Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials.

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.

These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.

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.

Brain development in autism follows an abnormal pattern, with accelerated growth in early life that results in brain enlargement in childhood. Brain volume in adolescents and adults with autism is, however, normal, and appears to be due to a slight decrease in brain volume for these individuals at the same time that normal children are experiencing a slight increase.

Objective-PREDICT-HD is a large-scale international study of people with the Huntington Disease CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine at what stage in the HD prodrome cognitive differences from CAG-normal controls can be reliably detected.Method-For each of 738 HD CAG-expanded participants, we computed estimated years to clinical diagnosis and probability of diagnosis in five years, based on age and CAG repeat expansion number (Langbehn, Brinkman, Falush, Paulsen, & Hayden, 2004). We then stratified the sample into groups: "NEAR," estimated to be ≤ 9 years, "MID," between 9 and 15 years, and "FAR," ≥ 15 years. The control sample included 168 CAG-normal participants. Nineteen cognitive tasks were used to assess attention, working memory, psychomotor functions, episodic memory, language, recognition of facial emotion, sensory-perceptual functions, and executive functions.Results-Compared to the controls, the NEAR group showed significantly poorer performance on nearly all, and the MID group on about half of the cognitive tests (p = 0.05, Cohen's d Near as large as −1.17, Mid as large as −0.61). One test even revealed significantly poorer performance in the FAR group (Cohen's d = −0.26). Individual tasks accounted for 0.2% to 9.7% of the variance in estimated proximity to diagnosis. Overall, the cognitive battery accounted for 34% of the variance; in comparison, the UHDRS Motor Score accounted for 11.7%. Conclusions-Neurocognitive tests are robust clinical indicators of the disease process prior to reaching criteria for motor diagnosis of HD.Keywords cognitive assessment; presymptomatic; neuropsychology; psychomotor; prediagnosis 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,...

BackgroundThe 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.ObjectiveTo define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion.MethodsWe collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls.ResultsWhen 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.ConclusionsThe 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.

Striatal atrophy begins many years prior to diagnosable HD, and assessment of atrophy on MRI may be very useful in both predicting HD onset and in tracking progression in future therapeutic trials in preclinical subjects.