Referral Sources Across Racial and Ethnic Groups at Alzheimer's Disease Research Centers.

Background: Despite the need to increase engagement of underrepresented groups (URG) in Alzheimer's disease and related dementias (ADRD) studies, enrollment remains low. Objective: Compare referral sources across racial and ethnic groups among participants enrolled in ADRC studies. Methods: Data for this cross-sectional secondary analysis were extracted from the National Alzheimer's Coordinating Center Uniform Data Set. We performed mixed effects logistic regression models using generalized estimating equations for professional referral versus non-professional referral by racial and ethnic group, adjusted for age, gender, education, visit year, and Clinical Dementia Rating scale (CDR) with a random effect for study site. Results: Included in the analysis were 48,330 participants across 46 ADRCs (mean [SD] age, 71.3 [10.5] years; 20,767 female [57%]; 4,138 Hispanic [8.6%]; 1,392 non-Hispanic Asian [2.9%]; 6,766 non-Hispanic Black [14%] individuals; and 676 individuals [1.4%] of other races. Non-Hispanic Black and Asian participants had lower odds of being referred by a professional contact compared to non-Hispanic White participants (Black: adjusted OR = 0.61, 95% CI = 0.44-0.86, p = 0.005; Asian: adjusted OR = 0.65, 95% CI, p = 0.004). In participants who had completed an MRI, there was no significant difference in referral source across ethnic and racial groups. Conclusions: Further studies are needed to better understand the systemic and structural factors that contribute to differences in referral sources and disparities in recruitment of URG into ADRD studies.

Pathway enrichment in genome-wide analysis of longitudinal Alzheimer's disease biomarker endophenotypes.

INTRODUCTION: The genetic pathways that influence longitudinal heterogeneous changes in Alzheimer's disease (AD) may provide insight into disease mechanisms and potential therapeutic targets. METHODS: Longitudinal endophenotypes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) representing amyloid, tau, neurodegeneration (A/T/N), and cognition were selected. Genome-wide association analysis was performed using a linear mixed model (LMM) approach, followed by gene and pathway enrichment with significant and functionally relevant SNPs. RESULTS: A total of 33 and 19 statistically significant pathways were identified associating with the intercept and longitudinal trajectory, respectively. The longitudinal intercept pathways represent eight groups: immune, metabolic, cell growth and survival, DNA maintenance, neuronal signaling, RAS/MAPK/ERK signaling pathways, vesicle and lysosomal transport, and transcription modification. Longitudinal trajectory pathways represented six groups: Immune, metabolic, cell signaling, cytoskeleton, and glycosylation. DISCUSSION: Longitudinal enrichment identified pathways that uniquely associate with trajectories of key AD biomarkers and cognition, providing new insight into AD course-related mechanisms and potential new therapeutic targets. HIGHLIGHTS: A systematic genome-wide analysis with longitudinal AD biomarker endophenotypes was performed. Enriched pathways were identified with functionally derived SNP to gene analysis. Fifty-two pathways were associated with longitudinal trajectory and intercept. Many of the identified pathways are specific steps in larger pathways implicated in AD. The identified pathways may provide therapeutic targets and areas for further study.

CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET.

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Independent and joint associations of cardiometabolic multimorbidity and depression on cognitive function: findings from multi-regional cohorts and generalisation from community to clinic.

Background: Cardiometabolic multimorbidity (CMM) and depression are often co-occurring in older adults and associated with neurodegenerative outcomes. The present study aimed to estimate the independent and joint associations of CMM and depression on cognitive function in multi-regional cohorts, and to validate the generalizability of the findings in additional settings, including clinical. Methods: Data harmonization was performed across 14 longitudinal cohort studies within the Cohort Studies of Memory in an International Consortium (COSMIC) group, spanning North America, South America, Europe, Africa, Asia, and Australia. Three external validation studies with distinct settings were employed for generalization. Participants were eligible for inclusion if they had data for CMM and were free of dementia at baseline. Baseline CMM was defined as: 1) CMM 5, ≥2 among hypertension, hyperlipidemia, diabetes, stroke, and heart disease and 2) CMM 3 (aligned with previous studies), ≥2 among diabetes, stroke, and heart disease. Baseline depression was primarily characterized by binary classification of depressive symptom measurements, employing the Geriatric Depression Scale and the Center for Epidemiological Studies-Depression scale. Global cognition was standardized as z-scores through harmonizing multiple cognitive measures. Longitudinal cognition was calculated as changes in global cognitive z-scores. A pooled individual participant data (IPD) analysis was utilized to estimate the independent and joint associations of CMM and depression on cognitive outcomes in COSMIC studies, both cross-sectionally and longitudinally. Repeated analyses were performed in three external validation studies. Findings: Of the 32,931 older adults in the 14 COSMIC cohorts, we included 30,382 participants with complete data on baseline CMM, depression, and cognitive assessments for cross-sectional analyses. Among them, 22,599 who had at least 1 follow-up cognitive assessment were included in the longitudinal analyses. The three external studies for validation had 1964 participants from 3 multi-ethnic Asian older adult cohorts in different settings (community-based, memory clinic, and post-stroke study). In COSMIC studies, each of CMM and depression was independently associated with cross-sectional and longitudinal cognitive function, without significant interactions between them (Ps > 0.05). Participants with both CMM and depression had lower cross-sectional cognitive performance (e.g. ß = -0.207, 95% CI = (-0.255, -0.159) for CMM5 (+)/depression (+)) and a faster rate of cognitive decline (e.g. ß = -0.040, 95% CI = (-0.047, -0.034) for CMM5 (+)/depression (+)), compared with those without either condition. These associations remained consistent after additional adjustment for APOE genotype and were robust in two-step random-effects IPD analyses. The findings regarding the joint association of CMM and depression on cognitive function were reproduced in the three external validation studies. Interpretation: Our findings highlighted the importance of investigating age-related co-morbidities in a multi-dimensional perspective. Targeting both cardiometabolic and psychological conditions to prevent cognitive decline could enhance effectiveness. Funding: Natural Science Foundation of China and National Institute on Aging/National Institutes of Health.

Association of Heart Failure With Cognitive Decline and Development of Mild Cognitive Impairment and Dementia.

BACKGROUND: Incidence of cognitive impairment and its consequences have not been fully examined in heart failure (HF). OBJECTIVE: The aim of this study was to examine associations of HF with cognitive decline, frequencies and risks of, and time-to-develop mild cognitive impairment (MCI) or dementia during 15-year follow-up. METHODS: For this retrospective cohort study, data were retrieved from the National Alzheimer's Coordinating Center. Cognitive decline was assessed using the Uniform Data Set neuropsychological battery. Development of MCI and dementia was assessed using clinically diagnosed cognitive status. RESULTS: Compared with participants without HF (n = 12 904), participants with HF (n = 256) had more decline in attention, executive function, and memory while controlling for covariates including apolipoprotein E4. Participants with HF developed MCI or dementia more frequently (44.9% vs 34.4%), developed dementia faster from normal cognition, and had a lower risk of dementia from MCI after controlling for covariates (hazard ratio, 0.71) than participants without HF. CONCLUSIONS: Heart failure was associated with accelerated cognitive decline.

Blood Pressure, Antihypertensive Use, and Late-Life Alzheimer and Non-Alzheimer Dementia Risk: An Individual Participant Data Meta-Analysis.

BACKGROUND AND OBJECTIVES: Previous randomized controlled trials and longitudinal studies have indicated that ongoing antihypertensive use in late life reduces all-cause dementia risk, but the specific impact on Alzheimer dementia (AD) and non-AD risk remains unclear. This study investigates whether previous hypertension or antihypertensive use modifies AD or non-AD risk in late life and the ideal blood pressure (BP) for risk reduction in a diverse consortium of cohort studies. METHODS: This individual participant data meta-analysis included community-based longitudinal studies of aging from a preexisting consortium. The main outcomes were risk of developing AD and non-AD. The main exposures were hypertension history/antihypertensive use and baseline systolic BP/diastolic BP. Mixed-effects Cox proportional hazards models were used to assess risk and natural splines were applied to model the relationship between BP and the dementia outcomes. The main model controlled for age, age2, sex, education, ethnoracial group, and study cohort. Supplementary analyses included a fully adjusted model, an analysis restricting to those with >5 years of follow-up and models that examined the moderating effect of age, sex, and ethnoracial group. RESULTS: There were 31,250 participants from 14 nations in the analysis (41% male) with a mean baseline age of 72 (SD 7.5, range 60-110) years. Participants with untreated hypertension had a 36% (hazard ratio [HR] 1.36, 95% CI 1.01-1.83, p = 0.0406) and 42% (HR 1.42, 95% CI 1.08-1.87, p = 0.0135) increased risk of AD compared with "healthy controls" and those with treated hypertension, respectively. Compared with "healthy controls" both those with treated (HR 1.29, 95% CI 1.03-1.60, p = 0.0267) and untreated hypertension (HR 1.69, 95% CI 1.19-2.40, p = 0.0032) had greater non-AD risk, but there was no difference between the treated and untreated groups. Baseline diastolic BP had a significant U-shaped relationship (p = 0.0227) with non-AD risk in an analysis restricted to those with 5-year follow-up, but otherwise there was no significant relationship between baseline BP and either AD or non-AD risk. DISCUSSION: Antihypertensive use was associated with decreased AD but not non-AD risk throughout late life. This suggests that treating hypertension throughout late life continues to be crucial in AD risk mitigation. A single measure of BP was not associated with AD risk, but DBP may have a U-shaped relationship with non-AD risk over longer periods in late life.

Extended genome-wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry.

INTRODUCTION: Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts. METHODS: Genome-wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within-dataset results were meta-analyzed, followed by functional genomics analyses. RESULTS: A novel AD-risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, p = 3.68×10-9). Two additional novel common and nine rare loci were identified with suggestive associations (P < 9×10-7). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that this association is modulated by regional origin of local African ancestry. DISCUSSION: These analyses identified novel AD-associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects. HIGHLIGHTS: Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies. The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa. Single variant meta-analysis identified a novel genome-wide significant AD-risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome-wide significance at p < 9×10-7. Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus. These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry-informed genetic screening tools and therapeutic interventions.

Neuropsychiatric symptom burden in early-onset and late-onset Alzheimer's disease as a function of age.

INTRODUCTION: We examined the burden of neuropsychiatric symptoms (NPSs) in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD) and adjusted for age effects via the inclusion of cognitively unimpaired (CU) individuals. METHODS: Cross-sectional data from 2940 EOAD, 8665 LOAD, and 8775 age-stratified CU individuals (early-CU, n = 2433; late-CU, n = 6342) from the National Alzheimer's Coordinating Center database were included. Fisher's exact tests compared EOAD and LOAD on the presence and severity of NPSs. Multiple logistic regression models included an age*diagnosis interaction to examine age effects. RESULTS: Presence (ps < 0.0001) and severity (ps < 0.05) of NPS were greater in EOAD than in LOAD. However, after adjusting for base rates in NPS in CU individuals (age effects), only elation and eating behaviors were more frequent in EOAD (ps < 0.05) and nighttime behaviors more frequent and severe in LOAD (ps < 0.05). DISCUSSION: Few NPSs were specific to the EOAD versus LOAD. Previous findings of greater NPS burden in EOAD may partially reflect age effects. HIGHLIGHTS: Adjusting for age effect, elation and eating problems are more frequent in EOAD. Adjusting for age effect, sleep disturbances are more frequent and severe in LOAD. Age effects underlie higher neuropsychiatric symptom presentation in EOAD than in LOAD.

Selenium Status Associates with Thyroid Hormone and Thyroid Dysfunction in Older Chinese Adults.

Selenium (Se) is physiologically essential for thyroid function. However, epidemiological studies on the association between Se status and thyroid function are limited and the results are inconsistent. Therefore, we explored this association in an elderly Chinese population sample. Participants in the cross-sectional study were people aged 65 years or older who provided fingernail and whole blood samples. Hyperthyroidism and hypothyroidism were defined by serum thyroid hormones concentrations, including thyroid stimulating hormone (TSH), total triiodothyronine (TT3), total thyroxine (TT4), free thyroxine (FT3), and free thyrotropin (FT4). Significant positive association was observed between whole blood and fingernail Se concentrations (r = 0.672, P < 0.001). Compared with the lowest Se quartile (Q1), the other fingernail Se quartile groups had lower TSH, higher FT3 and FT4 levels, and Q2 had higher TT3 levels after adjusting for covariates; the other whole blood Se quartile groups had lower TSH levels, Q2 had higher FT3, FT4 and TT3 levels, Q3 had higher FT3 levels, and Q4 had higher FT4 levels after adjusting for covariates. Compared with Q1, the adjusted odds ratios (OR) and 95% confidence intervals (95%CIs) of hypothyroidism for Q4 of whole blood Se was 0.141 (0.029,0.675), and the adjusted OR (95%CIs) of hyperthyroidism for Q2 and Q3 of fingernail Se were 4.121 (1.233,13.733) and 3.614 (1.095,11.926). Higher Se levels were significantly associated with lower TSH levels and higher levels of TT3, FT3 and FT4. Meanwhile, higher Se levels were associated with lower risk of hypothyroidism and higher risk of hyperthyroidism.

Collaborative Care for Injured Older Adults: The Trauma Medical Home Randomized Clinical Trial.

Importance: Older adults with recent injuries can have impaired long-term biopsychosocial function and may benefit from interventions adapted to their needs. Objective: To determine if a collaborative care intervention, Trauma Medical Home (TMH), improved the biopsychosocial function of older patients in the year after injury. Design, Setting, and Participants: This was a single-blinded, randomized clinical trial conducted at 4 level I trauma centers in Indianapolis, Indiana, and Madison, Wisconsin. Between October 2017 and October 2021, patients aged 50 years and older with an Injury Severity Score (ISS) of 9 or greater and without traumatic brain or spinal cord injury were enrolled. Exclusions were significant brain injury or a spinal cord injury with a persistent neurologic deficit at the time of enrollment, extensive burns, pregnancy, incarceration, neurodegenerative disease, visual or auditory impairment that would preclude study participation, a life expectancy of less than 1 year, significant alcohol or drug use history, and acute stroke during admission. Of 10 276 patients screened, 430 were randomized and 299 completed 12-month follow-up. Data were analyzed from March to July 2023. Intervention: Intervention patients received 6 months of TMH delivered by a nurse care coordinator guided by an interdisciplinary team (trauma surgeon, pulmonary critical care and geriatrician physicians, nurses, and psychologist) in partnership with primary care. The care coordinator used standard protocols to monitor and treat biopsychosocial symptoms. Main Outcomes and Measures: Primary outcomes were Medical Outcome Study Short Form-36 (SF-36) score and Short Physical Performance Battery (SPPB) score at 12 months. Secondary outcomes were Patient Health Questionnaire-9 (PHQ-9) score, the Generalized Anxiety Disorder scale-7 (GAD-7) score, and health care utilization. Results: A total of 429 participants (228 [53.1%] female; mean [SD] age, 69.3 [10.8] years; mean [SD] ISS, 12.3 [4.6]) completed baseline assessments and were randomized. Follow-up was 76% (n = 324) at 6 months and 70% (n = 299) at 12 months. There were no differences between the TMH and usual care groups at 12 months in SF-36 Physical Component Summary score (mean [SD], 40.42 [12.82] vs 39.18 [12.43]), SF-36 Mental Component Summary score (mean [SD], 53.92 [10.02] vs 53.21 [10.82]), or SPPB score (mean [SD], 8.00 [3.60] vs 8.28 [3.88]). Secondary outcomes were also no different. Planned subgroup analysis revealed patients with baseline symptoms of anxiety or depression (high GAD-7 and PHQ-9 scores) experienced improvement in the Mental Component Summary score when randomized to the TMH intervention. Conclusions and Relevance: The TMH intervention did not significantly influence quality of life, depressive and anxiety symptoms, or physical function of older adults with injury at 12 months. Subgroup analysis showed positive impact in patients with a high burden of anxiety and depression symptoms at enrollment. Collaborative care interventions may improve long-term outcomes of select patients, but further research is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03108820.

Surgical intervention combined with weight-bearing walking training promotes recovery in patients with chronic spinal cord injury: a randomized controlled study.

JOURNAL/nrgr/04.03/01300535-202412000-00032/figure1/v/2024-04-08T165401Z/r/image-tiff For patients with chronic spinal cord injury, the conventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection, pressure sores, osteoporosis, and deep vein thrombosis. Surgery is rarely performed on spinal cord injury in the chronic phase, and few treatments have been proven effective in chronic spinal cord injury patients. Development of effective therapies for chronic spinal cord injury patients is needed. We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal cord injury to compare intensive rehabilitation (weight-bearing walking training) alone with surgical intervention plus intensive rehabilitation. This clinical trial was registered at ClinicalTrials.gov (NCT02663310). The goal of surgical intervention was spinal cord detethering, restoration of cerebrospinal fluid flow, and elimination of residual spinal cord compression. We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement, reduced spasticity, and more rapid bowel and bladder functional recovery than weight-bearing walking training alone. Overall, the surgical procedures and intensive rehabilitation were safe. American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries. Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.

Spatial transcriptomic patterns underlying amyloid-ß and tau pathology are associated with cognitive dysfunction in Alzheimer's disease.

Amyloid-ß (Aß) and tau proteins accumulate within distinct neuronal systems in Alzheimer's disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aß and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aß (gene-to-Aß associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aß and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aß and the gene-to-tau associations. These findings may explain the discordance between regional Aß and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.

Mobile Critical Care Recovery Program for Survivors of Acute Respiratory Failure: A Randomized Clinical Trial.

Importance: Over 50% of Acute Respiratory Failure (ARF) survivors experience cognitive, physical, and psychological impairments that negatively impact their quality of life (QOL). Objective: To evaluate the efficacy of a post-intensive care unit (ICU) program, the Mobile Critical Care Recovery Program (m-CCRP) consisting of a nurse care coordinator supported by an interdisciplinary team, in improving the QOL of ARF survivors. Design, Setting, and Participants: This randomized clinical trial with concealed outcome assessments among ARF survivors was conducted from March 1, 2017, to April 30, 2022, with a 12-month follow-up. Patients were admitted to the ICU services of 4 Indiana hospitals (1 community, 1 county, 2 academic), affiliated with the Indiana University School of Medicine. Intervention: A 12-month nurse-led collaborative care intervention (m-CCRP) supported by an interdisciplinary group of clinicians (2 intensivists, 1 geriatrician, 1 ICU nurse, and 1 neuropsychologist) was compared with a telephone-based control. The intervention comprised longitudinal symptom monitoring coupled with nurse-delivered care protocols targeting cognition, physical function, personal care, mobility, sleep disturbances, pain, depression, anxiety, agitation or aggression, delusions or hallucinations, stress and physical health, legal and financial needs, and medication adherence. Main Outcomes and Measures: The primary outcome was QOL as measured by the 36-item Medical Outcomes Study Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS), with scores on each component ranging from 0-100, and higher scores indicating better health status. Results: In an intention-to-treat analysis among 466 ARF survivors (mean [SD] age, 56.1 [14.4] years; 250 [53.6%] female; 233 assigned to each group), the m-CCRP intervention for 12 months did not significantly improve the QOL compared with the control group (estimated difference in change from baseline between m-CCRP and control group: 1.61 [95% CI, -1.06 to 4.29] for SF-36 PCS; -2.50 [95% CI, -5.29 to 0.30] for SF-36 MCS. Compared with the control group, the rates of hospitalization were higher in the m-CCRP group (117 [50.2%] vs 95 [40.8%]; P = .04), whereas the 12-month mortality rates were not statistically significantly lower (24 [10.3%] vs 38 [16.3%]; P = .05). Conclusions and Relevance: Findings from this randomized clinical trial indicated that a nurse-led 12-month comprehensive interdisciplinary care intervention did not significantly improve the QOL of ARF survivors after ICU hospitalization. These results suggest that further research is needed to identify specific patient groups who could benefit from tailored post-ICU interventions. Trial Registration: ClinicalTrials.gov Identifier: NCT03053245.

Serum proteomic analysis in esophagectomy patients with postoperative delirium: A case-control study.

BACKGROUND: Postoperative delirium occurs in up to 80% of patients undergoing esophagectomy. We performed an exploratory proteomic analysis to identify protein pathways that may be associated with delirium post-esophagectomy. OBJECTIVES: Identify proteins associated with delirium and delirium severity in a younger and higher-risk surgical population. METHODS: We performed a case-control study using blood samples collected from patients enrolled in a negative, randomized, double-blind clinical trial. English speaking adults aged 18 years or older, undergoing esophagectomy, who had blood samples obtained were included. Cases were defined by a positive delirium screen after surgery while controls were patients with negative delirium assessments. Delirium was assessed using Richmond Agitation Sedation Scale and Confusion Assessment Method for the Intensive Care Unit, and delirium severity was assessed by Delirium Rating Scale-Revised-98. Blood samples were collected pre-operatively and on post-operative day 1, and discovery proteomic analysis was performed. Between-group differences in median abundance ratios were reported using Wilcoxon-Mann-Whitney Odds (WMWodds1) test. RESULTS: 52 (26 cases, 26 controls) patients were included in the study with a mean age of 64 (SD 9.6) years, 1.9% were females and 25% were African American. The median duration of delirium was 1 day (IQR: 1-2), and the median delirium/coma duration was 2.5 days (IQR: 2-4). Two proteins with greater relative abundance ratio in patients with delirium were: Coagulation factor IX (WMWodds: 1.89 95%CI: 1.0-4.2) and mannosyl-oligosaccharide 1,2-alpha-mannosidase (WMWodds: 2.4 95%CI: 1.03-9.9). Protein abundance ratios associated with mean delirium severity at postoperative day 1 were Complement C2 (Spearman rs = -0.31, 95%CI [-0.55, -0.02]) and Mannosyl-oligosaccharide 1,2-alpha-mannosidase (rs = 0.61, 95%CI = [0.29, 0.81]). CONCLUSIONS: We identified changes in proteins associated with coagulation, inflammation, and protein handling; larger, follow-up studies are needed to confirm our hypothesis-generating findings.

Thirty-Day Readmissions Are Largely Not Preventable in Patients With Cirrhosis.

INTRODUCTION: Hospital readmissions are common in patients with cirrhosis, but there are few studies describing readmission preventability. We aimed to describe the incidence, causes, and risk factors for preventable readmission in this population. METHODS: We performed a prospective cohort study of patients with cirrhosis hospitalized at a single center between June 2014 and March 2020 and followed up for 30 days postdischarge. Demographic, clinical, and socioeconomic data, functional status, and quality of life were collected. Readmission preventability was independently and systematically adjudicated by 3 reviewers. Multinomial logistic regression was used to compare those with (i) preventable readmission, (ii) nonpreventable readmission/death, and (iii) no readmission. RESULTS: Of 654 patients, 246 (38%) were readmitted, and 29 (12%) were preventable readmissions. Reviewers agreed on preventability for 70% of readmissions. Twenty-two (including 2 with preventable readmission) died. The most common reasons for readmission were hepatic encephalopathy (22%), gastrointestinal bleeding (13%), acute kidney injury (13%), and ascites (6%), and these reasons were similar between preventable and nonpreventable readmissions. Preventable readmission was often related to paracentesis timeliness, diuretic adjustment monitoring, and hepatic encephalopathy treatment. Compared with nonreadmitted patients, preventable readmission was independently associated with racial and ethnic minoritized individuals (odds ratio [OR] 5.80; 95% CI, 1.96-17.13), nonmarried marital status (OR 2.88; 95% CI, 1.18-7.05), and admission in the prior 30 days (OR 3.45; 95% CI, 1.48-8.04). DISCUSSION: For patients with cirrhosis, readmission is common, but most are not preventable. Preventable readmissions are often related to ascites and hepatic encephalopathy and are associated with racial and ethnic minorities, nonmarried status, and prior admissions.

Risk factors for dementia in older intensive care unit (ICU) survivors.

INTRODUCTION: As the number of older intensive care unit (ICU) survivors grows, there is an urgent need to identify modifiable risk factors for post-ICU dementia. METHODS: We performed a secondary data analysis of 3144 ICU patients ≥ 50 years of age without a history of dementia or severe mental illness who were screened as part of the Pharmacological Management of Delirium (PMD) study. Delirium was assessed using the Confusion Assessment Method for the ICU. Dementia was identified using International Classification of Diseases Ninth and Tenth revision codes for dementia or prescription of anti-dementia medication. RESULTS: Average age (standard deviation) was 65.2 ± 9.5 years; 50.4% were female; and 37.3% were Black. Analyses identified stroke (adjusted hazard ratio [HR] 2.49; 95% confidence interval [CI: 1.52, 4.07], P < 0.001), and depression (adjusted HR 3.03; 95% CI [1.80, 5.10], P < 0.001) as post-ICU risk factors for dementia. DISCUSSION: Future studies will need to examine whether interventions targeting post-ICU stroke and depression can lower dementia incidence in ICU survivors. HIGHLIGHTS: Risk factors for post-intensive care unit (ICU) dementia were distinct from those of Alzheimer's disease. Cardiovascular risk factors were not associated with dementia in older ICU survivors. Post-ICU stroke was associated with a higher risk of dementia in older ICU survivors. Post-ICU depression was associated with a higher risk of dementia in older ICU survivors.

Multi-element Exposure and Cognitive Function in Rural Elderly Chinese.

To investigate the relationship between selenium (Se) based multi-element combined exposure and cognitive function in rural elderly individuals, a cross-sectional study was conducted. The study involved 416 older adults aged 60 and above, residing in four different areas of Enshi county, China, with varying soil Se levels. Inductively coupled plasma mass spectrometry (ICP-MS) was employed to measure the concentrations of Se, copper (Cu), iron (Fe), zinc (Zn), calcium (Ca), magnesium (Mg), cadmium (Cd), arsenic (As), and lead (Pb) in whole blood. Nine standard cognitive tests were applied to assess cognitive function. Analysis of the least absolute shrinkage and selection operator regression (LASSO), covariance (ANCOVA), and generalized linear model (GLM) were utilized to investigate the relationship between element exposure and cognitive function. The results of LASSO revealed that Se, Cu, Fe, Zn, Ca, and Pb were independently identified to be associated with cognition. Both ANCOVA and GLM demonstrated that Se and Ca were correlated with cognitive function. The multi-element model showed higher composite Z scores of 0.32 (95% CI: 0.09 to 0.55) for log-transformed Se (P = 0.007), 0.75 (95% CI: 0.01 to 1.49) for log-transformed Cu (P = 0.048), and a lower score of - 0.67 (95% CI: - 1.26 to - 0.08) for log-transformed Ca (P = 0.025). Furthermore, there was evidence that Se could counteract the negative impact of Ca on cognitive function (P for interaction = 0.031). Our findings suggested that higher levels of Se and Cu were associated with better cognitive function in the elderly and Se can counteract the cognitive damage caused by Ca.

Associations between Two Dietary Quality Scores and Pancreatic Cancer Risk in a US National Prospective Cohort Study.

OBJECTIVE: Most previous studies investigated the associations between intake of individual nutrients and risk of disease, which failed to consider the potential interactions and correlations between various nutrients contained in food. Although dietary quality scores provide a comprehensive evaluation of the entire diet, it remains elusive whether they are associated with the risk of pancreatic cancer. METHODS: Dietary intake data collected with the Dietary Questionnaire (DQX) and Diet History Questionnaire (DHQ) were used to calculate HEI-2015 and DQI-R scores for participants in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. A high score indicates an increased intake of adequacy components and a decreased intake of moderation components. This study included 252 cases of pancreatic cancer documented from 58,477 persons during a median follow-up of 12.2 years in the DQX cohort and 372 cases of pancreatic cancer ascertained from 101,721 persons during a median follow-up of 8.9 years in the DHQ cohort. Cox proportional hazards regression analysis was performed to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between the two dietary quality scores and pancreatic cancer risk. RESULTS: After adjustment for confounders, HEI-2015 and DQI-R scores were not significantly associated with pancreatic cancer risk. However, a significantly lower risk was observed for overweight persons with a higher HEI-2015 score in the DQX cohort (HR [95% CI] comparing the highest with lowest tertile: 0.52 [0.32, 0.85], p for trend = 0.009) and those with higher scores of some individual components. CONCLUSION: Collectively, overall dietary quality is not associated with an altered risk of pancreatic cancer in this US population.

Previous studies evaluating the roles of individual nutrients in the etiology of pancreatic cancer fails to consider the potential interactions and correlations between various nutrients contained in food. We investigated the associations between overall dietary quality scores (HEI-2015 and DQI-R) and pancreatic cancer risk in a large prospective cohort study. The findings of this study can help inform a novel and practical approach to primary prevention of this deadly disease through dietary modification and intervention.

BrainAGE Estimation: Influence of Field Strength, Voxel Size, Race, and Ethnicity.

The BrainAGE method is used to estimate biological brain age using structural neuroimaging. However, the stability of the model across different scan parameters and races/ethnicities has not been thoroughly investigated. Estimated brain age was compared within- and across- MRI field strength and across voxel sizes. Estimated brain age gap (BAG) was compared across demographically matched groups of different self-reported races and ethnicities in ADNI and IMAS cohorts. Longitudinal ComBat was used to correct for potential scanner effects. The brain age method was stable within field strength, but less stable across different field strengths. The method was stable across voxel sizes. There was a significant difference in BAG between races, but not ethnicities. Correction procedures are suggested to eliminate variation across scanner field strength while maintaining accurate brain age estimation. Further studies are warranted to determine the factors contributing to racial differences in BAG.

Genome-Wide Association Analysis across Endophenotypes in Alzheimer's Disease: Main Effects and Disease Stage-Specific Interactions.

The underlying genetic susceptibility for Alzheimer's disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-ß, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs.