HDBuzz

Picture a quiet neighborhood. Things used to run smoothly here. Kids played outside, front yards were mowed, and the neurons — the longtime residents — looked out for one another. But lately, fires are breaking out. And worst of all? The neighborhood’s most important firefighter, PKD1, has stopped showing up.

That metaphor details findings from a new study published in Cell Death and Disease. Researchers have found that a protein called protein kinase D1 (PKD1), long thought to be part of the brain’s emergency response system, is mysteriously missing in the brains of people with Huntington’s disease (HD). And when it’s gone, the damage gets a lot worse.

The Usual Suspects: Glutamate, Calcium, and Cell Death

Let’s rewind and talk about what usually sets the neighborhood ablaze. In the brains of people with HD, a specific group of neurons called medium spiny neurons (MSNs) are the most vulnerable. These cells are found in the center of the brain, in a region called the striatum. They are sensitive to a chemical called glutamate, one of the brain’s main message-sending molecules.

But when there’s too much glutamate activity, what scientists call excitotoxicity, the neurons get overwhelmed. Think electrical wires sparking, fires starting, no one around to stop them. This overactivity floods the cells with calcium, which in turn activates destructive enzymes like Calpain — basically a demolition crew that wasn’t invited.

Over time, the neighborhood falls into disrepair. A critical protein that MSNs need to stay alive, called DARPP-32, starts to vanish. This loss is a bad sign, like watching upstanding citizens move out of your neighborhood while bad actors move in.

Enter PKD1: The First Responder

For years, researchers believed PKD1 was one of the good guys, like a firefighter who runs toward the flames. In other types of brain injury, like stroke, PKD1 gets switched on and helps neurons survive. It does this in part by boosting another molecule that cleans up toxic waste known as oxidative stress.

In lab experiments run in HD mouse models, the scientists even engineered a version of PKD1 that’s always active, like a firefighter that never clocks out. That version, called PKD1-Ca, protected neurons from both excitotoxicity and oxidative stress. So far, so good.

Plot Twist: The Firefighter Goes Missing

But here’s where the mystery deepens. In brains affected by HD, both human and mouse models, PKD1 levels seemed to be decreasing. Not just in activity, but in the amount of protein. And that drop started early, especially in the striatum, a part of the brain most impacted by HD. These changes seem to be happening long before the cortex (the outer wrinkly part of the brain) was heavily affected.

In mice that model HD, the drop in PKD1 protein lined up with a drop in the levels of the mRNA message molecules which encodes the instructions to make PKD1. But in human brains? The instructions were still there, yet the protein was still missing. It’s like having the firehouse blueprints in hand, but no one’s building the station.

The disconnect between the amount of message and protein is still unclear. Maybe the PKD1 protein is being broken down too quickly. Maybe it’s getting misrouted. Or maybe there’s a larger system failure, like the emergency dispatch is offline and no one’s getting the call.

Researchers have found that a protein called protein kinase D1 (PKD1), long thought to be part of the brain’s emergency response system, is mysteriously missing in the brains of people with Huntington’s disease (HD). And when it’s gone, the damage gets a lot worse.

Support Crew Shifting Into Overdrive 

Here’s another wrinkle in the plot: researchers found PKD1 showing up in unexpected places, like reactive astrocytes. Astrocytes are a type of glial cell, the brain’s unsung support crew. They don’t send electrical signals like neurons, but they’re essential for keeping the brain running smoothly. Think of them as the neighborhood’s utility workers: regulating energy supply, cleaning up waste, and maintaining the environment so neurons can do their jobs.

Under normal conditions, astrocytes stay mostly behind the scenes. But in disease, they often shift into high gear, swelling in size, changing their behavior, and releasing signals that can either help or hurt. This state is called reactive gliosis, and it’s especially pronounced in HD brains.

The new twist is that researchers think PKD1, previously thought to live mostly in neurons, may be showing up in these reactive astrocytes, both in human HD brains and in parts of the mouse brain. The researchers aren’t quite sure how to interpret these findings. 

Are the astrocytes trying to rescue their neighborhood? Are they sending distress signals? Or is this just another sign that the brain’s usual systems are getting scrambled? Whatever the case, the discovery adds another layer to the mystery and suggests we may need to look beyond neurons to fully understand HD.

Putting It to the Test: What Happens Without PKD1?

To see if PKD1 was really making a difference, the scientists tested what happened when it was intentionally blocked. In a dish of rat neurons, they used a tool drug to shut PKD1 down. When those neurons were exposed to NMDA (a glutamate-like chemical that mimics excitotoxic stress), the results were disastrous: more neuron death, faster loss of the MSN-protecting protein DARPP-32, and full-blown cellular collapse.

Worse yet, just removing PKD1, even without adding stress, seemed to be enough to start the damage. It turns out this protein may not just be helpful during a crisis, it could be critical for normal daily maintenance, like checking the smoke alarms and fixing faulty wiring.

The Comeback Kid: Turning PKD1 Back On

Here’s the good news. When the researchers turned PKD1 back on using their always-active version (PKD1-Ca), the effect was dramatic. In HD neurons grown in a dish, PKD1-Ca protected the cells. It preserved DARPP-32 levels and blocked cell death. It gave the neurons a fighting chance.

The researchers also tested it in mice that model HD, delivering PKD1-Ca straight into the striatum. It worked there too. Not only did it seem to preserve DARPP-32 in the treated area, but there were signs that it might have helped nearby neurons as well, like one house getting reinforced and then sending help to the neighbors.

PKD1 could be more than just background noise in HD. This study suggests it may play an important role in protecting vulnerable neurons, and that its early loss could make those cells more susceptible to damage.

What It All Means

So what’s the takeaway? PKD1 could be more than just background noise in HD. This study suggests it may play an important role in protecting vulnerable neurons, and that its early loss could make those cells more susceptible to damage. Restoring or enhancing PKD1 function might offer one potential strategy for intervention, but much more work is needed to understand how, when, and whether this could translate into a treatment.

There are still big, unanswered questions: Why does PKD1 disappear in the first place? Why do mouse and human brains show different patterns of loss? Can boosting PKD1 be done safely, and what role are other cells, like astrocytes, playing in this story? These are important directions for future research.

What this study does offer is a compelling new piece of the HD puzzle. It pushes the field to think differently about the molecular players involved — not just about those sparking the fires in the brain, but about the protectors that may be missing when the flames start to spread.

TL;DR — What You Really Need to Know

• Huntington’s disease causes specific neurons in the striatum to die, partly due to overstimulation by glutamate (called excitotoxicity).
• A protein called PKD1 is normally protective, like a firefighter putting out molecular fires.
• In both human HD brains and mouse models, PKD1 protein levels are significantly reduced, especially early in the disease.
• Blocking PKD1 made things worse; restoring PKD1 protected neurons and preserved key proteins like DARPP-32.
• Boosting PKD1 in mice showed promise, not just in treated areas but potentially in neighboring cells too.
• PKD1 could be a potential therapeutic target, and understanding why it disappears may help us uncover how the brain’s defenses break down in HD, and how we might reinforce them.

Learn More

Original research article, “Down-regulation of neuroprotective protein kinase D in Huntington´s disease” (open access).

Spark Therapeutics, recently integrated into Roche Pharmaceuticals, has been working on an HD gene therapy. It’s delivered via a one-time brain surgery and is designed to lower levels of the huntingtin protein. A (very) small safety study has recently begun, and so far, one brave individual has received this experimental therapy, known as RG6662 (or SPK-10001). Let’s discuss how company relationships fuel clinical progress, and what’s next in the development of the drug. 

The relationship between Spark and Roche

To capture your interest with a romance, let’s talk about how these companies found themselves holding hands. Spark began as a biotech company about a decade ago, based on academic research at the University of Pennsylvania. They developed the first ever gene therapy for an inherited disease (Luxterna) to treat a type of vision loss. Roche became particularly interested in this, as well as their work on a blood disorder called hemophilia, ultimately purchasing the company in 2019. 

While fully owned by Roche, Spark continued to grow, building a big scientific campus for discovery and manufacturing, and working on more gene therapies, including one for HD. In 2024-2025 the company went through a bunch of restructuring, and in May of 2025, Roche announced a new relationship status: Spark has been fully integrated. That means Roche now has full control of how Spark is managed, how it operates, and the future of the drugs they have developed. 

Taking an HD drug from its academic research origins, starting then growing a company, and partnering with an even larger one to enable clinical development – that’s a story arc we can commit to following! 

RG6662/SPK-10001

When a big company acquires a drug in development, they usually rename or renumber it according to their own system. We’ve mentioned SPK-10001 in our coverage of major HD conferences like the 2024 annual meeting of the Huntington Study Group and the 2025 CHDI HD Therapeutics Conference. Now (gasp) it’s taken Roche’s name: RG6662.

It is an experimental gene therapy, packaged inside of a harmless virus called an AAV. When it is injected directly into the brain, it can spread to many brain areas and deliver genetic instructions (creating a microRNA) to tell the cells to stop producing the huntingtin protein. RG6662 lowers both expanded huntingtin – the kind that arises from extra CAG repeats and can harm brain cells – and wild type huntingtin – the kind that is a healthy length. The goal is to lower huntingtin for a very long period of time with a single treatment, in hopes that this could slow or stop the worsening of HD symptoms. 

Going public

Now that we’ve binged the first few seasons, let’s get up to date on the storyline. The Spark-Roche connection has birthed a new gene therapy trial of RG6662/SPK-10001. A June 12^th letter directed specifically to HD families and shared by advocacy organizations, stated that the first patient had been dosed in a small clinical trial. If it feels like this baby came out of the blue, rest assured that there have been massive efforts behind the scenes to take this new HD drug from bench to bedside. 

Notably, Spark representatives have presented updates on the pre-clinical science at the biggest recent HD conferences. Last November we touched on their efforts in primates to test the drug’s safety and confirm its ability to spread to different areas of the brain, lowering huntingtin for up to a year. In February they shared data from mouse and primate studies that looked more closely at dosing, delivery, and biomarkers like NfL. They have also talked about their work to optimize the surgical procedure, and their plans for the upcoming trial. 

The trial itself

The study will have multiple parts and it will move forward over several years. Spark and Roche announced initiation of the first part of the study (Part A), which will now pass fully into Roche’s hands. It will run in the USA and is planned to involve participants with early HD aged 25-65, with a CAG repeat length of 40 or more, who are mostly independent in their activities and care, and have a loved one who can be their study companion. In Part A, 8 participants will receive RG6662, as an injection into the caudate and putamen – the parts of the brain most vulnerable in HD.

Part A takes it slow, checking very carefully for safety. If all seems to be going well for the first recipient of RG6662 (they will be monitored for at least a few months), then Roche will proceed with the next participant. There may also be a “dose escalation” to test whether a higher amount of drug might be better. “Our team will learn from each participant’s experience, and we will adjust the study based on learnings,” Roche and Spark shared in the joint announcement.  

Part B of the study will include a placebo arm, so some of the participants will receive a “sham” brain surgery with no drug delivered. Then Part C would allow those who were assigned a placebo to receive RG662 later on, and Part D will involve long-term follow-up of all of the participants to look at safety and effectiveness over a much longer period of time. 

Looking to the future

We’ll have our eyes peeled for more news around the progress of this trial, of course – and we’re excited that another gene therapy has reached the clinic. What’s also notable here is the public display of affection partnership and engagement. Not all companies make joint community-facing announcements about the initiation of a study. Both Spark and Roche have a history of partnering with advocacy organizations early in drug development, and Roche’s learnings from the GENERATION HD1 and GENERATION HD2 trials will surely inform their strategy in HD moving forward. They have partnered with the Huntington Study Group, an organization with many years of experience running HD trials, to carry out the study. 

All in all, years of data and exploration in animals as well as many touchpoints with the HD community allowed Spark and Roche to move ahead with the design of a clinical trial in people. It’s particularly encouraging when companies use their knowledge, partnerships, and community connections not only to make scientific decisions around dosing and delivery, but also to integrate safety and support measures that meet the needs of people with HD and their companions. We’ll be sure to keep you in the loop as more sparks fly. 

TL;DR

• Spark Therapeutics, now fully integrated into Roche, has launched a small safety trial of a one-time gene therapy for HD called RG6662 (formerly SPK-10001).
• Delivered via brain surgery, the therapy uses an AAV vector to lower both mutant and normal huntingtin protein levels.
• The first participant has received the treatment, marking a major milestone after years of research.
• The multi-phase trial, starting in the U.S. with early-stage HD patients, will gradually assess safety and dosing before expanding.
• Spark and Roche’s collaboration emphasizes transparency and patient engagement, building on past HD trial experiences to guide their approach.

Community letter

The latest instalment in a series of big studies to understand the genetics of Huntington disease (HD) just hit the shelves. These studies have focused on how small changes in the genetic letters of a person with HD can impact when they develop symptoms of the disease. The previous instalments in this series have been particularly important for opening up new ways to understand HD and to develop new treatments. So let’s have a look at how this study was done, and what this newest volume tells us that is different from the previous ones.

The genome is a book, but we all have spelling changes

The genome of every person is made up of 4 letters – C, A, G, and T. They’re combined in different ways to make every gene in our body, like how the 26 letters of alphabet can spell out all sorts of different words on each page of a book. 

But we each have spelling changes on individual pages of our personal book (our genome) that differ from other people. You can think of these spelling changes as differences of a few letters that spell a similar word, like gray and grey. Sometimes a T is replaced by a G, or C is replaced by a A, just to give two examples. These changes can be shared with many other people – what we call common variants – or they might only be found in few other people around the world – which we call rare variants.

For many years, a group of talented scientists called the Genetic Modifiers of HD Consortium, or GeM-HD for short, have been looking at the impact of common variants – common genetic spelling changes – on how people develop HD. What this means is that they found common genetic spelling changes in people with HD and then looked to see if their symptoms of HD differed based on the spelling changes. 

To date, the GeM-HD consortium has studied thousands of people with HD and hundreds of thousands of spelling changes in every single person. That’s a lot of data to analyze! So new volumes in the series are only published about once every 5 years. 

The latest volume

This new study from the GeM-HD Consortium is the third. It comes after two big studies that the Consortium published in 2015 and 2019. 

The first study, published in 2015, was a true bestseller. It revealed that spelling changes in people who develop HD earlier or later happen on very specific pages (genes) of the human genome. Many of these pages (genes) with spelling changes that make HD appear earlier or later seem to be connected with how the CAG repeat that causes HD becomes longer or shorter. 

The discoveries by the Consortium in the first volume set off a major change in how scientists think HD develops – focused on how the CAG repeat gets longer or shorter in the body, a process called somatic instability. It also changed how drug companies think about developing new medications to treat HD.

The GeM-HD sequel, which hit the shelves in 2019, told us even more: that there are multiple spelling changes on specific pages (genes) that can impact HD in opposite ways. For example, one spelling change might make HD develop faster, but a different spelling change further down the page might make HD develop slower. 

The GeM-HD consortium has studied thousands of people with HD and hundreds of thousands of spelling changes in every single person. That’s a lot of data to analyze!

But this second volume ended with a cliffhanger mystery: do the spelling changes in people who develop HD earlier or later also change the length of the CAG repeat in people? Up to that point, it was mostly guessing, based on the pages where the spelling changes were found. That’s what this third instalment is about.

The plot twist

To explore whether the spelling changes that impact symptoms of HD also alter the length of the CAG repeat, the Consortium scientists took a clever approach: they compared the previously studied spelling changes on those pages (genes) with the number of letters for the CAG repeat on the HD page (gene), each on different pages of the book. 

Surprisingly, and perhaps confusingly, the answer is not always yes, and sometimes no. The Consortium scientists found that sometimes a spelling change can make symptoms of HD worse but have no impact on the length of the CAG repeat at all. The opposite can also occur – sometimes there are spelling changes that change the CAG repeat but don’t change the symptoms of HD. 

Does this mean that new drugs being designed to stop changes in the CAG repeat will not work? It’s not clear, since the Consortium scientists were only looking at changes in CAG repeats in the blood, which may have little to do with what’s happening the brain. That’s a story for another volume. But the third volume ends with one clear glimmer of hope.

A hero for the next story?

One of the pages (genes) where the spelling changes do what scientists hoped they would is MSH3. You might have already heard of MSH3 as a new drug target for HD, a strategy based on work from other skilled HD scientists, including teams in the UK and US. 

On the page (gene) for MSH3, the GeM-HD Consortium scientists found that spelling changes impact the CAG repeat in blood in a way that matches what drug hunters are now trying to imitate. This means that there is good evidence from the genetics of people with HD that the therapeutic approach of targeting MSH3 may work. However, we still don’t know exactly how all the spelling changes in MSH3 and other genes are impacting HD in the brain.

Perhaps we will find out more in the next volume from these scientists! But fans of the series may not want to wait another five years. 

Science made possible thanks to HD families

These pioneering studies of genetic spelling changes and how they impact HD could not have happened without the participation of thousands of people with HD and their families who donated their blood and DNA for research. Every person with HD who donated their blood and DNA to research helped to make these discoveries possible.

TL;DR

• GeM-HD scientists have released their third major study exploring how small genetic variations (spelling changes in DNA) influence when symptoms of HD begin.
• Earlier studies revealed some changes are linked to how the CAG repeat in the HTT gene changes, a key factor in HD. This new study asked whether those same genetic changes also directly affect the CAG repeat’s length.
• The answer? It’s complicated. Some variants influence symptoms without changing the CAG repeat, and others change the repeat without affecting symptoms. So, while CAG repeat instability matters, it’s not the whole story.
• One key finding supports the current drug-development strategy: changes in the gene MSH3 both affect the CAG repeat and align with symptom changes, reinforcing MSH3 as a promising drug target.
• This work, made possible by thousands of HD families donating DNA, continues to shape how we understand and treat HD, and hints at more discoveries to come in future “volumes.”

Learn more

Original research article, Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease highlight shared and tissue-specific effects (open access).

We all have days when we feel irritable, like when you’re stuck in traffic, or someone cuts in line at the grocery store. But for people living with Huntington’s disease (HD), irritability isn’t just a passing mood. It can feel like a thunderstorm that arrives suddenly, often without warning, and affects not only the person with HD but also everyone around them.

In a recent study, Dr Sarah Gunn and her team of researchers from Leicester, UK, set out to explore what irritability really feels like for people with HD and their families. By hearing directly from people with HD, the researchers painted a clearer, more honest picture of irritability for folks impacted by this disease. This study showed that irritability is much more than just a mood. It is a real and challenging problem that impacts emotional regulation, relationships, and general wellbeing.

It’s Like a Volcano 

One common, but lesser-understood symptom of HD is irritability. Irritability can be deeply distressing for the person with HD, who is experiencing these intense emotions. However, it can also cause significant emotional strain for family and friends, leaving everyone involved feeling frustrated, isolated, and misunderstood.

Imagine holding a bottle of fizzy drink (soda) that’s been shaken. You try to keep it closed, but eventually, the pressure builds, and it explodes. This image helps us understand how irritability feels for people with HD: sudden, intense, and difficult to control. It’s like a volcano bubbling beneath the surface, calm one moment, then suddenly erupting over something that might seem small or insignificant to others. It’s not that people with HD want to lash out; they may feel helpless because they notice their irritation rising but cannot control their reactions.

Inside the Storm

Instead of relying on medical tests or numbers, Dr Gunn and her team wanted to understand irritability from the perspective of those who live with HD. They investigated irritability in people with pre-manifest and manifest HD. ‘Pre-manifest’ HD refers to people who have tested positive for the gene that causes HD (CAG number is 40 or more), but they do not yet display any recognisable symptoms (equivalent to HD Integrated Staging System (HD-ISS) Stage 0). Whereas ‘manifest’ HD refers to people who have tested positive for the HD gene and the person is showing recognisable symptoms of HD (HD-ISS Stage 1 and beyond). In this study, 42% of individuals had pre-manifest HD, while 58% had manifest HD.

The researchers conducted interviews, giving people with HD a chance to share their experiences, in their own words. The conversations covered how people with HD felt about the word “irritability,” how they experienced it, what triggered it, how they managed it, and how it affected their relationships.

Once the interviews were complete, the researchers carefully reviewed the interviews, focussing on irritability and how it affected people with HD. They identified three main themes (categories) that came up repeatedly:

1. The Triggers
2. The Challenges
3. Soothing the Struggle 

The Triggers 

Dr Gunn and her team of researchers noted common ideas across different participants with HD, for the category, ‘The Triggers’. One key idea was, ‘It’s not me, it’s the HD’. Participants had complicated feelings about the word “irritability.” Some participants felt uncomfortable identifying with irritability, as it can carry negative connotations, while others felt it accurately described their experience with HD.

Many participants explained how the stress of living with HD made them feel more irritable. Worries about their future and concerns for their family members added to the strain, making it harder to stay calm, and increasing the chance of snapping at others.

Feeling out of control or overwhelmed could contribute to heightened feelings of irritability in people with HD. Participants commented that life events such as grief, past trauma, or busy, chaotic environments, made it harder to manage emotions. Interestingly, all participants talked about how basic physical needs, like being hungry, tired, in pain, or too hot or cold, could quickly push their irritability over the edge. It’s a bit like how anyone might feel more impatient or upset when they are hungry, or in pain.

The Challenges

Participants remarked how even tiny annoyances, like a door slamming while you are trying to talk, could quickly explode into intense anger. These feelings might linger, making it hard to stay calm or think clearly. This could lead to snapping or saying hurtful things. Some felt powerless over these feelings, which left them scared and worried about their own outbursts and how it affected those around them.

Irritability in HD can cause misunderstandings, especially with loved ones who may feel hurt or distant, this study found. Some people with HD tried to hide difficult feelings at work, or around new friends, but this often made them to more frustrated at home. Many people with HD reported cancelling plans with friends and spending more time alone, to protect themselves and others. 

Soothing the Struggle

During the interviews, participants shared different methods they used to keep irritability from boiling over. Taking breaks, distracting themselves, or leaning on supportive friends and professionals were common strategies. Alternatively, some suggested that medication and small lifestyle changes, like avoiding stressors, helped them to stay calm and protect their peace.

A Call for Compassion

Studies like this document in the scientific literature what many people from HD families already know. This type of research is critical so that patient organisations, clinicians and other HD stakeholders can lobby for resources, support services, and treatment strategies that address the full spectrum of HD symptoms. HD is more than just movement issues; it involves emotional, cognitive, and behavioral challenges that can deeply affect quality of life. Recognizing and validating these symptoms through research ensures they are not overlooked in care plans or drug development efforts.

If you are living with HD or caring for someone who is, know that you are not alone. Irritability is not a sign of weakness or bad character. It’s a real and painful part of HD. With understanding, patience, and the right strategies, it can be managed.

Just like you would make room for someone using a wheelchair, or help someone with a broken leg, people with HD need compassion for the challenges you can’t always see, like irritability. Let’s look past the surface and recognise the storm for what it is. Irritability is a symptom, not the whole person.

TL;DR

• Irritability in HD is more than just a bad mood; it’s a real, distressing symptom that can feel like a sudden storm, affecting both the person with HD and those around them.
• A UK-based study led by Dr. Sarah Gunn explored how people with HD experience and manage irritability. Through interviews, researchers identified key triggers (like stress, fatigue, or chaotic environments), emotional and social challenges, and coping strategies (like taking breaks or seeking support).
• The study emphasizes that irritability is a valid, often invisible part of HD that deserves understanding, compassion, and targeted support in care and treatment.

Learn more

Original research article, “‘It’s more than just irritability’: perspectives and experiences of irritability among people affected by Huntington’s disease” (open access).

Welcome to Brainland, the bustling, 24/7 theme park in your head. There’s Memory Maze, Logic Log Flume, and of course, the Emotion Coaster, where your brain races through tracks themed around happiness, sadness, and anger. However, for some people who carry the gene for Huntington’s disease (HD), some of these rides start acting up long before the big attractions like Movement Mountain or Memory Maze show signs of trouble. Strangely, even when everything else seems fine, the Emotion Coaster may begin to stall, especially on the tracks of anger, sadness, and fear. 

This isn’t a theme park glitch; it’s real science, explored by Dr. Shahin Nasr and his team at Massachusetts General Hospital and Harvard Medical School. 

When the Emotion Coaster Goes Off Track

Most of us don’t think twice about reading someone’s face. A smile reflects happiness. A furrowed brow? Maybe anger. It’s automatic, like muscle memory because our brains are wired to pick up on emotional signals. But what happens when the brain can’t understand how others feel?

Reading facial expressions is crucial because it helps us navigate daily social life. It helps us understand how others feel, respond with empathy, and avoid misunderstandings. Whether it’s noticing a friend’s sadness behind a smile, picking up on a colleague’s confusion in a meeting, or sensing when to give someone space, facial cues guide how we connect, communicate, and make social decisions every single day. 

When this ability fades, as it can in HD, relationships can suffer. This is not because people with HD don’t care, but because they may struggle to understand emotional expressions in other people, a skill which many take for granted.

Buckle Up for the Emotion Tracks

Dr. Shahin Nasr and his team ran an important study on emotion recognition in people with pre-manifest HD. ‘Pre-manifest’ HD refers to people who have tested positive for the gene that causes HD (CAG number is 40 or more), but they do not yet display any recognisable symptoms (equivalent to HD Integrated Staging System (HD-ISS) Stage 0). 21 people with pre-manifest HD and 16 people who did not have HD were recruited in this study. 

Each participant was shown 70 different photographs of people. These photographs displayed different facial expressions reflecting different emotions, including happiness, anger, sadness, fear, surprise, disgust, and ‘neutral’ faces. Participants were provided with name cards for each emotion. The task was simple, choose one name card that best identifies the emotion being shown in the photograph.

Interestingly, the participants with pre-manifest HD were less accurate at recognising anger, sadness, and fear from facial expressions displayed in the photographs compared to the control group. These early struggles to recognise particular emotions from other people’s faces suggests that even during the pre-manifest stage of HD, the inner ability to read negative emotions (anger, sadness, and fear) may already be decreasing.

Under the Hood of the Emotion Coaster

To dig deeper, a smaller sub-group of participants had their brains scanned using functional MRI (fMRI) while they looked at images of faces showing different emotions (neutral, happy, and angry). 

Think of the brain scans like a theme park map that shows which rides are busiest. But instead of tracking people, it shows which parts of the brain are most active, based on where the blood flows. Dr. Nasr and his team wanted to see what was happening in the brain while participants looked at faces reflecting different emotions. Specifically, how busy the Emotion Coaster was in people with pre-manifest HD (meaning the brain area that helps us understand facial expressions in other people).

When this ability fades, as it can in HD, relationships can suffer. This is not because people with HD don’t care, but because they may struggle to understand emotional expressions in other people, a skill which many take for granted.

Interestingly, there is one particular region of the brain that helps us to understand what someone is feeling or thinking by looking at their face, body, or tone of voice. However, in people with pre-manifest HD, this area of the brain showed reduced activity. This wasn’t just about having difficulty seeing faces clearly or understanding faces in general. It was more like the Emotion Coaster wasn’t working properly, making it harder for people with pre-manifest HD to understand emotions through facial expressions in other people.

Fixing the Emotion Coaster Before It Breaks Down

These findings are important because they show that small changes in the brain can happen early, even before movement symptoms begin. This can affect how people with pre-manifest HD understand emotions through facial expressions in other people.

However, this isn’t just something interesting to note. If people with pre-manifest HD have trouble reading emotions, it can cause big problems in relationships, work, and mental health. They might not react the right way in tense situations, which can lead to fights, feeling alone, or more stress.

This research gives us hope. By spotting early warning signs, such as changes in brain activity, we may be able to better support emotional and cognitive health, in people with pre-manifest HD before other symptoms appear.

End of the Ride

HD doesn’t just appear overnight, it starts gradually, with little changes that may be easy to miss. This study highlights that one of the earlier signs of HD might be in how we understand facial expressions in other people. For example, spotting a frown, a worried look, or a hint of anger.

Dr. Nasr and his team confirmed that a specific part of the brain which is important in understanding emotions by looking at facial expressions, was not as active in people with pre-manifest HD. This is equivalent to spotting a problem on the Emotion Coaster, before it fully breaks down.

It is important to remember that this study is more than just science, it’s a step towards changing lives for people with HD. By spotting very early brain changes linked to emotion recognition, this is not just identifying a faulty ride, it is uncovering a potential early warning sign of HD. The earlier we see the signs, the sooner we can act. It also provides us with a chance to support the daily interactions for people with pre-manifest HD, protect their relationships and even their quality of life.

TL;DR

• Emotion Coaster Starts to Wobble Early – Even before classic HD symptoms like movement or memory issues appear, people with the gene may struggle to recognise facial expressions showing anger, sadness, or fear.
• Study in Pre-manifest HD Shows Reduced Accuracy – In a study by Dr. Shahin Nasr, participants with pre-manifest HD were less accurate at identifying negative emotions in photos of facial expressions, suggesting early emotional processing changes.
• Brain Scans Reveal Decreased Activity – fMRI scans showed that brain regions involved in recognising others’ emotions are less active in people with pre-manifest HD, even though they had no visible symptoms.
• Real-Life Impact – This difficulty reading emotions can affect relationships, cause misunderstandings, and increase stress, not due to a lack of empathy, but reduced ability to interpret social cues.
• Early Detection = Early Support – Spotting these changes could help clinicians intervene earlier to support emotional wellbeing, social functioning, and quality of life before HD symptoms fully develop.
• Hope on the Horizon – This research adds to our understanding of HD progression and offers a potential early marker for future interventions targeting emotional and cognitive health.

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Original research article, “Are you angry? Neural basis of impaired facial expression recognition in pre-manifest Huntington’s” (open access)