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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

Abstract

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.

Keywords

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

Notes

Acknowledgements

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.

Funding

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.

References

  1. Alexander, G. E., Delong, M. R., & Strick, P. L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9, 357–381.CrossRefPubMedGoogle Scholar
  2. Aliaga, S. M., Slater, H. R., Francis, D., Du Sart, D., Li, X., Amor, D. J., Alliende, A. M., Santa Maria, L., Faundes, V., Morales, P., Trigo, C., Salas, I., Curotto, B. & Godler, D. E. 2016. Identification of males with cryptic fragile X alleles by methylation-specific quantitative melt analysis. Clinical Chemistry, 62, 343–352.Google Scholar
  3. Bamford, K. A., Caine, E. D., Kido, D. K., Cox, C., & Shoulson, I. (1995). A prospective evaluation of cognitive decline in early Huntington's disease: Functional and radiographic correlates. Neurology, 45, 1867–1873.CrossRefPubMedGoogle Scholar
  4. Batista, S., Zivadinov, R., Hoogs, M., Bergsland, N., Heininen-Brown, M., Dwyer, M., Weinstock-Guttman, B., & Benedict, R. B. (2012). Basal ganglia, thalamus and neocortical atrophy predicting slowed cognitive processing in multiple sclerosis. Journal of Neurology, 259, 139–146.CrossRefPubMedGoogle Scholar
  5. Birch, R. C., Cornish, K. M., Hocking, D. R., & Trollor, J. N. (2014). Understanding the neuropsychiatric phenotype of fragile X-associated tremor ataxia syndrome: A systematic review. Neuropsychology Review, 24, 491–513.CrossRefPubMedGoogle Scholar
  6. Birch, R. C., Hocking, D. R., Cornish, K. M., Menant, J. C., Georgiou-Karistianis, N., Godler, D. E., Wen, W., Hackett, A., Rogers, C., & Trollor, J. N. (2015). Preliminary evidence of an effect of cerebellar volume on postural sway in FMR1 premutation males. Genes, Brain and Behavior, 14, 251–259.CrossRefGoogle Scholar
  7. Birch, R. C., Hocking, D. R., Cornish, K. M., Menant, J. C., Lord, S. R., Georgiou-Karistianis, N., Godler, D. E., Wen, W., Rogers, C., & Trollor, J. N. (2017). Selective subcortical contributions to gait impairments in males with the FMR1 premutation. Journal of Neurology, Neurosurgery & Psychiatry, 88, 188–190.CrossRefGoogle Scholar
  8. Buckner, R. L., Head, D., Parker, J., Fotenos, A. F., Marcus, D., Morris, J. C., & Snyder, A. Z. (2004). A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: Reliability and validation against manual measurement of total intracranial volume. NeuroImage, 23, 724–738.CrossRefPubMedGoogle Scholar
  9. Cornish, K. M., Li, L., Kogan, C. S., Jacquemont, S., Turk, J., Dalton, A., Hagerman, R. J., & Hagerman, P. J. (2008). Age-dependent cognitive changes in carriers of the fragile X syndrome. Cortex, 44, 628–636.CrossRefPubMedGoogle Scholar
  10. Cornish, K. M., Hocking, D. R., Moss, S. A., & Kogan, C. S. (2011). Selective executive markers of at-risk profiles associated with the fragile X premutation. Neurology, 77, 618–622.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Domínguez, D. J. F., Egan, G. F., Gray, M. A., Poudel, G. R., Churchyard, A., Chua, P., Stout, J. C., & Georgiou-Karistianis, N. (2013). Multi-modal neuroimaging in Premanifest and early Huntington?S disease: 18 month longitudinal data from the IMAGE-HD study. PLoS One, e74131, 8.Google Scholar
  12. Esposito, G., Ruggiero, R., Savarese, G., Savarese, M., Tremolaterra, M. R., Salvatore, F., & Carsana, A. (2013). A 15-year case-mix experience for fragile X syndrome molecular diagnosis and comparison between conventional and alternative techniques leading to a novel diagnostic procedure. Clinica Chimica Acta, 417, 85–89.CrossRefGoogle Scholar
  13. Filley, C. M., Brown, M. S., Onderko, K., Ray, M., Bennett, R., Berry-Kravis, E., & Grigsby, J. (2015). White matter disease and cognitive impairment in FMR1 premutation carriers. Neurology, 84, 1–7.CrossRefGoogle Scholar
  14. Golden, C. J., & Freshwater, S. M. (2002). The Stroop color and word test: A manual for clinical and experimental uses. Chicago: Stoelting.Google Scholar
  15. Grigsby, J., & Kaye, K. (1996). The behavioral Dyscontrol scale: Manual (2nd ed.). Denver: Authors.Google Scholar
  16. Grigsby, J., Brega, A. G., Engle, K., Leehey, M. A., Hagerman, R. J., Tassone, F., Hessl, D., Hagerman, P. J., Cogswell, J. B., Bennett, R. E., Cook, K., Hall, D. A., Bounds, L. S., Paulich, M. J., & Reynolds, A. (2008). Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome. Neuropsychology, 22, 48–60.CrossRefPubMedGoogle Scholar
  17. Hagerman, R. J., Leehey, M., Heinrichs, W., Tassone, F., Wilson, R., Hills, J., Grigsby, J., Gage, B., & Hagerman, P. J. (2001). Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology, 57, 127–130.CrossRefPubMedGoogle Scholar
  18. Harrington, D. L., Liu, D., Smith, M. M., Mills, J. A., Long, J. D., Aylward, E. H., Paulsen, J. S. & Group, P.-H. I. C. O. T. H. S. (2014). Neuroanatomical correlates of cognitive functioning in prodromal Huntington disease. Brain and Behavior, 4, 29–40.CrossRefGoogle Scholar
  19. Ho, A. K., Sahakian, B. J., Brown, R. G., Barker, R. A., Hodges, J. R., N., A. M., Snowden, J., Thompson, J., Esmonde, T., Gentry, R., Moore, J. W., Bodner, T. & Nest-Hd Consortium. (2003). Profile of cognitive progression in early Huntington's disease. Neurology, 23, 1702–1706.Google Scholar
  20. Hocking, D. R., Kogan, C. S., Cornish, K. M., Hocking, D. R., Kogan, C. S., & Cornish, K. M. (2012). Selective spatial processing deficits in an at-risk subgroup of the fragile X premutation. Brain and Cognition, 79, 39–44.CrossRefPubMedGoogle Scholar
  21. Hunter, J. E., Allen, E. G., Abramowitz, A., Rusin, M., Leslie, M., Novak, G., Hamilton, D., Shubeck, L., Charen, K., & Sherman, S. L. (2008). No evidence for a difference in neuropsychological profile among carriers and noncarriers of the FMR1 premutation in adults under the age of 50. American Journal of Human Genetics, 83, 692–702.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Jenkinson, M., Beckmann, C. F., Behrens, T. E. J., Woolrich, M. W., & Smith, S. M. (2012). FSL. NeuroImage, 62, 782–790.CrossRefPubMedGoogle Scholar
  23. Price, C. C., Tanner, J., Nguyen, P. T., Schwab, N. A., Mitchell, S., Slonena, E., Brumback, B., Okun, M. S., Mareci, T. H., & Bowers, D. (2016). Gray and white matter contributions to cognitive Frontostriatal deficits in non-demented Parkinson's disease. PLoS One, 11, e0147332.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Robinson, J. L., Laird, A. R., Glahn, D. C., Blangero, J., Sanghera, M. K., Pessoa, L., Fox, P. M., Uecker, A., Friehs, G., Young, K. A., Griffin, J. L., Lovallo, W. R., & Fox, P. T. (2012). The functional connectivity of the human caudate: An application of meta-analytic connectivity modeling with behavioral filtering. Neuroimage, 60, 117–129.CrossRefPubMedGoogle Scholar
  25. Rodriguez-Revenga, L., Madrigal, I., Pagonabarraga, J., Xuncla, M., Badenas, C., Kulisevsky, J., Gomez, B., & Mila, M. (2009). Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. European Journal of Human Genetics, 17, 1359–1362.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Seneca, S., Lissens, W., Endels, K., Caljon, B., Bonduelle, M., Keymolen, K., De Rademaeker, M., Ullmann, U., Haentjens, P., Van Berkel, K. & Van Dooren, S. 2012. Reliable and sensitive detection of fragile X (expanded) alleles in clinical prenatal DNA samples with a fast turnaround time. The Journal of Molecular Diagnostics, 14, 560–568.Google Scholar
  27. Shelton, A. L. P., Cornish, K. M. P., Godler, D. P., Bui, Q. M. P., Kolbe, S. P., & Fielding, J. P. (2017). White matter microstructure, cognition, and molecular markers in fragile X premutation females. Neurology, 88 , 2080–2088.Google Scholar
  28. Spreen, O., & Benton, A. L. (1977). Neurosensory center comprehensive examination for aphasia. Victoria BC: University of Victoria, Neuropsychology Laboratory.Google Scholar
  29. Wang, J. Y., Hagerman, R. J., & Rivera, S. (2013). A multimodal imaging analysis of subcortical gray matter in fragile X premutation carriers. Movement Disorders, 28, 1278–1284.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Wang, J. Y., Hessl, D., Hagerman, R. J., Simon, T. J., Tassone, F., Ferrer, E., & Rivera, S. M. (2017). Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation. Neurobiology of Aging, 55, 11–19.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Wechsler, D. (1997). WAIS-III Administration and scoring manual. San Antonio: The Psychological Corporation.Google Scholar
  32. Wechsler, D. (1999). Wechsler abbreviated scale of intelligence. New York: The Psychological Corporation: Harcourt Brace & Company.Google Scholar
  33. Yang, J., Chan, S., Khan, S., Schneider, A., Nanakul, R., Teichholtz, S., Niu, Y., Seritan, A., Tassone, F., Grigsby, J., Hagerman, P. J., Hagerman, R. J., & Olichney, J. M. (2013). Neural substrates of executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS): A brain potential study. Cerebral Cortex, 23, 2657–2666.CrossRefPubMedGoogle Scholar

Copyright information

© 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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