Cerebral Microbleeds in Fragile X-Associated Tremor/Ataxia Syndrome
María Jimena Salcedo-Arellano1,2,3,4, Jun Yi Wang2,5, Yingratana A McLennan1,2,3
1Department of Pediatrics, University of California Davis School of Medicine, Sacramento, California, USA.
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.
Insights
Fragile X-associated tremor/ataxia syndrome (FXTAS) brains show increased cerebral microbleeds and vascular dysfunction. Amyloid-beta in capillaries may link to disease progression in FXTAS patients.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of the FMR1 gene premutation.
- Pathological hallmarks include toxic FMR1 mRNA levels, ubiquitin inclusions, white matter disease, iron accumulation, and inflammation.
Purpose of the Study:
- To investigate cerebral microbleeds in FXTAS patients.
- To explore potential causes of microbleeds in FXTAS.
Main Methods:
- Examined brain tissue from 15 FXTAS cases and 15 controls.
- Performed histological and immunohistochemical staining (H&E, Perls, Congo red, ubiquitin, amyloid-beta).
- Quantified microbleeds, iron, amyloid-beta in capillaries, and endothelial intranuclear inclusions.
Main Results:
- Found increased cerebral microbleeds and intranuclear inclusions in capillary endothelial cells in FXTAS brains, indicating cerebrovascular dysfunction.
- Observed a potential association between cerebral cortex capillary amyloid-beta and disease progression rate.
Conclusions:
- Microangiopathy is proposed as a pathological feature of FXTAS.
- Cerebrovascular dysfunction is implicated in the pathogenesis of FXTAS.
