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. 2017 Jul:55:11-19.
doi: 10.1016/j.neurobiolaging.2017.03.018. Epub 2017 Mar 18.

Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation

Jun Yi Wang  1 , David Hessl  2 , Randi J Hagerman  3 , Tony J Simon  2 , Flora Tassone  4 , Emilio Ferrer  5 , Susan M Rivera  6
Affiliations

Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation

Jun Yi Wang et al. Neurobiol Aging. 2017 Jul.

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder typically affecting male premutation carriers with 55-200 CGG trinucleotide repeat expansions in the FMR1 gene after age 50. The aim of this study was to examine whether cerebellar and brainstem changes emerge during development or aging in late life. We retrospectively analyzed magnetic resonance imaging scans from 322 males (age 8-81 years). Volume changes in the cerebellum and brainstem were contrasted with those in the ventricles and whole brain. Compared to the controls, premutation carriers without FXTAS showed significantly accelerated volume decrease in the cerebellum and whole brain, flatter inverted U-shaped trajectory of the brainstem, and larger ventricles. Compared to both older controls and premutation carriers without FXTAS, carriers with FXTAS exhibited significant volume decrease in the cerebellum and whole brain and accelerated volume decrease in the brainstem. We therefore conclude that cerebellar and brainstem volumes were likely affected during both development and progression of neurodegeneration in premutation carriers, suggesting that interventions may need to start early in adulthood to be most effective.

Keywords: FMR1; FXTAS; Fragile X; Fragile X premutation; MRI; Neurodegenerative disorder.

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Figures

Fig. 1
Fig. 1. SaFmples of segmented cerebellum and brainstem and plots of age-related volume changes
Segmented cerebellum and brainstem from (A) a 68-year-old healthy control, (B) a 69-year-old premutation carrier at FXTAS stage 1, and (C) a 68-year-old premutation carrier at FXTAS stage 4. Scatter plots showing age-related changed in cerebellar, brainstem, and ventricular volumes in (D) premutation carriers without FXTAS (FXPC−, at FXTAS stage 0 or 1) and healthy controls and (E) older groups (age > 50 years).
Fig. 2
Fig. 2. The effect of FXTAS stage and molecular measurements on brain volumes in premutation carriers
(A) Cerebellar volume, (B) brainstem volume, (C) ventricular volume, and (D) whole brain volume. For FXTAS stage, brain volumetrics adjusted for age and brain scaling factor are shown. For CGG repeat length and FMR1 mRNA, brain volumetrics adjusted for age, brain scaling factor and FXTAS stage are shown. Shaded areas represent 95% confidence intervals of the regression lines.
See this image and copyright information in PMC

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