Clinical and Molecular Correlates of Abnormal Changes in the Cerebellum and Globus Pallidus in Fragile X Premutation

Jun Yi Wang; Jim Grigsby; Diego Placido; Hongjiang Wei; Flora Tassone; Kyoungmi Kim; David Hessl; Susan M Rivera; Randi J Hagerman

doi:10.3389/fneur.2022.797649

Clinical and Molecular Correlates of Abnormal Changes in the Cerebellum and Globus Pallidus in Fragile X Premutation

Front Neurol. 2022 Feb 8:13:797649. doi: 10.3389/fneur.2022.797649. eCollection 2022.

Authors

Jun Yi Wang¹, Jim Grigsby², Diego Placido³, Hongjiang Wei^{4

5}, Flora Tassone^{6

7}, Kyoungmi Kim⁸, David Hessl^{7

9}, Susan M Rivera^{1

2

7}, Randi J Hagerman^{7

10}

Affiliations

¹ Center for Mind and Brain, University of California, Davis, Davis, CA, United States.
² Departments of Psychology and Medicine, University of Colorado Denver, Denver, CO, United States.
³ Department of Psychology, University of California, Davis, Davis, CA, United States.
⁴ School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
⁵ Institute for Medical Robotics, Shanghai Jiao Tong University, Shanghai, China.
⁶ Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, CA, United States.
⁷ The MIND Institute, University of California Davis Medical Center, Sacramento, CA, United States.
⁸ Department of Public Health Sciences, University of California Davis School of Medicine, Sacramento, CA, United States.
⁹ Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, United States.
¹⁰ Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, United States.

Abstract

Background: Fragile X premutation carriers (55-200 CGG triplets) may develop a progressive neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), after the age of 50. The neuroradiologic markers of FXTAS are hyperintense T2-signals in the middle cerebellar peduncle-the MCP sign. We recently noticed abnormal T2-signals in the globus pallidus in male premutation carriers and controls but the prevalence and clinical significance were unknown.

Methods: We estimated the prevalence of the MCP sign and pallidal T2-abnormalities in 230 male premutation carriers and 144 controls (aged 8-86), and examined the associations with FXTAS symptoms, CGG repeat length, and iron content in the cerebellar dentate nucleus and globus pallidus.

Results: Among participants aged ≥45 years (175 premutation carriers and 82 controls), MCP sign was observed only in premutation carriers (52 vs. 0%) whereas the prevalence of pallidal T2-abnormalities approached significance in premutation carriers compared with controls after age-adjustment (25.1 vs. 13.4%, p = 0.069). MCP sign was associated with impaired motor and executive functioning, and the additional presence of pallidal T2-abnormalities was associated with greater impaired executive functioning. Among premutation carriers, significant iron accumulation was observed in the dentate nucleus, and neither pallidal or MCP T2-abnormalities affected measures of the dentate nucleus. While the MCP sign was associated with CGG repeat length >75 and dentate nucleus volume correlated negatively with CGG repeat length, pallidal T2-abnormalities did not correlate with CGG repeat length. However, pallidal signal changes were associated with age-related accelerated iron depletion and variability and having both MCP and pallidal signs further increased iron variability in the globus pallidus.

Conclusions: Only the MCP sign, not pallidal abnormalities, revealed independent associations with motor and cognitive impairment; however, the occurrence of combined MCP and pallidal T2-abnormalities may present a risk for greater cognitive impairment and increased iron variability in the globus pallidus.

Keywords: FXTAS; brain iron accumulation; cognitive impairment; eye-of-the-tiger sign; fragile X premutation; globus pallidus; neurodegenerative disorder; the MCP sign.

Abstract

Grants and funding