Biology subjects

Koscik, R. L.

Publications and source records attributed to Koscik, R. L..

7 recordsLinked to original sources

bioRxiv2018

Longitudinal plasma metabolomics of aging and sex

Understanding how metabolites are longitudinally influenced by age and sex could facilitate the identification of metabolomic profiles and trajectories that indicate disease risk. We investigated the metabolomics of age and sex using longitudinal plasma samples from the Wisconsin Registry for Alzheimers Prevention (WRAP), a cohort of participants who were dementia free at enrollment. Metabolomic profiles were quantified for 2,316 fasting plasma samples among 1,187 participants, each with up to three study visits. Of 1,097 metabolites tested, 608 (55.4%) were associated with age and 680 (62.0%) with sex after correcting for multiple testing. Approximately twice as many metabolites were associated with age in stratified analyses of women versus men, and 63 metabolite trajectories significantly differed by sex, most notably including sphingolipids, which tended to increase in women and decrease in men with age. Using genome-wide genotyping, we also report the heritabilities of metabolites investigated, which ranged dramatically (0.2-99.2%); however, the median heritability of 36.2% suggests that many metabolites are highly influenced by a complex combination of genomic and environmental influences. These findings offer a more profound description of the aging process and may inform many new hypotheses regarding the role metabolites play in healthy and accelerated aging.

molecular biology↗

bioRxiv2018

Metabolites associated with early cognitive changes implicated in Alzheimer’s disease

We investigated the metabolomics of early cognitive changes related to Alzheimers disease (AD) in order to better understand mechanisms that could contribute to early stages and progression of this disease. This investigation used longitudinal plasma samples from the Wisconsin Registry for Alzheimers Prevention (WRAP), a cohort of participants who were dementia free at enrollment and enriched with a parental history of AD. Metabolomic profiles were quantified for 2,338 fasting plasma samples among 1,206 participants, each with up to three study visits. Of 1,097 metabolites tested, levels of seven were associated with executive function trajectories, including an amino acid and three fatty acids, but none were associated with delayed recall trajectories. Our time-varying metabolomic results suggest potential mechanisms that could contribute to the earliest signs of cognitive decline. In particular, fatty acids may be associated with cognition in a manner that is more complex than previously suspected.

neuroscience↗

bioRxiv2017

Characterizing the effects of sex, APOE 4, and literacy on mid-life cognitive trajectories: Application of Information-Theoretic model-averaging and multi-model inference techniques to the Wisconsin Registry for Alzheimer’s Prevention Study

In this paper we apply Information-Theoretic (IT) model averaging to characterize a set of complex interactions in a longitudinal study on cognitive decline. Prior research has identified numerous genetic (including sex), education, health and lifestyle factors that predict abnormal cognitive decline.Traditional model selection approaches (e.g., backward or stepwise selection), attempt to find models that best fit the observed data; these techniques risk interpretations that only the selected predictors are important. In reality, several models may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates), and inference from a single model chosen after a selection procedure can lead to overly simplistic conclusions. Here we utilize longitudinal cognitive data from the Wisconsin Registry for Alzheimers Prevention to examine the effects of sex and the Apolipoprotein E (APOE) 4 allele (non-modifiable factors), and reading literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a model set with combinations of interactions among sex, APOE, literacy, and age. For a list-learning test, model-averaged results showed better performance for women vs men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less effect in this age range (~40-70). These results illustrate the utility of the IT approach and point to verbal ability as a potential modifier of decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work.

neuroscience↗

bioRxiv2017

Modifiable risk factors moderate the relationship between amyloid and cognition in midlife

Although evidence suggests a relationship between elevated beta-amyloid and cognitive decline, approximately 30% of older adults with positive markers of amyloid remain cognitively healthy. Our objective was to test if the presence of modifiable risk factors (i.e., central obesity, hypertension, and depressive symptoms) moderated the relationship between amyloid and longitudinal cognitive performance. Data were from 207 adults (140 females; age range=40-70) enriched for Alzheimers disease risk (73% parental history of Alzheimers disease) enrolled in the Wisconsin Registry for Alzheimers Prevention study. Participants completed at least two neuropsychological evaluations and one biomarker visit ([C11] Pittsburgh Compound B PET scan or lumbar puncture). Participants were characterized as high or low on amyloid using cutoffs developed for [C11] Pittsburgh Compound B-PET distribution volume ratio or CSF amyloid beta 1-42 values. Participants were also coded as high or low risk on obesity, hypertension, and depressive symptoms. Linear mixed effects regression models examined three-way interactions between modifiable risk factor status x amyloid group x age at each study visit on longitudinal Verbal Learning & Memory and Speed & Flexibility factor scores. Results indicated that the relationship between beta-amyloid and Verbal Learning & Memory decline was associated with hypertension status (Likelihood ratio test for significance of hypertension status age x amyloid status x visit age interaction term;{chi} 2 (1) = 5.28, p = .02). The relationship between beta-amyloid and Speed & Flexibility decline was associated with depression status (Likelihood ratio test for significance of amyloid status x depression status x visit age interaction term;{chi} 2 (1) = 7.10, p = .03). The presence of obesity did not significantly moderate the relationship between beta-amyloid status and cognitive performance, although the direction of relationship was similar to above relationships (Likelihood ratio test for significance of obesity status x amyloid status x visit age interaction term;{chi} 2 (1) = 1.52, p = .21). In this at-risk for Alzheimers disease cohort, the modifiable risk factors of hypertension and depression significantly moderated the relationship between beta-amyloid and cognitive decline. Identification and modification of these risk factors in late middle age may slow the effect of amyloid on the progression of cognitive symptoms.

neuroscience↗

bioRxiv2017

Longitudinal standards for mid-life cognitive performance: Identifying abnormal within-person changes in the Wisconsin Registry for Alzheimer’s Prevention

A major challenge in the field of cognitive aging is differentiating disease-related cognitive change that has not yet become overt impairment from the more gradual decline in performance expected with normal aging. Published normative reference values are nearly always for single time point performances rather than longitudinal change in performance. To gain insight into how we might tackle the problem of identifying worrisome trajectories, we borrow a method from anthropometry: the development of standards that are conditional on an individuals past measurements. We use quantile regression to create growth-curve-like models of performance on several common neuropsychological tests of memory and executive function while accounting for age, sex, education, estimated verbal ability, and past performance on the test, and then use these to estimate individuals percentile ranks. Choosing the 7th percentile as a threshold (corresponding to approximately 1.5 standard deviations below the expected mean), we then explore relationships between subthreshold performance, clinical outcomes, and subjective impairment. Participants whose performance fell below the 7th percentile were more likely to be given an abnormal research diagnosis at the current visit, but not at later visits. Performance below this threshold was also linked to subjective and informant reports of worsening memory function. We discuss potential uses of this method in theoretical and applied research and clinical settings.

neuroscience↗

bioRxiv2017

The Wisconsin Registry for Alzheimer’s Prevention: A Review of findings and current directions

The Wisconsin Registry for Alzheimers Prevention (WRAP) is a longitudinal observational cohort study enriched with persons with a parental history (PH) of probable Alzheimers Disease (AD) dementia. Since late 2001, WRAP has enrolled 1,561 people at a mean baseline age of 54. Participants return for a second visit four years after baseline and subsequent visits occur every two years. Eighty-one percent (1270) of participants remain active in the study at a current mean age of 64 and 9 years of follow-up. Serially assessed cognition, self-reported medical and lifestyle histories (e.g. diet, physical and cognitive activity, sleep, and mood), laboratory tests, genetics, and linked studies comprising molecular imaging, structural imaging and cerebrospinal fluid data, have yielded many important findings. In this cohort, PH of probable AD is associated with 46% APOE {varepsilon}4 positivity, more than twice the rate of 22% among persons without PH. Subclinical or worse cognitive decline relative to internal normative data has been observed in 17.6% of the cohort. Twenty-eight percent exhibit amyloid and/or tau positivity. Biomarker elevations, but not APOE or PH status, are associated with cognitive decline. Salutary health and lifestyle factors are associated with better cognition and brain structure, and lower AD pathophysiologic burden. Of paramount importance is establishing the amyloid and tau AD endophenotypes to which cognitive outcomes can be linked. Such data will provide new knowledge on the early temporal course of AD pathophysiology and inform the design of secondary prevention clinical trials.

neuroscience↗

bioRxiv2016

Temporal order of Alzheimer’s disease-related cognitive marker changes in BLSA and WRAP longitudinal studies

Investigation of the temporal trajectories of currently used neuropsychological tests is critical to identifying earliest changing measures on the path to dementia due to Alzheimers disease (AD). We used the Progression Score (PS) method to characterize the temporal trajectories of measures of verbal memory, executive function, attention, processing speed, language, and mental state using data spanning normal cognition, mild cognitive impairment (MCI), and AD from 1661 participants with a total of 7839 visits (age at last visit 77.6 SD 9.2) in the Baltimore Longitudinal Study of Aging and 1542 participants with a total of 4467 visits (age at last visit 59.9 SD 7.3) in the Wisconsin Registry for Alzheimers Prevention. This method aligns individuals in time based on the similarity of their longitudinal measurements to reveal temporal trajectories. As a validation of our methodology, we explored the associations between the individualized cognitive progression scores (Cog-PS) computed by our method and clinical diagnosis. Digit span tests were the first to show declines in both data sets, and were detected mainly among cognitively normal individuals. These were followed by tests of verbal memory, which were in turn followed by Trail Making Tests, Boston Naming Test, and Mini-Mental State Examination. Differences in Cog-PS across the clinical diagnosis groups were statistically significant, highlighting the potential use of Cog-PS as individualized indicators of disease progression. Identifying cognitive measures that are changing in preclinical AD can lead to the development of novel cognitive tests that are finely tuned to detecting earliest changes.\n\nABBREVIATIONS

neuroscience↗