Shannon A. Johnson

Detection of Huntington’s disease decades before diagnosis: the Predict-HD study

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.

Neurocognitive Signs in Prodromal Huntington Disease

OBJECTIVE PREDICT-HD is a large-scale international study of people with the Huntington disease (HD) CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine the stage in the HD prodrome at which 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 5 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 with the controls, the NEAR group showed significantly poorer performance on nearly all of the cognitive tests and the MID group on about half of the cognitive tests (p = .05, Cohens d NEAR as large as -1.17, MID as large as -0.61). One test even revealed significantly poorer performance in the FAR group (Cohens 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 Unified Huntingtons Disease Rating Scale 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.

Discrepancies Between Self- and Parent-Perceptions of Autistic Traits and Empathy in High Functioning Children and Adolescents on the Autism Spectrum

Self-perception in high-functioning children and adolescents with Autism Spectrum Disorder (ASD) was examined by comparing parent- and self-reports on the Autism Spectrum, Empathy, and Systemizing Quotients (AQ, EQ and SQ). Participants were 20 youths with ASD and 22 typically developing controls. Both parents and participants in the ASD group reported more autistic traits (higher AQ) and less empathy (lower EQ) than the control group. SQ ratings did not differ between groups. Comparisons of self- and parent-reports indicated that youths with ASD reported significantly fewer autistic traits and more empathic features than their parents attributed to them. There were no discrepancies between parent- and self-reports in the control group. Implications regarding the use of self-report in ASD are discussed.

Distinct cognitive profiles of cortical and subcortical dementia in advanced illness

Article abstract—We administered the Mattis Dementia Rating Scale (DRS) to 120 patients to evaluate the effect of dementia severity on distinct cognitive profiles. Sixty patients with Huntingtons disease (HD) and 60 patients with Alzheimers disease (AD) were separated by dementia severity into three groups: mildly demented (DRS mean total = 129), moderately demented (DRS mean total = 117), and severely demented (DRS mean total = 102). At all levels of dementia severity, HD patients demonstrated greater impairment than AD patients on the Initiation/Perseveration sub-scale, whereas AD patients demonstrated greater impairment than HD patients on the Memory subscale. At moderate and severe levels of dementia, HD patients demonstrated an additional impairment in constructional praxis. These profile differences were independent of dementia severity and continued to differentiate between so-called cortical and subcortical dernentias in later stages of dementia severity.

Motivational processes and autonomic responsivity in Asperger's disorder: evidence from the Iowa Gambling Task.

Aspergers disorder (ASP), like other autism spectrum disorders, is associated with altered responsiveness to social stimuli. This study investigated learning and responsiveness to nonsocial, but motivational, stimuli in ASP. We examined choice behavior and galvanic skin conductance responses (SCRs) during the Iowa Gambling Task (IGT; Bechara et al., 1994) in 15 adolescents and young adults with ASP and 14 comparison subjects. We examined aspects of learning, attention to wins and losses, and response style with a formal cognitive model, the Expectancy-Valence Learning model (Busemeyer & Stout, 2002). The ASP group did not differ from the comparison group in proportions of selections from advantageous decks. However, ASP participants showed a distinct pattern of selection characterized by frequent shifts between the four IGT decks, whereas comparison participants developed clear deck preferences. SCR results showed some evidence of reduced responsiveness in the ASP group during the IGT. Results from the cognitive model indicated that, in contrast to the comparison group, the ASP groups selections were less consistent with the motivational significance they assigned to decks. Findings are discussed in the context of the neurobiological substrates associated with IGT performance.

Frontal behavioral syndromes and functional status in probable Alzheimer disease.

OBJECTIVE / METHOD The authors used the Frontal Systems Behavior Scale (FrSBe) to determine the frequency of frontal behavioral syndromes in 49 subjects with mild-to-moderate dementia and 23 subjects with severe dementia of Alzheimer disease (AD) and 23 healthy control (HC) participants. RESULTS / CONCLUSIONS Frontal behavior syndromes occurred with higher frequency in AD. Apathy and executive dysfunction were elevated both in mild-to-moderate and severe AD. Disinhibition was elevated only in severe AD. In AD, apathy was associated with difficulty in basic activities of daily living (ADL), whereas executive dysfunction was related to impairment in instrumental ADLs.

Semantic network abnormality predicts rate of cognitive decline in patients with probable Alzheimer's disease

The present study examined the relationship between rate of cognitive decline in patients with Alzheimers disease (AD) and the integrity of the network of associations that comprise their semantic knowledge. The integrity of the semantic network of 12 AD patients was determined by comparing their networks to a standard normal control network derived with Pathfinder analysis, a multidimensional graphic analysis technique. A simple linear regression analysis, comparing the degree of semantic network deterioration with rate of cognitive decline as measured by the difference between the Dementia Rating Scale (DRS) scores obtained at the time of the testing of semantic knowledge (Year 1) and one year later (Year 2), was highly significant (r2 = .84; p < .001). These results suggest that a sensitive measure of the structural deterioration of semantic knowledge may be useful for predicting the rate of progression of cognitive changes in patients with AD.

Retrograde Amnesia in Dementia: Comparison of HIV-Associated Dementia, Alzheimer's Disease, and Huntington's Disease

Remote memory was assessed in persons with HIV-associated dementia (HIV-D), probable Alzheimers disease (AD), and Huntingtons disease (HD) and in healthy controls. The clinical groups were similar in overall dementia severity. Each clinical group exhibited impairments on remote memory tests relative to controls; however, temporally graded memory loss with selective preservation of older information was observed in the AD group but not the HD or HIV-D group. Analysis of cued retrieval indicated a preferential cuing benefit for the HIV-D and HD groups relative to the AD group. The similar pattern of remote memory performance demonstrated by the HIV-D and HD groups is a novel finding and suggests a subcortically mediated retrograde amnesia in HIV-D. The temporally graded pattern and the abnormal cued retrieval performance in the AD group are consistent with a consolidation deficit associated with extrahippocampal (cortical) and hippocampal damage.

Are cognitive changes progressive in prediagnostic HD

ObjectiveTo characterize neurocognitive signs of disease progression in prediagnosis and early Huntington disease (HD) and compare the sensitivity of 2 disease staging classification schemes for detecting these signs. MethodsThree hundred and six individuals at-risk for or recently diagnosed with HD completed the Unified Huntingtons Disease Rating Scale, genetic testing, and a neurocognitive battery. Two schemes were used to estimate latency to onset of disease. One was based on genetic information (CAG repeat length) and the other was based on the extent of motor signs. Effect sizes were compared to assess the relative sensitivity of the 2 schemes for detecting signs of disease progression. ResultsCAG-expanded participants far from estimated diagnosis performed similarly to controls, whereas those near to estimated diagnosis were impaired relative to controls. Overall, the method employing genetic information yielded larger effect sizes than the motor scheme, particularly for strategic and executive function measures; the motor scheme resulted in a larger effect size for a measure of motor/psychomotor function. ConclusionsNeurocognitive function is not uniformly affected in prediagnosis and early HD; individuals near to their estimated age of diagnosis have cognitive signs similar to HD, whereas individuals far from estimated diagnosis appear cognitively normal. Classification schemes that incorporate both genetic and phenotypic information may be more sensitive for tracking neurocognitive signs of disease progression.

Self-reported and parent-reported pain for common painful events in high-functioning children and adolescents with autism spectrum disorder

Objectives:Previous research suggests that children with autism spectrum disorders (ASD) are at a higher risk for painful experiences, but there is limited research examining pain in children with ASD. Methods:The current study examined self-reported and parent-reported pain in 20 high-functioning youth with ASD (17 boys; 3 girls) and 20 typically developing controls (16 boys; 4 girls) ranging in age from 9 to 18 years and matched on age and IQ. Participants with and without ASD rated their hypothetical pain in a series of pictures depicting common childhood situations. They also rated the amount of pain they would expect to feel (using the Faces Pain Scale—Revised and a Numeric Rating Scale) in a series of validated hypothetical pain situations depicted in cartooned images (eg, scraping knee on sidewalk). Parents rated the amount of pain they would expect their child to show in each of the same cartoon stimuli. Results:There were no significant differences between pain vignette ratings of youth with ASD and their non-ASD peers or in the ratings provided by their parents. High-functioning youth with ASD were able to successfully use both of the self-report scales to rate pain. Discussion:This is the first study to successfully obtain self-report of pain from youth with ASD. Implications for the understanding of pain and pain assessment in high-functioning youth with ASD are discussed.