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IMPORTANCE: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-β (Aβ). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aβ pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined. OBJECTIVE: To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aβ immunoglobulin G titers. DESIGN, SETTING, AND PARTICIPANTS: This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up. INTERVENTIONS: Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 μg or 1000 μg, or placebo. MAIN OUTCOMES AND MEASURES: Primary outcomes were measures of safety and tolerability as well as antibody titers. RESULTS: Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aβ immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 μg and 2 receiving 1000 μg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aβ1-40 and Aβ1-42 levels among individuals receiving ACI-24. CONCLUSIONS AND RELEVANCE: In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aβ antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02738450

Background: Pediatric brain tumor survivors can experience detrimental effects from radiation treatment. This cross-sectional study examined psychosocial and executive functioning in pediatric patients treated with proton radiation (PRT). Procedure: Parents of 187 brain tumor survivors completed standardized scales ≥1 year after PRT. One-way analysis of variance, Pearson correlation, and chi-square analysis were used to determine the impact of demographic, diagnostic or treatment-related characteristics. One-sample t-tests compared mean scores with published normative means. Rates of impairment (T-score >65) were calculated. Results: Mean age at PRT (baseline) was 8.49 years; mean follow-up interval 3.84 years. Approximately one-third (36.9%) received craniospinal irradiation (CSI). All mean T-scores for psychosocial and executive functioning were within the normal range. Younger age at baseline correlated with more behavior problems; older age with more problems with adaptive skills. Baseline age was not correlated with executive functioning. Follow-up interval and radiation field (CSI; focal) were not related to psychosocial or executive problems. Significantly elevated mean T-scores were in withdrawal ( pppConclusions: Psychosocial and executive functioning was within the normal range, on average, at follow-up. However, elevated impairment rates were observed in specific aspects of functioning (e.g., withdrawal, metacognitive executive functioning). Targeted screening and proactive intervention are needed.

Background: Pediatric brain tumor survivors can experience detrimental effects from radiation treatment. Proton radiation therapy (PRT), which enables better targeting of radiation to tumors, may result in fewer sequelae. This follow-up cross-sectional study examined psychosocial and executive functioning in children and young adults treated with PRT. Procedure: Psychosocial and executive functioning was assessed by standardized parent rating scales for 187 patients. The sample was divided by age at baseline (Results: Mean age was 8.49 years at baseline; mean follow-up interval was 3.84 years. All mean scores were within the normal range and within normative expectation. Younger CSI group had significantly more problem behaviors and lower adaptive skills compared to older CSI or focal groups; however, no significant differences were found between younger PRT groups. There were no significant differences in executive functioning between the four age-by-PRT-field groups. Rates of impairment exceeded expected rates in social withdrawal, somatic concerns, activities of daily living, and metacognitive executive functioning. Age group was not significantly related to impairment rates, although the younger group had more problems with withdrawal, anxiety, activities of daily living, and executive functioning with relatively higher anxiety and withdrawal in the younger CSI group. Conclusions: Psychosocial and executive functioning was within the normal range at follow-up. Younger patients, particularly those treated with CSI, appeared more vulnerable. Screening and proactive intervention are needed to support psychosocial well-being and executive functions.

The development of valid methods to diagnose prodromal Alzheimer's disease (AD) in adults with Down syndrome (DS) is one of the many goals of the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS).The diagnostic utility of a modified Cued Recall Test (mCRT) was evaluated in 332 adults with DS ranging from 25 to 81 years of age. Total recall was selected a priori, as the primary indicator of performance. Multiple regression and receiver-operating characteristic (ROC) analyses were used to compare diagnostic groups.Performance on the mCRT, as indicated by the total recall score, was highly sensitive to differences between diagnostic groups. ROC areas under the curve (AUCs) ranging from 0.843 to 0.955, were observed.The mCRT has strong empirical support for its use in clinical settings, as a valuable tool in studies targeting biomarkers of AD, and as a potential outcome measure in clinical trials targeting AD in this high-risk population.

Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p0·0001) and in people with Down syndrome (n=32; r=-0·801; p0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome.Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome.The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

Research suggests a link between Alzheimer's Disease in Down Syndrome (DS) and the overproduction of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creating a brain atlas is to segment a participant's structural Magnetic Resonance Imaging (MRI) scan. Acquiring an MRI is often challenging in intellectually-imparied populations because of contraindications or data exclusion due to significant motion artifacts or incomplete sequences related to general discomfort. When an MRI cannot be acquired, it is typically replaced with a standardized brain atlas derived from neurotypical populations (i.e. healthy individuals without DS) which may be inappropriate for use in DS. In this project, we create a series of disease and diagnosis-specific (cognitively stable (CS-DS), mild cognitive impairment (MCI-DS), and dementia (DEM-DS)) probabilistic group atlases of participants with DS and evaluate their accuracy of quantifying regional amyloid load compared to the individually-based MRI segmentations. Further, we compare the diagnostic-specific atlases with a probabilistic atlas constructed from similar-aged cognitively-stable neurotypical participants. We hypothesized that regional PET signals will best match the individually-based MRI segmentations by using DS group atlases that aligns with a participant's disorder and disease status (e.g. DS and MCI-DS). Our results vary by brain region but generally show that using a disorder-specific atlas in DS better matches the individually-based MRI segmentations than using an atlas constructed from cognitively-stable neurotypical participants. We found no additional benefit of using diagnose-specific atlases matching disease status. All atlases are made publicly available for the research community.HighlightDown syndrome (DS) joint-label-fusion atlases provide accurate positron emission tomography (PET) amyloid measurements.A disorder-specific DS atlas is better than a neurotypical atlas for PET quantification.It is not necessary to use a disease-state-specific atlas for quantification in aged DS.Dorsal striatum results vary, possibly due to this region and dementia progression.

In a study of 66 in-utero drug exposed (IUDE) infants, we evaluated infant cognitive status with the Mental Scale of the Bayley Scales of Infant Development (Second Edition), caregiver-infant interaction using the Nursing Child Assessment Feeding Scale (NCAFS), and caregiver cognitive functioning (IQ) to determine which caregiver variables were associated with infant cognitive status. Mean score on the Bayley Mental Development Index was 87.4 (SD, 10.8). Almost half (44%) of the caregiver-infant dyads were categorized as “At Risk” for poor caregiver-infant interaction based on scores of the NCAFS. Mean caregiver IQ was 76.9. Logistic regression analysis indicated that care-giver IQ was the only statistically significant coefficient in the model predicting poor infant cognitive status (p = .009); however, caregiver-infant interaction showed a moderate effect (p = .08).

Shared decision making in health care is a mutual partnership between the health care provider and the patient. Traditionally, children have had little involvement during their medical care visits or in decisions regarding their health care. Shared decision making in children with asthma may enhance their self-confidence as well as improve their self-management skills. Allowing the child to participate during the visit requires assessing the child’s competence at different ages and abilities. Specific communication techniques to use with children during medical encounters include visual aids, turn-taking, clarifying communication, and role modeling. Providers additionally can offer strategies to parents on how to provide general information about asthma and treatments based on the child’s questions and interest. The goal for school age children with asthma is to change dyadic interactions between the provider and parent into triadic interactions to improve the child’s asthma management.