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, 69 (3), 551-8

Lifespan Changes in Working Memory in Fragile X Premutation Males

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Lifespan Changes in Working Memory in Fragile X Premutation Males

Kim M Cornish et al. Brain Cogn.

Abstract

Fragile X syndrome is the world's most common hereditary cause of developmental delay in males and is now well characterized at the biological, brain and cognitive levels. The disorder is caused by the silencing of a single gene on the X chromosome, the FMR1 gene. The premutation (carrier) status, however, is less well documented but has an emerging literature that highlights a more subtle profile of executive cognitive deficiencies that mirror those reported in fully affected males. Rarely, however, has the issue of age-related declines in cognitive performance in premutation males been addressed. In the present study, we focus specifically on the cognitive domain of working memory and its subcomponents (verbal, spatial and central executive memory) and explore performance across a broad sample of premutation males aged 18-69 years matched on age and IQ to unaffected comparison males. We further tease apart the premutation status into those males with symptoms of the newly identified neurodegenerative disorder, the fragile X-associated tremor/ataxia syndrome (FXTAS) and those males currently symptom-free. Our findings indicate a specific vulnerability in premutation males on tasks that require simultaneous manipulation and storage of new information, so-called executive control of memory. Furthermore, this vulnerability appears to exist regardless of the presence of FXTAS symptoms. Males with FXTAS symptoms demonstrated a more general impairment encompassing phonological working memory in addition to central executive working memory. Among asymptomatic premutation males, we observed the novel finding of a relationship between increased CGG repeat size and impairment to central executive working memory.

Figures

Figure 1
Figure 1
Age trajectories by decade across the central executive subcomponent of working memory in premutation males versus comparison normal control males. Premutation males exhibit significant impairment in cognitive control beginning in the 4th decade of life, which worsens with each subsequent decade.
Figure 2
Figure 2
Age trajectories by decade across the phonological loop subcomponent of working memory in premutation males versus comparison normal control males. Both groups of participants exhibit a significant decline in functioning with age.
Figure 3
Figure 3
Age trajectories by decade across the visual-spatial sketchpad subcomponent of working memory in premutation males versus comparison normal control males. Both groups of participants exhibit a significant decline in functioning with age.
Figure 4
Figure 4
Central executive functioning is plotted for participants divided according to a cut score of age 50, which represents the mean age of onset for the fragile X tremor and ataxia syndrome (FXTAS). Data for premutation males with a diagnosis of FXTAS, premutation males without FXTAS, and comparison normal control males are illustrated. Data for those premutation individuals with a diagnosis of FXTAS who were younger than 50 at the time of testing were not included in the statistical analysis because of small sample size (n = 2). Premutation males with FXTAS demonstrate significantly worse performance than comparison normal control males. This is not the case for asymptomatic males without FXTAS, who perform as well as normal control males.

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