Phillip G D Ward1,2,3, Ian H Harding2, Thomas G Close1, Louise A Corben2,4,5, Martin B Delatycki2,4,5,6, Elsdon Storey7, Nellie Georgiou-Karistianis2, Gary F Egan1,2,3. 1. Monash Biomedical Imaging, Monash University, Melbourne, Australia. 2. School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia. 3. Australian Research Council Centre of Excellence for Integrative Brain Function, Melbourne, Australia. 4. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia. 5. Department of Paediatrics, University of Melbourne, Parkville, Australia. 6. Victorian Clinical Genetics Service, Parkville, Australia. 7. Department of Medicine, Monash University, Melbourne, Australia.
Abstract
BACKGROUND: Friedreich ataxia is a recessively inherited, progressive neurological disease characterized by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of abnormalities in these structures. METHODS: Using in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n = 20) and healthy controls (n = 18) over a 2-year period. RESULTS: The longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Specifically, atrophy was maximal in individuals early in the disease course, whereas the rate of iron concentration increased with disease progression. CONCLUSIONS: Progressive dentate nucleus abnormalities are evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a 2-year period highlight the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.
BACKGROUND:Friedreich ataxia is a recessively inherited, progressive neurological disease characterized by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of abnormalities in these structures. METHODS: Using in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n = 20) and healthy controls (n = 18) over a 2-year period. RESULTS: The longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Specifically, atrophy was maximal in individuals early in the disease course, whereas the rate of iron concentration increased with disease progression. CONCLUSIONS: Progressive dentate nucleus abnormalities are evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a 2-year period highlight the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.
Authors: Ian H Harding; Louise A Corben; Louisa P Selvadurai; Nellie Georgiou-Karistianis; Rosita Shishegar; Cathlin Sheridan; Gary F Egan; Martin B Delatycki Journal: J Neurol Date: 2021-04-15 Impact factor: 4.849
Authors: Anjan Bhattarai; Zhaolin Chen; Phillip G D Ward; Paul Talman; Susan Mathers; Thanh G Phan; Caron Chapman; James Howe; Sarah Lee; Yennie Lie; Gary F Egan; Phyllis Chua Journal: Quant Imaging Med Surg Date: 2020-07
Authors: Rosita Shishegar; Ian H Harding; Louisa P Selvadurai; Louise A Corben; Martin B Delatycki; Gary F Egan; Nellie Georgiou-Karistianis Journal: Brain Struct Funct Date: 2021-10-23 Impact factor: 3.270
Authors: Gary F Egan; Paul M Thompson; Ian H Harding; Sidhant Chopra; Filippo Arrigoni; Sylvia Boesch; Arturo Brunetti; Sirio Cocozza; Louise A Corben; Andreas Deistung; Martin Delatycki; Stefano Diciotti; Imis Dogan; Stefania Evangelisti; Marcondes C França; Sophia L Göricke; Nellie Georgiou-Karistianis; Laura L Gramegna; Pierre-Gilles Henry; Carlos R Hernandez-Castillo; Diane Hutter; Neda Jahanshad; James M Joers; Christophe Lenglet; Raffaele Lodi; David N Manners; Alberto R M Martinez; Andrea Martinuzzi; Chiara Marzi; Mario Mascalchi; Wolfgang Nachbauer; Chiara Pane; Denis Peruzzo; Pramod K Pisharady; Giuseppe Pontillo; Kathrin Reetz; Thiago J R Rezende; Sandro Romanzetti; Francesco Saccà; Christoph Scherfler; Jörg B Schulz; Ambra Stefani; Claudia Testa; Sophia I Thomopoulos; Dagmar Timmann; Stefania Tirelli; Caterina Tonon; Marinela Vavla Journal: Ann Neurol Date: 2021-09-17 Impact factor: 11.274
Authors: Louisa P Selvadurai; Louise A Corben; Martin B Delatycki; Elsdon Storey; Gary F Egan; Nellie Georgiou-Karistianis; Ian H Harding Journal: Hum Brain Mapp Date: 2020-01-06 Impact factor: 5.038