Assessing amyloid PET positivity and cognitive function in Down syndrome to guide clinical trials targeting amyloid.

INTRODUCTION: Trisomy 21, or Down syndrome (DS), predisposes individuals to early-onset Alzheimer's disease (AD). While monoclonal antibodies (mAbs) targeting amyloid are approved for older AD patients, their efficacy in DS remains unexplored. This study examines amyloid positron emission tomography (PET) positivity (A+), memory function, and clinical status across ages in DS to guide mAb trial designs. METHODS: Cross-sectional data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) was analyzed. PET amyloid beta in Centiloids classified amyloid status using various cutoffs. Episodic memory was assessed using the modified Cued Recall Test, and clinical status was determined through consensus processes. RESULTS: Four hundred nine DS adults (mean age = 44.83 years) were evaluated. A+ rates increased with age, with mean amyloid load rising significantly. Memory decline and cognitive impairment are also correlated with age. DISCUSSION: These findings emphasize the necessity of tailoring mAb trials for DS, considering age-related AD characteristics. HIGHLIGHTS: There is rapid increase in prevalence of amyloid beta (Aß) positron emission tomography (PET) positivity in Down syndrome (DS) after the age of 40 years. Aß PET positivity thresholds have significant impact on prevalence rates in DS. There is a significant lag between Aß PET positivity and clinical symptom onset in DS.

Direct observation in a large-scale randomized trial of parent training in children with autism spectrum disorder and disruptive behavior.

A direct observation strategy (Standardized Observation Analogue Procedure, SOAP) was used in a large-scale randomized trial of parent training versus parent education in young children with autism spectrum disorder (ASD) and disruptive behavior. The 16-minute SOAP, modified from an earlier version of this same measure, included parentchild interaction to assess child behavior in a clinical laboratory setting. Despite study entry criteria for all child participants requiring moderate levels of disruptive behavior in this project, 126 of 168 children with complete SOAP data at baseline showed no disruptive behavior on this measure. Although the primary purpose of the study was to determine whether the SOAP could detect differences between the two conditions (i.e.,parent training (PT) and parent education (PE)), baseline observation data was not consistent with parent ratings at baseline or subsequent follow up visits, leaving little room to demonstrate improvement with this observation measure. This and the challenging, time-consuming and resource intensive effort involved in using such a measure in a large randomized scale trial, raises fundamental questions about the validity of the SOAP as an outcome measure in such a study. Further consideration related to the feasibility and practicality of using direct observation as a primary measure in larger scale efforts overall are also discussed.

Imaging neurodegeneration in Down syndrome: brain templates for amyloid burden and tissue segmentation.

The focus of Alzheimer's disease (AD) neuroimaging research has shifted towards an investigation of the earliest stages of AD pathogenesis, which manifests in every young adult with Down syndrome (DS; trisomy 21) resulting from a deterministic genetic predisposition to amyloid precursor protein overproduction. Due to morphological differences in brain structure in the DS population, special consideration must be given to processing pipelines and the use of normative atlases developed for the non-DS population. Further, the use of typical MRI to MRI template spatial normalization is less desirable in this cohort due to a greater presence of motion artefacts in MRI images. The diffuse nature of PiB uptake and comparatively lower spatial resolution of the PET image permits the purposing of this modality as a template for spatial normalization, which can substantially improve the robustness of this procedure in the cases of MRI images with motion. The aim of this work was to establish standardized methods for spatial normalization and tissue type segmentation using DS specific templates in order to perform voxel-wise analyses. A total of 72 adults with DS underwent [11C]PiB PET to assess brain amyloid burden and volumetric MRI imaging. A DS specific PiB template for spatial normalization and a set of DS specific prior probability templates were created with two-pass methods. With implementation of this DS specific PiB template, no participants were excluded due to poor spatial normalization, thus maximizing the sample size for PiB analyses in standardized space. In addition, difference images between prior probability templates created from the general population and the DS population reflected known morphological differences, particularly in the frontal cortex. In conclusion, DS specific templates that account for unique challenges improve spatial normalization and tissue type segmentation, and provide a framework for reliable voxel-wise analysis of AD biomarkers in this atypical population.

Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-ß Burden in Down Syndrome.

BACKGROUND: The Down syndrome (DS) population is genetically predisposed to amyloid-ß protein precursor overproduction and Alzheimer's disease (AD). OBJECTIVE: The temporal ordering and spatial association between amyloid-ß, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. METHODS: Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. RESULTS: Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. CONCLUSIONS: In adults with DS, early amyloid-ß accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-ß, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

Longitudinal changes in amyloid positron emission tomography and volumetric magnetic resonance imaging in the nondemented Down syndrome population.

INTRODUCTION: Down syndrome (DS) arises from a triplication of chromosome 21, causing overproduction of the amyloid precursor protein and predisposes individuals to early Alzheimer's disease (AD). METHODS: Fifty-two nondemented adults with DS underwent two cycles of carbon 11-labeled Pittsburgh compound B ([11C]PiB) and T1 weighted magnetic resonance imaging (MRI) scans 3.0 ± 0.6 years apart. Standard uptake value ratio (SUVR) images (50-70 minutes; cerebellar gray matter [GM]) and GM volumes were analyzed in standardized space (Montreal Neurological Institute space). RESULTS: 85% of PiB(-) subjects remained PiB(-), whereas 15% converted to PiB(+), predominantly in the striatum. None reverted from PiB(+) to PiB(-). Increases in SUVR were distributed globally, but there were no decreases in GM volume. The PiB positivity groups differed in the percent rate of change in SUVR [PiB(-): 0.5%/year, PiB converters: 4.9%/year, and PiB(+): 3.7%/year], but not in GM volume. DISCUSSION: Despite the characteristic striatum-first pattern, the global rate of amyloid accumulation differs by pre-existing amyloid burden and precedes atrophy or dementia in the DS population, similar to general AD progression.