[en] The minority nature of Huntington's disease has meant, in comparison to other more frequent neurodegenerative processes, an imbalanced and slow progress in the understanding of the neuropathological mechanisms responsible for the disease and in the identification and detailed description of the clinical phenotypes that characterize it. Historically, the clinical manifestations of Huntington's disease have been preferentially attributed to the characteristic subcortical atrophy that all patients present. In correspondence with this atrophy of the basal ganglia, from the neuropsychological point of view, Huntington's disease has been considered a paradigm of subcortical dementia with a frontal-dysexecutive neurocognitive profile characterized by cognitive slowing, executive dysfunction, apathy and personality changes. Over the last 15 years, the development of multicenter and international observational studies has made it possible to significantly deepen our knowledge of the disease thanks to the follow-up of large cohorts of affected people. These studies have illustrated that, from the early stages of the disease and even during the asymptomatic phase, some of the most obvious neuropathological changes extend beyond the basal ganglia and affect extensive cortical territories, mainly in parieto-occipital and temporal areas. Parallel to these findings, studies that have explored the correspondence of brain abnormalities with the clinical manifestations of the disease have revealed that cognitive disturbances go far beyond the dysexecutive profile and that the alteration of multiple domains and processes illustrate a fairly cognitive phenotype more complex and diverse than initially described. Despite this, many unknowns remain to be resolved. We now know that subtle cognitive and behavioral changes, observable through performance in certain tasks, can become apparent up to 15 years before the first motor manifestations are evident. This has meant that the scientific community dedicated to the disease has focused important efforts on exploring the cognitive variables that characterize the disease and that predict its progression, as well as the way in which we can efficiently capture the first preclinical manifestations. We also know that regardless of the genetic load of the disease, there is a notable variability both in the age of onset and in the form and course that the disease acquires throughout its evolution. Expanding our field of vision beyond the basal ganglia has contributed to uncovering a set of elements that are still difficult to fit precisely into the disease as a whole, but which reaffirm the need to deepen the study of its causal mechanisms. We still do not clearly understand: 1) why the disease behaves differently in people whose genetic makeup and age is the same; 2) what role do some of the most subtle and early brain changes that occur in the course of the disease have; 3) what is the pattern of brain neurodegeneration associated with certain neuropsychiatric manifestations with the limitation that this entails for therapeutic approaches; 4) what is the specific neurocognitive profile of severe forms of cognitive impairment in the disease, or how can we measure these profiles in their mild and severe forms, or 5) what is the neurodegenerative pattern that patients who develop dementia present. The objectives of this thesis, as evidenced by the published works that comprise it, have been aimed at finding some answers to these unknowns that represent concrete advances in the knowledge and clinical management of this devastating disease.

[es] El carácter minoritario de la enfermedad de Huntington ha supuesto, en comparación a otros procesos neurodegenerativos más frecuentes, un desajustado y lento avance en la comprensión de los mecanismos neuropatológicos responsables de la enfermedad y en la identificación y descripción pormenorizada de los fenotipos clínicos que la caracterizan. Históricamente, las manifestaciones clínicas de la enfermedad de Huntington, han sido preferentemente atribuidas a la característica atrofia subcortical que presentan todos los pacientes. En correspondencia con esta atrofia de los ganglios basales, desde el punto de vista neuropsicológico, la enfermedad de Huntington ha sido considerada un paradigma de demencia subcortical con un perfil neurocognitivo frontal-disejecutivo caracterizado por enlentecimiento cognitivo, disfunción ejecutiva, apatía y cambios de personalidad. El desarrollo de estudios observacionales de carácter multicéntrico e internacional, ha permitido a lo largo de los últimos 15 años, ahondar de manera notable en el conocimiento de la enfermedad gracias al seguimiento de grandes cohortes de personas afectadas. Estos estudios han ilustrado que, desde etapas tempranas de la enfermedad e incluso durante la fase asintomática, algunos de los cambios neuropatológicos más evidentes se extienden más allá de los ganglios basales y afectan a extensos territorios corticales, principalmente en áreas parieto-occipitales y temporales. Los objetivos de esta tesis, como ponen de manifiesto los trabajos publicados que la conforman, se han dirigido a la búsqueda de algunas respuestas para estas incógnitas que supongan avances concretos para el conocimiento y el manejo clínico de esta devastadora enfermedad.