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Researchers Agree that Alzheimer’s Test Results Could be Released to Research Participants

A leading group of Alzheimer’s researchers contends that, as biomarkers to detect signals of the disease improve at providing clinically meaningful information, researchers will need guidance on how to constructively disclose test results and track how disclosure impacts both patients and the data collected in research studies. A survey conducted by a group including experts from the Perelman School of Medicine at the University of Pennsylvania found that a majority of Alzheimer’s researchers supported disclosure of results to study participants. The study is published online in Neurology.

“While this is not a call to immediately tell subjects their biomarker results, it does show that the field is moving to a point where experts want to share valid and meaningful results with participants,” said co-senior author Jason Karlawish, MD, professor of Medicine and Medical Ethics and Health Policy. “As we gain more data on the predictive abilities of these measurements, we will need models and methods to effectively reveal results.”

The study surveyed 139 Alzheimer’s clinical trial leaders and coordinators from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) in April 2012, just before the U.S. Food and Drug Administration approved the amyloid-binding radiotracer known as Amyvid (florbetapir). 73 percent of respondents supported disclosing amyloid imaging results to study participants with mild cognitive impairment, whereas 58 percent supported giving amyloid imaging results to those with normal cognition.

Six themes emerged from the survey, regarding participant preferences and cognition levels, researchers’ requests to develop standardized counseling procedures, participant education, and standardization of data-gathering, and concerns regarding potential harms and benefits to participants, as well as the ways disclosure could impact study results.

Currently, ADNI has a policy to not disclose results to participants, but the survey showed a growing trend of experts who would favor revising this policy. In addition to finding amyloid imaging results valuable, Alzheimer’s experts also valued other biomarker data collected in ADNI, such as spinal fluid tests, PET imaging, and other psychometric tests, suggesting that if amyloid imaging results were allowed to be disclosed, it would likely lead to disclosure of other test results.

Study: Using AD biomarker research results for clinical care [Neurology] 

Source: EurekAlert!

Spinal Fluid Biomarkers of AD and Brain Functional Network Integrity on Imaging Studies

Both Aß and tau pathology appear to be associated with default mode network integrity before clinical onset of Alzheimer disease (AD), according to a study by Liang Wang, M.D., and colleagues at Washington University in St. Louis, Missouri.

Accumulation of Aß and tau proteins, the pathologic hallmarks of AD, starts years before clinical onset. Pathophysiological abnormalities in the preclinical phase of AD may be detected using cerebrospinal fluid (CSF) or neuroimaging biomarkers, according to the study background.

A total of 207 older adults with normal cognition participated in the cross-sectional group study. Researchers examined the relationship between default mode network integrity and cerebrospinal fluid biomarkers of Alzheimer disease pathology in cognitively normal older individuals using resting-state functional connectivity magnetic resonance imaging.

According to the study results, decreased cerebrospinal fluid Aß42 and increased cerebrospinal fluid phosphorylated tau181 were independently associated with reduced default mode network integrity, with the most prominent decreases in functional connectivity observed between the posterior cingulate and medial temporal regions (regions of the brain associated with memory). Observed reductions in functional connectivity were unattributable to age or structural atrophy in the posterior cingulate and medial temporal areas.

Study: Cerebrospinal Fluid Aβ42, Phosphorylated Tau181, and Resting-State Functional Connectivity [JAMA Neurology]

Source: EurekAlert!

Path of Plaque Buildup in Brain Shows Promise as Early Biomarker for Alzheimer’s Disease

The trajectory of amyloid plaque buildup—clumps of abnormal proteins in the brain linked to Alzheimer’s disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine’s Department of Radiology suggest in a new study published online July 15 in Neurobiology of Aging.

Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. “Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer’s,” said senior author Christos Davatzikos, PhD, professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.

Today, memory decline and Alzheimer’s—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it’s more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.

Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging’s Imaging Study and discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.

“It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,” Dr. Davatzikos said. “This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it’s that pattern growth that may determine whether your memory declines.”

The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analyzed the PET PiB scans of 64 patients from the NIA’s Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients’ brains by combining and analyzing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.

Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).

Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.

A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.

“This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,” said Dr Davatzikos. “The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer’s.”

Study: Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden

Source: EurekAlert!

Big Data From Alzheimer’s Disease Whole Genome Sequencing Will Be Available to Researchers Due to Novel Global Research Database

The Alzheimer’s Association and the Brin Wojcicki Foundation announced recently that massive amounts of new data have been generated by the first “Big Data” project for Alzheimer’s disease. The data will be made freely available to researchers worldwide to quickly advance Alzheimer’s science.

Discussed recently at the Alzheimer’s Association International Conference (AAIC) 2013 in Boston, the project obtained whole genome sequences on the largest cohort of individuals related to a single disease – more than 800 people enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

The genome sequencing data – estimated to be 200 terabytes – will be housed in and available through the Global Alzheimer’s Association Interactive Network (GAAIN), a planned massive network of Alzheimer’s disease research data made available by the world’s foremost Alzheimer’s researchers from their own laboratories, and which also is being publicly announced today at AAIC 2013. GAAIN is funded by an initial $5 million dollar investment by the Alzheimer’s Association, made possible due to the generous support of donors.

“The Alzheimer’s Association is committed to creating open access to research data, and we believe GAAIN will transform how neuroscience data is shared and accessed by scientists throughout the world,” said Maria Carrillo, Ph.D., Alzheimer’s Association vice president of Medical and Scientific Relations. “By fostering a higher level of global data sharing, GAAIN will accelerate investigation and discovery in Alzheimer’s through a system comparable to a search engine like Google or Bing for relevant data.”

“With the addition of more than 800 whole genomes on ADNI subjects that can be linked to the current rich dataset, ADNI data will be even more useful to scientists who are seeking new approaches to treatment and prevention of Alzheimer’s disease,” said Robert C. Green, M.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, who led the ADNI sequencing project. “ADNI is a leader in open data sharing, having provided clinical, imaging and biomarker data to over 4,000 qualified scientists around the world, which has generated over 700 scientific manuscripts.

First, Massive Whole Genome Sequencing Project in Alzheimer’s Disease

Whole genome sequencing determines all six billion letters in an individual’s DNA in one comprehensive analysis. The raw data from the ADNI project is being made available to qualified scientists around the globe to mine for novel targets for risk assessment, new therapies, and much-needed insight into the causes of the fatal brain disease. The new data may enable scientists to better understand how our genes cause and are affected by bodily changes associated with Alzheimer’s disease.

ADNI enrolls people with Alzheimer’s disease, mild cognitive impairment, and normal cognition who have agreed to be studied in great detail over time. The goal is to identify and understand markers of the disease in body fluids, structural changes in the brain, and measures of memory; the hope is to improve early diagnosis and accelerate the discovery of new treatments. ADNI is led by Principal Investigator Michael W. Weiner, M.D., of the University of California San Francisco and the San Francisco VA Medical Center. Dr. Green collaborated on managing the sequencing efforts with Arthur Toga, Ph.D., of UCLA and Andrew J. Saykin, Psy.D., of Indiana University. The actual genome sequencing was performed at Illumina, Inc.

ADNI is a public-private research project led by the National Institutes of Health (NIH) with private sector support through the Foundation for NIH. Launched in 2004, ADNI’s public-private funding consortium includes pharmaceutical companies, science-related businesses, and nonprofit organizations including the Alzheimer’s Association and the Northern California Institute for Research and Education.

The Global Alzheimer’s Association Interactive Network (GAAIN)

Data-sharing has already greatly benefitted scientific disciplines such as genetics, molecular biology, and the physical sciences. Data-sharing in genetics has led to dramatic advances in understanding the risk factors underlying complex diseases. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a compelling example of dozens of geographically-dispersed researchers working together to share their data while making it freely available to others for analysis and publication.

“GAAIN is similar in spirit and goals to other ‘big data’ initiatives that seek to greatly improve the tools and techniques needed to access, organize, and make discoveries from huge volumes of digital data,” Carrillo said. “The advent of cloud computing makes it possible to link databases throughout the world and expand their data processing capability significantly to benefit the research community.”

Carrillo will supervise the development of GAAIN in conjunction with co-principal investigators Art Toga, Ph.D., of the Laboratory of Neuro Imaging (LONI) at the University of Southern California and Giovanni Frisoni, M.D., of the National Center for Alzheimer’s Disease Research and Care and the Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fatebenefratelli Hospital, Italy. Enrique Castro-Leon, Ph.D., who will serve as a consultant, is an enterprise and data center architect for strategic partner Intel Digital Enterprise Group.

GAAIN is built on an international database framework already in use by thousands of scientists and local computational facilities in North America and Europe. The network makes research data available free-of-charge for searching, downloading, and processing across a cloud-based, grid-network infrastructure accessible anywhere through Internet access.

The key to GAAIN’s innovation is its federation of data, which is unprecedented for such a system. GAAIN leadership will invite scientists conducting qualified studies to become partners by permitting GAAIN to link directly to their databases. This will enable researchers to add continually to their data sets and keep all data in GAAIN current and dynamic. It also will enable the scientists to retain control over access to their data, which the Association believes will be important to encouraging participation.

“This is unprecedented and of the utmost importance in brain research, where sometimes thousands of examples are required to observe even the smallest change in the brain,” said Giovanni Frisoni, M.D., neurologist and deputy scientific director at the National Center for Alzheimer’s Disease Research and Care at the IRCCS. He will lead the work of GAAIN in Europe.

“Through GAAIN we envision combining massive amounts of data from multiple sources across many subjects participating in numerous studies,” said Art Toga, Ph.D., professor of neurology at UCLA and director of LONI. “This will provide more statistical power than ever before.”

Source: Alzheimer’s Association

Atrophy in Key Region of Brain Associated with Multiple Sclerosis

Magnetic resonance imaging (MRI) measurements of atrophy in an important area of the brain are an accurate predictor of multiple sclerosis (MS), according to a new study published online in the journal Radiology. According to the researchers, these atrophy measurements offer an improvement over current methods for evaluating patients at risk for MS.

MS develops as the body’s immune system attacks and damages myelin, the protective layer of fatty tissue that surrounds nerve cells within the brain and spinal cord. Symptoms include visual disturbances, muscle weakness and trouble with coordination and balance. People with severe cases can lose the ability to speak or walk.

Approximately 85 percent of people with MS suffer an initial, short-term neurological episode known as clinically isolated syndrome (CIS). A definitive MS diagnosis is based on a combination of factors, including medical history, neurological exams, development of a second clinical attack and detection of new and enlarging lesions with contrast-enhanced or T2-weighted MRI.

“For some time we’ve been trying to understand MRI biomarkers that predict MS development from the first onset of the disease,” said Robert Zivadinov, M.D., Ph.D., FAAN, from the Buffalo Neuroimaging Analysis Center of the University at Buffalo in Buffalo, N.Y. “In the last couple of years, research has become much more focused on the thalamus.”

The thalamus is a structure of gray matter deep within the brain that acts as a kind of relay center for nervous impulses. Recent studies found atrophy of the thalamus in all different MS disease types and detected thalamic volume loss in pediatric MS patients.

“Thalamic atrophy may become a hallmark of how we look at the disease and how we develop drugs to treat it,” Dr. Zivadinov said.

For this study, Dr. Zivadinov and colleagues investigated the association between the development of thalamic atrophy and conversion to clinically definite MS.

“One of the most important reasons for the study was to understand which regions of the brain are most predictive of a second clinical attack,” he said. “No one has really looked at this over the long term in a clinical trial.”

The researchers used contrast-enhanced MRI for initial assessment of 216 CIS patients. They performed follow-up scans at six months, one year and two years. Over two years, 92 of 216 patients, or 42.6 percent, converted to clinically definite MS. Decreases in thalamic volume and increase in lateral ventricle volumes were the only MRI measures independently associated with the development of clinically definite MS.

“First, these results show that atrophy of the thalamus is associated with MS,” Dr. Zivadinov said. “Second, they show that thalamic atrophy is a better predictor of clinically definite MS than accumulation of T2-weighted and contrast-enhanced lesions.”

The findings suggest that measurement of thalamic atrophy and increase in ventricular size may help identify patients at high risk for conversion to clinically definite MS in future clinical trials involving CIS patients.

“Thalamic atrophy is an ideal MRI biomarker because it’s detectable at very early stage,” Dr. Zivadinov said. “It has very good predictive value, and you will see it used more and more in the future.”

The research team continues to follow the study group, with plans to publish results from the four-year follow-up next summer. They are also trying to learn more about the physiology of the thalamic involvement in MS.

“The next step is to look at where the lesions develop over two years with respect to the location of the atrophy,” Dr. Zivadinov said. “Thalamic atrophy cannot be explained entirely by accumulation of lesions; there must be an independent component that leads to loss of thalamus.”

MS affects more than 2 million people worldwide, according to the Multiple Sclerosis International Foundation. There is no cure, but early diagnosis and treatment can slow development of the disease.

Source: Thalamic Atrophy is Associated with Development of Clinically Definite Multiple Sclerosis

Source: EurekAlert!