New biomarker in cerebrospinal fluid helps distinguish corticobasal degeneration (CBD) from similar neurological disorders, enroll patients in CBD-specific clinical trials, and identify targeted treatments for the disorder There is a possibility.
Researchers at Washington University School of Medicine in St. Louis have identified a novel cerebrospinal fluid (CSF) biomarker that may distinguish corticobasal degeneration (CBD) and similar neurological disorders with 80-89% accuracy .
24 November 2022, natural medicine.
For over a decade, biomarkers have become available to facilitate the diagnosis of Alzheimer’s disease (AD). This includes an expanding range of PET neuroimaging scans, CSF assays, and more recently blood-based biomarker tests. These biomarkers are also essential for the development of new therapeutics such as aducanumab, lecanemab, and many other drugs in various stages of the development pipeline.
However, in the case of primary tauopathies (diseases in which tau protein deposition is believed to be a major factor underlying the neurodegenerative process), accurate biologics for diagnosis, staging, research, and drug development are needed. Identifying the markers has proven to be much more difficult.
These diseases such as CBD, progressive supranuclear palsy (PSP), Pick’s disease, globular glial tauopathy (GGT), senescence-associated tauastrogliopathy (ARTAG), argyrophilic grain disease (AGD), etc. are associated with Alzheimer’s disease. less common than disease.
Estimates vary, but some studies report about 3-5 new cases of PSP and CBD per 100,000 people. Combined Diagnosed annually. CBD and PSP are the most common in the so-called “quadruple repeat tauopathy” (4RT) category due to the appearance of 4-repeat tau aggregates in these diseases. (There are also triplicate tauopathies, the most common being Pick’s disease.)
Primary tauopathies present with a wide variety of clinical manifestations, often overlapping with each other and with other neurological disorders such as Parkinson’s disease and Alzheimer’s disease.
A study published about 10 years ago found that Neurological AnnalsThe research team, led by Suzee Lee, MD, associate professor of neurology at the University of California, San Francisco and director of the Dementia Imaging Genetics Institute, found that behavioral or cognitive symptoms were the first symptom in 15 of 18 patients. I discovered something. Movement disorders were present at his onset in only 4 of her 18 patients, others developed years after the onset of cognitive or behavioral symptoms.
Georges Naasan, MD, Associate Professor of Neurology, Medical Director of the Department of Behavioral Neurology and Neuropsychiatry, and Co-Medical Director of the Barbara and Maurice Dean Center, said: Studied wellness and cognitive health at Icahn School of Medicine, Mount Sinai, New York. “This is very complicated in the sense that the underlying pathology does not necessarily correlate with clinical symptoms.”
Historically, as was the case with AD, an autopsy has been the only way to know which primary tauopathy a person has. And diagnostic accuracy for CBD has proven particularly difficult. April 29, 2022, Research JAMA network openThe magnetic resonance parkinsonism index was used to diagnose 4RT.
“Patients come in with stiffness, balance problems, slurred speech, memory problems. It could be CBD, but it could also be PSP, Alzheimer’s disease, or something else.” Co-lead author and assistant professor Chihiro Sato, Ph.D. He holds a PhD in Neurology from the University of Washington. “Because biomarkers can reliably identify people with CBD, they can be used to enroll people in clinical trials and, in the future, may be the key to initiating treatment.”
“This is a major breakthrough and will be very exciting if it is confirmed by other researchers in autopsy-confirmed cases,” said Tasch Endowed Professor of Neurology and director of the Center for Parkinson’s and Other Movement Disorders. said Irene Litvan, MD, FAAN. She received an award for excellence from the University of California, San Diego.
“To date, there have been few small-scale studies on CBD, but this will open the door to new research. It is clear that CBD and PSP are different diseases, but we do know that the fibrils are different. But it’s great to think that we can distinguish between them and not get confused or misdiagnosed as we used to.”
The University of Washington team used a highly sensitive mass spectrometry-based technique developed in 2020 by lead author Dr. Kanta Horie to detect specific fragments of tau in CSF. of tau in AD patients.
A new study looked at brain tissue and antemortem CSF from people who died of dementia and movement disorders and had autopsy-confirmed disease. The study population included any of the five major tauopathies: CBD, PSP, AGD, frontotemporal lobar degeneration with microtubule-associated protein tau mutations (FTLD-MAPT), Pick’s disease, Alzheimer’s disease and other neurodegenerative diseases. A total of 59 people with Diseases in which tau is not the predominant pathology.
For comparison, we also examined a sample of three controls who had not been diagnosed with dementia or other neurodegenerative diseases.
The researchers found that two specific fragments containing the microtubule-binding domain (MTBR) of tau, MTBR-tau 275 and MTBR-tau 282, were present in abnormally high concentrations in the brains of CBD patients and a subset of patients. , found to be present at low concentrations in CSF. in FTLD-MAPT.
“In the brain, we found an approximately five-fold increase in the ratio of MTBR-tau 275 and 282 to total tau in people with CBD compared to most other tauopathies and normal controls. FTLD-MAPT was three times higher,” said Alexander Pantelyat, M.D., Ph.D., assistant professor of neurology and director of the Center for Atypical Parkinsonism at Johns Hopkins University School of Medicine.
On the other hand, the CSF of patients with autopsy-confirmed CBD found the opposite of brain findings. MTBR-tau 275 and 282 were decreased. People who had CBD, FTLD-MAPT, or AD had about 20% fewer of both MTBR fragments in their CSF than people with other tauopathies or controls, and as these fragments accumulate in the brain Among the 54 participants for whom brain and CSF samples were available, the latter MTBR-275 and MTBR-282 levels were inversely related to brain levels. I was.
“This is consistent with many previous studies finding expected levels of tau deposition in the brain that are often inconsistent with elevated levels of CSF, although to varying degrees depending on the stage of the disease.” Dr. Pantelyat said.
said Hugo Botha, MBChB, assistant professor of neurology at the Mayo Clinic in Rochester, Minnesota and assistant professor of neurology at the Mayo Clinic College of Medicine and Science.
Dr. Botha suggested that biomarkers can help with more than diagnosing CBD. “For example, if a patient had an increase in his MTBR-tau 275 and 282 in the brain and intermediate levels in the CSF, it may be more suggestive of another type of tauopathy, such as PSP or AGD.” he said. “This will be a valuable test for CBD, but it may also help distinguish other tauopathies from each other.”
While there are multiple trials of potential treatments for PSP patients, no such trials have yet been conducted for CBD, Dr. Litvan said. If we had the exact biomarkers to distinguish, that could change relatively quickly.
“The hypothesis is that the normal tau protein changes its composition, forming abnormal proteins that alter its function, causing cells to communicate with each other and thus spread disease in an almost prion-like manner.” In , we reported trial results for tirabonumab. [ABBV-8E12], a monoclonal antibody that binds to the human tau N-terminus of PSP. Apparently it was the wrong destination. The microtubule binding domain appears to be more involved in disease pathogenesis. Therefore, it is exciting to think that new antibodies are now being developed that target that region, and that studies of these agents may be conducted in patients with clearly identified CBD. ”
She added: “While we cannot immediately confirm these findings, we hope that they will soon, but this allows us to use existing diagnostic criteria for CBD with this biomarker.” This opens up the possibility of more accurately diagnosing and hospitalizing patients, not only for treatment, but also for environmental research.”
Dr. Naasan agrees. “Looking at the world of Alzheimer’s disease, it was when we had a really good biomarker that drugs designed for Alzheimer’s started targeting this protein. Our study relied almost entirely on clinical manifestations: all memory impairment and dementia were lumped together as Alzheimer’s disease, diluting the effects of any treatment we were trying to test. Until we had defined biomarkers, we could not truly enroll AD patients alone and conduct drug trials to track their success.
“Now with CBD, we are where we were with AD in the 1990s. We can design studies that
The group’s next steps include further work to increase the sensitivity and specificity of the assay, Dr. Sato said. “If this assay could be applied to blood biomarkers, that would be helpful, but the amount of this fragment is already very low compared to phosphorylated tau in the CSF, and even less in the blood, so that’s why we don’t want to do it.” It’s very difficult,” she said.
Dr. Pantelyat also suggested that it might be of value to assess the levels of CSF tau fractions in living patients with primary tauopathies, particularly 4RT. “Previous studies involving AD have confirmed that CSF tau levels have a curve, and that levels may rise during certain stages of the disease, but then plateau or even decline. Where a patient is in the disease course appears to have a significant impact on tau levels in the CSF, so this should be considered in all studies of tau in living patients.”
Dr. Sato (and some co-authors) may earn income based on technology licensed from the University of Washington to C2N Diagnostics, a method for detecting MTBR tau isoforms. Dr. Pantelyat is a member of the Scientific Advisory Board and has served as a consultant to MedRhythms, Inc. Dr. Litvan has made no disclosures..