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New Biomarker Could Reveal Alzheimer’s Disease Years Before Onset

A study published recently reported the identification of what may be the earliest known biomarker associated with the risk of developing Alzheimer’s disease (AD). The results suggest that this novel potential biomarker is present in cerebral spinal fluid (CSF) at least a decade before signs of dementia manifest.

“If our initial findings can be replicated by other laboratories, the results will change the way we currently think about the causes of Alzheimer’s disease,” said Dr. Ramon Trullas, research professor at the CSIC Institute of Biomedical Research of Barcelona and lead author of the study that was published in Annals of Neurology. “This discovery may enable us to search for more effective treatments that can be administered during the preclinical stage.”

Difficult Diagnosis

Alzheimer’s disease affects more than five million Americans and is the sixth leading cause of death in the United States. At present, the only way to accurately diagnose the disease is by post-mortem neuropathological analysis. The relationship of currently known biomarkers with the cause of the disease is unclear, making it nearly impossible to diagnose preclinical stages of the disease with any real certainty.

The CSIC researchers demonstrated that a decrease in the content of mitochondrial DNA (mtDNA) in CSF may be a preclinical indicator for Alzheimer’s disease; furthermore, there may be a directly causative relationship. The hypothesis is that decreased mtDNA levels in CSF reflect the diminished ability of mitochondria to power the brain’s neurons, triggering their death. The decrease in the concentration of mtDNA precedes the appearance of well-known biochemical Alzheimer’s biomarkers (the Aβ1-42, t-tau, and p-tau proteins), suggesting that the pathophysiological process of Alzheimer’s disease starts earlier than previously thought and that mtDNA depletion may be one of the earliest predictors for the disease.

In addition to enabling an investigation of the potential causal relationship of mtDNA and Alzheimer’s progression, the use of mtDNA as an index of preclinical Alzheimer’s disease provides an important advantage over previous biochemical markers: the detection of this novel nucleic acid biomarker is unhampered by the technical difficulties associated with protein detection. mtDNA can be readily quantified by real-time quantitative PCR (qPCR) or droplet digital PCR (ddPCR).

Quantitation of mtDNA

Prior to this study, researchers had not reported that circulating cell-free mtDNA could be detected in human CSF. But with this study, Dr. Trullas’ team was able to both detect and reproducibly quantitate mtDNA using qPCR, carefully optimized by adhering to the MIQE guidelines.

To validate their qPCR findings, Dr. Trullas’ team used Bio-Rad Laboratories’ QX100™ Droplet Digital™ PCR system. Unlike qPCR assays, the QX100 system provides an absolute quantification of target DNA molecules without the need for a standard curve. In addition, an important factor for their CSF analysis was that the Droplet Digital PCR system did not require sample purification to remove PCR inhibitors, as is necessary for qPCR assays.

“Droplet Digital PCR allowed us to validate our initial qPCR measurements because it provides absolute quantitation at the single-molecule level without relying on a standard curve,” said Dr. Trullas. “As the technology becomes more widely adopted, we anticipate that Droplet Digital PCR will be the future of detecting mtDNA in cerebral spinal fluid.”

Dr. Trullas hopes that other laboratories and hospitals will successfully replicate his group’s research results, confirming that reduced mtDNA levels should be investigated as a possible cause of Alzheimer’s disease. By finding a way to block this degeneration, clinicians may be able to diagnose and treat Alzheimer’s disease before symptoms appear.

Study: Low CSF concentration of mitochondrial DNA in preclinical Alzheimer’s disease [Annals of Neurology]

Source: Bio-Rad

One Step Closer to a Blood Test for Alzheimer’s

Australian scientists are much closer to developing a screening test for the early detection of Alzheimer’s disease. They identified blood-based biological markers that are associated with the build up of a toxic protein in the brain which occurs years before symptoms appear and irreversible brain damage has occurred.

“Early detection is critical if we are to make any real difference in the battle against Alzheimer’s, giving those at risk a much better chance of receiving treatment earlier, before it’s too late to do much about it,” said Dr Samantha Burnham from CSIRO’s Preventative Health Flagship.

Alzheimer’s is the leading cause of dementia. One quarter of a million Australians currently suffer from dementia and given our ageing population, this is predicted to increase to one million people by 2050.

Sophisticated mathematical models were used to analyse data from 273 participants in the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL).

This identified nine markers that correlate with brain positron emission tomography (PET) imaging measurements of a toxic protein, amyloid beta, which deposits in the brain as plaques early in disease development.

“The progressive build up of the toxic protein, amyloid beta, is one of the earliest changes in the brain associated with the development of Alzheimer’s disease,” said Dr Noel Faux, from the Florey Institute for Neuroscience and Mental Health.

“A recent study from the AIBL team showed that amyloid beta levels become abnormal about 17 years before dementia symptoms appear. This gives us a much longer time to intervene to try to slow disease progression if we are able to detect cases early.”

Dr Burnham adds “We hope our continued research will lead to the development of a low cost, minimally invasive population based screening test for Alzheimer’s.”

“A blood test would be the ideal first stage to help identify many more people at risk before a diagnosis is confirmed with cognitive tests and PET imaging or cerebral spinal fluid (CSF) testing.”

The results have been published in the journal Molecular Psychiatry.

Study: A blood-based predictor for neocortical Abeta burden in Alzheimer’s disease: results from the AIBL study

Source: Commonwealth Scientific and Industrial Research Organisation (CSIRO)

AgedBrainSYSBIO, a Medium-scale Research Initiative Against Neurodegenerative Diseases

The AgedBrainSYSBIO project on systems biology of synapse proteins & ageing was officially launched recently in Paris, France. AgedBrainSYSBIO is a European collaborative research project funded by the European Commission under the Health Work Programme of the 7th Framework Programme. This multidisciplinary consortium assembles 14 academic and industrial internationally renowned research teams from Belgium, Estonia, France, Germany, Israel, United Kingdom and Switzerland.

Ageing is undisputedly a complex process because it affects the deterioration of most (if not all) aspects of life. Cognitive decline is emerging as one of the greatest public health challenges of the old age, with nearly 50% of adults over 85 afflicted by Alzheimer’s disease, the most common type of dementia.

As other chronic and neurodegenerative diseases, Alzheimer’s disease develops slowly and gradually; but is distinctive in that it forces patients to endure many years of steadily-lessening contact with others, because of memory loss, difficulty with orientation, loss of language and speaking abilities, judging things and depression amongst numerous other symptoms. In 2013, it is estimated that there are worldly more than 24 million people with Alzheimer’s disease, with 4.6 million new cases each year, which means a new case each 7 seconds. It is thus one of the greatest challenges in public health for modern societies, in terms of costs but also in terms of cause, cure and care. To address all these issues, European Commission-funded research effort is crucial as there are still no curative drugs, with only symptomatic treatment able to delay the disease progression.

Over the last years, Genome-Wide Association Studies (GWAS) have been instrumental to identify genes that mediate genetic risk associated to Late-Onset Alzheimer Diseases (LOAD). These approaches based on the genetic comparison of large cohorts of patients and healthy aged persons, and for which three academic partners have been involved (Inserm U894; Institut Pasteur Lille, University of Antwerpen), have been largely funded by Europe. Additionally, a variety of new sets of data have been built and have delivered the state-of-the art of protein-protein interactions, their localisation in subregions of human neurons and genome-wide transcriptome analysis of human neurons derived from aged patient fibroblasts. In another field, new drosophila and mouse models have been also generated via academic partners involved in European Commission-supported large-scale programmes. Finally, the analysis of genes displaying an accelerated evolution in humans as non-human primates do not display these human-specific neurodegenerative diseases has open interesting research paths. So far however, in spite of a huge amount of data available and existing in vitro and in vivo models, these approaches have not been successfully translated into the clinic separately.

The AgedBrainSYSBIO will take advantage of these large set of data, will cross them to other large-scale ageing databases and will include all of these know-how, technologies and results. Thanks to the involvement of four European SMEs, this program is expected to get results readily translated into preclinical studies.

AgedBrainSYSBIO project assembles 13 well-established research teams both from academia and industry. The scientists will share results and know how on LOAD GWAS gene discovery, comparative functional genomics in mouse and drosophila models, in mouse transgenic approaches research on human induced pluripotent stem cells (hiPSC) and their differentiation in vitro and modelling pathways with emphasis on comparative and evolutionary aspects. Importantly, the four European SMEs involved will bring their complementary expertise. QURETEC (Estonia) will be a key partner for data management solutions and bioinformatics data analyses; HYBRIGENICS (France) is a world leader in comparative proteomics and protein-protein interaction analyses; GENEBRIDGES (Germany) is marketing novel strategies for DNA engineering in mammalian cells; reMYND (Belgium) is a leader for development of protein misfolding-modifying treatments against LOAD .

Together, researchers will address the basis of brain ageing by studying the pathways involved in Late-Onset Alzheimer Diseases combining integrative systems biology and comparative genomics. One of the first steps will be to identify the interactions through which the ageing phenotype develops in normal and in disease conditions; on this basis, novel pathways and their evolutionary properties will be modelled and experimentally tested in order to identify druggable targets. This work will finally allow the validation of new druggable targets and markers as a proof-of-concept towards the prevention and cure of aging cognitive defects.

Michel Simonneau, MD PhD, Professor at Ecole Normale Supérieure de Cachan, who coordinates this effort states that “this ambitious project integrates the numerous European initiatives, such as JPND , as well as national research programmes, which addresse the scientific and societal challenge of neurodegenerative diseases. This project receives the decisive input of 4 small to medium size enterprises (SMEs) that allow us to get candidate solutions for curing and preventing common age-related diseases. The links between academia and industry is the driving force of this work programme and in the end will hopefully benefit to all of us.”

Source: EurekAlert!

Alzheimer’s Disease and Dementia Early-Diagnostic Clinic Launched in Iceland

MentisCura Diagnostics (www.mentiscura.com) recently announced the launch of its first clinical center for the early detection of Alzheimer’s disease and other dementias. The operational launch brings sophisticated biomarkers capable of assisting early, differential diagnosis into a clinical setting and provides for the first time cutting edge electrophysiological analysis developed by MentisCura to the general public through community physicians.

Both the high prevalence and rapidly increasing incidence of CNS disorders are raising alarm on account of the growing burden of care associated with these diseases. According to data published by the Alzheimer’s Association, Alzheimer’s disease is the sixth-leading cause of death in the United States, with as many as one in eight older Americans having Alzheimer’s disease in 2012. A recent World Alzheimer’s Report estimated the 2010 worldwide cost of dementia to be more than $600bn.

“Our new service fulfills an important role addressing the key issues of earlier and more accurate diagnosis. Current diagnostic tools such as fMRI and PET are in a price range that precludes their use as screening tools for dementias. The low cost, high-throughput and non-invasive nature of our test makes it uniquely useful in a real world clinical setting, where physicians need to assess patients and make diagnostic decisions before these diseases have reached a late and untreatable stage. From a five-minute EEG recording using the international standard 10-20 testing protocol, our powerful analytical systems are able to provide same-day results back to physicians,” said Kristinn Gretarsson, CEO of MentisCura.

“MentisCura provides a welcome and reliable tool for diagnosing the causes of cognitive impairment and dementia. It plays a key role in our diagnostic protocol for dementia and is an important part of our follow up on disease progression and treatment efficacy,” commented Jon Snaedal, MD, Chief Physician of the Memory Clinic at the National Hospital of Iceland.

MentisCura’s clinic offers a complete, integrated service to hospitals and general practitioners through sampling, processing and analysis of patient EEG data. The MentisCura Analysis System is a CE marked diagnostic aid, based on advanced, proprietary EEG-biomarker technology platform that accurately maps changes in electrophysiology to specific disease pathologies, through correlation with the world´s most comprehensive proprietary EEG database for dementia and cognitive disorders. The platform supports diagnoses for most common types of dementia, including Alzheimer’s disease and Lewy Body Dementia.

Source: Business Wire

Quest Diagnostics Launches Dementia Diagnostic Panel, First in Industry for Treatable Forms of Cognitive Impairment Based on Medical Guidelines

Quest Diagnostics (NYSE: DGX), the world’s leading provider of diagnostic information services, recently announced the availability of the first clinical test panel for aiding the diagnosis of suspected dementia due to treatable forms of cognitive impairment. The test panel is believed to be the first commercial service from a clinical laboratory to combine several guideline-recommended tests for identifying secondary, treatable causes of dementia as a single blood test and report.