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Viewing all children as active participants in their own learning is central to inclusion. That children with atypical development experience a level of belonging that enables this in mainstream early childhood education and care (ECEC) settings remains a topic of hot debate and very much an unmet goal across the sector. Children with autism spectrum disorder (ASD), in particular, face significant challenges in ECEC settings, their educators continually seeking solutions for greater support. Given the escalating demand on mainstream ECEC settings to include these children, it was important to identify the specific supports needed by educators to achieve this with confidence and competence. This study investigated the outcomes of applying an evidence-based model of intervention to mainstream services via a targeted professional development program. Results of the study found that the benefits of engagement with mainstream ECEC settings extended beyond child outcomes to educators who were supported to develop the knowledge, understanding, and strategies to engage and teach children with ASD and manage their behaviours.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8–17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts., Females are less frequently diagnosed with autism than males. Using functional brain imaging and genetic analyses, Jack et al. show that differences in the striatum, a part of the brain involved in attaching motivational value to stimuli in the environment, may contribute to autism risk in girls.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8–17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

SummaryThe age at onset of motor symptoms in Huntington’s disease (HD) is driven by HTT CAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier onset HD. Nuclease activities of these variants correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion comparable to those observed with complete FAN1 knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

Rationale: Asthma in children generally starts as being mild but may progress to being severe and may stay severe for unknown reasons. Objectives: To identify factors in childhood that predict the persistence of severe asthma in late adolescence and early adulthood. Methods: The CAMP (Childhood Asthma Management Program) is, to our knowledge, the largest and longest asthma trial to date; it includes 1,041 children aged 5–12 years with mild to moderate asthma. We evaluated 682 program participants with analyzable data in late adolescence (age, 17–19 yr) and early adulthood (age, 21–23 yr). Measurements and Main Results: To best capture the cases of severe asthma, a status of severe asthma was defined by using criteria from the American Thoracic Society and the National Asthma Education and Prevention Program. Logistic regression with stepwise elimination was used to analyze the clinical features, biomarkers, and lung function that are predictive of the persistence of severe asthma. In late adolescence and early adulthood, 12% and 19% of the participants had severe asthma, respectively; only 6% at both time points had severe cases. For every 5% decrease in the postbronchodilator FEV(1)/FVC ratio in childhood, the odds of the persistence of severe asthma increased by 2.36-fold (95% confidence interval [CI], 1.70–3.28; P

Autism is hypothesized to be in part driven by a reduced sensitivity to the inherently rewarding nature of social stimuli. Previous neuroimaging studies have indicated that autistic males do indeed display reduced neural activity to social rewards, but it is unknown whether this finding extends to autistic females, particularly as behavioral evidence suggests that affected females may not exhibit the same reduction in social motivation as their male peers. We therefore used functional magnetic resonance imaging to examine social reward processing during an instrumental implicit learning task in 154 children and adolescents (ages 8–17): 39 autistic girls, 43 autistic boys, 33 typically developing girls, and 39 typically developing boys. We found that autistic girls displayed increased activity to socially rewarding stimuli, including greater activity in the nucleus accumbens relative to autistic boys, as well as greater activity in lateral frontal cortices and the anterior insula compared with typically developing girls. These results demonstrate for the first time that autistic girls do not exhibit the same reduction in activity within social reward systems as autistic boys. Instead, autistic girls display increased neural activation to such stimuli in areas related to reward processing and salience detection. Our findings indicate that a reduced sensitivity to social rewards, as assessed with a rewarded instrumental implicit learning task, does not generalize to affected female youth and highlight the importance of studying potential sex differences in autism to improve our understanding of the condition and its heterogeneity.

Understanding sex differences in brain function and genetics is critical to delineating the systems biology of autism spectrum disorder (ASD), but female ASD is understudied. We integrate imaging and genetic data in a sex-balanced sample of ASD and neurotypical youth to evaluate the hypothesis that there are female-specific pathways of ASD risk and resilience. FMRI data reveal a neurofunctional profile of female ASD characterized by motor, striatal, and frontal involvement not observed in male ASD. Further, we observe greater recruitment of salience and executive control networks among neurotypical girls versus neurotypical boys and autistic girls, suggesting neural correlates of the “Female Protective Effect.” Larger copy number variants containing gene(s) expressed in striatal cortex in autistic girls versus boys suggest a female-specific etiological role for potential impacts to this brain region. Our findings advocate caution in drawing conclusions regarding autistic girls based on male-predominant samples.

Context Behavioral studies suggest that responses to food consumption are altered in children with obesity (OB). Objective To test central nervous system and peripheral hormone response by functional MRI and satiety-regulating hormone levels before and after a meal. Design and Setting Cross-sectional study comparing children with OB and children of healthy weight (HW) recruited from across the Puget Sound region of Washington. Participants Children (9 to 11 years old; OB, n = 54; HW, n = 22), matched for age and sex. Intervention and Outcome Measures Neural activation to images of high- and low-calorie food and objects was evaluated across a set of a priori appetite-processing regions that included the ventral and dorsal striatum, amygdala, substantia nigra/ventral tegmental area, insula, and medial orbitofrontal cortex. Premeal and postmeal hormones (insulin, peptide YY, glucagon-like peptide-1, active ghrelin) were measured. Results In response to a meal, average brain activation by high-calorie food cues vs objects in a priori regions was reduced after meals in children of HW (Z = −3.5, P < 0.0001), but not in children with OB (z = 0.28, P = 0.78) despite appropriate meal responses by gut hormones. Although premeal average brain activation by high-calorie food cues was lower in children with OB vs children of HW, postmeal activation was higher in children with OB (Z = −2.1, P = 0.04 and Z = 2.3, P = 0.02, respectively). An attenuated central response to a meal was associated with greater degree of insulin resistance. Conclusions Our data suggest that children with OB exhibit an attenuated central, as opposed to gut hormone, response to a meal, which may predispose them to overconsumption of food or difficulty with weight loss.

Age at onset of Huntington disease, an inherited neurodegenerative disorder, is influenced by the size of the disease-causing CAG trinucleotide repeat expansion in HTT and by genetic modifier loci on chromosomes 8 and 15. Stratifying by modifier genotype, we have examined putamen volume, total motor score (TMS), and symbol digit modalities test (SDMT) scores, both at study entry and longitudinally, in normal controls and CAG-expansion carriers who were enrolled prior to the emergence of manifest HD in the PREDICT-HD study. The modifiers, which included onset-hastening and onset-delaying alleles on chromosome 15 and an onset-hastening allele on chromosome 8, revealed no major effect in controls but distinct patterns of modification in prediagnosis HD subjects. Putamen volume at study entry showed evidence of reciprocal modification by the chromosome 15 alleles, but the rate of loss of putamen volume was modified only by the deleterious chromosome 15 allele. By contrast, both alleles modified the rate of change of the SDMT score, but neither had an effect on the TMS. The influence of the chromosome 8 modifier was evident only in the rate of TMS increase. The data indicate that (1) modification of pathogenesis can occur early in the prediagnosis phase, (2) the modifier loci act in genetic interaction with the HD mutation rather than through independent additive effects, and (3) HD subclinical phenotypes are differentially influenced by each modifier, implying distinct effects in different cells or tissues. Together, these findings indicate the potential benefit of using genetic modifier strategies for dissecting the prediagnosis pathogenic process in HD.

AIM:To evaluate the characteristics that are associated with successful transition to school outcomes in preschool aged children with autism. METHODS:Twenty-one participants transitioning from an early intervention program were assessed at two time points; at the end of their preschool placement and approximately 5 mo later following their transition to school. Child characteristics were assessed using the Mullen Scales of Early Learning, Vineland Adaptive Behaviour Scales, Social Communication Questionnaire and the Repetitive Behaviour Scale. Transition outcomes were assessed using Teacher Rating Scale of School Adjustment and the Social Skills Improvement System Rating Scales to provide an understanding of each child's school adjustment. The relationship between child characteristics and school outcomes was evaluated. RESULTS:Cognitive ability and adaptive behaviour were shown to be associated with successful transition to school outcomes including participation in the classroom and being comfortable with the classroom teacher. These factors were also associated with social skills in the classroom including assertiveness and engagement. CONCLUSION:Supporting children on the spectrum in the domains of adaptive behaviour and cognitive ability, including language skills, is important for a successful transition to school. Providing the appropriate support within structured transition programs will assist children on the spectrum with this important transition, allowing them to maximise their learning and behavioural potential.

Objectives The purpose of this study was to inform the design of randomized clinical trials in early-stage manifest Huntington's disease through analysis of longitudinal data from TRACK-Huntington's Disease (TRACK-HD), a multicenter observational study. Methods We compute sample sizes required for trials with candidate clinical, functional, and imaging outcomes, whose aims are to reduce rates of change. The calculations use a 2-stage approach: first using linear mixed models to estimate mean rates of change and components of variability from TRACK-HD data and second using these to predict sample sizes for a range of trial designs. Results For each outcome, the primary drivers of the required sample size were the anticipated treatment effect and the duration of treatment. Extending durations from 1 to 2 years yielded large sample size reductions. Including interim visits and incorporating stratified randomization on predictors of outcome together with covariate adjustment gave more modest, but nontrivial, benefits. Caudate atrophy, expressed as a percentage of its baseline, was the outcome that gave smallest required sample sizes. Discussion Here we consider potential required sample sizes for clinical trials estimated from naturalistic observation of longitudinal change. Choice among outcome measures for a trial must additionally consider their relevance to patients and the expected effect of the treatment under study. For all outcomes considered, our results provide compelling arguments for 2-year trials, and we also demonstrate the benefits of incorporating stratified randomization coupled with covariate adjustment, particularly for trials with caudate atrophy as the primary outcome. The benefits of enrichment are more debatable, with statistical benefits offset by potential recruitment difficulties and reduced generalizability. © 2017 International Parkinson and Movement Disorder Society

OBJECTIVE Single-suture craniosynostosis (SSC), the premature fusion of a cranial suture, is characterized by dysmorphology of the craniofacial skeleton. Evidence to suggest that children with SSC are at an elevated risk of mild to moderate developmental delays and neurocognitive deficits is mounting, but the associations among premature suture fusion, neuroanatomy, and neurocognition are unexplained. The goals of this study were to determine 1) whether differences in the brain are present in young children with the 2 most common forms of SSC (sagittal and metopic) several years following surgical correction, and 2) whether the pattern of differences varies by affected suture (sagittal or metopic). Examination of differences in the brains of children with SSC several years after surgery may illuminate the growth trajectory of the brain after the potential constraint of the dysmorphic cranium has been relieved. METHODS The authors compared quantitative measures of the brain acquired from MR images obtained from children with sagittal or metopic craniosynostosis (n = 36) at 7 years of age to those obtained from a group of unaffected controls (n = 27) at the same age. The authors measured the volumes of the whole brain, cerebral cortex, cerebral white matter, cerebral cortex by lobe, and ventricles. Additionally, they measured the midsagittal area of the corpus callosum and its segments and of the cerebellar vermis and its component lobules. Measurements obtained from children with SSC and controls were compared using linear regression models. RESULTS No volume measures of the cerebrum or of the whole brain differed significantly between patients with SSC and controls (p > 0.05). However, ventricle volume was significantly increased in patients with SSC (p = 0.001), particularly in those with sagittal craniosynostosis (p < 0.001). In contrast, the area of the corpus callosum was significantly reduced in patients with metopic synostosis (p = 0.04), particularly in the posterior segments (p = 0.004). Similarly, the area of lobules VI–VII of the cerebellar vermis was reduced in patients with SSC (p = 0.03), with those with metopic craniosynostosis showing the greatest reduction (p = 0.01). CONCLUSIONS The lack of differences in overall brain size or regional differences in the size of the lobes of the cerebrum in children with metopic and sagittal synostosis suggests that the elevated risk of neurodevelopmental deficits is not likely to be associated with differences in the cerebral cortex. Instead, this study showed localized differences between sagittal and metopic craniosynostosis cases as compared with controls in the ventricles and in the midsagittal structures of the corpus callosum and the cerebellum. It remains to be tested whether these structural differences are associated with the increased risk for developmental delay and neurocognitive deficits in children with SSC.

Autism spectrum disorder (ASD) is associated with the altered functional connectivity of 3 neurocognitive networks that are hypothesized to be central to the symptomatology of ASD: the salience network (SN), default mode network (DMN), and central executive network (CEN). Due to the considerably higher prevalence of ASD in males, however, previous studies examining these networks in ASD have used primarily male samples. It is thus unknown how these networks may be differentially impacted among females with ASD compared to males with ASD, and how such differences may compare to those observed in neurotypical individuals. Here, we investigated the functional connectivity of the SN, DMN, and CEN in a large, well-matched sample of girls and boys with and without ASD (169 youth, ages 8–17). Girls with ASD displayed greater functional connectivity between the DMN and CEN than boys with ASD, whereas typically developing girls and boys differed in SN functional connectivity only. Together, these results demonstrate that youth with ASD exhibit altered sex differences in these networks relative to what is observed in typical development, and highlight the importance of considering sex-related biological factors and participant sex when characterizing the neural mechanisms underlying ASD.

Objective To test differences in neural sensitivity to facial expressions, including expressions with open versus closed mouths, exhibited by (1) adults with autism spectrum disorder (ASD) compared to neurotypical adults, and by (2) short versus long serotonin transporter allele ( SLC6A4 ) carriers. Methods Event related potentials (ERPs) to happy, fearful, and neutral expressions were collected from neurotypical adults ( n =25) and adults with ASD ( n =27)–of whom 32 had short and 13 had homozygous long SLC6A4 alleles. Results In the neurotypical group, we confirmed that the N170, VPP and EPN, but not the P1, were influenced by emotional expressions, and determined the EPN was the earliest component modulated by open mouth. Compared to the neurotypical group, individuals with ASD exhibited differences in EPN amplitude in response to open versus closed mouths and in hemispheric distribution. Across groups, short serotonin transporter allele carriers had reduced P1 amplitude compared to long allele carriers. Conclusions Individuals with ASD exhibited a different pattern of neural response when encoding and recognizing facial expressions at the EPN component. Across groups, SLC6A4 allele type modulated early sensory attention at the P1. Significance These results provide insight into the nature of early responses to emotional information according to genetic variation and clinical condition.

THIS RESEARCH EXPLORED THE perspectives of parents who have enrolled their child with a developmental disability in a mainstream early childhood education service. It asked questions about their experience of engagement with the service, and the extent to which they felt participation in this service was beneficial for their child. Fifteen families whose children had been attending a mainstream service for at least six months were recruited to the study and participated in qualitative interviews. There were four key findings from this study: parents are primarily motivated to enrol their children in mainstream early childhood services because they seek social interactions for their children with typically developing peers; despite increasing support at the policy level for inclusive early childhood education, families encountered many challenges in securing a place for their child at a centre that was willing and able to meet their child's needs; parents felt that their child's development was supported by attendance at a mainstream centre, particularly in relation to communication and behaviour; and parents believed that positive developmental change in their child was the direct result of service quality and imitation through peer interaction.

Huntington disease (HD) is a neurodegenerative condition with prominent motor (including oculomotor), cognitive, and psychiatric effects. While neuropsychological deficits are present in HD, motor impairments may impact performance on neuropsychological measures, especially those requiring a speeded response, as has been demonstrated in multiple sclerosis and schizophrenia. The current study is the first to explore associations between oculomotor functions and neuropsychological performance in HD. Participants with impaired oculomotor functioning performed worse than those with normal oculomotor functioning on cognitive tasks requiring oculomotor involvement, particularly on psychomotor speed tasks, controlling for covariates. Consideration of oculomotor dysfunction on neuropsychological performance is critical, particularly for populations with motor deficits.

Summary Background Although the association between cytosine-adenine-guanine (CAG) repeat length and age at onset of Huntington's disease is well known, improved prediction of onset would be advantageous for clinical trial design and prognostic counselling. We compared various measures for tracking progression and predicting conversion to manifest Huntington's disease. Methods In this prospective observational study, we assessed the ability of 40 measures in five domains (motor, cognitive, psychiatric, functional, and imaging) to predict time to motor diagnosis of Huntington's disease, accounting for CAG repeat length, age, and the interaction of CAG repeat length and age. Eligible participants were individuals from the PREDICT-HD study (from 33 centres in six countries [USA, Canada, Germany, Australia, Spain, UK]) with the gene mutation for Huntington's disease but without a motor diagnosis (a rating below 4 on the diagnostic confidence level from the 15-item motor assessment of the Unified Huntington's Disease Rating Scale). Participants were followed up between September, 2002, and July, 2014. We used joint modelling of longitudinal and survival data to examine the extent to which baseline and change of measures analysed separately was predictive of CAG-adjusted age at motor diagnosis. Findings 1078 individuals with a CAG expansion were included in this analysis. Participants were followed up for a mean of 5·1 years (SD 3·3, range 0·0–12·0). 225 (21%) of these participants received a motor diagnosis of Huntington's disease during the study. 37 of 40 cross-sectional and longitudinal clinical and imaging measures were significant predictors of motor diagnosis beyond CAG repeat length and age. The strongest predictors were in the motor, imaging, and cognitive domains: an increase of one SD in total motor score (motor domain) increased the risk of a motor diagnosis by 3·07 times (95% CI 2·26–4·16), a reduction of one SD in putamen volume (imaging domain) increased risk by 3·32 times (2·37–4·65), and a reduction of one SD in Stroop word score (cognitive domain) increased risk by 2·32 times (1·88–2·87). Interpretation Prediction of diagnosis of Huntington's disease can be improved beyond that obtained by CAG repeat length and age alone. Such knowledge about potential predictors of manifest Huntington's disease should inform discussions about guidelines for diagnosis, prognosis, and counselling, and might be useful in guiding the selection of participants and outcome measures for clinical trials. Funding US National Institutes of Health, US National Institute of Neurological Disorders and Stroke, and CHDI Foundation.

Huntington disease (HD) neuropathology has a devastating effect on brain structure and consequently brain function; neuroimaging provides a means to assess these effects in gene carriers. In this chapter we first outline the unique utility of structural imaging in understanding HD and discuss some of the acquisition and analysis techniques currently available. We review the existing literature to summarize what we know so far about structural brain changes across the spectrum of disease from premanifest through to manifest disease. We then consider how these neuroimaging findings relate to patient function and nonimaging biomarkers, and can be used to predict disease onset. Finally we review the utility of imaging measures for assessment of treatment efficacy in clinical trials.

A biomarker (also known as a biological marker) is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [1]. This definition is generally equivalent to Mildvan’s definition of a “natural history” biomarker [2], a “marker of disease severity that reflects underlying pathogenesis and predicts clinical events in the absence of treatment, thus establishing the biological plausibility of the marker.” Based on these two definitions, potential biomarkers can be evaluated for utility according to three criteria [3]: They must be (1) objectively measureable; (2) able to predict known endpoints; and (3) associated with known mechanisms of pathology of the disease. As will be demonstrated, volumetric striatal measures from MRI meet these three criteria, as well as other desirable qualities of a biomarker for clinical trials. Although evidence exists that supports the use of volumetric measures of other brain regions as potential outcome measures [4], the greatest amount of research and the most consistent results across studies support the use of striatal volumes, with measurement of caudate, putamen, and total striatum generally showing equally strong potential. Other neuroimaging methods, including MRS, DTI, and fMRI, have been studied as well, but to date findings have either been inconsistent or insufficient to justify their use as outcome measures. Further study may, of course, demonstrate better utility for these methods than for volumetric striatal measures, especially as it is possible that these measures might be able to detect change earlier or faster than structural MRI, and may be sensitive to reversal of the disease process, which is unexpected for structural volumes.

The precise pathogenic mechanisms of Huntington's disease (HD) are unknown but can be tested in vivo using proton magnetic resonance spectroscopy (1H MRS) to measure neurochemical changes. The objective of this study was to evaluate neurochemical differences in HD gene mutation carriers (HGMCs) versus controls and to investigate relationships among function, brain structure, and neurochemistry in HD. Because previous 1H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two 1H MRS data analysis approaches. HGMCs with premanifest to early HD and controls underwent evaluation of motor function, magnetic resonance imaging, and localized 1H MRS in the caudate and the frontal lobe. Analytical approaches that were tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). We identified a suite of neurochemicals that were reduced in concentration proportionally to loss of caudate volume in HGMCs. Caudate concentrations of N-acetylaspartate (NAA), creatine, choline, and caudate and frontal lobe concentrations of glutamate plus glutamine (Glx) and glutamate were correlated with caudate volume in HGMCs. The relative, but not the absolute, quantitation approach revealed disease-related differences; the Glx signal was decreased relative to other neurochemicals in the caudate of HGMCs versus controls. This is the first study to demonstrate a correlation among structure, function, and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable the magnification of subtle differences between groups. Observation of decreased Glx suggests that glutamate signaling may be disrupted relatively early in HD, which has important implications for therapeutic approaches. © 2014 International Parkinson and Movement Disorder Society

Atypical inhibitory function is often present in individuals with autism spectrum disorder (ASD), who may have difficulty suppressing context-inappropriate behaviors. We investigated the neural correlates of inhibition in ASD in response to both emotional and non-emotional stimuli using an fMRI Go/NoGo inhibition task with human faces and letters. We also related neural activation to behavioral dysfunction in ASD. Our sample consisted of 19 individuals with ASD (mean age=25.84) and 22 typically developing (TD) control participants (mean age=29.03). As expected, no group differences in task performance (inhibition accuracy and response time) were found. However, adults with ASD exhibited greater angular gyrus activation in face response inhibition blocks, as well as greater fusiform gyrus activation than controls, in a condition comparing face inhibition to letter inhibition. In contrast, control participants yielded significantly greater anterior cingulate cortex (ACC) activation in letter inhibition blocks. A positive relationship between communication and language impairment and angular gyrus activation during face inhibition was also found. Group activation differences during inhibition tasks in the context of comparable task performance and the relationship between activation and dysfunction highlight brain regions that may be related to ASD-specific dysfunction.

Introduction The brain mechanisms of cognitive impairment in prodromal Huntington disease (prHD) are not well understood. Although striatal atrophy correlates with some cognitive abilities, few studies of prHD have investigated whether cortical gray matter morphometry correlates in a regionally specific manner with functioning in different cognitive domains. This knowledge would inform the selection of cognitive measures for clinical trials that would be most sensitive to the target of a treatment intervention. Method In this study, random forest analysis was used to identify neuroanatomical correlates of functioning in five cognitive domains including attention and information processing speed, working memory, verbal learning and memory, negative emotion recognition, and temporal processing. Participants included 325 prHD individuals with varying levels of disease progression and 119 gene-negative controls with a family history of HD. In intermediate analyses, we identified brain regions that showed significant differences between the prHD and the control groups in cortical thickness and striatal volume. Brain morphometry in these regions was then correlated with cognitive functioning in each of the domains in the prHD group using random forest methods. We hypothesized that different regional patterns of brain morphometry would be associated with performances in distinct cognitive domains. Results The results showed that performances in different cognitive domains that are vulnerable to decline in prHD were correlated with regionally specific patterns of cortical and striatal morphometry. Putamen and/or caudate volumes were top-ranked correlates of performance across all cognitive domains, as was cortical thickness in regions related to the processing demands of each domain. Conclusions The results underscore the importance of identifying structural magnetic resonance imaging (sMRI) markers of functioning in different cognitive domains, as their relative sensitivity depends on the extent to which processing is called upon by different brain networks. The findings have implications for identifying neuroimaging and cognitive outcome measures for use in clinical trials.

Huntington's disease (HD) results in progressive impairment of motor and cognitive function and neuropsychiatric disturbance. There are no disease-modifying treatments available, but HD research is entering a critical phase where promising disease-specific therapies are on the horizon. Thus, a pressing need exists for biomarkers capable of monitoring progression and ultimately determining drug efficacy. Neuroimaging provides a powerful tool for assessing disease progression. However, in order to be accepted as biomarkers for clinical trials, imaging measures must be reproducible, robust to scanner differences, sensitive to disease-related change and demonstrate a relationship to clinically meaningful measures. We provide a review of the current structural imaging literature in HD and highlight inconsistencies between studies. We make recommendations for the standardisation of reporting for future studies, such as appropriate cohort characterisation and documentation of methodologies to facilitate comparisons and inform trial design. We also argue for an intensified effort to consider issues highlighted here so that we have the best chance of assessing the efficacy of the therapeutic benefit in forestalling this devastating disease.

Huntington disease (HD) is a neurodegenerative disorder that involves preferential atrophy in the striatal complex and related subcortical nuclei. In this article, which is based on a dataset extracted from the PREDICT-HD study, we use statistical shape analysis with deformation markers obtained through "Large Deformation Diffeomorphic Metric Mapping" of cortical surfaces to highlight specific atrophy patterns in the caudate, putamen, and globus pallidus, at different prodromal stages of the disease. On the basis of the relation to cortico-basal ganglia circuitry, we propose that statistical shape analysis, along with other structural and functional imaging studies, may help expand our understanding of the brain circuitry affected and other aspects of the neurobiology of HD, and also guide the most effective strategies for intervention.

The purpose of this study was to inform the design of randomized clinical trials in early-stage manifest Huntington's disease through analysis of longitudinal data from TRACK-Huntington's Disease (TRACK-HD), a multicenter observational study.We compute sample sizes required for trials with candidate clinical, functional, and imaging outcomes, whose aims are to reduce rates of change. The calculations use a 2-stage approach: first using linear mixed models to estimate mean rates of change and components of variability from TRACK-HD data and second using these to predict sample sizes for a range of trial designs.For each outcome, the primary drivers of the required sample size were the anticipated treatment effect and the duration of treatment. Extending durations from 1 to 2 years yielded large sample size reductions. Including interim visits and incorporating stratified randomization on predictors of outcome together with covariate adjustment gave more modest, but nontrivial, benefits. Caudate atrophy, expressed as a percentage of its baseline, was the outcome that gave smallest required sample sizes.Here we consider potential required sample sizes for clinical trials estimated from naturalistic observation of longitudinal change. Choice among outcome measures for a trial must additionally consider their relevance to patients and the expected effect of the treatment under study. For all outcomes considered, our results provide compelling arguments for 2-year trials, and we also demonstrate the benefits of incorporating stratified randomization coupled with covariate adjustment, particularly for trials with caudate atrophy as the primary outcome. The benefits of enrichment are more debatable, with statistical benefits offset by potential recruitment difficulties and reduced generalizability. © 2017 International Parkinson and Movement Disorder Society.

Abnormal fMRI habituation in autism spectrum disorders (ASDs) has been proposed as a critical component in social impairment. This study investigated habituation to fearful faces and houses in ASD and whether fMRI measures of brain activity discriminate between ASD and typically developing (TD) controls. Two identical fMRI runs presenting masked fearful faces, houses, and scrambled images were collected. We found significantly slower fMRI responses to fearful faces but not houses in ASD. In addition, the pattern of slow to emerge amygdala activation to faces had robust discriminability [ASD vs. TD; area under the curve (AUC) = .852, p < .001]. In contrast, habituation to houses had no predictive value (AUC = .573, p = .365). Amygdala habituation to emotional faces may be useful for quantifying risk in ASD.

Background Previous neuroimaging research indicates that brain atrophy in Huntington disease (HD) begins many years before movement abnormalities become severe enough to warrant diagnosis. Most clinical trials being planned for individuals in the prediagnostic stage of HD propose to use delay of disease onset as the primary outcome measure. Although formulas have been developed based on age and CAG repeat length, to predict when HD motor onset will occur, it would be useful to have additional measures that can improve the accuracy of prediction of disease onset. Methods The current study examined magnetic resonance imaging (MRI) measures of striatum and white matter volume in 85 individuals prospectively followed from pre-HD stage through diagnosable motor onset (incident cases) and 85 individuals individually matched with incident cases on CAG repeat length, sex, and age, who were not diagnosed with HD during the course of the study. Results Volumes of striatum and white matter were significantly smaller in individuals who would be diagnosed 1 to 4 years following the initial MRI scan, compared with those who would remain in the pre-HD stage. Putamen volume was the measure that best distinguished between the two groups. Conclusions Results suggest that MRI volumetric measures may be helpful in selecting individuals for future clinical trials in pre-HD where HD motor onset is the primary outcome measure. In planning for multisite clinical trials in pre-HD, investigators may also want to consider using more objective measures, such as MRI volumes, in addition to onset of diagnosable movement disorder, as major outcome measures.

Children and adolescents with externalizing behavior disorders including attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) often present with symptoms of comorbid internalizing psychopathology. However, few studies have examined central nervous system correlates of such comorbidity. We evaluated interactions between externalizing and internalizing symptoms in predicting mesolimbic, septo-hippocampal, and anterior cingulate volumes among 12- to 16-year-old boys with either ADHD, ADHD and CD, or no psychiatric condition (n = 35). These regions were chosen given established links to trait impulsivity, trait anxiety, and behavior regulation, respectively. Collapsed across groups, Externalizing × Internalizing symptom interactions accounted for individual differences in gray matter densities in each region. Externalizing youth with comorbid internalizing symptoms showed smaller reductions in gray matter than individuals with externalizing psychopathology alone. These results suggest that internalizing symptoms are associated with less severe structural compromises in brain regions subserving motivation and behavior regulation among externalizing boys.

Infants with deformational plagiocephaly (DP) have been shown to exhibit developmental delays relative to unaffected infants. Although the mechanisms accounting for these delays are unknown, one hypothesis focuses on underlying differences in brain development. In this study, we used MRI to examine brain volume and shape in infants with and without DP.Participants included 20 infants with DP (mean age = 7.9 months, SD = 1.2; n = 12 male) and 21 controls (mean age = 7.9 months, SD = 1.3; n = 11 male). Measures included volumes of the total brain and cerebellum; midsagittal areas of the corpus callosum and cerebellar vermis; and linear distance measures used to quantify the shape of selected brain structures. We also evaluated the association between shape measures and developmental scores on the Bayley Scales of Infant and Toddler Development-III (BSID-III).Brain volume did not distinguish cases and controls (p = .214-.976). However, cases exhibited greater asymmetry and flattening of the posterior brain (p.001-.002) and cerebellar vermis (p = .035), shortening of the corpus callosum (p = .012), and differences in the orientation of the corpus callosum (p = .005). Asymmetry and flattening of brain structures were associated with worse developmental outcomes on the BSID-III.Infants with DP show differences in brain shape, consistent with the skull deformity characteristic of this condition, and shape measures were associated with infant development. Longitudinal studies, beginning in the neonatal period, are needed to clarify whether developmental effects precede or follow brain deformation.

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Huntington disease (HD) is a progressive, fatal, autosomal dominant neurodegenerative disease that primarily affects movement, cognition, and psychiatric functions. Diagnosis of HD is based on the presence of unequivocal motor signs of HD, in conjunction with a positive genetic test for the HD CAG expansion or a confirmed family history of HD. Most people with the HD gene appear healthy throughout their youth and early adulthood, and then gradually develop signs and symptoms of HD, often leading to a diagnosis in middle age. The age of diagnosis varies in accordance with the number of CAG repeats on the expanded allele, although there is also substantial individual variability not accounted for by this genetic factor (Andrew et al., 1993; Gusella, MacDonald, Ambrose, & Duyao, 1993). A growing community of researchers is directing efforts at finding treatments to delay onset or slow the progression of early pathological changes in an attempt to reduce the tremendous personal and social costs of HD. Finding effective therapeutic or preventive treatments for HD depends critically on the ability to reliably and sensitively measure clinical signs of disease. Cognitive measures have excellent potential both for identifying individuals beginning to show subtle signs prior to the diagnosis of HD who might be suitable for clinical trials, and as sensitive outcome measures in HD trials. Cognition is an important target for therapeutic trials because even subtle cognitive changes can affect functional abilities like work performance, driving, and financial management. Cognition is actively studied in the HD prodrome, with more than 150 empirical reports of neurocognitive function published since the genetic mutation for HD was identified in 1993. In early studies, the evidence of cognitive dysfunction was inconsistent. But more recent, adequately powered studies have revealed that people with the HD prodrome have poorer performance on measures of attention, working memory, processing speed, psychomotor functions, episodic memory, emotion processing, sensory-perceptual functions, and executive functions (Johnson et al., 2007; Kirkwood et al., 2000; Paulsen et al., 2006a; Paulsen et al., 2008; Paulsen et al., 2001; Pirogovsky et al., 2007; e.g., Stout et al., 2007). The use of cognitive measures in clinical trials requires a substantial knowledge base, indicating when in the HD prodrome cognitive changes can be reliably detected, and which measures show adequate sensitivity. The PREDICT-HD study was designed to address these questions. PREDICT-HD is a 31-site international study of potential clinical and biological markers of HD in individuals with the CAG-expansion for HD, but who did not meet criteria based on motor impairment for diagnosis at the time of enrolment. The PREDICT-HD cohort is large, with more than 700 non-diagnosed CAG-expanded (prodromal) participants. For each participant, age-conditioned estimates of time to onset of motor disease were derived using a survival analysis regression equation based on CAG repeat length (Langbehn et al., 2004). Estimated time to motor disease onset in the sample varies from 5 to 25 years. The size and diversity of this sample makes it possible to stratify participants based on their estimated proximities to diagnosis, allowing an estimation of when, in the extended period leading up to HD diagnosis, cognitive signs can be detected, and which cognitive measures appear to have the most promise for detecting change in longitudinal studies. We report findings based on three stratified prodromal HD groups, a far from diagnosis group (FAR) estimated to be more than 15 years from diagnosis, a middle group, estimated to be between 9 and 15 years from diagnosis (MID), and a near diagnosis group, estimated to be less than 9 years from diagnosis (NEAR). For each of these groups compared to controls, we computed effect sizes for individual cognitive measures, allowing a direct comparison of all the tasks in our cognitive assessment. This allows a determination of which tasks are most adversely affected during the HD prodrome, and an upper-limit estimate of how early in the prodromal phase significant effects could be detected (Paulsen et al., 2008). Additionally, we examined the associations between cognitive findings and results of the clinical motor examination, which also reveals subtle signs prior to diagnosis (Biglan et al., 2009). Thus, this study provides a comprehensive depiction of the cognitive prodrome for HD.

Difficulty interpreting facial expressions has been reported in autism spectrum disorders (ASD) and is thought to be associated with amygdala abnormalities. To further explore the neural basis of abnormal emotional face processing in ASD, we conducted an fMRI study of emotional face matching in high-functioning adults with ASD and age, IQ, and gender matched controls. In addition, we investigated whether there was a relationship between self-reported social anxiety and fMRI activation. During fMRI scanning, study participants were instructed to match facial expressions depicting fear or anger. The control condition was a comparable shape - matching task. The control group evidenced significantly increased left prefrontal activation and decreased activation in the occipital lobes compared to the ASD group during emotional face matching. Further, within the ASD group, greater social anxiety was associated with increased activation in right amygdala and left middle temporal gyrus, and decreased activation in the fusiform face area. These results indicate that level of social anxiety mediates the neural response to emotional face perception in ASD.

As therapeutics are being developed to target the underlying neuropathology of Huntington disease, interest is increasing in methodologies for conducting clinical trials in the prodromal phase. This study was designed to examine the potential utility of structural MRI measures as outcome measures for such trials.Data are presented from 211 prodromal individuals and 60 controls, scanned both at baseline and at the 2-year follow-up. Prodromal participants were divided into groups based on proximity to estimated onset of diagnosable clinical disease: far (15 years from estimated onset), mid (9-15 years) and near (9 years). Volumetric measurements of caudate, putamen, total striatum, globus pallidus, thalamus, total grey and white matter and cerebrospinal fluid were performed.All prodromal groups showed a faster rate of atrophy than controls in striatum, total brain and cerebral white matter (especially in the frontal lobe). Neither prodromal participants nor controls showed any significant longitudinal change in cortex (either total cortical grey or within individual lobes). When normal age-related atrophy (ie, change observed in the control group) was taken into account, there was more statistically significant disease-related atrophy in white matter than in striatum.Measures of volume change in striatum and white-matter volume, particularly in the frontal lobe, may serve as excellent outcome measures for future clinical trials in prodromal Huntington disease. Clinical trials using white matter or striatal volume change as an outcome measure will be most efficient if the sample is restricted to individuals who are within 15 years of estimated onset of diagnosable disease.

Individuals with autism spectrum disorders (ASD) have pervasive impairments in social functioning, which may include problems with processing and remembering faces. In this study, we examined whether posterior ERP components associated with identity processing (P2, N250 and face-N400) and components associated with early-stage face processing (P1 and N170) are atypical in ASD. We collected ERP responses to a familiar repeated face (Familiar), an unfamiliar repeated face (Other) and novel faces (Novels) in 29 high functioning adults with ASD and matched controls. For both groups, the P2 and N250 were sensitive to repetition (Other vs. Novels) and personal familiarity (Familiar vs. Other), and the face-N400 was sensitive to repetition. Adults with ASD did not show significantly atypical processing of facial familiarity and repetition in an ERP paradigm, despite showing significantly poorer performance than controls on a behavioral test of face memory. This study found no evidence that early-stage facial identity processing is a primary contributor to the face recognition deficit in high functioning ASD.

Magnetic resonance (MR) technology offers noninvasive methods for in vivo assessment of neuroabnormalities. A comprehensive neuropsychological/behavioral, MR imaging (MRI), MR spectroscopy (MRS) and functional MRI (fMRI) assessment was administered to children with fetal alcohol spectrum disorders (FASD) to determine whether global and/or focal abnormalities could be identified and to distinguish diagnostic subclassifications across the spectrum. The four study groups included (1) FAS/partial FAS; (2) static encephalopathy/alcohol exposed (SE/AE); (3) neurobehavioral disorder/alcohol exposed (ND/AE) as diagnosed with the FASD 4-Digit Code; and (4) healthy peers with no prenatal alcohol exposure. Results are presented in four separate reports: MRS (reported here) and neuropsychological/behavioral, MRI and fMRI outcomes (reported separately). MRS was used to compare neurometabolite concentrations [choline (Cho), n-acetyl-aspartate (NAA) and creatine (Cre)] in a white matter region and a hippocampal region between the four study groups. Choline concentration in the frontal/parietal white matter region, lateral to the midsection of the corpus callosum, was significantly lower in FAS/PFAS relative to all other study groups. Choline decreased significantly with decreasing frontal white matter volume and corpus callosum length. These outcomes suggest low choline concentrations may reflect white matter deficits among FAS/PFAS. Choline also decreased significantly with increasing severity of the 4-Digit FAS facial phenotype, increasing impairment in psychological performance and increasing alcohol exposure. NAA and Cre concentrations did not vary significantly. This study provides further evidence of the vulnerability of the cholinergic system in FASD.

Individuals with autism spectrum disorders (ASD) have documented deficits in face processing, face memory and abnormal activation of the neural circuitry that supports these functions. To examine speed of processing of faces in ASD, high density event-related brain potentials were recorded to images of faces, inverted faces and non-face objects from 32 high-functioning adults with ASD and controls. Participants were instructed to focus on a cross hair prior to stimulus onset; the cross-hair location directed the participant's eye gaze to the eye region at stimulus onset. Although the ASD group preformed more poorly on behavioral tests of face and object memory, both groups demonstrated similar ERP responses, characterized by greater (positive) P1 and (negative) N170 amplitude to faces vs houses. N170 speed of processing to faces did not differ between groups. However, only the control group demonstrated differential responses to upright vs inverted faces. For the ASD group, the differential response to inverted vs upright faces was associated with better performance on face memory and self-reported social skills. It is possible that the use of attention cues may facilitate face processing in high-functioning adults with ASD, suggesting that the underlying neural circuitry can be activated in adults with ASD under specific demands.

Amygdala dysfunction has been proposed as a critical component in social impairment in autism spectrum disorders. This study was designed to investigate whether abnormal habituation characterizes amygdala dysfunction in autism spectrum disorders and whether the rate of amygdala habituation is related to social impairment.Using functional MRI, the authors measured change over time in activation of the amygdala and fusiform gyrus to neutral facial stimuli in adults with autism spectrum disorders and healthy comparison adults.The comparison group evidenced significantly greater amygdala habituation bilaterally than the autism spectrum group. There were no group differences in overall fusiform habituation. For the autism spectrum group, lower levels of habituation of the amygdala to the face stimuli were associated with more severe social impairment.These results suggest amygdala hyperarousal in autism spectrum disorders in response to socially relevant stimuli. Further, sustained amygdala arousal may contribute to the social deficits observed in autism spectrum disorders.

Brain activity patterns during face processing have been extensively explored with functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs). ERP source localization adds a spatial dimension to the ERP time series recordings, which allows for a more direct comparison and integration with fMRI findings. The goals for this study were (1) to compare the spatial descriptions of neuronal activity during face processing obtained with fMRI and ERP source localization using low-resolution electro-magnetic tomography (LORETA), and (2) to use the combined information from source localization and fMRI to explore how the temporal sequence of brain activity during face processing is summarized in fMRI activation maps. fMRI and high-density ERP data were acquired in separate sessions for 17 healthy adult males for a face and object processing task. LORETA statistical maps for the comparison of viewing faces and viewing houses were coregistered and compared to fMRI statistical maps for the same conditions. The spatial locations of face processing-sensitive activity measured by fMRI and LORETA were found to overlap in a number of areas including the bilateral fusiform gyri, the right superior, middle and inferior temporal gyri, and the bilateral precuneus. Both the fMRI and LORETA solutions additionally demon-strated activity in regions that did not overlap. fMRI and LORETA statistical maps of face processing-sensitive brain activity were found to converge spatially primarily at LORETA solution latencies that were within 18 ms of the N170 latency. The combination of data from these techniques suggested that electrical brain activity at the latency of the N170 is highly represented in fMRI statistical maps.

Individuals with Down syndrome (DS), a disorder of known genetic etiology (trisomy of chromosome 21), exhibit several types of structural brain abnormalities that are detectable pathologically and by MRI. In addition, in middle age, individuals with DS develop histological and, in some cases, clinical features of Alzheimer's disease (AD). Abnormalities in MRI scans of 50 adults with DS, 11 of whom had clinical dementia, are described and compared with those of 23 cognitively normal, healthy subjects who were matched for age, sex, and race. Qualitative visual analogue scale (VAS) ratings on MRI hard copies for all subjects and computer-aided volume measures for a subsample of subjects were carried out. On VAS, subjects with DS had larger lateral ventricles, a higher frequency of posterior fossa arachnoid cysts/megacisterna magna and fewer scans rated as normal compared with controls. Quantitatively, total brain and gray-matter volumes were reduced in DS, as were the volumes of the left hippocampus and amygdala; ventricle volumes were larger. Post hoc comparisons of subjects with DS with and without dementia revealed that on VAS the former had more generalized atrophy for age, mesial temporal shrinkage, and third ventricular enlargement. Similarly, total brain, left hippocampus, and left amygdala volumes were reduced quantitatively in subjects with DS with dementia, while ventricular volumes were increased.

Obsessive and compulsive symptoms (OCS) are more prevalent in patients with diagnosed Huntington's disease (HD) than in the general population. Although psychiatric symptoms have been reported in individuals with the HD gene expansion prior to clinical diagnosis (pre-HD), little is known about OCS in this phase of disease.The goal of this study was to assess OCS in 300 pre-HD individuals and 108 non-gene-expanded controls from the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) study (enrolled between November 2002 and April 2007) using a multidimensional, self-report measure of OCS, the Schedule of Compulsions, Obsessions, and Pathologic Impulses (SCOPI). Additionally, pre-HD individuals were classified into 3 prognostic groups on the basis of age and CAG repeat length as "near-to-onset" (9 estimated years to onset), "mid-to-onset" (9-15 years to onset), and "far-to-onset" (15 years to onset). We compared the 3 pre-HD groups to the controls on SCOPI total score and 5 subscales (checking, cleanliness, compulsive rituals, hoarding, and pathologic impulses), controlling for age and gender.All models showed a significant (p.05) group effect except for hoarding, with an inverted-U pattern of increasing symptoms: controlsfar-to-onsetmid-to-onset, with the near-to-onset group being similar to controls. Although the mid-to-onset group showed the most pathology, mean scores were below those of patients with diagnosed obsessive-compulsive disorder. SCOPI items that separated pre-HD individuals from controls were focused on perceived cognitive errors and obsessive worrying.Subclinical OCS were present in pre-HD participants compared to controls. The OCS phenotype in pre-HD may present with obsessive worrying and checking related to cognitive errors and may be a useful target for clinical screening as it could contribute to functional status.

Objective: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington’s disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. Methods: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. Results: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. Conclusions: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

The apolipoprotein varepsilon4 allele (APOE*4) is a major genetic risk factor for Alzheimer's disease (AD) and has been associated with altered cortical activation as assessed by functional neuroimaging in cognitively normal younger and older carriers. We chose to evaluate medial temporal lobe (MTL) activation during encoding and recognition using a perspective-dependent (route or survey) visuospatial memory task by monitoring the blood-oxygen-level-dependent (BOLD) fMRI response in older, non-demented APOE*4 carriers (APOE*4+) and non-carriers (APOE*4-). During encoding, the APOE*4- group had greater average task-associated BOLD responses in ventral visual pathways, including the MTLs, as compared to the APOE*4+ group. Furthermore, MTL activation was greater during route encoding than survey encoding on average in APOE*4-, but not APOE*4+, subjects. During recognition, both groups performed similarly and no BOLD signal differences were found. Finally, within-group analysis revealed MTL activation during encoding was correlated with recognition performance in APOE*4-, but not APOE*4+ subjects. Reduced task-associated MTL activation that does not correlate with either visuospatial perspective or task performance suggests that MTL dysregulation occurs prior to clinical symptoms of dementia in APOE*4 carriers.

It has been shown that individuals with autism spectrum disorders (ASD) demonstrate normal activation in the fusiform gyrus when viewing familiar, but not unfamiliar faces. The current study utilized eye tracking to investigate patterns of attention underlying familiar versus unfamiliar face processing in ASD. Eye movements of 18 typically developing participants and 17 individuals with ASD were recorded while passively viewing three face categories: unfamiliar non-repeating faces, a repeating highly familiar face, and a repeating previously unfamiliar face. Results suggest that individuals with ASD do not exhibit more normative gaze patterns when viewing familiar faces. A second task assessed facial recognition accuracy and response time for familiar and novel faces. The groups did not differ on accuracy or reaction times.

Abnormalities in the interactions between functionally linked brain regions have been suggested to be associated with the clinical impairments observed in autism spectrum disorders (ASD). We investigated functional connectivity within the limbic system during face identification; a primary component of social cognition, in 19 high-functioning adults with ASD and 21 age-and IQ-matched control adults. Activation during identification of previously viewed faces and houses using a one-back paradigm was compared. The fusiform face area (FFA) was individually localized in each participant and used as the seed point for functional connectivity analyses. The degree of correlation between FFA and the extended neural circuitry involved in face identification was tested. A whole brain analysis was also conducted in order to determine whether connectivity from the FFA to aberrant brain locations was present in the ASD group. Measures of clinical severity (ADOS social score and ADI-R social score) were included as independent variables into the functional connectivity analyses. Significant FFA-amygdala and FFA-superior temporal sulcus functional connectivity was found in both the ASD and control participants. However, the control group had significantly increased connectivity to the left amygdala and the posterior cingulate compared to ASD. Post hoc analyses additionally found increased connectivity to the thalamus in the controls. A significant relationship between abnormal functional connectivity and clinical severity in the ASD group was observed. Specifically, greater social impairment was associated with reduced FFA-amygdala connectivity and increased FFA-right inferior frontal connectivity. These results suggest that abnormal neural connections within the limbic system may contribute to the social impairments observed in ASD.

Previous studies of emotion recognition suggest that detection of disgust relies on processing within the basal ganglia and insula. Research involving individuals with symptomatic and pre-diagnostic Huntington's disease (HD), a disease with known basal ganglia atrophy, has generally indicated a relative impairment in recognizing disgust. However, some data have suggested that recognition of other emotions (particularly fear and anger) may also be affected in HD, and a recent study found fear recognition deficits in the absence of other emotion-recognition impairments, including disgust. To further examine emotion recognition in HD, we administered a computerized facial emotion recognition task to 475 individuals with the HD CAG expansion and 57 individuals without. Logistic regression was used to examine associations of emotion recognition performance with estimated proximity to clinical diagnosis (based on CAG repeat length and current age) and striatal volumes. Recognition of anger, disgust, fear, sadness and surprise (but not happiness) was associated with estimated years to clinical diagnosis; performance was unrelated to striatal volumes. Compared to a CAG-normal control group, the CAG-expanded group demonstrated significantly less accurate recognition of all negative emotions (anger, disgust, fear, sadness). Additionally, participants with more pronounced motor signs of HD were significantly less accurate at recognizing negative emotions than were individuals with fewer motor signs. Findings indicate that recognition of all negative emotions declines early in the disease process, and poorer performance is associated with closer proximity to clinical diagnosis. In contrast to previous results, we found no evidence of relative impairments in recognizing disgust or fear, and no evidence to support a link between the striatum and disgust recognition.

This article discusses the need for biomarkers and surrogate endpoints for future clinical trials in individuals at risk for Huntington's disease. Definitions and criteria are presented for biomarkers and surrogate endpoints, and data are presented suggesting that striatal volumes, as measured on MRI scans, meet the criteria for a biomarker. Biomarkers can be used in lieu of clinical endpoints in treatment trials if there is evidence that treatment affects the biomarker in a way that is predictive of endpoint status. Because there are currently no effective treatments for Huntington's disease, it is not yet possible to validate whether change in MRI striatal volumes can serve as an effective surrogate endpoint. It is recommended that future clinical trials be designed using MRI striatal volumes to "screen" potential treatments. Those treatments that reduce the rate of striatal atrophy can then be tested with delay of symptom onset as the clinical endpoint. This strategy is essential if efficient and cost-effective clinical trials are to be conducted in the preclinical stage of Huntington's disease.