Biomarkers are measurable signs of what’s happening inside the body and are essential for running successful Huntington’s disease (HD) trials. Right now, neurofilament light (NfL) is the star of the HD biomarker world, but we need more players on the team. A new study from Cyprus scanned every type and amount of protein molecules found in blood samples, to see how these changed over time in people with HD. They found two potential biomarker candidates, CAP1 and CAPZB, which seem to be linked to very early changes in HD. With follow up studies, these findings could add powerful new tools for tracking disease progression and measuring the impact of future treatments.
Biomarkers Are Critical For HD Research
Imagine running a race without a finish line. That’s what testing an HD treatment would be like without biomarkers. You could hand someone a promising new drug, but without a way to measure what’s happening in the brain, you wouldn’t know if it’s helping, hurting, or doing nothing at all.
That’s why biomarkers are so important. In HD, one of the best so far is neurofilament light (NfL), a protein released when neurons are damaged. NfL seems to be reliable, it’s being used in many ongoing trials, seems to track with some of the earliest changes that HD causes, and it’s taught us a lot about how possible HD treatments might impact brain health. But no single biomarker can capture the whole progressive story of HD, or how things might change with different treatments. We need a team of biomarkers that can cover different angles, especially ones that show up before the earliest of symptoms start.
Enter this new research study, which is a wide-angle look at the blood for signs of HD, even in its earliest days.
So, What’s A Proteome, Anyway?
Think of your body as a giant city. Your genes are the blueprints for all the buildings, roads, and systems. Proteins are the workers – the electricians, the bus drivers, the teachers, the police officers. They’re the ones making things actually happen.
The proteome is the full roster of those workers at any given moment. And just like in a real city, the lineup changes depending on what’s going on, like if there’s a festival, a storm, or a traffic jam, the people you would want on your crew would change. Proteomics is the science of counting and studying all those workers to see who’s showing up, who’s missing, and who’s acting differently than usual.
In this study, the “city” in question was the blood of people with and without HD.
The Study Breakdown
The researchers studied 36 people with the gene for HD, split into three groups:
- Asymptomatic: gene-positive but no clinical signs yet
- Early symptomatic: subtle movement or thinking changes
- Advanced symptomatic: more pronounced symptoms affecting daily life
They also included 36 healthy controls, all from Cyprus. Using blood serum (the clear liquid part of blood), they analyzed thousands of proteins to see which ones changed at each stage of HD.
The advantage of blood serum is that it’s far easier to collect than spinal fluid, no lumbar punctures required, making it a practical (and much desired!) source for future biomarker testing.
Early Trouble In The Cell’s Skeleton
The first finding from this research seemed to show up before symptoms appeared, suggesting there may be changes in proteins linked to the cell’s cytoskeleton. The cytoskeleton is the internal scaffolding that gives cells their shape and allows them to move and connect.
This work suggests the city’s buildings may be losing their supporting beams before any cracks appear in the walls. Identifying changes that happen early in HD, before symptoms are readily apparent, will help researchers identify key molecular events in HD progression.
As the disease advanced, two other themes emerged. First, the complement system, a frontline part of the immune response, seemed to be stuck in an overactive state, which in the brain could mean inflammation and loss of brain cell connections. Second, lipid and cholesterol regulation appeared to go off balance, which matters because cholesterol is vital for healthy brain cell communication.
While all of these are interesting findings, none of this is particularly new for HD researchers. There have been several studies looking at cytoskeleton differences in brain cells, changes to the complement system, and cholesterol dysregulation in HD before. But those studies have largely focused on the molecular changes HD causes within those biological functions, and not using those changes to identify biomarkers.
Biomarkers are measurable signs of what’s happening inside the body and are essential for running successful Huntington’s disease (HD) trials. Right now, neurofilament light (NfL) is the star of the HD biomarker world, but we need more players on the team.
Meet CAP1 And CAPZB
From the long list of changing proteins identified in this study, two stood out for the researchers:
- CAP1 seemed to be lower in people with HD, especially in the asymptomatic group. This made it stand out to the scientists as a strong candidate for an early-warning biomarker, one that changes before symptoms. CAP1’s role in the cell is to help keep the cytoskeleton stable.
- CAPZB seemed to be higher in all HD stages, piquing interest as a potential general disease marker that could be useful for tracking HD once it’s underway. CAPZB also works on the cytoskeleton, specifically regulating actin, a key structural protein.
The More the Merrier
If validated in larger, more diverse groups, CAP1 and CAPZB could join NfL in the HD biomarker toolkit. Together, they could help flag HD-related changes years before symptoms start, which will be critical for advancing trials aimed at treating HD before the more obvious symptoms of the disease begin. They could help track how fast the disease is progressing, which could help people with planning life events. And they could help show whether a treatment is making a difference, which is why biomarkers are so critical for HD research.
This is especially important in prevention trials, where the goal is to treat people before the disease has visibly started. Without early biomarkers, we’d have no way to see if those treatments are working.
Some Things To Keep In Mind
This study was done on a very specific population of people – those from the small island of Cyprus. Because this is a limited population of people, there could be “founder effects” at play, which means that the population of people with HD on Cyprus could have started from one person or just a few individuals that, over time, produced the family(ies) on Cyprus with HD.
In theory, that limited initial person/people could have had unique genetic signatures that made the biomarkers identified in this study specific for them and their progeny. Because of that, a more diverse set of people needs to be studied before we could say if these are solid biomarkers to chase for HD.
Another thing to keep in mind here is that only 36 people were assessed in this study. That’s a small number of people when it comes to a biological study. Combined with the fact that the diversity is limited, and that small pool of participants could really mask results or skew findings.
Even Still, These Types of Studies Are Critical
While the points above are important caveats that suggest we should interpret these findings with a healthy pinch of salt until larger studies are done, the importance of these types of studies for advancing HD research cannot be overstated.
Having biomarkers that track with disease progression, particularly in people that are at the earliest stages of HD, is essential for advancing disease modifying drugs. This is especially important as we move toward trials aimed at treating people with HD earlier on in their HD journey, perhaps even before notable symptoms arise.
Another important note from this work is that it was done using blood serum, showing that researchers are committed to discovering biomarkers that track with early disease progression that can be measured in a minimally invasive way. We know everyone would appreciate not having to get a spinal tap at every appointment! So while we’re not quite there yet, it is certainly something scientists are working toward.
Lastly, the results from this study were made possible by “omics” studies – giant, detailed inventories of all the parts in a living thing, whether that’s all the genes, all the proteins, all the fats, or all the other molecules that keep it alive. These types of research studies that look at how everything changes, then narrow in on those things that change the most have transformed our understanding of HD over the past decade. It was omics studies that initially defined genetic modifiers from the GeM-HD Consortium study, contributing to the discovery of somatic instability. And omics studies will undoubtedly help usher in the forthcoming treatments we’re all eagerly awaiting.
Having biomarkers that track with disease progression, particularly in people that are at the earliest stages of HD, is essential for advancing disease modifying drugs. This is especially important as we move toward trials aimed at treating people with HD earlier on in their HD journey, perhaps even before notable symptoms arise.
The Road Ahead
First and foremost, before CAP1 and CAPZB can move from research to clinic, it’s critical that scientists test them in bigger, global HD cohorts. They also need to follow people over time to see how levels might shift as HD progresses in those larger populations. They should also check whether they’re unique to HD or also change in other brain diseases.
So, while there’s a long road ahead for CAP1 and CAPZB, work advancing new biomarkers for HD is critical, and it’s ongoing. It’s especially important as we move toward clinical trials aimed at treating HD earlier, perhaps even before symptoms arise. And the added benefit of blood biomarkers is incredibly exciting. Imagine having a simple blood test that could tell researchers, with confidence, that a new drug is slowing HD in its tracks. That’s the kind of advancements that these biomarker studies could bring.
Summary
- Biomarkers are crucial in HD research for measuring treatment effects.
- NfL is a strong HD biomarker, but more are needed for a complete picture.
- This study scanned the blood proteome of people with and without the gene for HD from the small island of Cyprus.
- Two proteins seemed to stand out: CAP1 (lower in people with early HD) and CAPZB (higher across all stages of HD), both linked to early cell structure problems.
- If validated in larger more diverse populations of people, they could help detect and track HD years before symptoms, a critical advancement for future clinical trials aimed at treating HD earlier, perhaps even before symptoms arise.
Learn More
Original research article, “Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease Progression” (open access).