Abstract The overarching goal of this R01 project (“A Cognitive Test Battery for Intellectual Disabilities”) is to develop and validate an assessment battery to measure cognitive outcomes of individuals with intellectual and developmental disability (IDD) in clinical trials. To achieve this goal, over the past 7 years we have been compiling data, making appropriate accommodations for this unique and challenging-to-test population, and carefully examining the psychometric properties (including feasibility, reliability, validity, and sensitivity to change) of the NIH Toolbox Cognitive Battery (NIHTB-CB), an iPad-based and norm-referenced set of tests measuring Fluid Reasoning (Processing Speed, Working Memory, Episodic Memory, Inhibitory Control and Attention, and Cognitive Flexibility) and Crystallized Language (Receptive Vocabulary and Reading) in children and youth with IDD, including those with fragile X syndrome (FXS), Down syndrome (DS), autism and idiopathic/other IDDs. The purpose of the present Administrative Supplement application is to request additional funds to extend data collection to older adults with IDD, including DS and FXS. Aging in IDDs is understudied, and older individuals are often excluded from research in part due to limitations in available assessment tools. The supplement will allow collection of NIHTB-CB data, standardized IQ and adaptive behavior data and measures from the ABC-Down Syndrome consortium harmonized core from 100 adult participants (50 with DS, 50 with FXS; ages 26 and up, stratified across young and older adult groups), as well as blood samples for biomarker characterization in collaboration with the ABC-DS group. Based upon the ABC- DC dementia assessment, we plan to include 20 with dementia to allow examination the potential sensitivity of the NIHTB-CB to dementia-related cognitive changes. Our extended data collection with adults will fall primarily within the scope of project Aims 1 and 3, which focus on optimization of the battery for lower functioning persons and sensitivity of the battery to developmental changes. In particular, we will examine the newly collected data from aging persons to determine whether modifications may be necessary, whether new tests may need to be developed, and whether it shows potential for detecting deterioration in cognition associated with aging or neurodegeneration, as in some participants with DS. As aging in DS is associated with high risk of early developing Alzheimer’s disease (AD), it is important to develop and validate cognitive tests that may be used to track the disease process and response to intervention. Cognition and neurodegeneration in older adults with FXS have been largely ignored, despite evidence of AD-related biomarker abnormalities and cognitive decline in some patients. The supplemental data collection from the FXS cohort will help to determine whether larger, more extensive longitudinal studies are justified to describe the natural history of this population and open the door for their participation in other research. The supplemental NIHTB-CB data collected from this aging group will provide critical preliminary information about its potential utility in future natural history or treatment studies.

Narrative This project will continue to advance a cognitive test battery for use as a set of outcome measures for clinical trials in intellectual and developmental disabilities (IDD), covering domains such as processing speed, memory, cognitive flexibility, attention, and language. The research will improve measurement sensitivity of the NIH Toolbox Cognitive Battery (NIHTB-CB) for lower functioning individuals, expand the scope of the battery to include early numerical and conceptual reasoning, and it will detail the developmental trajectories of these domains of function in children and youth with IDD. It will explore the feasibility of measuring cognition in older adults with IDD, in particular those with fragile X and Down syndromes who are at increased risk to develop dementia or other forms of cognitive deterioration with age. Finally, the ability of the NIHTB-CB to detect improvement related to treatment will be evaluated in a controlled trial of a medication known to improve attention and behavior in IDD.