Summary: A newly developed blood test can detect brain-derived protein tau (BD-tau), a biomarker of neurodegeneration in Alzheimer’s disease.
Source: University of Pittsburgh
A group of neuroscientists led by a researcher at the University of Pittsburgh School of Medicine has developed a test to detect a new marker of Alzheimer’s disease neurodegeneration in a blood sample.
A study of their results was published today in Brain.
The biomarker, called “brain-derived tau” or BD-tau, outperforms current blood diagnostic tests used to clinically detect neurodegeneration linked to Alzheimer’s disease. It is specific to Alzheimer’s disease and correlates well with biomarkers of Alzheimer’s disease neurodegeneration in cerebrospinal fluid (CSF).
“Currently, the diagnosis of Alzheimer’s disease requires neuroimaging,” said lead author Thomas Karikari, Ph.D., assistant professor of psychiatry at Pitt. “These tests are expensive and time-consuming to schedule, and many patients, even in the United States, don’t have access to MRI and PET scanners. Accessibility is a major issue. »
Currently, to diagnose Alzheimer’s disease, clinicians use guidelines established in 2011 by the National Institute on Aging and the Alzheimer’s Association. The guidelines, called the AT(N) Framework, require the detection of three distinct components of Alzheimer’s pathology – the presence of amyloid plaques, tau tangles and neurodegeneration in the brain – either by imaging or by analysis of CSF samples.
Unfortunately, both approaches suffer from economic and practical limitations, dictating the need to develop convenient and reliable AT(N) biomarkers in blood samples, the collection of which is minimally invasive and requires fewer resources.
Developing simple tools that detect signs of Alzheimer’s disease in blood without compromising quality is an important step towards greater accessibility, Karikari said.
“The most important benefit of blood biomarkers is to improve people’s lives and improve clinical confidence and risk prediction in the diagnosis of Alzheimer’s disease,” Karikari said.
Current blood diagnostic methods can accurately detect abnormalities in plasma beta-amyloid and phosphorylated form of tau, achieving two of the three tick marks needed to confidently diagnose Alzheimer’s disease.
But the biggest obstacle to applying the AT(N) framework to blood samples is the difficulty of detecting brain-specific markers of neurodegeneration that are not influenced by potentially misleading contaminants produced elsewhere in the body.
For example, blood levels of neurofilamentary light, a protein marker of nerve cell damage, become elevated in Alzheimer’s disease, Parkinson’s disease, and other dementias, making it less useful in differentiating the disease from Alzheimer’s from other neurodegenerative diseases. On the other hand, detecting total tau in blood has been found to be less informative than monitoring its levels in CSF.
By applying their knowledge of molecular biology and biochemistry of tau proteins in different tissues, such as the brain, Karikari and his team, including scientists from the University of Gothenburg, Sweden, developed a technique to selectively detect BD- tau while avoiding free floating. “big tau” proteins produced by cells outside the brain.
To do this, they designed a special antibody that selectively binds to BD-tau, making it easily detectable in the blood. They validated their test on more than 600 patient samples from five independent cohorts, including those from patients who were diagnosed with Alzheimer’s disease after death, as well as patients with memory impairments indicating a early stage of Alzheimer’s disease.
The tests showed that BD-tau levels detected in blood samples from Alzheimer’s disease patients using the new test matched tau levels in CSF and reliably distinguished Alzheimer’s disease. Alzheimer’s from other neurodegenerative diseases. BD-tau levels were also correlated with the severity of amyloid plaques and tau tangles in brain tissue confirmed by brain autopsy analyses.
Scientists hope that monitoring blood levels of BD-tau could improve clinical trial design and facilitate the screening and recruitment of patients from populations that historically have not been included in research cohorts.
“There is a huge need for diversity in clinical research, not only by skin color but also by socioeconomic background,” Karikari said.
To develop better drugs, trials need to recruit people from diverse backgrounds, not just those who live near academic medical centers. A blood test is cheaper, safer and easier to administer, and it can improve clinical confidence in the diagnosis of Alzheimer’s disease and the selection of participants in clinical trials and monitoring of the disease.
Karikari and his team plan to conduct large-scale clinical validation of BD-tau blood in a wide range of research groups, including those recruiting participants from diverse racial and ethnic backgrounds, memory clinics and the community. In addition, these studies will include older people without biological evidence of Alzheimer’s disease as well as people at different stages of the disease.
These projects are crucial in ensuring that biomarker results are generalizable to people of all backgrounds, and will pave the way for the commercialization of BD-tau for widespread clinical and prognostic use.
The other authors of this study are Fernando Gonzalez-Ortiz, BS, Przemysław Kac, BS, Nicholas Ashton, Ph.D., and Henrik Zetterberg, MD, Ph.D., University of Gothenburg, Sweden; Michael Turton, Ph.D., and Peter Harrison, Ph.D., of Bioventix Plc, Farnham, UK; Denis Smirnov, BS, and Douglas Galasko, MD, of the University of California, San Diego; Enrico Premi, MD, Valentina Cantoni, Ph.D., Jasmine Rivolta, Ph.D., and Barbara Borroni, MD, from the University of Brescia, Italy; and Roberta Ghidoni, Ph.D., Luisa Benussi, Ph.D., and Claudia Saraceno, Ph.D., of RCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Funding: This research was supported by the Swedish Research Council (Vetenskåpradet; #2021-03244), Alzheimer’s Association (#AARF-21-850325), BrightFocus Foundation (#A2020812F), Career Development Grant from International Society of Neurochemistry, Swedish Alzheimer Foundation Foundation (Alzheimerfonden; #AF-930627), Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), Swedish Dementia Foundation (Demensförbundet), Swedish Dementia Foundation Parkinson (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 and Anna Lisa and Brother Björnsson, among other sources.
About this Alzheimer’s disease research news
Author: Anastasia Gorelova
Source: University of Pittsburgh
Contact: Anastasia Gorelova – University of Pittsburgh
Image: Image is in public domain
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Original research: free access.
“Brain-derived tau: a new blood biomarker for Alzheimer’s-like neurodegenerationby Thomas Karikari et al. Brain
Abstract
Brain-derived tau: a new blood biomarker for Alzheimer’s-like neurodegeneration
Blood biomarkers for beta-amyloid and phosphorylated tau show good diagnostic accuracies and agreement with their corresponding CSF and neuroimaging biomarkers in amyloid/tau/neurodegeneration [A/T/(N)] Framework for Alzheimer’s disease.
However, the blood-based marker neurofilament light of neurodegeneration is not specific for Alzheimer’s disease, while total tau shows a lack of correlation with CSF total tau. Recent studies suggest that total blood tau comes primarily from non-brain peripheral sources.
We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau protein and avoids the peripherally expressed “big tau” isoform. We applied this antibody to develop a highly sensitive blood test for brain-derived tau protein and validated it in five independent cohorts (not = 609) including an autopsy blood cohort, CSF biomarker-graded cohorts, and memory clinic cohorts.
In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 0.0001), whereas total serum and CSF tau was not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as total CSF tau and CSF brain-derived tau in separating biomarker-positive Alzheimer’s disease participants from biomarker negative controls.
Furthermore, plasma brain-derived tau protein accurately distinguished autopsy-confirmed Alzheimer’s disease from other neurodegenerative diseases (area under the curve = 86.4%) whereas neurofilament lumen did not (area under the curve = 86.4%). curve = 54.3%). These performances were independent of the presence of concomitant pathologies. Plasma brain-derived tau (rho = 0.52–0.67, P = 0.003), but not neurofilament lumen (rho = −0.14–0.17, P = 0.501), was associated with global and regional number of amyloid plaques and neurofibrillary tangles.
These findings were then verified in two cohorts of memory clinics where brain-derived tau differentiated Alzheimer’s disease from a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%).
Notably, brain-derived plasma/serum tau correlated with neurofilament lumen only in Alzheimer’s disease, but not in other neurodegenerative diseases. In all cohorts, brain-derived plasma/serum tau was associated with CSF and plasma AT(N) biomarkers and cognitive function.
Brain-derived tau is a new blood biomarker that outperforms total plasma tau and, unlike neurofilament lumen, shows specificity for Alzheimer’s disease-like neurodegeneration.
Thus, brain-derived tau protein demonstrates potential to complement the AT(N) pattern in blood and will be useful in assessing Alzheimer’s disease-dependent neurodegenerative processes for clinical and research purposes.
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