Breakthrough in Diagnosing Deadly Brain Disorder PSP – Neuroscience News

Summary: Researchers identified protein biomarkers in spinal fluid that can diagnose progressive supranuclear palsy (PSP) in living patients. Using high-throughput technology, they found a distinct protein pattern in PSP patients, offering hope for early diagnosis and targeted treatments.

This development could lead to a diagnostic test, crucial as PSP is often mistaken for Parkinson’s and progresses rapidly. Accurate early diagnosis is essential for effective treatment and improving patient outcomes.

Key Facts:

1. Protein Biomarkers Identified: Researchers discovered distinct protein patterns in PSP patients’ spinal fluid.
2. Early Diagnosis: This breakthrough offers hope for diagnosing PSP early, essential for effective treatment.
3. Rapid Progression: PSP progresses faster than Parkinson’s, with most patients dying within seven years of symptom onset.

Source: UCSF

Progressive supranuclear palsy (PSP), a mysterious and deadly neurological disorder, usually goes undiagnosed until after a patient dies and an autopsy is performed. But now, UC San Francisco researchers have found a way to identify the condition while patients are still alive.  
 
A study appearing in Neurology on July 3 has found a pattern in the spinal fluid of PSP patients, using a 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 stall the disease’s fatal trajectory.  

The disorder crossed the public’s radar 25 years ago, when Dudley Moore, the star of “10” and “Arthur,” shared his PSP diagnosis. It is frequently mistaken for Parkinson’s disease, but PSP develops faster, and patients do not respond to treatments for Parkinson’s. Most PSP patients die within about seven years after their symptoms have started. 
 
Diagnosis is key, because treatments work best early on  
 
PSP is believed 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 hallmark symptoms include poor balance with frequent backward falls and difficulties moving eyes up and down.  
 
“Unlike Alzheimer’s disease, there are no tau scans, blood tests or MRIs that provide a definitive diagnosis of 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 the Weill Institute for Neurosciences. 
 
“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,” he said.  
 
The inability to identify PSP has hampered the development of new treatments, according to co-senior author Adam Boxer, MD, PhD, endowed professor in memory and aging at the UCSF Department of Neurology, and director of the Alzheimer’s Disease and Frontotemporal Dementia Clinical Trials Program. 
 
 “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,” he said.  
 
The researchers measured the protein biomarkers using the high-throughput technology for protein analysis, which is based on molecules that bind to proteins with high selectivity and specificity.  
 
The study had 136 participants, with an average age of 70, and included patients from UCSF and other institutions with symptoms that are consistent with PSP, as well as autopsy-confirmed PSP cases. Scientists compared biomarkers from these cases to the living patients, as well as to healthy participants and to patients with other forms of FTD. 
 
The researchers found lower levels of most proteins in those with confirmed or suspected PSP, compared to the healthy participants in the study. The protein signature of the autopsy-confirmed PSP cases also differed from the autopsy-confirmed cases of other forms of FTD, as well as the living patients.  
 
All those with confirmed or suspected PSP had higher levels of proteins associated with neurodegeneration. The researchers also found some inflammatory proteins that correlated with disease severity and decreased proteins relevant to several critical brain cell functions that could be manipulated with 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 currently 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 lumbar puncture, can provide definitive diagnostic and prognostic results for PSP.” 
 
Funding: 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, Association for Frontotemporal Degeneration, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Association, AlzOut – Alzheimer’s Research, John Douglas French Alzheimer’s Foundation. 

About this PSP and neurology research news

Author: Suzanne Leigh
Source: UCSF
Contact: Suzanne Leigh – UCSF
Image: The image is credited to Neuroscience News

Original Research: Closed access.
“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 critical to enhance therapeutic development. We implemented unbiased DNA aptamer (SOMAmer) proteomics to identify novel CSF PSP biomarkers.

Methods

This is a cross-sectional study in original (18 clinically diagnosed PSP-Richardson syndrome [PSP-RS], 28 cognitively healthy controls]), validation (23 PSP-RS, 26 healthy controls), and neuropathology-confirmed (21 PSP, 52 non-PSP frontotemporal lobar degeneration) cohorts.

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 with the PSP Rating Scale (PSPRS). CSF proteomic data were analyzed to identify differentially expressed targets, implicated biological pathways using enrichment and weighted consensus gene coexpression analyses, diagnostic value of top 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%] women). 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 original, validation, and neuropathology-confirmed cohorts, with most of the SOMAmers showing reduced signal (83.1%, 95.1%, and 73.2%, respectively).

Three coexpression modules were associated with PSP across cohorts: (1) synaptic function/JAK-STAT (β = −0.044, corrected p = 0.002), (2) vesicle cytoskeletal trafficking (β = 0.039, p = 0.007), and (3) cytokine-cytokine receptor interaction (β = −0.032, p = 0.035) pathways. Axon guidance was the top dysregulated pathway in PSP in original (strength = 1.71, p p p 

A panel of axon guidance pathway proteins discriminated between PSP and controls in original (area under the curve [AUC] = 0.924), validation (AUC = 0.815), and neuropathology-confirmed (AUC = 0.932) cohorts. Two inflammatory proteins, galectin-10 and cytotoxic T lymphocyte-associated protein-4, correlated with PSPRS scores across cohorts.

Discussion

Axon guidance pathway proteins and several other molecular pathways are downregulated in PSP, compared with controls. Proteins in these pathways may be useful targets for biomarker or therapeutic development.