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Discovered a Genetic Biomarker that Detects Lewy Body Dementia

The Germans Trias i Pujol Health Sciences Research Institute (IGTP) and the Universitat Autònoma de Barcelona (UAB) have discovered the first genetic biomarker to detect Lewy body dementia (LBD), a disease that can be confused with Alzheimer’s. This biomarker is found in 20% of cases and differentiates one of the sub-groups of the pathology. Licensed to the Grifols company, it will lead to more precise diagnosis and treatment.

Lewy body dementia (LBD) is the second cause of dementia after Alzheimer’s disease. The symptoms of both diseases are very similar, since in both cases there is a gradual deterioration in mental capacity, affecting memory, thought processes, behaviour and physical activity. These similarities mean that some patients with LBD are wrongly diagnosed and treated with the usual drugs for Alzheimer’s. But this treatment causes adverse reactions in approximately half of these patients, making the disease much worse in some cases.

Currently there is no specific test to diagnose LBD. In practice, various neurological and neuropsychological tests are used to detect the disease and its possible overlap with other disorders, but clinical diagnosis of LBD is not very accurate.

The research, conducted by the IGTP and the UAB, has led to the discovery of the first genetic biomarker, found in 20% of LBD cases, and differentiating between one sub-group of LBD and Alzheimer’s disease. “Although this marker only detects a certain number of LBD sufferers, it significantly increases diagnostic sensitivity to the disease and these patients can get an accurate diagnosis and therefore the right treatment”, explains Dr Katrin Beyer, head of the research project and belonging to the Group of Structural and Molecular Pathology, Department of Pathology at the Germans Trias Hospital and Institute.

The researchers first detected the marker through a study of post mortem brain samples, in which they observed an alteration in the expression of the enzyme butyrylcholinesterase (BCHE) in the brains of patients with LBD. These data indicated that there could be genetic alterations in the BCHE gene promoter, causing changes in the expression of the gene. In fact, they found four polymorphisms in the LBD promoter region that, in certain combinations, are associated with LBD. These findings, which have been patented, make it possible to determine if a patient has LBD, distinguishing it from Alzheimer’s disease.

Currently, the patent is in its last stage of validation, which is being carried out in collaboration with neurologists from the Neurodegenerative Disease Unit of the Germans Trias Hospital and Bellvitge Hospital.

The licensing agreement with the Grifols company means the results can be applied, thus providing a simple, rapid, and effective procedure for diagnosing LBD in hospitals. Moreover, the marker can also be used to design clinical studies to help identify groups of patients with a more accurate diagnosis, removing, for example, LBD cases from a group of Alzheimer’s patients.

Grifols is a global company that for over 70 years has been providing therapeutic treatments with plasmatic proteins, technology for clinical diagnosis and pharmaceutical products for hospital use. It is now the third worldwide producer of biological drugs derived from plasma, is present in over 100 countries and is a world leader in plasma supplies, with 150 blood donation centres in the United States.

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!

Faster, Simpler Diagnosis for Fibromyalgia May be on the Horizon

Researchers have developed a reliable way to use a finger-stick blood sample to detect fibromyalgia syndrome, a complicated pain disorder that often is difficult to diagnose.

If it were someday made available to primary care physicians, the test could knock up to five years off of the wait for a diagnosis, researchers predict.

In a pilot study, the scientists used a high-powered and specialized microscope to detect the presence of small molecules in blood-spot samples from patients known to have fibromyalgia.

By “training” the equipment to recognize that molecular pattern, the researchers then showed that the microscope could tell the difference between fibromyalgia and two types of arthritis that share some of the same symptoms.

Though more analysis is needed to identify exactly which molecules are related to development of the disorder itself, the researchers say their pilot data are promising.

“We’ve got really good evidence of a test that could be an important aid in the diagnosis of fibromyalgia patients,” said Tony Buffington, professor of veterinary clinical sciences at The Ohio State University and senior author of the study. “We would like this to lead to an objective test for primary care doctors to use, which could produce a diagnosis as much as five years before it usually occurs.”

Patients with fibromyalgia are often desperate by the time they receive treatment because of the lengthy process required to make a diagnosis. The main symptoms, persistent pain and fatigue, mimic many other conditions, so physicians tend to rule out other potential causes before diagnosing fibromyalgia. Additional symptoms include disrupted sleep and memory or thought problems. An estimated 5 million American adults have the disorder, according to the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“The importance of producing a faster diagnosis cannot be overstated, because patients experience tremendous stress during the diagnostic process. Just getting the diagnosis actually makes patients feel better and lowers costs because of reductions in anxiety,” said Kevin Hackshaw, associate professor of medicine, division of rheumatology and immunology, at Ohio State’s Wexner Medical Center and lead author of the study.

The study is published in the Aug. 21, 2013, issue of the journal Analyst.

The technology used in this work is infrared microspectroscopy, which identifies the biochemical content of a blood sample based on where peaks of molecules appear in the infrared spectrum. The technology offers hints at the molecules present in the samples based on how molecular bonds vibrate when they are struck by light.

The spectroscopy works on dried blood, so just a few drops from a finger stick produce enough blood to run this test.

Researchers first obtained blood samples from patients diagnosed with fibromyalgia (14), rheumatoid arthritis (15) and osteoarthritis (12). These other conditions were chosen for comparison because they produce similar symptoms as fibromyalgia, but are easier to diagnose.

The scientists analyzed each sample with the infrared microspectroscopy to identify the molecular patterns associated with each disease. This functioned as a “training” phase of the study.

When the researchers then entered blinded blood samples into the same machinery, each condition was accurately identified based on its molecular patterns.

“It separated them completely, with no misclassifications,” Buffington said. “That’s very important. It never mistook a patient with fibromyalgia for a patient with arthritis. Clearly we need more numbers, but this showed the technique is quite effective.”

The researchers also analyzed some of the potential chemicals that could someday function as biomarkers in the fibromyalgia blood samples, but further studies are needed to identify the molecules responsible for the spectral patterns, he said.

Though an infrared microscope can be expensive, Buffington said the testing could be affordable if a central lab existed to run the samples. That the method can use dried blood samples makes this concept feasible because dried blood can be legally sent via U.S. mail, he noted.

Why is a veterinarian pursuing this type of research? Buffington is a renowned expert on domestic cats, including a painful bladder disorder they suffer called interstitial cystitis (IC). This syndrome also occurs in humans.

It turns out that the origins of IC, like such human disorders as irritable bowel syndrome and fibromyalgia, cannot be traced to the specific area of the anatomy most affected by the syndrome. These disorders are categorized as medically unexplained or functional syndromes, and Buffington has explored the possibility that a common link exists among these types of diseases, and that they might have origins in the central nervous system.

Buffington has filed two invention disclosures with the university, and Ohio State has filed multiple patent applications for the testing method, in the United States and internationally. In November, Ohio State was issued U.S. Patent 8,309,931 on a rapid diagnostic method for functional syndromes in humans and cats.

Additional co-authors include Luis Rodriguez-Saona and Marçal Plans of the Department of Food Science and Technology at Ohio State, and Lauren Bell of Metabolon Inc., based in Durham, N.C.

Study: A bloodspot-based diagnostic test for fibromyalgia syndrome and related disorders [Analyst]

Source: Ohio State University Wexner Medical Center

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