Levels of proteins tied to nerve cell function may help in PSP diagnosis
Goal is earlier diagnosis of condition that shares Parkinson's symptoms
Low levels in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — of proteins associated with nerve cell function may help in the early diagnosis of people with progressive supranuclear palsy (PSP), a form of atypical parkinsonism, according to a new study from scientists at the University of California, San Francisco (UCSF).
PSP is a group of disorders that share some Parkinson’s symptoms and, as such, is often mistaken for the disease, especially in the early stages. However, it develops faster and patients do not usually respond to Parkinson’s treatments.
The researchers suggest that determining the levels of these proteins in the CSF may be a useful biological marker, or biomarker, that may help not only in the diagnosis of PSP but also in the development of new treatments for the condition.
“This work aims to create a framework for using these newly identified proteins in future clinical trials,” Amy Wise, formerly a researcher at UCSF’s department of neurology and the Memory and Aging Center, and the study’s first author, said in a university news story. “We hope to reach a point where a single biomarker, or a panel of biomarkers from a blood test or lumbar puncture, can provide definitive diagnostic and prognostic results for PSP.”
The study, “CSF Proteomics in Patients With Progressive Supranuclear Palsy,” was published in Neurology.
No current tests provide a definitive PSP diagnosis for patients
PSP is thought to result from the abnormal buildup of tau proteins within nerve cells, ultimately leading to their progressive degeneration and death. The condition is a form of frontotemporal dementia, known as FTD, which impacts cognitive abilities, motor functions, and behavior. Its hallmark symptoms include balance issues, frequent backward falls, and abnormal eye movements.
To date, however, “there are no tau scans, blood tests or MRIs that provide a definitive diagnosis of PSP,” said Julio Rojas, MD, PhD, an associate professor of neurology and the co-senior author of the study.
“For many patients the disease goes unnoticed,” Rojas said.
In fact, confirmation of the disease now typically relies on autopsy findings to definitively diagnose the condition.
There are no tau [protein] scans, blood tests or MRIs that provide a definitive diagnosis of PSP. … For many patients the disease goes unnoticed.
According to Adam Boxer, MD, PhD, a professor of memory and aging and the study’s co-senior author, the difficulty of obtaining a PSP diagnosis has delayed the development of new treatments for the disease.
Now, the team of researchers used new technology to identify CSF biomarkers for PSP. The tech is based on molecules that bind to proteins with high selectivity and specificity, which can measure thousands of proteins in a single drop of fluid.
A total of 136 patients, with a median age of 70.6 years, were involved in the study. Included were participants with symptoms consistent with the disease as well as autopsy-confirmed PSP cases. The proteins identified in these patients were compared with those in healthy participants and patients with other forms of FTD.
The researchers divided patients into three groups: an initial analysis group, comprised of 18 living patients with a clinical PSP diagnosis and 28 cognitively healthy controls; the validation group, with 23 PSP patients and 26 healthy controls; and the autopsy-confirmed cases group, composed of 21 with PSP and 52 with non-PSP frontotemporal degeneration.
Panel of proteins found to discriminate between PSP and Parkinson’s
Most identified proteins were found at lower levels in individuals with confirmed or suspected PSP when compared with healthy individuals. Moreover, the protein signature observed in autopsy-confirmed PSP cases was distinct from that found in autopsy-confirmed cases of other forms of FTD and that seen in living patients.
Specifically, proteins associated with axon guidance — a critical process in which nerve cells extend cell projections called axons to form precise connections within the nervous system — exhibited the most substantial alterations in patients with PSP.
A panel of such proteins was able to discriminate between PSP and controls in all three patient groups.
“Proteins in these pathways may be useful targets for biomarker or therapeutic development,” the researchers wrote.
Participants with confirmed or suspected PSP also had higher levels of proteins associated with nerve cell degeneration, the data showed. The researchers found that two inflammatory proteins — galectin-10 and cytotoxic T lymphocyte-associated protein-4 — correlated with disease severity, as assessed by the PSP Rating Scale.
“Previous research has underscored the value of several non-specific neurodegeneration biomarkers in PSP, but they have had limited sensitivity and specificity for diagnosis, particularly at this critical early disease stage,” Boxer said.
Rojas and the other researchers noted that the ultimate goal is to improve treatment for people with PSP.
“When new medications are approved for PSP, the best chance for patients will be receiving treatment at the earliest phase of the disease when it is most likely to be effective,” Rojas said.
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