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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.
[recommended-reading id=77275]
<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.
[recommended-reading id=88900]
<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 research team at Ball State University has received a $20,000 donation from the <a href="https://www.bigtopen.com/" rel="nofollow">Todd Siebert Memorial Foundation</a> supporting work into better understanding and treating <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) caused by C9orf72 mutations.
Awarded to Philip Smaldino, PhD, a cell biology professor at the Indiana school, and his team, the gift prompted the formation of the Smaldino ALS/FTD Research Project Fund as part of the university&#8217;s foundation. A related neurodegenerative disorder, FTD or <a href="https://alsnewstoday.com/news/about-35-als-patients-show-signs-frontotemporal-dementia/"> frontotemporal dementia also can affect ALS patients</a>.
The project aims to contribute to further understand the underlying mechanisms of C9orf72-associated ALS and to find new treatments. In particular, the team will focus on developing therapeutic approaches that target DHX36, a protein whose inhibition may improve outcomes for people with this ALS subtype.
[recommended-reading id=89682]
<h3>C9orf72 mutations are the most common genetic cause of ALS</h3>
The Todd Siebert Memorial Foundation, which supports patients and research into C9orf72-linked ALS,  was established in 2021 to honor of Siebert, who died from disease complications that year.
Its support came on the heels of a campus visit last year by Tina Siebert, Todd Siebert&#8217;s widow, and Erin Eckerle, the foundation&#8217;s president.
“I was honored and inspired by the visit from Tina and Erin,” Smaldino said in a <a href="https://www.bsu.edu/news/press-center/archives/2024/02/todd-siebert-memorial-foundation-boosts-als-research-at-ball-state-university">university press release</a>. “The Siebert Foundation has been working tirelessly since 2021 to raise awareness and funds to support Indiana families affected by ALS.”
Mutations in the C9orf72 gene are the most common <a href="https://alsnewstoday.com/causes-of-als/#Genetics_of_ALS">genetic cause of ALS</a>, found in up to 50% of people with <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a> and up to 10% of those with <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a>. Similar mutations also can be found in some FTD patients.
These mutations usually are characterized by the excessive repetition of six DNA building blocks, GGGGCC, in the gene’s sequence. These regions form &#8220;knot-like&#8221; structures that regulate the process of protein production in healthy cells. However, excessive or aberrant forms of these structures can help to drive disease processes.
DHX36 is an enzyme, a type of protein responsible for untying these knot-like structures. According to Smaldino, lowering its levels has shown potential in reducing the protein&#8217;s toxic forms in cell and mouse models of C9orf72-linked ALS.
The donation will support further exploration of this treatment approach, and contribute to the training of student scientists in innovative ALS research.
“I try to remind my students that what we are doing in the lab may someday help real people. The visit with Tina and Erin brought that idea to light in ways that my words could never have,” Smaldino said.

$20K gift supports Ball State work into C9orf72-linked ALS

Having higher blood levels of uric acid may prevent or delay the decline in cognitive function in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to a new study from Italy.
High levels of uric acid are also associated with reduced odds of frontotemporal dementia, a form of dementia especially common in ALS patients that&#8217;s marked by damage to the brain’s frontal and temporal regions, data show.
The study, “<a href="https://link.springer.com/article/10.1007/s00415-023-12056-8">High serum uric acid levels are protective against cognitive impairment in amyotrophic lateral sclerosis</a>,” was published in the <a href="https://www.springer.com/journal/415">Journal of Neurology</a>.
Recent research has shown a significant proportion of people with ALS experience <a href="https://alsnewstoday.com/symptoms-of-als/#Cognitive_issues">cognitive or behavioral changes</a>. These most commonly affect a person&#8217;s ability to plan actions or regulate behaviors, but up to 20% of patients develop overt dementia, in which their thinking, memory, and social skills become so affected as to interfere with daily life.
[recommended-reading id=82931]
<h3>Uric acid produced from breakdown of natural substances called purines</h3>
Uric acid has emerged as a factor that can improve cognitive function, both in the general population and in people with neurodegenerative disorders. The molecule is produced from the breakdown of purines, natural substances found in the body, and can also be found in certain foods and beverages.
Data have suggested uric acid can protect nerve cells from damage, leading to better cognitive function in some patients with neurodegenerative disorders and in elderly people. However, it can also have detrimental effects in people with systemic conditions, in whom higher levels of the molecule are associated with worse cognition.
The correlation between uric acid levels and cognitive impairment has not been well-studied in people with ALS. To know more, researchers in Italy examined data from 841 patients at the Turin ALS Center from 2007 to 2018, who had undergone cognitive and behavioral testing and whose uric acid levels had been measured as part of their diagnostic workup.
Their mean age at cognitive examination was 66.8 years, and more than half (58.5%) were men.
After undergoing a battery of neuropsychological tests, 50.2% of patients were deemed as having normal cognition. The remaining had some form of cognitive impairment: 32.2% had intermediate cognitive impairment and 17.6% had frontotemporal dementia (FTD).
Results showed uric acid levels were significantly different among the three groups, being lower in FTD patients (271.8 micromol/L) compared with the other two groups (288.5 and 289.7 micromol/L). Similar results were obtained in a group of patients with C9orf72 mutations, the most common ALS-related mutations.
The proportion of patients with ALS-FTD was significantly higher in the 33% of people with the lower levels of uric acid, data showed.
Also, when people with no or intermediate cognitive impairment were compared with FTD patients, data showed that a 1 micromol/L decrease in uric acid levels increased the likelihood of having FTD by 20%-32%.
[recommended-reading id=83944]
<h3>Higher uric acid at diagnosis can be protective for mild cognitive impairment</h3>
In turn, uric acid levels were not associated with the presence of intermediate cognitive impairment. Only an older age at onset was linked to this type of cognitive impairment, which each year increase being correlated with a 3% higher likelihood of developing cognitive impairment.
“This finding could indicate that higher [uric acid] levels at diagnosis can be protective in patients with mild cognitive impairment, preventing their progression to full-blown [frontotemporal dementia],” the researchers wrote.
Blood levels of uric acid correlated with scores on tests assessing executive function, cognitive flexibility, verbal memory, non-verbal intelligence, and language.
“Together with the proposed role of [uric acid] as a prognostic factor in ALS, our data show that [it] can also be a protective factor for the cognitive-behavioral component of the disease,” the researchers wrote.
However, “further study on [uric acid] will better elucidate the mechanisms through which this metabolite may exert its protective activity in ALS,” they added.

High uric acid levels may protect against cognitive decline in ALS

A new home-based neurocognitive platform from <a href="https://cumulusneuro.com/">Cumulus Neurosciences</a> is feasible to use and patient-friendly, and shows potential to identify cognitive problems and to discriminate between people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), those with frontotemporal dementia (FTD), and healthy individuals.
That’s according to preliminary data from a first-in-class study, dubbed CNS-102, that&#8217;s testing the new platform. The study is being conducted by Cumulus together with <a href="https://www.precisionals.ie/">Precision ALS</a>, an Irish <a href="https://alsnewstoday.com/news/e10m-european-collaborative-project-hopes-use-ai-als-precision-medicine/">collaborative research program</a> hosted by Trinity College Dublin, in Ireland.
The Cumulus platform aims to collect data through repeated, intensive at-home sampling — which could one day allow people with ALS, FTD, and other disorders to take part in decentralized clinical trials.
“We are encouraged by the analysis from our CNS-102 feasibility study, which confirms that patients living with these devastating conditions are willing and able to participate in home-based studies with intensive protocols,” Brian Murphy, PhD, Cumulus’ founder and chief scientific officer, said in a <a href="https://www.prnewswire.com/news-releases/cumulus-neuroscience-presents-key-data-at-the-2023-encals-annual-meeting-on-patients-with-amyotrophic-lateral-sclerosis-als-and-frontotemporal-dementia-ftd-301874954.html">company press release</a>.
According to Orla Hardiman, MD, the study’s principal investigator, “the results of CNS-102 provide preliminary evidence that the Cumulus platform can identify cognitive deficits across these patient groups.”
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<h3>Platform aims to differentiate between ALS and FTD</h3>
The preliminary findings of CNS-102 were presented in two posters at the <a href="https://www.encals.eu/meetings/barcelona/">European Network to Cure ALS (ENCALS) Annual Meeting</a>, held July 12-14, in Spain. The study had focused on the feasibility of use of the Cumulus platform.
“Importantly, across study [groups] we saw very high rates of successfully completed sessions, which confirms that the platform is patient friendly and easy to use,” said Hardiman, who also serves as the lead investigator of Precision ALS, and is head of Trinity College Dublin’s academic unit of neurology,.
ALS is a progressive neurodegenerative disease that affects the nerve cells in the brain and spinal cord that control voluntary movements, causing these cells to degenerate and die. This leads to a gradual loss of muscle control, affecting the patient’s ability to perform everyday tasks.
Besides motor impairments, about half of all ALS patients <a href="https://www.sciencedirect.com/science/article/pii/S0304394021002767#:~:text=Approximately%20half%20of%20patents%20with%20ALS%20experience%20cognitive%20(ALSci)%20or%20behavioural%20impairment%20(ALSbi)">experience cognitive problems and behavioral issues</a>. These include deficits in social and emotional cognition, language difficulties, apathy, and irritability, as well as impaired executive function — meaning problems with the set of mental skills that include working memory, planning, attention, flexible thinking, and self-control. In this context, social and emotional cognition refers to how people process, understand, and use information from others to interact with them.
In some patients, these cognitive and behavioral symptoms reach clinical relevance and lead to the diagnosis of frontotemporal dementia, known as FTD, a neurodegenerative condition that shares biological mechanisms with ALS.
[quote=&#8221;center&#8221;]Importantly, across study [groups] we saw very high rates of successfully completed sessions, which confirms that the platform is patient friendly and easy to use.[/quote]
“Detection of cognitive or behavioral changes in patients living with ALS or FTD can be challenging during clinical visits due to a variety of factors including fatigue and white coat syndrome,” Murphy said.
White coat syndrome refers to a patient’s anxiety in a medical environment — often manifested, for example, as abnormally high blood pressure readings in a doctor’s office.
As such, according to the researchers, at-home, regular monitoring may provide more accurate results relating to patients’ cognitive function and behavior, as well as in changes over time.
“A longitudinal home-based approach is more ecologically valid and provides less variable estimates of true performance,&#8221; the researchers wrote in on of the posters.
[recommended-reading id=83744]
<h3>Testing focused on cognitive problems and behavior issues</h3>
The <a href="https://cumulusneuro.com/#platform">Cumulus neuroassessment platform</a>, which uses digital tablets, provides a set of functional assessments and simultaneous non-invasive monitoring of the brain’s electrical activity. To measure such electrical activity, the platform uses its U.S. Food and Drug Administration-cleared, self-applied electroencephalogram (EEG) headset.
The belief is that, by allowing the remote monitoring of patients at home, the platform may be more effective at detecting relevant changes, and may be a valuable tool for patient care and clinical trials testing potential ALS therapies.
The CNS-102 study, conducted in Ireland, enrolled 10 ALS patients, seven FTD patients, and 10 age- and education-matched healthy people, who served as controls.
Participants completed a full neuropsychological assessment covering cognitive function and behavior at the study’s start, and after four and eight months. At the same time, they were asked to complete three 25-minute Cumulus platform sessions every two weeks.
These sessions included gamified tasks to assess mood and emotion processing, language, executive function, memory, and motor skills, while measuring the brain’s electrical activity with the EEG headset. Key cognitive-behavioral and EEG measures were evaluated based on data from the first five sessions.
In the first poster, “<a href="https://www.encals.eu/wp-content/uploads/2023/07/Posters_0607_design.pdf">Patient and technical feasibility of real-world sampling of cognition and functional neurophysiology in Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)</a> (abstract #286), Cumulus researchers showed that 47.3% of ALS patients, 68.9% of FTD patients, and 68.2% of the controls adhered to the platform. Moreover, all groups successfully completed more than 85% of the sessions.
These interim data “from this first-in-class study suggest that older individuals, and those with FTD and ALS are capable and willing to participate in home-based studies with intensive repeated sampling protocols,” the researchers wrote.
[recommended-reading id=84278]
<h3>Cognitive problems found to be worse in FTD, then ALS</h3>
In a second poster, titled “Longitudinal cognitive assessment using the Cumulus home-based EEG platform in ALS and FTD&#8221; (abstract #272), researchers at Precision ALS and Trinity Biomedical Science Institute (a Precision ALS host) shared data on the platform’s ability to differentiate the groups.
The full neuropsychological assessment showed significant group differences in terms of cognitive function. Cumulus platform data also revealed significant differences between the ALS, FTD, and control groups in tasks related to psychomotor skills, general cognitive function, and descriptive speech rate.
The team noted that people with FTD performed worse in both Cumulus and full battery measures, followed by those with ALS, and then healthy controls.
These findings confirmed that the platform can identify cognitive deficits in these groups and separate them, “constituting positive initial evidence for task validity and technical feasibility,” the researchers wrote.
“Further research will establish how comparable the Cumulus platform is with gold-standard neuropsychological assessment and its sensitivity in detecting cognitive decline,” the researchers wrote.
The Cumulus researchers said the CNS-102 study results highlight a role for the platform in helping to develop new therapies — particularly those addressing cognitive problems — for both ALS and FTD.
“We are deeply grateful to the patients, caregivers and collaborators who dedicated their time to this important first-in-class study,” Murphy said.

Tag: frontotemporal dementia

Cryptic protein fragments may detect ALS in early stages: Study

$20K gift supports Ball State work into C9orf72-linked ALS

High uric acid levels may protect against cognitive decline in ALS

New platform may help to ID cognitive problems in ALS