PET Imaging Reveals Tau-Related Brain Pattern in Living Huntington's Disease Patients for the First Time
核心洞察
Researchers at Sant Pau Research Institute (搜索) identified a tau protein (搜索)-related brain pattern in living Huntington's disease (搜索) patients using PET imaging and the radiotracer [¹⁸F]PI-2620 (搜索) for the first time.
The tau-sensitive signal was detected in 45–55% of premanifest mutation carriers and 75–85% of manifest disease patients, concentrated primarily in the globus pallidus region of the basal ganglia.
The signal showed progressive increase and organized anatomical spread correlating with cumulative genetic burden, motor impairment, and overall disease severity.
A landmark study conducted by the Sant Pau Research Institute (搜索) (IR Sant Pau) and Hospital de Sant Pau (搜索) has identified, for the first time in living individuals, a brain pattern related to the tau protein (搜索) that changes according to the stage of Huntington's disease (搜索). Published in the European Journal of Nuclear Medicine and Molecular Imaging, the discovery opens the door to new biomarkers for disease monitoring and the development of treatments for a condition that currently has no therapeutic options available.
Using positron emission tomography (PET) with the second-generation radiotracer [¹⁸F]PI-2620 (搜索), researchers demonstrated that the tau-sensitive signal can already be detected in some mutation carriers who have not yet developed clinically manifest disease. As the disease progresses, the signal increases and spreads according to an organized anatomical distribution.
"We have known for some time that tau may play a role in Huntington's disease (搜索), 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," said Dr. Saül Martínez-Horta, a neuropsychologist in the Movement Disorders Unit of the Neurology Department at Hospital de Sant Pau (搜索), researcher at IR Sant Pau, and first author of the study.
A Complex Disease Beyond the Genetic Mutation
Huntington's disease (搜索) is a rare, hereditary neurodegenerative disease caused by an abnormal expansion of CAG repeats in the HTT gene (搜索), which disrupts the function of the huntingtin protein and initiates 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.
Critically, 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. Furthermore, therapeutic strategies directly targeting the primary genetic mechanism have not yet demonstrated conclusive clinical efficacy.
"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. Martínez-Horta explained.
Study Design and Key Findings
The study included 54 participants: 13 healthy controls, 9 mutation carriers in the premanifest stage, and 32 individuals with manifest Huntington's disease (搜索). All participants underwent high-resolution brain magnetic resonance imaging and a 60-minute dynamic PET scan using [¹⁸F]PI-2620 (搜索). The team analyzed the distribution of the tracer and examined its relationship with clinical stage, cumulative genetic burden, motor and functional impairment, cognitive performance, and neuropsychiatric symptoms.
The findings showed that the signal followed an organized anatomical pattern dependent on disease stage, rather than a diffuse or random distribution. The most consistent alterations were found in subcortical structures within the basal ganglia, regions particularly vulnerable in Huntington's disease (搜索).
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 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," Dr. Martínez-Horta noted.
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—a finding that does not necessarily indicate an absence of tau-related alterations, as the caudate is one of the regions most severely affected by atrophy in Huntington's disease (搜索), and tissue loss may reduce the signal that PET can measure.
Cortical and Limbic Involvement
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 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.
Correlation with Disease Burden
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," Dr. Martínez-Horta emphasized.
The findings also revealed that different brain regions did not follow the same pattern or relate to the same symptoms, offering a potential explanation for why Huntington's disease (搜索) can manifest so differently among individuals who share the same genetic alteration.
Therapeutic Implications and Future Directions
The discovery does not mean that tau is the cause of Huntington's disease (搜索)—the mutation in the HTT gene (搜索) remains the initiating mechanism. 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 observed uptake corresponds directly to deposits of pathological tau. Although [¹⁸F]PI-2620 (搜索) 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 (搜索). 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 (搜索). This validation will be essential to fully understand the biological significance of the findings," Dr. Martínez-Horta said.
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, opening 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 (搜索) 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," Dr. Martínez-Horta concluded.
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. Direct validation of tracer binding in brain tissue from individuals with Huntington's disease (搜索) is also planned. In the future, the PET signal could be incorporated into a multimodal strategy alongside MRI, clinical and genetic measures, and biomarkers in blood or cerebrospinal fluid to improve patient selection for clinical trials and assess therapeutic intervention effects.
The study was funded by the Carlos III Health Institute through the Health Research Fund and co-funded by the European Regional Development Fund. Hospital de Sant Pau (搜索) is a national referral center within Spain's CSUR network for rare diseases involving movement disorders.