Frederic Sampedro1,2,3,4, Saul Martínez-Horta1,2,3, Jesus Pérez-Pérez1,2,3, Rocío Pérez-González1,2,3, Andrea Horta-Barba1,2,3, Antonia Campolongo1,2,3, Cristina Izquierdo1,2,3, Ignacio Aracil-Bolaños1,2,3, Elisa Rivas1,2,3, Arnau Puig-Davi1,2,3, Javier Pagonabarraga1,2,3, Beatriz Gómez-Ansón5, Jaime Kulisevsky6,7,8. 1. Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Mas Casanovas 90, 08041, Barcelona, Spain. 2. Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain. 3. Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. 4. Radiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 5. Neuroradiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 6. Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Mas Casanovas 90, 08041, Barcelona, Spain. jkulisevsky@santpau.cat. 7. Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain. jkulisevsky@santpau.cat. 8. Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. jkulisevsky@santpau.cat.
Abstract
PURPOSE: Huntington's disease (HD) is a monogenic neurodegenerative disease with no effective treatment currently available. The pathological hallmark of HD is the aggregation of mutant huntingtin in the medium spiny neurons of the striatum, leading to severe subcortical atrophy. Cortical degeneration also occurs in HD from its very early stages, although its biological origin is poorly understood. Among the possible pathological mechanisms that could promote cortical damage in HD, the in vivo study of TDP-43 pathology remains to be explored, which was the main objective of this work. METHODS: We investigated the clinical and structural brain correlates of plasma TDP-43 levels in a sample of 36 HD patients. Neuroimaging alterations were assessed both at the macrostructural (cortical thickness) and microstructural (intracortical diffusivity) levels. Importantly, we controlled for mutant huntingtin and tau biomarkers in order to assess the independent role of TDP-43 in HD neurodegeneration. RESULTS: Plasma TDP-43 levels in HD specifically correlated with the presence and severity of apathy (p = 0.003). The TDP-43 levels also reflected cortical thinning and microstructural degeneration, especially in frontal and anterior-temporal regions (p < 0.05 corrected). These TDP-43-related brain alterations correlated, in turn, with the severity of cognitive, motor and behavioral symptoms. CONCLUSION: Our results suggest that the presence of TDP-43 pathology in HD has an independent contribution to the severity of neuropsychiatric symptoms and frontotemporal degeneration. These findings point out the importance of TDP-43 as an additional pathological process to be taken into consideration in this devastating disorder.
PURPOSE: Huntington's disease (HD) is a monogenic neurodegenerative disease with no effective treatment currently available. The pathological hallmark of HD is the aggregation of mutant huntingtin in the medium spiny neurons of the striatum, leading to severe subcortical atrophy. Cortical degeneration also occurs in HD from its very early stages, although its biological origin is poorly understood. Among the possible pathological mechanisms that could promote cortical damage in HD, the in vivo study of TDP-43 pathology remains to be explored, which was the main objective of this work. METHODS: We investigated the clinical and structural brain correlates of plasma TDP-43 levels in a sample of 36 HD patients. Neuroimaging alterations were assessed both at the macrostructural (cortical thickness) and microstructural (intracortical diffusivity) levels. Importantly, we controlled for mutant huntingtin and tau biomarkers in order to assess the independent role of TDP-43 in HD neurodegeneration. RESULTS: Plasma TDP-43 levels in HD specifically correlated with the presence and severity of apathy (p = 0.003). The TDP-43 levels also reflected cortical thinning and microstructural degeneration, especially in frontal and anterior-temporal regions (p < 0.05 corrected). These TDP-43-related brain alterations correlated, in turn, with the severity of cognitive, motor and behavioral symptoms. CONCLUSION: Our results suggest that the presence of TDP-43 pathology in HD has an independent contribution to the severity of neuropsychiatric symptoms and frontotemporal degeneration. These findings point out the importance of TDP-43 as an additional pathological process to be taken into consideration in this devastating disorder.
Authors: F Sampedro; S Martínez-Horta; J Perez-Perez; A Horta-Barba; J Martin-Lahoz; A Alonso-Solís; I Corripio; B Gomez-Anson; J Kulisevsky Journal: AJNR Am J Neuroradiol Date: 2019-09 Impact factor: 3.825