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A biomarker test that identifies abnormal protein fragments called cryptic peptides may help detect <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and frontotemporal dementia (FTD) in the early stages, a study found.
Cryptic peptides from the HDGFL2 protein were elevated in fluid samples from people with ALS/FTD, including in those who had disease-causing mutations but no evident symptoms, according to the study, &#8220;<a href="https://www.nature.com/articles/s41591-023-02788-5">A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD</a>,&#8221; published in Nature Medicine.
&#8220;We believe we’ve discovered a biomarker that could potentially be used to detect ALS and FTD in their earliest stages — even before symptoms appear,&#8221; Philip Wong, PhD, professor at Johns Hopkins University School of Medicine and the study&#8217;s senior author, said in a <a href="https://www.hopkinsmedicine.org/news/newsroom/news-releases/2024/03/johns-hopkins-medicine-led-team-develops-fluid-biomarker-for-early-detection-of-degenerative-diseases-als-and-ftd">university press release</a>.
The team is collecting samples from ALS and FTD patients around the world to continue evaluating their approach and moving it toward the clinic.
“We hope to support the effectiveness, reliability, and sensitivity of our biomarker by testing it on thousands of patient samples, and once validated, encourage its use as a clinical tool,” said the study&#8217;s first author, Katie Irwin, a graduate student at Johns Hopkins.
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<h3>Protein accumulates where it shouldn&#8217;t</h3>
Toxic accumulation of the TDP-43 protein is evident in most ALS cases and is believed to contribute to nerve cell damage. While the protein is usually found in the cell&#8217;s nucleus, the core where DNA is contained, TDP-43 aberrantly clumps outside the nucleus in ALS and FTD.
TDP-43’s usual role is to help in the proper formation of messenger RNA (mRNA), a genetic template produced when the information in DNA is being used to make a protein.
When the protein wrongly accumulates where it shouldn’t, this process becomes corrupted. Some mRNA templates will contain problematic sequences called cryptic exons, which affect the production of proteins important for brain health.
Because the presence of these cryptic sequences in some proteins reflects TDP-43 dysfunction, the researchers had the idea that protein fragments (peptides) containing them could be possible biomarkers of the early stages of ALS or FTD.
Prior to this study, TDP-43 pathology could only be seen during a postmortem tissue analysis, so it wasn&#8217;t known to what degree these types of abnormalities might be seen early on.
[quote=”center”]Pathogenic mechanisms often begin years before the emergence of clinically relevant symptoms.[/quote]
The team sought to develop antibodies that could bind to cryptic sequences in a blood or spinal fluid sample and be visualized in the lab. They decided to focus on the one protein that seemed the most reliable: HDGFL2.
“Of all the cryptic peptides for which we made &#8230; antibodies, the one that worked best was the one designed for the cryptic HDGFL2 protein,” Irwin said. “We used that &#8230; antibody to develop an extremely sensitive detection test for the cryptic HDGFL2 protein in body fluids.”
The researchers evaluated their approach by measuring levels of cryptic HDGLF2 in cerebrospinal fluid (CSF) — the fluid surrounding the brain and spinal cord — and blood samples from people with <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a>/FTD caused by mutations in the C9orf72 gene, <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a>/FTD without any known mutations, and presymptomatic patients with mutations in C9orf72.
Cryptic HDGLF2 was detectable across all patient groups in both types of bodily fluids, including in those who did not yet have any symptoms of the disease. Samples from all ALS/FTD patients had higher levels of the cryptic peptide than samples from healthy people or people with other brain diseases.
“Our test found cryptic HDGFL2 in the presymptomatic stages of patients who were genetically predisposed to ALS and FTD, and were expected to go on to develop the diseases, giving the method credibility as a potential preclinical biomarker for predicting risk of ALS and FTD,” Irwin said.
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<h3>Disease drivers may appear years before symptoms</h3>
Based on their findings, the researchers believe that cryptic HDGFL2 levels might peak before symptom onset and then decrease as the disease progresses.
The study highlights a &#8220;common theme of neurodegenerative diseases — that pathogenic [disease-driving] mechanisms often begin years before the emergence of clinically relevant symptoms,&#8221; the researchers said.
When compared with neurofilament light chain (NfL), an established biomarker across multiple neurodegenerative diseases that reflects the degree of nerve damage, increases in HDGFL2 followed a similar trajectory, but appeared to rise earlier than NfL levels.
The scientists believe the two markers could be used together to help understand the trajectory from presymptomatic to symptomatic disease, noting that more extensive and long-term studies are need to clarify those dynamics.
Such knowledge could guide clinical trial enrollment, helping patients access therapies sooner, &#8220;at a time when it might truly make a difference,&#8221; said Wong.
Irwin said the team will explore whether the biomarker test can be used to determine the effectiveness of therapies &#8220;by looking for reductions in cryptic HDGFL2 levels — and restoration of TDP-43 function — after treatment.”

Cryptic protein fragments may detect ALS in early stages: Study

A test that assesses the electrical activity associated with blinking may help speed the <a href="https://alsnewstoday.com/als-diagnosis/">diagnosis</a> of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and monitor disease progression in people with the condition, a study found.
Findings showed that certain electrical waves can significantly distinguish people with ALS from healthy controls or people with diseases affecting the nerves outside the brain and spinal cord.
Also, among those with the disease, the timing of these waves was associated significantly with their disability status and <a href="https://alsnewstoday.com/forms-of-als/#Clinical_onset">ALS clinical subtype</a>, which can meaningfully affect prognosis.
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“[Blink reflex] might help with earlier interventions in order to maintain a better functional status in ALS patients,” the researchers wrote in the study, “<a href="https://www.mdpi.com/2076-3425/13/10/1384">Blink Reflex Examination in Patients with Amyotrophic Lateral Sclerosis Compared to Diseases Affecting the Peripheral Nervous System and Healthy Controls</a>,” published in the journal <a href="https://www.mdpi.com/journal/brainsci">Brain Sciences</a>.
<a href="https://alsnewstoday.com/causes-of-als/">ALS is caused</a> by the progressive dysfunction of motor neurons, the nerve cells that control voluntary movements. This renders the brain unable to control muscles, and patients progressively lose their ability to perform everyday tasks.
Diagnosing the disease in its early stages is critical to ensure patients receive timely treatments before significant disability sets in. <a href="https://alsnewstoday.com/als-treatment/">Current ALS therapies</a> can slow the progression of the disease, but they cannot reverse damage that has already occurred.
But because <a href="https://alsnewstoday.com/als-symptoms/">ALS symptoms</a> can overlap with a number of other neurological conditions, it often takes <a href="https://www.sciencedirect.com/science/article/pii/S0022510X20303919">several months</a> before patients receive a formal diagnosis and begin appropriate treatments.
<h3>How the blink reflex test works</h3>
The blink reflex test is a simple, noninvasive, and inexpensive test that can detect alterations in the brainstem, an area at the base of the brain that connects to the spinal cord. The test measures the electrical activity of facial nerves involved in blinking after being stimulated, but it&#8217;s unknown if it could serve as an easy-to-use diagnostic tool in ALS.
To find out, researchers in Hungary examined blink reflex parameters in 29 people with ALS, 50 healthy controls, and 61 people with other diseases affecting the peripheral nervous system — the nerves that branch out from the brain and spinal cord and into all body parts.
The test is based on an electric stimulus applied to the supraorbital nerve (a facial nerve located above the eye) and responses are obtained from electrodes placed over the muscle that closes the eyelid, namely in the lower lid.
Generally, patients experience an initial, rapid blink reflex on the side where the stimulus was applied, whose corresponding electrical signal is called R1. This is followed by a more sustained and prolonged closure of both eyelids, measured as R2 waves. There are two R2 waves: one on the stimulated side, called the ipsilateral R2 or R2i, and one on the opposite side, called contralateral R2 or R2c.
<h3>Different latencies for different waves</h3>
Results showed that the timing of the R1 wave, called latency, was similar for ALS patients and healthy controls, but patients had longer latencies of both R2i and R2c, indicating they took longer to close both eyelids after the stimulus.
There were six patients for whom no R2c wave was recorded, suggesting the  blinking response did not occur. This supports the loss of neuronal connectivity in ALS, according to the researchers.
The latencies of these R-waves also were different between ALS patients and people with diseases of the peripheral nervous system. A particular difference was the normal R1 wave in ALS patients, which was altered in at least one eye in people with all other examined conditions.
“The pathological latencies were increased and showed a pattern that could be well distinguished from the &#8216;ALS pattern,&#8217;” the researchers wrote.
Results also showed notable differences in R-wave latencies in ALS patients whose symptoms first began the muscles around the face and throat — called <a href="https://alsnewstoday.com/symptoms-of-als/">bulbar-onset disease</a> — from those with spinal-onset ALS, where symptoms of muscle weakness are first evident in the arms and legs.
More precisely, the latencies of R1, R2i, and R2c were all higher in people with bulbar-onset ALS, which typically have a faster disease progression and worse prognosis, than in those with spinal-onset.
Consistently, higher latencies in all three waves were associated with a more severe functional disability, as measured by the ALS Functional Rating Scale—Revised (ALSFRS-R), regardless of clinical onset.
<h3>Promising tool to diagnose, monitor disease progression</h3>
The findings point to the blink reflex as a promising tool to diagnose and monitor disease progression in people with ALS, according to the researchers.
“[Blink reflex] examination might be a promising tool to monitor the course of the disease and to serve as a biomarker in patients with ALS, due to its correlation with ALSFRS-R score,” the researchers wrote.
However, its use as a prognosis ALS biomarker should be assessed in more studies, including in larger samples of ALS patients who would be followed for longer periods.

Blink reflex test may be biomarker to diagnose, monitor ALS: Study

Elevated blood levels of the Cystatin C protein are significantly associated with faster disease progression and shorter survival in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to a study in China.
The protein may serve as a biomarker to predict disease outcomes in people with ALS and identify those who need more invasive strategies earlier in the disease course, the findings suggest.
Cystatin C “has the potential to be a widely used and reproducible biomarker for monitoring disease progression in ALS,” the researchers wrote in “<a href="https://link.springer.com/article/10.1007/s10072-023-06957-9">Serum Cystatin C is a potential biomarker for predicting amyotrophic lateral sclerosis survival</a>,” which was published in <a href="https://www.springer.com/journal/10072">Neurological Sciences</a>.
ALS is caused by the damage and death of motor neurons, the nerve cells that control voluntary movements. This causes a loss of control of muscle movements, and patients progressively become less able to go about their daily lives without assistance.
About 90% of cases are <a href="https://alsnewstoday.com/sporadic-als/">sporadic</a>, meaning they occur spontaneously. The remaining 10%, which run in families, are called <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a>. Although many studies have focused on the genetic causes of familial ALS, less is known about the mechanisms leading to sporadic ALS.
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<h3>Connecting Cystatin C levels to disease progression, survival</h3>
Cystatin C is a small protein used to monitor kidney problems and has also been associated with disease severity in ALS. Yet, studies examining the link between Cystatin C and ALS survival and progression have yielded conflicting results, leading researchers in China to assess the potential biomarker&#8217;s levels in 356 patients with sporadic ALS at their hospital between 2016-2019 to shed more light on this association.
Most participants (57%) were men, with a mean age at disease onset of 53.3 and a mean interval between symptom onset and <a href="https://alsnewstoday.com/als-diagnosis/">diagnosis</a> of 13.8 months. They were followed by neurologists via phone or in-person interviews every six months until January 2022. During that time, 226 patients (63.5%) died and 26 (7.3%) were lost to follow-up.
On average, the levels of Cystatin C in serum (the liquid portion of blood) at diagnosis were 1 mg/L. Based on that average, patients were divided into two groups: those with levels of 1 mg/L or higher and those with levels below the average.
The high Cystatin C group had a significantly higher proportion of men (71.5% vs. 44.5%) and of patients with limb-onset disease (89.1% vs. 55.5%), a form of the disease in which the first <a href="https://alsnewstoday.com/als-symptoms/">symptoms of muscle weakness</a> appear in the limbs. This group was also significantly older at the onset of the disease (57.7 vs. 49.5%).
The participants in the high and low Cystatin C groups also had differences in clinical measures. In fact, the high group had significantly less disease severity, as measured with the ALS Functional Rating Scale-Revised (ALSFRS-R), but a faster rate of disease progression.
The higher the Cystatin C levels, the less severe the disease was, but the faster it progressed, according to statistical analyses that looked at Cystatin C levels as a continuous variable.
This suggests “serum [Cystatin C] may be a useful indicator for assessing disease severity, [and that] patients with higher [Cystatin C] levels might have faster disease progression,&#8221; the researchers wrote.
The median survival time for all the patients was 42 months (around 3.5 years). However, consistent with the faster rate of disease progression in those with high Cystatin C levels, this group also had a significantly shorter survival compared with the group with low levels (38 vs. 48 months). In a multivariate analysis, which took into account potential confounding factors such as age and sex, low serum Cystatin C remained associated with a longer survival time with ALS.
Other factors significantly associated with longer survival included a lower age at disease onset, limb onset, a longer time between the appearance of the first symptoms and diagnosis, a slower disease progression rate, and being male.
“Our study found that serum [Cystatin C] seems to be associated with ALS survival and serum [Cystatin C] may be an independent predictor of ALS survival,” the researchers said.

Cystatin C may be biomarker to predict survival, disease progression

Levels of the TDP-43 protein in spinal fluid show promise as biomarkers for <a class="editor-rtfLink" href="https://alsnewstoday.com/what-is-als/" target="_blank" rel="noopener">amyotrophic lateral sclerosis</a> (ALS) and may aid in diagnosing the neurological disease, according to a new review of several published studies.
That review discovered that these protein levels are increased in the cerebrospinal fluid (CSF) — the liquid that surrounds the brain and spinal cord — of patients as compared with people without ALS.
This finding suggests that TDP-43 levels may be a biomarker to help diagnose the disease. However, the scientists noted that the analysis included a small number of studies and participants, and stressed that more research is needed to validate this hypothesis.
“CSF TDP-43 could represent a biomarker of ALS, but further studies are mandatory before drawing conclusions,” the team wrote.
The study, “<a class="editor-rtfLink" href="https://www.mdpi.com/2075-4418/13/3/416" target="_blank" rel="noopener">The Role of TAR DNA Binding Protein 43 (TDP-43) as a CandiDate Biomarker of Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis</a>,” was published in <a class="editor-rtfLink" href="https://www.mdpi.com/journal/diagnostics" target="_blank" rel="noopener">Diagnostics</a>.
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<h3>Searching for new biomarkers for use in diagnosis</h3>
<a class="editor-rtfLink" href="https://alsnewstoday.com/causes-of-als/" target="_blank" rel="noopener">ALS is caused</a> by the progressive death of motor neurons, the nerve cells in the brain and spinal cord that control voluntary movements. This gives rise to a range of <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a>, such as muscle stiffness and weakness, that also are signs of other diseases.
Thus, confirming an <a href="https://alsnewstoday.com/als-diagnosis/">ALS diagnosis</a> remains a challenge for clinicians, who need to conduct multiple tests to rule out other conditions and track the progression of symptoms before attributing them to ALS. As a result, it generally takes <a href="https://www.sciencedirect.com/science/article/pii/S0022510X20303919">about 10-16 months</a> from the onset of symptoms to an ALS diagnosis.
Identifying biomarkers that reflect disease mechanisms has been a main focus of ALS research in recent years. These biomarkers could help distinguish patients with ALS from those with other distinct neurological conditions, helping to shorten the diagnostic journey. Such ALS biomarkers also might aid in tracking disease progression and responses to treatment.
 TDP-43 is a protein abundantly expressed in the brain and spinal cord. It is normally located in the cell nucleus, where it regulates the first step of protein production from a gene, but can shuttle between this compartment and the cytoplasm — the fluid surrounding the nucleus. 
In ALS, however, TDP-43 accumulates and forms toxic clumps in the cytoplasm of motor neurons, causing their dysfunction. This buildup is found in approximately 97% of ALS patients — even in those who do not have mutations in the gene coding for TDP-43. Indeed, it now is recognized as a hallmark of ALS.
But while studies support the role of this protein in ALS development and progression, its function “as a biomarker of ALS is controversial,” the researchers wrote.
To learn more, researchers in Italy now conducted an analysis of studies published up to April 2022, with available measurements of TDP-43 levels in both ALS patients and those without the disorder, who served as controls.
A total of seven studies, involving 452 participants — 254 ALS patients and 198 controls — were eligible for the analysis. Some studies used healthy individuals as controls, but controls in most studies were patients with neurological diseases that should not influence TDP-43 levels, such as <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a>.
A meta-analysis — a statistical analysis combining results from all studies — revealed that TDP-43 levels in the cerebrospinal fluid were significantly increased in ALS patients compared with controls.
[quote align=&#8221;center&#8221;]The findings of this meta-analysis encourage further studies to validate the possible role of TDP-43 as a biomarker of ALS.[/quote]
Some studies also evaluated TDP-43 in the blood, but the results were inconsistent, possibly due to differences in the methods used to measure the protein, the team noted.
Only a few studies further investigated the diagnostic potential of CSF TDP-43 in ALS — but all reported good diagnostic performance.
Together, the findings suggest that CSF TDP-43 may be a potential biomarker of ALS, but “much effort is needed before introducing it in clinical practice,” the researchers wrote, noting, &#8220;A significant limitation of most studies is the small sample size.&#8221;
“The findings of this meta-analysis encourage further studies to validate the possible role of TDP-43 as a biomarker of ALS,” the team concluded.

Tag: ALS biomarker

Cryptic protein fragments may detect ALS in early stages: Study

Blink reflex test may be biomarker to diagnose, monitor ALS: Study

Cystatin C may be biomarker to predict survival, disease progression

TDP-43 protein levels show promise as ALS biomarker: Review