Noelle E. Carlozzi

Neurocognitive Signs in Prodromal Huntington Disease

OBJECTIVE PREDICT-HD is a large-scale international study of people with the Huntington disease (HD) CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine the stage in the HD prodrome at which cognitive differences from CAG-normal controls can be reliably detected. METHOD For each of 738 HD CAG-expanded participants, we computed estimated years to clinical diagnosis and probability of diagnosis in 5 years based on age and CAG-repeat expansion number (Langbehn, Brinkman, Falush, Paulsen, & Hayden, 2004). We then stratified the sample into groups: NEAR, estimated to be ≤9 years; MID, between 9 and 15 years; and FAR, ≥15 years. The control sample included 168 CAG-normal participants. Nineteen cognitive tasks were used to assess attention, working memory, psychomotor functions, episodic memory, language, recognition of facial emotion, sensory-perceptual functions, and executive functions. RESULTS Compared with the controls, the NEAR group showed significantly poorer performance on nearly all of the cognitive tests and the MID group on about half of the cognitive tests (p = .05, Cohens d NEAR as large as -1.17, MID as large as -0.61). One test even revealed significantly poorer performance in the FAR group (Cohens d = -0.26). Individual tasks accounted for 0.2% to 9.7% of the variance in estimated proximity to diagnosis. Overall, the cognitive battery accounted for 34% of the variance; in comparison, the Unified Huntingtons Disease Rating Scale motor score accounted for 11.7%. CONCLUSIONS Neurocognitive tests are robust clinical indicators of the disease process prior to reaching criteria for motor diagnosis of HD.

Cognition assessment using the NIH Toolbox

Vision is a sensation that is created from complex processes and provides us with a representation of the world around us. There are many important aspects of vision, but visual acuity was judged to be the most appropriate vision assessment for the NIH Toolbox for Assessment of Neurological and Behavioral Function, both because of its central role in visual health and because acuity testing is common and relatively inexpensive to implement broadly. The impact of visual impairments on health-related quality of life also was viewed as important to assess, in order to gain a broad view of ones visual function. To test visual acuity, an easy-to-use software program was developed, based on the protocol used by the E-ETDRS. Children younger than 7 years were administered a version with only the letters H, O, T, and V. Reliability and validity of the Toolbox visual acuity test were very good. A 53-item vision-targeted, health-related quality of life survey was also developed.

Motor abnormalities in premanifest persons with Huntington's disease: the PREDICT-HD study.

The PREDICT‐HD study seeks to identify clinical and biological markers of Huntingtons disease in premanifest individuals who have undergone predictive genetic testing. We compared baseline motor data between gene‐expansion carriers (cases) and nongene‐expansion carriers (controls) using t‐tests and Chi‐square. Cases were categorized as near, mid, or far from diagnosis using a CAG‐based formula. Striatal volumes were calculated using volumetric magnetic resonance imaging measurements. Multiple linear regression associated total motor score, motor domains, and individual motor items with estimated diagnosis and striatal volumes. Elevated total motor scores at baseline were associated with higher genetic probability of disease diagnosis in the near future (partial R2 0.14, P < 0.0001) and smaller striatal volumes (partial R2 0.15, P < 0.0001). Nearly all motor domain scores showed greater abnormality with increasing proximity to diagnosis, although bradykinesia and chorea were most highly associated with diagnostic immediacy. Among individual motor items, worse scores on finger tapping, tandem gait, Luria, saccade initiation, and chorea show unique association with diagnosis probability. Even in this premanifest population, subtle motor abnormalities were associated with a higher probability of disease diagnosis and smaller striatal volumes. Longitudinal assessment will help inform whether motor items will be useful measures in preventive clinical trials.

Environmental Barriers and Supports to Everyday Participation: A Qualitative Insider Perspective From People With Disabilities

OBJECTIVE To describe environmental factors that influence participation of people with disabilities. DESIGN Constant comparative, qualitative analyses of transcripts from 36 focus groups across 5 research projects. SETTING Home, community, work, and social participation settings. PARTICIPANTS Community-dwelling people (N=201) with diverse disabilities (primarily spinal cord injury, traumatic brain injury, and stroke) from 8 states. INTERVENTIONS None. MAIN OUTCOME MEASURES Environmental barriers and supports to participation. RESULTS We developed a conceptual framework to describe how environmental factors influence the participation of people with disabilities, highlighting 8 domains of environmental facilitators and barriers (built, natural, assistive technology, transportation, information and technology access, social support and attitudes, systems and policies, economics) and a transactional model showing the influence of environmental factors on participation at the micro (individual), mesa (community), and macro (societal) levels. Focus group data validated some International Classification of Functioning, Disability and Health environmental categories while also bringing unique factors (eg, information and technology access, economic quality of life) to the fore. Data were used to construct items to enable people with disabilities to assess the impact of environmental factors on everyday participation from their firsthand experience. CONCLUSIONS Participants with disabilities voiced the need to evaluate the impact of the environment on their participation at the immediate, community, and societal levels. The results have implications for assessing environmental facilitators and barriers to participation within rehabilitation and community settings, evaluating outcomes of environmental interventions, and effecting system and policy changes to target environmental barriers that may result in societal participation disparities versus opportunities.

Cognitive domains that predict time to diagnosis in prodromal Huntington disease

Background Prodromal Huntingtons disease (prHD) is associated with a myriad of cognitive changes but the domains that best predict time to clinical diagnosis have not been studied. This is a notable gap because some domains may be more sensitive to cognitive decline, which would inform clinical trials. Objectives The present study sought to characterise cognitive domains underlying a large test battery and for the first time, evaluate their ability to predict time to diagnosis. Methods Participants included gene negative and gene positive prHD participants who were enrolled in the PREDICT-HD study. The CAG–age product (CAP) score was the measure of an individuals genetic signature. A factor analysis of 18 tests was performed to identify sets of measures or latent factors that elucidated core constructs of tests. Factor scores were then fit to a survival model to evaluate their ability to predict time to diagnosis. Results Six factors were identified: (1) speed/inhibition, (2) verbal working memory, (3) motor planning/speed, (4) attention–information integration, (5) sensory–perceptual processing and (6) verbal learning/memory. Factor scores were sensitive to worsening of cognitive functioning in prHD, typically more so than performances on individual tests comprising the factors. Only the motor planning/speed and sensory–perceptual processing factors predicted time to diagnosis, after controlling for CAP scores and motor symptoms. Conclusions The results suggest that motor planning/speed and sensory–perceptual processing are important markers of disease prognosis. The findings also have implications for using composite indices of cognition in preventive Huntingtons disease trials where they may be more sensitive than individual tests.

The Cognition Battery of the NIH Toolbox for Assessment of Neurological and Behavioral Function: Validation in an Adult Sample

This study introduces a special series on validity studies of the Cognition Battery (CB) from the U.S. National Institutes of Health Toolbox for the Assessment of Neurological and Behavioral Function (NIHTB) (Gershon, Wagster et al., 2013) in an adult sample. This first study in the series describes the sample, each of the seven instruments in the NIHTB-CB briefly, and the general approach to data analysis. Data are provided on test-retest reliability and practice effects, and raw scores (mean, standard deviation, range) are presented for each instrument and the gold standard instruments used to measure construct validity. Accompanying papers provide details on each instrument, including information about instrument development, psychometric properties, age and education effects on performance, and convergent and discriminant construct validity. One study in the series is devoted to a factor analysis of the NIHTB-CB in adults and another describes the psychometric properties of three composite scores derived from the individual measures representing fluid and crystallized abilities and their combination. The NIHTB-CB is designed to provide a brief, comprehensive, common set of measures to allow comparisons among disparate studies and to improve scientific communication.

Environmental factors item development for persons with stroke, traumatic brain injury, and spinal cord injury.

OBJECTIVES To describe methods used in operationalizing environmental factors; to describe the results of a research project to develop measures of environmental factors that affect participation; and to define an initial item set of facilitators and barriers to participation after stroke, traumatic brain injury, and spinal cord injury. DESIGN Instrument development included an extensive literature review, item classification and selection, item writing, and cognitive testing following the approach of the Patient-Reported Outcomes Measurement Information System. SETTING Community. PARTICIPANTS Content area and outcome measurement experts (n=10) contributed to instrument development; individuals (n=200) with the target conditions participated in focus groups and in cognitive testing (n=15). INTERVENTIONS None. MAIN OUTCOME MEASURES Environmental factor items were categorized in 6 domains: assistive technology; built and natural environment; social environment; services, systems, and policies; access to information and technology; and economic quality of life. RESULTS We binned 2273 items across the 6 domains, winnowed this pool to 291 items for cognitive testing, and recommended 274 items for pilot data collection. CONCLUSIONS Five of the 6 domains correspond closely to the International Classification of Functioning, Disability and Health taxonomy of environmental factors; the sixth domain, economic quality of life, reflects an important construct that reflects financial resources that affect participation. Testing with a new and larger sample is underway to evaluate reliability, validity, and sensitivity.

The Trail Making Test in prodromal Huntington disease: Contributions of disease progression to test performance

We examined the Trail Making Test (TMT) in a sample of 767 participants with prodromal Huntington disease (prodromal HD) and 217 healthy comparisons to determine the contributions of motor, psychiatric, and cognitive changes to TMT scores. Eight traditional and derived TMT scores were also evaluated for their ability to differentiate prodromal participants closer to estimated age of diagnosis from those farther away and prodromal individuals from healthy comparisons. Results indicate that motor signs only mildly affected Part A, and psychiatric symptoms did not affect either part. Tests of perceptual processing, visual scanning, and attention were primarily associated with Part A, and executive functioning (response inhibition, set-shifting), processing speed, and working memory were associated with Part B. Additionally, TMT scores differentiated between healthy comparisons and prodromal HD individuals as far as 9–15 years before estimated diagnosis. In participants manifesting prodromal motor signs and psychiatric symptoms, the TMT primarily measures cognition and is able to discriminate between groups based on health status and estimated time to diagnosis.

NIH toolbox cognition battery (CB): Introduction and pediatric data

This monograph presents the pediatric portion of the National Institutes of Health (NIH) Toolbox Cognition Battery (CB) of the NIH Toolbox for the Assessment of Neurological and Behavioral Function. The NIH Toolbox is an initiative of the Neuroscience Blueprint, a collaborative framework through which 16 NIH Institutes, Centers, and Offices jointly support neuroscience-related research, to accelerate discoveries and reduce the burden of nervous system disorders. The CB is one of four modules that measure cognitive, emotional, sensory, and motor health across the lifespan. The CB is unique in its continuity across childhood, adolescence, early adulthood, and old age, and in order to help create a common currency among disparate studies, it is also available at low cost to researchers for use in large-scale longitudinal and epidemiologic studies. This chapter describes the evolution of the CB; methods for selecting cognitive subdomains and instruments; the rationale for test design; and a validation study in children and adolescents, ages 3-15 years. Subsequent chapters feature detailed discussions of each test measure and its psychometric properties (Chapters 2-6), the factor structure of the test battery (Chapter 7), the effects of age and education on composite test scores (Chapter 8), and a final summary and discussion (Chapter 9). As the chapters in this monograph demonstrate, the CB has excellent psychometric properties, and the validation study provided evidence for the increasing differentiation of cognitive abilities with age.

TBI-QOL: Development and Calibration of Item Banks to Measure Patient Reported Outcomes Following Traumatic Brain Injury.

Objective:To use a patient-centered approach or participatory action research design combined with advanced psychometrics to develop a comprehensive patient-reported outcomes (PRO) measurement system specifically for individuals with traumatic brain injury (TBI). This TBI Quality-of-Life (TBI-QOL) measurement system expands the work of other large PRO measurement initiatives, that is, the Patient-Reported Outcomes Measurement Information System and the Neurology Quality-of-Life measurement initiative. Setting:Five TBI Model Systems centers across the United States. Participants:Adults with TBI. Design:Classical and modern test development methodologies were used. Qualitative input was obtained from individuals with TBI, TBI clinicians, and caregivers of individuals with TBI through multiple methods, including focus groups, individual interviews, patient consultation, and cognitive debriefing interviews. Item pools were field tested in a large multisite sample (n = 675) and calibrated using item response theory methods. Main Outcomes Measures:Twenty-two TBI-QOL item banks/scales. Results:The TBI-QOL consists of 20 independent calibrated item banks and 2 uncalibrated scales that measure physical, emotional, cognitive, and social aspects of health-related quality of life. Conclusions:The TBI-QOL measurement system has potential as a common data element in TBI research and to enhance collection of health-related quality-of-life and PRO data in rehabilitation research and clinical settings.