Impairment of Cognitive Function Increases Mortality Risk in Relation to Cardiac Sympathetic Denervation and Renal Dysfunction in Patients With Systolic Heart Failure.

BACKGROUND: In contrast to the well-known prognostic values of the cardiorenal linkage, it remains unclear whether impaired cognitive function affects cardiac prognosis in relation to cardiac sympathetic innervation and renal function in patients with heart failure (HF). METHODS AND RESULTS: A total of 433 consecutive HF patients with left ventricular ejection fraction (LVEF) <50% underwent the Mini-Mental State Examination (MMSE) and a neuropsychological test for screening of cognition impairment or subclinical dementia. Following metaiodobenzylguanidine (MIBG) scintigraphy, patient outcomes with a primary endpoint of lethal cardiac events (CEs) were evaluated for a mean period of 14.8 months. CEs were documented in 84 HF patients during follow-up. MMSE score, estimated glomerular filtration rate (eGFR) and standardized heart-to-mediastinum ratio of MIBG activity (sHMR) were significantly reduced in patients with CEs compared with patients without CEs. Furthermore, overall multivariate analysis revealed that these parameters were significant independent determinants of CEs. The cutoff values of MMSE score (<26), sHMR (<1.80) and eGFR (<47.0 mL/min/1.73 m2) determined by receiver operating characteristic (ROC) analysis successfully differentiated HF patients at more increased risk for CEs from other HF patients. CONCLUSIONS: Impairment of cognitive function is not only independently related to but also synergistically increases cardiac mortality risk in association with cardiac sympathetic function and renal function in patients with HF.

Frailty, but not cognitive impairment, improves mortality risk prediction among those with chronic kidney disease-a nationally representative study.

BACKGROUND: Though older adults with chronic kidney disease (CKD) have a greater mortality risk than those without CKD, traditional risk factors poorly predict mortality in this population. Therefore, we tested our hypothesis that two common geriatric risk factors, frailty and cognitive impairment, and their co-occurrence, might improve mortality risk prediction in CKD. METHODS: Among participants aged ≥ 60 years from National Health and Nutrition Examination Survey (2011-2014), we quantified associations between frailty (physical frailty phenotype) and global/domain-specific cognitive function (immediate-recall [CERAD-WL], delayed-recall [CERAD-DL], verbal fluency [AF], executive function/processing speed [DSST], and global [standardized-average of 4 domain-specific tests]) using linear regression, and tested whether associations differed by CKD using a Wald test. We then tested whether frailty, global cognitive impairment (1.5SD below the mean), or their combination improved prediction of mortality (Cox models, c-statistics) compared to base models (likelihood-ratios) among those with and without CKD. RESULTS: Among 3,211 participants, 1.4% were cognitively impaired, and 10.0% were frail; frailty and cognitive impairment co-occurrence was greater among those with CKD versus those without (1.2%vs.0.1%). Frailty was associated with worse global cognitive function (Cohen's d = -0.26SD,95%CI -0.36,-0.17), and worse cognitive function across all domains; these associations did not differ by CKD (pinteractions > 0.05). Mortality risk prediction improved only among those with CKD when accounting for frailty (p[likelihood ratio test] < 0.001) but not cognitive impairment. CONCLUSIONS: Frailty is associated with worse cognitive function regardless of CKD status. While CKD and frailty improved mortality prediction, cognitive impairment did not. Risk prediction tools should incorporate frailty to improve mortality prediction among those with CKD.

The impact of postoperative cognitive impairment on mid-term survival after heart transplantation.

BACKGROUND: Heart transplantation is the definitive therapy for patients with end-stage heart failure. Antecedent studies reported that a substantial proportion of heart transplant recipients developed postoperative cognitive impairment in the long term. However, no studies have explored the association between postoperative cognitive impairment and survival after heart transplantation. METHODS: The data of 43 adult patients who underwent heart transplantation were consecutively enrolled and assessed using the MMSE and MoCA neuropsychological tests. Kaplan-Meier curves and Cox proportional hazards models were used for survival analyses. Primary component analysis was performed to integrate MoCA subtests into the "Attention factor," "Naming factor," and "Orientation factor." RESULTS: About 30% of the patients were diagnosed with short-term postoperative cognitive impairment. The impairment group was older and had lower baseline cognitive performances, larger LV diameter, worse MMSE decline and higher ratio of significant MoCA decline. Postoperative cognitive impairment was significantly associated with worse survival (P = .028). Multivariate Cox analyses showed that higher postoperative MoCA score was significantly associated with lower mid-term post-transplant mortality (HR = .744 [.584, .949], P = .017), in which "Attention factor" contributed to this association most (HR = .345 [.123, .970], P = .044) rather than "Naming factor" or "Orientation factor." Notably, preoperative cognitive impairment was closely related with postoperative cognitive impairment and also indicated the worse post-transplant survival (P = .015). CONCLUSION: Postoperative as well as preoperative cognitive impairments were associated with a worse mid-term survival after heart transplantation, indicating that neuropsychological assessments before and after heart transplantation should be routinely performed for heart transplant recipients for better risk stratification.

Cognitive Impairment after Lacunar Stroke and the Risk of Recurrent Stroke and Death.

INTRODUCTION: Patients with poststroke cognitive impairment appear to be at higher risk of recurrent stroke and death. However, whether cognitive impairment after lacunar stroke is associated with recurrent stroke and death remains unclear. We assessed whether global or domain-specific cognitive impairment after lacunar stroke is associated with recurrent stroke and death. METHODS: We considered patients from the Secondary Prevention of Small Subcortical Strokes (SPS3) trial with a baseline cognitive exam administered in English by certified SPS3 personnel, 14-180 days after qualifying lacunar stroke. We considered a baseline score of ≤86 on the Cognitive Assessment Screening Instrument to indicate global cognitive impairment, <10 on the Clock Drawing on Command test to indicate executive function impairment, and domain-specific summary scores in the lowest quartile to indicate memory and nonmemory impairment. We used Cox proportional hazards models to estimate the association between poststroke cognitive impairment and subsequent risk of recurrent stroke and death. RESULTS: The study included 1,528 participants with a median enrollment time of 62 days after qualifying stroke. During a mean follow-up of 3.9 years, 11.4% of participants had recurrent stroke and 8.2% died. In the fully adjusted models, memory impairment was independently associated with an increased risk of recurrent stroke (hazard ratio, 1.48; 95% confidence interval [95% CI]: 1.04-2.09) and death (hazard ratio, 1.87; 95% CI: 1.25-2.79). Global impairment (hazard ratio, 1.66; 95% CI: 1.06-2.59) and nonmemory impairment (hazard ratio, 1.74; 95% CI: 1.14-2.67) were associated with an increased risk of death. DISCUSSION/CONCLUSION: After lacunar stroke, memory impairment was an independent predictor of recurrent stroke and death, while global and nonmemory impairment were associated with death. Cognitive screening in lacunar stroke may help identify populations at higher risk of recurrent stroke and death.

Correlates of cognitive impairment in adult cancer survivors who have received chemotherapy and report cognitive problems.

OBJECTIVE: Cognitive impairment negatively affects some cancer survivors who have completed chemotherapy; however, factors underlying this cognitive impairment remain poorly understood. We aimed to investigate (1) the relative importance of demographics, medical, and psychological characteristics associated with cognitive impairment and (2) the specific variables associated with cognitive impairment in adult cancer survivors who completed adjuvant chemotherapy. METHODS: We performed post hoc analyses of baseline data from early-stage cancer survivors with cognitive complaints who received adjuvant chemotherapy 0.5-5 years earlier and volunteered for a trial designed to improve cognition. The primary outcome of self-reported cognitive impairment was measured using a questionnaire; secondary outcome of objective cognitive impairment was measured using a computerized neuropsychological test battery. Hierarchical linear regression determined the relative importance of demographics, medical, and psychological characteristics in associations with both self-reported and objective cognitive impairment. RESULTS: The sample was 95% female and 89% breast cancer patients. The final model accounted for 33% of variation in self-reported cognitive impairment (n = 212, demographics 5%, medical 3%, and psychological 25%), with fatigue and stress as significant individual correlates (p values ≤ 0.0001). For the secondary analysis, the final model accounted for 19% of variation in objective cognitive impairment (n = 206, demographics 10%, medical 5%, and psychological 4%), with age, smoking history, and number of chemotherapy cycles as significant individual correlates. CONCLUSION: We found that psychological characteristics are more important than demographic and medical characteristics in self-reported cognitive impairment, whereas other characteristics are more important in objective cognitive impairment. This suggests clinicians should investigate possible psychological problems in cancer survivors who self-report cognitive impairment.

Cognitive Function, Access to Kidney Transplantation, and Waitlist Mortality Among Kidney Transplant Candidates With or Without Diabetes.

RATIONALE & OBJECTIVE: Intact cognition is generally a prerequisite for navigating through and completing evaluation for kidney transplantation. Despite kidney transplantation being contraindicated for those with severe dementia, screening for more mild forms of cognitive impairment before referral is rare. Candidates may have unrecognized cognitive impairment, which may prolong evaluation, elevate mortality risk, and hinder access to kidney transplantation. We estimated the burden of cognitive impairment and its association with access to kidney transplantation and waitlist mortality. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,630 participants (January 2009 to June 2018) with cognitive function measured (by the Modified Mini-Mental State Examination [3MS]) at kidney transplantation evaluation at 1 of 2 transplantation centers. PREDICTORS: Cognitive impairment (3MS score<80). OUTCOMES: Listing, waitlist mortality, and kidney transplantation. ANALYTICAL APPROACH: We estimated the adjusted chance of listing (Cox regression), risk for waitlist mortality (competing-risks regression), and kidney transplantation rate (Poisson regression) by cognitive impairment. Given potential differences in cause of cognitive impairment among those with and without diabetes, we tested whether these associations differed by diabetes status using a Wald test. RESULTS: At evaluation, 6.4% of participants had cognitive impairment, which was independently associated with 25% lower chance of listing (adjusted HR, 0.75; 95% CI, 0.61-0.91); this association did not differ by diabetes status (Pinteraction=0.07). There was a nominal difference by diabetes status for the association between cognitive impairment and kidney transplantation rate (Pinteraction=0.05), while the association between cognitive impairment and waitlist mortality differed by diabetes status kidney transplantation rates (Pinteraction=0.02). Among candidates without diabetes, those with cognitive impairment were at 2.47 (95% CI, 1.31-4.66) times greater risk for waitlist mortality; cognitive impairment was not associated with this outcome among candidates with diabetes. LIMITATIONS: Single measure of cognitive impairment. CONCLUSIONS: Cognitive impairment is associated with a lower chance of being placed on the waitlist, and among patients without diabetes, with increased mortality on the waitlist. Future studies should investigate whether implementation of screening for cognitive impairment improves these outcomes.

Cognitive impairment, endothelial biomarkers and mortality in maintenance haemodialysis patients: a prospective cohort study.

BACKGROUND: Haemodialysis (HD) patients have a high prevalence of cardiovascular disease risk factors as well as cognitive impairment. The objective of the present study was to evaluate the interrelationship between cognitive impairment, endothelium-related biomarkers and cardiovascular/non-cardiovascular mortality. METHODS: A total of 216 outpatients were recruited from three centres in a dialysis network in Brazil between June 2016 and June 2019. Sociodemographic and clinical data were obtained by applying a patient questionnaire, reviewing medical records data and conducting patient interviews. Cognitive function was assessed using the Cambridge Cognitive Examination. Plasma endothelium-related biomarkers [syndecan-1, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1) and angiopoietin-2 (AGPT2)] were measured. Patients were followed for 30 months. Cox proportional hazards regression models were used to assess the associations of the cognitive function scores and each endothelium-related biomarker with cardiovascular/non-cardiovascular mortality. RESULTS: Cognitive function was associated with cardiovascular mortality {each standard deviation [SD] better cognitive score was associated with a 69% lower risk for cardiovascular mortality [hazard ratio (HR) 0.31 [95% confidence interval (CI) 0.17-0.58]} but not with non-cardiovascular mortality. Moreover, cognitive function was also correlated with all endothelial-related biomarkers, except VCAM-1. ICAM-1, AGPT2 and syndecan-1 were also associated with cardiovascular mortality. The association between cognitive function and cardiovascular mortality remained significant with no HR value attenuation [fully adjusted HR 0.32 (95% CI 0.16-0.59)] after individually including each endothelial-related biomarker in the Cox model. CONCLUSIONS: In conclusion, cognitive impairment was associated with several endothelium-related biomarkers. Moreover, cognitive impairment was associated with cardiovascular mortality but not with non-cardiovascular mortality, and the association between cognitive impairment and cardiovascular mortality in HD patients was not explained by any of the endothelial-related biomarkers.

Cognitive impairment three months after surgery is an independent predictor of survival time in glioblastoma patients.

PURPOSE: Cognitive functioning is increasingly investigated for its prognostic value in glioblastoma (GBM) patients, but the association of cognitive status during early adjuvant treatment with survival time is unclear. The aim of this study was to determine whether cognitive performance three months after surgical resection predicted survival time, while using a clinically intuitive time ratio (TR) statistic. METHODS: Newly diagnosed patients with GBM undergoing resection between November 2010 and February 2018 completed computerized cognitive assessment 3 months after surgery with the CNS Vital Signs battery (8 measures). The association of cognitive performance (continuous Z scores and dichotomous impairment status; impaired vs. unimpaired) with survival time was assessed with multivariate Accelerated Failure Time (AFT) models that also included clinical prognostic factors and covariates related to cognitive performances. RESULTS: 114 patients were included in the analyses (median survival time 16.4 months). Of the clinical factors, postoperative Karnofsky Performance Status (TR 1.51), surgical (TR 2.20) and non-surgical (TR 1.94) salvage treatment, and pre-surgical tumor volume (cm3, TR 1.003) were significant independent predictors of survival time. Independently of the base model factors and covariates, impairment on Stroop test I and Stroop test III estimated 23% and 26% reduction of survival time (TR 0.77, TR 0.74) respectively, as compared to unimpaired performance. CONCLUSION: These findings suggest that impaired performances on tests of executive control and processing speed in the early phase of adjuvant treatment can reflect a worse prognostic outlook rather than an early treatment effect, and their assessment might allow for early refinement of current prognostic stratification.

Association of cognitive impairment and elderly mortality: differences between two cohorts ascertained 6-years apart in China.

BACKGROUND: Cognitive impairment is a major contributor to mortality among the elderly. However, the relationship between cognitive impairment evaluated by educational levels and mortality and the trend between cognitive impairment and mortality with time are unclear. We aim to evaluate the differences in associations of cognitive impairment, taking the stratification by educational levels into account, with all-cause mortality and further explore the relationship of cognitive impairment with mortality in different age and sex groups in two cohorts ascertained 6 years apart in China. METHODS: A total of 13,906 and 13,873 Chinese elderly aged 65 years and older were included in the 2002-2008 and 2008-2014 cohorts from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Mortality data was ascertained from interviews with family members or relatives of participants. Cognitive function, evaluated by the Mini-Mental State Examination (MMSE), were defined by different cut-offs taking educational background into account. Cox models were used to explore the relationship of cognitive impairment with mortality. RESULTS: For the 2002-2008 and 2008-2014 cohorts, 55,277 and 53,267 person-years were followed up, and the mean (SD) age were 86.5 (11.6) and 87.2 (11.3) years, respectively. Compared to normal cognition, cognitive impairment was independently associated with higher mortality risk after controlling for potential confounders, with hazard ratios (HRs) of 1.32 (95% confidence interval [CI], 1.25-1.39) in 2002-2008 cohort and 1.26 (95% CI, 1.19-1.32) in 2008-2014 cohort, stratified by educational levels. The trend of cognitive impairment with all-cause mortality risk decreased from 2002 to 2008 to 2008-2014 cohort, while no significant interaction of cognitive impairment with cohort for all-cause mortality was observed. The associations of cognitive impairment and mortality were decreased with age in the two cohorts. CONCLUSIONS: Cognitive impairment evaluated by different cut-offs were associated with increased risk of mortality, especially among those aged 65-79 years in the two cohorts; this advocates that periodic screening for cognitive impairment among the elderly is warranted.

Disability trajectories and mortality in older adults with different cognitive and physical profiles.

BACKGROUND: Cognitive and physical deficits independently raise the risk for negative events in older adults. Less is known about whether their co-occurrence constitutes a distinct risk profile. This study quantifies the association between cognitive impairment, no dementia (CIND), slow walking speed (WS) and their combination and disability and mortality. METHODS: We examined 2546 dementia-free people aged ≥ 60 years, part of the Swedish National study on Aging and Care in Kungsholmen (SNAC-K) up to 12 years. The following four profiles were created: (1) healthy profile; (2) isolated CIND (scoring 1.5 SD below age-specific means on at least one cognitive domain); (3) isolated slow WS (< 0.8 m/s); (4) CIND+ slow WS. Disability was defined as the sum of impaired activities of daily living and trajectories of disability were derived from mixed-effect linear regression models. Piecewise proportional hazard models were used to estimate mortality rate [hazard ratios (HRs)]. Population attributable risks of death were calculated. RESULTS: Participants with both CIND and slow WS had the worst prognosis, especially in the short-term period. They experienced the steepest increase in disability and five times the mortality rate (HR 5.1; 95% CI 3.5-7.4) of participants free from these conditions. Similar but attenuated results were observed for longer follow-ups. Co-occurring CIND and slow WS accounted for 30% of short-term deaths. CONCLUSIONS: Co-occurring cognitive and physical limitations constitute a distinct risk profile in older people, and account for a large proportion of short-term deaths. Assessing cognitive and physical function could enable early identification of people at high risk for adverse events.

Heterogeneous Disease Progression in a Mouse Model of Vascular Cognitive Impairment.

Recently, an asymmetric vascular compromise approach that replicates many aspects of human vascular cognitive impairment (VCI) has been reported. The present study aimed to first investigate on the reproducibility in the disease progression of this newly reported VCI model using wild-type C57BL6/J mice. The second aim was to assess how this approach will affect the disease progression of transgenic Alzheimer's disease (AD) 5XFAD mice subjected to VCI. C57BL6/J and 5XFAD mice were subjected to VCI by placing an ameroid constrictor on the right CCA and a microcoil on the left CCA. Infarcts and hippocampal neuronal loss did not appear predominantly in the right (ameroid side) as expected but randomly in both hemispheres. The mortality rate of C57BL6/J mice was unexpectedly high. Inducing VCI reduced amyloid burden in the hippocampi of 5XFAD mice. Since VCI is known to be complex and complicated, the heterogeneous disease progression observed from this current study shares close resemblance to the clinical manifestation of VCI. This heterogeneity, however, makes it challenging to test novel treatment options using this model. Further study is warranted to tackle the heterogeneous nature of VCI.

Associations of Cognitive Function and Education Level With All-Cause Mortality in Adults on Hemodialysis: Findings From the COGNITIVE-HD Study.

RATIONALE & OBJECTIVE: In the general population, cognitive impairment is associated with increased mortality, and higher levels of education are associated with lower risks for cognitive impairment and mortality. These associations are not well studied in patients receiving long-term hemodialysis and were the focus of the current investigation. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adult hemodialysis patients treated in 20 Italian dialysis clinics. EXPOSURES: Patients' cognitive function across 5 domains (memory, attention, executive function, language, and perceptual-motor function), measured using a neuropsychological assessment comprising 10 tests; and patients' self-reported years of education. OUTCOME: All-cause mortality. ANALYTICAL APPROACH: Nested multivariable Cox regression models were used to examine associations of cognition (any domain impaired, number of domains impaired, and global function score from principal components analysis of unadjusted test scores) and education with mortality and whether there were interactions between them. RESULTS: 676 (70.6%) patients participated, with a median age of 70.9 years and including 38.8% women. Cognitive impairment was present in 79.4% (527/664; 95% CI, 76.3%-82.5%). During a median follow-up of 3.3 years (1,874 person-years), 206 deaths occurred. Compared to no cognitive impairment, adjusted HRs for mortality were 1.77 (95% CI, 1.07-2.93) for any impairment, 1.48 (95% CI, 0.82-2.68) for 1 domain impaired, 1.88 (95% CI, 1.01-3.53) for 2 domains, and 2.01 (95% CI, 1.14-3.55) for 3 to 5 domains. The adjusted HR was 0.68 (95% CI, 0.51-0.92) per standard deviation increase in global cognitive function score. Compared with primary or lower education, adjusted HRs were 0.79 (95% CI, 0.53-1.20) for lower secondary and 1.13 (95% CI, 0.80-1.59) for upper secondary or higher. The cognition-by-education interaction was not significant (P=0.7). LIMITATIONS: Potential selection bias from nonparticipation and missing data; no data for cognitive decline; associations with education were not adjusted for other socioeconomic factors. CONCLUSIONS: Cognitive impairment is associated with premature mortality in hemodialysis patients. Education does not appear to be associated with mortality.

Incident Mobility Disability, Mild Cognitive Impairment, and Mortality in Community-Dwelling Older Adults.

BACKGROUND/AIMS: Mobility disability and mild cognitive impairment (MCI) are common in aging and both are associated with risk of death. This study tested the hypothesis that risk of death differs by the order in which mobility disability and MCI occurred. METHODS: One thousand two hundred and sixty-two community-dwelling older adults were unimpaired at baseline and followed annually. Mobility disability was based on measured gait speed, and MCI was based on cognitive performance tests. A multistate Cox model simultaneously examined incidences of mobility disability and MCI to determine whether the order of their occurrence is differentially associated with risk of death. RESULTS: The average age was 75.3 years and 70% were female. While mobility disability occurred more frequently than incident MCI, the subsequent risk of death was higher in participants who developed MCI alone compared to those who developed mobility disability alone (hazard ratio [HR] 1.70, p = 0.018). Of the participants who initially developed mobility disability, about half subsequently developed MCI that doubled their risk of death (HR 2.17, p < 0.001). By contrast, over two-third who developed MCI subsequently developed mobility disability, which did not further increase their risk of death. CONCLUSION: Mobility disability occurs more frequently in community-dwelling older adults, but MCI is more strongly associated with mortality.

The Loss in Expectation of Life due to Early-Onset Mild Cognitive Impairment and Early-Onset Dementia in Norway.

INTRODUCTION: Whether patients with early-onset dementia have poorer or improved survival compared with those with a late onset largely depends on the survival measure. Survival estimates for early-onset mild cognitive impairment (MCI) diagnosis are particularly scarce. We aimed to estimate life expectancy (LE) in patients with early-onset dementia or early MCI, and loss in expectation of life (LEL) for these groups. Comparisons were made with the general Norwegian population and a subgroup of patients with late-onset dementia. METHODS: Early onset was defined as receiving a diagnosis of MCI or dementia before age 65 years. LE and LEL were predicted using flexible parametric survival models. Our study population was comprised of newly diagnosed (incident) cases (n = 4,906), aged 50-90 years at the time of diagnosis (672 were diagnosed before age 65 years, of which 291 were diagnosed with dementia), in the Norwegian register of persons assessed for cognitive symptoms (NorCog) between 2009 and 2017, and patients were followed up for mortality or censorship until January 2018. RESULTS: Among the early-onset patients, 8 and 23% died during follow-up, in the MCI and dementia groups, respectively. Both early-onset MCI and especially early-onset dementia were associated with lower LE than in the general Norwegian population; LE for 60-year-old women in 2016 was 26 years in the general population, 20 years in MCI patients, and 7 years in dementia patients. The corresponding LE at 80 years was 10, 6, and 5 years. Thus, LEL were particularly pronounced for patients with early dementia. The diagnosis-specific LE pattern in men was similar to that in women. DISCUSSION: Early-onset MCI was associated with substantial life years lost (5-6 years), but the loss was particularly pronounced for those with early-onset dementia, reducing the expected life length by 2 decades.

Diagnostic Failure of Cognitive Impairment in Nursing Home Residents May Lead to Impaired Medical Care.

BACKGROUND/OBJECTIVES: Dementia and cognitive impairment are common in nursing homes. Few studies have studied the impact of unnoted cognitive impairment on medical care. This study aimed to estimate the prevalence of diagnostic failure of cognitive impairment in a sample of Swedish nursing home residents and to analyze whether diagnostic failure was associated with impaired medical care. METHOD: A total of 428 nursing home residents were investigated during 2008-2011. Subjects without dementia diagnosis were grouped by result of the Mini Mental State Examination (MMSE), where subjects with <24 points formed a possible dementia group and the remaining subjects a control group. A third group consisted of subjects with diagnosed dementia. These three groups were compared according to baseline data, laboratory findings, drug use, and mortality. RESULTS: Dementia was previously diagnosed in 181 subjects (42%). Among subjects without a dementia diagnosis, 72% were cognitively impaired with possible dementia (MMSE <24). These subjects were significantly older, did not get anti-dementia treatment, and had higher levels of brain natriuretic peptide compared to the diagnosed dementia group, but the risks of malnutrition and pressure ulcers were similar to the dementia group. CONCLUSIONS: Unnoted cognitive impairment is common in nursing home residents and may conceal other potentially treatable conditions such as heart failure. The results highlight a need to pay increased attention to cognitive impairment among nursing home residents.

Design and sample size considerations for Alzheimer's disease prevention trials using multistate models.

BACKGROUND/AIMS: Clinical trials for Alzheimer's disease have been aimed primarily at persons who have cognitive symptoms at enrollment. However, researchers are now recognizing that the pathophysiological process of Alzheimer's disease begins years, if not decades, prior to the onset of clinical symptoms. Successful intervention may require intervening early in the disease process. Critical issues arise in designing clinical trials for primary and secondary prevention of Alzheimer's disease including determination of sample sizes and follow-up duration. We address a number of these issues through application of a unifying multistate model for the preclinical course of Alzheimer's disease. A multistate model allows us to specify at which points during the long disease process the intervention exerts its effects. METHODS: We used a nonhomogeneous Markov multistate model for the progression of Alzheimer's disease through preclinical disease states defined by biomarkers, mild cognitive impairment and Alzheimer's disease dementia. We used transition probabilities based on several published cohort studies. Sample size methods were developed that account for factors including the initial preclinical disease state of trial participants, the primary endpoint, age-dependent transition and mortality rates and specifications of which transition rates are the targets of the intervention. RESULTS: We find that Alzheimer's disease prevention trials with a clinical primary endpoint of mild cognitive impairment or Alzheimer's disease dementia will require sample sizes of the order many thousands of individuals with at least 5 years of follow-up, which is larger than most Alzheimer's disease therapeutic trials conducted to date. The reasons for the large trial sizes include the long and variable preclinical period that spans decades, high rates of attrition among elderly populations due to mortality and losses to follow-up and potential selection effects, whereby healthier subjects enroll in prevention trials. A web application is available to perform sample size calculations using the methods reported here. CONCLUSION: Sample sizes based on multistate models can account for the points in the disease process when interventions exert their effects and may lead to more accurate sample size determinations. We will need innovative strategies to help design Alzheimer's disease prevention trials with feasible sample size requirements and durations of follow-up.

Association of cognitive impairment and grip strength trajectories with mortality among middle-aged and elderly adults.

ABSTRACTBackground:This study investigates whether maintaining high levels of cognitive impairment and weak grip strength will predict a higher risk for mortality. METHODS: Data from the Korean Longitudinal Study of Aging (KLoSA) from 2006 to 2014 was assessed using longitudinal data analysis and included 5,812 research subjects. Our modeling approach jointly estimated multi-period trajectories of grip strength and cognitive impairment, and the primary analysis was based on Cox proportional hazards models. RESULTS: A four-class linear solution fit the data best in both cognitive impairment and grip strength based on the model fitness, respectively. The hazard ratio (HR) of mortality in group 1 (consistently low) of cognitive impairment and of grip strength were 2.114 times higher (p-value 0.001) and 3.405 times higher (p-value <.0001) compared with group 3 (consistently high) and group 4 (consistently high), respectively. CONCLUSION: This study provides insightful scientific evidence into the specificity of longitudinal changes in grip strength and cognitive impairment on mortality. Our findings suggest that declined cognitive ability and weak grip strength are predictors of mortality in older Korean people.

The Incidence Prognosis and Risk Factors of Cognitive Impairment in Maintenance Haemodialysis Patients.

OBJECTIVE: To investigate the incidence and the prognosis of cognitive impairment (CI) and to find out the risk factors associated with the outcome in maintenance haemodialysis (MHD) patients. METHODS: Enrolled the patients who met the criteria as below: MHD (≥3 months) patients before July 2014, ≥18 years old and could carry on the cognitive function test (Montreal Cognitive Assessment [MoCA]). All enrolled patients were divided into 2 groups: CI group (MoCA < 26) and non-CI group (MoCA ≥26). All patients were followed up for 36 months. The incidence, demography data, medical history, haemodialysis data, laboratory examination and prognosis of CI in haemodialysis patients were prospectively compared and analyzed. Multivariate logistic regression analysis was used to investigate the risk factors of CI. Kaplan-Meier survival curve was used for survival analysis. RESULTS: In the present study, 219 patients were enrolled. The ratio of male to female was 1.46: 1. Age was 60.07 ± 12.44 and dialysis vintage was 100.79 ± 70.23 months. One hundred thirteen patients' MoCA scores were lower than 26 were divided into CI group. Education status (OR 3.428), post-dialysis diastolic pressure (OR 2.234) and spKt/V (OR 1.982) were independent risk factors for CI in MHD patients. During the follow-up period, 15 patients died (13.2%) in the CI group and 5 died (4.72%) in the non-CI group (p < 0.05). The Kaplan-Meier survival curve analysis showed that the survival rate of patients with CI was lower than that of non-CI group in MHD patients during 3 years follow-up (p = 0.046). CONCLUSION: CI is one of the most common complications in MHD patients. The mortality is high in patients who had CI. Education status, post-dialysis diastolic pressure and spKt/V are independent risk factors for CI in MHD patients.

Sepsis Survivors Admitted to Skilled Nursing Facilities: Cognitive Impairment, Activities of Daily Living Dependence, and Survival.

OBJECTIVE: Severe sepsis survivors frequently experience cognitive and physical functional impairment. The degree of impairment and its association with mortality is understudied, particularly among those discharged to a skilled nursing facility. Our objective was to quantify the cognitive and physical impairment among severe sepsis survivors discharged to a skilled nursing facility and to investigate the relationship between impairment and long-term mortality. DESIGN: Retrospective cohort study. SETTING: United States. SUBJECTS: Random 5% sample of Medicare patients discharged following severe sepsis hospitalization, 2005-2009 (n = 135,370). MEASUREMENT AND MAIN RESULTS: Medicare data were linked with the Minimum Data Set; Minimum Data Set-Cognition Scale was used to assess cognitive function, and the Minimum Data Set activities of daily living hierarchical scale was used to assess functional dependence. Associations were evaluated using multivariable logistic regression, Kaplan-Meier curves, and Cox proportional hazards regression. Of 66,540 beneficiaries admitted to a skilled nursing facility following severe sepsis, 34% had severe or very severe cognitive impairment, and 72.5% had maximal, dependence, or total dependence in activities of daily living. Median survival was 19.4 months for those discharged to a skilled nursing facility without having been in a skilled nursing facility in the preceding 1 year and 10.4 months for those discharged to a skilled nursing facility who had spent time in a skilled nursing facility in the prior year. The adjusted hazard ratio for death was 3.1 for those with very severe cognitive impairment relative to those who were cognitively intact (95% CI, 2.9-3.2; p < 0.001) and 4.3 for those with "total dependence" in activities of daily livings relative to those who were independent (95% CI, 3.8-5.0; p < 0.001). CONCLUSIONS: Discharge to a skilled nursing facility following severe sepsis hospitalization among Medicare beneficiaries was associated with shorter survival, and cognitive impairment and activities of daily living dependence were each strongly associated with shortened survival. These findings can inform decision-making by patients and physicians and underscores high palliative care needs among sepsis survivors discharged to skilled nursing facility.