Elsevier

Brain and Cognition

Volume 148, March 2021, 105694
Brain and Cognition

Word retrieval difficulty in adult females with the FMR1 premutation: Changes over time and across contexts

https://doi.org/10.1016/j.bandc.2021.105694Get rights and content

Highlights

  • We examined word retrieval difficulty in female premutation carriers over eight years.

  • As women aged, they produced fewer words, fewer different words, and had more errors.

  • Word retrieval difficulty occurred much earlier than can be expected in healthy aging.

  • Subtle cognitive decline may be a factor of premutation carrier status for women.

Abstract

Individuals with a premutation of the fragile X mental retardation (FMR1) gene are at risk for a variety of psychological, physical, and cognitive issues, including difficulty with word retrieval. The present study examined three indicators of word retrieval difficulty; reduced productivity, reduced lexical diversity, and increased errors in word retrieval in a group of 38 female premutation carriers during standard-length speech samples collected over a period of eight years. Our results revealed that as women aged, they produced fewer words, produced fewer different words, and had greater word retrieval errors. In addition, the rate of word retrieval errors was highly correlated between two speaking contexts, indicating that this difficulty was pervasive and not solely the result of speaking in monologue. Our results suggest that subtle areas of cognitive decline emerge at a much earlier age among female premutation carriers than would be expected during healthy aging.

Introduction

In the general population of the US a premutation of the fragile X mental retardation gene (FMR1 gene) is relatively common with estimates of over one million carriers and is more prevalent among women than men with estimates ranging from 1 in 113–207 women and 1 in 194–530 men (Maenner et al., 2013). The FMR1 gene is responsible for producing the fragile X mental retardation protein (FMRP), which is essential for normal cognitive development. The premutation is defined as the presence of a CGG trinucleotide repeat expansion of 55–200 repeats on the long arm of the X chromosome (at position Xq23.11) in the 5′ untranslated region of FMR1 gene. The normal gene has between 5 and 44 CGG repeats. Alleles with 45 and 54 repeats are considered in the “gray zone”, and more than 200 CGG repeats constitute a full mutation of the FMR1 gene.

A consequence of the premutation allele is an increase in FMR1 mRNA levels and a decrease in FMRP levels most notably at higher repeat sizes over >120 (Garcia-Arocena & Hagerman, 2010). Two known conditions are associated with the premutation, fragile X-associated primary ovarian insufficiency [FXPOI; (Sullivan, Marcus, & Epstein, 2005)] which occurs in approximately 16–24% of carriers (Sullivan, Welt, & Sherman, 2011), and fragile X-associated tremor/ataxia syndrome [FXTAS; (Hagerman & Hagerman, 2013)] which affects approximately 45.5% of male premutation carriers and 16.5% of female carriers over the age of 50 (Rodriguez-Revenga et al., 2009). However, there is a growing body of evidence that premutation carriers may suffer from a variety of psychological, physical, and cognitive issues that are not encompassed by these two conditions. (Hagerman et al., 2018, Wheeler et al., 2014). Indeed, the full significance of being a fragile X premutation carrier is unclear and there is a need for further research regarding conditions associated with the premutation (Johnson, Herring, & Richstein, 2020).

For example, researchers have found an increased difficulty with word retrieval, as measured by verbal dysfluency, in premutation carrier men with FXTAS compared to normative data (Grigsby et al., 2006). Increased dysfluencies were also noted in premutation carrier women without a diagnosis of FXTAS who were compared to a group of women matched for age and stress level (Klusek et al., 2018, Sterling et al., 2013). These latter findings suggest that there may be subtle specific areas of deficit in cognitive functioning in a substantial portion of premutation carriers, even without a diagnosis of FXTAS. That is, word retrieval difficulty may be an early indicator of fragile X-associated conditions.

In addition to finding group differences between women with and without the premutation, Sterling et al. (Sterling et al., 2013) found a significant positive correlation between the number of verbal dysfluencies during connected speech and age for the premutation carrier group but this relationship did not hold for the comparison group of mothers of children with autism spectrum disorder. That is, older women with the premutation had a greater number of dysfluencies than younger female premutation carriers in this cross-sectional study.

Difficulty with word retrieval, of which verbal dysfluency is a part, is prevalent among adults with aphasia but older adults who are cognitively healthy commonly complain of this difficulty as well (Condret-Santi et al., 2013). Presumably, difficulty with word retrieval arises because the connection in the lexicon between the semantic representation of a word and its phonological representation deteriorates with increasing age. This weak connection causes a representation to not be fully activated and production of the word fails (Burke & Shafto, 2004). An important question is, at what age do these word finding problems begin to manifest?

Kavé and Goral (2017) conducted a narrative review of studies comparing word retrieval during connected speech in healthy aging to word retrieval in adults with aphasia. They reasoned that if difficulty with word retrieval was evident in healthy aging there would be (1) reduced overall productivity in connected speech (i.e., fewer spoken words); (2) more limited lexical variety (i.e., fewer different words), based on the assumption that adults who have difficulty with word retrieval are likely to use words that are more easily accessed and to use these same words repeatedly, and (3) that they would have an increase in retrieval errors (i.e., greater dysfluency), just as they found in studies of adults with aphasia that they reviewed. Unfortunately, none of the studies they reviewed were longitudinal; rather, they were cross-sectional across a range of ages.

In contrast to their assumption, Kavé and Goral (2017) found that many studies reported an increase in number of produced words with age and, therefore, concluded that there was no reliable evidence that difficulty with productivity was common in connected speech by older cognitively healthy adults. Furthermore, studies they reviewed did not support the assumption that older cognitively healthy adults produced fewer different words (i.e., had restricted lexical variety) during connected speech. That is, reduced productivity and limited lexical variety during connected speech are not features of healthy aging.

Regarding retrieval errors, specifically, dysfluencies such as revisions, repeated words, and filled pauses (e.g., uh, um), the results from Kavé and Goral’s review (2017) as well as other studies are mixed. Two studies found an effect for age (i.e., (Bortfeld et al., 2001, Manning and Monte, 1981). Other studies found an effect for age only under some conditions, such as describing pictures with negative or unpleasant content compared to neutral pictures (i.e., (Castro & James, 2014), or when producing infrequent words compared to more common words (i.e., (Dennis & Hess, 2016). Schmitter-Edgecombe and colleagues (Schmitter-Edgecombe, Vesneski, & Jones, 2000) found an age effect for only one type of dysfluency—revisions. In contrast, two other studies found no effect for age across participants in their 20 s to 80 s (i.e., (Cooper, 1990, Duchin and Mysak, 1987).

When an effect for age was found in the above noted studies, it was in age groups that were 55 years or greater. Only three studies included a middle age group that more closely resembles the participants of the current study, that is, women in their mid-forties. Bortfeld and colleagues (2001) found that while their oldest group (M = 67;2 years) produced a higher rate of dysfluencies at 6.65 per 100 words, the middle age group (M = 47;11 years) did not differ from the youngest group (M = 28;10 years) with rates of 5.69 and 5.55 per 100 words, respectively. Duchin and Mysak (1987) found no difference in rates of dysfluencies among their five age groups of young adults (M = 25 years), middle age adults I (M = 49 years), middle age adults II (M = 60 years), elder adults I (M = 68 years), and elder adults II (M = 80 years). Similarly, Cooper (1990) found no effect for age when they compared six age groups ranging in age from their 20 s through 70 s and concluded that aspects of expressive language, including dysfluencies do not change as a function of age among healthy adults. Cooper (1990) asserts that if language differences are found, some process other than normal aging (i.e., disease) may be present.

Cross-sectional studies of different age groups can suggest a relationship between age and various outcomes, but a more definitive approach is a longitudinal study that follows the same cohort of participants over an extended period of years. This allows each subject to be compared to their own baseline instead of some group statistic. In this study, we present data from a cohort of premutation carrier mothers who have a child with fragile X syndrome (FXS). Data were collected over a span of eight years. Following the findings of Sterling and colleagues (2013) that older premutation carrier mothers may be at greater risk for difficulty with word retrieval as measured by verbal dysfluency, we asked if fragile X premutation carrier mothers showed impaired word retrieval abilities over time.

Evidence of word retrieval difficulty at an earlier age than would be expected in healthy adults may lead to earlier detection of a dysexecutive syndrome, a syndrome marked by impairments in executive functioning evident in neurologic disease, that can progress to early dementia (Berry-Kravis & Hall, 2011). Furthermore, clearer delineation of the phenotype of female premutation carriers is key to possible treatment options for this relatively large population.

We used the same set of assumptions that Kavé and Goral (2017) employed regarding difficulty with word retrieval. Namely, we determined if the total number of spoken fluent words (i.e., productivity) and the total number of different words (i.e., lexical variety) declined over time, and if word retrieval errors (i.e., dysfluencies and abandoned utterances) increased over time. In addition, we examined several biomarkers (i.e., CGG repeat length, activation ratio, and FMRP levels) to determine whether there was a relationship between these biomarkers and difficulty with word retrieval.

Both the study by Sterling and colleagues (2013) and the study be Klusek and colleagues (2018) described above, included a comparison group of mothers of children with autism spectrum disorder (ASD) to control for the stress of raising a difficult child and found higher rates of dysfluencies in the premutation carrier groups, indicating that stress was not a contributing factor. However, a study by Mahl (1987) found that higher rates of dysfluency were correlated with higher rates of anxiety in women (r = 0.59, p < .01) but not men (r = −0.47, p < .16).

Because our speech samples focused on a personal reflection of the mothers’ relationship with their child, we compared two measures of participants’ mental health to the rates of word retrieval difficulty in our sample of 38 premutation mothers. Specifically, we hypothesized that anxiety may be related to difficulty with word retrieval. We also tested whether the ASD status and challenging behaviors of their child with FXS were related to word retrieval errors. Previous research has found a relationship between negative or unpleasant content and increased difficulty with word retrieval (Castro & James, 2014); however, an examination of the content of the mothers’ speech samples regarding the relationship with their child did not reveal any negativity toward their child.

Finally, we examined the proportion of word retrieval errors (i.e., dysfluencies) in two different speaking contexts—a five-minute monologue and a dyadic semi-structured interview—to determine if word retrieval difficulty was dependent on context. We hypothesized that speaking extemporaneously in monologue for five minutes without feedback from the listener may be a more challenging language production task than engaging in a back-and-forth conversation with an active listener and, therefore, more word retrieval errors may be evident during the five-minute speech sample.

Our specific research questions were:

  • (1)

    Does the total number of fluent words produced in a standard speech sample (i.e., overall productivity) change over time?

  • (2)

    Does the number of different words produced in a standard speech sample (i.e., lexical variety) change over time?

  • (3)

    Does the proportion of utterances produced in a standard speech sample that contains a word retrieval error (i.e., dysfluencies) change over time?

  • (4)

    Does context (i.e., monologue versus dialogue) affect the amount of word retrieval errors?

  • (5)

    Are specific biomarkers related to difficulty with word retrieval?

  • (6)

    Is anxiety related to difficulty with word retrieval?

  • (7)

    Are child characteristics that may cause anxiety, such as ASD status, related to difficulty with word retrieval?

Section snippets

Participants

Thirty-eight premutation carrier women participated in this longitudinal study over the span of eight years. All participants gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Human Research Protection Program at the University of Kansas. All women had at least one child with FXS and were part of a larger longitudinal study (Warren, Brady, Sterling,

Results

Growth curve models were conducted for the three measures of word retrieval difficulty with age centered at 40 years. The education categorical variable and the interaction term for education and maternal age were added to each model as fixed effects. Neither variable was significant (all p values were greater than 0.20); therefore, they were dropped from all models.

Discussion

This study examined word retrieval difficulties in fragile X premutation carrier women over a span of eight years. An effect for age was found on all three aspects of word retrieval. As women aged, they produced fewer words, produced fewer different words, and had greater word retrieval errors during a standard five-minute speech sample that was administered three or four times in eight years. Reduced productivity and limited lexical variety are not typical in healthy aging (Kavé & Goral, 2017

CRediT authorship contribution statement

Shelley L. Bredin-Oja: Conceptualization, Methodology, Investigation, Writing - original draft, Writing - review & editing, Project administration. Steven F. Warren: Conceptualization, Writing - review & editing, Supervision, Funding acquisition. Rebecca E. Swinburne Romine: Methodology, Writing - original draft, Writing - review & editing, Visualization, Formal analysis. Kandace K. Fleming: Methodology, Writing - review & editing, Visualization, Formal analysis. Nancy Brady: Writing - review &

Acknowledgments

We wish to express our profound gratitude to the women and their families who have been a part of our larger longitudinal study, from which this data came, for the past 15 years.

Funding

This research was supported by NICHD grants P30-HD003110, P30-HD002528, R01-HD084663 and U54 HD090216.

Data Statement

The data analyzed in this study are not publicly available. Participants were assured data would be presented in aggregate form only and language transcripts and other raw data would not be shared.

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