MSGID: 1:317/3 64b0cfaa   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Tau-based biomarker tracks Alzheimer's progression    
    Novel marker found in cerebrospinal fluid also could speed development of   
   Alzheimer's drugs    
      
     Date:   
         July 13, 2023   
     Source:   
         Washington University School of Medicine   
     Summary:   
         Researchers have discovered a biomarker for Alzheimer's disease in   
         the cerebrospinal fluid known as MTBR-tau243 can be used to track   
         the progression of the disease and could speed drug development.   
      
      
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   Two pathologies drive the progression of Alzheimer's disease. Early on,   
   amyloid beta plaques lead the way, but around the time cognitive symptoms   
   arise, tau tangles take over as the driving force and cognition steadily   
   declines.   
      
   Tracking the course of the disease in individual patients has been   
   challenging because there's been no easy way to measure tau tangles in   
   the brain.   
      
   But now, researchers at Washington University School of Medicine in   
   St. Louis and Lund University in Lund, Sweden, have identified a form of   
   tau that could serve as a marker to track Alzheimer's progression. The   
   marker also could be used by Alzheimer's drug developers to assess whether   
   investigational tau-based drugs -- the next frontier in Alzheimer's drug   
   development -- are effective against the disease. Such drugs theoretically   
   would benefit people in later stages of the disease, when tau tangles   
   play a crucial role.   
      
   By studying 667 people in Sweden and the U.S. at various stages of   
   Alzheimer's disease, the researchers discovered in the cerebrospinal   
   fluid that levels of a specific form of tau -- known as microtubule   
   binding region (MTBR)-tau243 - - track with the amount of damaging tau   
   tangles in the brain and with the degree of cognitive decline.   
      
   The findings, published July 13 in Nature Medicine, are a major step   
   toward a better approach to diagnosing and staging Alzheimer's disease. A   
   test based on MTBR-tau243 could speed up drug development by providing a   
   relatively simple and inexpensive way to identify and monitor participants   
   in clinical trials and assess whether the experimental therapies,   
   including tau-based drugs, can change the course of the disease.   
      
   "This discovery provides biomarkers to specifically track the progression   
   of tau tangles, the major pathology that predicts dementia and cognition,   
   which is something that hasn't been within reach until now," said   
   co-senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight   
   Distinguished Professor of Neurology at Washington University. "These   
   findings will help accelerate drug development for patients with symptoms   
   of Alzheimer's disease.   
      
   We are also working on developing these biomarkers as a clinical test to   
   stage individual patients and improve patient care."  The gold standard   
   for measuring tau tangles in the brain is the tau-positron emission   
   tomography (tau-PET) brain scan, which costs thousands of dollars and   
   requires expensive equipment and specialized expertise not available   
   at most hospitals, making such scans impractical for patient care and   
   costly for research studies.   
      
   In 2020, Bateman and Kanta Horie, PhD, a research associate professor   
   of neurology and co-first author on the new paper, showed that levels of   
   MTBR- tau243 in the cerebrospinal fluid reflect the amount of tau tangles   
   in the brain. In this new study, Bateman and Horie teamed up with Lund   
   University's Oskar Hansson, MD, PhD, a professor of neurology and study   
   co-senior author, and Gemma Salvado', PhD, a postdoctoral researcher   
   and co-first author, to extend the analysis to a larger number of people   
   and to compare MTBR-tau243 to other tau biomarkers.   
      
   The researchers analyzed data from people who volunteered for Alzheimer's   
   research studies through the Biomarkers For Identifying Neurodegenerative   
   Disorders Early and Reliably (BioFINDER)-2 (448 people) study in southern   
   Sweden or the Knight Alzheimer Disease Research Center (219 people) in St.   
      
   Louis. The average age of participants was 71, and the group included   
   healthy people as well as people at all stages of disease, ranging from   
   those with some amyloid in their brains but no cognitive symptoms, to   
   those with extensive amyloid and tau in their brains and a diagnosis   
   of dementia. The researchers compared cognitive function with levels   
   of various forms of tau in the cerebrospinal fluid and with levels of   
   amyloid and tau in the brain, as measured by amyloid and tau PET scans.   
      
   Levels of MTBR-tau243 in the cerebrospinal fluid correlated strongly   
   with brain tau tangle levels and cognitive function. As MTBR-tau243   
   levels went up, tau levels in the brain also went up, and scores on   
   cognitive tests went down. In contrast, levels of another form of tau in   
   the cerebrospinal fluid, phosphorylated tau, tracked mainly with brain   
   amyloid levels but not with brain tau levels or cognitive function.   
      
   "To accurately diagnose Alzheimer's disease in patients with cognitive   
   symptoms, we need biomarker-based evidence of both amyloid beta plaques   
   and tau tangle pathology," Hansson said. "With this new biomarker,   
   representing tau pathology, we can do this using a single cerebrospinal   
   fluid sample. This has the potential to clearly improve the diagnostic   
   as well as prognostic work-up of Alzheimer's worldwide. We hope that   
   we soon can do the same using a simple blood test."  By combining the   
   two forms of tau in the cerebrospinal fluid -- phosphorylated tau and   
   MTBR-tau243 -- the researchers were able to predict cognitive function   
   almost as well as by using tau-PET.   
      
   "A combination of phosphorylated tau and MTBR-tau243 in the cerebrospinal   
   fluid reveals not only whether an individual has Alzheimer's disease   
   but identifies the stage of illness -- from presymptomatic disease to   
   full-blown dementia," Horie said.   
      
   By taking repeated samples of cerebrospinal fluid, researchers could track   
   the progression of the disease and determine the effect of interventions   
   such as experimental anti-tau therapeutics on the disease trajectory.   
      
   "In late stages of Alzheimer's disease, the effectiveness of anti-amyloid   
   therapies may weaken because amyloid is no longer playing a major   
   role in driving the disease," Horie said. "But that's when tau becomes   
   relevant. By stopping the tau pathology, we may be able to stop further   
   cognitive decline including memory loss. By maintaining individuals at   
   the level of mild cognitive impairment and preventing further cognitive   
   decline, we can help people maintain a good quality of life. That's what   
   we're working toward."   
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   Journal Reference:   
      1. Kanta Horie, Gemma Salvado', Nicolas R. Barthe'lemy, Shorena   
      Janelidze,   
         Yan Li, Yingxin He, Benjamin Saef, Charles D. Chen, Hong Jiang,   
         Olof Strandberg, Alexa Pichet Binette, Sebastian Palmqvist,   
         Chihiro Sato, Pallavi Sachdev, Akihiko Koyama, Brian A. Gordon,   
         Tammie L. S. Benzinger, David M. Holtzman, John C. Morris,   
         Niklas Mattsson-Carlgren, Erik Stomrud, Rik Ossenkoppele, Suzanne   
         E. Schindler, Oskar Hansson, Randall J. Bateman. CSF MTBR-tau243   
         is a specific biomarker of tau tangle pathology in Alzheimer's   
         disease. Nature Medicine, 2023; DOI: 10.1038/ s41591-023-02443-z   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230713141940.htm   
      
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