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Long term verbal memory recall deficits in fragile X premutation females
Accepted Manuscript Long Term Verbal Memory Recall Deficits in Fragile X Premutation Females Annie L Shelton, Kim Cornish, Joanne Fielding PII: DOI: Reference:
S1074-7427(17)30107-7 http://dx.doi.org/10.1016/j.nlm.2017.07.002 YNLME 6702
To appear in:
Neurobiology of Learning and Memory
Received Date: Revised Date: Accepted Date:
3 April 2017 20 June 2017 5 July 2017
Please cite this article as: Shelton, A.L., Cornish, K., Fielding, J., Long Term Verbal Memory Recall Deficits in Fragile X Premutation Females, Neurobiology of Learning and Memory (2017), doi: http://dx.doi.org/10.1016/j.nlm. 2017.07.002
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Long Delay Memory Recall Deficits
Long Term Verbal Memory Recall Deficits in Fragile X Premutation Females
Annie L Shelton1,., Kim Cornish1., & Joanne Fielding1,2 1
School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia 2 Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
Corresponding author: Joanne Fielding, PhD School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences (MICCN) Faculty of Medicine, Nursing and Health Sciences 18 Innovation Walk Monash University, Clayton, 3800 Victoria, Australia (03) 9905 3935 Email: [email protected]
Financial disclosures This work was funded by Australian Research Council (ARC) Discovery grant (DP110103346) to K. Cornish and J. Fielding. A. Shelton was an Australian Postgraduate Award Scholarship holder. All authors have no further financial disclosures to make.
Conflict of Interests The authors report no conflict of interests.
Running title: Long Delay Memory Recall Deficits
Long Delay Memory Recall Deficits
Abstract Carriers of a FMR1 premutation allele (between 55 and 199 CGG repeats) are at risk of developing a wide range of medical, psychiatric and cognitive disorders, including executive dysfunction. These cognitive deficits are often less severe for female premutation carriers compared to male premutation carriers, albeit similar in nature. However, it remains unclear whether female premutation carriers who exhibit executive dysfunction also record verbal learning and memory deficits like those of their male counterparts. Here we employed the CVLT to assess verbal learning and memory function in 19 female premutation carriers, contrasting performance with 19 age- and IQ-matched controls. Group comparisons revealed similar performance during the learning and short delay recall phases of the CVLT. However, after a long delay period, female premutation carriers remembered fewer words for both free and cued recall trials, but not during recognition trials. These findings are consistent with reports for male premutation carriers, and suggest that aspects of long term memory may be adversely affect in a subgroup of premutation carriers with signs of executive dysfunction.
Key words: FMR1, executive function, verbal memory, CVLT
Long Delay Memory Recall Deficits
1. Introduction Premutation expansions (55-199 CGG repeats) within the 5’ untranslated region of the fragile X mental retardation 1 (FMR1) gene confer a risk of a number of medical, psychiatric and cognitive disorders. While penetrance and severity are highly variable, deficits are often less severe in female compared to male premutation carriers (Grigsby et al., 2014; Kraan et al., 2013). This certainly appears to be case for the prevalence and severity of Fragile Xassociated tremor/ataxia syndrome (FXTAS), a neurological disorder characterised clinically by a host of motor control difficulties as well as cognitive impairment. Premutation specific cognitive deficits can be anywhere from mild to severe (dementia like), and affect a broad range of skills such as executive function, memory, linguistic, athematic, sensory, social, and mental control/planning [as previously reviewed by Grigsby et al. (2014) and Wheeler et al. (2014)]. Indeed, evidence suggests that mild executive dysfunction is common amongst subsets of male and female premutation carriers without FXTAS (Grigsby et al., 2014; Kraan et al., 2013). Specific executive function weakness on tasks reliant on response inhibition (Cornish, Hocking, Moss, & Kogan, 2011; Cornish et al., 2015; Cornish et al., 2008; Grigsby et al., 2008; Kraan, Hocking, Bradshaw, et al., 2014; Kraan, Hocking, Georgiou-Karistianis, et al., 2014) and working memory processes have been reported for male and female premutation carriers without FXTAS (Cornish et al., 2011; Cornish et al., 2009; Cornish et al., 2015; Hashimoto, Backer, Tassone, Hagerman, & Rivera, 2011; Hunsaker, Goodrich-Hunsaker, Willemsen, & Berman, 2010; Kraan, Hocking, Bradshaw, et al., 2014). Linguistic deficits have also been reported for premutation carriers without FXTAS, with verbal IQ scores found to be reduced in male and females carrying the premutation allele (Adams et al., 2007; Allen et al., 2011; Allen et al., 2005; Franke et al., 1999). Verbal learning and memory deficits have been reported for male premutation carriers, whom also reported concurrent executive function weakness (Brega et al., 2008; Grigsby et al., 2008; Hippolyte et al., 2014). However, verbal learning and memory ability in female premutation carriers appears to be unaffected - however these skills have only been assessed in cohorts of premutation females without dysexecutive issues (Franke et al., 1999; Hunter et al., 2008; J-C Yang et al., 2013).
Long Delay Memory Recall Deficits In this study, we investigated whether verbal learning and memory are similarly affected in female premutation carriers whom have been previously reported to have executive function weakness (Shelton, Cornish, Clough, et al., 2016; Shelton, Cornish, Kraan, et al., 2016). This will disseminate whether or not a subgroup of cognitive impaired female premutation carriers show a range of deficits, or whether they are specific to executive dysfunction. Overall, insight regarding the complex nature of domain specific cognitive deficits in a subgroup of premutation carriers will be provided, and further the current understanding of the female specific cognitive phenotype and more generally for premutation carriers.
2. Methods 2.1
Participants
A total of 41 female participants between the ages of 22 and 54 years (20 premutation carriers, 21 healthy controls) were recruited from support groups, population-based fragile X carrier screening studies (Metcalfe et al., 2008), as well as local networks and via online advertisements. All participants were English speaking with no history of any serious neurological damage/disease including FXTAS, which they were screened for using the FXTAS Rating Scale (Leehey, 2009). CGG repeat size was analysed for all participants to confirm FMR1 allele status as either premutation (CGG between 55 to 199 repeats; Mean=83.58, Standard Deviation=15.51, Range= 59-113) or normal/healthy controls (less than 45 CGG repeats; Mean=30.39, Standard Deviation=3.18, Range=20-36), using DNA from peripheral blood and the Asuragen® AmplideX™ FMR1 PCR Kit (Asuragen: Austin, TX, USA). All participants completed the California Verbal Learning Task (CVLT), as part of a larger cognitive battery which included assessments of executive function. The results of the executive function tasks have been previously reported (Shelton, Cornish, Clough, et al., 2016; Shelton et al., 2014; Shelton et al., 2015; Shelton, Cornish, Kolbe, et al., 2016; Shelton, Cornish, Kraan, et al., 2016), and suggest that this group of premutation women have a dysexecutive phenotype compared to controls.
Long Delay Memory Recall Deficits Table 1. Description and statistics for participant demographic measures Healthy Controls
Premutation Carriers
Mean
SD
Range
Mean
SD
Range
p-value
Cohen’s d
Age
38.84
8.70
24-54
39.53
9.43
22-54
0.822
0.076
Education
16.58
3.50
12-26
14.89
3.04
9-19
0.132
0.516
FSIQ
114.62
8.65
97-130
110.85
9.32
88-127
0.035
0.419
Note: SD = standard deviation; Age and education in years; FSIQ = full scale IQ. Figures in bold indicate p<0.05.
Data from 3 participants were removed from the CVLT analyses due to : 1) disruption during the learning phase of the CVLT by a fire alarm (healthy control); 2) results were on average 3.6 standard deviations (range 3.29-4.03) from the group mean across all recall trials (healthy control); and 3) recollection of fewer than 10 stimuli in the learning phase (premutation carrier). This yielded 2 groups (premutation and healthy control) of 19 participants each, which were matched for age and education in years. The IQ of all participants was measured using the composite full scale IQ (FSIQ) as determined by the Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler, 1999) (Table 1). Ethics approval for this study was granted by Monash University and Southern Health Human Research Committees (Project Number 10147B); all participants gave their informed consent prior to inclusion in the study in accordance with the declaration of Helsinki.
2.2
Verbal Learning and Memory Task
The CVLT second edition standard form (Delis, Kramer, Kaplan, & Ober, 2000) requires participants to learn and recall a series of 16 words. The 16 words are divided into four categories which are later used as semantic recall cues: furniture, vegetable, ways of travelling and animals. The task is split into 3 sections: 1) learning (total number of words recalled over 5 trials), 2) short delay recall [free (no cue given) and cued recall], and 3) long delay recall (free and cued recall, and recognition) – yielding a total of 6 CVLT scores.
Long Delay Memory Recall Deficits Between sections 2 and 3 of the CVLT, participants completed a visual attention task lasting between 18-20mins which required a finger-press response.
2.3
Statistical Analysis
Each of the 6 CVLT scores were assessed separately for normality (via skewness and kurtosis tests) and equal variance (Levene’s test) for each group. Least squares or robust (if an outlier was present) regression analyses were used to ascertain whether CVLT scores were related to age, education, FSIQ, or learning scores. Where age, education, FSIQ, or learning scores were not related to a particular CVLT score, an independent samples t-test (equal or unequal variances) or Mann Whitney U was used, to assess group differences. Where age, education, FSIQ, or learning scores were related to a CVLT score, ANCOVA was used, with the confounding variable as the covariate/s. Bonferroni corrections were applied and the significance level of p<0.008 was set for all analyses, given the six CVLT scores assessed. All analyses were performed using STATA statistical software (version 14, StataCorp, College Station, Texas, USA).
3. Results Age, education and FSIQ were not found to associate with any CVLT measure (Table 2). However, learning scores were seen to correlate with all measures of memory recall, and therefore was used as a covariate in the following group analyses (Table 3). No between group differences were revealed for CVLT learning scores or after a short delay period, when controlling for learning scores (Table 3). However, after a long delay period, female premutation carriers recalled fewer words for both free and cued trials compared to controls, but not during recognition trials (Table 3). Interestingly, a significant main effect for learning score was found for all CVLT recall scores (free/cued and short/long) (p<0.008), while the only significant interaction (group x learning score) was revealed for long delay cued recall (Table 3).
Long Delay Memory Recall Deficits Table 2. Relationships between CVLT scores and possible covariates (age, education, FSIQ and learning score) for all participants. Age Education FSIQ Learning Score Learning Score
0.033
-0.055
0.278
-
Short Delay Free Recall
-0.011
0.067*
0.066
0.188
Short Delay Cued Recall
0.003*
0.103*
0.056*
0.156
Long Delay Free Recall
-0.024
0.146
0.068
0.161
Long Delay Cued Recall
-0.005*
0.092
0.074
0.156
Recognition
-0.014
0.058
0.002
0.028
Note: Table provides regression coefficients. *indicates robust regression was used, given the presence of an outlier. Figures in bold indicate p<0.05.
Table 3. Mean, standard deviation (SD) and group comparison for CVLT measures for premutation carriers and healthy controls. Healthy Controls
Premutation Carriers
Group
Learning score effect
Interaction p-value
Mean
SD
Mean
SD
p-value
p-value
Learning Score+
61.316
9.013
58.263
8.432
0.288
-
Short Delay Free Recall^
14.368
1.571
12.421
2.567
0.031
0.000
0.072
Short Delay Cued Recall^
14.579
1.261
13.105
2.514
0.035
0.000
0.064
Long Delay Free Recall^
14.632
1.257
12.895
2.582
0.004
0.000
0.011
Long Delay Cued Recall^
15.000
0.816
13.421
2.589
0.001
0.000
0.002
^
15.842
0.375
15.421
0.902
0.120
0.050
0.177
Recognition
-
Note: +t-test equal variance, ^Comparison adjusted for learning score (covariate) using ANCOVA. Figures in bold indicate p<0.008 Bonferroni correction.
4. Discussion The present study investigated the integrity of verbal learning and memory in a cohort of female premutation carriers with previously reported executive dysfunction (Shelton, Cornish, Clough, et al., 2016; Shelton et al., 2014; Shelton et al., 2015; Shelton, Cornish, Kolbe, et al., 2016; Shelton, Cornish, Kraan, et al., 2016). CVLT verbal memory deficits were found only after a long delay period, but not during the final recognition trial. This parallels
Long Delay Memory Recall Deficits the long delayed verbal recall deficits identified across a range of verbal memory tasks (Grigsby et al., 2008; Hippolyte et al., 2014; Moore et al., 2004), as well preserved final recognition scores on the CVLT (Hippolyte et al., 2014), previously reported for male premutation carriers without FXTAS but with signs of executive dysfunction. The CVLT, although adapted over time, has been used extensively to quantitatively assess verbal learning and memory in healthy control, as well as a range of clinical populations. Results of the CVLT have been shown to correlate highly with other measures of memory, particularly verbal memory tests included within the Wechsler memory scale (WMS) (Delis, Cullum, Butters, Carins, & Prifitera, 1988; Helmstaedter, Wietzke, & Lutz, 2009; McDowell, Bayless, Moser, Meyers, & Paulsen, 2004; Randolph et al., 1994). Indeed, similar findings have been demonstrated on the CVLT and WMS tests in both male (Grigsby et al., 2008; Hippolyte et al., 2014) and female (Hunter et al., 2008; J-C Yang et al., 2013) premutation carriers without FXTAS. Preserved short-term verbal memory and recognition abilities were seen in this study as well as past investigations for male and female premutation carriers without FXTAS (Franke et al., 1999; Grigsby et al., 2008; Hippolyte et al., 2014; Hunter et al., 2008; Moore et al., 2004; J-C Yang et al., 2013). Indeed, the verbal memory deficits revealed during the long delay recall phase, but not in the presence of a recognition cue for female premutation carriers, parallel CVLT findings reported for male premutation carriers without FXTAS (mean age 46.7 years, range 20-70 years) (Hippolyte et al., 2014). Hippolyte and colleagues (2014), revealed that age was significantly associated with delayed recall (p=0.01), but not recognition (p=0.2). While the current study did not find these age correlates, it is likely that deficits in delayed recall, may not only be related to verbal learning abilities (as reported in this study), but also deteriorate with increasing age – as you approach 70 years of age. Further, deficits in long term memory recall have previously been associated with altered microstructural alterations in the left hippocampal fimbria/fornix and stria terminalis (Hippolyte et al., 2014). Thus, we hypothesize that the ability to activate memory traces within the hippocampus after a long period of delay may be disrupted for premutation carriers, and requires direct activation cues (such as those provided in the recognition section of the task) for memory retrieval; rather than the less informative/triggering semantic cues provided in the long delay cued trials. Such direct cues will reduce the
Long Delay Memory Recall Deficits cognitive demand necessary for retrieval (Moscovitch, 1992; Volk, McDermott, Roediger, & Todd, 2016), thus aiding memory in those with executive function deficits. However, the deficits reported herein are in contrast to previous studies for female premutation carriers without FXTAS, in which verbal learning or memory performance was comparable to controls (Franke et al., 1999; Hunter et al., 2008; J-C Yang et al., 2013). There are a number of possible explanations for these differences. Firstly, executive dysfunction has been shown to correlate with reduced verbal memory performance in both healthy and clinical populations with suspected neurological or psychiatric conditions (Duff, Schoenberg, Scott, & Adams, 2005; McCabe, Roediger, McDaniel, Balota, & Hambrick, 2010). Therefore, it is expected that premutation cohorts with intact executive function, also exhibit intact verbal memory as previously demonstrated (Franke et al., 1999; Hunter et al., 2008; J-C Yang et al., 2013). Secondly, Hunter et al. (2008) used measures from the WMS and Wechsler Adult Intelligence Scale to compute a verbal comprehension and memory score, using principle component analysis, which together is likely to have reduced sensitivity to detect verbal memory recall deficits. Finally, in this study, age did not correlate with any of the CVLT measures, nor was it different between our groups. This is in contrast to J-C. Yang et al. (2013), who reported significant differences in the ages of their premutation cohorts with and without FXTAS (approximately 15 years older than the current study). Given that CVLT learning and memory (long-term free recall) performance has been shown to deteriorate with age (Lamar, Resnick, & Zonderman, 2003), it is likely that in the study by J-C Yang et al. (2013), controlling for differences in age between the groups may have minimised power and sensitivity – yielding a null result. Therefore, it will be critical that future studies examines verbal memory across the lifespan of premutation carriers, with and without signs of executive dysfunction. In summary, we have provided possible explanations for the juxtaposition of our current results with previous verbal memory findings in female premutation carriers without FXTAS; however the verbal memory deficits reported herein parallel those reported for premutation males (Grigsby et al., 2008; Hippolyte et al., 2014; Moore et al., 2004). Although it must be acknowledged that this study may be limited by its cross sectional design, small sample size, and ascertainment bias, we have identified a subgroup of female premutation carriers without FXTAS who concurrent executive dysfunction and long-term
Long Delay Memory Recall Deficits memory deficits. This suggests that verbal memory deficits are similar between male and female premutation carriers. Further, we have added to the developing premutationspecific cognitive phenotype, through the notion that premutation carriers who experience cognitive impairment have domain specific deficits over multiple domains (i.e. executive function and verbal memory), which are best detected using sensitive targeted tests.
Acknowledgments We express our thanks to the Fragile X Association of Australia and Fragile X Alliance for their support in recruitment. We also thank Jonathan Whitty from Healthscope Pathology and Erin Turbitt from the Murdoch Childrens Research Institute for their assistance on the molecular procedures. Finally, we are indebted to all the families who participated in this research.
Long Delay Memory Recall Deficits
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Long Delay Memory Recall Deficits Leehey, M. A. (2009). Fragile X-associated tremor/ataxia syndrome; clinical phenotype diagnosis, and treatment. Journal of Investigative Medicine, 57, 830-836. doi:10.231/JIM.0b013e3181af59c4 McCabe, D. P., Roediger, H. L., McDaniel, M. A., Balota, D. A., & Hambrick, D. Z. (2010). The Relationship Between Working Memory Capacity and Executive Functioning: Evidence for a Common Executive Attention Construct. Neuropsychology, 24(2), 222-243. doi:10.1037/a0017619 McDowell, B. D., Bayless, J. D., Moser, D. J., Meyers, J. E., & Paulsen, J. S. (2004). Concordance between the CVLT and the WMS-III word lists test. Archives of Clinical Neuropsychology, 19(2), 319-324. doi:10.1016/S0887-6177(03)00023-4 Metcalfe, S., Jacques, A., Archibald, A., Burgess, T., Collins, V., Henry, A., . . . Cohen, J. (2008). A model for offering carrier screening for fragile X syndrome to nonpregnant women: results from a pilot study. Genetics in Medicine: official journal of the American College of Medical Genetics, 10(7), 525-535. doi:10.1097/GIM.0b013e31817c036e Moore, C. J., Daly, E. M., Schmitz, N., Tassone, F., Tysoe, C., Hagerman, R. J., . . . Murphy, D. G. (2004). A neuropsychological investigation of male premutation carriers of fragile X syndrome. Neuropsychologia, 42(14), 1934-1947. doi:10.1016/j.neuropsychologia.2004.05.002 Moscovitch, M. (1992). A neuropsychological model of memory and consciousness. In L. R. Squire & N. Butters (Eds.), Neuropsychology of Memory: Guilford Press. Randolph, C., Gold, J. M., Kozora, E., Cullum, C. M., Hermann, B. P., & Wyler, A. R. (1994). Estimating memory function: Disparity of Wechsler Memory Scale-Revised and California Verbal Learning Test indices in clinical and normal samples. Clinical Neuropsychologist, 8(1), 99-108. Shelton, A. L., Cornish, K., Clough, M., Gajamange, S., Kolbe, S., & Fielding, J. (2016). Disassociation between brain activation and executive function in fragile X premutation females. Human Brain mapping, 38(2), 1056-1067. doi:10.1002/hbm.23438 Shelton, A. L., Cornish, K., Kraan, C., Georgiou-Karistianis, N., Metcalfe, S. A., Bradshaw, J. L., . . . Fielding, J. (2014). Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: through eye movements. Brain and Cognition, 85, 201-208. doi:10.1016/j.bandc.2013.12.006#sthash.LKvgQDdz.dpuf Shelton, A. L., Cornish, K. M., Godler, D. E., Clough, M., Kraan, C., Bui, M. Q., & Fielding, J. (2015). Delineation of the working memory profile in female FMR1 premutation carriers: The effect of cognitive load on ocular motor responses. Behavioural Brain Research, 282(1), 194-200. doi:10.1016/j.bbr.2015.01.011 Shelton, A. L., Cornish, K. M., Kolbe, S., Clough, M. C., Slater, H. R., Li, X., . . . Fielding, J. (2016). Brain structure and intragenic DNA methylation are correlated, and predict executive dysfunction in fragile X premutation females. Translational Psychiatry, 6(12), e984. doi:10.1038/tp.2016.250 Shelton, A. L., Cornish, K. M., Kraan, C. M., Lozano, R., Bui, M., & Fielding, J. (2016). Executive Dysfunction in Female FMR1 Premutation Carriers. Cerebellum, 15(5), 565-569. doi:10.1007/s12311-016-0782-0
Long Delay Memory Recall Deficits Volk, H. E., McDermott, K. B., Roediger, H. L., & Todd, R. D. (2016). Genetic influences on free and cued recall in long-term memory tasks. Twin Research and Human Genetics, 9(5), 623631. Wechsler, D. (1999). Wechsler abbreviated scale of intelligence (WASI). San Antonio: Pearson Inc Wheeler, A. C., Bailey, D. B., Berry-Kravis, E., Greenberg, J., Losh, M., Mailick, M., . . . Hagerman, R. (2014). Associated features in females with an FMR1 premutation. Journal of Neurodevelopmental Disorders, 6(1). doi:10.1186/1866-1955-6-30 Yang, J.-C., Chan, S.-H., Khan, S., Schneider, A., Nanakul, R., Teichholtz, S., . . . Olichney, J. M. (2013). Neural substrates of executive dysfunction in fragile x-associated tremor/ataxia syndrome (FXTAS): a Brain potential study. Cerebral Cortex, 23(11), 2657-2666. doi:10.1093/cercor/bhs251 Yang, J.-C., Simon, C., Niu, Y.-Q., Bogost, M., Schneider, A., Tassone, F., . . . Olichney, J. M. (2013). Phenotypes of hypofrontality in older female fragile x premutation carriers. Ann Neurol, 74(2), 275-283. doi:10.1002/ana.23933
Long Term Verbal Memory Recall Deficits in Fragile X Premutation Females
Annie L Shelton1,., Kim Cornish1., & Joanne Fielding1,2 1
School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia 2 Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
Highlights:
Verbal learning and memory was examined in a population of females carrying the fragile X premutation allele who were reported to have executive dysfunction. Female fragile X premutation carriers were found to have intact verbal learning and short-delay memory. Long-delay free and cued recall was impaired for female fragile X premutation carriers. These findings suggest that subgroups of both female and male premutation carriers have similar and concurrent executive function and long-term verbal memory deficits.
Long Delay Memory Recall Deficits
S1074-7427(17)30107-7 http://dx.doi.org/10.1016/j.nlm.2017.07.002 YNLME 6702
To appear in:
Neurobiology of Learning and Memory
Received Date: Revised Date: Accepted Date:
3 April 2017 20 June 2017 5 July 2017
Please cite this article as: Shelton, A.L., Cornish, K., Fielding, J., Long Term Verbal Memory Recall Deficits in Fragile X Premutation Females, Neurobiology of Learning and Memory (2017), doi: http://dx.doi.org/10.1016/j.nlm. 2017.07.002
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Long Delay Memory Recall Deficits
Long Term Verbal Memory Recall Deficits in Fragile X Premutation Females
Annie L Shelton1,., Kim Cornish1., & Joanne Fielding1,2 1
School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia 2 Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
Corresponding author: Joanne Fielding, PhD School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences (MICCN) Faculty of Medicine, Nursing and Health Sciences 18 Innovation Walk Monash University, Clayton, 3800 Victoria, Australia (03) 9905 3935 Email: [email protected]
Financial disclosures This work was funded by Australian Research Council (ARC) Discovery grant (DP110103346) to K. Cornish and J. Fielding. A. Shelton was an Australian Postgraduate Award Scholarship holder. All authors have no further financial disclosures to make.
Conflict of Interests The authors report no conflict of interests.
Running title: Long Delay Memory Recall Deficits
Long Delay Memory Recall Deficits
Abstract Carriers of a FMR1 premutation allele (between 55 and 199 CGG repeats) are at risk of developing a wide range of medical, psychiatric and cognitive disorders, including executive dysfunction. These cognitive deficits are often less severe for female premutation carriers compared to male premutation carriers, albeit similar in nature. However, it remains unclear whether female premutation carriers who exhibit executive dysfunction also record verbal learning and memory deficits like those of their male counterparts. Here we employed the CVLT to assess verbal learning and memory function in 19 female premutation carriers, contrasting performance with 19 age- and IQ-matched controls. Group comparisons revealed similar performance during the learning and short delay recall phases of the CVLT. However, after a long delay period, female premutation carriers remembered fewer words for both free and cued recall trials, but not during recognition trials. These findings are consistent with reports for male premutation carriers, and suggest that aspects of long term memory may be adversely affect in a subgroup of premutation carriers with signs of executive dysfunction.
Key words: FMR1, executive function, verbal memory, CVLT
Long Delay Memory Recall Deficits
1. Introduction Premutation expansions (55-199 CGG repeats) within the 5’ untranslated region of the fragile X mental retardation 1 (FMR1) gene confer a risk of a number of medical, psychiatric and cognitive disorders. While penetrance and severity are highly variable, deficits are often less severe in female compared to male premutation carriers (Grigsby et al., 2014; Kraan et al., 2013). This certainly appears to be case for the prevalence and severity of Fragile Xassociated tremor/ataxia syndrome (FXTAS), a neurological disorder characterised clinically by a host of motor control difficulties as well as cognitive impairment. Premutation specific cognitive deficits can be anywhere from mild to severe (dementia like), and affect a broad range of skills such as executive function, memory, linguistic, athematic, sensory, social, and mental control/planning [as previously reviewed by Grigsby et al. (2014) and Wheeler et al. (2014)]. Indeed, evidence suggests that mild executive dysfunction is common amongst subsets of male and female premutation carriers without FXTAS (Grigsby et al., 2014; Kraan et al., 2013). Specific executive function weakness on tasks reliant on response inhibition (Cornish, Hocking, Moss, & Kogan, 2011; Cornish et al., 2015; Cornish et al., 2008; Grigsby et al., 2008; Kraan, Hocking, Bradshaw, et al., 2014; Kraan, Hocking, Georgiou-Karistianis, et al., 2014) and working memory processes have been reported for male and female premutation carriers without FXTAS (Cornish et al., 2011; Cornish et al., 2009; Cornish et al., 2015; Hashimoto, Backer, Tassone, Hagerman, & Rivera, 2011; Hunsaker, Goodrich-Hunsaker, Willemsen, & Berman, 2010; Kraan, Hocking, Bradshaw, et al., 2014). Linguistic deficits have also been reported for premutation carriers without FXTAS, with verbal IQ scores found to be reduced in male and females carrying the premutation allele (Adams et al., 2007; Allen et al., 2011; Allen et al., 2005; Franke et al., 1999). Verbal learning and memory deficits have been reported for male premutation carriers, whom also reported concurrent executive function weakness (Brega et al., 2008; Grigsby et al., 2008; Hippolyte et al., 2014). However, verbal learning and memory ability in female premutation carriers appears to be unaffected - however these skills have only been assessed in cohorts of premutation females without dysexecutive issues (Franke et al., 1999; Hunter et al., 2008; J-C Yang et al., 2013).
Long Delay Memory Recall Deficits In this study, we investigated whether verbal learning and memory are similarly affected in female premutation carriers whom have been previously reported to have executive function weakness (Shelton, Cornish, Clough, et al., 2016; Shelton, Cornish, Kraan, et al., 2016). This will disseminate whether or not a subgroup of cognitive impaired female premutation carriers show a range of deficits, or whether they are specific to executive dysfunction. Overall, insight regarding the complex nature of domain specific cognitive deficits in a subgroup of premutation carriers will be provided, and further the current understanding of the female specific cognitive phenotype and more generally for premutation carriers.
2. Methods 2.1
Participants
A total of 41 female participants between the ages of 22 and 54 years (20 premutation carriers, 21 healthy controls) were recruited from support groups, population-based fragile X carrier screening studies (Metcalfe et al., 2008), as well as local networks and via online advertisements. All participants were English speaking with no history of any serious neurological damage/disease including FXTAS, which they were screened for using the FXTAS Rating Scale (Leehey, 2009). CGG repeat size was analysed for all participants to confirm FMR1 allele status as either premutation (CGG between 55 to 199 repeats; Mean=83.58, Standard Deviation=15.51, Range= 59-113) or normal/healthy controls (less than 45 CGG repeats; Mean=30.39, Standard Deviation=3.18, Range=20-36), using DNA from peripheral blood and the Asuragen® AmplideX™ FMR1 PCR Kit (Asuragen: Austin, TX, USA). All participants completed the California Verbal Learning Task (CVLT), as part of a larger cognitive battery which included assessments of executive function. The results of the executive function tasks have been previously reported (Shelton, Cornish, Clough, et al., 2016; Shelton et al., 2014; Shelton et al., 2015; Shelton, Cornish, Kolbe, et al., 2016; Shelton, Cornish, Kraan, et al., 2016), and suggest that this group of premutation women have a dysexecutive phenotype compared to controls.
Long Delay Memory Recall Deficits Table 1. Description and statistics for participant demographic measures Healthy Controls
Premutation Carriers
Mean
SD
Range
Mean
SD
Range
p-value
Cohen’s d
Age
38.84
8.70
24-54
39.53
9.43
22-54
0.822
0.076
Education
16.58
3.50
12-26
14.89
3.04
9-19
0.132
0.516
FSIQ
114.62
8.65
97-130
110.85
9.32
88-127
0.035
0.419
Note: SD = standard deviation; Age and education in years; FSIQ = full scale IQ. Figures in bold indicate p<0.05.
Data from 3 participants were removed from the CVLT analyses due to : 1) disruption during the learning phase of the CVLT by a fire alarm (healthy control); 2) results were on average 3.6 standard deviations (range 3.29-4.03) from the group mean across all recall trials (healthy control); and 3) recollection of fewer than 10 stimuli in the learning phase (premutation carrier). This yielded 2 groups (premutation and healthy control) of 19 participants each, which were matched for age and education in years. The IQ of all participants was measured using the composite full scale IQ (FSIQ) as determined by the Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler, 1999) (Table 1). Ethics approval for this study was granted by Monash University and Southern Health Human Research Committees (Project Number 10147B); all participants gave their informed consent prior to inclusion in the study in accordance with the declaration of Helsinki.
2.2
Verbal Learning and Memory Task
The CVLT second edition standard form (Delis, Kramer, Kaplan, & Ober, 2000) requires participants to learn and recall a series of 16 words. The 16 words are divided into four categories which are later used as semantic recall cues: furniture, vegetable, ways of travelling and animals. The task is split into 3 sections: 1) learning (total number of words recalled over 5 trials), 2) short delay recall [free (no cue given) and cued recall], and 3) long delay recall (free and cued recall, and recognition) – yielding a total of 6 CVLT scores.
Long Delay Memory Recall Deficits Between sections 2 and 3 of the CVLT, participants completed a visual attention task lasting between 18-20mins which required a finger-press response.
2.3
Statistical Analysis
Each of the 6 CVLT scores were assessed separately for normality (via skewness and kurtosis tests) and equal variance (Levene’s test) for each group. Least squares or robust (if an outlier was present) regression analyses were used to ascertain whether CVLT scores were related to age, education, FSIQ, or learning scores. Where age, education, FSIQ, or learning scores were not related to a particular CVLT score, an independent samples t-test (equal or unequal variances) or Mann Whitney U was used, to assess group differences. Where age, education, FSIQ, or learning scores were related to a CVLT score, ANCOVA was used, with the confounding variable as the covariate/s. Bonferroni corrections were applied and the significance level of p<0.008 was set for all analyses, given the six CVLT scores assessed. All analyses were performed using STATA statistical software (version 14, StataCorp, College Station, Texas, USA).
3. Results Age, education and FSIQ were not found to associate with any CVLT measure (Table 2). However, learning scores were seen to correlate with all measures of memory recall, and therefore was used as a covariate in the following group analyses (Table 3). No between group differences were revealed for CVLT learning scores or after a short delay period, when controlling for learning scores (Table 3). However, after a long delay period, female premutation carriers recalled fewer words for both free and cued trials compared to controls, but not during recognition trials (Table 3). Interestingly, a significant main effect for learning score was found for all CVLT recall scores (free/cued and short/long) (p<0.008), while the only significant interaction (group x learning score) was revealed for long delay cued recall (Table 3).
Long Delay Memory Recall Deficits Table 2. Relationships between CVLT scores and possible covariates (age, education, FSIQ and learning score) for all participants. Age Education FSIQ Learning Score Learning Score
0.033
-0.055
0.278
-
Short Delay Free Recall
-0.011
0.067*
0.066
0.188
Short Delay Cued Recall
0.003*
0.103*
0.056*
0.156
Long Delay Free Recall
-0.024
0.146
0.068
0.161
Long Delay Cued Recall
-0.005*
0.092
0.074
0.156
Recognition
-0.014
0.058
0.002
0.028
Note: Table provides regression coefficients. *indicates robust regression was used, given the presence of an outlier. Figures in bold indicate p<0.05.
Table 3. Mean, standard deviation (SD) and group comparison for CVLT measures for premutation carriers and healthy controls. Healthy Controls
Premutation Carriers
Group
Learning score effect
Interaction p-value
Mean
SD
Mean
SD
p-value
p-value
Learning Score+
61.316
9.013
58.263
8.432
0.288
-
Short Delay Free Recall^
14.368
1.571
12.421
2.567
0.031
0.000
0.072
Short Delay Cued Recall^
14.579
1.261
13.105
2.514
0.035
0.000
0.064
Long Delay Free Recall^
14.632
1.257
12.895
2.582
0.004
0.000
0.011
Long Delay Cued Recall^
15.000
0.816
13.421
2.589
0.001
0.000
0.002
^
15.842
0.375
15.421
0.902
0.120
0.050
0.177
Recognition
-
Note: +t-test equal variance, ^Comparison adjusted for learning score (covariate) using ANCOVA. Figures in bold indicate p<0.008 Bonferroni correction.
4. Discussion The present study investigated the integrity of verbal learning and memory in a cohort of female premutation carriers with previously reported executive dysfunction (Shelton, Cornish, Clough, et al., 2016; Shelton et al., 2014; Shelton et al., 2015; Shelton, Cornish, Kolbe, et al., 2016; Shelton, Cornish, Kraan, et al., 2016). CVLT verbal memory deficits were found only after a long delay period, but not during the final recognition trial. This parallels
Long Delay Memory Recall Deficits the long delayed verbal recall deficits identified across a range of verbal memory tasks (Grigsby et al., 2008; Hippolyte et al., 2014; Moore et al., 2004), as well preserved final recognition scores on the CVLT (Hippolyte et al., 2014), previously reported for male premutation carriers without FXTAS but with signs of executive dysfunction. The CVLT, although adapted over time, has been used extensively to quantitatively assess verbal learning and memory in healthy control, as well as a range of clinical populations. Results of the CVLT have been shown to correlate highly with other measures of memory, particularly verbal memory tests included within the Wechsler memory scale (WMS) (Delis, Cullum, Butters, Carins, & Prifitera, 1988; Helmstaedter, Wietzke, & Lutz, 2009; McDowell, Bayless, Moser, Meyers, & Paulsen, 2004; Randolph et al., 1994). Indeed, similar findings have been demonstrated on the CVLT and WMS tests in both male (Grigsby et al., 2008; Hippolyte et al., 2014) and female (Hunter et al., 2008; J-C Yang et al., 2013) premutation carriers without FXTAS. Preserved short-term verbal memory and recognition abilities were seen in this study as well as past investigations for male and female premutation carriers without FXTAS (Franke et al., 1999; Grigsby et al., 2008; Hippolyte et al., 2014; Hunter et al., 2008; Moore et al., 2004; J-C Yang et al., 2013). Indeed, the verbal memory deficits revealed during the long delay recall phase, but not in the presence of a recognition cue for female premutation carriers, parallel CVLT findings reported for male premutation carriers without FXTAS (mean age 46.7 years, range 20-70 years) (Hippolyte et al., 2014). Hippolyte and colleagues (2014), revealed that age was significantly associated with delayed recall (p=0.01), but not recognition (p=0.2). While the current study did not find these age correlates, it is likely that deficits in delayed recall, may not only be related to verbal learning abilities (as reported in this study), but also deteriorate with increasing age – as you approach 70 years of age. Further, deficits in long term memory recall have previously been associated with altered microstructural alterations in the left hippocampal fimbria/fornix and stria terminalis (Hippolyte et al., 2014). Thus, we hypothesize that the ability to activate memory traces within the hippocampus after a long period of delay may be disrupted for premutation carriers, and requires direct activation cues (such as those provided in the recognition section of the task) for memory retrieval; rather than the less informative/triggering semantic cues provided in the long delay cued trials. Such direct cues will reduce the
Long Delay Memory Recall Deficits cognitive demand necessary for retrieval (Moscovitch, 1992; Volk, McDermott, Roediger, & Todd, 2016), thus aiding memory in those with executive function deficits. However, the deficits reported herein are in contrast to previous studies for female premutation carriers without FXTAS, in which verbal learning or memory performance was comparable to controls (Franke et al., 1999; Hunter et al., 2008; J-C Yang et al., 2013). There are a number of possible explanations for these differences. Firstly, executive dysfunction has been shown to correlate with reduced verbal memory performance in both healthy and clinical populations with suspected neurological or psychiatric conditions (Duff, Schoenberg, Scott, & Adams, 2005; McCabe, Roediger, McDaniel, Balota, & Hambrick, 2010). Therefore, it is expected that premutation cohorts with intact executive function, also exhibit intact verbal memory as previously demonstrated (Franke et al., 1999; Hunter et al., 2008; J-C Yang et al., 2013). Secondly, Hunter et al. (2008) used measures from the WMS and Wechsler Adult Intelligence Scale to compute a verbal comprehension and memory score, using principle component analysis, which together is likely to have reduced sensitivity to detect verbal memory recall deficits. Finally, in this study, age did not correlate with any of the CVLT measures, nor was it different between our groups. This is in contrast to J-C. Yang et al. (2013), who reported significant differences in the ages of their premutation cohorts with and without FXTAS (approximately 15 years older than the current study). Given that CVLT learning and memory (long-term free recall) performance has been shown to deteriorate with age (Lamar, Resnick, & Zonderman, 2003), it is likely that in the study by J-C Yang et al. (2013), controlling for differences in age between the groups may have minimised power and sensitivity – yielding a null result. Therefore, it will be critical that future studies examines verbal memory across the lifespan of premutation carriers, with and without signs of executive dysfunction. In summary, we have provided possible explanations for the juxtaposition of our current results with previous verbal memory findings in female premutation carriers without FXTAS; however the verbal memory deficits reported herein parallel those reported for premutation males (Grigsby et al., 2008; Hippolyte et al., 2014; Moore et al., 2004). Although it must be acknowledged that this study may be limited by its cross sectional design, small sample size, and ascertainment bias, we have identified a subgroup of female premutation carriers without FXTAS who concurrent executive dysfunction and long-term
Long Delay Memory Recall Deficits memory deficits. This suggests that verbal memory deficits are similar between male and female premutation carriers. Further, we have added to the developing premutationspecific cognitive phenotype, through the notion that premutation carriers who experience cognitive impairment have domain specific deficits over multiple domains (i.e. executive function and verbal memory), which are best detected using sensitive targeted tests.
Acknowledgments We express our thanks to the Fragile X Association of Australia and Fragile X Alliance for their support in recruitment. We also thank Jonathan Whitty from Healthscope Pathology and Erin Turbitt from the Murdoch Childrens Research Institute for their assistance on the molecular procedures. Finally, we are indebted to all the families who participated in this research.
Long Delay Memory Recall Deficits
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Long Term Verbal Memory Recall Deficits in Fragile X Premutation Females
Annie L Shelton1,., Kim Cornish1., & Joanne Fielding1,2 1
School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia 2 Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
Highlights:
Verbal learning and memory was examined in a population of females carrying the fragile X premutation allele who were reported to have executive dysfunction. Female fragile X premutation carriers were found to have intact verbal learning and short-delay memory. Long-delay free and cued recall was impaired for female fragile X premutation carriers. These findings suggest that subgroups of both female and male premutation carriers have similar and concurrent executive function and long-term verbal memory deficits.
Long Delay Memory Recall Deficits