Darren R. Hocking

Selective executive markers of at-risk profiles associated with the fragile X premutation

Objective: This study determined whether CGG repeat length moderates the relationship between age and performance on selective measures of executive function in premutation carriers (PM) who are asymptomatic for a recently described late-onset neurodegenerative disorder, fragile X–associated tremor/ataxia syndrome (FXTAS). Methods: Forty PM men aged 18–69 years with a family history of fragile X syndrome underwent neuropsychological tests of inhibition and working memory. We examined only men who are asymptomatic for FXTAS. Multiple regression analyses were conducted to examine the moderating role of CGG repeat length on the relation between age and performance on inhibition and working memory tasks. Results: With increasing age and only in men with an FMR1 expansion in the upper premutation range (>100 CGG repeats) was there an association between age and poorer task performance on selective executive function measures involving inhibition (p < 0.05) and executive working memory (p < 0.01). Men in the lower premutation range (<100 CGG repeats) were relatively risk-free from any cognitive aging effects associated with CGG repeat expansions. Conclusions: We conclude that neural networks in the prefrontal cortex may be highly susceptible to age-related neurotoxic effects in the upper size range of the FMR1 premutation. Future longitudinal studies will be needed to determine whether specific executive markers may serve to distinguish those at greatest risk for severe cognitive decline or dementia associated with FXTAS.

Neurobehavioural evidence for the involvement of the FMR1 gene in female carriers of fragile X syndrome

For years, premutation-carriers of fragile X-syndrome (FXS) were assumed free from any deleterious phenotype. In this review, we discuss the current literature on neurocognitive, emotional and neuromotor profiles emerging in females with the fragile-X premutation, and discuss phenotypic profiles in male premutation-carriers to gain insights into possible underlying mechanisms associated with FMR1 gene expression. We contend that this emerging phenotypic profile in females with the fragile-X premutation needs further investigation using experimentally-driven tasks sensitive to neural networks especially vulnerable to FMR1 gene expression. Further investigation of developmental aspects of the female carrier profile is needed to determine the extent to which emotional, cognitive and neurobehavioural challenges indicate at-risk profiles for later degenerative decline, or rather a stable developmental phenotype. These future research avenues will provide critical new information which will enable identification of women at greatest risk for subtle age-dependent neurobehavioural changes well before the onset of more serious clinical consequences alongside the identification of biomarkers which may be useful in establishing the efficacy of future therapeutic interventions.

Special- savanna patterns of energy and carbon integrated across the landscape

Savannas are highly significant global ecosystems that consist of a mix of trees and grasses and that are highly spatially varied in their physical structure, species composition, and physiological function (i.e., leaf area and function, stem density, albedo, and roughness). Variability in ecosystem characteristics alters biophysical and biogeochemical processes that can affect regional to global circulation patterns, which are not well characterized by land surface models. We initiated a multidisciplinary field campaign called Savanna Patterns of Energy and Carbon Integrated across the Landscape (SPECIAL) during the dry season in Australian savannas to understand the spatial patterns and processes of land surface–atmosphere exchanges (radiation, heat, moisture, CO2, and other trace gasses). We utilized a combination of multiscale measurements including fixed flux towers, aircraft-based flux transects, aircraft boundary layer budgets, and satellite remote sensing to quantify the spatial variability across a continental-scale rainfall gradient (transect). We found that the structure of vegetation changed along the transect in response to declining average rainfall. Tree basal area decreased from 9.6 m2 ha−1 in the coastal woodland savanna (annual rainfall 1,714 mm yr−1) to 0 m2 ha−1 at the grassland site (annual rainfall 535 mm yr−1), with dry-season green leaf area index (LAI) ranging from 1.04 to 0, respectively. Leaf-level measurements showed that photosynthetic properties were similar along the transect. Flux tower measurements showed that latent heat fluxes (LEs) decreased from north to south with resultant changes in the Bowen ratios (H/LE) from a minimum of 1.7 to a maximum of 15.8, respectively. Gross primary productivity, net carbon dioxide exchange, and LE showed similar declines along the transect and were well correlated with canopy LAI, and fluxes were more closely coupled to structure than floristic change.

The cognitive neuropsychological phenotype of carriers of the FMR1 premutation

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer’s disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation - both female and male - demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny.

Selective spatial processing deficits in an at-risk subgroup of the fragile X premutation

Until a decade ago, it was assumed that males with the fragile X premutation were unaffected by any cognitive phenotype. Here we examined the extent to which CGG repeat toxicity extends to visuospatial functioning in male fragile X premutation carriers who are asymptomatic for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Thirty-three premutation males aged 20-68 years [divided into two groups: 16 low-repeat carriers (CGG ≥ 55 ≤ 100) and 17 high-repeat carriers (CGG>100)] with a family history of fragile X syndrome and 62 non-affected adult males with normal FMR1 alleles were recruited. Subjects underwent neuropsychological tests of visuospatial and visual working memory functioning and visuoperceptual processing. On measures of visuospatial processing, the high-repeat carriers performed significantly worse than the normal allele group when age and IQ were covaried out. With increasing age and only in carriers of a larger (>100 repeats) premutation allele was there a greater decrement in visuospatial working memory functioning. Performance on spatial and perceptual judgement tasks failed to show similar specificity in males within the upper premutation range. We conclude that identification of selective visuospatial impairments in carriers of a larger premutation allele indicates greater CGG repeat toxicity in specific neural regions. Longitudinal follow-up studies will be needed to determine whether subtle decline in visuospatial functioning is associated with the later onset of motor symptoms of FXTAS.

Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers

Fragile X Mental Retardation 1 (FMR1) premutation carriers (PM‐carriers) have a defective trinucleotide expansion on the FMR1 gene that is associated with continuum of neuropsychological and mental disorders. Currently, little is known about the distinct subcomponents of executive function potentially impaired in female PM‐carriers, and there have been no investigations into associations between executive function and incidences of mental disorders. A total of 35 female PM‐carriers confirmed by Asuragen triple primed PCR DNA testing and 35 age‐ and intelligence‐matched controls completed tests of executive function (i.e., response inhibition and working memory) and self‐reported on social anxiety, depression, and ADHD predominantly inattentive (ADHD‐PI) symptoms. Compared to controls, PM‐carriers were significantly elevated on self‐reported social anxiety and ADHD‐PI symptoms. Irrespective of mental symptoms, female PM‐carries performed significantly worse than controls on a response inhibition test, and further investigations revealed significant correlations between executive function performance and self‐reported symptoms of anxiety, depression and ADHD‐PI. Critically, among PM‐carriers with good executive function performance, no women exceeded threshold markers for probable caseness of mental disorder. However, rates of probable caseness were elevated in those with average performance (response inhibition: social anxiety: 41.7%; depression: 20%; ADHD: 44.4%; working memory: social anxiety: 27.3%; depression: 9.1%; ADHD: 18.2%) and highly elevated for those with poor executive function performance (response inhibition: social anxiety: 58.3%; depression: 80%; ADHD: 55.6%; working memory: social anxiety: 100%; depression: 50%; ADHD: 83.3%). These data suggest that subtle executive dysfunction may be a useful neuropsychological indicator for a range of mental disorders previously reported in female PM‐carriers.

Fronto-parietal and cerebellar contributions to motor dysfunction in Williams syndrome : A review and future directions

Williams syndrome (WS) is a rare genetically based neurodevelopmental disorder which is associated with mental retardation and a distinctive cognitive and behavioural profile, including weaknesses in visuospatial processing but preserved language abilities and face recognition. Relative to the cognitive characteristics of WS, there is a dearth of research into the movement problems associated with this syndrome. This is despite the evidence from clinical and experimental studies that indicate disordered movement may be an important neuromotor characteristic of WS. This article reviews the current neuroanatomical and behavioural literature on visuomotor deficits in WS, and examines the differential role of fronto-parietal and cerebellar regions in motor dysfunction. The role of these brain regions in disturbances of visuomotor control is discussed in the context of the important interaction with attention, executive and planning deficits in WS. Finally, directions are provided for future research emphasising the need to examine developmental changes in motor functioning across a range of movement parameters and to investigate the functional correlates of abnormal neural connectivity in WS. It is concluded that further investigation of motor dysfunction in WS may provide us with a greater understanding of how important movement-related brain regions develop and operate.

Gait function in adults with Williams syndrome

Despite early neurological reports of gait abnormalities in Williams syndrome (WS), a rare genetically based neurodevelopmental disorder, there has not yet been any systematic investigation of gait dysfunction in this disorder. The current study examined the gait characteristics in adults with WS and a neurologically normal control group as they walked at self-selected slow, preferred and fast speeds using the GAITRite walkway. The WS group showed hypokinetic gait, which manifested as reduced gait speed and stride length, but with a disproportionate increase in cadence (stepping frequency) as speed was increased. The WS group also showed increased variability of stride length and a broad based stepping pattern implicating a compensatory strategy for postural instability. Performance IQ correlated significantly with stride length in the WS group. While these results should be considered preliminary due to the small sample size, these findings have implications for our understanding of the neural basis of gait dysfunction in WS.

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

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 IQ-matched 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 = 0.006 to 0.037; odds ratio = 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.

Linking social behaviour and anxiety to attention to emotional faces in Williams syndrome.

The neurodevelopmental disorder Williams syndrome (WS) has been associated with a social phenotype of hypersociability, non-social anxiety and an unusual attraction to faces. The current study uses eye tracking to explore attention allocation to emotionally expressive faces. Eye gaze and behavioural measures of anxiety and social reciprocity were investigated in adolescents and adults with WS when compared to typically developing individuals of comparable verbal mental age (VMA) and chronological age (CA). Results showed significant associations between high levels of behavioural anxiety and attention allocation away from the eye regions of threatening facial expressions in WS. The results challenge early claims of a unique attraction to the eyes in WS and suggest that individual differences in anxiety may mediate the allocation of attention to faces in WS.