Cerebral Microbleeds in Fragile X–Associated Tremor/Ataxia Syndrome

• Published in: Movement disorders 2021-08, Vol.36 (8), p.1935-1943
• Main Authors: Salcedo‐Arellano, María Jimena, Wang, Jun Yi, McLennan, Yingratana A., Doan, Mai, Cabal‐Herrera, Ana Maria, Jimenez, Sara, Wolf‐Ochoa, Marisol W., Sanchez, Desiree, Juarez, Pablo, Tassone, Flora, Durbin‐Johnson, Blythe, Hagerman, Randi J., Martínez‐Cerdeño, Verónica
• Format: Article
• Language: English
• Subjects: Amyloid; Ataxia; Ataxia - complications; Ataxia - genetics; Capillaries; Cerebellum; Cerebral cortex; Cerebral Hemorrhage - complications; Cerebral Hemorrhage - diagnostic imaging; cerebral microbleeds; Correlation analysis; Endothelial Cells; FMR1 premutation; FMR1 protein; Fragile X Mental Retardation Protein - genetics; Fragile X syndrome; Fragile X Syndrome - complications; Fragile X Syndrome - genetics; FXTAS; Humans; Inclusion bodies; Inflammation; Intellectual disabilities; Iron; Movement disorders; mRNA; Neurodegeneration; Neurodegenerative Diseases; Substantia alba; Tremor; Tremor (Muscular contraction); Tremor - complications; Tremor - genetics; Ubiquitin
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.28559

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. © 2021 International Parkinson and Movement Disorder Society