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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.

Highlights • Neurofibrillary tau deposition in Down syndrome follows the Braak staging pathology. • Neurofibrillary tau emerges in individuals with very low amyloid burden. • There is a short latency between the onset of amyloid and tau in Down syndrome. • Elevated tau was observed in Braak stages I-II with very low amyloid burden, and in stages III-VI with greater amyloid burden., Introduction Adults with Down syndrome are genetically predisposed to develop Alzheimer’s disease and accumulate beta-amyloid plaques (Aβ) early in life. While Aβ has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aβ burden. Methods A total of 161 adults with Down syndrome (mean age = 39.2 (8.50) years) and 40 healthy, non-Down syndrome sibling controls (43.2 (12.6) years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans. PET images were converted to units of standardized uptake value ratios (SUVrs). Aβ burden was calculated using the amyloid load metric (AβL); a measure of global Aβ burden that improves quantification from SUVrs by suppressing the nonspecific binding signal component and computing the specific Aβ signal from all Aβ-carrying voxels from the image. Regional tau was assessed using control-standardized AV-1451 SUVr. Control-standardized SUVrs were compared across Down syndrome groups of Aβ-negative (A-) (AβL

Author(s): Handen, Benjamin L; Lott, Ira T; Christian, Bradley T; Schupf, Nicole; OBryant, Sid; Mapstone, Mark; Fagan, Anne M; Lee, Joseph H; Tudorascu, Dana; Wang, Mei-Cheng; Head, Elizabeth; Klunk, William; Ances, Beau; Lai, Florence; Zaman, Shahid; Krinsky-McHale, Sharon; Brickman, Adam M; Rosas, H Diana; Cohen, Annie; Andrews, Howard; Hartley, Sigan; Silverman, Wayne; Alzheimer's Biomarker Consortium‐Down Syndrome (ABC‐DS) | Abstract: IntroductionAdults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments.MethodsWe describe the development of a multi-center, longitudinal study of biomarkers of AD in DS. The protocol includes longitudinal examination of clinical, cognitive, blood and cerebrospinal fluid-based biomarkers, magnetic resonance imaging and positron emission tomography measures (at 16-month intervals), as well as genetic modifiers of AD risk and progression.ResultsApproximately 400 individuals will be enrolled in the study (more than 370 to date). The methodological approach from the administrative, clinical, neuroimaging, omics, neuropathology, and statistical cores is provided.DiscussionThis represents the largest U.S.-based, multi-site, biomarker initiative of AD in DS. Findings can inform other multidisciplinary networks studying AD in the general population.

The National Institute on Aging in conjunction with the Alzheimer's Association (NIA‐AA) recently proposed a biological framework for defining the Alzheimer's disease (AD) continuum. This new framework is based upon the key AD biomarkers (amyloid, tau, neurodegeneration, AT[N]) instead of clinical symptoms and represents the latest understanding that the pathological processes underlying AD begin decades before the manifestation of symptoms. By using these same biomarkers, individuals with Down syndrome (DS), who are genetically predisposed to developing AD, can also be placed more precisely along the AD continuum. The A/T(N) framework is therefore thought to provide an objective manner by which to select and enrich samples for clinical trials. This new framework is highly flexible and allows the addition of newly confirmed AD biomarkers into the existing AT(N) groups. As biomarkers for other pathological processes are validated, they can also be added to the AT(N) classification scheme, which will allow for better characterization and staging of AD in DS. These biological classifications can then be merged with clinical staging for an examination of factors that impact the biological and clinical progression of the disease. Here, we leverage previously published guidelines for the AT(N) framework to generate such a plan for AD among adults with DS.

Introduction Comorbid Alzheimer disease pathologies are frequently found in people with Down syndrome (DS). We report a deep phenotyping study undertaken over 7 years in a participant with DS who was nondemented at baseline but developed dementia after 5 years. Methods Throughout the course of the study, the participant was seen 4 times (2010, 2013, 2015, and 2017). Multimodal neuroimaging, including three serial scans of [11C]-PiB-PET, four structural magnetic resonance imagings, as well as a [18F]-AV1451 scan, was interpreted alongside detailed neuropsychological assessments over the study period. Results Amyloid beta accumulation preceded the onset of dementia and cognitive decline, which in turn corresponded to the predominant deposition of tau in temporoparietal cortices. Discussion Until now, data on the longitudinal trajectories of amyloid accumulation, tau pathology, and brain atrophy over multiple time points remain scarce in DS. This case report highlights the potential for deep phenotyping imaging to elucidate the substrates of cognitive decline in DS, although further longitudinal studies are necessary to clarify the relative contributions of both amyloid and tau.

Author(s): Petersen, Melissa E; Zhang, Fan; Schupf, Nicole; Krinsky-McHale, Sharon J; Hall, James; Mapstone, Mark; Cheema, Amrita; Silverman, Wayne; Lott, Ira; Rafii, Michael S; Handen, Benjamin; Klunk, William; Head, Elizabeth; Christian, Brad; Foroud, Tatiana; Lai, Florence; Rosas, H Diana; Zaman, Shahid; Ances, Beau M; Wang, Mei-Cheng; Tycko, Benjamin; Lee, Joseph H; O'Bryant, Sid; Alzheimer's Biomarker Consortium – Down Syndrome (ABC‐DS) | Abstract: Introduction:Previously generated serum and plasma proteomic profiles were examined among adults with Down syndrome (DS) to determine whether these profiles could discriminate those with mild cognitive impairment (MCI-DS) and Alzheimer's disease (DS-AD) from those cognitively stable (CS). Methods:Data were analyzed on nn=n305 (nn=n225 CS; nn=n44 MCI-DS; nn=n36 DS-AD) enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS). Results:Distinguishing MCI-DS from CS, the serum profile produced an area under the curve (AUC)n=n0.95 (sensitivity [SN]n=n0.91; specificity [SP]n=n0.99) and an AUCn=n0.98 (SNn=n0.96; SPn=n0.97) for plasma when using an optimized cut-off score. Distinguishing DS-AD from CS, the serum profile produced an AUCn=n0.93 (SNn=n0.81; SPn=n0.99) and an AUCn=n0.95 (SNn=n0.86; SPn=n1.0) for plasma when using an optimized cut-off score. AUC remained unchanged to slightly improved when age and sex were included. Eotaxin3, interleukin (IL)-10, C-reactive protein, IL-18, serum amyloid A , and FABP3 correlated fractions at r2ngn=n0.90. Discussion:Proteomic profiles showed excellent detection accuracy for MCI-DS and DS-AD.

Background: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, virtually all adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by age 40 and are at high risk for dementia given their increased life expectancy. Comparison of cerebrospinal fluid (CSF) biomarker patterns with those of autosomal dominant AD (ADAD) mutation carriers (MC) will enhance our understanding of disease mechanisms in these two genetically defined groups. Methods: CSF samples obtained from adults with DS (n=41) and similarly-aged ADAD MC (n=192) and non-carrier (NC, n=108) siblings (aged 30-61 years) were analyzed for markers of amyloid-β (Aβ40, Aβ42), phosphorylated tau-related processes (pTau181), neuronal/axonal/synaptic injury (total tau, visinin-like protein 1 [VILIP-1], neurofilament light chain [NfL], synaptosomal-associated protein 25 [SNAP-25]), and astrogliosis/neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic/symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker levels and age among groups. Findings: Adults with DS exhibited patterns of AD-related CSF biomarkers remarkably similar to ADAD MC, including reductions in the Aβ42/Aβ40 ratio and increases in markers of phosphorylated tau-related processes, neuronal/axonal/synaptic injury, and astrogliosis/neuroinflammation, with greater degrees of abnormality in those with dementia. Differences included overall higher levels of Aβ and YKL-40 in DS and potential elevations in CSF tau and NfL in the asymptomatic (non-demented) stage. Interpretation: CSF biomarker profiles are useful for identifying and tracking AD-related processes in DS and will likely have utility for clinical care and clinical trial design in this understudied at-risk population. Funding: National Institute on Aging (U01 AG051406, U01 AG051412, UF1AG032438), Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Research and Development Grants for Dementia from Japan Agency for Medical Research and Development. Conflict of Interest: AMF has received research funding from the National Institutes of Health /National Institute on Aging, Biogen, Centene, Fujirebio, and Roche Diagnostics. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and AbbVie and also consults for Araclon/Grifols, DiademRes, DiamiR, and Otsuka Pharmaceuticals. There are no conflicts. RJB has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. He receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US nonprovisional patent application “Cerebrospinal fluid (CSF) tau rate of phosphorylation measurement to define stages of Alzheimer’s disease and monitor brain kinases/phosphatases activity.” He has received honoraria from Janssen and Pfizer as a speaker, and from Merck and Pfizer as an advisory board member. He has been an invited speaker, advisory board member, and consultant for F. Hoffman La Roche, Ltd., an invited speaker and consultant for AC Immune and Janssen, and a consultant for Amgen and Eisai. There are no conflicts. AMG has consulted for Eisai, Biogen, Pfizer, AbbVie, Cognition Therapeutics, and GSK. She also served on the Scientific Advisory Board of Denali Therapeutics (2015–2018). There are no conflicts. Ethical Approval: Informed consent was obtained directly from all participants whenever possible; otherwise, assent was obtained, and informed consent obtained from the participant’s legally authorized representative. Institutional Review Board approval was obtained at all sites.

Introduction There is a critical need to identify measures of cognitive functioning sensitive to early Alzheimer's disease (AD) pathophysiology in Down syndrome to advance clinical trial research in this at‐risk population. The objective of the study was to longitudinally track performance on cognitive measures in relation to neocortical and striatal amyloid beta (Aβ) in non‐demented Down syndrome. Methods The study included 118 non‐demented adults with Down syndrome who participated in two to five points of data collection, spanning 1.5 to 8 years. Episodic memory, visual attention and executive functioning, and motor planning and coordination were assessed. Aβ was measured via [C‐11] Pittsburgh Compound‐B (PiB) PET. Results PiB was associated with level and rate of decline in cognitive performance in episodic memory, visual attention, executive functioning, and visuospatial ability in models controlling for chronological age. Discussion The Cued Recall Test emerged as a promising indicator of transition from preclinical to prodromal AD.

Harmonization of magnetic resonance imaging (MRI) and positron emission tomography (PET) scans from multi-scanner and multi-site studies presents a challenging problem. We applied the Removal of Artificial Voxel Effect by Linear regression (RAVEL) method to normalize T1-MRI intensities collected on two different scanners across two different sites as part of the Neurodegeneration in Aging Down syndrome (NiAD) study. The effects on FreeSurfer regional cortical thickness and volume outcome measures, in addition to FreeSurfer-based regional quantification of amyloid PET standardized uptake value ratio (SUVR) outcomes, were evaluated. A neuroradiologist visually assessed the accuracy of FreeSurfer hippocampus segmentations with and without the application of RAVEL. Quantitative results demonstrated that the application of RAVEL intensity normalization prior to running FreeSurfer significantly impacted both FreeSurfer volume and cortical thickness outcome measures. Visual assessment demonstrated that the application of RAVEL significantly improved FreeSurfer hippocampal segmentation accuracy. The RAVEL intensity normalization had little impact on PET SUVR measures.

Introduction Individuals with Down syndrome (DS) show enhanced amyloid beta (Aβ) deposition in the brain. A new positron emission tomography (PET) index of amyloid load (AβL) was recently developed as an alternative to standardized uptake value ratios (SUVrs) to quantify Aβ burden with high sensitivity for detecting and tracking Aβ change.1 Methods AβL was calculated in a DS cohort (N = 169, mean age ± SD = 39.6 ± 8.7 years) using [C‐11]Pittsburgh compound B (PiB) PET imaging. DS‐specific PiB templates were created for Aβ carrying capacity (K) and non‐specific binding (NS). Results The highest values of Aβ carrying capacity were found in the striatum and precuneus. Longitudinal changes in AβL displayed less variability when compared to SUVrs. Discussion These results highlight the utility of AβL for characterizing Aβ deposition in DS. Rates of Aβ accumulation in DS were found to be similar to that observed in late‐onset Alzheimer's disease (AD; ≈3% to 4% per year), suggesting that AD progression in DS is of earlier onset but not accelerated.

Background Intelligence tests are a fundamental component of diagnostic assessments for children with suspected autism spectrum disorder (ASD). There are many assessments available, but scores across tests may not be comparable in children with ASD. Method Eighty children (68 boys) age 4–14 years with ASD completed the Stanford-Binet Intelligence Scales, 5th Edition (SB5), a verbal measure of intelligence, and the Leiter International Performance Scale – Revised (Leiter-R), a nonverbal measure of intelligence. Results Although discrepancies went in both directions, we found significantly higher mean scores on the Leiter-R than SB5 (9.6 point difference). Children younger than 8 years had more pronounced discrepancies (13.8 points vs. 3.5 points for >8 years), and children with less-developed language skills had greater discrepancies (13.1 points vs. 5.8 points for higher language skills). Conclusion This suggests these IQ tests are not interchangeable and language demands may produce different results that could impact clinician interpretation. Both clinicians and researchers should be aware of the likely impact of adopting primarily verbal vs. nonverbal tests when assessing children with ASD, especially those with less language.

Objectives: Studies in humans and rodents suggest that metformin, a medicine typically used to treat type 2 diabetes, may have beneficial effects on memory. We sought to determine whether metformin improved spatial or verbal memory in children with autism spectrum disorder (ASD) and overweight associated with atypical antipsychotic use. Methods: We studied the effects of metformin (Riomet®) concentrate on spatial and verbal memory in 51 youth with ASD, ages 6 through 17 years, who were taking atypical antipsychotic medications, had gained significant weight, and were enrolled in a trial of metformin for weight management. Phase 1 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group comparison of metformin (500–850 mg given twice a day) versus placebo. During Phase 2, all participants took open-label metformin from week 17 through week 32. We assessed spatial and verbal memory using the Neuropsychological Assessment 2nd Edition (NEPSY–II) and a modified children's verbal learning task. Results: No measures differed between participants randomized to metformin versus placebo, at either 16 or 32 weeks, after adjustment for multiple comparisons. Sixteen-week change in memory for spatial location on the NEPSY–II was nominally better among participants randomized to placebo. However, patterns of treatment response across all measures revealed no systematic differences in performance, suggesting that metformin had no effect on spatial or verbal memory in these children. Conclusions: Although further study is needed to support these null effects, the overall impression is that metformin does not affect memory in overweight youth with ASD who were taking atypical antipsychotic medications.

Objective: Sleep disturbance is often a problem for children with either autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD). Psychostimulant medications used to treat ADHD symptoms can exacerbate this problem. For children with ASD and ADHD, atomoxetine (ATX) is a viable alternative to psychostimulants. We investigated the effects of ATX and a manualized parent training (PT) program targeting noncompliance, on the sleep quality of children with ASD and ADHD. Methods: Participants in a randomized clinical trial were treated with ATX + PT, ATX alone, PT alone, or placebo (PBO) alone, for 10 weeks. Fifty-four of 128 (42%) caregivers completed the Children's Sleep Habits Questionnaire (CSHQ) at baseline and endpoint. Analysis of covariance was used to investigate possible differences between treatment groups. Results: There were no significant differences between treatment groups, including PBO on the CSHQ 33-Item total score, total hours of sleep per day, and total minutes awake after sleep onset at the study endpoint. Conclusion: ATX appears sleep neutral. Clinicians who treat ADHD symptoms in children and adolescents with ASD may prefer ATX over psychostimulants when sleep disturbance is an issue.

The newest edition of the Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-5) introduced substantial changes to the diagnostic criteria for autism spectrum disorder, including new severity level ratings for social communication and restricted and repetitive behavior domains. The purpose of this study was to evaluate the use of these new severity ratings and to examine their relation to other measures of severity and clinical features. Participants included 248 children with autism spectrum disorder who received diagnostic evaluations at one of six Autism Treatment Network sites. Higher severity ratings in both domains were associated with younger age, lower intelligence quotient, and greater Autism Diagnostic Observation Schedule–Second Edition domain-specific symptom severity. Greater restricted and repetitive behavior severity was associated with higher parent-reported stereotyped behaviors. Severity ratings were not associated with emotional or behavioral problems. The new DSM-5 severity ratings in both domains were significantly associated with behavioral observations of autism severity but not with measures of other behavioral or emotional symptoms. However, the strong associations between intelligence quotient and DSM-5 severity ratings in both domains suggest that clinicians may be including cognitive functioning in their overall determination of severity. Further research is needed to examine clinician decision-making and interpretation of these specifiers.

Limited information about self-injurious behavior (SIB) is known for children and adolescents with Autism Spectrum Disorder (ASD) who require intensive behavioral health interventions. We examined risk-factors for SIB in 302 individuals with ASD (ages 4-20) admitted to six specialized psychiatric inpatient units. Seventy-four percent were reported by a caregiver to display SIB, however, only 25% were observed to engage in daily SIB during hospitalization. Those exhibiting SIB across environments had significantly higher ratings on caregiver questionnaires of SIB severity. Tree-structured classification was used to develop and validate two predictive models, one indicating which inpatient youth with ASD are likely to have SIB and a second indicating which individuals with SIB at home are likely to continue in an inpatient setting.

Adults with Down syndrome are at a high risk for disordered sleep. These sleep problems could have marked effects on aging and Alzheimer’s disease, potentially altering white matter integrity. This study examined the associations between disordered sleep assessed via an actigraph accelerometer worn on 7 consecutive nights, presence of diagnosis of obstructive sleep apnea, and diffusion tensor imaging indices of white matter integrity in 29 non-demented adults with Down Syndrome (48% female, aged 33–54 years). Average total sleep time was associated with lower mean diffusivity in the left superior longitudinal fasciculus (r = −0.398, p = 0.040). Average sleep efficiency, length of awakenings, and movement index were related to fractional anisotropy in the right inferior longitudinal fasciculus (r = −0.614 to 0.387, p ≤ 0.050). Diagnosis of obstructive sleep apnea was associated with fractional anisotropy in the right inferior longitudinal fasciculus (r = −0.373, p = 0.050). Findings suggest that more disrupted sleep is associated with lower white matter integrity in the major association tracts in middle-aged adults with Down syndrome. Longitudinal work is needed to confirm the directionally of associations. Sleep interventions could be an important component for promoting optimal brain aging in the Down syndrome population.

BackgroundAcute regression has been reported in some individuals with Down syndrome (DS), typically occurring between the teenage years and mid to late 20s. Characterized by sudden, and often unexplained, reductions in language skills, functional living skills and reduced psychomotor activity, some individuals have been incorrectly diagnosed with Alzheimer's disease (AD).MethodsThis paper compares five individuals with DS who previously experienced acute regression with a matched group of 15 unaffected individuals with DS using a set of AD biomarkers.ResultsWhile the sample was too small to conduct statistical analyses, findings suggest there are possible meaningful differences between the groups on proteomics biomarkers (e.g., NfL, total tau). Hippocampal, caudate and putamen volumes were slightly larger in the regression group, the opposite of what was hypothesized. A slightly lower amyloid load was found on the PET scans for the regression group, but no differences were noted on tau PET.ConclusionsSome proteomics biomarker findings suggest that individuals with DS who experience acute regression may be at increased risk for AD at an earlier age in comparison to unaffected adults with DS. However, due to the age of the group (mean 38 years), it may be too early to observe meaningful group differences on image-based biomarkers.

We previously reported a 2 × 2 randomized clinical trial of atomoxetine (ATX) and parent training (PT) for attention deficit hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 children with autism spectrum disorder, ages 5–14 years. Children were randomized to one of four conditions: ATX alone, placebo alone, ATX + PT, or PT + placebo. Both ATX and PT improved some indices of ADHD and behavioral compliance. In this report, we describe parent stress over time and across conditions. All four treatments improved parent self-rated stress from baseline to week 10. However, there were no statistically significant differences between treatment groups. Significantly more improvement in parent stress scores was observed for clinical responders than non-responders. ClinicalTrials.gov Title: Atomoxetine, Placebo and Parent Management Training in Autism (Strattera) ClinicalTrials.gov Identifier: NCT00844753.

Adults with Down syndrome (DS) have a high incidence of Alzheimer's disease (AD), providing a unique opportunity to explore the early, preclinical stages of AD neuropathology. We examined change in brain amyloid-β accumulation via the positron emission tomography tracer [11C] Pittsburgh compound B (PiB) across 2 data collection cycles, spaced 3 years apart, and decline in cognitive functioning in 58 adults with DS without clinical AD. PiB retention increased in the anterior cingulate gyrus, precuneus cortex, parietal cortex, and anterior ventral striatum. Across the 2 cycles, 14 (27.5%) participants were consistently PiB+, 31 (60.8%) were consistently PiB−, and 6 (11.7%) converted from PiB− at cycle 1 to PiB+ at cycle 2. Increased global amyloid-β was related to decline in verbal episodic memory, visual episodic memory, executive functioning, and fine motor processing speed. Participants who were consistently PiB+ demonstrated worsening of episodic memory, whereas participants who were consistently PiB− evidenced stable or improved performance. Amyloid-β accumulation may be a contributor to or biomarker of declining cognitive functioning in preclinical AD in DS.

The transition from DSM-IV to DSM-5 criteria for autism spectrum disorder (ASD) sparked considerable concern about the potential implications of these changes. This study was designed to address limitations of prior studies by prospectively examining the concordance of DSM-IV and final DSM-5 criteria on a consecutive sample of 439 children referred for autism diagnostic evaluations. Concordance and discordance were assessed using a consistent diagnostic battery. DSM-5 criteria demonstrated excellent overall specificity and good sensitivity relative to DSM-IV criteria. Sensitivity and specificity were strongest for children meeting DSM-IV criteria for autistic disorder, but poor for those meeting criteria for Asperger's disorder and pervasive developmental disorder. Higher IQ, older age, female sex, and less pronounced ASD symptoms were associated with greater discordance.

The present study examined leisure activity and its association with caregiver involvement (i.e., residence and time spent with primary caregiver) in 62 middle-aged and older adults with Down syndrome (aged 30–53 years). Findings indicated that middle-aged and older adults with Down syndrome frequently participated in social and passive leisure activities, with low participation in physical and mentally stimulating leisure activities. Residence and time spent with primary caregiver were associated with participation in physical leisure activity. The findings suggest a need for support services aimed at increasing opportunities for participating in physical and mentally stimulating leisure activity by middle-aged and older adults with Down syndrome. These support services should partner with primary caregivers in order to best foster participation in physical leisure activity.

In children with autism spectrum disorder, there have been equivocal results regarding primary caregiver education level and its influence on sleep. Thus, we assessed if lower primary caregiver education level is associated with more sleep problems. We evaluated 4,636 children with autism spectrum disorder in the Autism Speaks Autism Treatment Network's United States and Canadian registry, whose caregivers completed the Children's Sleep Habits Questionnaire. Using regression analysis, there was an association between lower primary caregiver education level and more sleep problems. Secondary analyses demonstrated that younger age, Hispanic ethnicity, higher IQ, autism diagnosis and lower adaptive function were also associated with more sleep problems. The finding that lower primary caregiver education level was associated with increased sleep problems in a large sample of children with autism spectrum disorder highlights the importance of screening for risk factors affecting sleep to help moderate sleep problems.

Contains fulltext : 215751.pdf (Publisher’s version ) (Open Access) BACKGROUND: Measures of general cognitive and adaptive ability in adults with Down syndrome (DS) used by previous studies vary substantially. This review summarises the different ability measures used previously, focusing on tests of intelligence quotient (IQ) and adaptive behaviour (AB), and where possible examines floor effects and differences between DS subpopulations. We aimed to use information regarding existing measures to provide recommendations for individual researchers and the DS research community. RESULTS: Nineteen studies reporting IQ test data met inclusion for this review, with 17 different IQ tests used. Twelve of these IQ tests were used in only one study while five were used in two different studies. Eleven studies reporting AB test data met inclusion for this review, with seven different AB tests used. The only AB scales to be used by more than one study were the Vineland Adaptive Behaviour Scale (VABS; used by three studies) and the Vineland Adaptive Behavior Scale 2nd Edition (VABS-II; used by two studies). A variety of additional factors were identified which make comparison of test scores between studies problematic, including different score types provided between studies (e.g. raw scores compared to age-equivalent scores) and different participant inclusion criteria (e.g. whether individuals with cognitive decline were excluded). Floor effects were common for IQ tests (particularly for standardised test scores). Data exists to suggest that floor effects may be minimised by the use of raw test scores rather than standardised test scores. Raw scores may, therefore, be particularly useful in longitudinal studies to track change in cognitive ability over time. CONCLUSIONS: Studies assessing general ability in adults with DS are likely to benefit from the use of both IQ and AB scales. The DS research community may benefit from the development of reporting standards for IQ and AB data, and from the sharing of raw study data enabling further in-depth investigation of issues highlighted by this review.

Down syndrome (DS) results in an overproduction of amyloid-β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits detectable histologically as young as 12-30years of age, primarily in the form of diffuse plaques, the type of early amyloid pathology also seen at pre-clinical (i.e., pathological aging) and prodromal stages of sporadic late onset AD. In DS subjects aged >40years, levels of cortical Aβ deposition are similar to those observed in late onset AD and in addition to diffuse plaques involve cored plaques associated with dystrophic neurites (neuritic plaques), which are of neuropathological diagnostic significance in AD. The purpose of this review is to summarize and discuss findings from amyloid PET imaging studies of DS in reference to postmortem amyloid-based neuropathology. PET neuroimaging applied to subjects with DS has the potential to (a) track the natural progression of brain pathology, including the earliest stages of amyloid accumulation, and (b) determine whether amyloid PET biomarkers predict the onset of dementia. In addition, the question that is still incompletely understood and relevant to both applications is the ability of amyloid PET to detect Aβ deposits in their earliest form.

Objective Impairments associated with attention-deficit/hyperactivity disorder (ADHD) and noncompliance are prevalent in children with autism spectrum disorder (ASD). However, ADHD response to stimulants is well below rates in typically developing children, with frequent side effects. Group studies of treatments for noncompliance are rare in ASD. We examined individual and combined-effectiveness of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance. Method In a 3-site, 10-week, double-blind, 2 × 2 trial of ATX and PT, 128 children (ages 5–14 years) with ASD and ADHD symptoms were randomized to ATX, ATX+PT, placebo+PT, or placebo. ATX was adjusted to optimal dose (capped at 1.8 mg/kg/day) over 6 weeks and maintained for 4 additional weeks. Nine PT sessions were provided. Primary outcome measures were the parent-rated DSM ADHD symptoms on the Swanson, Nolan and Pelham (SNAP) scale and Home Situations Questionnaire (HSQ). Results On the SNAP, ATX, ATX+PT and placebo+PT were each superior to placebo (effect sizes 0.57–0.98; p values of .0005, .0004, and .025, respectively). For noncompliance, ATX and ATX+PT were superior to placebo (effect sizes 0.47–0.64; p values .03 and .0028, respectively). ATX was associated with decreased appetite but was otherwise well tolerated. Conclusion Both ATX and PT resulted in significant improvement on ADHD symptoms, whereas ATX (both alone and combined with PT) was associated with significant decreases on measures of noncompliance. ATX appears to have a better side effects profile than psychostimulants in the population with ASD. Clinical Trial Registration Information Atomoxetine, Placebo and Parent Management Training in Autism; http://clinicaltrials.gov/; NCT00844753.

Frequent non-pathogenic genetic variants may act as moderators of phenotypic severity for complex disorders such as autism spectrum disorder (ASD). We previously identified polymorphisms affecting mRNA expression of candidate genes, including tryptophan hydroxylase 2 (TPH2), dopamine beta hydroxylase (DBH), and dopamine transporter (DAT, SLC6A3). We compare genotypes and (1) clinical response to atomoxetine, (2) scores from the Autism Diagnostic Interview-Revised (ADI-R), and (3) severity of Attention Deficit Hyperactivity Disorder (ADHD) symptoms in a cohort of patients with ASD from multiple study sites. There was no association between CYP2D6 metabolizer status and atomoxetine response. TPH2 rs7305115 genotype was associated with ADI-R Restrictive/Repetitive Behavior score (p = 0.03). DBH rs1611115 genotype was associated with ADI-R Social score (p = 0.002), and Restrictive/Repetitive Behavior score (p = 0.04). The DAT intron 8 5/6 repeat was associated with ADHD symptoms (ABC Hyperactivity p = 0.01 and SNAP ADHD p = 0.03), replicating a previous finding. We find associations between ASD phenotypes and regulatory variants in catecholamine biosynthesis genes. This work may help guide future genetics studies related to ASD.

The RUBI Autism Network has developed and tested a structured parent training manual for children with autism spectrum disorder (ASD) and disruptive behaviors. The manual is based on principles of applied behavior analysis and is designed for therapists to use with parents of children with ASD and co-occurring challenging behaviors, such as tantrums, noncompliance, difficulties with transitions, and aggression. A trained therapist utilizes the manual and parent workbook to guide the parent in applying techniques and tools to help manage the child’s challenging behaviors. The treatment includes 11 Core sessions, 7 Supplemental sessions, a home visit, and follow-up telephone booster sessions. Each of the sessions contains a therapist script, activity sheets, a parent handout, and treatment fidelity checklists. Additionally, accompanying each core session are video vignettes that the therapist uses to demonstrate concepts taught in the session. The videos include 30- to 60-second vignettes demonstrating common parenting mistakes as well as implementation (to varying degrees of success) of the strategies being taught. The treatment is designed to be delivered individually to parents in weekly outpatient visits. Parents are given homework assignments between sessions that focus on applying techniques to specific behaviors.

We thank Dr. Higdon et al. for their interest in our article on metformin and children with autism spectrum disorders (ASD) and for providing information about the MOBILITY study (a Patient-Centered Outcomes Research Institute (PCORI)-funded pragmatic clinical trial to examine the relative effectiveness of metformin plus healthy lifestyle instruction versus healthy lifestyle instruction alone).1 In our October 2017 article,2 we reported the results of a 16-week open-label extension study of a group of 61 children and adolescents with ASD prescribed second-generation antipsychotic medications (SGAs) who previously participated in a randomized controlled trial (RCT) of metformin for management of weight gain. Although Higdon et al. indicated that our study results were encouraging, they believed that the conclusion of the accompanying JAACAP editorial3 stating metformin be considered as an adjunct treatment for any child who is overweight and prescribed SGAs was premature. Instead, they recommended that the results of their current pragmatic trial for children with bipolar disorder (which includes some children with ASD and intellectual disability) would better provide information on relevant moderators and mediators of metformin's effects. Such information would be of use to clinicians in determining whether to prescribe metformin to their patients or to focus on lifestyle changes (or a combination of the 2).

This chapter provides the in-session activity sheets, homework data sheet, and parent handout for the Planned Ignoring Session. This module is about a particular type of consequence—planned ignoring—and includes the proper use of planned ignoring, possible challenges to its use, and the development of a planned ignoring program at home.

In this session, the parent will learn to increase the use of social reinforcement for appropriate behaviors during interactions with the child. This can involve “catching the child being good” throughout the day or during a more formal play time.

This chapter provides the in-session activity sheets, homework data sheet, and parent handout for the Daily Schedules Session. This session focuses on obtaining a daily schedule for the child and helping the parent identify ways to adapt the schedule to prevent behavior problems from occurring. This session also introduces the use of visual schedules. The clinician can focus on schedule changes, visual schedules, or both (doing both is recommended).

This session provides an overview of the basic principles of the behavioral approach, the ABC model, and the importance of assessment in deciding upon strategies to address challenging behavior.

This chapter provides the in-session activity sheets, homework data sheet, and parent handout for the Teaching Skills 2 Session. This session continues with teaching skills by reviewing a variety of prompts that can be used to enhance a child’s skill acquisition.

This chapter provides the in-session activity sheets, homework data sheet, and parent handout for the Generalization and Maintenance Session. This session reviews the concepts of generalization and maintenance. These strategies promote continuation of behavioral changes and the extension of learned behaviors from one context to another.

This chapter provides the in-session activity sheets, homework data sheet, and parent handout for the Prevention Strategies Session. This session provides information on antecedent management of behavior. The ABC data collected during the previous week and the ideas generated in the review of prevention strategies are used to develop approaches to preventing behavior problems.

This chapter provides the in-session activity sheets, homework data sheet, and parent handout for the Behavioral Principles Session. This session provides an overview of the basic principles of the behavioral approach, the ABC model, and the importance of assessment in deciding upon strategies to address challenging behavior.

This session has parents focus on the child’s appropriate behaviors, rather than behaviors they want to decrease or eliminate. Emphasis should be placed on daily living skills that are within the child’s capabilities but are not consistently performed independently. Parents will identify reinforcers for their child and learn to use them to increase target behaviors.

This chapter provides the in-session activity sheets, homework data sheet, and parent handout for the Functional Communication Training Session. Because challenging behaviors typically serve a function for the child, this session introduces the idea of teaching an alternative and more appropriate functional communication behavior to replace the inappropriate or undesirable behavior.

The RUBI Autism Network has developed and tested a structured parent training manual for children with autism spectrum disorder and disruptive behaviors. The manual is based on principles of applied behavior analysis and is designed for therapists to use with parents of children with autism spectrum disorder and co-occurring challenging behaviors, such as tantrums, noncompliance, difficulties with transitions, and aggression. A trained therapist utilizes the manual to guide the parent in applying techniques and tools to help manage the child’s challenging behaviors. The treatment includes 11 Core sessions, 7 Supplemental sessions, a home visit, and follow-up telephone booster sessions. Each of the sessions contains a therapist script, activity sheets, a parent handout, and treatment fidelity checklists. Additionally, accompanying each core session are video vignettes that the therapist uses to demonstrate concepts taught in the session. The videos include 30- to 60-second vignettes demonstrating common parenting mistakes as well as implementation (to varying degrees of success) of the strategies being taught. The treatment manual is designed to be delivered individually to parents in weekly outpatient visits. Parents are given homework assignments between sessions that focus on applying techniques to specific behaviors.

This chapter provides the in-session activity sheets, homework data sheet, and parent handout for the Compliance Training Session. This module provides instruction on the Four-Step Compliance Procedure, including how to reinforce compliance and how to manage episodes of noncompliance.

This chapter provides an introduction to autism spectrum disorder (ASD) and parent training in ASD. This is followed by an introduction to the development of the RUBI Parent Training program, including its theoretical foundation and empirical evidence supporting its use as a treatment for disruptive behaviors in youth with ASD. Appropriate clinical populations and therapist training procedures are also addressed.