Saul Martinez-Horta, MsC

Clinical Researcher, Jaime Kulisevsky, MD, PhD, Sant Pau Hospital, Barcelona

Neurobiological mechanisms subserving the differential expression and rate of progression of cognitive impairment in Huntington's disease

Many years of research have contributed to a better understanding of the great complexity of Huntington’s disease (HD) and the multitude of brain regions that are affected. Beyond the primary genetic cause (CAG repeat expansion), multiple additional mechanisms may contribute to symptom presentation and progression. Cognitive impairments (difficulties with thinking and planning) are an essential feature of HD, but there is vast variability in the severity and rate of progression of these symptoms that cannot be solely explained by differences in CAG repeat length. Current efforts are directed at lowering the amount of the toxic protein that leads to HD. To optimize therapeutic strategies and to understand differences in the pattern of patient responses to future gene-silencing therapies, it will be necessary to investigate other mechanisms that may contribute to the clinical expression of HD. To this end, we want to better understand the cognitive profile of HD and how environmental and biological mechanisms contribute to differences in the deterioration of thinking. To do that, we will assess the cognitive profile of symptomatic patients and will obtain “biomarkers” in the plasma and cerebrospinal fluid that are known to be associated with neuronal damage and neurodegeneration. We will specifically look at brain structure and function in patients with dissimilar cognitive phenotypes. We will also explore the influence of environmental variables, genetic differences, and certain types of brain pathology on patients’ ability to think and function in daily life.