Investigation of memory, executive functions, and anatomic correlates in asymptomatic FMR1 premutation carriers

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset movement disorder associated with FMR1 premutation alleles. Asymptomatic premutation (aPM) carriers have preserved cognitive functions, but they present subtle executive deficits. Current efforts are focusing on the identification of specific cognitive markers that can detect aPM carriers at higher risk of developing FXTAS. This study aims at evaluating verbal memory and executive functions as early markers of disease progression while exploring associated brain structure changes using diffusion tensor imaging. We assessed 30 aPM men and 38 intrafamilial controls. The groups perform similarly in the executive domain except for decreased performance in motor planning in aPM carriers. In the memory domain, aPM carriers present a significant decrease in verbal encoding and retrieval. Retrieval is associated with microstructural changes of the white matter (WM) of the left hippocampal fimbria. Encoding is associated with changes in the WM under the right dorsolateral prefrontal cortex, a region implicated in relational memory encoding. These associations were found in the aPM group only and did not show age-related decline. This may be interpreted as a neurodevelopmental effect of the premutation, and longitudinal studies are required to better understand these mechanisms.

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

“…For example, fluent language production relies heavily on language processes that support word-finding, such as phonological and lexical access (Levelt, 1992; Postma, 2000; Hartsuiker and Notebaert, 2010). Although cognitive-executive deficits have been researched more extensively in the FMR1 premutation, the literature suggests that the specific language deficits may also occur in this group, such as abnormalities in semantic activation (Yang et al, 2014a,b), verbal recall (Shelton et al, 2017), verbal encoding (Hippolyte et al, 2014), and pragmatic language (Losh et al, 2012; Klusek et al, 2016). The present study raises the possibility that language-related deficits of the FMR1 premutation may occur independent of an executive dysfunction phenotype.…”

The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology

“…An important but unresolved issue at this stage is whether these mild deficits reflect a neurodevelopmental characteristic of the premutation, are early signs of FXTAS, or both (Hunter, Sherman, Grigsby, et al, 2011; Hippolyte, Battistella, Perrin, et al, 2014; Moore, Daly, Schmitz, et al, 2004; Moore, Daly, Tassone, et al, 2004). Cornish and her colleagues reported a subtle age-related decline in inhibitory control using the Hayling Task (Burgess & Shallice, 1997), and of working memory on Letter-Number sequencing, beginning in early adulthood and continuing throughout the lifespan (Cornish, Hocking, Moss, et al, 2011; Cornish, Kogan, Li, et al, 2009; Cornish, Li, Kogan, et al, 2008).…”

Prevalence and predictors of subjective memory complaints in adult male carriers of the FMR1 premutation

“…Accompanying non-motor symptoms of FXTAS may include deficits in executive function and short-term memory (Jacquemont et al, 2003). Poorer performance on these cognitive domains has also been reported in PM males without FXTAS, indicating that early cognitive signs may be observable before the onset of motor symptoms (Cornish, Hocking, Moss, & Kogan, 2011;Cornish et al, 2008;Grigsby et al, 2008;Hippolyte et al, 2014;Hunter, Sherman, Grigsby, Kogan, & Cornish, 2012). While it remains unclear whether early cognitive changes observable in some PM carriers may herald further decline associated with FXTAS, prompt identification of those at most risk of cognitive dysfunction has important implications for facilitating early intervention and management of non-motor symptoms that may negatively impact upon quality of life.…”