A Novel Cognitive Stress Paradigm to Assess Subtle Cognitive Differences in Women With the FMR1 Premutation

Fragile X premutation (FXPM) is a genetic mutation of the FMR1 gene characterized by having between 55-200 CGG repetitions. FXPM women are at risk for a variety of reproductive, cognitive, and neuropsychiatric deficits, including fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is a late-onset neurodegenerative disorder characterized by tremor, gait ataxia, cognitive decline, brain atrophy, and deficits in executive functions. With the evidence supporting premature aging, prevalence of cognitive deficits, and risk of developing FXTAS and dementia, it is imperative to find a reliable measure that identifies at-risk FXPM women and their subtle cognitive phenotype. The LASSI-L is a novel cognitive stress paradigm that identifies cognitively impaired elderly adults from cognitively normal elderly adults. In the present study, we investigated the performance of FXPM women compared to non-carrier women to determine the sensitivity of the LASSI-L with regards to the subtle cognitive impairments associated with the FXPM. We hypothesized that FXPM women would have more vulnerability to proactive semantic interference, thus decreasing their ability to recover from proactive semantic interference. Moreover, we predicted that FXPM women would have higher percent intrusion errors (PIE) for both B1 Cued Recall and B2 Cued Recall. Lastly, we hypothesized that there would be a curvilinear relationship between the failure to recover from proactive semantic interference and CGG repeat length with the lowest scores being associated with the mid-range CGG repeat length (approximately 80-110). Results indicated increased vulnerability to proactive semantic interference and increased failure to recover from proactive semantic interference in FXPM women relative to controls. Findings also showed that FXPM women had more semantic intrusion errors during recall. Additionally, FXPM performance on B1 and B2 Cued Recall were associated with CGG repeat length and educational attainment. FXPM women with CGGs in the mid-range repeat length (approximately 80- 110) who had less than a bachelor’s degree recalled fewer target words in B1 and B2 Cued Recall. These findings supported the hypotheses. The current study underscores the need for further research investigating MCI and AD prevalence in FXPM women