The impact of genomic biomarkers on a clinical risk prediction model for upgrading/upstaging among men with favorable-risk prostate cancer.

BACKGROUND: The challenge of distinguishing indolent from aggressive prostate cancer (PCa) complicates decision-making for men considering active surveillance (AS). Genomic classifiers (GCs) may improve risk stratification by predicting end points such as upgrading or upstaging (UG/US). The aim of this study was to assess the impact of GCs on UG/US risk prediction in a clinicopathologic model. METHODS: Participants had favorable-risk PCa (cT1-2, prostate-specific antigen [PSA] ≤15 ng/mL, and Gleason grade group 1 [GG1]/low-volume GG2). A prediction model was developed for 864 men at the University of California, San Francisco, with standard clinical variables (cohort 1), and the model was validated for 2267 participants from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (cohort 2). Logistic regression was used to compute the area under the receiver operating characteristic curve (AUC) to develop a prediction model for UG/US at prostatectomy. A GC (Oncotype Dx Genomic Prostate Score [GPS] or Prolaris) was then assessed to improve risk prediction. RESULTS: The prediction model included biopsy GG1 versus GG2 (odds ratio [OR], 5.83; 95% confidence interval [CI], 3.73-9.10); PSA (OR, 1.10; 95% CI, 1.01-1.20; per 1 ng/mL), percent positive cores (OR, 1.01; 95% CI, 1.01-1.02; per 1%), prostate volume (OR, 0.98; 95% CI, 0.97-0.99; per mL), and age (OR, 1.05; 95% CI, 1.02-1.07; per year), with AUC 0.70 (cohort 1) and AUC 0.69 (cohort 2). GPS was associated with UG/US (OR, 1.03; 95% CI, 1.01-1.06; p < .01) and AUC 0.72, which indicates a comparable performance to the prediction model. CONCLUSIONS: GCs did not substantially improve a clinical prediction model for UG/US, a short-term and imperfect surrogate for clinically relevant disease outcomes.

Associations between Social Adversity and Biomarkers of Inflammation, Stress, and Aging in Children.

BACKGROUND: Prior work has found relationships between childhood social adversity and biomarkers of stress, but knowledge gaps remain. To help address these gaps, we explored associations between social adversity and biomarkers of inflammation (interleukin-1ß [IL-1ß], IL-6, IL-8, tumor necrosis factor-alpha [TNF-α], and salivary cytokine hierarchical "clusters" based on the three interleukins), neuroendocrine function (cortisol, cortisone, dehydroepiandrosterone, testosterone, and progesterone), neuromodulation (N-arachidonoylethanolamine, stearoylethanolamine, oleoylethanolamide, and palmitoylethanolamide), and epigenetic aging (Pediatric-Buccal-Epigenetic clock). METHODS: We collected biomarker samples of children ages 0-17 recruited from an acute care pediatrics clinic and examined their associations with caregiver-endorsed education, income, social risk factors, and cumulative adversity. We calculated regression-adjusted means for each biomarker and compared associations with social factors using Wald tests. We used logistic regression to predict being in the highest cytokine cluster based on social predictors. RESULTS: Our final sample included 537 children but varied based on each biomarker. Cumulative social adversity was significantly associated with having higher levels of all inflammatory markers and with cortisol, displaying a U-shaped distribution. There were no significant relationships between cumulative social adversity and cortisone, neuromodulation biomarkers or epigenetic aging. CONCLUSION: Our findings support prior work suggesting that social stress exposures contribute to increased inflammation in children. IMPACT: Our study is one of the largest studies examining associations between childhood social adversity and biomarkers of inflammation, neuroendocrine function, neuromodulation, and epigenetic aging. It is one of the largest studies to link childhood social adversity to biomarkers of inflammation, and the first of which we are aware to link cumulative social adversity to cytokine clusters. It is also one of the largest studies to examine associations between steroids and epigenetic aging among children, and one of the only studies of which we are aware to examine associations between social adversity and endocannabinoids among children. CLINICAL TRIAL REGISTRATION: NCT02746393.

Flagging unusual clusters based on linear mixed models using weighted and self-calibrated predictors.

Statistical models incorporating cluster-specific intercepts are commonly used in hierarchical settings, for example, observations clustered within patients or patients clustered within hospitals. Predicted values of these intercepts are often used to identify or "flag" extreme or outlying clusters, such as poorly performing hospitals or patients with rapid declines in their health. We consider a variety of flagging rules, assessing different predictors, and using different accuracy measures. Using theoretical calculations and comprehensive numerical evaluation, we show that previously proposed rules based on the 2 most commonly used predictors, the usual best linear unbiased predictor and fixed effects predictor, perform extremely poorly: the incorrect flagging rates are either unacceptably high (approaching 0.5 in the limit) or overly conservative (eg, much <0.05 for reasonable parameter values, leading to very low correct flagging rates). We develop novel methods for flagging extreme clusters that can control the incorrect flagging rates, including very simple-to-use versions that we call "self-calibrated." The new methods have substantially higher correct flagging rates than previously proposed methods for flagging extreme values, while controlling the incorrect flagging rates. We illustrate their application using data on length of stay in pediatric hospitals for children admitted for asthma diagnoses.

Identifying opportunities for prevention of adverse outcomes following female genital fistula repair: protocol for a mixed-methods study in Uganda.

BACKGROUND: Female genital fistula is a traumatic debilitating injury, frequently caused by prolonged obstructed labor, affecting between 500,000-2 million women in lower-resource settings. Vesicovaginal fistula causes urinary incontinence, and other morbidity may occur during fistula development. Women with fistula are stigmatized, limit social and economic engagement, and experience psychiatric morbidity. Improved surgical access has reduced fistula consequences yet post-repair risks impacting quality of life and well-being include fistula repair breakdown or recurrence and ongoing or changing urine leakage or incontinence. Limited evidence on risk factors contributing to adverse outcomes hinders interventions to mitigate adverse events. This study aims to quantify these adverse risks and inform clinical and counseling interventions to optimize women's health and quality of life following fistula repair through: identifying predictors and characteristics of post-repair fistula breakdown and recurrence (Objective 1) and post-repair incontinence (Objective 2), and to identify feasible and acceptable intervention strategies (Objective 3). METHODS: This mixed-methods study incorporates a prospective cohort of women with successful vesicovaginal fistula repair at approximately 12 fistula repair centers in Uganda (Objectives 1-2) followed by qualitative inquiry among key stakeholders (Objective 3). Cohort participants will have a baseline visit at the time of surgery followed by data collection at 2 weeks, 6 weeks, 3 months and quarterly thereafter for 3 years. Primary predictors to be evaluated include patient-related factors, fistula-related factors, fistula repair-related factors, and post-repair behaviors and exposures, collected via structured questionnaire at all data collection points. Clinical exams will be conducted at baseline, 2 weeks post-surgery, and for outcome confirmation at symptom development. Primary outcomes are fistula repair breakdown or fistula recurrence and post-repair incontinence. In-depth interviews will be conducted with cohort participants (n ~ 40) and other key stakeholders (~ 40 including family, peers, community members and clinical/social service providers) to inform feasibility and acceptability of recommendations. DISCUSSION: Participant recruitment is underway. This study is expected to identify key predictors that can directly improve fistula repair and post-repair programs and women's outcomes, optimizing health and quality of life. Furthermore, our study will create a comprehensive longitudinal dataset capable of supporting broad inquiry into post-fistula repair health. Trial Registration ClinicalTrials.gov Identifier: NCT05437939.

Female genital fistula is a traumatic birth injury which occurs where access to emergency childbirth care is poor. It causes uncontrollable urine leakage and is associated with other physical and psychological symptoms. Due to the urine leakage and its odor, women with fistula are stigmatized which has mental health and economic consequences. Ensuring women's access to fistula surgery and ongoing wellbeing is important for limiting the impact of fistula. After fistula surgery, health risks such as fistula repair breakdown or recurrence or changes to urine leakage can happen, but studies during this time are limited. Our study seeks to measure these health risks and factors influencing these risks quantitatively, and work with patients, community members, and fistula care providers to come up with solutions. We will recruit up to 1000 participants into our study at the time of fistula surgery and follow them for three years. We will collect data on patient sociodemographic characteristics, clinical history, and behavior after fistula repair through patient survey and medical record review. If participants have changes in urine leakage, they will be asked to return to the fistula repair hospital for exam. We will interview about 80 individuals to obtain their ideas for feasible and acceptable intervention options. We expect that this study will help to understand risk factors for poor health following fistula repair and, eventually, improve women's health and quality of life after fistula.

Withdrawal during outpatient low dose buprenorphine initiation in people who use fentanyl: a retrospective cohort study.

BACKGROUND: Buprenorphine is an effective treatment for opioid use disorder (OUD); however, buprenorphine initiation can be complicated by withdrawal symptoms including precipitated withdrawal. There has been increasing interest in using low dose initiation (LDI) strategies to reduce this withdrawal risk. As there are limited data on withdrawal symptoms during LDI, we characterize withdrawal symptoms in people with daily fentanyl use who underwent initiation using these strategies as outpatients. METHODS: We conducted a retrospective chart review of patients with OUD using daily fentanyl who were prescribed 7-day or 4-day LDI at 2 substance use disorder treatment clinics in San Francisco. Two addiction medicine experts assessed extracted chart documentation for withdrawal severity and precipitated withdrawal, defined as acute worsening of withdrawal symptoms immediately after taking buprenorphine. A third expert adjudicated disagreements. Data were analyzed using descriptive statistics. RESULTS: There were 175 initiations in 126 patients. The mean age was 37 (SD 10 years). 71% were men, 26% women, and 2% non-binary. 21% identified as Black, 16% Latine, and 52% white. 60% were unstably housed and 75% had Medicaid insurance. Substance co-use included 74% who used amphetamines, 29% cocaine, 22% benzodiazepines, and 19% alcohol. Follow up was available for 118 (67%) initiations. There was deviation from protocol instructions in 22% of these initiations with follow up. 31% had any withdrawal, including 21% with mild symptoms, 8% moderate and 2% severe. Precipitated withdrawal occurred in 10 cases, or 8% of initiations with follow up. Of these, 7 had deviation from protocol instructions; thus, there were 3 cases with follow up (3%) in which precipitated withdrawal occurred without protocol deviation. CONCLUSIONS: Withdrawal was relatively common in our cohort but was mostly mild, and precipitated withdrawal was rare. Deviation from instructions, structural barriers, and varying fentanyl use characteristics may contribute to withdrawal. Clinicians should counsel patients who use fentanyl that mild withdrawal symptoms are likely during LDI, and there is still a low risk for precipitated withdrawal. Future studies should compare withdrawal across initiation types, seek ways to support patients in initiating buprenorphine, and qualitatively elicit patients' withdrawal experiences.

Microglial Correlates of Late Life Physical Activity: Relationship with Synaptic and Cognitive Aging in Older Adults.

Physical activity relates to reduced dementia risk, but the cellular and molecular mechanisms are unknown. We translated animal and in vitro studies demonstrating a causal link between physical activity and microglial homeostasis into humans. Decedents from Rush Memory and Aging Project completed actigraphy monitoring (average daily activity) and cognitive evaluation in life, and neuropathological examination at autopsy. Brain tissue was analyzed for microglial activation via immunohistochemistry (anti-human HLA-DP-DQ-DR) and morphology (% Stage I, II, or III), and synaptic protein levels (SNAP-25, synaptophysin, complexin-I, VAMP, syntaxin, synaptotagmin-1). Proportion of morphologically activated microglia (PAM) was estimated in ventromedial caudate, posterior putamen, inferior temporal (IT), and middle frontal gyrus. The 167 decedents averaged 90 years at death, two-thirds were nondemented, and 60% evidenced pathologic Alzheimer's disease (AD). Adjusting for age, sex, education, and motor performances, greater physical activity associated with lower PAM in the ventromedial caudate and IT. Relationships between physical activity and PAM in the ventromedial caudate or IT were particularly prominent in adults evidencing microinfarcts or AD pathology, respectively. Mediational analyses indicated that PAM IT mediated ∼30% of the relationships between (1) physical activity and synaptic protein in IT, and (2) physical activity and global cognition, in separate models. However, the size of the mediation depended on AD pathology ranging from >40% in adults with high AD burden, but <10% in adults with low AD burden. Lower microglial activation may be a pathway linking physical activity to age-related brain health in humans. Physical activity may promote AD-related synaptic and cognitive resilience through reduction of pro-inflammatory microglial states.SIGNIFICANCE STATEMENT Physical activity relates to better cognitive aging and reduced risk of neurodegenerative disease, yet the cellular and molecular pathways linking behavior-to-brain in humans are unknown. Animal studies indicate that increasing physical activity leads to decreased microglial activation and corresponding increases in synaptogenesis and neurogenesis. We objectively monitored physical activity (accelerometer-based actigraphy) and cognitive performances in life, and quantified microglial activation and synaptic markers in brain tissue at death in older adults. These are the first data supporting microglial activation as a physiological pathway by which physical activity relates to brain heath in humans. Although more interventional work is needed, we suggest that physical activity may be a modifiable behavior leveraged to reduce pro-inflammatory microglial states in humans.

Post-diagnostic health behaviour scores and risk of prostate cancer progression and mortality.

BACKGROUND: Individual behaviours are associated with prostate cancer (PC) progression. Behavioural scores, comprised of multiple risk factors, allow assessment of the combined impact of multiple behaviours. METHODS: We examined the association between six a priori scores and risk of PC progression and mortality among 2156 men with PC in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) cohort: two scores developed based on the PC survivorship literature ('2021 Score [+ Diet]'); a score developed based on pre-diagnostic PC literature ('2015 Score'); and three scores based on US recommendations for cancer prevention ('WCRF/AICR Score') and survival ('ACS Score [+ Alcohol]'). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for progression and PC mortality via parametric survival models (interval censoring) and Cox models, respectively. RESULTS: Over a median (IQR) of 6.4 (1.3, 13.7) years, we observed 192 progression and 73 PC mortality events. Higher (i.e., healthier) 2021 Score + Diet and WCRF/AICR Scores were inversely associated with risk of PC progression (2021 + Diet: HRcontinuous = 0.76, 95% CI: 0.63-0.90. WCRF/AICR: HRcontinuous = 0.83, 95% CI: 0.67-1.02) and mortality (2021 + Diet: HRcontinuous = 0.65, 95% CI: 0.45-0.93. WCRF/AICR: HRcontinuous = 0.71; 95% CI: 0.57-0.89). The ACS Score + Alcohol was only associated with progression (HRcontinuous = 0.89, 95% CI: 0.81-0.98) while the 2021 Score was only associated with PC mortality (HRcontinuous = 0.62, 95% CI: 0.45-0.85). The 2015 was not associated with PC progression or mortality. CONCLUSION: Findings strengthen the evidence that behavioural modifications following a prostate cancer diagnosis may improve clinical outcomes.

Racial/ethnic disparities in wait-list outcomes are only partly explained by socioeconomic deprivation among children awaiting liver transplantation.

BACKGROUND AND AIMS: Racial/ethnic minority children have worse liver transplant (LT) outcomes. We evaluated whether neighborhood socioeconomic deprivation affected associations between race/ethnicity and wait-list mortality. APPROACH AND RESULTS: We included children (age <18) listed 2005-2015 in the Scientific Registry of Transplant Recipients. We categorized patients as non-Hispanic White, Black, Hispanic, and other. We matched patient ZIP codes to a neighborhood socioeconomic deprivation index (range, 0-1; higher values indicate worse deprivation). Primary outcomes were wait-list mortality, defined as death/delisting for too sick, and receipt of living donor liver transplant (LDLT). Competing risk analyses modeled the association between race/ethnicity and wait-list mortality, with deceased donor liver transplant (DDLT) and LDLT as competing risks, and race/ethnicity and LDLT, with wait-list mortality and DDLT as competing risks. Of 7716 children, 17% and 24% identified as Black and Hispanic, respectively. Compared to White children, Black and Hispanic children had increased unadjusted hazard of wait-list mortality (subhazard ratio [sHR], 1.44; 95% CI, 1.18, 1.75 and sHR, 1.48; 95% CI, 1.25, 1.76, respectively). After adjusting for neighborhood deprivation, insurance, and listing laboratory Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease, Black and Hispanic children did not have increased hazard of wait-list mortality (sHR, 1.12; 95% CI, 0.91, 1.39 and sHR, 1.21; 95% CI, 1.00, 1.47, respectively). Similarly, Black and Hispanic children had a decreased likelihood of LDLT (sHR, 0.58; 95% CI, 0.45, 0.75 and sHR, 0.61; 95% CI, 0.49, 0.75, respectively). Adjustment attenuated the effect of Black and Hispanic race/ethnicity on likelihood of LDLT (sHR, 0.79; 95% CI, 0.60, 1.02 and sHR, 0.89; 95% CI, 0.70, 1.11, respectively). CONCLUSIONS: Household and neighborhood socioeconomic factors and disease severity at wait-list entry help explain racial/ethnic disparities for children awaiting transplant. A nuanced understanding of how social adversity contributes to wait-list outcomes may inform strategies to improve outcomes.

A Critical Examination of Independent Medical Review Decision-making for Cardiovascular Procedures Shows Low Rate of Evidence Citation in Reviews.

BACKGROUND: The California Independent Medical Review (IMR) program was created in 2001 to provide an independent, external evaluation of insurers' denials of coverage of health services. OBJECTIVE: We sought to evaluate the quality and comprehensiveness of data used to support IMR decision-making between 2015 and 2020. RESULTS: Of the 159 cases submitted to IMR regarding denials of cardiovascular procedures, 52% of these denials were overturned by IMR, thus restoring coverage. Despite a state-wide requirement that specific references to medical and scientific evidence should be provided in IMR reviews, fewer than a quarter of reviews cited any evidence to support decision-making. Slightly more than one third of IMR review decisions were inconsistent with recommendations from professional societies and peer-reviewed evidence; the primary reason for these inconsistencies was that invasive interventions were often recommended by reviewers before utilizing guideline-directed medical or less invasive therapies. CONCLUSION: Our findings highlight an opportunity for improvement in the quality of IMR decision-making through a more consistent use of available scientific evidence to guide clinical reasoning.

Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

BACKGROUND: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).

Pattern and predictors of sites of relapse in neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.

PURPOSE: We sought to analyze biologic, clinical, and prognostic differences according to pattern of failure at the time of first relapse in neuroblastoma. PATIENTS AND METHODS: Children <21 years diagnosed with neuroblastoma between 1989 and 2017 with known site of first relapse (isolated local vs. distant only vs. combined local and distant sites) were identified from the International Neuroblastoma Risk Group (INRG) database. Data were compared between sites of relapse according to clinical features, biologic features, initial treatment, time to first relapse, and overall survival (OS) from time of first relapse. RESULTS: Pattern of first relapse among 1833 children was 19% isolated local; 65% distant only; and 16% combined sites. All evaluated clinical and biologic variables with exception of tumor diagnosis differed statistically by relapse pattern, with patients with isolated local failure having more favorable prognostic features. Patients with stage 3 disease were more likely to have isolated local failure compared to all other stages (49% vs. 16%; p < .001). OS significantly differed by relapse pattern (5-year OS ± SE): isolated local: 64% ± 3%; distant only: 23% ± 2%; and combined: 26% ± 4% (p < .001). After controlling for age, stage, and MYCN status, patients with isolated local failure (adjusted hazard ratio [HR] = 0.46; 95% confidence interval [CI]: 0.33-0.62; p < .001) and distant-only failure (adjusted HR = 0.57; 95% CI: 0.45-0.71; p < .001) remained at decreased risk for death as compared to patients with combined failure. CONCLUSION: Patients with distant-only and combined failures have a higher proportion of unfavorable clinical and biological features, and a lower survival than those with isolated local relapse.

Do changes in women's household status in Nepal improve access to food and nutrition?

Women's nutritional status remains poor in South Asia, impacting maternal and infant health outcomes. Women's household status is also low, as evidenced by eating behaviours. We started with triadic qualitative interviews with newly married women, husbands and mothers-in-law to explore the link between women's status and eating patterns, followed by longitudinal data from a cohort of 200 newly married women in rural Nepal to measure associations over time. Quantitative data were collected every 6 months for 18 months (four rounds of data) between 2018 and 2020. Interviews suggested that household relationships, women's status, and how much and what types of food she was given were intricately linked. Using mixed effects logistic regression models, we explore the association between markers of changing women's status (becoming pregnant, giving birth and working outside the home) on two outcomes (eating last always/usually and achieving minimum dietary diversity). We also explore for interaction between women's status and household food insecurity. Pregnancy increases women's dietary diversity, but this is not sustained post-partum. Women who work outside the home are less likely to eat last in the household. Food insecurity is associated with both the order of household eating and dietary diversity. Interactions between food insecurity and giving birth suggested that women who give birth in food insecure households are more likely to eat last in the household. Changes in women's household status are associated with some improvements in dietary diversity and order of household eating, but the associations are not long-lasting and depend on food security status.

Diagnostic methods for uncovering outcome dependent visit processes.

With the advent of electronic health records, information collected in the course of regular health care is increasingly being used for clinical research. The hope is that the wealth of clinical data and the realistic setting (compared with information derived from highly controlled experiments like randomized trials) will aid in the investigation of determinants of disease and understanding of which treatments are effective in regular practice and for which patients. The availability of information in such databases is often driven by how a patient feels and may therefore be associated with the health outcomes being considered. We call this an outcome dependent visit process and recent work has shown that ignoring the outcome dependence can produce significant bias in the regression coefficients when fitting longitudinal data models. It is therefore important to have tools to recognize datasets exhibiting outcome dependence. We develop a score statistic to motivate the form of diagnostic test statistics, suggest a variety of approaches for diagnosing such situations, and evaluate their performance. Simple diagnostic tests achieve high power for diagnosing outcome dependent visit processes. This occurs when generalized estimating equations methods begin to be exhibit bias in estimating regression coefficients and before likelihood based methods are substantially biased.

Worth the Wait: Delayed Recall after 1 Week Predicts Cognitive and Medial Temporal Lobe Trajectories in Older Adults.

METHOD: Clinically normal older adults (52-92 years old) were followed longitudinally for up to 8 years after completing a memory paradigm at baseline [Story Recall Test (SRT)] that assessed delayed recall at 30 min and 1 week. Subsets of the cohort underwent neuroimaging (N = 134, mean age = 75) and neuropsychological testing (N = 178-207, mean ages = 74-76) at annual study visits occurring approximately 15-18 months apart. Mixed-effects regression models evaluated if baseline SRT performance predicted longitudinal changes in gray matter volumes and cognitive composite scores, controlling for demographics. RESULTS: Worse SRT 1-week recall was associated with more precipitous rates of longitudinal decline in medial temporal lobe volumes (p = .037), episodic memory (p = .003), and executive functioning (p = .011), but not occipital lobe or total gray matter volumes (demonstrating neuroanatomical specificity; p > .58). By contrast, SRT 30-min recall was only associated with longitudinal decline in executive functioning (p = .044). CONCLUSIONS: Memory paradigms that capture longer-term recall may be particularly sensitive to age-related medial temporal lobe changes and neurodegenerative disease trajectories. (JINS, 2020, xx, xx-xx).

The search for a convenient procedure to detect one of the earliest signs of Alzheimer's disease: A systematic review of the prediction of brain amyloid status.

INTRODUCTION: Convenient, cost-effective tests for amyloid beta (Aß) are needed to identify those at higher risk for developing Alzheimer's disease (AD). This systematic review evaluates recent models that predict dichotomous Aß. (PROSPERO: CRD42020144734). METHODS: We searched Embase and identified 73 studies from 29,581 for review. We assessed study quality using established tools, extracted information, and reported results narratively. RESULTS: We identified few high-quality studies due to concerns about Aß determination and analytical issues. The most promising convenient, inexpensive classifiers consist of age, apolipoprotein E genotype, cognitive measures, and/or plasma Aß. Plasma Aß may be sufficient if pre-analytical variables are standardized and scalable assays developed. Some models lowered costs associated with clinical trial recruitment or clinical screening. DISCUSSION: Conclusions about models are difficult due to study heterogeneity and quality. Promising prediction models used demographic, cognitive/neuropsychological, imaging, and plasma Aß measures. Further studies using standardized Aß determination, and improved model validation are required.

Neuropathological correlates of structural and functional imaging biomarkers in 4-repeat tauopathies.

Neurodegenerative dementia syndromes are characterized by spreading of pathological protein deposition along syndrome-specific neural networks. Structural and functional MRI measures can assess the integrity of these networks and have been proposed as biomarkers of disease progression for clinical trials. The relationship between in vivo imaging measures and pathological features, at the single subject level, remains largely unknown. Patient-specific maps of atrophy and seed-based intrinsic connectivity disruption, as compared to normal controls, were obtained for 27 patients subsequently diagnosed with progressive supranuclear palsy (n = 16, seven males, age at death 68.9 ± 6.0 years, imaging-to-pathology interval = 670.2 ± 425.1 days) or corticobasal degeneration (n = 11, two males, age at death 66.7 ± 5.4 years, imaging-to-pathology interval = 696.2 ± 482.2 days). A linear mixed effect model with crossed random effects was used to test regional and single-subject level associations between post-mortem regional measures of neurodegeneration and tau inclusion burden, on the one hand, and regional volume loss and seed-based intrinsic connectivity reduction, on the other. A significant association was found between tau inclusion burden and in vivo volume loss, at the regional level and independent of neurodegeneration severity, in both progressive supranuclear palsy [n = 340 regions; beta 0.036; 95% confidence interval (CI): 0.001, 0.072; P = 0.046] and corticobasal degeneration (n = 215 regions; beta 0.044; 95% CI: 0.009, 0.079; P = 0.013). We also found a significant association between post-mortem neurodegeneration and in vivo volume loss in both progressive supranuclear palsy (n = 340 regions; beta 0.155; 95% CI: 0.061, 0.248; P = 0.001) and corticobasal degeneration (n = 215 regions; beta 0.277; 95% CI: 0.104, 0.450; P = 0.002). We found a significant association between regional neurodegeneration and intrinsic connectivity dysfunction in corticobasal degeneration (n = 215 regions; beta 0.074; 95% CI: 0.005, 0.143; P = 0.035), but no other associations between post-mortem measures of tauopathy and intrinsic connectivity dysfunction reached statistical significance. Our data suggest that in vivo structural imaging measures reflect independent contributions from neurodegeneration and tau burden in progressive supranuclear palsy and corticobasal degeneration. Seed-based measures of intrinsic connectivity dysfunction showed less reliable predictive value when used as in vivo biomarkers of tauopathy. The findings provide important guidance for the use of imaging biomarkers as indirect in vivo assays of microscopic pathology.

Validation of online functional measures in cognitively impaired older adults.

INTRODUCTION: Assessment of functional status is associated with risk of cognitive decline and diagnosis of dementia, and can be assessed by participants and study partners (SPs). METHODS: In 770 older adults enrolled in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study and the online Brain Health Registry (BHR), we estimated associations between online assessments and clinical variables related to Alzheimer's disease (AD) risk. RESULTS: Worse online learning scores and SP-reported functional decline were associated with higher probability of AD dementia diagnosis and poor in-clinic cognitive assessment, and with higher odds of amyloid beta (Aß) positivity when combined with participants' report of less decline. SP report of functional decline conferred predictive value independent of online cognitive assessments. Participants underreported decline compared to SPs. DISCUSSION: The results support the validity of online assessments and their greater utilization in healthcare and research settings. Online SP-reported functional decline is an indicator of dementia and AD risk.

The Longitudinal Trajectory of Default Mode Network Connectivity in Healthy Older Adults Varies As a Function of Age and Is Associated with Changes in Episodic Memory and Processing Speed.

The default mode network (DMN) supports memory functioning and may be sensitive to preclinical Alzheimer's pathology. Little is known, however, about the longitudinal trajectory of this network's intrinsic functional connectivity (FC). In this study, we evaluated longitudinal FC in 111 cognitively normal older human adults (ages 49-87, 46 women/65 men), 92 of whom had at least three task-free fMRI scans (n = 353 total scans). Whole-brain FC and three DMN subnetworks were assessed: (1) within-DMN, (2) between anterior and posterior DMN, and (3) between medial temporal lobe network and posterior DMN. Linear mixed-effects models demonstrated significant baseline age × time interactions, indicating a nonlinear trajectory. There was a trend toward increasing FC between ages 50-66 and significantly accelerating declines after age 74. A similar interaction was observed for whole-brain FC. APOE status did not predict baseline connectivity or change in connectivity. After adjusting for network volume, changes in within-DMN connectivity were specifically associated with changes in episodic memory and processing speed but not working memory or executive functions. The relationship with processing speed was attenuated after covarying for white matter hyperintensities (WMH) and whole-brain FC, whereas within-DMN connectivity remained associated with memory above and beyond WMH and whole-brain FC. Whole-brain and DMN FC exhibit a nonlinear trajectory, with more rapid declines in older age and possibly increases in connectivity early in the aging process. Within-DMN connectivity is a marker of episodic memory performance even among cognitively healthy older adults.SIGNIFICANCE STATEMENT Default mode network and whole-brain connectivity, measured using task-free fMRI, changed nonlinearly as a function of age, with some suggestion of early increases in connectivity. For the first time, longitudinal changes in DMN connectivity were shown to correlate with changes in episodic memory, whereas volume changes in relevant brain regions did not. This relationship was not accounted for by white matter hyperintensities or mean whole-brain connectivity. Functional connectivity may be an early biomarker of changes in aging but should be used with caution given its nonmonotonic nature, which could complicate interpretation. Future studies investigating longitudinal network changes should consider whole-brain changes in connectivity.

Perceived Stress is Associated with Accelerated Monocyte/Macrophage Aging Trajectories in Clinically Normal Adults.

OBJECTIVES: Chronic stress is associated with poorer age-related cognition, but the mechanisms of this relationship are not well understood. Aging increases expression of activated macrophages, leading to exacerbated immune responses to stressors. We examined the impact of stress and aging on macrophage-related inflammation and cognition in clinically normal adults. METHODS: Three hundred eighty clinically normal adults were followed longitudinally (age M = 73 years; visit range: 1-8; M = 2.5 visits). Participants completed the Perceived Stress Scale, a neuropsychological battery, and blood draws. Plasma was analyzed for cytokines related to macrophage function (interleukin 6, tumor necrosis factor alpha, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta). Linear mixed-effects examined the effects of age, baseline stress, and their interaction predicting macrophage cytokines, adjusting for sex, education, and depressive symptoms. Latent growth curve models assessed the mediating role of macrophage cytokines in the relationship between age and cognition in high or low stress. RESULTS: Baseline perceived stress interacted with age to predict macrophage cytokines longitudinally. Specifically, high-stress adults demonstrated accelerated age-related elevations in macrophage cytokines across time. Macrophage cytokines negatively tracked with executive functioning longitudinally. Macrophage cytokines mediated 19% of the relationship between age and executive function in high-stress, but not low-stress, adults. CONCLUSIONS: Our data provide evidence of accelerated immune aging among individuals with high stress. Elevated macrophage cytokine trajectories mediated the effect of age on executive function only in individuals with high stress, suggesting these constructs may be more tightly linked in elevated stress contexts. Stress interventions are warranted to optimize immune aging, with possible downstream cognitive benefits among even clinically normal adults.

Analysis of longitudinal data from outcome-dependent visit processes: Failure of proposed methods in realistic settings and potential improvements.

The timing and frequency of the measurement of longitudinal outcomes in databases may be associated with the value of the outcome. Such visit processes are termed outcome dependent, and previous work showed that conducting standard analyses that ignore outcome-dependent visit times can produce highly biased estimates of the associations of covariates with outcomes. The literature contains several classes of approaches to analyze longitudinal data subject to outcome-dependent visit times, and all of these are based on simplifying assumptions about the visit process. Based on extensive discussions with subject matter investigators, we identified common characteristics of outcome-dependent visit processes that allowed us to evaluate the performance of existing methods in settings with more realistic visit processes than have been previously investigated. This paper uses the analysis of data from a study of kidney function, theory, and simulation studies to examine a range of settings that vary from those where all visits have a low degree of missingness and outcome dependence (which we call "regular" visits) to those where all visits have a high degree of missingness and outcome dependence (which we call "irregular" visits). Our results show that while all the approaches we studied can yield biased estimates of some covariate effects, other covariate effects can be estimated with little bias. In particular, mixed effects models fit by maximum likelihood yielded little bias in estimates of the effects of covariates not associated with the random effects and small bias in estimates of the effects of covariates associated with the random effects. Other approaches produced estimates with greater bias. Our results also show that the presence of some regular visits in the data set protects mixed model analyses from bias but not other methods.