physicals often include a urine test for cotinine to ensure that a potential client is a non-smoker.

Working with Switzerland research and development company HiQScreen, Terry’s research team looked at frog cells with human DNA in them that enabled them to see if a compound binds with a receptor and what kind of response it generates. They found a narrow range of cotinine concentrations that amplify the effect of the natural neurotransmitter acetylcholine.

“It works in conjunction with acetylcholine to improve learning and memory,” Terry said. Cotinine activated some of the same receptors. In related studies in rats, they also found cotinine has a synergistic effect with the commonly used Alzheimer’s drug Aricept or donepezil, which, as with most drugs for the disease, work to improve acetylcholine survival by blocking an enzyme that breaks it down.

The researchers noted that it did not take a deficit in cholinergic activity, as might be found in Alzheimer’s or advanced age, to make the duo effective, a finding which potentially widens its therapeutic potential.

“It’s like a booster,” Terry said. “The holy grail is to keep acetylcholine receptors functioning.” Cotinine essentially had no effect on wide range of other pharmaceutical targets including receptors for other neurotransmitters such as dopamine and serotonin.

Cotinine was also helpful in some models that predict antipsychotic behavior, called prepulse inhibition. Patients with Alzheimer’s as well as psychiatric conditions such as schizophrenia may have trouble controlling themselves on many different levels. “One of the things that gets people put in a nursing home very commonly is psychiatric outbursts,” Terry said. “As your brain degenerates, Alzheimer’s is not just a disease of cognition. Some patients hallucinate, some have delusions, as well as aggressive behavior sometimes,” Terry said.

Cotinine has already been shown by Terry and others to be generally protective of brain cells. When brain cells are placed in a dish with amyloid, the infamous brain plaque found in Alzheimer’s, cotinine keeps them from being killed.

Terry and longtime collaborator, the late Dr. Jerry Buccafusco, found in the early 1990s that despite the short half-life of nicotine — about a half hour — monkeys taking the drug continued to benefit from memory improvements days later. That had them wondering if possibly some longer-lasting nicotine metabolite could help explain the unexpected, lasting effect. They began looking at nicotine’s major metabolite, cotinine, which has a half-life of about 18 hours, and were among the first scientists to document its positive effects in the brain.

“The body pretty much views nicotine as a poison, something unnatural that needs to be eliminated,” Terry said. “It’s a classic reaction where nicotine is converted to cotinine through an oxidative process in your liver.”

Even when purified nicotine just sits on a shelf for a few months, a natural oxidation process occurs that will convert a percentage of it to cotinine, just not as efficiently as the liver, he said. “Where there is oxygen around, there is going to be a very small amount of it formed anyway. But the liver is much more efficient at making that conversion.”

Nicotinic receptors in the brain and elsewhere got their name because nicotine was the first substance scientists found that binds to them but they are actually one of two receptor types in the body for the neurotransmitter acetylcholine.

Citation
Journal Reference:

  1. A. V. Terry, P. M. Callahan, D. Bertrand. R-( ) and S-(-) Isomers of Cotinine Augment Cholinergic Responses In Vitro and In Vivo. Journal of Pharmacology and Experimental Therapeutics, 2014; 352 (2): 405 DOI: 10.1124/jpet.114.219881

Medical College of Georgia at Georgia Regents University. (2015, February 18). Nicotine metabolite amplifies action of the primary chemical messenger for learning, memory. ScienceDaily. Retrieved February 22, 2015 from www.sciencedaily.com/releases/2015/02/150218101829.htm

 

Alzheimer’s Disease Research Summit 2015: Part 2

(Alzheimer’s Forum) The first day of the Alzheimer’s Disease Research Summit 2015, hosted by the National Institutes of Health February 9-10 in Washington, D.C., focused on finding therapeutic targets for Alzheimer’s and testing them in clinical trials. On the second day, speakers switched gears and brainstormed creative ways to share and analyze big data sets, attract more research participants, and use developing technology to glean data from novel sources. These talks seemed to inspire a renewed sense of energy and excitement from audience members. “A number of the topics this year were quite different than we had in 2012,” said Neil Buckholtz, National Institute on Aging (NIA), Bethesda, Maryland. Buckholtz especially highlighted discussions on patient-oriented groups and technological developments. Steve Estus, University of Kentucky, Lexington, wrote to Alzforum that he considered these talks the most interesting at the summit. Laurie Ryan, NIA, also called attention to the potential for citizen science to expedite data analysis, and easier informed consent to draw in new participants.

Maximizing the Available Data

A prominent theme at the summit focused on means of sharing data. Several speakers noted that data sets could gain new life in the hands of more researchers, who could reanalyze the information for new knowledge about AD. A prime example comes from the Accelerating Medicines Partnership (AMP), which aims to find new biomarkers and therapeutic targets for AD. It will help pay for four research groups to generate data on molecular pathways involved in the disease and make it publicly available online prior to publication (see Feb 2014 newsSep 2013 news). The four projects—one headed jointly by Philip De Jager, Brigham and Women’s Hospital in Boston, and David Bennett, Rush University Medical Center in Chicago, the others by Eric Schadt, Icahn School of Medicine at Mount Sinai, New York, Todd Golde, University of Florida, Gainesville, and Allan Levey, Emory University, Atlanta—are generating clinical, pathological, genomic, epigenomic, transcriptomic, and proteomic data on both human brain tissue and animal models of AD (for details, see the FNIH AMP webpage. So far, these researchers have been collaborating every other week to look across the raw data sets on a shared online platform and draw connections between them.

This month, the first of this network analysis data will be released publicly. It will be available upon request on the AMP-AD Data Portal, accessible through the Synapse online registry hosted by Sage Bionetworks in Seattle. As more data are generated, periodic additions will follow this first release, said Stephen Friend of Sage Bionetworks, who collaborates with the AMP on this project. “The ultimate goal is to encourage as many users as possible to query [the data], develop new methods, and look for AD targets,” Bennett told Alzforum. He has already seen others use his data in ways that would not have occurred to him. For instance, one research group used his data to validate their integrated-systems approach to finding gene networks involved in late-onset AD (see Zhang et al., 2013). Bennett has since hired an author on that paper to develop the technique further and apply it more systematically to his own data.

Golde added, “If the public paid for these data sets to be generated, they should be shared to do the greatest good.” Golde said the investigators had felt some reservation about sharing the data before publication. They were especially concerned about junior investigators on the team receiving proper credit for generating the data. Other speakers at the summit, too, urged that ways be found for junior investigators in large, shared group projects to be recognized in ways that support their careers. Meanwhile, the AMP project has given Golde new opportunities to collaborate with people outside his specialty who offer new perspectives and suggest ways to analyze his data. Both Bennett and Golde said that to undertake these projects, they needed no preconceived notion of particular targets to seek, allowing them to take an unbiased, data-driven approach.

Continuing the theme of aggressively expanding data collection and sharing, Simon Lovestone, University of Oxford, described initiatives in Britain. He announced that Alzheimer’s Research UK is funding a new, £30 million ($46.3 million) Drug Discovery Alliance. It will launch three drug-discovery institutes at Cambridge and Oxford universities, as well as University College London. The aim is to hire up to 90 research scientists to work over the next five years. They will build on ideas from academic researchers at these institutions and elsewhere, and identify and develop AD targets, by, for example, solving their structures, generating assays, and screening for early stage compounds. All this data will be made freely available.

Lovestone also highlighted the Dementias Platform UK. t aims to repurpose 22 current research cohorts, as well as their data and samples. This initiative brings together data on more than 2 million people aged 50 and older, he said. One cohort in particular, the UK Biobank, is being enhanced.Half a million volunteers have given genomic data and biological samples to the biobank, 100,000 will have whole-body MRIs, and 10,000 will have repeat scans. In a separate pilot study, a cohort of 24 people with preclinical AD will undergo amyloid and tau imaging once, followed by structural and functional MRI, magnetoencephalography, electroencephalography, optical tomography, assessment of gait and cognition, as well as blood and CSF collection, about every two months for half a year. After researchers determine how often patients are willing and able to undergo this kind of intensive, frequent testing, they will enroll for a larger trial of 300 people. All of that data will be made freely accessible, so that researchers can look for a signature of change in preclinical AD, Lovestone said.

While these initiatives will obtain and share network analysis and drug-discovery data, the Alzheimer’s Association is funding an effort to link results from clinical studies, said Maria Carrillo of the Association. Called the Global Alzheimer’s Association Interactive Network, GAAIN is a big-data community. This platform so far includes clinical data about Alzheimer’s and other neurodegenerative diseases on more than 280,000 patients from 11 so-called data partners, Carrillo said. The partners include the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the National Alzheimer’s Coordinating Center (NACC), and the French National Alzheimer Disease Database (see the GAAIN scoreboard). GAAIN is a federated platform where each data partner retains rights and access rules to their data, but registered researchers can query the combined data sets via interactive graphs. With a feature called the GAAIN Interrogator, researchers can define their own patient groups and variables of interest. GAAIN is meant to bridge silos of existing data sets and allow other researchers to mine them for new insights, said Carrillo.

The Alzheimer’s Drug Discovery Foundation (ADDF) has developed its own project to bridge the gap between basic and translational science. Called ADDF Access, the new, Web-based platform operates a bit like Match.com for drug development scientists, quipped Diana Shineman, director of scientific affairs at ADDF. It connects scientists in academia, biotech, or pharma who need particular services for translational or drug-discovery research, with providers of such services, primarily contract research organizations (CROs). In essence, service providers can register and describe their services at no cost, academic or pharma scientists can find those services, and when they contract with a service provider, ADDF charges a broker’s fee. The site also provides project management tools and links for other useful research services. Through ADDF Access, scientists can message providers directly, issue requests for proposals, compare bids, and even provide anonymous feedback about these communications. Ultimately, ADDF hopes this will speed the development of therapies for dementia.

Engaging More Patients

Meanwhile, several speakers showcased innovative ways by which other fields engage more people and patients in research projects. Sharon Terry of Genetic Alliance, Washington, D.C., launched the Platform for Engaging Everyone Responsibly. PEER originated in the orphan disease field and helps build cohorts for participant tracking. Participants upload health data and genomic information, answer research questions, and set up privacy layers. Sally Okun, of Patients Like Me in Cambridge, Massachusetts, talked about her company’s similar platform. Patients sign up for their condition to connect with others who have that disease and learn from them. They can track their symptoms and responses to various treatments, and share and discuss that data with others.

While the main purpose of both sites is to help connect and empower patients, they also allow their members to participate in research. Most participants in Patients Like Me want to do that, said Okun. They generate a rich set of de-identified and aggregated longitudinal health data, which can be used to answer research questions, she said, noting that 50 publications have come out of Patients Like Me data (e.g., Tran et al., 2014). Okun recommended that Alzheimer’s researchers engage their patients through these types of platform to help develop active communities and harness their interest in research.

Another theme that emerged at the summit was the need for more diversity in clinical trials. “Racial, ethnic, and educational factors are not just nuisance variables to get out of way,” said Jennifer Manly, Columbia University Medical Center, New York. “They offer rich, important variability critical for understanding the biology of Alzheimer’s disease.” Minorities will make up the majority of the U.S. population in the coming decades, said Lisa Barnes of Rush University. They carry greater risk for Alzheimer’s, and their health will increasingly determine that of the nation, she said. Based on successful recruitment strategies at Rush, Barnes recommended that researchers cultivate relationships with communities before asking them to participate in research. Building networks with leaders, creating culturally tailored programs, and including minority staff in their studies all work to build trust. Stephanie Monroe of the African American Network Against Alzheimer’s added that institutions should employ a community-outreach representative and actively engage primary physicians, who are often the first people potential participants ask when they are interested in joining a study. Contradicting common notions about distrust of medical research among African-Americans, Monroe cited surveys indicating that 80 to 90 percent of African-Americans say they would indeed be willing to participate in studies if only they were asked.

To make it easier for more people to enroll in studies, John Wilbanks at Sage Bionetworks is tackling the problem of onerous consent forms. Informed consent is legally required, but the language used is often shrouded in legalese and can stop some people from signing up for a study. Wilbanks is working on digitizing the process into a mobile app. Using graphic icons to represent items on the consent form, and simple language to explain each point, he aims to break down a complicated set of information into simple concepts. A toolkit to adapt this consent process for other research studies is freely available.

Mining New and Improved Sources of Data

Besides broadening data-sharing and attracting new interest in research participation, innovation is also needed in the type of behavioral data researchers collect in clinical trials, said Jeffrey Kaye, Oregon Health and Science University, Portland. The cognitive performance of research participants varies day to day, he said, so the sparse data points gathered in quarterly tests during clinic visits capture, at best, a coarse trajectory of change. By contrast, passive sensors built into the home or wearable technology can generate data on movement between rooms, computer use, gait speed, and sleep. This enables scientists to track behavioral factors continuously in a natural setting, Kaye said. By outfitting several hundred homes in Portland with such sensors, Kaye and colleagues have found that physical activity is much more variable in people with MCI than in people who are aging normally. They walk more slowly, wake less during the night, forget their medication more often, and gradually use their computers less. The latter variable correlates with atrophy in the temporal lobe, Kaye’s group has found. Using these types of measures to build models of behavior in clinical trials could track disease progress at high resolution, lower required sample sizes, and reduce the time it takes trials to read out, he proposed.

Barry Greenberg, Toronto Dementia Research Alliance, asked how Kaye would cross-validate those outcomes against standard clinical trial measures. Kaye responded that he would prefer to see proof-of-concept trials that test whether a treatment improves sleep, physical activity, or medication use. In response to an audience question about when this technology will be ready for routine home health care, Kaye said that it requires more work but may be useful for clinical trials in the near future.

Given all the data that will pour in from big cohorts and continuous monitoring, how will researchers analyze it? Pietro Michelucci, of the Human Computation Institute in Fairfax, Virginia, touted the power of citizen science to tackle the challenge. The general idea is that instead of a small team analyzing all the data, the task of analysis gets broken down into manageable parts and distributed among thousands of people, each of whom spends a small amount of time on them. Michelucci highlighted one project in which his institute is crowd-sourcing the analysis of brain microvessels in AD. This particular analysis is a time-consuming, manual task, and Michelucci estimates that his distributed strategy will reduce analysis time from 60 years to two. “Citizen-science projects give the general public the feeling of being part of something bigger, and of making a real difference,” Michelucci said.

The NIH also has a citizen-science working group. Its co-coordinator, Jennifer Couch of the National Cancer Institute, said that much of the data that will be coming from sensors described by Kaye will lend itself to this kind of analysis. By turning data analysis into a “game” and giving people the tools they need to answer a question, researchers can benefit from the problem-solving skills of the public. “People are creative and interested in helping,” Couch told the audience. “There are opportunities for data collection and also insights that wouldn’t be obtainable through conventional research approaches.” Couch cited examples in protein-folding and cancer, where research has benefitted from this approach. She noted that the group is still working out the ethical, legal, social implications of citizen science.

Scientific research journals can also play a role in improving the research landscape, said Diane Stephenson of the Critical Path Institute in Tucson, Arizona. She suggested that when a journal publishes a paper about a new biomarker, the NIA could fund independent replication of the results, and the same journal that ran the original report should commit to publishing the replication attempt as well, regardless of whether it is positive or negative. That will give the field and regulatory agencies confidence that the biomarker finding is robust enough for use in clinical trials, Stephenson said. Preclinical treatment studies sometimes are followed up in this way (see May 2013 news). Stephenson further recommended that funders require researchers to share their raw biomarker data, as well as encourage researchers to use data standards created by the Clinical Data Interchange Standards Consortium (CDISC) in ongoing and prospective clinical trials (see Nov 2011 news). Starting in 2016, the FDA will require new drug applications to conform to CDISC standards.

The Way Forward

Immediately following the summit, world health leaders from the G7 countries, Alzheimer’s advocates, and others held follow-up meetings in Washington, D.C. A writing group of AD experts, NIH staff, and representatives from other funding agencies and the National Alzheimer’s Project Act Council distilled recommendations from the summit meeting to refine the NAPA research milestones and assign a dollar value to research needed to fulfill the requirements of the Alzheimer’s Accountability Act (see Apr 2014 news). Separately, the health ministers of the G7 countries gathered for an update on their respective countries’ research efforts in AD, while the World Dementia Council met to review progress in 2014 and strategies to maintain their momentum in 2015.

On February 11, the Alzheimer’s Association, Weston Brain Institute in Canada, and Alzheimer’s Research UK announced their launch of an $1.25 million international research funding initiative called MEND, short for MEchanisms of cellular death in NeuroDegeneration. It will support new projects, especially research collaborations that examine the reasons behind brain cell death underlying multiple types of dementia.

Citation

Gwyneth Dickey Zakaib
http://www.alzforum.org/news/conference-coverage/alzheimers-disease-research-summit-2015-expanding-horizon

Copyright © 1996–2015 Biomedical Research Forum, LLC. All Rights Reserved.

 

Alzheimer’s Disease Research Summit 2015: Part 1

(Alzheimer’s Forum) On February 9 and 10, leaders from academia, industry, and non-profit organizations gathered at the Natcher Auditorium of the National Institutes of Health (NIH) in Bethesda, Maryland, for the Alzheimer’s Disease Research Summit 2015. They discussed the progress made since the last such meeting in 2012 (see May 2012 conference series) and outlined new recommendations going forward. The first day’s sessions were on current and future clinical trials, finding new drug targets, and seeking methods of prevention. The second day covered ongoing projects to share data more widely, ways to engage participants in research, and how to involve citizen scientists in helping analyze large datasets. Overall, the meeting served to refresh the field’s plan to prevent and better treat Alzheimer’s disease by 2025.

“This was an attempt on the part of the NIA to step back, take a survey of the field, and try figure out what has been working, what hasn’t been working, and what new things should we be trying,” said David Bennett, Rush University Medical Center, Chicago.

“The field has begun to come together in ways that it never has before, in identifying an overall strategy for the field,” George Vradenburg of UsAgainstAlzheimer’s in Chevy Chase, Maryland, commented after the meeting. “There’s a sense of urgency associated with the 2025—it’s finally taking hold in a real way.”

NIH director Francis Collins set the tone when he said in his opening remarks, “Our charge for this meeting is to rededicate ourselves to this critically important work and to identify the highest priorities for biomedical research on Alzheimer’s disease and related conditions.” Richard Hodes, who directs the National Institute on Aging (NIA) in Bethesda, added that the recommendations from the meeting would serve to update the National Plan to Address Alzheimer’s disease.

Altering the Scope of Clinical Trials

A key area of progress in the field is that four secondary prevention trials of Aβ monotherapies are underway and several more are in the planning stages (see Dec 2014 news). However, at the summit Reisa Sperling of Harvard Medical School, who is directing one of those trials, urged researchers to start planning the next set of therapeutic trials. She advocated treating even earlier in disease, and evaluating combinations of investigational drugs. FDA official Rusty Katz forcefully recommends combination trials as well (see Nov 2014 conference news). Reminding the audience of Katz’s recent speech, Sperling pointed out that the current prevention trials will take years to read out, and argued that the field cannot wait to see if they work before taking the next step. She advised combining an Aβ therapy with a tau therapy, given that tau pathology leads to faster memory decline in the presence of Aβ buildup (see Jan 2015 conference news). Since such trials may require cooperation between companies, she suggested building resources that encourage pharmaceutical cooperation, such as trial-ready cohorts of participants and easier communication with regulatory authorities.

Julie Stone, from Merck in West Point Pennsylvania, cautioned that combination trials are highly complex, given that researchers still struggle to interpret trials with one drug candidate. Stone uses quantitative systems pharmacology. This discipline integrates experimental data from different sources to model complex biological systems and help design late-stage trials. This approach lets her map out an underlying disease process, figure out what doses of drugs might perturb it, and predict outcomes of trials. Stone explained how Merck has partnered with academic researchers to build a model of the amyloid pathway, with secretases and biomarkers, and empirical results from multiple Phase 1 studies of Merck’s BACE inhibitor. This model used data on the degree of Aβ reduction achieved in smaller studies and helped the company choose the doses of MK-8931 now used in the Phase 3 program. Given that the researchers now know more about the drug’s effects on amyloid, the resulting trial should be a solid test of the amyloid hypothesis, Stone said. She encouraged experimental scientists to partner with systems pharmacologists to help build similar models. They help scientists revisit data from previous failed trials and figure out whether they actually tested their underlying hypothesis, she said.

Careful analysis of failed trials would accelerate the field’s efforts toward its 2025 goal, agreed Samantha Budd Haeberlein from Biogen Idec in Cambridge, Massachusetts. Since papers on negative trials are rarely published, at least not with full data, some of the reasons for failure are doomed to be repeated. Rather, these analyses could be encouraged and openly shared, Budd proposed.

Hunting for Effective Targets

Even as trials are underway for Aβ therapies, and drugs aimed at tau are entering early stage trials, researchers are actively searching for new targets for Alzheimer’s disease. At the summit, David Bennett of Rush University, Chicago, reviewed the complexity of the protein pathologies underlying age-related dementing disorders. In his view, even if Aβ and tau treatments prove successful, they might treat only half of all people with AD dementia, Bennett said.

Speakers at the summit recommended going after a wide range of candidates. One prime suspect is the immune system, which research indicates is highly involved in AD but has been elusive in terms of yielding druggable new targets. Philip de Jager, Brigham and Women’s Hospital, Boston, described some of his recent work, including his finding that monocytes are more important in AD than T cells (see May 2014 news). De Jager proposed studying communication between the peripheral and central immune systems and how this could render someone susceptible to AD. He also suggested gaining a better understanding of how the immune system ages, and how that could contribute to the disease.

Vascular changes themselves could make an interesting target, said Berislav Zlokovic, University of Southern California, Los Angeles. His recent studies suggest that in aging, the blood-brain barrier starts to break down in the hippocampus, more so in people with mild cognitive impairment (see related Webinar). He proposed testing whether such vascular changes precede Alzheimer’s, if AD genes affect vascular function, and if treating dysfunction influences neurological disorders.

What about the synapse? As the functional unit of the nervous system vulnerable to both Aβ and tau, the synapse could hold new insights into the biology of AD. Several speakers at the summit, particularly Li-Huei Tsai of MIT and Bradley Hyman of Harvard University, advocated using modern techniques such as optogenetics to gain a deeper understanding of synaptic biology in aging and neurodegenerative diseases, and urged neurochemists to get involved in developing PET ligands that image synaptic function in patients to track the disease.

Gerard Schellenberg, University of Pennsylvania, Philadelphia, argued that new therapeutic targets could be found by ramping up genetics research to unravel the full genetic burden of Alzheimer’s disease. Sometimes rare functional variants prove to be good starting points for therapy development. Schellenberg cited a recent success in heart disease, where a cholesterol-clearing, loss-of-function mutation in the PCSK9 gene was first reported to be protective in 2006 (see Cohen et al., 2006). This inspired the development of therapeutic antibodies to the affected protein, which have proven safe and effective in Phase 2 and 3 trials (see Rodriguez and Knowles, 2015). For AD, Schellenberg proposed boosting sample sizes in genetics studies by sharing data, while using more high-throughput biology methods to translate findings into therapeutic targets.

Alison Goate, Mt. Sinai Hospital, New York, suggested the time was right to focus on finding protective variants against AD. In particular, she recommended looking at people who carry two copies of the ApoE4 allele but have maintained normal cognition into old age, or who have an autosomal-dominant mutation but stay cognitively healthy past their family’s mean age of onset. Both these types of person are rare, but some are known to science and willing to participate in research.

Moving beyond the genome, Jonathan Mill, King’s College London, noted that epigenetic changes are reversible and could make therapeutic targets. He reviewed work on methylation differences in ANK1, a gene involved in cell mobility and structure, in the cortices of people with AD (see Aug 2014 news). This gene also emerges as a hit from GWAS of Type 2 diabetes. Since it is unclear whether epigenetic changes are a cause or a result of neurodegeneration, Mill recommended conducting longitudinal studies to assess when they occur relative to better-known brain markers of AD. He also suggested developing methods to sample purified cell cultures from the brain to look at epigenetic changes with higher resolution.

Claes Wahlestedt, University of Miami, pointed out that hundreds of enzymes modify chromatin in a redundant way, and drugs can therefore target some of those enzymes without wide-ranging side effects. As examples, he mentioned BET bromodomain inhibitors, which are entering clinical trials for cancer. Compared to HDAC inhibitors, these drugs affect far fewer genes in the brain, Wahlestedt said. Similar therapies could hit epigenetic targets that simultaneously affect a number of factors relevant to AD.

Clues to Prevention

While many scientists are looking into potential treatment targets for AD, others are vetting factors that could prevent it. Kenneth Langa, University of Michigan, Ann Arbor, said that global trends in AD hint that better education and control of cardiovascular risk factors are lowering incidence in some high-income countries. This decline is a public health success that could moderate the steep growth in AD cases otherwise expected in the coming decades as a consequence of rising obesity and diabetes in aging populations (see Jul 2014 news). Langa suggested performing more research on these potential preventative pathways. Martin Prince, Kings College, London, followed with data on global dementia trends that suggest low education in early life, as well as hypertension, diabetes, and smoking in mid- to later life, all contribute to the risk for AD. He advocated that countries launch public health campaigns that actively promote the idea of AD as a preventable condition. Above all, more countries should closely monitor rates of dementia over time and see how they correlate with other risk factors, Prince said.

Some scientists would like to systematically probe environmental factors that could alter risk for AD. Chirag Patel, Harvard Medical School, introduced the concept of the exposome, the sum total of a person’s exposures during their lifetime. Patel proposed conducting environment-wide association studies for AD, cataloging chemicals, pesticides, vitamins, drugs, metal, etc., to see how such factors modify a person’s risk for AD. Several technologies could help give an unbiased look at possible exposures, such as methods that measure analytes in serum and urine, he added. Patel recommended building a database to store publicly available longitudinal data on environmental exposures (see Patel and Ioannidis, 2014). Using similar biochemical tools, Rima Kaddurah-Daouk, Duke University, Durham, North Carolina, is working with scientists in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) consortium to characterize changes in the metabolome over the course of AD. By adding a metabolomics layer to the genomic, neuropsychological, and imaging data already collected, researchers may find new biomarkers and therapeutic targets relevant for Alzheimer’s, she said.

A good night’s slumber might also protect against AD, according to David Holtzman of Washington University in St. Louis. During sleep, the brain generates fewer and clears more Aβ monomers (see May 2014 news). Holtzman advised the NIH to encourage more research on how sleep affects underlying Alzheimer’s pathology, and suggested it could lead to better diagnosis and treatment. Holtzman also made the argument that while more money is going toward Alzheimer’s research, it has not funded enough additional R01 grants. He strongly recommended that the NIH boost the percentiles of funded R01s to support more basic and translational science that could address priorities articulated at the summit. His comment garnered a round of applause.

With a number of proposed targets presented on day one, Howard Fillit, Alzheimer’s Drug Discovery Foundation in New York City, wondered how to prioritize them given that the field has limited resources with which to develop a therapy by 2025. Bennett responded that choosing the best candidates will depend in part on data being shared among scientists, who should rigorously try to replicate each other’s work and run extensive computational models before preclinical or clinical testing.

Some scientists remarked privately to Alzforum that they had hoped the meeting would include more cutting-edge science. Others were disappointed that most speakers had pitched their own area, rather than seeking a broader consensus on the most promising ones to take forward.

Click here to view the webcast for day 1.

Citation

Gwyneth Dickey Zakaib

http://www.alzforum.org/news/conference-coverage/alzheimers-disease-research-summit-2015-three-years

Copyright © 1996–2015 Biomedical Research Forum, LLC. All Rights Reserved.

 

Science Behind the Headlines: How to Reduce Your Risk of Dementia

(Alzheimer’s Society, UK) The best way to reduce your risk of dementia is to adapt various aspects of your lifestyle, including eating certain foods, taking regular exercise, not smoking, and maintaining normal blood pressure and cholesterol levels (read more information on cholesterol here). There is good evidence that eating a Mediterranean-style diet can reduce the risk of developing problems with memory and thinking, and getting some forms of dementia.

Mediterranean Diets

Mediterranean diets are traditionally high in fruits, vegetables, legumes and cereals, with moderate consumption of oily fish and dairy, and low in meat, sugar and saturated fat. Most fat in this type of diet comes from olive oil, and alcohol is consumed in moderation with meals. Research in the 1960s showed that men from Mediterranean regions who adhered to traditional diets had lower rates of heart attacks. This prompted continual investigation into the potential health benefits of the diet.

Investigations have shown that this kind of diet is associated with lower levels of stroke, type 2 diabetes, cardiovascular diseases and death from any cause. They have also shown that sticking to the diet more strictly might be associated with slower rates of decline in memory and thinking.

Mediterranean Diets and Dementia Risk

A recent study pulled together all the existing evidence about the Mediterranean diet relating to problems with memory and thinking and dementia, to assess the potential benefits. This type of study is called a systematic review. A systematic review is a good tool for evaluating existing evidence and understanding where a consensus lies, if there is one. A lot of research was not included in this study because it was not stringent enough or it did not look at the diet as a whole. The studies that remained seem to show an association between the Mediterranean diet and lower levels of memory and thinking problems.

Why Mediterranean Diets Might Affect Dementia Risk

High levels of antioxidants from the high intake of fruits and vegetables may help to protect against some of the damage to brain cells associated with Alzheimer’s disease, as well as increasing the levels of proteins in the brain that protect brain cells from this damage. Inflammation in the brain is associated with Alzheimer’s disease (although in this context we mean chemical changes within the brain’s immune system, rather than swelling). There are suggestions that the diet reduces the signs of this inflammation. The diet is also linked to lower levels of cholesterol, which recent research has suggested may be associated with memory and thinking problems (read more about cholesterol here).

Although the evidence from this analysis of multiple studies is very promising, it is worth noting that other recent large studies have not shown similar trends. It is also important to recognise that the studies were observational so they are unable to show any direct cause and effect in the way that a trial might. This means that people who follow Mediterranean diets may lead healthier lifestyles in general, so it may be this – rather than the diet itself – that causes the difference in memory and thinking problems.

For most people, following the Mediterranean diet is a good way to ensure a healthy diet, which may be important for maintaining good brain function.

Citation

http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=2211&pageNumber=2

All content © 2015 Alzheimer’s Society.

 

Diabetes and Depression Predict Dementia Risk in People with Slowing Minds

(University College London) People with mild cognitive impairment are at higher risk of developing dementia if they have diabetes or psychiatric symptoms such as depression, finds a new review led by UCL researchers.

Mild cognitive impairment (MCI) is a state between normal ageing and dementia, where someone’s mind is functioning less well than would be expected for their age. It affects 19% of people aged 65 and over, and around 46% of people with MCI develop dementia within 3 years compared with 3% of the general population.

The latest review paper, published in the American Journal of Psychiatry, analysed data from 62 separate studies, following a total of 15,950 people diagnosed with MCI. The study found that among people with MCI, those with diabetes were 65% more likely to progress to dementia and those with psychiatric symptoms were more than twice as likely to develop the condition.

“There are strong links between mental and physical health, so keeping your body healthy can also help to keep your brain working properly,” explains lead author Dr Claudia Cooper (UCL Psychiatry).

“Lifestyle changes to improve diet and mood might help people with MCI to avoid dementia, and bring many other health benefits.

This doesn’t necessarily mean that addressing diabetes, psychiatric symptoms and diet will reduce an individual’s risk, but our review provides the best evidence to date about what might help.”

The Alzheimer’s Society charity recommends that people stay socially and physically active to help prevent dementia. Their guidelines also suggest eating a diet high in fruit and vegetables and low in meat and saturated fats, such as the Mediterranean diet.

“Some damage is already done in those with MCI but these results give a good idea about what it makes sense to target to reduce the chance of dementia,” says senior author Professor Gill Livingston (UCL Psychiatry). “Randomised controlled trials are now needed.”

Professor Alan Thompson, Dean of the UCL Faculty of Brain Sciences, says:

“This impressive Systematic Review and meta-analysis from The Faculty of Brain Science’s Division of Psychiatry underlines two important messages.

Firstly, the impact of medical and psychiatric co-morbidities in individuals with mild cognitive impairment and secondly, the importance and therapeutic potential of early intervention in the prevention of dementia.

Confirming these findings and incorporating appropriate preventative strategies could play an important part in lessening the ever-increasing societal burden of dementia in our ageing population.”

Citation

http://www.ucl.ac.uk/news/news-articles/0215/200215-diabetes-depression-dementia-link

Journal Reference:

Claudia Cooper, Andrew Sommerlad, Constantine G. Lyketsos, Gill Livingston. Modifiable Predictors of Dementia in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. American Journal of Psychiatry, 2015; appi.ajp.2014.1 DOI: 10.1176/appi.ajp.2014.14070878

© UCL 1999–2015

 

Alzheimer’s and Dementia Caregivers Find Support

(Rutgers University) Care2Caregivers provides a peer-support lifeline to people caring for loved ones with dementia and Alzheimer’s disease.

Elvis Gardin likens being a caregiver to a loved one with dementia or Alzheimer’s disease to being alone on an island.

“When a family member is diagnosed, those who assume their care enter uncharted territory with few people they can relate to,” says the Highland Park resident, who has been caring for his 88-year-old mother, Dilcie, in his home for the past year.

He decided to remove his mother, who has Alzheimer’s disease, from the assisted living facility where she resided for three years, after noticing a sharp decline in her physical and mental states.

“My mom has always been a lively person – highly social and witty – but her spirit was slipping away,” he says. “It was something beyond the disease. She dropped a considerable amount of weight in a short time and started to isolate herself from the group. I knew she would have a more fulfilled life with me.”

A chef and wellness coach by profession, Gardin focused on nutrition and engaging her mind. Today, he reports, his mother has regained her vitality, usually joining him when he addresses Rutgers University medical students or the general public about caregiving. Despite his success, caregiving has been a lonely journey for Gardin, who has few family members who can help and no friends who understand the unique challenges he faces.

That changed when he spoke to Barbara Surina, a peer support counselor at Care2Caregivers (800-424-2494), a recently created helpline for caregivers to people with dementia and Alzheimer’s disease, operated by Rutgers University Behavioral Health Care.

“We just really connected,” he says. “As soon as I began to tell Barbara my story, it was magic and sparks. She got it.”

Surina understands what Gardin is going through because she’s been there, too: For more than a decade, she served as a caregiver for her mother, who had cancer, and her father, who had dementia. After they both passed away, she channeled her experience into a career working with people suffering from dementia.

“Caregiving is an exhausting, overwhelming, 24/7 responsibility,” she says. “I know the toll it can take and how vital support is.”

Care2Caregivers – funded by New Jersey’s Department of Human Services through the Comprehensive Services on Aging Institute for Alzheimer’s Disease and Related Disorders (COPSA) at UBHC – has made approximately 3,000 contacts since it launched in August 2014.

“Caregivers don’t know what they’re getting into when their loved ones are diagnosed,” says program coordinator Mary Catherine Lundquist.

Often, she says, the person could be living with the disease for years before the family realizes something is wrong. The family reaches out to get help but they don’t know what they need. The helpline assists callers in all stages: from pre-diagnosis and caregiving to hospice and bereavement when a loved one passes away.

Like Surina, the peer counselors who answer the helpline have been caregivers to loved ones and have worked professionally with dementia patients. This unique skill set allows them to understand the callers’ concerns and be familiar with services that can help. “Many callers are looking for someone to just tell them that, yes, they are doing a good job,” she says. “But sometimes, they are so stressed they don’t even know why they are calling. They just need an outlet.”

Peer counselors advise on issues such as how to manage difficult behavior, develop smoother daily routines and navigate the maze of community resources.

“There’s no training for a family member whose loved one with dementia gets into the car and drives, hallucinates or shadows them all day long,” Lundquist says. “It’s essential for them to be educated, but there are few places where they can turn to learn more. This is where the helpline comes in.”

Calls to Care2Caregivers are confidential and can be anonymous. Counselors make follow-up calls to check in. The helpline counselors operate Monday through Friday from 8:30 a.m. to 4:30 p.m., with plans in the works to expand those hours. Beyond 4:30 p.m., caregivers can send emails via the website that counselors will answer the following day.

Care2Caregivers also offers a variety of support groups through the COPSA Institute, including “Just for the Fellas” for male caregivers and “Young Wives” for women in their 40s to 60s who are caring for spouses. An online live chat support group is planned for early 2015.

The options for support are a relief for caregivers such as Gardin, who can’t predict what their daily schedules may be.

“Talking – whether in person, on the phone or online – makes such a huge different in our mental state,” he says. “When we are at wits’ end, it’s a relief to know that we can have a conversation with someone who has walked that very same road we are on.”

For more information, contact Patti Verbanas at 848-932-0551 or patti.verbanas@rutgers.edu

Citation

http://www.newswise.com/articles/alzheimer-s-and-dementia-caregivers-find-support

©2015 Newswise, Inc.

 

Compound Found in Grapes, Red Wine May Help Prevent Memory Loss

(Texas A&M University) A compound found in common foods such as red grapes and peanuts may help prevent age-related decline in memory, according to new research published by a faculty member in the Texas A&M Health Science Center College of Medicine.

Ashok K. Shetty, Ph.D., a professor in the Department of Molecular and Cellular Medicine and Director of Neurosciences at the Institute for Regenerative Medicine, has been studying the potential benefit of resveratrol, an antioxidant that is found in the skin of red grapes, as well as in red wine, peanuts and some berries.

Resveratrol has been widely touted for its potential to prevent heart disease, but Shetty and a team that includes other researchers from the health science center believe it also has positive effects on the hippocampus, an area of the brain that is critical to functions such as memory, learning and mood.

Because both humans and animals show a decline in cognitive capacity after middle age, the findings may have implications for treating memory loss in the elderly. Resveratrol may even be able to help people afflicted with severe neurodegenerative conditions such as Alzheimer’s disease.

In a study published online Jan. 28 in Scientific Reports, Shetty and his research team members reported that treatment with resveratrol had apparent benefits in terms of learning, memory and mood function in aged rats.

“The results of the study were striking,” Shetty said. “They indicated that for the control rats who did not receive resveratrol, spatial learning ability was largely maintained but ability to make new spatial memories significantly declined between 22 and 25 months. By contrast, both spatial learning and memory improved in the resveratrol-treated rats.”

Shetty said neurogenesis (the growth and development of neurons) approximately doubled in the rats given resveratrol compared to the control rats. The resveratrol-treated rats also had significantly improved microvasculature, indicating improved blood flow, and had a lower level of chronic inflammation in the hippocampus.

“The study provides novel evidence that resveratrol treatment in late middle age can help improve memory and mood function in old age,” Shetty said.

This study was funded primarily by the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health. Shetty’s lab is now examining the molecular mechanisms that underlie the improved cognitive function following resveratrol treatment. He also plans to conduct studies to see whether lower doses of resveratrol in the diet for prolonged periods would offer similar benefits to the aged brain.

Citation

Ellen Davis

http://news.tamhsc.edu/?post=compound-found-in-grapes-red-wine-may-help-reverse-memory-loss

Journal Reference:

  1. Maheedhar Kodali, Vipan K. Parihar, Bharathi Hattiangady, Vikas Mishra, Bing Shuai, Ashok K. Shetty. Resveratrol Prevents Age-Related Memory and Mood Dysfunction with Increased Hippocampal Neurogenesis and Microvasculature, and Reduced Glial Activation. Scientific Reports, 2015; 5: 8075 DOI: 10.1038/srep08075

Copyright 2015 Texas A & M University