María Jimena Salcedo-Arellano1,2,3,4, Jun Yi Wang2,5, Yingratana A McLennan1,2,3, Mai Doan3,4, Ana Maria Cabal-Herrera6, Sara Jimenez3,4, Marisol W Wolf-Ochoa3,4, Desiree Sanchez3,4, Pablo Juarez3,4, Flora Tassone2,7, Blythe Durbin-Johnson8, Randi J Hagerman1,2, Verónica Martínez-Cerdeño2,3,4. 1. Department of Pediatrics, University of California Davis School of Medicine, Sacramento, California, USA. 2. Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, California, USA. 3. Institute for Pediatric Regenerative Medicine and Shriners Hospitals for Children Northern California, Sacramento, California, USA. 4. Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, California, USA. 5. Center for Mind and Brain, University of California Davis, Davis, California, USA. 6. Group on Congenital Malformations and Dysmorphology, Faculty of Health, Universidad del Valle (MACOS), Cali, Colombia. 7. Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, California, USA. 8. Division of Biostatistics, Department of Public Health Sciences, UC Davis School of Medicine, Sacramento, California, USA.
Abstract
BACKGROUND: Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disease of late onset developed by carriers of the premutation in the fragile x mental retardation 1 (FMR1) gene. Pathological features of neurodegeneration in fragile X-associated tremor/ataxia syndrome include toxic levels of FMR1 mRNA, ubiquitin-positive intranuclear inclusions, white matter disease, iron accumulation, and a proinflammatory state. OBJECTIVE: The objective of this study was to analyze the presence of cerebral microbleeds in the brains of patients with fragile X-associated tremor/ataxia syndrome and investigate plausible causes for cerebral microbleeds in fragile X-associated tremor/ataxia syndrome. METHODS: We collected cerebral and cerebellar tissue from 15 fragile X-associated tremor/ataxia syndrome cases and 15 control cases carrying FMR1 normal alleles. We performed hematoxylin and eosin, Perls and Congo red stains, ubiquitin, and amyloid β protein immunostaining. We quantified the number of cerebral microbleeds, amount of iron, presence of amyloid β within the capillaries, and number of endothelial cells containing intranuclear inclusions. We evaluated the relationships between pathological findings using correlation analysis. RESULTS: We found intranuclear inclusions in the endothelial cells of capillaries and an increased number of cerebral microbleeds in the brains of those with fragile X-associated tremor/ataxia syndrome, both of which are indicators of cerebrovascular dysfunction. We also found a suggestive association between the amount of capillaries that contain amyloid β in the cerebral cortex and the rate of disease progression. CONCLUSION: We propose microangiopathy as a pathologic feature of fragile X-associated tremor/ataxia syndrome.
BACKGROUND: Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disease of late onset developed by carriers of the premutation in the fragile x mental retardation 1 (FMR1) gene. Pathological features of neurodegeneration in fragile X-associated tremor/ataxia syndrome include toxic levels of FMR1 mRNA, ubiquitin-positive intranuclear inclusions, white matter disease, iron accumulation, and a proinflammatory state. OBJECTIVE: The objective of this study was to analyze the presence of cerebral microbleeds in the brains of patients with fragile X-associated tremor/ataxia syndrome and investigate plausible causes for cerebral microbleeds in fragile X-associated tremor/ataxia syndrome. METHODS: We collected cerebral and cerebellar tissue from 15 fragile X-associated tremor/ataxia syndrome cases and 15 control cases carrying FMR1 normal alleles. We performed hematoxylin and eosin, Perls and Congo red stains, ubiquitin, and amyloid β protein immunostaining. We quantified the number of cerebral microbleeds, amount of iron, presence of amyloid β within the capillaries, and number of endothelial cells containing intranuclear inclusions. We evaluated the relationships between pathological findings using correlation analysis. RESULTS: We found intranuclear inclusions in the endothelial cells of capillaries and an increased number of cerebral microbleeds in the brains of those with fragile X-associated tremor/ataxia syndrome, both of which are indicators of cerebrovascular dysfunction. We also found a suggestive association between the amount of capillaries that contain amyloid β in the cerebral cortex and the rate of disease progression. CONCLUSION: We propose microangiopathy as a pathologic feature of fragile X-associated tremor/ataxia syndrome.
Authors: Maria Jimena Salcedo-Arellano; Desiree Sanchez; Jun Yi Wang; Yingratana A McLennan; Courtney Jessica Clark; Pablo Juarez; Andrea Schneider; Flora Tassone; Randi J Hagerman; Verónica Martínez-Cerdeño Journal: Front Neurosci Date: 2021-09-17 Impact factor: 4.677
Authors: Brett D Dufour; Lilia Albores-Gallo; Jose Luna-Muñoz; Randi Hagerman; Amaya Miquelajauregui; Efrain Buriticá; Wilmar Saldarriaga; Mar Pacheco-Herrero; Ana Yris Silvestre-Sosa; Carla Mazefsky; Holly Gastgeb; Julia Kofler; Manuel Casanova; Patrick R Hof; Eric London; Paul Hagerman; Verónica Martínez-Cerdeño Journal: Brain Pathol Date: 2021-09-13 Impact factor: 6.508
Authors: Jun Yi Wang; Jim Grigsby; Diego Placido; Hongjiang Wei; Flora Tassone; Kyoungmi Kim; David Hessl; Susan M Rivera; Randi J Hagerman Journal: Front Neurol Date: 2022-02-08 Impact factor: 4.003
Authors: Michelle H S Tosin; Glenn T Stebbins; Christopher G Goetz; Randi J Hagerman; David Hessl; Melissa A Zolecki; Peter K Todd; Maureen A Leehey; Deborah A Hall Journal: Front Neurol Date: 2022-09-14 Impact factor: 4.086