Pioneering a Multi-Phase Framework to Harmonize Self-Reported Sleep Data Across Cohorts.

STUDY OBJECTIVES: Harmonizing and aggregating data across studies enable pooled analyses that support external validation and enhance replicability and generalizability. However, the multidimensional nature of sleep poses challenges for data harmonization and aggregation. Here we describe and implement our process for harmonizing self-reported sleep data. METHODS: We established a multi-phase framework to harmonize self-reported sleep data: (1) compile items; (2) group items into domains; (3) harmonize items; and (4) evaluate harmonizability. We applied this process to produce a pooled multi-cohort sample of five United States cohorts plus a separate yet fully harmonized sample from Rotterdam, Netherlands. Sleep and sociodemographic data are described and compared to demonstrate the utility of harmonization and aggregation. RESULTS: We collected 190 unique self-reported sleep items and grouped them into 15 conceptual domains. Using these domains as guiderails, we developed 14 harmonized items measuring aspects of Satisfaction, Alertness/Sleepiness, Timing, Efficiency, Duration, Insomnia, and Sleep Apnea. External raters determined that 13 of these 14 items had moderate-to-high harmonizability. Alertness/Sleepiness items had lower harmonizability, while continuous, quantitative items (e.g., timing, total sleep time, efficiency) had higher harmonizability. Descriptive statistics identified features that are more consistent (e.g., wake-up time, duration) and more heterogeneous (e.g., time in bed, bedtime) across samples. CONCLUSIONS: Our process can guide researchers and cohort stewards towards effective sleep harmonization and provides a foundation for further methodological development in this expanding field. Broader national and international initiatives promoting common data elements across cohorts are needed to enhance future harmonization and aggregation efforts.

Correlates of Person-Specific Rates of Change in Sensor-Derived Physical Activity Metrics of Daily Living in the Rush Memory and Aging Project.

This study characterized person-specific rates of change of total daily physical activity (TDPA) and identified correlates of this change. TDPA metrics were extracted from multiday wrist-sensor recordings from 1083 older adults (average age 81 years; 76% female). Thirty-two covariates were collected at baseline. A series of linear mixed-effect models were used to identify covariates independently associated with the level and annual rate of change of TDPA. Though, person-specific rates of change varied during a mean follow-up of 5 years, 1079 of 1083 showed declining TDPA. The average decline was 16%/year, with a 4% increased rate of decline for every 10 years of age older at baseline. Following variable selection using multivariate modeling with forward and then backward elimination, age, sex, education, and 3 of 27 non-demographic covariates including motor abilities, a fractal metric, and IADL disability remained significantly associated with declining TDPA accounting for 21% of its variance (9% non-demographic and 12% demographics covariates). These results show that declining TDPA occurs in many very old adults. Few covariates remained correlated with this decline and the majority of its variance remained unexplained. Further work is needed to elucidate the biology underlying TDPA and to identify other factors that account for its decline.

Sex differences in associations between APOE ε2 and longitudinal cognitive decline.

INTRODUCTION: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples. METHODS: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately. RESULTS: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010). DISCUSSION: In NHW adults, APOE ε2 may protect men but not women against cognitive decline. HIGHLIGHTS: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.

Fragmentation of rest periods, astrocyte activation, and cognitive decline in older adults with and without Alzheimer's disease.

INTRODUCTION: Sleep disruption is associated with astrocyte activation and impaired cognition in model organisms. However, the relationship among sleep, astrocyte activation, and cognition in humans is uncertain. METHODS: We used RNA-seq to quantify the prefrontal cortex expression of a panel of human activated astrocyte marker genes in 1076 older adults in the Religious Orders Study and Rush Memory and Aging Project, 411 of whom had multi-day actigraphy prior to death. We related this to rest fragmentation, a proxy for sleep fragmentation, and to longitudinal cognitive function. RESULTS: Fragmentation of rest periods was associated with higher expression of activated astrocyte marker genes, which was associated with a lower level and faster decline of cognitive function. DISCUSSION: Astrocyte activation and fragmented rest are associated with each other and with accelerated cognitive decline. If experimental studies confirm a causal relationship, targeting sleep fragmentation and astrocyte activation may benefit cognition in older adults. HIGHLIGHTS: Greater fragmentation of rest periods, a proxy for sleep fragmentation, is associated with higher composite expression of a panel of genes characteristic of activated astrocytes. Increased expression of genes characteristic of activated astrocytes was associated with a lower level and more rapid decline of cognitive function, beyond that accounted for by the burden of amyloid and neurofibrillary tangle pathology. Longitudinal and experimental studies are needed to delineate the causal relationships among sleep, astrocyte activation, and cognition.

Investigating changes in cognition associated with the use of CPAP in cognitive impairment and dementia: A retrospective study.

STUDY OBJECTIVES: To characterize the impact of CPAP use on cognition in a clinical cohort with obstructive sleep apnea (OSA) and cognitive impairment due to neurodegenerative or vascular etiologies after controlling for baseline sleepiness. METHODS: We retrospectively analyzed data from 171 patients with cognitive impairment and an OSA diagnosis confirmed with in-laboratory polysomnography or home sleep apnea testing (mean age 69.8 ± 10.6; 66% male) who were eligible to use CPAP. Baseline and follow-up Epworth Sleepiness Score (ESS), Montreal Cognitive Assessment (MoCA), and Mini-Mental Status Examination (MMSE) were obtained from clinical and research visits conducted before and after CPAP initiation. Good CPAP adherence was defined as CPAP use ≥4 h/night, for 7 days/week at follow-up. Associations between CPAP adherence and follow-up cognitive scores were analyzed using multivariable linear mixed-effects models. RESULTS: After adjusting for age, sex, body mass index, baseline ESS, duration of CPAP therapy, relevant comorbidities and the random effect of research study cohort, good CPAP adherence (compared to poor CPAP adherence or no use of CPAP) for a duration of 2-12 months was associated with a 2.3-point (1.2-3.3 95% CI) higher follow-up MoCA score (p < 0.001) and a 1.2-point (0.3-2.3 95% CI) higher follow-up MMSE score (p = 0.01). CONCLUSIONS: In patients with OSA and cognitive impairment due to a neurodegenerative or vascular etiology, use of CPAP is associated with improved cognitive outcomes. The findings of this study may aid in motivating patients to use CPAP and support future randomized controlled trials in this area.

Association of accelerometer-derived sleep measures with lifetime psychiatric diagnoses: A cross-sectional study of 89,205 participants from the UK Biobank.

BACKGROUND: Sleep problems are both symptoms of and modifiable risk factors for many psychiatric disorders. Wrist-worn accelerometers enable objective measurement of sleep at scale. Here, we aimed to examine the association of accelerometer-derived sleep measures with psychiatric diagnoses and polygenic risk scores in a large community-based cohort. METHODS AND FINDINGS: In this post hoc cross-sectional analysis of the UK Biobank cohort, 10 interpretable sleep measures-bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration-were derived from 7-day accelerometry recordings across 89,205 participants (aged 43 to 79, 56% female, 97% self-reported white) taken between 2013 and 2015. These measures were examined for association with lifetime inpatient diagnoses of major depressive disorder, anxiety disorders, bipolar disorder/mania, and schizophrenia spectrum disorders from any time before the date of accelerometry, as well as polygenic risk scores for major depression, bipolar disorder, and schizophrenia. Covariates consisted of age and season at the time of the accelerometry recording, sex, Townsend deprivation index (an indicator of socioeconomic status), and the top 10 genotype principal components. We found that sleep pattern differences were ubiquitous across diagnoses: each diagnosis was associated with a median of 8.5 of the 10 accelerometer-derived sleep measures, with measures of sleep quality (for instance, sleep efficiency) generally more affected than mere sleep duration. Effect sizes were generally small: for instance, the largest magnitude effect size across the 4 diagnoses was ß = -0.11 (95% confidence interval -0.13 to -0.10, p = 3 × 10-56, FDR = 6 × 10-55) for the association between lifetime inpatient major depressive disorder diagnosis and sleep efficiency. Associations largely replicated across ancestries and sexes, and accelerometry-derived measures were concordant with self-reported sleep properties. Limitations include the use of accelerometer-based sleep measurement and the time lag between psychiatric diagnoses and accelerometry. CONCLUSIONS: In this study, we observed that sleep pattern differences are a transdiagnostic feature of individuals with lifetime mental illness, suggesting that they should be considered regardless of diagnosis. Accelerometry provides a scalable way to objectively measure sleep properties in psychiatric clinical research and practice, even across tens of thousands of individuals.

High-Dose Rate Interstitial Spine Brachytherapy Using an Intraoperative Mobile Computed Tomography-Guided Surgical Navigation System.

BACKGROUND: Up to 15% of previously irradiated metastatic spine tumors will progress. Re-irradiation of these tumors poses a significant risk of exceeding the radiation tolerance to the spinal cord. High-dose rate (HDR) brachytherapy is a treatment alternative. OBJECTIVE: To develop a novel HDR spine brachytherapy technique using an intraoperative computed tomography-guided navigation (iCT navigation). METHODS: Patients with progressive metastatic spine tumors were included in the study. HDR brachytherapy catheters were placed under iCT navigation. CT-based planning with magnetic resonance imaging fusion was performed to ensure conformal dose delivery to the target while sparing normal tissue, including the spinal cord. Patients received single fraction radiation treatment. RESULTS: Five patients with thoracolumbar tumors were treated with HDR brachytherapy. Four patients previously received radiotherapy to the same spinal level. Preimplant plans demonstrated median clinical target volume (CTV) D90 of 116.5% (110.8%-147.7%), V100 of 95.7% (95.5%-99.6%), and Dmax of 8.08 Gy (7.65-9.8 Gy) to the spinal cord/cauda equina. Postimplant plans provided median CTV D90 of 113.8% (93.6%-120.1%), V100 of 95.9% (87%-99%), and Dmax of 9.48 Gy (6.5-10.3 Gy) to cord/cauda equina. Patients who presented with back pain (n = 3) noted symptomatic improvement at a median follow-up of 22 d after treatment. Four patients demonstrated local tumor control of spinal metastatic tumor at a median follow-up of 92 d after treatment. One patient demonstrated radiographic evidence of local tumor progression 2.7 mo after treatment. CONCLUSION: HDR spine brachytherapy with iCT navigation is a promising treatment alternative to induce local tumor control and reduce pain symptoms associated with metastatic spine disease.

Utility of machine learning of apparent diffusion coefficient (ADC) and T2-weighted (T2W) radiomic features in PI-RADS version 2.1 category 3 lesions to predict prostate cancer diagnosis.

PURPOSE: To evaluate if machine learning (ML) of radiomic features extracted from apparent diffusion coefficient (ADC) and T2-weighted (T2W) MRI can predict prostate cancer (PCa) diagnosis in Prostate Imaging-Reporting and Data System (PI-RADS) version 2.1 category 3 lesions. METHODS: This multi-institutional review board-approved retrospective case-control study evaluated 158 men with 160 PI-RADS category 3 lesions (79 peripheral zone, 81 transition zone) diagnosed at 3-Tesla MRI with histopathology diagnosis by MRI-TRUS-guided targeted biopsy. A blinded radiologist confirmed PI-RADS v2.1 score and segmented lesions on axial T2W and ADC images using 3D Slicer, extracting radiomic features with an open-source software (Pyradiomics). Diagnostic accuracy for (1) any PCa and (2) clinically significant (CS; International Society of Urogenital Pathology Grade Group ≥ 2) PCa was assessed using XGBoost with tenfold cross -validation. RESULTS: From 160 PI-RADS 3 lesions, there were 50.0% (80/160) PCa, including 36.3% (29/80) CS-PCa (63.8% [51/80] ISUP 1, 23.8% [19/80] ISUP 2, 8.8% [7/80] ISUP 3, 3.8% [3/80] ISUP 4). The remaining 50.0% (80/160) lesions were benign. ML of all radiomic features from T2W and ADC achieved area under receiver operating characteristic curve (AUC) for diagnosis of (1) CS-PCa 0.547 (95% Confidence Intervals 0.510-0.584) for T2W and 0.684 (CI 0.652-0.715) for ADC and (2) any PCa 0.608 (CI 0.579-0.636) for T2W and 0.642 (CI 0.614-0.0.670) for ADC. CONCLUSION: Our results indicate ML of radiomic features extracted from T2W and ADC achieved at best moderate accuracy for determining which PI-RADS category 3 lesions represent PCa.

Diurnal and seasonal molecular rhythms in the human brain and their relation to Alzheimer disease.

Diurnal and seasonal rhythms influence many aspects of human physiology including brain function. Moreover, altered diurnal and seasonal behavioral and physiological rhythms have been linked to Alzheimer's disease and related dementias (ADRD). Understanding the molecular basis for these links may lead to identification of novel targets to mitigate the negative impact of normal and abnormal diurnal and seasonal rhythms on ADRD or to alleviate the adverse consequences of ADRD on normal diurnal and seasonal rhythms. Diurnally and seasonally rhythmic gene expression and epigenetic modification in the human neocortex may be a key mechanism underlying these links. This chapter will first review the observed epidemiological links between normal and abnormal diurnal and seasonal rhythmicity, cognitive impairment, and ADRD. Then it will review normal diurnal and seasonal rhythms of brain epigenetic modification and gene expression in model organisms. Finally, it will review evidence for diurnal and seasonal rhythms of epigenetic modification and gene expression the human brain in aging, Alzheimer's disease, and other brain disorders.

Disrupted Rest-Activity Rhythms and Cerebral Small Vessel Disease Pathology in Older Adults.

BACKGROUND AND PURPOSE: The pathogenesis of cerebral small vessel disease remains incompletely understood. The relationship between circadian rhythm disturbances and histopathologic measures of cerebral small vessel disease has not been studied. We hypothesized that disrupted circadian rest-activity rhythms would be associated with a higher burden of cerebral small vessel disease pathology. METHODS: We studied 561 community-dwelling older adults (mean age at death, 91.2, 27.4% male) from the Rush Memory and Aging Project. We used actigraphy to quantify several measures of 24-hour rest-activity rhythmicity, including interdaily stability, intradaily variability, and amplitude, and used ordinal logistic regression models to relate these measures to the severity of cerebral arteriolosclerosis, atherosclerosis, macroinfarcts, and microinfarcts, assessed at autopsy. RESULTS: Lower interdaily stability was associated with a higher burden of arteriolosclerosis, higher intradaily variability was associated with a higher burden of atherosclerosis and subcortical infarcts, and lower amplitude was associated with a higher burden of arteriosclerosis, atherosclerosis and subcortical macroinfarcts. Moreover, the associations between interdaily stability and arteriolosclerosis and intradaily variability and subcortical infarcts were independent of cardiovascular risk factors, sleep fragmentation, and medical comorbidities. CONCLUSIONS: Disrupted rest-activity rhythms are associated with a greater burden of cerebral small vessel disease in older adults.

Sleep Fragmentation and Cognitive Trajectories After Critical Illness.

BACKGROUND: ICU survivors can experience both cognitive dysfunction and persistent sleep disturbances after hospitalization. Sleep disturbances have been linked with cognitive impairment in various patient populations, and the apolipoprotein E (APOE) genotype has been linked to sleep-related impairments in cognition. RESEARCH QUESTION: Is there an association between sleep, long-term cognition, and APOE status in ICU survivors? STUDY DESIGN AND METHODS: We enrolled 150 patients from five centers who had been mechanically ventilated for at least 3 days; 102 patients survived to ICU discharge. Actigraphy and cognitive testing were undertaken at 7 days, 6 months, and 12 months after ICU discharge, and sleep duration, quality, and timing were estimated by actigraphy. APOE single nucleotide polymorphisms were assessed for each patient. RESULTS: Actigraphy-estimated sleep fragmentation, but not total sleep time or interdaily stability (estimate of circadian rhythmicity), was associated with worse cognitive impairment at 7 days of ICU discharge. No actigraphy-estimated variable of sleep estimation at 7 days post-ICU discharge predicted cognitive impairment or persistent sleep abnormalities at 6 and 12 months of follow-up in subsequently assessed survivors. Possessing the APOE ε4 allele was not significantly associated with sleep disturbances and its presence did not modify the risk of sleep-related cognitive impairment at follow-up. INTERPRETATION: Sleep fragmentation estimated by actigraphy was associated with worse cognitive performance in hospital, but not at later time intervals. Further research is needed to better delineate the relationship between persistent sleep disturbances and cognition in larger numbers of ICU survivors. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02086877; URL: www.clinicaltrials.gov.

Feasibility of unattended home sleep apnea testing in a cognitively impaired clinic population.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) increases the risk of developing dementia. Home sleep apnea testing (HSAT) is a convenient and validated method to screen for OSA among cognitively well individuals; however, it is unknown if it is a clinically feasible and practical approach in clinic patients with cognitive impairment. We evaluated if HSAT was a feasible and practical approach to screen for OSA in clinic patients with cognitive impairment. METHODS: Patients with cognitive impairment due to neurodegenerative and/or vascular etiologies completed OSA screening using HSAT. HSAT was considered a feasible technique if ≥ 80% of those who attempted HSAT obtained analyzable data (ie, ≥ 4 hours of flow, effort, and oxygen evaluation), and a practical technique if ≥ 50% of all patients approached for study inclusion obtained analyzable data. RESULTS: Of the 119 patients who were approached for participation, 83 were enrolled and offered HSAT; 5 did not complete HSAT screening, and the remaining 78 patients attempted HSAT; mean age (± standard deviation) of 72.86 (± 9.89) years and 46% were male. In those that attempted HSAT, 85.9% (67/78) obtained analyzable data and 56.3% (67/119) of eligible patients approached for study inclusion obtained analyzable data. CONCLUSIONS: HSAT is a feasible and practical technique in a clinic population with cognitive impairment. As OSA is a modifiable risk factor for patients with dementia, HSAT has the potential to lead to expedited treatment for OSA, which may potentially improve health-related outcomes such as cognition.

Fragmentation of Rest/Activity Patterns in Community-Based Elderly Individuals Predicts Incident Heart Failure.

STUDY OBJECTIVES: Heart failure has previously been linked to sleep disorders that are often associated with frequent disturbances to human rest/activity patterns. We tested whether fragmentation of sustained rest/activity patterns derived from actigraphic recordings at baseline predicts incident heart failure in community-based elderly individuals. METHODS: We studied 1099 community-based elderly adults participating in the Rush Memory and Aging Project who had baseline motor activity monitoring up to 11 days and were followed annually for up to 14 years. Fragmentation was assessed using previously validated indexes, derived from the probability of transitions once sustained rest or activity has been established. Heart failure was recorded via a clinical interview during the annual follow-up. Cox proportional hazards models were constructed to examine the relationship between rest fragmentation index and incident heart failure. Covariates grouped in terms of demographics, lifestyle factors and co-morbidities and cardiovascular risk factors/diseases were included. RESULTS: Increased rest fragmentation (but not activity fragmentation) was associated with higher risk for incident heart failure. Specifically, a subject with a rest fragmentation at the 90th percentile showed a 57% increased risk of developing incident heart failure compared to a subject at the 10th percentile in this cohort. This effect was equivalent to that of being over a decade older. These observations were consistent after adjusting for all covariates. CONCLUSION: Increased rest fragmentation, a potential surrogate for sleep fragmentation, is independently associated with a higher risk of developing heart failure in community-based elderly adults during up to 14 years of follow-up. Further work is required to examine the specific contributions from daytime napping versus nighttime sleep periods in the elderly, as well as the underlying autonomic and cardio-dynamic pathways that may explain the effects on heart function.

Circadian disturbances in Alzheimer's disease progression: a prospective observational cohort study of community-based older adults.

BACKGROUND: Circadian disturbances are commonly seen in people with Alzheimer's disease and have been reported in individuals without symptoms of dementia but with Alzheimer's pathology. We aimed to assess the temporal relationship between circadian disturbances and Alzheimer's progression. METHODS: We did a prospective cohort study of 1401 healthy older adults (aged >59 years) enrolled in the Rush Memory and Aging Project (Rush University Medical Center, Chicago, IL, USA) who had been followed up for up to 15 years. Participants underwent annual assessments of cognition (with a battery of 21 cognitive performance tests) and motor activities (with actigraphy). Four measures were extracted from actigraphy to quantify daily and circadian rhythmicity, which were amplitude of 24-h activity rhythm, acrophase (representing peak activity time), interdaily stability of 24-h activity rhythm, and intradaily variability for hourly fragmentation of activity rhythm. We used Cox proportional hazards models and logistic regressions to assess whether circadian disturbances predict an increased risk of incident Alzheimer's dementia and conversion of mild cognitive impairment to Alzheimer's dementia. We used linear mixed-effects models to investigate how circadian rhythms changed longitudinally and how the change integrated to Alzheimer's progression. FINDINGS: Participants had a median age of 81·8 (IQR 76·3-85·7) years. Risk of developing Alzheimer's dementia was increased with lower amplitude (1 SD decrease, hazard ratio [HR] 1·39, 95% CI 1·19-1·62) and higher intradaily variability (1 SD increase, 1·22, 1·04-1·43). In participants with mild cognitive impairment, increased risk of Alzheimer's dementia was predicted by lower amplitude (1 SD decrease, HR 1·46, 95% CI 1·24-1·72), higher intradaily variability (1 SD increase, 1·36, 1·15-1·60), and lower interdaily stability (1 SD decrease, 1·21, 1·02-1·44). A faster transition to Alzheimer's dementia in participants with mild cognitive impairment was predicted by lower amplitude (1 SD decrease, odds ratio [OR] 2·08, 95% CI 1·53-2·93), increased intradaily variability (1 SD increase, 1·97, 1·43-2·79), and decreased interdaily stability (1 SD decrease, 1·35, 1·01-1·84). Circadian amplitude, acrophase, and interdaily stability progressively decreased over time, and intradaily variability progressively increased over time. Alzheimer's progression accelerated these aging effects by doubling or more than doubling the annual changes in these measures after the diagnosis of mild cognitive impairment, and further doubled them after the diagnosis of Alzheimer's dementia. The longitudinal change of global cognition positively correlated with the longitudinal changes in amplitude and interdaily stability and negatively correlated with the longitudinal change in intradaily variability. INTERPRETATION: Our results indicate a link between circadian dysregulation and Alzheimer's progression, implying either a bidirectional relation or shared common underlying pathophysiological mechanisms. FUNDING: National Institutes of Health, and the BrightFocus Foundation.

Sleep fragmentation, microglial aging, and cognitive impairment in adults with and without Alzheimer's dementia.

Sleep disruption is associated with cognitive decline and dementia in older adults; however, the underlying mechanisms are unclear. In rodents, sleep disruption causes microglial activation, inhibition of which improves cognition. However, data from humans are lacking. We studied participants in two cohort studies of older persons-the Rush Memory and Aging Project and the Religious Orders Study. We assessed sleep fragmentation by actigraphy and related this to cognitive function, to neocortical microglial marker gene expression measured by RNA sequencing, and to the neocortical density of microglia assessed by immunohistochemistry. Greater sleep fragmentation was associated with higher neocortical expression of genes characteristic of aged microglia, and a higher proportion of morphologically activated microglia, independent of chronological age- and dementia-related neuropathologies. Furthermore, these were, in turn, associated with worse cognition. This suggests that sleep fragmentation is accompanied by accelerated microglial aging and activation, which may partially underlie its association with cognitive impairment.

Small Polar Hits against S. aureus: Screening, Initial Hit Optimization, and Metabolomic Studies.

The global prevalence of antibacterial resistance requires new antibacterial drugs with novel chemical scaffolds and modes of action. It is also vital to design compounds with optimal physicochemical properties to permeate the bacterial cell envelope. We described an approach of combining and integrating whole cell screening and metabolomics into early antibacterial drug discovery using a library of small polar compounds. Whole cell screening of a diverse library of small polar compounds against Staphylococcus aureus gave compound 2. Hit expansion was carried out to determine structure-activity relationships. A selection of compounds from this series, together with other screened active compounds, was subjected to an initial metabolomics study to provide a metabolic fingerprint of the mode of action. It was found that compound 2 and its analogues have a different mode of action from some of the known antibacterial compounds tested. This early study highlighted the potential of whole cell screening and metabolomics in early antibacterial drug discovery. Future works will require improving potency and performing orthogonal studies to confirm the modes of action.

More random motor activity fluctuations predict incident frailty, disability, and mortality.

Mobile healthcare increasingly relies on analytical tools that can extract meaningful information from ambulatory physiological recordings. We tested whether a nonlinear tool of fractal physiology could predict long-term health consequences in a large, elderly cohort. Fractal physiology is an emerging field that aims to study how fractal temporal structures in physiological fluctuations generated by complex physiological networks can provide important information about system adaptability. We assessed fractal temporal correlations in the spontaneous fluctuations of ambulatory motor activity of 1275 older participants at baseline, with a follow-up period of up to 13 years. We found that people with reduced temporal correlations (more random activity fluctuations) at baseline had increased risk of frailty, disability, and all-cause death during follow-up. Specifically, for 1-SD decrease in the temporal activity correlations of this studied cohort, the risk of frailty increased by 31%, the risk of disability increased by 15 to 25%, and the risk of death increased by 26%. These incidences occurred on average 4.7 years (frailty), 3 to 4.2 years (disability), and 5.8 years (death) after baseline. These observations were independent of age, sex, education, chronic health conditions, depressive symptoms, cognition, motor function, and total daily activity. The temporal structures in daily motor activity fluctuations may contain unique prognostic information regarding wellness and health in the elderly population.

Actigraphic measures of sleep on the wards after ICU discharge.

BACKGROUND: The purpose of this study was to use an objective measure to evaluate sleep quality on the ward after ICU discharge in survivors of critical illness. MATERIALS AND METHODS: This was a prospective cohort study of 94 patients admitted to a multidisciplinary intensive care unit (ICU) between December 2013 and June 2017. Adult patients received ≥3 days of mechanical ventilation. Sleep quality was measured using multi-night sleep actigraphy. Baseline sleep quality (i.e. sleep prior to hospitalization) was evaluated using the Pittsburgh Sleep Quality Index. RESULTS: A total of 65% of patients had poor sleep quality measured with the PSQI. The average (SD) sleep time and sleep efficiency was 6.03 h (3.70 h) and 44% (27%), respectively. An admission diagnosis of sepsis was associated with shorter total sleep time (TST; p = .03) and reduced sleep efficiency (SE; p = .04) as were severity of illness and duration of sedative exposure (p = .12 and 0.03; p = .09 and < 0.01; respectively for TST and SE). Weak correlations were seen between pro-inflammatory biomarkers and sleep quality. CONCLUSIONS: This study highlights the important role that future interventions might have in patients at high-risk of sleep disorders after critical illness.

Seasonal plasticity of cognition and related biological measures in adults with and without Alzheimer disease: Analysis of multiple cohorts.

BACKGROUND: There are few data concerning the association between season and cognition and its neurobiological correlates in older persons-effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects. METHODS AND FINDINGS: We analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07-0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07-0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years' difference in age (95% CI 2.1-8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10-1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aß 42 level (amplitude 0.30 SD [95% CI 0.10-0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21-0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27-0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24-0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20-0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere. CONCLUSIONS: Season has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD.