Integrating Biomarker Outcomes into Clinical Trials for Alzheimer's Disease in Down Syndrome.

The NIH-funded Alzheimer's Biomarker Consortium Down Syndrome (ABC-DS) and the European Horizon 21 Consortium are collecting critical new information on the natural history of Alzheimer's Disease (AD) biomarkers in adults with Down syndrome (DS), a population genetically predisposed to developing AD. These studies are also providing key insights into which biomarkers best represent clinically meaningful outcomes that are most feasible in clinical trials. This paper considers how these data can be integrated in clinical trials for individuals with DS. The Alzheimer's Clinical Trial Consortium - Down syndrome (ACTC-DS) is a platform that brings expert researchers from both networks together to conduct clinical trials for AD in DS across international sites while building on their expertise and experience.

Relationship of amyloid beta and neurofibrillary tau deposition in Neurodegeneration in Aging Down Syndrome (NiAD) study at baseline.

IMPORTANCE: Adults with Down syndrome (DS) are at high-risk of revealing Alzheimer's disease (AD) pathology, in part due to the triplication of chromosome 21 encoding the amyloid precursor protein. Adults with DS are uniformly affected by AD pathology by their 30's and have a 70% to 80% chance of clinical dementia by their 60's. Our previous studies have assessed longitudinal changes in amyloid beta (Aß) accumulation in DS. OBJECTIVE: The goal of the present study was to assess the presence of brain tau using [18F]AV-1451 positron emission tomography (PET) in DS and to assess the relationship of brain tau pathology to Aß using Pittsburgh Compound B (PiB)-PET. DESIGN: Cohort study. SETTING: Multi-center study. PARTICIPANTS: Participants consisted of a sample of individuals with DS and sibling controls recruited from the community; exclusion criteria included contraindications for magnetic resonance imaging (MRI) and/or a medical or psychiatric condition that impaired cognitive functioning. EXPOSURES: PET brain scans to assess Aß ([11C]PiB) and tau ([18F]AV-1451) burden. MAIN OUTCOMES AND MEASURES: Multiple linear regression models (adjusted for chronological age, sex and performance site) were used to examine associations between regional [18F]AV-1451 standard uptake value ratio (SUVR) (based on regions associated with Braak stages 1-6) and global [11C]PiB SUVR (as both a continuous and dichotomous variable). RESULTS: A cohort of 156 participants (mean age = 39.05, SD(8.4)) were examined. These results revealed a significant relationship between in vivo Aß and tau pathology in DS. As a dichotomous variable, [18F]AV-1451 retention was higher in each Braak region in PiB(+) participants. We also found, based on our statistical models, starting with the Braak 3 region of interest (ROI), an acceleration of [18F]AV-1451 SUVR deposition with [11C]PiB SUVR increases.

Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.

Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.

The Home Situations Questionnaire-PDD version: factor structure and psychometric properties.

BACKGROUND: The Home Situations Questionnaire (HSQ) is a caregiver-rated scale designed to assess behavioural non-compliance in everyday settings that has been used in several studies in typically developing children. Currently there is no accepted measure of behavioural non-compliance in children with pervasive developmental disorders (PDDs). METHODS: Investigators of the Research Units on Pediatric Psychopharmacology Autism Network modified the HSQ for children with PDDs by adding five items (making 25 total items), and used it as the primary outcome measure in a clinical trial. In the current investigation, we examined the factor structure and psychometric properties of the modified scale, the HSQ-PDD. RESULTS: An exploratory factor analysis with oblique rotations yielded two factors: 'Socially Inflexible' (14 items) and 'Demand-Specific' (six items). Item content of both factors appeared to fit well with the rubric of PDDs. Internal consistency, using Cronbach's alpha statistic, was 0.90 for 'Socially Inflexible', and 0.80 for 'Demand-Specific.' The obtained sub-scales and HSQ-PDD Total score showed moderate correlations with selected sub-scales of the Aberrant Behavior Checklist, Child and Adolescent Symptom Inventory, and Children's Yale-Brown Obsessive Compulsive Scale, and low correlations with the Vineland Adaptive Behavior sub-scales. CONCLUSIONS: The HSQ-PDD appears to be well suited for children with PDDs, although the Demand-Specific sub-scale may benefit from addition of more items. We provided sub-scale means and standard deviations for this relatively severe group of children with PDDs, and discussed the factor structure with respect to previous research.

Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder.

OBJECTIVE: To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances--for example, hyperactivity and irritability--in children with autism. METHOD: Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. RESULTS: When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. CONCLUSIONS: Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.

Efficacy of methylphenidate among children with autism and symptoms of attention-deficit hyperactivity disorder.

Thirteen children (ages 5.6 to 11.2 years) with autism and symptoms of attention-deficit hyperactivity disorder (ADHD) participated in a double-blind, placebo-controlled crossover study of methylphenidate (0.3 and 0.6 mg/kg per dose). Eight subjects responded positively, based upon a minimum 50% decrease on the Conners Hyperactivity Index. Ratings of stereotypy and inappropriate speech, which are often associated with autistic core features, also decreased. However, no changes were found on the Child Autism Rating Scale, a global assessment of autistic symptomotology. Significant adverse side effects occurred in some children including social withdrawal and irritability, especially at the 0.6 mg/kg dose. Results suggest that methylphenidate can be efficacious for children with autism and ADHD symptoms. However, this group of children seems to be particularly susceptible to adverse side effects.

Efficacy of methylphenidate among preschool children with developmental disabilities and ADHD.

OBJECTIVE: This was a double-blind, placebo-controlled, crossover design study of the safety and efficacy of methylphenidate (MPH) in 11 preschool children (aged 4.0-5.11 years) with developmental disabilities and attention-deficit hyperactivity disorder (ADHD). METHOD: MPH doses of 0.3 and 0.6 mg/kg per dose and a placebo were given. Drug response was evaluated via teacher-completed behavior checklists and clinic-based observations of activity level, attention, and compliance to adult requests. A side effects checklist was also completed by teachers and parents. RESULTS: Significant improvement on teacher ratings of hyperactivity and inattention as well as clinic-based observations of activity level and compliance were associated with MPH. Eight of 11 preschool children were medication responders (based on a minimum 40% decrease between placebo and one drug condition on either the teacher-rated Conners Hyperactivity Index or the Hyperactive-Distractible subscale of the Preschool Behavior Questionnaire). Five children exhibited significant adverse drug side effects such as severe social withdrawal, increased crying, and irritability, especially at the higher dose (0.6 mg/kg). CONCLUSIONS: Results suggest that preschool children with developmental disabilities and ADHD respond to MPH at rates similar to those of school-age children with mental retardation and ADHD. However, this population appears to be especially susceptible to adverse drug side effects.

A playroom observation procedure to assess children with mental retardation and ADHD.

Forty-two children (ages 6 to 12 years old) with moderate mental retardation to borderline intellectual functioning were studied in a laboratory playroom setting to determine whether children identified as ADHD (attention deficit hyperactivity disorder) or controls differed on activity and attentional measures. Children with ADHD were further divided into ADHD + conduct problems (ADHD + CD) and ADHD-only subgroups (with an ADHD-combined group comprising children of both subgroups). An interval recording system was used to code observations of independent play and a restricted academic task. Results indicated that the ADHD-combined group was significantly more vocal and engaged in a significantly greater number of toy changes than controls during independent play. Significant group differences were also noted during the restricted academic task, with the ADHD-combined and ADHD + CD groups more off-task and engaging in a greater number of toy touches than controls. Discriminant analyses found independent play measures to predict group membership in 70 percent of cases (ADHD-combined vs. controls), but in only 64 percent of cases using measures from the restricted academic task. No significant findings resulted when the ADHD subjects were further divided into two subgroups. Despite some inconsistent findings, such laboratory-based observations may be of value in the diagnosis of ADHD in children with moderate mental retardation to borderline intellectual functioning.

Naltrexone in young autistic children: replication study and learning measures.

OBJECTIVE: This study expanded upon previous work on naltrexone efficacy and safety in young autistic children and assessed performance on learning measures. METHOD: Eleven children with autistic disorder, aged 3.0 to 8.3 years, were studied in home, school, and outpatient laboratory, bringing to 24 the combined study sample. Naltrexone, 1.0 mg/kg, was given daily in a randomized, double-blind, crossover design. Dependent measures were parent and teacher Clinical Global Impressions (CGI) and Naltrexone Side Effects Rating Scale (SE), Conners Parent Impulsivity/Hyperactivity Factor, Teacher Hyperactivity Factor, laboratory CGI, and analysis of videotaped behavior. Learning measures were the Early Intervention Developmental Profile-Language and paired-associate learning. RESULTS: Comparisons between naltrexone and baseline, but not naltrexone and placebo, on parent and teacher ratings showed statistical significance. Three of 11 subjects improved in two or more settings. Side effects were mild. Administering naltrexone was a challenge. The combined study sample showed improvement on all parent measures and on Teacher CGI and SE-Restlessness compared with baseline and placebo. Eleven of the 24 children improved in two or more settings. Scores on learning measures did not change across conditions. CONCLUSIONS: Naltrexone was associated with modest improvement of behavior in 11 of 24 children, but learning did not improve.

Long-term follow-up of children with mental retardation/borderline intellectual functioning and ADHD.

Fifty-two children (ages 7 to 14 years) with moderate retardation to borderline intellectual functioning were recontacted 12 to 65 months following participation in a double-blind, placebo-controlled trial of methylphenidate (MPH). Sixty-nine percent of subjects continued to be prescribed medication for behavior control at follow-up. While 72% of the sample evidenced improvement, over two-thirds continued to be rated at or above the 98th percentile on the Hyperactivity Index of the Parent Conners. In fact, 22% of subjects had received inpatient psychiatric treatment between the time of the initial MPH trial and follow-up. Finally, subjects with high initial ratings on the Parent Conners Conduct Problems scale were more likely to be suspended from school or receive inpatient psychiatric treatment than subjects with low initial ratings. The results suggested that children with ADHD and mental retardation of borderline intellectual functioning continued to exhibit significant symptoms associated with attention deficit hyperactivity disorder (ADHD) at follow-up and that early conduct problems were predictive of continuing behavioral difficulties.

Four-year follow-up of children with low intelligence and ADHD.

Twenty-six of 30 participants (87%) who took part in a medication study for treatment of ADHD were followed up 2.9 to 4.8 years (Mean = 3.9 years) later. Parent ratings on the Aberrant Behavior Checklist Community (ABC-C) indicated continued problems on the acting-out subscales, and parent assessments on the Stony Brook Checklist-3R showed a high rate of difficulty on domains called ADHD. Conduct Disorder, and Separation Anxiety Disorder. A high percentage of children (69%) were taking psychotropic drugs, substantial numbers of their families had sought nonmedical treatments, children's friendships were often rudimentary, and a significant minority of children had disciplinary problems in school or difficulty with the law. Using Pearson correlations, we identified a number of initial variables that predicted follow-up parent ratings on the ABC-C and Stony Brook. The ABC-C Irritability subscale was useful in predicting both internalizing and externalizing problems at follow-up, whereas parent and teacher hyperactivity subscales failed to predict later hyperactivity. Children identified with both low intelligence and ADHD appear to have significant behavioral and emotional problems in their early adolescence, and there may be some important qualitative differences in the outcome of these youngsters as compared with that of children identified with ADHD and normal IQ.

Affective disorders in hospitalized children and adolescents with mental retardation: a retrospective study.

We contrasted a sample of children and adolescents with affective disorders and mental retardation with a comparison group on behavioral symptoms, associated diagnoses, and psychopharmacologic treatment. Fifty consecutive patients with both impaired intellectual functioning and at least one affective disorder admitted to a psychiatric inpatient unit for children and adolescents with developmental disabilities and psychiatric disorders were matched to a group of 50 inpatients without depression. Behavioral symptoms such as suicidal ideation or gestures, crying, irritability, sleep problems, agitation, mood lability, and social withdrawal/isolation occurred significantly more often in the affective group than in the comparison group. Aggression, however, was the most frequent behavior concern for both groups, whereas disruption/destruction was identified significantly more often in the comparison group. Regarding Axis I diagnoses, the comparison group was more often identified with externalizing disorders (ADHD, ODD), though there was a high rate of comorbidity in the affective disorder group. The behavioral symptoms used to diagnosis normally developing children and adolescents appear to be applied in making affective disorders diagnoses in this sample of children and adolescents with mental retardation.

Naltrexone in young autistic children: a double-blind, placebo-controlled crossover study.

OBJECTIVE: This study evaluated the efficacy and safety of naltrexone, an opiate blocker, in the treatment of autism. METHOD: Thirteen children with autistic disorder, aged 3.4 to 8.3 years (mean 5.4), were studied in home, school, and outpatient laboratory. Naltrexone, 1.0 mg/kg, was given daily in a randomized, double-blind, placebo-controlled crossover design. Dependent measures included parent and teacher Clinical Global Impressions (CGI), Conners Rating Scales, and Naltrexone Side-Effects (SE) Rating Scale; laboratory CGI, movement actometer readings, and a 10-second interval recording system analysis of on-task, communication initiations, disruptive behavior, and self-stimulation. RESULTS: Eight of 13 subjects improved in two or more settings. Changes in parent measures (CGI, Conners Impulsivity-Hyperactivity Factor, and SE-Restlessness) and Teacher CGI achieved statistical significance. Teacher SE-Restlessness and initiation of communication in the clinic showed a trend toward improvement. Actometer readings improved in two children who were very active at baseline. Adverse side effects were behavioral, mild, and transient. Administering the bitter tablet was a challenge. CONCLUSIONS: Naltrexone offers promise as an agent for modest improvement of behavior and social communication in young children with autism. Parent and teacher measures can be useful in outpatient trials to evaluate change.

Prediction of response to methylphenidate among children with ADHD and mental retardation.

OBJECTIVE: The primary purpose of this study was to predict stimulant medication response among children with attention-deficit hyperactivity disorder (ADHD) and mental retardation (MR). METHOD: Forty-seven children with ADHD and MR (IQs of 48 to 77) served as subjects; ages ranged from 6.1 to 12.5 years. Subjects participated in a double-blind, placebo-controlled study of two doses of methylphenidate (0.3 and 0.6 mg/kg per dose) and a placebo. Data were collected in each child's weekday classroom and a Saturday laboratory classroom. Stepwise multiple regression analyses were used to predict drug responses in both settings. RESULTS: Higher parent ratings of impulsivity and activity level at baseline were associated with greater gains in weekday classroom dependent measures. Similarly, higher weekday teacher measures of activity level, impulsivity, inattention, and conduct problems at baseline were related to improvement on Saturday laboratory classroom dependent measures. Finally, gender, race, and socioeconomic status (SES) were found to be important predictors, with males, Caucasian subjects, and subjects from families of higher SES more likely to evidence clinical gains on a number of variables than other subjects. CONCLUSION: These results were generally consistent with research conducted among children with ADHD but without MR. However, factors such as race and conduct problems appear to have predictive utility specific to children with MR.

Efficacy of methylphenidate and behavioral intervention on classroom behavior in children with ADHD and mental retardation.

Using a combination of an alternating treatment and double-blind placebo-controlled drug design, the independent and combined effects of two behavioral interventions and two doses of methylphenidate (MPH) in 3 children with Attention Deficit Hyperactivity Disorder (ADHD) and mental retardation (MR) were assessed. In this single subject design, 2 of the 3 subjects responded positively to medication as measured by increased on-task behavior. The first behavioral intervention, a token economy for on-task behavior, was ineffective for increasing either on-task behavior or work accuracy when combined with placebo. However, improvement in work accuracy was realized with implementation of a second behavioral intervention that specifically targeted accuracy independent of drug conditions. The current findings highlight both the positive effects and limitations of the two commonly used treatment modalities for ADHD. Future studies should continue to extend this area of investigative efforts to produce more data-based knowledge as to the appropriate doses of treatment, both pharmacological and behavioral, with children with both ADHD and mental retardation.

Classroom behavior and children with mental retardation: comparison of children with and without ADHD.

Thirty-four children (ages 6-12 years) with moderate to borderline mental retardation were studied in a laboratory classroom setting to determine whether children identified as having attention deficit hyperactivity disorder on the basis of Conners Questionnaires differed in classroom behavior. Half of the children scored 15 or greater on both the Parent and Teacher Conners; the remaining children scored 11 or less. All were participants in a Saturday Education Program serving children with mental retardation. Direct observation of the laboratory classroom documented significant differences between groups on measures of on-task behavior and fidgetiness, especially during situations where little direct teacher feedback or supervision was available. Saturday Education Program staff, while blind as to group designation, rated the two groups as differing significantly on all scales of two standardized behavior problem checklists. Checklists by parents and teachers appear to be valid measures of classroom behavior of children with moderate to borderline mental retardation.

Effects and noneffects of methylphenidate in children with mental retardation and ADHD.

Stimulant medication efficacy was evaluated in 14 children with attention-deficit hyperactivity disorder and IQs of 48 to 74 in a double-blind crossover study of two methylphenidate doses and placebo. Dependent measures included behavioral ratings, work output, measures of learning, attention and impulsivity, and direct observation of peer social interactions. Nine children (64%) were methylphenidate-responders, based upon the Conners Hyperactivity Index. Significant gains in on-task behavior and attentional skills were noted with methylphenidate in comparison to placebo. No improvement on measures of learning or social interactions were observed. Results extend and replicate previous research conducted by the authors.

Using guided compliance versus time out to promote child compliance: a preliminary comparative analysis in an analogue context.

Children referred to child management clinics frequently exhibit noncompliance with adult requests. Using a counterbalanced ABAC design, the authors examined the relative efficacy of guided compliance versus time out as a method of promoting child adherence to adult requests. Time out effected larger increases in percentage compliance among four of five participating children.

Adverse side effects of methylphenidate among mentally retarded children with ADHD.

The adverse side effects of methylphenidate were evaluated in 27 children with attention deficit hyperactivity disorder and IQs of 48 to 74 who participated in a double-blind study of two doses of methylphenidate and placebo. A checklist of 13 side effects, generated from the Physician's Desk Reference, was completed by teachers. Rates of irritability, anxiety, moodiness, and activity level decreased significantly when comparing the placebo with drug conditions. However, medication for six (22%) of the children was discontinued because of the appearance of motor tics (three children) and severe social withdrawal (two children), suggesting that mentally retarded children with attention deficit hyperactivity disorder may be at a greater risk for developing these side effects than the nonretarded population.

Efficacy of methylphenidate among mentally retarded children with attention deficit hyperactivity disorder.

Twelve children with IQ scores of 50 to 74 (educable mental retardation) who met rigorous diagnostic criteria for attention deficit hyperactivity disorder participated in a double-blind crossover study of the efficacy of two doses of methylphenidate compared with placebo. Dependent measures included behavioral ratings, classroom work output, laboratory measures of attention and learning, and direct observations of social behavior. Improvement with medication on the Conners Hyperactivity Index was observed in 75% of subjects. Significant increases in work output, on-task behavior, and attentional skills were associated with methylphenidate. However, gains in measures of attention were not associated with improvement in learning, as measured by a paired associate learning task. Additionally, no significant increases in appropriate social interactions during free play were associated with methylphenidate. The results suggest that mentally retarded children with attention deficit hyperactivity disorder respond to methylphenidate at similar rates and in similar domains to that of the nonretarded population.