Pubertal Girls With Overweight/Obesity Have Higher Androgen Levels-Can Metabolomics Tell us Why?

CONTEXT: Pubertal girls with higher total body fat (TBF) demonstrate higher androgen levels. The cause of this association is unknown but is hypothesized to relate to insulin resistance. OBJECTIVE: This work aimed to investigate the association between higher TBF and higher androgens in pubertal girls using untargeted metabolomics. METHODS: Serum androgens were determined using a quantitative mass spectrometry (MS)-based assay. Metabolomic samples were analyzed using liquid chromatography high-resolution MS. Associations between TBF or body mass index (BMI) z score (exposure) and metabolomic features (outcome) and between metabolomic features (exposure) and serum hormones (outcome) were examined using gaussian generalized estimating equation models with the outcome lagged by one study visit. Benjamini-Hochberg false discovery rate (FDR) adjusted P values were calculated to account for multiple testing. RaMP-DB (relational database of metabolomic pathways) was used to conduct enriched pathway analyses among features nominally associated with body composition or hormones. RESULTS: Sixty-six pubertal, premenarchal girls (aged 10.9 ± 1.39 SD years; 60% White, 24% Black, 16% other; 63% normal weight, 37% overweight/obese) contributed an average of 2.29 blood samples. BMI and TBF were negatively associated with most features including raffinose (a plant trisaccharide) and several bile acids. For BMI, RaMP-DB identified many enriched pathways related to bile acids. Androstenedione also showed strong negative associations with raffinose and bile acids. CONCLUSION: Metabolomic analyses of samples from pubertal girls did not identify an insulin resistance signature to explain the association between higher TBF and androgens. Instead, we identified potential novel signaling pathways that may involve raffinose or bile acid action at the adrenal gland.

Probable Parasomnias and Mortality: A Prospective Study in US Men.

OBJECTIVE: To examine the association between parasomnias, including rapid eye movement sleep behavior disorder (RBD) and sleep walking (SW), and mortality risk in a large-scale population-based cohort. METHODS: This prospective cohort study was based on 25,695 participants from the Health Professionals Follow-up Study, a population-based cohort of male health professionals in the United States. Probable SW (pSW) and probable RBD (pRBD) were measured by questions adapted from the Mayo Sleep Questionnaire in 2012. All-cause mortality and cause-specific mortality were ascertained through the national registry, reports by the families, and the postal system from January 1, 2012, through June 30, 2018. RESULTS: Of the studied population, 223 reported pSW and 2720 reported pRBD. During 6 years of follow-up (2012 to 2018), 4743 mortality cases were documented. The co-occurrence of both probable parasomnias was associated with higher all-cause mortality risk (Ptrend=.008), and the adjusted hazard ratio (HR) of mortality was 1.65 (95% CI, 1.20 to 2.28) compared with participants without either probable parasomnia after adjustment for major lifestyle, sleep, and metabolic risk factors, and chronic diseases. Significant associations were found for mortality attributed to neurodegenerative diseases (adjusted HR for both parasomnias vs none, 4.57; 95% CI, 2.62 to 7.97) and accidents (adjusted HR for both parasomnias vs none, 7.36; 95% CI, 2.95 to 18.4). Having pSW alone was associated with all-cause mortality, and pSW and pRBD were individually associated with mortality attributed to neurodegenerative diseases and accidents too (P<.05 for all). CONCLUSION: Probable parasomnia was associated with a higher risk of all-cause mortality and mortality attributed to neurodegenerative diseases and accidents.

Long-Term Intake of Folate, Vitamin B6, and Vitamin B12 and the Incidence of Parkinson's Disease in a Sample of U.S. Women and Men.

BACKGROUND: Folate and vitamins B6 and B12 have been proposed as protective against the development of Parkinson's disease (PD). Two prior longitudinal studies were inconclusive. OBJECTIVE: The aim was to examine the association of long-term intake of folate, vitamin B6, and vitamin B12 with the incidence of PD. METHODS: The study population comprised 80,965 women (Nurses' Health Study, 1984-2016) and 48,837 men (Health Professionals Follow-up Study, 1986-2016) followed prospectively for the development of PD. Intake of B vitamins was measured at baseline and every 4 years thereafter using food frequency questionnaires. We estimated the hazard ratio (HR) and 95% confidence interval (CI) of PD based on quintiles of cumulative average intake adjusting for potential confounders. Secondary analyses considered different lagged exposure periods as well as baseline and recent intakes. RESULTS: In separate analyses of cumulative average intake, total folate, B6, and B12 were not associated with the risk of PD. Results from 8-, 12-, and 16-year lag analyses were consistent with these findings. Results for baseline intake of folate and B6 also pointed toward a null association. In contrast, a lower PD risk was observed among individuals with higher baseline total intake of B12 (pooled HR top vs. bottom quintile: 0.80; 95% CI: 0.67-0.95; P-trend = 0.01); results from 20-year lag analyses were consistent with this finding. CONCLUSIONS: Our results do not support the hypothesis that a higher intake of folate or vitamin B6 would reduce PD risk in this population. Our results provide moderate support for a possible protective effect of vitamin B12 on the development of PD. © 2023 International Parkinson and Movement Disorder Society.

Implementing machine learning methods with complex survey data: Lessons learned on the impacts of accounting sampling weights in gradient boosting.

Despite the prominent use of complex survey data and the growing popularity of machine learning methods in epidemiologic research, few machine learning software implementations offer options for handling complex samples. A major challenge impeding the broader incorporation of machine learning into epidemiologic research is incomplete guidance for analyzing complex survey data, including the importance of sampling weights for valid prediction in target populations. Using data from 15, 820 participants in the 1988-1994 National Health and Nutrition Examination Survey cohort, we determined whether ignoring weights in gradient boosting models of all-cause mortality affected prediction, as measured by the F1 score and corresponding 95% confidence intervals. In simulations, we additionally assessed the impact of sample size, weight variability, predictor strength, and model dimensionality. In the National Health and Nutrition Examination Survey data, unweighted model performance was inflated compared to the weighted model (F1 score 81.9% [95% confidence interval: 81.2%, 82.7%] vs 77.4% [95% confidence interval: 76.1%, 78.6%]). However, the error was mitigated if the F1 score was subsequently recalculated with observed outcomes from the weighted dataset (F1: 77.0%; 95% confidence interval: 75.7%, 78.4%). In simulations, this finding held in the largest sample size (N = 10,000) under all analytic conditions assessed. For sample sizes <5,000, sampling weights had little impact in simulations that more closely resembled a simple random sample (low weight variability) or in models with strong predictors, but findings were inconsistent under other analytic scenarios. Failing to account for sampling weights in gradient boosting models may limit generalizability for data from complex surveys, dependent on sample size and other analytic properties. In the absence of software for configuring weighted algorithms, post-hoc re-calculations of unweighted model performance using weighted observed outcomes may more accurately reflect model prediction in target populations than ignoring weights entirely.

Dynamic impairment classification through arrayed comparisons.

The multivariate normative comparison (MNC) method has been used for identifying cognitive impairment. When participants' cognitive brain domains are evaluated regularly, the longitudinal MNC (LMNC) has been introduced to correct for the intercorrelation among repeated assessments of multiple cognitive domains in the same participant. However, it may not be practical to wait until the end of study for diagnosis. For example, in participants of the Multicenter AIDS Cohort Study (MACS), cognitive functioning has been evaluated repeatedly for more than 35 years. Therefore, it is optimal to identify cognitive impairment at each assessment, while the family-wise error rate (FWER) is controlled with unknown number of assessments in future. In this work, we propose to use the difference of consecutive LMNC test statistics to construct independent tests. Frequency modeling can help predict how many assessments each participant will have, so Bonferroni-type correction can be easily adapted. A chi-squared test is used under the assumption of multivariate normality, and permutation test is proposed where this assumption is violated. We showed through simulation and the MACS data that our method controlled FWER below a predetermined level.

Who to Enroll in Parkinson Disease Prevention Trials? The Case for Composite Prodromal Cohorts.

Significant progress has been made in expanding our understanding of prodromal Parkinson disease (PD), particularly for recognition of early motor and nonmotor signs and symptoms. Although identification of these prodromal features may improve our understanding of the earliest stages of PD, they are individually insufficient for early disease detection and enrollment of participants in prevention trials in most cases because of low sensitivity, specificity, and positive predictive value. Composite cohorts, composed of individuals with multiple co-occurring prodromal features, are an important resource for conducting prodromal PD research and eventual prevention trials because they are more representative of the population at risk for PD, allow investigators to evaluate the efficacy of an intervention across individuals with varying prodromal feature patterns, are able to produce larger sample sizes, and capture individuals at different stages of prodromal PD. A key challenge in identifying individuals with prodromal disease for composite cohorts and prevention trial participation is that we know little about the natural history of prodromal PD. To move toward prevention trials, it is critical that we better understand common prodromal feature patterns and be able to predict the probability of progression and phenoconversion. Ongoing research in cohort studies and administrative databases is beginning to address these questions, but further longitudinal analyses in a large population-based sample are necessary to provide a convincing and definitive strategy for identifying individuals to be enrolled in a prevention trial.

Association of Diet and Physical Activity With All-Cause Mortality Among Adults With Parkinson Disease.

Importance: Greater diet quality and physical activity level are associated with a lower risk of developing Parkinson disease (PD). However, information regarding the association between lifestyle behaviors and survival after PD diagnosis remains limited. Objective: To examine the association of prediagnosis and postdiagnosis overall diet quality and physical activity with all-cause mortality among individuals with PD. Design, Setting, and Participants: This population-based cohort study analyzed male participants in the Health Professionals Follow-up Study from 1986 to 2012 and female participants in the Nurses' Health Study from 1984 to 2012. Participants who were diagnosed with PD and had complete baseline dietary assessment data were included. Data were analyzed from January 2021 to February 2022. Exposures: Prediagnosis diet quality, assessed by the Alternative Healthy Eating Index (AHEI), and physical activity, assessed by metabolic equivalent task (MET) hours per week reported on questionnaires, were the primary exposures of interest to minimize reverse causation. Main Outcomes and Measures: Mortality, which was followed up until 2018, was the primary outcome. Cox proportional hazards regression models were used to estimate the association of diet and physical activity with mortality individually and jointly, and the models were adjusted for age, total energy intake, caffeine intake, and other lifestyle risk factors. Results: The sample comprised 1251 individuals with PD, which included 652 men (52.1%) with a median (IQR) age at diagnosis of 73.4 (67.5-78.7) years. During the 32 to 34 years of follow-up, 942 participants died. The adjusted hazard ratio (HR) comparing the highest vs the lowest AHEI quartile was 0.69 (95% CI, 0.56- 0.85) for prediagnosis analyses and 0.57 (95% CI, 0.42-0.78) for postdiagnosis analyses. Similar results were obtained for cumulative mean MET hours per week in the prediagnosis analyses (HR, 0.71; 95% CI, 0.57-0.87) and postdiagnosis analyses (HR, 0.47; 95% CI, 0.35-0.63). The inverse association persisted for PD-specific mortality (postdiagnosis AHEI: HR, 0.52 [95% CI, 0.33-0.80]; postdiagnosis physical activity: HR, 0.37 [95% CI, 0.25-0.55]). In the joint analyses of diet quality and physical activity before the PD diagnosis, the adjusted HR was 0.51 (95% CI, 0.36-0.73) for individuals in the highest vs lowest tertiles for both variables. The HR for diet quality and physical activity after the diagnosis was 0.35 (95% CI, 0.23-0.52). Conclusions and Relevance: Results of this study showed that a healthy dietary pattern and an active lifestyle were associated with a lower rate of all-cause mortality among individuals with PD. Consuming a healthy diet and engaging in physical activity or exercise could be targeted to improve PD outcomes.

Serum antioxidant vitamins and respiratory morbidity and mortality: a pooled analysis.

BACKGROUND: Oxidative stress plays a key role in the pathogenesis of respiratory diseases; however, studies on antioxidant vitamins and respiratory outcomes have been conflicting. We evaluated whether lower serum levels of vitamins A, C, D, and E are associated with respiratory morbidity and mortality in the U.S. adult population. METHODS: We conducted a pooled analysis of data from the 1988-1994 and 1999-2006 National Health and Nutrition Examination Survey (participants aged ≥ 20 years). We estimated covariate-adjusted odds ratios (aOR) per interquartile decrease in each serum vitamin level to quantify associations with respiratory morbidity, and covariate-adjusted hazard ratios (aHR) to quantify associations with respiratory mortality assessed prospectively through 2015. Vitamin supplementation and smoking were evaluated as potential effect modifiers. RESULTS: Lower serum vitamin C increased the odds of wheeze among all participants (overall aOR: 1.08, 95% CI: 1.01-1.16). Among smokers, lower serum α-tocopherol vitamin E increased the odds of wheeze (aOR: 1.11, 95% CI: 1.04-1.19) and chronic bronchitis/emphysema (aOR: 1.13, 95% CI: 1.03-1.24). Conversely, lower serum γ-tocopherol vitamin E was associated with lower odds of wheeze and chronic bronchitis/emphysema (overall aORs: 0.85, 95% CI: 0.79-0.92 and 0.85, 95% CI: 0.76-0.95, respectively). Lower serum vitamin C was associated with increased chronic lower respiratory disease (CLRD) mortality in all participants (overall aHR: 1.27, 95% CI: 1.07-1.51), whereas lower serum 25-hydroxyvitamin D (25-OHD) tended to increase mortality from CLRD and influenza/pneumonia among smokers (aHR range: 1.33-1.75). Mortality from influenza/ pneumonia increased with decreasing serum vitamin A levels in all participants (overall aHR: 1.21, 95% CI: 0.99-1.48). In pooled analysis, vitamin C deficiency and 25-OHD insufficiency were associated with mortality from influenza/pneumonia, increasing mortality risk up to twofold. CONCLUSIONS: Our analysis of nationally representative data on over 34,000 participants showed that lower serum levels of vitamins A, C, D, and α-tocopherol vitamin E are associated with increased respiratory morbidity and/or mortality in U.S. adults. The results underscore the importance of antioxidant vitamins in respiratory health.

Intake of Flavonoids and Flavonoid-Rich Foods and Mortality Risk Among Individuals With Parkinson Disease: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Although flavonoids have the potential to exert neuroprotective benefits, evidence of their role in improving survival rates among individuals with Parkinson disease (PD) remains lacking. We aimed to prospectively study the association between prediagnosis and postdiagnosis flavonoid intakes and risk of mortality among individuals with PD identified from 2 large ongoing cohorts of US men and women. METHODS: Included in the current analysis were 599 women from the Nurses' Health Study and 652 men from the Health Professionals Follow-Up Study who were newly diagnosed with PD during follow-up. Dietary intakes of total flavonoid and its subclasses, together with major flavonoid-rich foods (tea, apples, berries, orange and orange juice, and red wine), were repeatedly assessed with a validated food frequency questionnaire every 4 years. Mortality was ascertained via the National Death Index and state vital statistics records. RESULTS: We documented 944 deaths during 32 to 34 years of follow-up. A higher total flavonoid intake before PD diagnosis was associated with a lower future risk for all-cause mortality in men (hazard ratio [HR] comparing 2 extreme quartiles 0.53, 95% confidence interval [CI] 0.39, 0.71; p for trend < 0.001) but not in women (HR 0.93, 95% CI 0.68, 1.28; p for trend = 0.69) after adjustment for age, smoking status, total energy intake, and other covariates. The pooled HR comparing the extreme quartiles was 0.70 (95% CI 0.40, 1.22; p for trend = 0.25) with significant heterogeneity (p = 0.01). For flavonoid subclasses, the highest quartile of anthocyanins, flavones, and flavan-3-ols intakes before diagnosis had a lower mortality risk compared to the lowest quartile (pooled HR 0.66, 0.78, and 0.69, respectively; p < 0.05 for all); for berries and red wine, participants consuming ≥3 servings per week had a lower risk (pooled HR 0.77, 95% CI 0.58, 1.02; and pooled HR 0.68, 95% CI 0.51, 0.91, respectively) compared to <1 serving per month. After PD diagnosis, greater consumptions of total flavonoid, subclasses including flavonols, anthocyanins, flavan-3-ols, and polymers, and berries and red wine were associated with lower mortality risk (p < 0.05 for all). DISCUSSION: Among individuals with PD, higher consumption of flavonoids, especially anthocyanins and flavan-3-ols, and flavonoid-rich food such as berries and red wine was likely to be associated with a lower risk of mortality.

Acute Sleep Disruption Does Not Diminish Pulsatile Growth Hormone Secretion in Pubertal Children.

Context: In children, growth hormone (GH) pulses occur after sleep onset in association with slow-wave sleep (SWS). There have been no studies in children to quantify the effect of disrupted sleep on GH secretion. Objective: This study aimed to investigate the effect of acute sleep disruption on GH secretion in pubertal children. Methods: Fourteen healthy individuals (aged 11.3-14.1 years) were randomly assigned to 2 overnight polysomnographic studies, 1 with and 1 without SWS disruption via auditory stimuli, with frequent blood sampling to measure GH. Results: Auditory stimuli delivered during the disrupted sleep night caused a 40.0 ± 7.8% decrease in SWS. On SWS-disrupted sleep nights, the rate of GH pulses during N2 sleep was significantly lower than during SWS (IRR = 0.56; 95% CI, 0.32-0.97). There were no differences in GH pulse rates during the various sleep stages or wakefulness in disrupted compared with undisrupted sleep nights. SWS disruption had no effect on GH pulse amplitude and frequency or basal GH secretion. Conclusion: In pubertal children, GH pulses were temporally associated with episodes of SWS. Acute disruption of sleep via auditory tones during SWS did not alter GH secretion. These results indicate that SWS may not be a direct stimulus of GH secretion.

Changes in plasma phospholipids and sphingomyelins with aging in men and women: A comprehensive systematic review of longitudinal cohort studies.

BACKGROUND: Aging affects the serum levels of various metabolites which may be involved in the pathogenesis of chronic diseases. The aim of this review article is to summarize the relationship between aging and alterations in the plasma phospholipids and sphingomyelins. METHODS: PRISMA guidelines were employed during all steps. MEDLINE (PubMed), Scopus, Embase and Web of Sciences databases and Google Scholar were searched up to October 2020. Cohort studies investigating the relationship between aging and within-person changes in sphingomyelin (SM), phosphatidyl choline (PC), lyso PC (LPC) and phosphatidyl ethanolamine (PE) were included. Newcastle-Ottawa scale was used to assess the quality of included studies. RESULTS: A total of 1425 studies were identified. After removing 610 duplicates and 723 irrelevant studies, full texts of 92 articles were evaluated. Of these 92, 6 studies (including data from 7 independent cohorts) met the inclusion criteria and are included in this review. All study populations were healthy and included both men and women. Results by sex were reported in 3 cohorts for PC, 5 cohorts for LPC, 3 cohorts for SM, and only 1 cohort for PE. In men, PC, SM, PE and LPC decreased with aging, although results for LPC were inconsistent. In women, LPC, SM, and PE increased age, whereas changes in PC were inconsistent. CONCLUSION: Within-person serum levels of phospholipids and sphingomyelins, decrease during aging in men and increase in women. Notably, however, there were some inconsistencies across studies of LPC in men and of PC in women.

Association of Sleepwalking and REM Sleep Behavior Disorder With Parkinson Disease in Men.

Importance: Previous studies conducted among patients with Parkinson disease (PD) reported that parasomnias other than rapid eye movement (REM) sleep behavior disorder (RBD), particularly sleepwalking (SW), are associated with PD severity. However, it remains unclear whether the presence of SW is associated with altered odds of having PD in a population-based study. Objective: To evaluate whether probable SW, either alone or co-occurring with probable RBD, is associated with higher odds of PD in men. Design, Setting, and Participants: This cross-sectional study included 25 694 men from the Health Professionals Follow-up Study, a population-based cohort of male health professionals in the US with information on probable SW and probable RBD. Data collection took place between January 2012 and June 2018, and data analysis took place from July 2020 to October 2020. Exposures: Probable SW and probable RBD were measured by questions adapted from the Mayo Sleep Questionnaire in 2012. Main Outcomes and Measures: PD, confirmed after review of medical records by a movement disorder specialist. Results: Of the 25 694 studied men (mean [SD] age, 75.6 [7.4] years), 223 (0.9%) had probable SW, 2720 (10.6%) had probable RBD, and 257 (1.0%) had PD. After adjusting for potential confounders (eg, age, smoking, caffeine intake, chronic disease status, and other sleep disorders), compared with individuals without probable SW and probable RBD, participants with probable SW, probable RBD, and both probable SW and probable RBD had higher odds of PD, (probable SW: odds ratio [OR], 4.80; 95% CI, 1.61-14.26; probable RBD: OR, 6.36; 95% CI, 4.83-8.37; both probable SW and probable RBD: OR, 8.44; 95% CI, 3.90-18.27). Conclusions and Relevance: In this cross-sectional study of a male population, probable sleep parasomnias, including both SW and RBD, were associated with higher odds of having PD. PD-related neurodegeneration may impair arousal regulation during sleep.

Brain structural correlates of trajectories to cognitive impairment in men with and without HIV disease.

There are distinct trajectories to cognitive impairment among participants in the Multicenter AIDS Cohort Study (MACS). Here we analyzed the relationship between regional brain volumes and the individual trajectories to impairment in a subsample (n = 302) of the cohort. 302 (167 HIV-infected; mean age = 55.7 yrs.; mean education: 16.2 yrs.) of the men enrolled in the MACS MRI study contributed data to this analysis. We used voxel-based morphometry (VBM) to segment the brain images to analyze gray and white matter volume at the voxel-level. A Mixed Membership Trajectory Model had previously identified three distinct profiles, and each study participant had a membership weight for each of these three trajectories. We estimated VBM model parameters for 100 imputations, manually performed the post-hoc contrasts, and pooled the results. We examined the associations between brain volume at the voxel level and the MMTM membership weights for two profiles: one considered "unhealthy" and the other considered "Premature aging." The unhealthy profile was linked to the volume of the posterior cingulate gyrus/precuneus, the inferior frontal cortex, and the insula, whereas the premature aging profile was independently associated with the integrity of a portion of the precuneus. Trajectories to cognitive impairment are the result, in part, of atrophy in cortical regions linked to normal and pathological aging. These data suggest the possibility of predicting cognitive morbidity based on patterns of CNS atrophy.

Metabolomic markers of antepartum depression and suicidal ideation.

BACKGROUND: Recent analyses have described metabolomic markers for depression and suicidal ideation in non-pregnant adults. We examined the metabolomic profile of antepartum depression and suicidal ideation during mid-pregnancy, a time of high susceptibility to mood disorders. METHODS: We collected fasting blood from 100 pregnant Peruvian women and profiled 307 plasma metabolites using liquid chromatography-mass spectrometry. We used the Patient Health Questionnaire 9 to define antepartum depression (score  ≥ 10) and suicidal ideation (having thoughts that you would be better off dead, or of hurting yourself). Logistic regression was used to calculate odds ratios (ORs). RESULTS: Three triacylglycerol metabolites (C48:5 triacylglycerol [OR = =1.89; 95% confidence interval (CI): 1.14-3.14], C50:6 triacylglycerol [OR = =1.88; 95%CI: 1.13-3.14], C46:4 triacylglycerol [OR = =1.89; 95%CI: 1.11-3.21]) were associated with higher odds of antepartum depression and 4 metabolites (betaine [OR = =0.56; 95%CI:0.33-0.95], citrulline [OR = =0.58; 95%CI: 0.34-0.98], C5 carnitine [OR = =0.59; 95%CI: 0.36-0.99], C5:1 carnitine [OR = =0.59; 95%CI: 0.35-1.00]) with lower odds of antepartum depression. Twenty-six metabolites, including 5-hydroxytryptophan (OR = =0.52; 95%CI: 0.30-0.92), phenylalanine (OR = =0.41; 95%CI: 0.19-0.91), and betaine (OR = =0.53; 95%CI: 0.28-0.99) were associated with lower odds of suicidal ideation. LIMITATIONS: Our cross-sectional study could not determine whether metabolites prospectively predict outcomes. No metabolites remained significant after multiple testing correction; these novel findings should be replicated in a larger sample. CONCLUSIONS: Antepartum suicidal ideation metabolomic markers are similar to markers of depression among non-pregnant adults, and distinct from markers of antepartum depression. Findings suggest that mood disorder in pregnancy shares metabolomic similarities to mood disorder at other times and may further understanding of these conditions' pathophysiology.

Cross-sectional analysis of cognitive function using multivariate normative comparisons in men with HIV disease.

BACKGROUND: Prevalence estimates of cognitive impairment in HIV disease vary widely. Here we used multivariate normative comparison (MNC) with identify individuals with impaired cognition, and to compare the results with those using the Frascati and Gisslén criteria. METHODS: The current project used data collected before October 2014 from bisexual/gay men from the Multicenter AIDS Cohort Study. A total of 2904 men (mean age 39.7 years, 52.7% seropositive) had complete data in six cognitive domains at their first neuropsychological evaluation. T-scores were computed for each domain and the MNC was applied to detect impairment among seronegative and seropositive groups. RESULTS: The MNC classified 6.26% of seronegative men as being impaired using a predetermined 5% false discovery rate. By contrast, the Frascati and the Gisslén criteria identified 24.54 and 11.36% of seronegative men as impaired. For seropositive men, the percentage impairment was 7.45, 25.73, and 11.69%, respectively, by the MNC, Frascati and Gisslén criteria. When we used seronegative men without medical comorbidities as the control group, the MNC, the Frascati and the Gisslén criteria identified 5.05, 27.07, and 4.21% of the seronegative men, and 4.34, 30.95, and 4.48% of the seropositive men as having cognitive impairment. For each method, serostatus was not associated with cognitive impairment. CONCLUSION: The MNC controls the false discovery rate and therefore avoids the low specificity that characterizes the Frascati and Gisslén criteria. More research is needed to evaluate the sensitivity of the MNC method in a seropositive population that may be sicker and older than the current study sample and that includes women.

Neuropsychological phenotypes among men with and without HIV disease in the multicenter AIDS cohort study.

OBJECTIVE: Mild forms of HIV-associated neurocognitive disorder (HAND) remain prevalent in the combination antiretroviral therapy (cART) era. This study's objective was to identify neuropsychological subgroups within the Multicenter AIDS Cohort Study (MACS) based on the participant-based latent structure of cognitive function and to identify factors associated with subgroups. DESIGN: The MACS is a four-site longitudinal study of the natural and treated history of HIV disease among gay and bisexual men. METHODS: Using neuropsychological domain scores, we used a cluster variable selection algorithm to identify the optimal subset of domains with cluster information. Latent profile analysis was applied using scores from identified domains. Exploratory and posthoc analyses were conducted to identify factors associated with cluster membership and the drivers of the observed associations. RESULTS: Cluster variable selection identified all domains as containing cluster information except for Working Memory. A three-profile solution produced the best fit for the data. Profile 1 performed below average on all domains, Profile 2 performed average on executive functioning, motor, and speed and below average on learning and memory, Profile 3 performed at or above average across all domains. Several demographic, cognitive, and social factors were associated with profile membership; these associations were driven by differences between Profile 1 and the other profiles. CONCLUSION: There is an identifiable pattern of neuropsychological performance among MACS members determined by all domains except Working Memory. Neither HIV nor HIV-related biomarkers were related with cluster membership, consistent with other findings that cognitive performance patterns do not map directly onto HIV serostatus.

Mixed membership trajectory models of cognitive impairment in the multicenter AIDS cohort study.

OBJECTIVE: The longitudinal trajectories that individuals may take from a state of normal cognition to HIV-associated dementia are unknown. We applied a novel statistical methodology to identify trajectories to cognitive impairment, and factors that affected the 'closeness' of an individual to one of the canonical trajectories. DESIGN: The Multicenter AIDS Cohort Study (MACS) is a four-site longitudinal study of the natural and treated history of HIV disease among gay and bisexual men. METHODS: Using data from 3892 men (both HIV-infected and HIV-uninfected) enrolled in the neuropsychology substudy of the MACS, a Mixed Membership Trajectory Model (MMTM) was applied to capture the pathways from normal cognitive function to mild impairment to severe impairment. MMTMs allow the data to identify canonical pathways and to model the effects of risk factors on an individual's 'closeness' to these trajectories. RESULTS: First, we identified three distinct trajectories to cognitive impairment: 'normal aging' (low probability of mild impairment until age 60); 'premature aging' (mild impairment starting at age 45-50); and 'unhealthy' (mild impairment in 20s and 30s) profiles. Second, clinically defined AIDS, and not simply HIV disease, was associated with closeness to the premature aging trajectory, and, third, hepatitis-C infection, depression, race, recruitment cohort and confounding conditions all affected individual's closeness to these trajectories. CONCLUSION: These results provide new insight into the natural history of cognitive dysfunction in HIV disease and provide evidence for a potential difference in the pathophysiology of the development of cognitive impairment based on trajectories to impairment.