Brain Mapping May Allow Earlier Detection of Brain Abnormalities Interview with:

dr_Aalex_d_leowAlex Leow, MD PhD
Psychiatric Institute
Chicago, IL 60612 and


Tony J. Simon, PhD University of California, Davis MIND Institute Sacramento, CA 95817Tony J. Simon, PhD
University of California,
Davis MIND Institute Sacramento,
CA 95817 What are the main findings of the study?

Answer: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and the most prevalent known single-gene cause of autism in males. The fragile X mental retardation 1 gene (FMR1) can be mutated with expanded numbers of CGG trinucleotide repeats in the 5’ untranslated region on the Xq27.3 site of the X chromosome. Normally, unaffected individuals have fewer than 45 CGG repeats in FMR1. When the size of the CGG repeat exceeds 200 FMR1 is silenced and the mutation is categorized as full, generating the FXS phenotype. If the expansion is between 55–200 repeats, then the individual is generally classified as a fragile X premutation carrier (fXPC). An estimated 40% of male and 8-16% of female premutation carriers later develop Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS), which is a late-onset (usually 50-70 years old) neurodegenerative disorder.

We recruited 46 neurologically symptomless young to middle aged carriers of the FMR1 gene mutation. They were age and gender matched with 42 unaffected control individuals without the gene mutation. Both groups were evaluated by cognitive testing as well as novel neuroimaging techniques termed “brain connectomics,” based on diffusion tensor imaging (DTI) whole-brain tractography.  A connectome is a comprehensive map, like a wiring diagram, of neural connections in the brain. Our study is the first-ever connectome study to compare fXPCs and controls.

In short, brain connectomics enable scientists for the first time to study the global organizational properties of the human brain by applying cutting edge computational techniques, based on graph theory, to these comprehensive maps of neural connections (i.e., the brain graphs). Our main finding was that, in neurologically symptomless male carriers  we detected a correlation between brain graphs’ efficiency in processing information and the number of CGG repeats in the mutated region of FMR1 (we estimated that each additional CGG repeat that in these males represents an effective increase of ~1.5 years  of “brain aging”). The correlation may prove to be an effective marker of early brain aging in otherwise neurologically symptomless premutation carriers. The study also further confirmed previous findings of smaller brain stem volumes in male fXPCS than in male controls.  Were any of the findings unexpected?

Answer: Unexpectedly, among the female participants, we detected volume differences in specific brain regions, with the premutation carriers having more tissue in those regions than controls. These areas were the superior temporal gyrus, the superior parietal gyrus, and the posterior cingulate in the right hemisphere. Since our behavioral testing also found subtle but significant impairments in some tasks involving processing information about space and time in these women, our novel findings suggest the presence of compensatory mechanisms in neurologically symptomless female but not similar male carriers of the gene mutation.  What should clinicians and patients take away from your report?

Answer: Our findings suggest that the brain changes of premutation carriers at risk for FXTAS may begin to develop about two decades before the symptoms occur. While we have not been able to confirm this by following those individuals with the greatest brain changes for later neurological symptoms, it might be the case that identifying these brain changes in premutation carriers is important because they could turn out to be “biomarkers” or indicators that might help to identify which individuals are at least or greatest risk for later developing FXTAS. What recommendations do you have for future research as a result of this study?

Answer: Since researchers are now investigating cutting edge medical interventions that may in near future lead to treatment options for such individuals, combining cognitive and imaging analyses in children and adults who are premutation carriers might indeed point out markers of risk and protection. With this new information, more carefully targeted cognitive functioning and imaging assessments need to be carried out based on what we learned. Then, exploring whether or not these can act as targets for behavioral and pharmacological interventions would allow researchers to determine whether identifying changes in childhood or young adulthood could help reduce or even eliminate subtle cognitive and later neurological and psychiatric problems.


Altered structural brain connectome in young adult fragile X premutation carriers

Leow A1, Harvey D, Goodrich-Hunsaker NJ, Gadelkarim J, Kumar A, Zhan L, Rivera SM, Simon TJ.
Hum Brain Mapp. 2014 Feb 27. doi: 10.1002/hbm.22491. [Epub ahead of print]


Last Updated on April 24, 2014 by Marie Benz MD FAAD