In the News
ALZHEIMER'S ASSOCIATION GLOBAL WORKGROUP RELEASES RECOMMENDATIONS ABOUT USE OF ALZHEIMER'S "BLOOD TESTS"
Coronavirus Jumped to Humans at Least Twice at Market in Wuhan, China
Get Ready for Back-to-School Season with Kyowa Hakko's Cognizin® Citicoline
ALZHEIMER'S ASSOCIATION GLOBAL WORKGROUP RELEASES RECOMMENDATIONS ABOUT USE OF ALZHEIMER'S "BLOOD TESTS"
Alzheimer's disease blood biomarkers (BBMs) may revolutionize the diagnosis of Alzheimer's in the future, but are not yet ready for widespread use, according to a newly-published article by leading international clinicians and researchers convened by the Alzheimer's Association®. At the same time, they are important and valuable for current research trials and cautious initial use in specialized memory clinics.
"Blood-based markers show promise for improving, and possibly even redefining, the diagnostic work-up for Alzheimer's," said Maria C. Carrillo, Ph.D., Alzheimer's Association chief science officer and a co-author of the article. "Remarkable progress has been made, but additional data are needed before BBMs can be used as a stand-alone test for diagnosis, and before considering broad use in primary care settings."
"In this article, the expert workgroup clearly defines both short- and long-term research priorities needed to fill significant knowledge gaps that still exist, such as how well these blood-based markers work in diverse communities and in those living with multiple health conditions," Carrillo added. "Also included are consensus appropriate use recommendations for use of BBMs in the clinic and in research trials."
"The Alzheimer's Association Appropriate Use Recommendations for Blood Biomarkers in Alzheimer's Disease," by Oskar Hansson, M.D., Ph.D., et al, is published online today by Alzheimer's & Dementia: The Journal of the Alzheimer's Association. The recommendations will be reported today and tomorrow at the Alzheimer's Association International Conference® (AAIC®) 2022 in San Diego and online.
"Blood-based biomarkers for Alzheimer's are already improving the design of clinical trials, and they are very likely to revolutionize the diagnosis of Alzheimer's in the future," said Oskar Hansson, M.D., Ph.D., director of the Center for Neurodegenerative Diseases at Lund University and Skane University Hospital, Malmo, Sweden, and first author on the newly published article. "That said, the implementation of such markers in trials and practice must be done in a careful and controlled way so as not to accidentally cause more harm than good. Much more research is needed before widespread clinical use of BBMs."
According to the article, BBMs show "great promise" — especially markers for Alzheimer's-related brain changes related to nerve cell damage/death, and tau and beta amyloid accumulation — for "future use in both clinical practice and trials. However, few prospective studies have investigated the implementation of such BBMs in more heterogeneous populations."
Not ready for "prime time"
The workgroup points out that no studies have extensively evaluated BBMs for neurodegenerative diseases in primary care, and calls for "well-performed BBM studies in diverse primary care populations." Such studies should also evaluate the impact of BBMs on diagnostic accuracy and change in patient management.
In addition, use of BBMs for general population risk screening and as direct-to-consumer risk tests are not recommended.
The workgroup also says that BBMs should not yet be used as primary endpoints in pivotal treatment trials. However, this does not preclude the use of certain BBMs for decision making in clinical trials with adaptive design, where they could be used to inform decisions on continuing a trial or not.
Many current uses
There are current uses for Alzheimer's BBMs, according to the workgroup. For example, they "recommend use of BBMs as (pre-)screeners to identify individuals likely to have Alzheimer's pathological changes for inclusion in trials evaluating disease-modifying therapies, provided Alzheimer's status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing."
BBMs can be used as exploratory outcomes in most clinical trials in Alzheimer's and other neurodegenerative dementias. In non-Alzheimer's trials, BBMs can be used to identify patients who likely have Alzheimer's-related brain changes, if that is a condition of exclusion from the study.
"We also recommend cautiously starting use of BBMs in specialized memory clinics as part of the diagnostic work-up of patients already experiencing cognitive symptoms, as long as the results are confirmed whenever possible with CSF or PET, which are the current reference standards," said Charlotte E. Teunissen, M.D., Ph.D., head of the Neurochemistry Laboratory at Amsterdam University Medical Centers, the Netherlands and senior author on the article.
"The implementation of BBMs in primary care will likely take a much longer time because there are very few relevant and high-quality research studies on Alzheimer's-related BBMs conducted in this setting, but more prospective studies are expected to launch in the coming years," Teunissen added.
Establishing the path for BBMs in research
The appropriate use recommendations (AURs) provide specific guidance for current use of, and research needed on, the four most advanced types of Alzheimer's plasma biomarkers: plasma amyloid-beta 42/ amyloid-beta 40 (Aβ42/Aβ40), phospho-tau (p-tau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP), as well as potential combinations of markers. For example, the need for:
- Real-world studies on the robustness of plasma Aβ42/Aβ40 as a diagnostic test for cerebral Aβ pathology.
- Head-to-head studies comparing the performance of different forms of p-tau in different clinical contexts and across disease stages.
Most important and enlightening are the recommendations repeated by the authors throughout the AURs or those they say apply across the biomarkers, including:
- Perform prospective studies in primary care settings, including representative and diverse populations with cognitive symptoms. Evaluate the causes of false positives and negatives; the reference standard must be of high quality and preferably include CSF or PET.
- Study whether BBMs outperform what is already available today in primary care, and if they also improve diagnosis and management, including treatment decisions.
- [Gain] better understanding of biological and disease-associated variability and potential impact of medical comorbidities and concomitant medications.
- [Learn whether] certain BBM-based algorithms can be used alone to support an Alzheimer's diagnosis, or should they only be used as a gatekeeper to CSF/PET.
- Eventually (a) perform head-to-head comparisons of different plasma biomarker assays, and (b) establish the most optimal combinations of easily accessible biomarkers.
Defining the need
According to the workgroup, about 25-30% of patients with a clinical diagnosis of Alzheimer's dementia are misdiagnosed when assessed at specialized dementia clinics, and the accuracy of clinical diagnosis is similar or even lower for other dementias, including frontotemporal dementia, dementia with Lewy bodies and vascular dementia. In fact, in most countries, most patients with cognitive or behavioral symptoms are managed in primary care where the misdiagnosis is even higher. The problem is especially acute in the earliest stages of the disease.
"There is a great global need for accurate BBM-based diagnostic and prognostic algorithms that can substantially improve the accuracy of a diagnostic work-up of Alzheimer's, particularly in the early stages of the disease," said Reisa Sperling, M.D., professor of Neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital and Massachusetts General Hospital, and a co-author of the article.
The established CSF and PET measures have excellent diagnostic properties, but are less useful outside very specialized clinics due to limited accessibility, invasiveness (e.g., CSF measures require a lumbar puncture, and PET requires infusion of stable isotopes and exposure to radiation) and high costs. This precludes use of CSF and PET biomarkers in most primary and secondary care settings worldwide.
"A major benefit of the use of blood-based biomarkers is that the collection of blood is less invasive and likely less costly than CSF or neuroimaging markers, and more feasible for primary care practitioners," said Adam Boxer, M.D., Ph.D., Endowed Professor in Memory in Aging at the Weill Institute for Neurosciences, University of California, San Francisco and a co-author of the article. "This may enable earlier and more equitable referral of individuals to dementia specialists and participation in clinical trials of potential new therapies."
For full disclosures from all authors, please see the published article. https://alz-journals.onlinelibrary.wiley.com/journal/15525279
Coronavirus Jumped to Humans at Least Twice at Market in Wuhan, China
In a pair of related studies, published July 26, 2022 online via First Release in Science, researchers at University of California San Diego, with colleagues on four continents, show that the origin of the COVID-19 pandemic in 2019 was at the Huanan Seafood Wholesale Market in Wuhan, China, and resulted from at least two instances of the SARS-CoV-2 virus jumping from live animal hosts to humans working or shopping there.
The findings, first reported in February after the papers were posted online as preprints awaiting peer review, garnered international attention, primarily focusing on identifying the market as the early epicenter of the COVID-19 pandemic. The World Health Organization estimates that there have been more than 566 million confirmed cases of COVID-19 worldwide and 6.3 million deaths since the pandemic was declared in early 2020.
“It’s vital that we know as much about the origin of COVID-19 as possible because only by understanding how pandemics get started can we hope to prevent them in the future,” said Joel O. Wertheim, PhD, associate professor in the Division of Infectious Diseases and Global Public Health at UC San Diego School of Medicine, and a co-author on both papers.
But elemental to understanding pandemic origins is pinpointing not just where, but how, a pathogen successfully jumps from a non-human animal host to human, known as a zoonotic event.
“I think there’s been consensus that this virus did in fact come from the Huanan Market, but a strong case for multiple introductions hasn’t been made by anyone else yet,” said Wertheim, senior author of the study that posits the SARS-CoV-2 virus, which causes COVID-19, jumped from animals to humans at least twice and perhaps as many as two dozen times.
According to researchers, two evolutionary branches of the virus were present early in the pandemic, differentiated only by two differences in nucleotides — the basic building blocks of DNA and RNA.
Lineage B, which included samples from people who worked at and visited the market, became globally dominant. Lineage A spread within China, and included samples from people pinpointed only to the vicinity the market. If the viruses in lineage A evolved from those in lineage B, or vice versa, Wertheim said this would suggest SARS-CoV-2 jumped only once from animals to humans.
But work by Wertheim and collaborators found that the earliest SARS-CoV-2 genomes were inconsistent with a single zoonotic jump into humans. Rather, the first zoonotic transmission likely occurred with lineage B viruses in late-November 2019 while the introduction of lineage A into humans likely occurred within weeks of the first event. Both strains were present at the market simultaneously.
Researchers arrived at this conclusion by deciphering the evolutionary rate of viral genomes to deduce whether or not the two lineages diverged from a single common ancestor in humans. They used a technique called molecular clock analysis and an epidemic simulation tool called FAVITES, invented by Wertheim team member Niema Moshiri, PhD, an assistant professor of computer science at Jacobs School of Engineering at UC San Diego and study co-author.
“None of this could have been done without FAVITES,” said Wertheim.
Validation
In February 2022, researchers at the Chinese Center for Disease Control and Prevention published a long-delayed analysis of genetic traces of the earliest environmental samples collected at the market two years earlier.
The samples were obtained after the first reports of a new, mysterious illness and after the market had already been shut down. The Huanan Seafood Wholesale Market in Wuhan is a so-called “wet market” where live animals are often slaughtered and sold for human consumption, including in some cases, wildlife.
However, no live wild mammals were left at the market after it was shut down. Instead, Chinese researchers swabbed walls, floors and other surfaces, tested meat still in freezers, sampled sewers and caught mice and stray cats and dogs around the market.
Their findings confirmed the not-yet-published predictions of Wertheim’s team that Lineage A was also at the market.
“We felt validated, but what we felt more was immense pressure because they beat our preprint to the punch by about 12 hours, and we could only discuss their findings in light of ours,” Wertheim said. “We were also shocked that they had been sitting on evidence for lineage A at the market for over a year without realizing its importance.”
The newly published data, said study authors, are powerful evidence that the two viral lineages evolved separately and that multiple spillover events occurred. The Wuhan market reportedly contained a robust live wild animal business, with snakes, badgers, muskrats, birds and raccoon dogs (a canid indigenous to Asia) and other species sold for food. Wertheim said he believes there were likely many viral introductions. At least two successfully made the animal-human leap; other viral strains went extinct.
“While I'm hesitant to call it proof, what we presented is the most comprehensive explanation for the SARS-CoV-2 genomic diversity at the outset of the pandemic,” Wertheim said. “There are really no other good explanations for both of these strains being at the market except for multiple jumps into humans.”
(The findings undercut a circulating and persistent theory that the SARS-CoV-2 virus escaped from the Wuhan Institute of Virology, located a few miles from the market.)
Jonathan E. Pekar, a doctoral student in Bioinformatics and Systems Biology who co-led the project with Wertheim and is lead author, said the pandemic was likely looming for years, awaiting only for the opportunity when humans would come into contact with an animal host capable of transmitting the virus.
“Everything complicated happened before that introduction,” Pekar said. “The last step is just extended contact and transmission from hosts to humans. At that point, it would actually be unusual to only have one introduction. We've seen this before with MERS-CoV (a similar zoonotic virus). We’ve seen it with humans giving SARS-CoV-2 to minks on farms and then minks giving it back to humans.
“This has happened before, and it's going to keep happening. Nature is a better lab than humans will ever be.”
The latest study continues a series of published papers by Wertheim and colleagues investigating and chronicling the origin and spread of COVID-19.
In September 2020, they published data explaining how the first, few cases of novel coronavirus in North America and Europe quickly spread due to insufficient testing and contact tracing. In March 2021, Wertheim, Pekar and colleagues characterized the brief time-period during which SARS-CoV-2 could have circulated undetected before the first human cases in Wuhan.
Co-authors of “The molecular epidemiology of multiple zoonotic origins of SARS-CoV-2” include: Andrew Magee, Karthik Gangavarapu and Marc A. Suchard, all at UCLA; Edyth Parker, Nathaniel L. Matteson, Mark Zeller, Joshua I. Levy and Kristian G. Andersen, all at The Scripps Research Institute; Katherine Izhikevich, Jennifer L. Havens and Tetyana I.Vasylyeva, all at UC San Diego; Lorena Mariana Malpica Serrano and Michael Worobey, both at University of Arizona; Alexander Crits-Christoph, Johns Hopkins Bloomberg School of Public Health; Jade C. Wang and Scott Hughes, both at New York City Department of Health; Jungmin Lee, Heedo Park, Man-Seong Park, Korea University; Katherine Ching Zi Yan and Raymond Tzer Pin Lin, all at National Centre for Infectious Diseases, Singapore; Mohd Noor Mat Isa and Yusuf Muhammad Noor, both at Malaysia Genome and Vaccine Institute; Robert F. Garry, Tulane University; Edward C. Holmes, University of Sydney, Australia; and Andrew Rambaut, University of Edinburgh.
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