Changes in Cognitive Function After Kidney Transplantation: A Longitudinal Cohort Study.

RATIONALE & OBJECTIVE: Kidney disease negatively affects cognition. We assessed the effect of kidney transplantation (KT) on different cognitive domains. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We examined pre- versus post-KT cognition in patients waitlisted for KT at an academic center. PREDICTORS: Transplant status. We measured cognitive function before KT (n=101), 3 months after KT (n=78), and 1 year after KT (n = 83). OUTCOMES: Our primary outcome was change in cognitive function before versus after KT. We used standard neuropsychological tests to assess global cognition (Mini-Mental State Exam [MMSE]), episodic/declarative memory (Logical Memory), psychomotor speed/visuospatial function (Digit Symbol Substitution Test [DSST], Trail Making Test [TMT] A), working memory/attention (Digit Span), executive function (TMT B), and semantic memory/verbal fluency/language (Category Fluency). ANALYTICAL APPROACH: Using linear mixed model analysis, we evaluated the changes in neuropsychological test scores adjusted for age, sex, race, education, and number of assessments. RESULTS: Before KT, Logical Memory I and II, DSST, MMSE, Category Fluency (animal naming), and Digit Span backward scores were low compared with normative values from the National Alzheimer's Coordinating Center data. Logical Memory I and II scores improved after KT (pre- vs post-KT, estimated group difference [d]=3.3, P<0.001 for Logical Memory I; d=4.27, P<0.001 for Logical Memory II), such that post-KT scores were similar to normative values (post-KT vs normative values, d = -0.37, P=0.06 for Logical Memory I; d = -0.89, P=0.08 for Logical Memory II). Category Fluency (animal naming; d=2.4, P<0.001) and DSST (d=3.12, P=0.01) scores also improved with KT, but post-KT DSST scores remained lower than normative values (post-KT vs normative values, d = -5.17, P<0.001). MMSE, Digit Span, and TMT A and B scores did not change after KT. LIMITATIONS: Single-center study. CONCLUSIONS: Episodic and verbal declarative memory normalize after KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function show partial improvement. Cognitive impairment in kidney disease is therefore at least partly reversible with KT. PLAIN-LANGUAGE SUMMARY: Cognitive impairment in kidney disease affects self-esteem, vocational abilities, quality of life, health care costs, and mortality. It is not clear whether kidney transplantation (KT) improves cognition and whether the improvement is uniform across cognitive domains. The distinction between reversible and irreversible cognitive impairment has important implications in the clinical care of patients before and after KT. We assessed cognition before KT and 3 months and 12 months after KT and discovered that episodic and verbal declarative memory normalized with KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function also improved with KT but did not reach normal levels. Cognitive impairment in kidney disease is therefore at least partly reversible.

Stochastic curtailment tests for phase II trial with time-to-event outcome using the concept of relative time in the case of non-proportional hazards.

As part of the drug development process, interim analysis is frequently used to design efficient phase II clinical trials. A stochastic curtailment framework is often deployed wherein a decision to continue or curtail the trial is taken at each interim look based on the likelihood of observing a positive or negative treatment effect if the trial were to continue to its anticipated end. Thus, curtailment can take place due to evidence of early efficacy or futility. Traditionally, in the case of time-to-event endpoints, interim monitoring is conducted in a two-arm clinical trial using the log-rank test, often with the assumption of proportional hazards. However, when this is violated, the log-rank test may not be appropriate, resulting in loss of power and subsequently inaccurate sample sizes. In this paper, we propose stochastic curtailment methods for two-arm phase II trial with the flexibility to allow non-proportional hazards. The proposed methods are built utilizing the concept of relative time assuming that the survival times in the two treatment arms follow two different Weibull distributions. Three methods - conditional power, predictive power and Bayesian predictive probability - are discussed along with corresponding sample size calculations. The monitoring strategy is discussed with a real-life example.

Association between the Estimated Glomerular Filtration Rate and Brain Atrophy in Older Adults.

End-stage kidney disease has been associated with cognitive impairment and brain atrophy. It remains unclear if mild to moderate kidney dysfunction is associated with brain atrophy, especially in older adults. We used cross-sectional data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), an NIH-funded multicenter longitudinal cohort study, to better understand the association between estimated glomerular filtration rate (eGFR) and brain volumes. We included all ADNI participants with both baseline serum creatinine values and MRI brain volume assessments. We used multiple linear regression modeling to assess cross-sectional associations between eGFR and whole-brain gray matter, hippocampus, entorhinal, fusiform, and middle temporal brain volumes. Participants (n = 1,596) were 74 ± 7 years old with a mean eGFR of 69.4 ± 14.8 mL/min/1.73 m2; 53% had mild cognitive impairment, and 19% had dementia. Unadjusted analysis showed an association between lower eGFR and smaller brain volumes. After adjusting for age, sex, and education, there was no association between eGFR brain volumes (p > 0.05 for all). These results remained consistent after subgroup analysis by age stratification and baseline cognitive status. Age was a confounding variable in the unadjusted association between the eGFR and brain volumes. Thus, a mild to moderately reduced eGFR was not associated with brain atrophy in ADNI participants.

Mild Cognitive Impairment and Donepezil Impact Mitochondrial Respiratory Capacity in Skeletal Muscle.

Alzheimer's Disease (ad) associates with insulin resistance and low aerobic capacity, suggestive of impaired skeletal muscle mitochondrial function. However, this has not been directly measured in AD. This study ( n  = 50) compared muscle mitochondrial respiratory function and gene expression profiling in cognitively healthy older adults (CH; n = 24) to 26 individuals in the earliest phase of ad-related cognitive decline, mild cognitive impairment (MCI; n  = 11) or MCI taking the ad medication donepezil (MCI + med; n  = 15). Mitochondrial respiratory kinetics were measured in permeabilized muscle fibers from muscle biopsies of the vastus lateralis. Untreated MCI exhibited lower lipid-stimulated skeletal muscle mitochondrial respiration (State 3, ADP-stimulated) than both CH ( P = .043) and MCI + med (P = .007) groups. MCI also exhibited poorer mitochondrial coupling control compared to CH (P = .014). RNA sequencing of skeletal muscle revealed unique differences in mitochondrial function and metabolism genes based on both MCI status (CH vs MCI) and medication treatment (MCI vs MCI + med). MCI + med modified over 600 skeletal muscle genes compared to MCI suggesting donepezil powerfully impacts the transcriptional profile of muscle. Overall, skeletal muscle mitochondrial respiration is altered in untreated MCI but normalized in donepezil-treated MCI participants while leak control is impaired regardless of medication status. These results provide evidence that mitochondrial changes occur in the early stages of AD, but are influenced by a common ad medicine. Further study of mitochondrial bioenergetics and the influence of transcriptional regulation in early ad is warranted.

CONSENSUS: a Shiny application of dementia evaluation and reporting for the KU ADC longitudinal Clinical Cohort database.

BACKGROUND: The University of Kansas Alzheimer's Disease Center (KU ADC) maintains several large databases to track participant recruitment, enrollment, and capture various research-related activities. It is challenging to manage and coordinate all the research-related activities. One of the crucial activities involves generating a consensus diagnosis and communicating with participants and their primary care providers. PROCESS: To effectively manage the cohort, the KU ADC utilizes a combination of open-source electronic data capture (EDC) (i.e. REDCap), along with other homegrown data management and analytic systems developed using R-studio and Shiny. PROCESS EVALUATION: In this article, we describe the method and utility of the user-friendly dashboard that was developed for the rapid reporting of dementia evaluations which allows clinical researchers to summarize recruitment metrics, automatically generate letters to both participants and healthcare providers, which ultimately help optimize workflows. CONCLUSIONS: We believe this general framework would be beneficial to any institution that build reports and summarizing key metrics of their research from longitudinal databases.

The Influence of Religious Belief on Burnout in Medical Students.

OBJECTIVE: Approximately half of all U.S. medical students are experiencing burnout. A previous study has demonstrated that higher levels of spirituality are associated with less burnout in medical students, yet no studies have examined the relationship between religious affiliation and burnout in medical students. The purpose of this study is to determine if specific religious affiliation and level of religious involvement is associated with less burnout in medical students. METHODS: A cross-sectional online survey was sent to all students attending five different osteopathic and allopathic medical schools in Kansas and Missouri. It contained a validated burnout measure, an item to identify religious affiliation, and items to quantify religious involvement. RESULTS: A response rate of 11.5% (495/4,300) was obtained. An ANOVA showed religious affiliations and burnout scores did not have any statistically significant relationships (F = 0.762, P = 0.619). Additionally, identification as an active participant within a religious affiliation had a statistically significant effect on burnout scores (F = 7.793, P = 0.005). CONCLUSIONS: This is the first study within the U.S. to show that religious affiliation is not associated with medical student burnout and that medical students who consider themselves to be active participants of their religion may be at lower risk of developing burnout, regardless of the faith they practice.

Normalization of Cerebral Blood Flow, Neurochemicals, and White Matter Integrity after Kidney Transplantation.

BACKGROUND: CKD is associated with abnormalities in cerebral blood flow, cerebral neurochemical concentrations, and white matter integrity. Each of these is associated with adverse clinical consequences in the non-CKD population, which may explain the high prevalence of dementia and stroke in ESKD. Because cognition improves after kidney transplantation, comparing these brain abnormalities before and after kidney transplantation may identify potential reversibility in ESKD-associated brain abnormalities. METHODS: In this study of patients with ESKD and age-matched healthy controls, we used arterial spin labeling to assess the effects of kidney transplantation on cerebral blood flow and magnetic resonance spectroscopic imaging to measure cerebral neurochemical concentrations (N-acetylaspartate, choline, glutamate, glutamine, myo-inositol, and total creatine). We also assessed white matter integrity measured by fractional anisotropy (FA) and mean diffusivity (MD) with diffusion tensor imaging. We used a linear mixed model analysis to compare longitudinal, repeated brain magnetic resonance imaging measurements before, 3 months after, and 12 months after transplantation and compared these findings with those of healthy controls. RESULTS: Study participants included 29 patients with ESKD and 19 controls; 22 patients completed post-transplant magnetic resonance imaging. Cerebral blood flow, which was higher in patients pretransplant compared with controls (P=0.003), decreased post-transplant (P<0.001) to values in controls. Concentrations of neurochemicals choline and myo-inositol that were higher pretransplant compared with controls (P=0.001 and P<0.001, respectively) also normalized post-transplant (P<0.001 and P<0.001, respectively). FA increased (P=0.001) and MD decreased (P<0.001) post-transplant. CONCLUSIONS: Certain brain abnormalities in CKD are reversible and normalize with kidney transplantation. Further studies are needed to understand the mechanisms underlying these brain abnormalities and to explore interventions to mitigate them even in patients who cannot be transplanted. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Cognitive Impairment and Imaging Correlates in End Stage Renal Disease, NCT01883349.

Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts.

INTRODUCTION: Inherited mitochondrial DNA (mtDNA) variants may influence Alzheimer's disease (AD) risk. METHODS: We sequenced mtDNA from 146 AD and 265 cognitively normal (CN) subjects from the University of Kansas AD Center (KUADC) and assigned haplogroups. We further considered 244 AD and 242 CN AD Neuroimaging Initiative (ADNI) subjects with equivalent data. RESULTS: Without applying multiple comparisons corrections, KUADC haplogroup J AD and CN frequencies were 16.4% versus 7.6% (P = .007), and haplogroup K AD and CN frequencies were 4.8% versus 10.2% (P = .063). ADNI haplogroup J AD and CN frequencies were 10.7% versus 7.0% (P = .20), and haplogroup K frequencies were 4.9% versus 8.7% (P = .11). For the combined 390 AD and 507 CN cases haplogroup J frequencies were 12.8% versus 7.3% (P = .006), odds ratio (OR) = 1.87, and haplogroup K frequencies were 4.9% versus 9.5% (P = .010), OR = 0.49. Associations remained significant after adjusting for apolipoprotein E, age, and sex. CONCLUSION: This exploratory analysis suggests inherited mtDNA variants influence AD risk.

Assessing accuracy of Weibull shape parameter estimate from historical studies for subsequent sample size calculation in clinical trials with time-to-event outcome.

BACKGROUND: Recent developments in literature on sample size calculations for time-to-event outcomes involve assumption of Weibull distributed times. These methods require a point estimate of the Weibull shape parameter obtained from historical studies. However, very limited guidance exists in published literature to assess how reliable this point estimate is when it is obtained from published results of a historical study. METHODS: We conduct simulations to assess how accurate and reliable the point estimate of the Weibull shape parameter is when it is estimated from published results of median survival time and/or corresponding interquartile range. Accuracy of this estimate is assessed using the criteria of average relative bias, root mean square error, and coefficient of variation for various combinations of sample sizes and censoring rates. Sensitivity of these calculations is assessed first, by increasing the number of survival quantiles used to calculate accuracy, and second, by using the full Kaplan Meier (KM) curve from the historical study. RESULTS: Our simulations suggest that point estimate of the shape parameter is reasonably accurate when estimated from historical studies with sample size ≥ 50 with censoring rate approximately 20%. Knowledge of the median and inter-quartile range seems to be adequate for this purpose. For historical studies with small sample sizes or higher censoring rates, more information needs to be abstracted from the published KM curves to improve accuracy. CONCLUSIONS: We conclude that assessing the accuracy of Weibull shape parameter estimate is important before it can be used to conduct sample size calculations for a subsequent trial.