The primary cognitive deficit among males with fragile X-associated tremor/ataxia syndrome (FXTAS) is a dysexecutive syndrome

Brega, Angela G.; Goodrich, Glenn K.; Bennett, Rachael E.; Hessl, David; Engle, Karen; Leehey, Maureen A.; Bounds, Lanee S.; Paulich, Marsha J.; Hagerman, Randi J.; Hagerman, Paul J.; Cogswell, Jennifer B.; Tassone, Flora; Reynolds, Ann; Kooken, Robert; Kenny, Michael; Grigsby, Jim

doi:10.1080/13803390701819044

Cited by 84 publications

(103 citation statements)

References 87 publications

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“…Brega and colleagues suggested that executive dysfunction might mediate impaired performance on tests in other cognitive domains [25]. The appearance of executive dysfunction in male carriers prior to developing FXTAS remains unclear.…”

Section: Cognitive Deficits In Premutation Carriersmentioning

confidence: 99%

Cognitive Dysfunction in FMR1 Premutation Carriers

Seritan¹,

Cogswell²,

Grigsby³

2013

CPSR

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Premutation carriers of the fragile X mental retardation gene (especially men) older than 50 may develop a neurodegenerative disease, the fragile X-associated tremor/ataxia syndrome (FXTAS). Carriers may present with varied cognitive impairments. Attention, working memory, declarative and procedural learning, information processing speed, and recall are among the cognitive domains affected. Executive dysfunction is a prominent deficit, which has been demonstrated mostly in men with FXTAS. In more advanced stages of FXTAS, both men and women may develop a mixed cortical-subcortical dementia, manifested by psychomotor slowing and deficits in attention, retrieval, recall, visuospatial skills, occasional apraxia, as well as overt personality changes. Studies have shown dementia rates as high as 37-42% in older men with FXTAS, although more research is needed to understand the prevalence and risk factors of dementia in women with FXTAS. Neuropsychiatric symptoms are common and reflect the dysfunction of underlying frontal-subcortical neural circuits, along with components of the cerebellar cognitive affective syndrome. These include labile or depressed mood, anxiety, disinhibition, impulsivity, and (rarely) psychotic symptoms. In this paper we review the information available to date regarding the prevalence and clinical picture of FXTAS dementia. Differential diagnosis may be difficult, given overlapping motor and non-motor signs with several other neurodegenerative diseases. Anecdotal response to cholinesterase inhibitors and memantine has been reported, while symptomatic treatments can address the neuropsychiatric manifestations of FXTAS dementia.

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Section: Cognitive Deficits In Premutation Carriersmentioning

confidence: 99%

Cognitive Dysfunction in FMR1 Premutation Carriers

Seritan¹,

Cogswell²,

Grigsby³

2013

CPSR

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“…White matter degeneration has been described as the most prominent neuropathologic characteristic of FXTAS, 8 and the presence of normal frontal cortical thickness and neuronal density 8 suggests that cortical degeneration is not the initial event leading to cognitive dysfunction. Moreover, the similarity of cognitive dysfunction in FXTAS [2][3][4][5][6]18 to a host of known white matter disorders 7 suggests that white matter damage may be a critical determinant of cognitive decline and dementia in this disease. 4 An intriguing implication of this work is that dementia related to primary white matter dysfunction may occur in the setting of neurodegenerative disease.…”

Section: Figure 2 Mrs Voxel Placementmentioning

confidence: 99%

“…associated with the FMR1 premutation, 2,3,18 and with widespread white matter degeneration in FXTAS that includes loss of both myelin and axons. 8 This is the first study to report white matter MRS data in association with cognitive dysfunction in FMR1 premutation carriers.…”

Section: Figure 2 Mrs Voxel Placementmentioning

confidence: 99%

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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“…There is strong evidence for the existence of a dysexecutive profile in asymptomatic PM-carriers (those without FXTAS) [16][17][18][19]. The male asymptomatic PM-carrier phenotype is currently characterised by impairments in executive processing, with specific deficits in tasks reliant upon working memory, inhibitory processing, visuospatial processing and attentional control [20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 97%