Reduced caudate volume and cognitive slowing in men at risk of fragile X-associated tremor ataxia syndrome

  • Rachael C. Cvejic
  • Darren R. Hocking
  • Wei Wen
  • Nellie Georgiou-Karistianis
  • Kim M. Cornish
  • David E. Godler
  • Carolyn Rogers
  • Julian N. TrollorEmail author
Original Research


Fragile X-associated tremor ataxia syndrome is an inherited neurodegenerative disorder caused by premutation expansions (55–200 CGG repeats) of the FMR1 gene. There is accumulating evidence to suggest that early cognitive and brain imaging signs may be observed in some premutation carriers without motor signs of FXTAS, but few studies have examined the relationships between subcortical brain volumes and cognitive performance in this group. This study examined the relationships between caudate volume and select cognitive measures (executive function and information processing speed) in men at risk of developing FXTAS and controls with normal FMR1 alleles (<45 CGG repeats). The results showed that men with premutation alleles performed worse on measures of executive function and information processing speed, and had significantly reduced caudate volume, compared to controls. Smaller caudate volume in the premutation group was associated with slower processing speed. These findings provide preliminary evidence that early reductions in caudate volume may be associated with cognitive slowing in men with the premutation who do not present with cardinal motor signs of FXTAS. If confirmed in future studies with larger PM cohorts, these findings will have important implications for the identification of sensitive measures with potential utility for tracking cognitive decline.


FMR1 premutation Fragile X-associated tremor ataxia syndrome Executive function Information processing speed Caudate 



The authors thank all the families who participated in this study. The authors also thank the Genetics of Learning Disability Service, the Victorian Clinical Genetics Service, the Fragile X Association of Australia and the Fragile X Alliance Clinic for assistance with the recruitment of participants.


This work was supported by The Australian Research Council (Discovery Project Grant DP110103346 to KMC, JNT, NG-K, and WW); The New South Wales Institute of Psychiatry (Training Fellowship in Psychiatric Research awarded to RCB); Monash Research Fellowship and ARC Discovery Early Career Researcher Grant (DE160100042) to DRH; the Dementia Collaborative Research Centre, UNSW Sydney as part of the Australian Government’s Dementia Initiative; and the Genetics of Learning Disability Service. Salary for the molecular component, in part, was supported by the National Health and Medical Research Council (Project Grants 104299 and 1103389) to DEG.

Compliance with ethical standards

Conflict of interest

RCB declares that she has no conflict of interest. DRH declares that he has no conflict of interest. WW declares that he has no conflict of interest. NGK declares that she has no conflict of interest. KMC declares that she has no conflict of interest. DEG declares that he has no conflict of interest. CR declares that she has no conflict of interest. JNT declares that he has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Developmental Disability Neuropsychiatry, School of PsychiatryUNSW SydneySydneyAustralia
  2. 2.Developmental Neuromotor & Cognition Lab, School of Psychology and Public HealthLa Trobe UniversityMelbourneAustralia
  3. 3.Centre for Healthy Brain Ageing, School of PsychiatryUNSW SydneySydneyAustralia
  4. 4.Monash Institute for Cognitive Clinical Neuroscience & School of Psychological Sciences, Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneAustralia
  5. 5.Cyto-molecular Diagnostic Research Laboratory, Murdoch Children’s Research InstituteRoyal Children’s HospitalMelbourneAustralia
  6. 6.Genetics of Learning Disability Service, Hunter GeneticsNewcastleAustralia

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