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An international collaboration between world leaders in Huntington’s disease (HD) that spans both academia and pharmaceutical companies is giving us new insight into how HD progresses. This study has given researchers a detailed timeline of how brain connectivity changes in HD. Using an advanced technique called MIND, researchers traced how brain communication networks shift over decades, from a chaotic overdrive to widespread breakdown. They found that these shifts aren’t random, they’re shaped by disease stage-specific changes that unfold in a dynamic, evolving way. Picture the brain as an orchestra, desperately trying to keep the music going, only to fall out of sync as the HD progresses.

Act I: The Brain’s Opening Crescendo – Hyperconnectivity

In the earliest stages of HD, years, even decades before symptoms arise, the brain isn’t going quiet. In fact, it’s playing louder. A new study used a large collection of data from the observational studies TRACK-HD, TrackOn-HD, and the HD Young Adult Study (YAS). These studies aren’t testing a drug, but are rather designed to follow people with HD as they naturally live and age. They have followed hundreds of people without and with HD for many years, spanning people aged 18 to 65 in all stages of HD. This is a huge dataset!

A major finding of this study is that hyperconnectivity, a state where brain regions are over-communicating, is one of the first detectable features of HD. It can emerge more than 20 years before motor symptoms begin, sometimes even in childhood.

You might expect that a brain with HD would steadily lose function over time. But that’s not what this research showed. Instead, the early HD brain looks like an orchestra where multiple sections begin to play too loudly, as if trying to compensate for someone in their section who was a no show. This might be the brain’s attempt to maintain performance despite early, subtle losses in some neurons.

However, just like an orchestra playing too loudly and out of sync, this early overactivity isn’t necessarily healthy. It was linked to changes in neurofilament light (NfL) levels, a marker that tracks with brain health and nerve cell breakdown and can be measured in blood or brain fluid. So while the early hyperconnectivity might reflect compensation, it’s also a sign of stress, suggesting the brain might be straining to keep the music going.

Act II: The Middle Movement – When the Conductor Walks Out

As HD progresses toward the late pre-manifest stage, a sharp transition appears to occur. That initial hyperactivity doesn’t seem to last. The overactive brain networks begin to falter, and the orchestra loses its timing. This is the point in the concert where the conductor might walk offstage, leaving the musicians to drift out of sync.

The study found that in this mid-stage of HD, a new mechanism kicks in: trans-neuronal spread. This is the idea that the disease-causing HD protein might propagate from one brain region to another along neural connections, almost like a bad note spreading from section to section. The brain’s communication network becomes a route for the disease to move and intensify.

Interestingly, researchers identified specific “epicenter” regions of the brain that seemed to play a role in this trans-neuronal spread only in this mid-stage. It’s as if the disease chooses a few critical players in the orchestra to sabotage the rest. But this is a limited window; the epicenter-driven spread fades as the disease continues, reinforcing the idea that HD progresses in distinct stages.

Using an advanced technique called MIND, researchers traced how brain communication networks shift over decades, from a chaotic overdrive to widespread breakdown.

Act III: The Finale in Dissonance – Hypoconnectivity and Breakdown

By the time someone reaches the stage of HD where symptoms are outwardly visible, the music has largely fallen apart. The orchestra is no longer too loud, instead it’s eerily quiet. The study revealed widespread hypoconnectivity, a dramatic reduction in communication across the brain’s major networks. This was observed in 48 out of 68 brain regions, suggesting a systemic breakdown.

The instruments, or more precisely, the brain’s long-range brain cell connections, appeared to no longer be functioning. Think of the violins missing half their strings, the wind section gasping for air, the percussion fading into silence. This breakdown strongly correlates with high levels of NfL, indicating extensive damage to the brain’s wiring.

Yet even here, a few sections persist. The occipital cortex, responsible for visual processing, showed some pockets of increased activity. Unlike the rest of the brain, these changes didn’t correlate with NfL, raising the possibility of resilience or compensation. Maybe a few musicians are still trying to play, even after the rest of the orchestra has gone silent.

Behind the Music: The Cellular Players and Their Shifting Roles

So what drives this shifting performance? The study points to a fascinating interplay between different biological mechanisms that dominate at different stages. Early on, the disruptions are primarily driven by toxic processes within individual neurons. It’s like certain musicians playing the wrong notes, regardless of what the conductor says.

These early-stage disruptions were closely linked to neurotransmitter systems, the brain’s chemical messengers. The study suggested changes in specific systems particularly involved in the brain’s initial hyperconnectivity. These neurotransmitters play crucial roles in learning, memory, mood, and adaptation, suggesting that the brain’s most flexible systems may be first to respond, and first to fail.

As the disease progressed, these players also changed. Neurotransmitters that regulate pain, mood, and reward seemed to be affected in early pre-HD. And in late pre-HD, systems around mood regulation and impulse control seemed to be affected. These findings match with what we know about some of the earliest changes people with HD start to experience.  

In the mid- and late stages, the dominant mechanisms seemed to shift toward genetic disruptions and mitochondrial dysfunction, more systemic issues that impair cellular function across the board. The music becomes not just off, but increasingly impossible to play.

What makes this study so valuable is the large collection of data used from 3 observational studies (TRACK-HD, TrackOn-HD, and HD-YAS), providing a layered and time-sensitive understanding.

A Stage-Specific Symphony of Decline

What makes this study so valuable is the large collection of data used from 3 observational studies (TRACK-HD, TrackOn-HD, and HD-YAS), providing a layered and time-sensitive understanding. So while clinic visits for these observational studies can be laborious, each blood draw, clinical assessment, and research visit provides incredibly valuable information that scientists are putting to good use to better understand HD. It’s time very well spent!

From this work, we’re learning that HD is not a simple, straight-line descent, it’s a multi-act drama with distinct biological players, turning points, and feedback loops. The research suggests that each stage of HD is defined by different mechanisms, from neurotransmitter disruption to cellular communication spread to full-scale network collapse.

It also shows that these changes are trackable over time, with brain imaging and blood-based biomarkers like NfL helping pinpoint when things go wrong. That means future treatments might not just focus on slowing decline, but on targeting the right process at the right time, catching the brain when it’s still trying to play, even if off-key.

TL;DR: The Big Takeaways

• Early HD isn’t quiet, it’s loud. Hyperconnectivity (over activation) appears decades before symptoms, likely as a mix of compensation and early damage.
• The brain acts like an orchestra, first overplaying to seemingly compensate, then falling apart as coordination fails.
• Disease progression is stage-specific. Early on, issues within cells seem to dominate; later, disease spread and systemic breakdown appear to take over.
• Different neurotransmitters seem to play key roles at each stage, with what appears to be distinct impacts on brain connectivity.
• NfL levels track with connectivity loss, making it a useful marker for identifying when the music begins to falter.
• This model opens the door to earlier, more precise interventions, targeting specific processes before full-blown symptoms appear.

Learn More

Original research article, “Cell-specific mechanisms drive connectivity across the time course of Huntington’s disease” (open access).

While the genetic change that causes Huntington’s disease (HD) leads to several problems for cells, researchers believe they could stem from one core issue: the length of the genetic change increasing over time, like a snowball gaining mass as it rolls downhill. This genetic phenomenon, known as somatic instability or somatic expansion, seems to be a key driver of disease progression. In a recent study, scientists developed a new variant of CRISPR, a powerful gene editing tool, to interrupt this genetic expansion, potentially paving the way to new therapeutic opportunities. 

A Genetic Snowball

HD is caused by a change in a gene called HTT, specifically where the genetic letters C-A-G are repeated several times. In people with HD, this CAG section is longer than normal, jump-starting a deadly chain reaction inside brain cells. Unlike most mutations, which remain the same throughout life, the CAG repeats in HTT grow longer with age, like a snowball picking up speed as it barrels downhill. 

At birth, most people with HD have around 40 to 50 CAG repeats in their HTT gene. Over time, that number grows exponentially inside cells, sometimes surpassing 500 repeats by the time symptoms develop! If the initial repeat is above a critical threshold (36 repeats), the expansion turns into a kind of genetic snowball over time and begins growing out of control.

However, HD is not alone; it belongs to a broader category of diseases called trinucleotide repeat disorders – a fancy term for 3 (tri) genetic letters (nucleotide) that repeat (repeat – ok that one was obvious…). These disorders all share a similar problem with snowballing mutations. One such example is Friedrich’s Ataxia, which is driven by a growing CTG repeat that also worsens over time. 

The observation that several brain diseases are caused by a growing trinucleotide repeat raises a key question: Why are growing trinucleotide sequences so toxic to brain cells? Normally, genes like HTT are used to produce messenger RNA, also called mRNA, a temporary copy of DNA that is used to make proteins, the machines of the cell. However, long trinucleotide repeats cause the RNA to twist into super-tangled and stable knots, clogging the cell’s protein-making machinery. As these tangled RNAs grow longer and more abundant, they increasingly disrupt protein production, eventually contributing to cell death.

Interrupting the Instability

What if there were a way to break this snowball effect before it spirals out of control? Scientists at Harvard University, led by Dr. David Liu, hypothesized that they could interrupt the repeating CAG sequence by simply replacing one of the CAGs with a similar, but harmless, CAA sequence. 

By interrupting the repeating CAGs, even with a similar CAA sequence, the underlying pathway that leads to the CAGs growing with age might get blocked! In other words, inserting a CAA sequence is like placing a patch of rocks on the hill, causing the snowball to smash into them and break its momentum! 

Liu and his team were inspired by previous research showing that CAA interruptions seem to delay disease onset. Typically, the number of CAG repeats strongly predicts when someone will develop HD, but genetic studies identified people with long repeats but delayed ages of onset. 

Examined more closely, these genetic outliers were discovered to contain short CAA interruptions within their CAG stretch. Remarkably, these simple interruptions were linked to a 12-year delay in disease onset! Motivated by these observations, Liu and his team wondered if they could intentionally insert CAA sequences into cells with the gene for HD, and if this could recreate the protective effect. 

Unlike most mutations, which remain the same throughout life, the CAG repeats in HTT grow longer with age, like a snowball picking up speed as it barrels downhill. 

CRISPR Cracks the Snowball

Precision genetic changes, like swapping a CAG to CAA, are simple in theory, but extremely challenging in practice. Liu and his team turned to CRISPR, a gene-editing tool that acts like molecular scissors to alter specific DNA sequences. They developed a special type of CRISPR, called base editing, that looks for CAG repeats and swaps some of them out for CAAs. 

Using human cells growing in petri dishes, they found that their CRISPR base editing strategy successfully modified the HTT CAG repeat in about 80% of cells, with no signs of toxicity. Even more promising, they found these simple CAA interruptions seemed to stop the CAG repeat expansions after 30 days. They even noticed the CRISPR-edited cells appeared to grow faster and look healthier!  

Because this type of CRISPR targets all CAG repeats (not just the one in HTT) and introduces CAA interruptions into them as well, they needed to confirm that other genes were not disrupted by accident. In total, they found about 250 other genes changed by CRISPR, likely because they contained similar CAG repeats. However, only about 50 of them are active in brain cells, and just one appeared to be significantly disrupted. While this finding doesn’t rule out risk, it does suggest that unintended edits are unlikely to cause serious issues. Regardless, minimizing accidental edits will be a top priority moving forward!

Interrupting CAGs with CRISPR

Now comes the big challenge: Can the team get the CRISPR machinery into cells in a living brain and successfully edit CAG sequences? Liu’s team used a mouse model of HD that carries 110 CAG repeats in its HTT gene, and this repeat grows rapidly as the mice age (repeat instability). To deliver CRISPR to the brain, the team packaged up CRISPR into a harmless virus, which acts like a gene delivery service, injecting the genetic editing tools directly into cells. 

Four weeks after injecting the CRISPR-loaded viruses into the mice, the researchers found that about 30% of the cells seemed to have picked up the gene editing tool. Of the 30% of cells containing CRISPR, around 75% appeared to have at least one CAA interruption in their HTT gene. That means about 1 in 5 brain cells successfully received the protective genetic change – not perfect, but a promising start! After 12 more weeks, the researchers examined the length of CAG repeats and found that expansion seemed to not only stop, but some CAG repeats may have even shortened! 

To investigate if their approach worked beyond HD, the researchers repeated their experiments in cell and mouse models of Friedreich’s Ataxia, another repeat expansion disorder. Excitingly, they observed similar results: up to 55% of brain cells seemed to contain repeat interruptions, and the repeats appeared stable over time, showing no signs of expansion with age. 

Collectively, these findings seem to show that the snowballing repeat expansion in HTT can be stopped, and this approach might even apply to other repeat disorders.

Will CRISPR Break the Ice?

Collectively, these findings seem to show that the snowballing repeat expansion in HTT can be stopped, and this approach might even apply to other repeat disorders. However, there are a couple of reasons for caution. This study focused on whether CRISPR could insert CAA interruptions and halt repeat growth, but it did not assess whether this intervention improves symptoms or delays disease. Knowing the impact of this type of therapeutic approach on HD signs and symptoms is essential for determining if it should move forward.

Additionally, reducing unintended changes to genes other than HTT will be critical before moving to human trials. Another issue is delivery – human brains are much bigger than mouse brains, and getting CRISPR into enough brain cells to make a difference will be particularly challenging. 

Regardless of these current limitations, these results are a major step forward. With advances in gene editing accuracy and more effective delivery methods, CRISPR is likely to become a powerful tool in the fight against HD and other trinucleotide repeat diseases. 

TL;DR: The Big Takeaways

• The problem: HD is caused by a mutation in the HTT gene, where CAG repeats grow over time, a process called somatic expansion. This “genetic snowball” seems to worsen brain cell function and drive disease progression.
• The insight: Even a small interruption in the repeating sequence, like swapping a CAG for a similar and harmless CAA, may be able to slow or stop expansion and delay symptom onset.
• The breakthrough: Scientists used a refined CRISPR tool (called base editing) to insert these potentially protective CAA interruptions into the HTT gene.
• In the lab: In human cells, CRISPR base editing worked in ~80% of cells, seeming to halt expansion and improve cell health.
• In mice: After CRISPR was delivered via viral injection, about 20% of brain cells had protective changes and CAG repeats appeared to stop growing.
• Bonus: Similar success was seen in mouse models of another repeat disorder, Friedreich’s Ataxia.
• The catch: More work is needed to:
  • Prove symptom improvement
  • Minimize unintended effects
  • Scale delivery to the much larger human brain
• Why it matters: This work shows that CRISPR could be used to interrupt repeat expansions in living brain tissue, offering real hope for treating HD and similar genetic disorders.

Learn More

Original research article, “Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice” (open access).

team of researchers from Roche and University College London (UCL) have developed a new clinical measure called the Huntington’s Disease Digital Motor Score (HDDMS). This score compiles data collected remotely using smartphones, to track certain signs and symptoms of Huntington’s disease (HD). This new technology helps collect rich datasets and could help reduce the number of people needed to power clinical studies. Let’s get into what the team did and what this means for the HD community. 

Gathering clues about the early signs of HD

Trying to spot some of the subtle early signs of HD, or how symptoms progress over time can be a lot of detective work from HD clinicians and scientists. Especially since HD can affect each person differently, the clues are not always big and obvious. Instead, symptoms and the way they change can be like tracking down lots of smaller clues and hints that need to be pieced together to help figure out what is really happening for a given person. 

For scientists and doctors studying HD, monitoring the subtle changes in symptoms of the disease is often like this type of detective work. One of the most characteristic groups of symptoms in HD is changes to movement, which can be impacted in many ways. This includes balance, walking, involuntary jerking motions, and how fast people with HD can tap their fingers. 

Each symptom is a clue about how the disease is progressing, which is important to understand in detail, so we can better measure the precise changes which come as HD progresses, and how they might differ between people. With many exciting clinical trials underway or in the pipeline, we are keen to see if these new experimental therapies can slow down or halt these symptoms, especially the earlier and more subtle features of disease. 

But catching these clues early and accurately has been a huge challenge. Traditional clinic visits for people with HD to see their neurologist only give snapshots in time. This means that subtle changes can go unnoticed until later stages, slowing down research and making it harder to tell if new treatments are really working.

A Digital Detective: The HD Digital Motor Score (HDDMS)

To help solve these problems, a team of researchers from UCL and Roche have developed a new kind of detective tool called the HDDMS. This is a score created from simple movement tests and measurements that can be recorded by anyone with HD via their smartphone, wherever they are. 

The measurements collected are part of the HD digital monitoring platform. Just like a detective gathering evidence, participants complete a series of quick motor tests using a smartphone app. These help to measure:

• Standing balance
• Finger tapping speed
• Walking patterns
• Involuntary movements (sometimes called chorea)

The app collects a lot of data as people go about their everyday lives. This means that data can also be collected more frequently than traditional data collection processes, where the person would have to go in to see their neurologist for each test. From all of these tests, the HDDMS combines lots of subtle movement clues into a single score that reflects how well motor function is holding up in people with HD, and how this is changing over time.

A lower score means better motor control; less clues for HD symptoms are found and the detective’s case is still cold. On the other hand, a higher score means more progression, and the clues show the disease is progressing.

Why This New Digital Detective Is a Game-Changer

The researchers tested this digital detective tool using data from over 1,000 people with HD, collected across four different studies. That’s a lot of data! 

Here’s what they found:

More sensitive than traditional tools: The HDDMS was about twice as sensitive in detecting real changes in motor symptoms compared to the commonly used clinical score, the composite unified Huntington’s disease rating scale, or cUHDRS. This means that scientists are able to pick up on clues earlier and more clearly than before.

Reliable and consistent: The score is very consistent when repeatedly calculated, just as a good detective would never miss the same clue twice.

Speeds up clinical trials: Because the HDDMS detects changes faster, it could help researchers run smaller and shorter clinical trials. This means testing new drugs might take less time and involve fewer people, speeding up the hunt for effective treatments.

Convenient and remote: People can complete the tests at home in just five minutes and may no longer need to travel to a clinic for long assessments. It’s like having a detective’s magnifying glass in your pocket, ready to spot clues anytime. This is especially great for people with HD who live in remote areas, very far from their neurologist, or have mobility issues. 

Professor Ed Wild from UCL, one of the lead scientists on this project, explains:

“Our findings suggest that incorporating the HDDMS in clinical trials will help to give clearer answers about whether a potential treatment is working, with fewer participants or shorter lead times than conventional measures…. HDDMS is evaluated in a five-minute assessment in people’s homes, [making] it convenient and potentially more meaningful than in-clinic measures of motor impairment.”

The Bigger Picture: Why Tracking Movement Matters

Movement problems are one of the most visible aspects of HD. They affect daily life, making walking, balance, and fine motor skills harder as the disease progresses.

By accurately tracking these changes, scientists get critical clues about how HD unfolds in each person with more precise timepoints through the process. This helps not only in testing new therapies but also in understanding the disease better.

This is a bit like a detective catching a villain earlier in a mystery, before they cause more havoc. The HDDMS gives doctors and researchers a sharper magnifying glass to track the disease’s subtle moves, allowing for faster intervention and better support.

The Road Ahead for the HDDMS

Of course, no detective tool is perfect. The HDDMS has mostly been tested in people who already show symptoms of HD, and more work is needed to see how well it works in very early or more advanced stages of the disease.

Also, while it detects changes quickly, researchers are still learning how well it predicts long-term outcomes, just like how a detective’s case might unfold over years.

Still, the potential is huge! As smartphone and wearable technologies improve, these digital tools could become standard detectives in monitoring not just HD, but other neurological diseases.

Spotlight on Hope

This new digital motor score is a beacon of hope in the HD research world. By turning everyday devices into powerful detective tools, it promises to accelerate research, reduce patient burden, and help uncover the hidden clues of HD progression. All of this brings us closer to effective treatments and better lives for everyone affected.

So next time you pick up your phone, remember, it might just be the detective helping to solve one of medicine’s toughest mysteries.

TL;DR

• HD Digital Motor Score (HDDMS) is a new smartphone-based tool to track HD motor symptoms remotely.
• It uses simple tests (balance, tapping, walking) via an app accessed at home, which is quick to complete.
• The HDDMS is twice as sensitive as traditional measures, like cUHDRS.
• This means smaller trials could be possible with richer datasets.
• The HDDMS has been tested and validated on data from 1,000+ people across 4 studies.
• It could become a standard tool for HD and other brain diseases, helping bring treatments faster, with less burden for patients.

Learn more

Full article: “A digital motor score for sensitive detection of progression in Huntington’s disease” (open access).

New research is challenging how we think about treating brain diseases, like Huntington’s disease (HD). A study from the lab of Dr. Steven Goldman shows that transplanting healthy early-stage support cells from humans into the brains of adult mice that model HD improves movement, memory, and even survival. But that’s not all — these cells, called “glial progenitor cells”, seemed to influence neurons in the mouse brain to behave more like young, healthy ones. By targeting glia, rather than the neurons primarily affected by HD, this work opens the door to a bold new possibility for treating the disease.

The Brain’s Backstage Crew Steps Into the Spotlight

When we think about HD, we usually picture the effect the disease has on neurons. And for good reason: HD is a brutal genetic condition that primarily damages neurons, which are responsible for movement, learning, and memory. Historically, treatments in development have tried to target those neurons directly by trying to rescue them, replace them, or trying to silence the gene that’s wreaking havoc.

But what if the health of those same neurons could be improved by targeting other key players in the brain? In new work from the Goldman lab, scientists looked beyond neurons and focused instead on the brain’s supporting cast: glial cells. These “helper” cells, long thought to simply keep neurons fed and cushioned, are gaining notoriety as active architects of brain health. And when they’re replaced with healthy ones, they might be able to rebuild broken circuits and better support brain functions.

Huntington’s Disease 101: A Genetic Domino Effect

HD is caused by an expansion of a genetic sequence of CAG repeats in a gene called HTT. If just one copy of this faulty gene is inherited, that person will develop symptoms if they live long enough. The disease hits the striatum hard, an area of the brain in the center of the head responsible for movement and learning. In the striatum, HD leads to the death of medium spiny neurons (MSNs), the cell type that acts as the region’s main communication hubs.

As MSNs die off, so does a person’s ability to move smoothly, think clearly, and regulate their mood. Many past approaches trying to develop treatments for HD have largely focused on the neurons themselves. But neurons don’t live in a vacuum, and this new research shows that maybe we’ve been ignoring the soil while trying to rescue the tree.

The Aha Moment: Glia Aren’t Just Scenery

Earlier studies hinted at something big: when scientists transplanted healthy human glial progenitor cells into newborn HD mice, the disease slowed down. The mice behaved more like mice without the HD gene, their neurons fired less erratically, and their brain structures stayed more intact. That was enough to get scientists asking if this could work in adult mice too.

This new study aimed to find out. Researchers took human cells destined to become glia (called glial progenitor cells) and transplanted them into the striatum of young adult mice that model HD. These weren’t baby mice with developing brains, they were five-week-old mice already showing signs of decline.

But neurons don’t live in a vacuum, and this new research shows that maybe we’ve been ignoring the soil while trying to rescue the tree.

Rebuilding From the Inside Out

The results were impressive and encouraging.

The transplanted glia didn’t just survive, they appeared to thrive. They migrated throughout the striatum, integrated into the mouse brain, and replaced the host’s damaged glial cells. Crucially, they didn’t seem to develop the toxic protein clumps that plague HD cells.

Also striking were the effects on the mice themselves. In tests of movement, HD mice treated with these cells seemed to run around like their healthy peers. On tests of memory and anxiety-like behavior, they seemed to perform almost normally. And they lived about two weeks longer, which is significant for an animal model that usually dies by 18 weeks. While there’s no 1:1 comparison to what that could mean for people, or even that this approach will work for people, that’s a huge improvement in mouse time.

Glia as Gene Whisperers

Next the researchers dove into the neurons themselves to better understand the influence the non-HD glia could be having on them. They used a technique called single nucleus RNA sequencing (snRNA-seq), which shows what genes are turned on or off in individual cells. In untreated HD mice, the MSNs had dialed down levels of genes for communication, structure, and synapse-building.

But when those healthy glia were around, the neurons started singing a different tune.

Key genes flipped back on. Pathways that help neurons grow, connect, and function seemed to be revived. Even the way the DNA was packaged inside the cells appeared to shift toward a healthier state. It’s as if the glia were sending out repair signals, coaxing the neurons into reactivating their own genetic programs to regrow.

Brains Rewired, Literally

And the recovery wasn’t just molecular. The scientists also saw changes in brain structure.

Using a clever tracing method with a modified rabies virus, they imaged the neurons’ dendrites — the branch-like structures that receive signals from other neurons. In HD, these become shriveled over time, like a withered tree. But in the treated HD mice, the dendrites of MSN appeared to be restored, like a healthy tree with lots of branches. 

In other words, the addition of new glia led to healthier neuron structure, which seemed to lead to better function. It seems the glia weren’t just band-aids, they were blueprints for rebuilding.

What’s Next? And What’s the Catch?

Of course, there are caveats. These glial transplants were done in young adult mice before full-blown symptoms. Whether the same effects can be achieved in much older human brains with HD is still unclear. Also, the mouse model used here progresses very quickly, at rates much faster than the human disease, so further studies in slower models are crucial.

And while the researchers uncovered some of the key pathways involved in the neuron-glia dialogue, we still don’t fully understand how glia orchestrate this repair. Are they releasing molecules? Forming special contacts? Changing the local environment? The answers could point the way to new drugs, or even glia-based transplantation therapies in humans.

It’s as if the glia were sending out repair signals, coaxing the neurons into reactivating their own genetic programs to regrow.

The Takeaway: A New Chapter in Brain Repair

This study offers more than just hope for a new HD treatment, it shifts our perspective on how we might treat this brain disease. And if future studies show that these results hold in older brains with more advanced disease, they could represent a sea change in when we might be able to treat HD.

Glial cells, once considered the backstage crew of the brain, are stepping into the spotlight as active healers, architects, and perhaps even directors of recovery. If they can rewire HD brains, might they be able to do the same in Alzheimer’s, Parkinson’s, or ALS?

We’re just beginning to understand the choreography between glia and neurons. But this research is a clear sign that to truly heal the brain, we need to stop looking at neurons in isolation and start thinking about the whole ensemble.

TL;DR: Glia Are the Brain’s Hidden Powerhouses

• Huntington’s disease damages neurons, but neurons don’t work in isolation, they are supported by glial cells.
• A new study transplanted healthy human glial progenitor cells into adult HD mice.
• The results seemed to show improved movement, memory, and lifespan.
• The glia also seemed to have an impressive effect on neurons, appearing to allow them to reactivate a healthy genetic program to grow and function like healthy neurons.
• This suggests glial cells could be a powerful new therapeutic tool, not just for HD, but potentially for other neurodegenerative diseases too.

Learn More

Original research article, “Human glial progenitors transplanted into Huntington disease mice normalize neuronal gene expression, dendritic structure, and behavior” (open access).

Do you remember playing “Simon Says” as a child? It was fun, silly, and surprisingly tricky. You had to listen carefully and only act when you heard “Simon says”. If you moved at the wrong time, you were out. It turns out that Simon Says isn’t just a playground game. It’s also a helpful way to understand what happens in the brains of people with early-stage Huntington’s disease (HD).

A recent study by Dr Marianne Vaugoyeau and her team of researchers from Marseille, France, investigated how HD affects attention and action impulsivity. Action impulsivity refers to the ability to stop ourselves from acting too quickly. This study showed that even before the more visible symptoms of HD appear, it may become harder for people with HD to manage their attentio, but not action impulsivity.

Everyday Life: Simon Says Moments

We’ve all had moments where our mind and body don’t quite sync up. Maybe you’ve started speaking before thinking, forgotten what you were about to say, or found your attention drifting in the middle of a task. It’s frustrating, and very human.

These everyday slips can occur more often and be more disruptive for people with early HD. They might interrupt a conversation even though they know they shouldn’t. Or they might buy an expensive fitness tracker on impulse, thinking it’ll be motivating,  you mostly use it to check the time.

These aren’t just moments of forgetfulness or distraction. They’re part of an invisible struggle in the brain, a tug-of-war between acting impulsively and trying to stay focused.

Why Does This Matter?

Understanding impulsive behaviour and attention issues in people with HD is important for several reasons:

• Early recognition: Subtle changes in attention and impulsivity could help doctors spot HD earlier and plan timely interventions.
• Better support: Families and caregivers might misread impulsive or inattentive behaviour as rudeness or laziness. Knowing it’s part of the condition can help reduce misunderstandings.
• New treatment possibilities: If we can target the brain systems involved in impulsivity and attention, we might improve quality of life, even in the early stages of HD.

The Adult Version of Simon Says

To explore these early changes, Dr Vaugoyeau and her team of researchers invited 20 people with early HDand 20 people without HD to take part in a computer task. 

In this study, ‘early HD’ refers to Stages 2 and 3 of the Huntington’s Disease Integrated Staging System (HD-ISS). For more information on HD-ISS categories, see our article about this system. In Stage 2, people with HD begin to experience symptoms. There may be changes in their movement, mind, and mood symptoms. The individuals affected can often still manage most daily tasks independently. In Stage 3, symptoms are more fully developed and have a bigger impact on daily life, meaning individuals usually need more support for everyday activities.

How to Play: Simon Says for Grown-Ups

The computer task was a bit like a grown-up version of Simon Says, and fittingly, it’s called the Simon task.

Here’s how it worked:

1. A green or red shape appeared on the screen. Participants then pressed a button on either their left or right hand, depending on the shape’s colour. Sounds easy? Not quite.
2. Sometimes the shape appeared on the correct side of the screen (e.g. shape on the left, press the left button). That’s like when Simon actually says what to do. No confusion, just follow the rule.
3. But other times the shape appeared on the opposite side of where you’d expect (e.g. shape on the left but press the right button). That’s similar to Simon being sneaky, your brain might want to follow the shape instead of the rule! 
4. The goal of this game? Ignore where the shape appears and focus only on its colour. It’s a fast-paced way to test how well people can stop, think, and act.

Thumbs on the Trigger (Sort Of)

During the Simon task, researchers placed tiny sensors on participants’ thumbs to measure muscle activity using electromyography (EMG). Sounds fancy, but it’s basically a way to eavesdrop on your muscles. EMG picks up the tiny electrical signals your muscles send out when they’re thinking about moving, sometimes even before you actually do anything. So even if a participant managed to stop themselves from pressing the button, the researchers could tell if their thumb had already whispered, “Let’s go!” This helped them figure out who was acting on impulse and who had better self-control, all by spying on a twitchy thumb!

What Did the Study Find?

People with early HD were able to do the Simon task, but they responded differently compared to those without HD:

1. People with early HD didn’t start moving their thumbs too quickly after the shape appeared on the screen. In other words, they weren’t acting on impulse.
2. Their brains took longer to figure out what to do. However, once they knew what to do, their physical movement was just as quick as people without HD.
3. They struggled to pay attention properly, like missing some of Simon’s instructions or getting distracted halfway through the task. Participant’s scores on attention-based surveys matched these findings.

Final Thoughts: More Than a Game

This study shows that even at the very earliest stages, HD begins to affect the way people respond, focus, and control their actions. But it doesn’t mean people with HD are acting impulsively all the time. Their brains just need more time to process what’s going on, and they may find it harder to stay focused. This research offers a hopeful message because it shows that even in early HD, the brain still retains control over actions and attention. Perhaps future treatments could focus on preserving these abilities, before more symptoms develop. It also gives people with HD and their families a clearer picture of what’s happening, making those frustrating moments feel less confusing.

After all, just like in Simon Says, the rules of attention can get tricky. But with the right tools and support, people with HD may stay in the game longer, and play it on their own terms.

TLDR:

• A “grown-up Simon Says” task helped researchers study attention and impulse control in early Huntington’s disease (HD).
• Electromyography (EMG) sensors detected tiny thumb muscle signals to see when movements were prepared, even if stopped.
• People with early HD showed slower processing and attention difficulties, but not increased impulsivity.
• Early changes in attention can help doctors spot HD sooner and guide better support and treatments in the future.

Learn More

Original research article, “Action impulsivity and attention deficits in patients at an early stage of Huntington disease” (paid access).