Summary: Researchers have identified protein biomarkers in cerebrospinal fluid that can diagnose progressive supranuclear palsy (PSP) in living patients. Using high-throughput technology, they discovered a distinct protein pattern in PSP patients, offering hope for early diagnosis and targeted treatments.
This advance could lead to a diagnostic test, which is crucial because PSP is often mistaken for Parkinson’s disease and progresses rapidly. Early, accurate diagnosis is essential for effective treatment and improving patient outcomes.
Highlights:
- Protein biomarkers identified: Researchers discovered distinct protein patterns in the cerebrospinal fluid of PSP patients.
- Early diagnosis: This advance offers hope for early diagnosis of PSP, essential for effective treatment.
- Rapid progression: PSP progresses more rapidly than Parkinson’s disease, with most patients dying within seven years of symptom onset.
Source: University of California, San Francisco
Progressive supranuclear palsy (PSP), a mysterious and deadly neurological disorder, is usually diagnosed only after the patient dies and an autopsy is performed. But now, researchers at the University of California, San Francisco, have found a way to identify the condition while patients are still alive.
A study published in Neurology On July 3, a team of researchers discovered a pattern in the cerebrospinal fluid of PSP patients, using new high-throughput technology that can measure thousands of proteins in a tiny drop of fluid.
Researchers hope the protein biomarkers will lead to the development of a diagnostic test and targeted therapies to slow the disease’s deadly trajectory.
The disease first hit the mainstream 25 years ago when Dudley Moore, the star of “10” and “Arthur,” announced his diagnosis with PSP. It’s often confused with Parkinson’s disease, but PSP develops more quickly and patients don’t respond to Parkinson’s treatments. Most PSP patients die about seven years after their symptoms start.
Diagnosis is essential, because treatments work best early on
PSP is thought to be triggered by a buildup of tau proteins that causes cells to weaken and die. It is a type of frontotemporal dementia (FTD) that affects cognition, movement, and behavior. Its characteristic symptoms include poor balance with frequent falls backward and difficulty moving the eyes up and down.
“Unlike Alzheimer’s disease, there is no tau scan, blood test or MRI that can definitively diagnose PSP. For many patients, the disease goes unnoticed,” said co-senior author Julio Rojas, MD, PhD, of the UCSF Department of Neurology, Memory and Aging Center and Weill Institute for Neurosciences.
“When new drugs are approved for PSP, the best chance for patients will be to receive treatment at the earliest stage of the disease, when it is most likely to be effective,” he said.
The inability to identify PSP has hampered the development of new treatments, according to co-senior author Adam Boxer, MD, PhD, professor of memory and aging in the UCSF Department of Neurology and director of the Alzheimer’s Disease and Frontotemporal Dementia Clinical Trials Program.
“Previous research has highlighted the value of several nonspecific neurodegeneration biomarkers in PSP, but they have had limited sensitivity and specificity for diagnosis, particularly at this critical early stage of the disease,” he said.
The researchers measured the protein biomarkers using high-throughput protein analysis technology, based on molecules that bind to proteins with high selectivity and specificity.
The study involved 136 participants, with an average age of 70, and included patients from UCSF and other institutions with symptoms consistent with PSP, as well as autopsy-confirmed cases of PSP. The scientists compared biomarkers from these cases to those from living patients, as well as to those from healthy participants and patients with other forms of FTD.
The researchers found lower levels of most proteins in people with confirmed or suspected PSP, compared with healthy study participants. The protein signature of autopsy-confirmed PSP cases also differed from those of autopsy-confirmed cases of other forms of FTD, as well as from living patients.
All patients with confirmed or suspected PSP had higher levels of proteins associated with neurodegeneration. The researchers also found certain inflammatory proteins correlated with disease severity and decreased proteins related to several critical brain cell functions that could be manipulated by future therapies.
“This work aims to create a framework for using these newly identified proteins in future clinical trials,” said first author Amy Wise, formerly of the UCSF Department of Neurology and the Memory and Aging Center, and now a medical student at UC Davis. “We hope to reach a point where a single biomarker, or a panel of biomarkers from a blood test or spinal tap, can provide definitive diagnostic and prognostic results for PSP.”
Funding: Part Number: NIH/NIA R01AG038791, U19AG063911, NIH/NIA K23AG59888, NIH R01AG078457, U19AG063911, R01AG073482, R56AG075744, R01AG038791, RF1AG077557, R01AG071756, U01AG045390, P01AG019724, P30AG062422, NINDS/NIH K08NS105916, NIH/NIA K23AG059891, NIH/NINDS U01NS102035, NIH/NIA R01AG038791, NIH K23AG073514.
Rainwater Charitable Foundation, GHR Foundation, Bluefield Project to Cure FTD, Gates Ventures, Frontotemporal Degeneration Association, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Association, AlzOut – Alzheimer’s Research, John Douglas French Alzheimer’s Foundation.
About this news on PSP and neurology research
Author: Suzanne Leigh
Source: University of California, San Francisco
Contact: Suzanne Leigh – UCSF
Picture: Image credited to Neuroscience News
Original research: Access closed.
“CSF proteomics in patients with progressive supranuclear palsy” by Julio Rojas et al. Neurology
Abstract
CSF proteomics in patients with progressive supranuclear palsy
Background and objectives
Identification of fluid biomarkers for progressive supranuclear palsy (PSP) is essential to improve therapeutic development. We implemented unbiased DNA aptamer (SOMAmer) proteomics to identify novel PSP biomarkers in CSF.
Methods
This is a cross-sectional study involving original cohorts (18 clinically diagnosed PSP-Richardson syndrome (PSP-RS), 28 cognitively healthy controls), validation (23 PSP-RS, 26 healthy controls) and neuropathologically confirmed (21 PSP, 52 non-PSP frontotemporal lobar degeneration).
Participants were recruited through the University of California, San Francisco and the 4-Repeat Neuroimaging Initiative. The original and neuropathology cohorts were analyzed with the SomaScan platform version 3.0 (5026-plex) and the validation cohort with version 4.1 (7595-plex).
Clinical severity was measured using the PSP Rating Scale (PSPRS). CSF proteomic data were analyzed to identify differentially expressed targets, biological pathways involved using enrichment and weighted consensus analyses of coexpression genes, diagnostic value of key targets with receiver operating characteristic curves, and associations with disease severity with linear regressions.
Results
A total of 136 participants were included (median age 70.6 ± 8 years, 68 (50%) female). One hundred fifty-five of 5,026 (3.1%), 959 of 7,595 (12.6%), and 321 of 5,026 (6.3%) SOMAmers were differentially expressed in PSP compared with controls in the original, validation, and neuropathology-confirmed cohorts, with most SOMAmers showing reduced signal (83.1%, 95.1%, and 73.2%, respectively).
Three coexpression modules were associated with PSP in the cohorts: (1) synaptic function/JAK-STAT (β = −0.044, corrected p = 0.002), (2) cytoskeletal trafficking of vesicles (β = 0.039, p = 0.007) and (3) cytokine-cytokine receptor interaction (β = −0.032, p = 0.035). Axon guidance was the most dysregulated pathway in PSP in the original (strength = 1.71, p < 0.001), validation (strength = 0.84, p < 0.001) and confirmed by neuropathology (strength = 0.78, p < 0.001) cohorts.
A panel of axon guidance pathway proteins distinguished PSPs from controls in the original (area under the curve (AUC) = 0.924), validation (AUC = 0.815), and neuropathologically confirmed (AUC = 0.932) cohorts. Two inflammatory proteins, galectin-10 and cytotoxic T-lymphocyte-associated protein-4, were correlated with PSPRS scores in all cohorts.
Discussion
Axon guidance pathway proteins and several other molecular pathways are downregulated in PSP compared to controls. Proteins in these pathways may be useful targets for biomarker or therapeutic development.