Impaired response inhibition is associated with self‐reported symptoms of depression, anxiety, and ADHD in female<i>FMR1</i>premutation carriers

Kraan, Claudine; Hocking, Darren R.; Georgiou‐Karistianis, Nellie; Metcalfe, Sylvia; Archibald, Alison D; Fielding, Joanne; Trollor, Julian N.; Bradshaw, John L.; Cohen, Jonathon; Cornish, Kim

doi:10.1002/ajmg.b.32203

Cited by 54 publications

(57 citation statements)

References 78 publications

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“…Executive dysfunction is the most notable cognitive deficit in the dementia of patients with FXTAS, and subtle executive impairment is also evident in FMR1 premutation carriers without FXTAS. [2][3][4][5][6] In FXTAS, both neuroimaging and neuropathologic evidence suggests preferential white matter involvement, potentially allying this disease with others in the category of white matter dementia. 7 The characteristic MRI finding in FXTAS is hyperintensity within the middle cerebellar peduncle, known as the MCP sign (figure 1), and this abnormality is seen in about 60% of affected men.…”

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“…14 Executive function and information processing speed were selected for testing because these domains are prominently affected in FXTAS [2][3][4][5][6] and in many disorders characterized by white matter neuropathology. 7 Before enrollment, all participants had been administered the Mini-Mental State Examination 15 to generate a measure of general cognitive function.…”

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White matter disease and cognitive impairment in FMR1 premutation carriers

Filley¹,

Brown²,

Onderko³

et al. 2015

Neurology

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Objective: This cross-sectional, observational study examined the role of white matter involvement in the cognitive impairment of individuals with the fragile X mental retardation 1 (FMR1) premutation.Methods: Eight asymptomatic premutation carriers, 5 participants with fragile X tremor/ataxia syndrome (FXTAS), and 7 noncarrier controls were studied. The mean age of the asymptomatic premutation carriers, participants with FXTAS, and noncarrier controls was 60, 71, and 67 years, respectively. Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) were used to examine the middle cerebellar peduncles (MCP) and the genu and splenium of the corpus callosum in relation to executive function and processing speed. MRS measures were N-acetyl aspartate/creatine (NAA/Cr) and choline/creatine, and fractional anisotropy (FA) was used for DTI. Executive function was assessed with the Behavioral Dyscontrol Scale and the Controlled Oral Word Association Test (COWAT), and processing speed with the Symbol Digit Modalities Test.Results: Among all 13 FMR1 premutation carriers, significant correlations were found between N-acetyl aspartate/creatine and choline/creatine in the MCP and COWAT scores, and between FA in the genu and performance on the Behavioral Dyscontrol Scale, COWAT, and Symbol Digit Modalities Test; a correlation was also found between FA in the splenium and COWAT performance. In all regions studied, participants with FXTAS had the lowest mean FA. Conclusion:Microstructural white matter disease as determined by MRS and DTI correlated with executive dysfunction and slowed processing speed in these FMR1 premutation carriers. Neuroimaging abnormalities in the genu and MCP suggest that disruption of white matter within frontocerebellar networks has an important role in the cognitive impairment associated with the FMR1 premutation. Neurology ® 2015;84:2146-2152 GLOSSARY CC 5 corpus callosum; Ch/Cr 5 choline/creatine; COWAT 5 Controlled Oral Word Association Test; DTI 5 diffusion tensor imaging; FA 5 fractional anisotropy; FMR1 5 fragile X mental retardation 1; FXS 5 fragile X syndrome; FXTAS 5 fragile X tremor/ataxia syndrome; MCP 5 middle cerebellar peduncle; MRS 5 magnetic resonance spectroscopy; NAA/Cr 5 N-acetyl aspartate/creatine; ROI 5 region of interest; TE 5 echo time; TR 5 repetition time; SDMT 5 Symbol Digit Modalities Test.Fragile X tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disease in which dementia often accompanies motor and other clinical manifestations.1 Although FXTAS can develop in women, the disease is more penetrant and severe in men.1 FXTAS is caused by a CGG repeat expansion in the premutation range (55-200) of the fragile X mental retardation 1 (FMR1) gene, in contrast to the fragile X syndrome (FXS), which is caused by .200 CGG repeats.1 Each disease has unique molecular pathogenetic features, with FXS related to transcriptional silencing with reduced or absent FMR1 protein, and FXTAS characterized by increased FMR1 messenger RNA, 1 which is thought t...

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White matter disease and cognitive impairment in FMR1 premutation carriers

Filley¹,

Brown²,

Onderko³

et al. 2015

Neurology

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“…The cohorts of 35 PM and 35 age-and IQmatched control (CGG ,45) women used in this study were recruited previously. 11 Further details are provided in note e-1 on the Neurology ® Web site at Neurology.org. The PM cohort included 6 families that were not large (one family with 3 women, and 5 families with 2 women).…”

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Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women

et al. 2015

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Objective: To examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women.Methods: A total of 35 FMR1 PM women aged between 22 and 55 years and 35 age-and IQmatched women controls (CGG ,45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders. The molecular measures included DNA methylation of the FMR1 CpG island in blood, presented as FMR1 activation ratio (AR), and 9 CpG sites located at the FMR1 exon1/intron 1 boundary, CGG size, and FMR1 mRNA levels. Results:We show that FMR1 intron 1 methylation levels could be used to dichotomize PM women into greater and lower risk categories (p 5 0.006 to 0.037; odds ratio 5 14-24.8), with only FMR1 intron 1 methylation, and to a lesser extent AR, being significantly correlated with the likelihood of probable dysexecutive or psychiatric symptoms (p , 0.05). Furthermore, the significant relationships between methylation and social anxiety were found to be mediated by executive function performance, but only in PM women. FMR1 exon 1 methylation, CGG size, and FMR1 mRNA could not predict probable dysexecutive/psychiatric disorders in PM women.Conclusions: This is the first study supporting presence of specific epigenetic etiology associated with increased risk of developing comorbid dysexecutive and social anxiety symptoms in PM women. These findings could have implications for early intervention and risk estimate recommendations aimed at improving the outcomes for PM women and their families. Neurology ® 2015;84:1631-1638 GLOSSARY 5-hmC 5 5-hydroxymethylacytosine; ADHD-PI 5 attention-deficit/hyperactivity disorder-predominantly inattentive; AR 5 FMR1 activation ratio; DASS 5 Depression Anxiety Stress Scale; ELVF 5 Excluded Letter Verbal Fluency; FM 5 full mutation; FMR1 5 fragile X mental retardation 1 gene; FMRP 5 fragile X mental retardation protein; FREE 5 fragile X-related epigenetic element; FXS 5 fragile X syndrome; GEE 5 generalized estimating equation; IQR 5 interquartile range; LNS 5 Letter-Number Sequencing; OR 5 odds ratio; PM 5 premutation; ROC 5 receiver operating characteristic.The common premutation (PM) CGG expansion (55-199 repeats) in the 59 UTR of the fragile X mental retardation 1 (FMR1) gene (;1 in 450 males and ;1 in 150 females) 1 leads to a number of late-onset disorders 2 and high rates of dysexecutive and psychiatric symptoms, all with incomplete penetrance. 3 The RNA gain-of-function toxicity 4 and deficient FMR1 protein (FMRP) translation 5 are primary molecular features of PM-related disorders and are directly related to the CGG size. However, their effects on the phenotype are diluted in PM females through methylation-related silencing as part of X-inactivation.

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“…Using a single symbolic form (verbal), it is possible to detect dissociations in development of the components of initiation and inhibition with indexes of cognitive flexibility that can characterize neurological and psychiatric frames. [10][11][12] Studies have shown evidence of a double dissociation between specific EF disorders, such as in planning and response inhibition. 13 This highlights the clinical value of the HT.…”

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Development of the Brazilian version of the Child Hayling Test

Siqueira

Gonçalves

Hübner

et al. 2016

Trends Psychiatry Psychother.

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Introduction: The Hayling Test assesses the components of initiation, inhibition, cognitive flexibility and verbal speed by means of a sentence completion task. This study presents the process of developing the Brazilian version of the Child Hayling Test (CHT) and reports evidence of its content validity. Methods: 139 people took part in the study. The adaptation was performed by seven translators and 12 specialist judges. An initial sample of 92 healthy children was recruited to test a selection of sentences adapted from previous adult and pediatric versions of the instrument, and a sample of 28 healthy children was recruited for pilot testing of the final version. The instrument was developed in seven stages: 1) translation, 2) back-translation, 3) comparison of translated versions, 4) preparation of new stimuli, 5) data collection with healthy children to analyze comprehension of the stimuli and analyses by the authors against the psycholinguistic criteria adopted, 6) analyses conducted by judges who are specialists in neuropsychology or linguistics, and 7) the pilot study. Results: Twenty-four of the 72 sentences constructed were selected on the basis of 70-100% agreement between judges evaluating what they assessed and level of comprehensibility. The pilot study revealed better performance by older children, providing evidence of the instrument's sensitivity to developmental factors. Conclusions: Future studies employing this version of CHT with clinical pediatric populations who have frontal lesions and dysfunctions and in related areas are needed to test functional and differential diagnoses of preserved or impaired executive functions.

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Impaired response inhibition is associated with self‐reported symptoms of depression, anxiety, and ADHD in femaleFMR1premutation carriers

Cited by 54 publications

References 78 publications

White matter disease and cognitive impairment in FMR1 premutation carriers

White matter disease and cognitive impairment in FMR1 premutation carriers

Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women

Development of the Brazilian version of the Child Hayling Test

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