Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer\u27s disease

Introduction: Down syndrome (DS), a genetic variant of early onset Alzheimer\u27s disease (AD), lacks a suitable outcome measure for prevention trials targeting pre-dementia stages. Methods: We used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composites that were sensitive to change over time. We then conducted additional analyses to provide support for the utility of the composites. The composites were presented to an expert panel to determine the most optimal cognitive battery based on predetermined criteria. Results: There were common cognitive domains across site composites, which were sensitive to early decline. The final composite consisted of memory, language/executive functioning, selective attention, orientation, and praxis tests. Discussion: We have identified a composite that is sensitive to early decline and thus may have utility as an outcome measure in trials to prevent or delay symptoms of AD in DS

The Effect of Homonymy on Learning Correctly Articulated Versus Misarticulated Words

This is the author's accepted manuscript. The original publication is available at http://jslhr.pubs.asha.org/article.aspx?articleid=1795801Purpose The goal of the current study was to examine the effect of homonymy (learning a second meaning for a known word form vs. learning a novel meaning and novel word form) and articulation accuracy (IN vs. OUT sounds) on word learning by preschool children. An added goal was to determine whether word frequency altered the effect of homonymy on word learning. Method Twenty-nine 3- to 4-year-old children were taught homonyms and novel words. Stimuli further varied in whether homonymy was present in both the adult input and the child's output (as for IN sounds) versus present only in the child's output (as for OUT sounds). Results For IN sounds, children learned homonyms more rapidly than novel words. Moreover, the homonym advantage was modulated by word frequency, such that children learned a new meaning for a high-frequency word more accurately than they learned a new meaning for a low-frequency word. In contrast, for OUT sounds, there was no evidence that homonymy influenced learning. Conclusions Homonymy in the adult input facilitates word learning by preschool children, whereas homonymy in the child's output alone does not. This effect is captured in a usage-based model of phonology and the lexicon

Additive Effects of Item-Specific and Congruency Sequence Effects in the Vocal Stroop Task

There is a growing interest in assessing how cognitive processes fluidly adjust across trials within a task. Dynamic adjustments of control are typically measured using the congruency sequence effect (CSE), which refers to the reduction in interference following an incongruent trial, relative to a congruent trial. However, it is unclear if this effect stems from a general control mechanism or a distinct process tied to cross-trial reengagement of the task set. We examine the relationship of the CSE with another measure of control referred to as the item-specific proportion congruency effect (ISPC), the finding that frequently occurring congruent items exhibit greater interference than items that are often incongruent. If the two effects reflect the same control mechanism, one should find interactive effects of CSE and ISPC. We report results from three experiments utilizing a vocal Stroop task that manipulated these two effects while controlling for variables that are often confounded in the literature. Across three experiments, we observed large CSE and ISPC effects. Importantly, these effects were robustly additive with one another (Bayes Factor for the null approaching 9). This finding indicates that the CSE and ISPC arise from independent mechanisms and suggests the CSE in Stroop may reflect a more general response adjustment process that is not directly tied to trial-by-trial changes in attentional control

Two-period linear mixed effects models to analyze clinical trials with run-in data when the primary outcome is continuous: Applications to Alzheimer\u27s disease.

Introduction: Study outcomes can be measured repeatedly based on the clinical trial protocol before randomization during what is known as the run-in period. However, it has not been established how best to incorporate run-in data into the primary analysis of the trial. Methods: We proposed two-period (run-in period and randomization period) linear mixed effects models to simultaneously model the run-in data and the postrandomization data. Results: Compared with the traditional models, the two-period linear mixed effects models can increase the power up to 15% and yield similar power for both unequal randomization and equal randomization. Discussion: Given that analysis of run-in data using the two-period linear mixed effects models allows more participants (unequal randomization) to be on the active treatment with similar power to that of the equal-randomization trials, it may reduce the dropout by assigning more participants to the active treatment and thus improve the efficiency of AD clinical trials

Alzheimer disease cerebrospinal fluid biomarkers moderate baseline differences and predict longitudinal change in attentional control and episodic memory composites in the adult children study

OBJECTIVE: Cognitive measures that are sensitive to biological markers of Alzheimer disease (AD) pathology are needed in order to (a) facilitate preclinical staging, (b) identify individuals who are at the highest risk for developing clinical symptoms and (c) serve as endpoints for evaluating the efficacy of interventions. The present study assesses the utility of two cognitive composite scores of attentional control and episodic memory as markers for preclinical AD pathology in a group of cognitively normal older adults (N = 238), as part of the Adult Children Study. METHOD: All participants were given a baseline cognitive assessment and follow-up assessments every 3 years over an 8-year period, as well as a lumbar puncture within two years of the initial assessment to collect cerebrospinal fluid (CSF) and a PET-PIB scan for amyloid imaging. RESULTS: Results indicated that attentional control was correlated with levels of Aβ42 at the initial assessment whereas episodic memory was not. Longitudinally, individuals with high CSF tau exhibited a decline in both attention and episodic memory over the course of the study. CONCLUSION: These results indicate that measures of attentional control and episodic memory can be utilized to evaluate cognitive decline in preclinical AD and provide support that CSF tau may be a key mechanism driving longitudinal cognitive change

The relation between personality and biomarkers in sensitivity and conversion to Alzheimer-type dementia

OBJECTIVES: The present study explored relationships among personality, Alzheimer\u27s disease (AD) biomarkers, and dementia by addressing the following questions: (1) Does personality discriminate healthy aging and earliest detectable stage of AD? (2) Does personality predict conversion from healthy aging to early-stage AD? (3) Do AD biomarkers mediate any observed relationships between personality and dementia status/conversion? METHODS: Both self- and informant ratings of personality were obtained in a large well-characterized longitudinal sample of cognitively normal older adults (N = 436) and individuals with early-stage dementia (N = 74). Biomarkers included amyloid imaging, hippocampal volume, cerebral spinal fluid (CSF) Aβ42, and CSF tau. RESULTS: Higher neuroticism, lower conscientiousness, along with all four biomarkers strongly discriminated cognitively normal controls from early-stage AD individuals. The direct effects of neuroticism and conscientiousness were only mediated by hippocampal volume. Conscientiousness along with all biomarkers predicted conversion from healthy aging to early-stage AD; however, none of the biomarkers mediated the relationship between conscientiousness and conversion. Conscientiousness predicted conversion as strongly as the biomarkers, with the exception of hippocampal volume. CONCLUSIONS: Conscientiousness and to a lesser extent neuroticism serve as important independent behavioral markers for AD risk

Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease

BACKGROUND: Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a sampling of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers. METHODS: Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer\u27s Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness. RESULTS: Hazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs \u3e 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong\u27s test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = - 0.13, ps \u3c 0.02) and cortical thickness in cognitively normal participants (rs = 0.15-0.16, ps \u3c 0.007). CONCLUSIONS: Both test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset

Proportional constrained longitudinal data analysis models for clinical trials in sporadic Alzheimer\u27s disease

INTRODUCTION: Clinical trials for sporadic Alzheimer\u27s disease generally use mixed models for repeated measures (MMRM) or, to a lesser degree, constrained longitudinal data analysis models (cLDA) as the analysis model with time since baseline as a categorical variable. Inferences using MMRM/cLDA focus on the between-group contrast at the pre-determined, end-of-study assessments, thus are less efficient (eg, less power). METHODS: The proportional cLDA (PcLDA) and proportional MMRM (pMMRM) with time as a categorical variable are proposed to use all the post-baseline data without the linearity assumption on disease progression. RESULTS: Compared with the traditional cLDA/MMRM models, PcLDA or pMMRM lead to greater gain in power (up to 20% to 30%) while maintaining type I error control. DISCUSSION: The PcLDA framework offers a variety of possibilities to model longitudinal data such as proportional MMRM (pMMRM) and two-part pMMRM which can model heterogeneous cohorts more efficiently and model co-primary endpoints simultaneously