Study provides new insights into biological processes linked to Huntington’s disease

A study conducted by the Sant Pau Research Institute (IR Sant Pau) and Hospital de Sant Pau has identified for the first time in living individuals a brain pattern related to the tau protein that changes according to the stage of Huntington's disease. This discovery opens the door both to the use of new biomarkers for monitoring the disease and to the development of treatments for a condition for which no therapeutic options are currently available.

Using positron emission tomography-a molecular neuroimaging technique known as PET-and the second-generation radiotracer [¹⁸F]PI-2620, the researchers demonstrated that this signal can already be detected in some mutation carriers who have not yet developed clinically manifest disease and that, as the disease progresses, the signal increases and spreads according to an organized anatomical distribution.

The study, published in the European Journal of Nuclear Medicine and Molecular Imaging, provides new insights into the biological processes that occur between the genetic alteration responsible for the disease and the onset of its motor, cognitive, and neuropsychiatric manifestations. The findings suggest that tau-related alterations may form part of a cascade of secondary mechanisms capable of amplifying, modifying, or influencing disease progression.

"We have known for some time that tau may play a role in Huntington's disease, but we had never been able to study in the brains of living individuals how this signal was distributed or how it varied across the different stages of the disease," explains Dr. Saül Martínez-Horta, a neuropsychologist in the Movement Disorders Unit of the Neurology Department at Hospital de Sant Pau, a researcher at IR Sant Pau, and first author of the study. "Our findings show that a tau-related biological process is already present before manifest disease develops and that it follows a clearly defined anatomical organization, particularly in certain subcortical regions," he adds.

Beyond the genetic mutation

Huntington's disease is a rare, hereditary neurodegenerative disease for which there is currently no cure. It is caused by an abnormal expansion of CAG repeats in the HTT gene, which disrupts the function of the huntingtin protein and initiates a progressive loss of neuronal function. Following a premanifest period that may last for years, mutation carriers develop a progressive and highly variable combination of motor, cognitive, and neuropsychiatric symptoms that can ultimately lead to a complete loss of independence.

However, the genetic mutation alone does not explain the full complexity of the disease. Individuals with similar CAG expansions may differ substantially in the age at which symptoms appear, the rate of progression, and the predominant type of manifestations.

Moreover, therapeutic strategies directly targeting the primary genetic mechanism have not yet demonstrated conclusive clinical efficacy. This underscores the need to identify other biological processes that occur after the initial genetic alteration and that may modify neuronal vulnerability and the way the disease is expressed in each individual.

One of these processes may involve the dysregulation of tau. This protein occurs naturally in neurons and is essential for maintaining their structure and function. When altered, it can contribute to mechanisms of neuronal damage and neurodegeneration, as occurs in Alzheimer's disease and other conditions known as tauopathies.

Previous studies had already described tau-related alterations in brain tissue from individuals with Huntington's disease. However, until now it had not been possible to observe in vivo how these alterations are distributed throughout the brain or how they change across the different stages of the disease.

The mutation in HTT is the origin of the disease, but an entire cascade of processes that we still do not fully understand takes place between this genetic alteration and the onset of symptoms. Tau may be one of the secondary mechanisms that amplify or modulate how the disease is expressed and progresses in each patient." 

Dr. Saül Martínez-Horta, neuropsychologist in the Movement Disorders Unit, Neurology Department, Hospital de Sant Pau

A brain signal that changes with disease stage

To investigate this possibility, the study included 54 participants: 13 healthy controls, 9 mutation carriers in the premanifest stage, and 32 individuals with manifest Huntington's disease. All participants underwent high-resolution brain magnetic resonance imaging and a 60-minute dynamic PET scan using [¹⁸F]PI-2620. The team analyzed the distribution of the tracer and examined its relationship with the clinical stage of the disease, cumulative genetic burden, motor and functional impairment, cognitive performance, and neuropsychiatric symptoms.

The findings showed that the signal was not distributed diffusely or randomly but instead followed an organized anatomical pattern that depended on the stage of the disease.

The most consistent alterations were found in subcortical structures within the basal ganglia, regions that are particularly vulnerable in Huntington's disease. Among these structures, the globus pallidus showed the most pronounced increase in signal anywhere in the brain, with values rising progressively from healthy controls to premanifest mutation carriers and individuals with manifest disease.

Between 45% and 55% of premanifest mutation carriers already showed values considered abnormal in the globus pallidus. Among individuals with manifest disease, this proportion increased to between 75% and 85%.

The putamen also showed an increase in signal, although to a lesser extent. By contrast, the caudate nucleus showed a reduction in individuals with manifest disease. This finding does not necessarily indicate an absence of tau-related alterations, because the caudate is one of the regions most severely affected by atrophy in Huntington's disease, and the loss of tissue may reduce the signal that PET can measure.

"The globus pallidus shows a robust, bilateral, and progressively increasing alteration, while other regions within the same circuit behave differently. This regional organization indicates that we are not observing a generalized change across the brain, but rather a biological process that impacts different components of brain circuits in distinct ways," explains Dr. Martínez-Horta.

Although the pattern was predominantly subcortical, the study also identified changes in cortical regions, particularly in posterior areas of the brain, including parietal, precuneal, and occipital regions. These findings suggest that the process is not restricted to the basal ganglia but may spread to different cortical territories as the disease progresses.

Limbic regions, including the amygdala and hippocampus, as well as certain areas of the brainstem, showed more heterogeneous profiles. In these regions, the signal was particularly associated with the presence of depressive symptoms and apathy.

Relationship with disease burden and clinical expression

In addition to identifying where the alterations were concentrated, the team analyzed their relationship with the biological burden and clinical manifestations of the disease. The globus pallidus showed the most consistent association with cumulative genetic burden. As this burden increased, so did the likelihood of an abnormal signal in this region. Tracer uptake was also associated with greater motor impairment and overall disease severity.

"The convergence of these findings is particularly relevant. The signal is not only more pronounced in manifest disease but is also associated with cumulative genetic burden and clinical impairment. This strengthens the hypothesis that we are observing a biological process linked to the disease," the researcher emphasizes.

The findings also showed that different brain regions did not follow the same pattern or relate to the same symptoms. This regional heterogeneity may help explain why Huntington's disease can manifest so differently among individuals who share the same genetic alteration.

A new avenue for understanding and treating the disease

The discovery does not mean that tau is the cause of Huntington's disease. The mutation in the HTT gene remains the mechanism that initiates the disease. However, the findings indicate that this initial alteration triggers other biological processes that may contribute to neuronal damage and modify the course of the disease.

It also cannot yet be concluded that all the observed uptake corresponds directly to deposits of pathological tau. Although [¹⁸F]PI-2620 has demonstrated affinity for this protein in other neurodegenerative diseases, its behavior still needs to be specifically validated in brain tissue from individuals with Huntington's disease. For this reason, the researchers refer to a tau-sensitive signal rather than a specific and exclusive measurement of this protein.

"The pattern is highly consistent from both an anatomical and clinical perspective, but we still need to determine precisely which molecular component the tracer is detecting in Huntington's disease. This validation will be essential to fully understand the biological significance of the findings," explains Dr. Martínez-Horta.

Beyond its potential use as a biomarker, the principal value of the study is that it makes it possible to observe in vivo one of the biological processes that may be involved in the pathophysiology of the disease. This opens the possibility of investigating whether tau or its associated molecular mechanisms could represent new therapeutic targets.

"For many years, we have tended to view Huntington's disease almost exclusively through the lens of the genetic mutation and the huntingtin protein. Our findings reinforce the idea that the disease is the result of a much more complex cascade involving interactions among multiple biological processes. Understanding this complexity may be essential for developing more effective treatments, potentially targeting several mechanisms rather than focusing exclusively on the initial genetic process," says the researcher.

In the future, the signal identified through PET could also be incorporated into a multimodal strategy alongside magnetic resonance imaging, clinical and genetic measures, and biomarkers in blood or cerebrospinal fluid. This combination could help identify groups of patients with different biological mechanisms, improve the selection of participants for clinical trials, and assess whether a therapeutic intervention modifies processes associated with disease progression.

The next steps will include larger longitudinal studies, specific methods for correcting the effects of brain atrophy, and the combination of PET with fluid biomarkers and magnetic resonance imaging. There will also be the direct validation of tracer binding in brain tissue from individuals with Huntington's disease.

Sant Pau, a referral center for Huntington's disease

Hospital de Sant Pau is a national referral center within Spain's CSUR network for rare diseases involving movement disorders and carries out extensive clinical, patient care, and research activities in Huntington's disease. This track record has established Sant Pau as one of the leading centers for the care and study of this disease, both nationally and internationally.

The study was funded by the Carlos III Health Institute through the Health Research Fund and co-funded by the European Regional Development Fund.