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

Does subclinical inflammation contribute to impairment of function of knee joints in aged individuals? High prevalence of ultrasound inflammatory findings

Objectives. To investigate the prevalence of knee US findings of inflammation and structural damage in aged individuals (≥60 years) of a long-term population-based cohort and to correlate these findings with demographic, clinical and laboratory parameters. Methods. Cross-sectional clinical and US investigation of both knee joints during the 2010 follow-up of the prospective population-based Bruneck Study. Demographic variables, physical activity, comorbidities, medications, pain, and functional scales related to the knee joints were recorded. US-assessed parameters were synovial hypertrophy, power Doppler signal, joint effusion, cartilage abnormalities, osteophytes, enthesopathy and bursitis. Statistics included univariate and multivariate regression analysis. Results. A total of 488 subjects (mean age 72.5 years; 53.5% females, 46.5% males) were examined by clinical assessment, and 433 of these underwent US examination of both knees. Both inflammatory and structural abnormalities were found in 296 (68.8%) subjects. Inflammatory abnormalities were significantly associated with age in years, male gender, diabetes and the presence of knee joint symptoms. In the multivariate analysis, age, male gender and knee swelling emerged as independent predictors of inflammation [odds ratio (OR) (95% CI) = 1.06 (1.03, 1.09), 2.55 (1.55, 4.21) and 5.92 (1.99, 17.58), respectively]. Conclusion. The present study showed a high prevalence of US inflammatory abnormalities in the knee joints of a normal aged population. These data suggest a substantial contribution of inflammation in progressive impairment of joint function with age

Bridging the technological divide: Stigmas and challenges with technology in digital brain health studies of older adults

The COVID-19 pandemic has increased adoption of remote assessments in clinical research. However, longstanding stereotypes persist regarding older adults\u27 technology familiarity and their willingness to participate in technology-enabled remote studies. We examined the validity of these stereotypes using a novel technology familiarity assessment

Diabetes is an independent predictor for severe osteoarthritis: Results from a longitudinal cohort study

OBJECTIVE-To evaluate if type 2 diabetes is an independent risk predictor for severe oste-oarthritis (OA). RESEARCH DESIGN AND METHODS-Population-based cohort study with an age-and sex-stratified random sample of 927 men and women aged 40-80 years and followed over 20 years (1990-2010). RESULTS-Rates of arthroplasty (95% CI) were 17.7 (9.4-30.2) per 1,000 person-years in patients with type 2 diabetes and 5.3 (4.1-6.6) per 1,000 person-years in those without (P < 0.001). Type 2 diabetes emerged as an independent risk predictor for arthroplasty: hazard ratios (95% CI), 3.8 (2.1-6.8) (P < 0.001) in an unadjusted analysis and 2.1 (1.1-3.8) (P = 0.023) after adjustment for age, BMI, and other risk factors for OA. The probability of arthroplasty increased with disease duration of type 2 diabetes and applied to men and women, as well as subgroups according to age and BMI. Our findings were corroborated in cross-sectional evaluation by more severe clinical symptoms of OA and structural joint changes in subjects with type 2 diabetes compared with those without type 2 diabetes. CONCLUSIONS-Type 2 diabetes predicts the development of severe OA independent of age and BMI. Our findings strengthen the concept of a strong metabolic component in the pathogenesis of OA.© 2013 by the American Diabetes Association

Relationships between big-five personality factors and Alzheimer\u27s disease pathology in autosomal dominant Alzheimer\u27s disease

Introduction: Changes in personality characteristics are associated with the onset of symptoms in Alzheimer\u27s disease (AD) and may even precede clinical diagnosis. However, personality changes caused by disease progression can be difficult to separate from changes that occur with normal aging. The Dominantly Inherited Alzheimer Network (DIAN) provides a unique cohort in which to relate measures of personality traits to in vivo markers of disease in a much younger sample than in typical late onset AD. Methods: Personality traits measured with the International Personality Item Pool at baseline from DIAN participants were analyzed as a function of estimated years to onset of clinical symptoms and well-established AD biomarkers. Results: Both neuroticism and conscientiousness were correlated with years to symptom onset and markers of tau pathology in the cerebrospinal fluid. Self-reported conscientiousness and both neuroticism and conscientiousness ratings from a collateral source were correlated with longitudinal rates of cognitive decline such that participants who were rated as higher on neuroticism and lower on conscientiousness exhibited accelerated rates of cognitive decline. Discussion: Personality traits are correlated with the accumulation of AD pathology and time to symptom onset, suggesting that AD progression can influence an individual\u27s personality characteristics. Together these findings suggest that measuring neuroticism and conscientiousness may hold utility in tracking disease progression in AD

Comparison of plasma and CSF biomarkers in predicting cognitive decline

OBJECTIVES: Concentrations of amyloid-β peptides (Aβ42/Aβ40) and neurofilament light (NfL) can be measured in plasma or cerebrospinal fluid (CSF) and are associated with Alzheimer\u27s disease brain pathology and cognitive impairment. This study directly compared plasma and CSF measures of Aβ42/Aβ40 and NfL as predictors of cognitive decline. METHODS: Participants were 65 years or older and cognitively normal at baseline with at least one follow-up cognitive assessment. Analytes were measured with the following types of assays: plasma Aβ42/Aβ40, immunoprecipitation-mass spectrometry; plasma NfL, Simoa; CSF Aβ42/Aβ40, automated immunoassay; CSF NfL plate-based immunoassay. Mixed effects models evaluated the global cognitive composite score over a maximum of 6 years as predicted by the fluid biomarkers. RESULTS: Analyses included 371 cognitively normal participants, aged 72.7 ± 5.2 years (mean ± standard deviation) with an average length of follow-up of 3.9 ± 1.6 years. Standardized concentrations of biomarkers were associated with annualized cognitive change: plasma Aβ42/Aβ40, 0.014 standard deviations (95% confidence intervals 0.002 to 0.026); CSF Aβ42/Aβ40, 0.020 (0.008 to 0.032); plasma Nfl, -0.018 (-0.030 to -0.005); and CSF NfL, -0.024 (-0.036 to -0.012). Power analyses estimated that 266 individuals in each treatment arm would be needed to detect a 50% slowing of decline if identified by abnormal plasma measures versus 229 for CSF measures. INTERPRETATION: Both plasma and CSF measures of Aβ42/Aβ40 and NfL predicted cognitive decline. A clinical trial that enrolled individuals based on abnormal plasma Aβ42/Aβ40 and NfL levels would require only a marginally larger cohort than if CSF measures were used