overview: A newly developed blood test can detect brain-derived tau (BD-tau), a biomarker of neurodegeneration in Alzheimer’s disease.
sauce: University of Pittsburgh
A group of neuroscientists led by researchers at the University of Pittsburgh School of Medicine have developed a test to detect new markers of Alzheimer’s neurodegeneration in blood samples.
A study of their results is published today brain.
Called ‘brain-derived tau’ or BD-tau, this biomarker outperforms current blood diagnostic tests used to clinically detect Alzheimer’s-related neurodegeneration. It is Alzheimer’s disease specific and correlates well with Alzheimer’s disease neurodegenerative biomarkers in cerebrospinal fluid (CSF).
“Neuroimaging is now required for the diagnosis of Alzheimer’s disease,” said senior author Dr. Thomas Karikari, assistant professor of psychiatry at Pitt University. “These tests are expensive and time-consuming to schedule. And even in the United States, many patients don’t have access to his MRI or his PET scanner. Accessibility is a big issue.”
Currently, clinicians use guidelines set in 2011 by the National Institute on Aging and the Alzheimer’s Association to diagnose Alzheimer’s disease. Called the AT(N) framework, this guideline calls for the detection of three distinct components of Alzheimer’s disease pathology: the presence of amyloid plaques, tau tangles, and neurodegeneration in the brain, either by imaging or analysis of CSF samples. there is.
Unfortunately, both approaches have economic and practical limitations, requiring the development of convenient and reliable AT(N) biomarkers in blood samples, the collection of which is less invasive. , requires fewer resources.
Developing a simple tool to detect signs of Alzheimer’s disease in blood without compromising quality is an important step towards improving accessibility, said Karikari.
“The most important utility of blood biomarkers is to improve people’s lives and improve clinical confidence and risk prediction in diagnosing Alzheimer’s disease,” said Karikari.
Current hematological diagnostics can accurately detect abnormalities in plasma amyloid-beta and phosphorylated forms of tau, hitting two of the three necessary checkmarks to confidently diagnose Alzheimer’s disease.
However, the biggest hurdle in applying the AT(N) framework to blood samples lies in the difficulty of detecting markers of neurodegeneration that are specific to the brain, overriding misconceptions generated elsewhere in the body. Unaffected by contaminants it may introduce.
For example, blood levels of neurofilament light, a protein marker of neuronal damage, are elevated in Alzheimer’s disease, Parkinson’s disease, and other dementias, helping to distinguish Alzheimer’s disease from other neurodegenerative diseases. On the other hand, detecting total tau in the blood proved less informative than monitoring its levels in the CSF.
By applying their knowledge of the molecular biology and biochemistry of the tau protein in various tissues such as the brain, Karikari and his team, which includes scientists from the University of Gothenburg, Sweden, have been able to develop BD-tau while avoiding free-floating. We have developed a technology to selectively detect A “big tau” protein produced by cells outside the brain.
To that end, we designed a special antibody that selectively binds to BD-tau, making it easily detectable in the blood. They validated the assay across more than 600 patient samples from five independent cohorts, including those whose Alzheimer’s disease diagnosis was confirmed postmortem and those with memory impairment indicative of early-stage Alzheimer’s disease.
Tests show that levels of BD-tau detected in blood samples from Alzheimer’s disease patients using the new assay match levels of tau in the CSF, reliably distinguishing Alzheimer’s disease from other neurodegenerative diseases. BD-tau levels also correlated with the severity of amyloid plaques and tau tangles in brain tissue confirmed by brain autopsy analysis.
By monitoring blood levels of BD-tau, scientists hope to improve clinical trial design and facilitate screening and enrollment of patients from populations historically not included in study cohorts. I hope you can do it.
“There is a great need for diversity in clinical research, not only by skin color but also by socioeconomic background,” said Karikari.
“In order to develop better drugs, we need to enroll people from different backgrounds into trials, not just those who live near university medical centers. , is easier to manage and can improve clinical confidence in diagnosing Alzheimer’s disease and selecting subjects for clinical trials and disease monitoring.”
Karikari and his team plan to conduct large-scale clinical validation of blood BD-tau in a wide range of research groups, including groups recruiting participants from different racial and ethnic backgrounds, memory clinics and communities. doing. In addition, these studies will include older adults with various stages of the disease, as well as those without biological evidence of Alzheimer’s disease.
These projects are important to ensure that biomarker results are generalizable to people of all backgrounds, and pave the way for broader clinical and prognostic use of BD-tau.
Additional authors of this study are Fernando Gonzalez-Ortiz, BS, Przemysław Kac, BS, Nicholas Ashton, Ph.D., and Henrik Zetterberg, MD, Ph.D., from the University of Gothenburg, Sweden. Dr Michael Turton and Dr Peter Harrison, Bioventix Plc, Farnham, UK. Denis Smirnov, BA, and Douglas Galasko, MD, from the University of California, San Diego. Enrico Premi, MD, Valentina Cantoni, Ph.D., Jasmine Rivolta, Ph.D., and Barbara Borroni, MD, University of Brescia, Italy; Dr. Roberta Guidoni, Dr. Luisa Benussi, Dr. Claudia Saraceno, RCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Funding: This study was supported by the Swedish Research Council (Vetenskåpradet; #2021-03244), the Alzheimer’s Association (#AARF-21-850325), the BrightFocus Foundation (#A2020812F), the Career Development Grant of the International Association for Neurochemistry, Alzheimer’s Disease, Sweden. Supported. Foundation (Alzheimerfonden; #AF-930627), Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), Swedish Dementia Foundation (Demensförbundet), Swedish Parkinson Foundation (Parkinsonfonden), Gamla Tjänarinnor Foundation, Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), Gun and Bertil Stohnes Foundation, Anna Lisa and Brother Björnsson’s Foundation, and other sources.
About this Alzheimer’s Disease Research News
author: Anastasia Gorelova
sauce: University of Pittsburgh
contact: Anastasia Gorelova – University of Pittsburgh
image: image is public domain
See also
Original research: open access.
“Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegenerationby Thomas Karikari et al. brain
overview
Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration
Blood-based biomarkers of amyloid-beta and phosphorylated tau show good diagnostic accuracy and concordance with corresponding CSF and neuroimaging biomarkers in amyloid/tau/neurodegeneration [A/T/(N)] A Framework for Alzheimer’s Disease.
However, the blood-based neurodegenerative marker neurofilament light is not specific for Alzheimer’s disease, whereas total tau shows a lack of correlation with CSF total tau. Recent studies suggest that circulating total tau is primarily derived from peripheral sources other than the brain.
We sought to address this challenge by generating anti-tau antibodies that selectively bind to brain-derived tau and avoid peripherally expressed ‘big tau’ isoforms. We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau and validated it in five independent cohorts (n = 609) including a blood-to-necropsy cohort, a CSF biomarker stratified cohort, and a memory clinic cohort.
In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P. < 0.0001), serum and CSF total tau did not (rho = 0.23, P. = 0.3364). Blood-based brain-derived tau showed comparable diagnostic performance to CSF total tau and his CSF brain-derived tau, separating biomarker-positive Alzheimer’s disease participants from biomarker-negative controls.
Moreover, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer’s disease from other neurodegenerative diseases (area under the curve = 86.4%), whereas neurofilament light did not (curve area below = 54.3%). These performances were independent of the presence of concomitant medical conditions. Plasma brain tau (rho = 0.52–0.67, P. = 0.003), not neurofilament light (rho = −0.14–0.17, P. = 0.501) were associated with the number of global and focal amyloid plaques and neurofibrillary tangles.
These results show that serum brain-derived tau differentiated Alzheimer’s disease from a range of other neurodegenerative diseases, including frontotemporal lobar degeneration and atypical Parkinson’s disease (area under the curve up to 99.6%) in two memory clinics. It was further validated in a cohort.
Notably, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer’s disease and not in other neurodegenerative diseases. Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function.
Brain-derived tau is a novel blood-based biomarker that is superior to plasma total tau and, unlike neurofilament light, shows specificity for Alzheimer’s disease-type neurodegeneration.
Thus, brain-derived tau has demonstrated the potential to complete the AT(N) scheme in blood and is useful for assessing Alzheimer’s disease-dependent neurodegenerative processes for clinical and research purposes.
