Measuring levels of toxic protein in blood may help diagnose ALS
US scientists say potential biomarker may speed what's now a lengthy process
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- A team of U.S. scientists has identified a potential blood-based biomarker that may help diagnose ALS.
- Measuring toxic TDP-43 protein levels in the blood was shown to accurately distinguish people with ALS from healthy controls.
- Most patients now wait more than a year for their ALS diagnosis to be confirmed.
Measuring blood levels of toxic TDP-43 protein in astrocyte-derived extracellular vesicles — packets of cellular material released from star-shaped brain support cells called astrocytes — may help diagnose amyotrophic lateral sclerosis (ALS), according to a new study from U.S. researchers.
Tests showed that differences in TDP-43 levels inside these extracellular vesicles accurately distinguished ALS patients from healthy individuals, the scientists noted.
“These findings support [this measure’s] potential as a biomarker candidate for ALS and for patient stratification in TDP-43-targeted clinical trials,” the team wrote, noting that such diagnostic biomarkers, “used to identify or confirm a disease or its subtypes, offer a critical opportunity to improve detection” and guide patient participation in clinical testing for potential treatments.
The study, “Astrocyte-derived extracellular vesicle phosphorylated TDP-43 as a blood-based biomarker for amyotrophic lateral sclerosis,” was published in the journal Neurobiology of Disease.
In ALS, the specialized nerve cells that control muscle movement, called motor neurons, are progressively lost, leading to muscle weakness that affects movement, speaking, and breathing. A hallmark of the disease is the buildup of toxic clumps of the TDP-43 protein, which damage motor neurons and contribute to disease progression.
ALS diagnosis typically takes 1 year, 3 doctor visits
Because its early symptoms overlap with those of other conditions, ALS is often difficult to diagnose. As a result, patients visit an average of three physicians and often wait more than one year before ALS is confirmed.
Such delays underscore “the urgent need for cost-effective, minimally invasive diagnostic biomarkers to reduce patient distress, enhance care, and expedite access to supportive therapies and clinical trials,” the researchers noted.
Aiming to accelerate that timeline, a team led by researchers at the Mailman School of Public Health at Columbia University in New York focused on a new biomarker that could be measured from a blood draw.
Specifically, the team examined astrocyte-derived extracellular vesicles (ADEVs), tiny membrane-bound particles released by astrocytes, a type of support cell in the brain and spinal cord. Because these vesicles can cross into the bloodstream and carry molecular material from the nervous system, they may offer a way to detect brain-related disease processes through simple blood tests, the scientists noted.
The researchers examined samples of whole blood and blood plasma, the liquid portion of blood without the cells, collected from both ALS patients and healthy individuals, who served as controls. The controls were matched by sex and age.
The team measured two forms of TDP-43 in these vesicles: total TDP-43 and its toxic form, pTDP-43. To account for natural differences in how many vesicles were detected from each sample, protein levels were adjusted using a ratio to CD81, a marker commonly found on the surface of extracellular vesicles.
Potential biomarker showed overall accuracy of 89%
After adjusting for age and sex, each one standard-deviation increase (a measure of variation) in the pTDP-43/CD81 ratio in whole blood was associated with 9.5 times higher odds of being an ALS case. The odds were 19.2 times higher in plasma. Raw pTDP-43 levels, without CD81 adjustments, were also elevated in ALS cases compared with healthy controls in both sample types.
In contrast, raw TDP-43 levels performed less consistently as a marker, and in plasma were actually associated with a 66% decrease in the odds of ALS per one standard deviation increase. The authors note this highlights the importance of adjusting measurements by vesicle quantity.
The plasma pTDP-43/CD81 ratio was the biomarker that best predicted ALS cases, with an overall accuracy of 89%, according to the researchers.
[This potential] biomarker …. may facilitate the timely identification of ALS.
The team also examined whether biomarker levels related to disease severity, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). After adjusting for age and sex, each one standard-deviation increase in plasma pTDP-43/CD81 ratio was associated with a 3.19-point higher ALSFRS-R score, indicating more severe functional impairment. By contrast, raw TDP-43 and pTDP-43 showed no association with disease severity.
The scientists noted that this study was not designed to assess disease progression. Therefore, this observation warrants further studies to determine whether pTDP-43/CD81 tracks changes in disease severity over time.
In ALS, the researchers noted, “diagnostic delay [is] a persistent challenge in … clinical management that can delay care and adversely impact prognosis.” The team said this study identified a possible measure that may aid in disease diagnosis.
“TDP-43-based ADEV biomarkers represent promising, minimally invasive, and potentially scalable biomarker candidates that may facilitate the timely identification of ALS, improve patient stratification, and support evaluation in TDP-43-targeted clinical trials,” the researchers concluded.
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