Lorenzo Nanetti1, Valeria Elisa Contarino2, Anna Castaldo1, Lidia Sarro1, Anne-Catherine Bachoud-Levi3, Maria Giavazzi4, Serena Frittoli5, Andrea Ciammola6, Elena Rizzo1, Cinzia Gellera1, Maria Grazia Bruzzone2, Franco Taroni1, Marina Grisoli2, Caterina Mariotti7. 1. Genetics of Neurodegenerative and Metabolic Diseases, IRCCS-Foundation Neurological Institute Carlo Besta, Milan, Italy. 2. Neuroradiology Department, IRCCS-Foundation Neurological Institute Carlo Besta, Milan, Italy. 3. Equipe neuropsychologie interventionnelle, Département d'études cognitives, École normale supérieure, PSL Research University, Institut Mondor de recherche Biomédicale, Université Paris-Est, INSERM U955 E01, 75005, Paris, Créteil, 94010, France; AP-HP, National Center of Reference for Huntington's Disease, Neurology Department, Henri Mondor Hospital, Créteil, 94010, France. 4. Equipe neuropsychologie interventionnelle, Département d'études cognitives, École normale supérieure, PSL Research University, Institut Mondor de recherche Biomédicale, Université Paris-Est, INSERM U955 E01, 75005, Paris, Créteil, 94010, France. 5. Neurology Department, Movement Disorders, IRCCS-Foundation Neurological Institute Carlo Besta, Milan, Italy. 6. Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy. 7. Genetics of Neurodegenerative and Metabolic Diseases, IRCCS-Foundation Neurological Institute Carlo Besta, Milan, Italy. Electronic address: caterina.mariotti@istituto-besta.it.
Abstract
BACKGROUND: Huntington disease (HD) is an inherited neurodegenerative disorder most commonly manifesting in adulthood. Identification of biomarkers tracking neurodegeneration before the onset of motor symptoms is important for future interventional studies. Our study aimed to contribute in the phenotypic characterization of the premanifest HD phase. METHODS: 28 premanifest subjects (preHD), 25 age-matched controls, and 12 manifest HD patients were enrolled for the study. The participants underwent a multimodal protocol including cognitive evaluations, arithmetic ability test, posturography, composite cerebellar functional test (CCFS), and brain 3T-MRI. PreHD were divided at the group median for predicted years to expected onset into "far-from-onset" (>15 years, PreHD-far), and "close-to-onset" (≤15 years, preHD-close). Basal ganglia volumes and cortical thickness were computed using FreeSurfer. RESULTS: PreHD-close showed significantly lower scores than controls in Symbol Digit Modalities Test (p = 0.017), Arithmetic subtraction task (p = 0.04), and MMSE (p < 0.006). At posturography, preHD-close showed increased sway velocity (<0.04) and distance (p < 0.02) compared to controls. PreHD-close had reduced striatum and globus pallidus volumes and left occipital cortical thinning compared to controls. Compared to PreHD far-from-onset, PreHD-close showed bilateral cortical thinning in occipital and parahippocampal regions, inversely correlating with burden score and prognostic index for HD. CCFS only differed between controls and manifest HD. PreHD far-from-onset did not show significant differences in comparison with controls. CONCLUSIONS: We confirmed that quantitative brain MRI represents a valid biomarker of neurodegeneration in preHD. Posturography and Arithmentic tests seem promising tools for detecting early changes in premanifest HD, but need to be further confirmed in large cohorts.
BACKGROUND:Huntington disease (HD) is an inherited neurodegenerative disorder most commonly manifesting in adulthood. Identification of biomarkers tracking neurodegeneration before the onset of motor symptoms is important for future interventional studies. Our study aimed to contribute in the phenotypic characterization of the premanifest HD phase. METHODS: 28 premanifest subjects (preHD), 25 age-matched controls, and 12 manifest HDpatients were enrolled for the study. The participants underwent a multimodal protocol including cognitive evaluations, arithmetic ability test, posturography, composite cerebellar functional test (CCFS), and brain 3T-MRI. PreHD were divided at the group median for predicted years to expected onset into "far-from-onset" (>15 years, PreHD-far), and "close-to-onset" (≤15 years, preHD-close). Basal ganglia volumes and cortical thickness were computed using FreeSurfer. RESULTS: PreHD-close showed significantly lower scores than controls in Symbol Digit Modalities Test (p = 0.017), Arithmetic subtraction task (p = 0.04), and MMSE (p < 0.006). At posturography, preHD-close showed increased sway velocity (<0.04) and distance (p < 0.02) compared to controls. PreHD-close had reduced striatum and globus pallidus volumes and left occipital cortical thinning compared to controls. Compared to PreHD far-from-onset, PreHD-close showed bilateral cortical thinning in occipital and parahippocampal regions, inversely correlating with burden score and prognostic index for HD. CCFS only differed between controls and manifest HD. PreHD far-from-onset did not show significant differences in comparison with controls. CONCLUSIONS: We confirmed that quantitative brain MRI represents a valid biomarker of neurodegeneration in preHD. Posturography and Arithmentic tests seem promising tools for detecting early changes in premanifest HD, but need to be further confirmed in large cohorts.