A brain-derived insulin signal encodes protein satiety for nutrient-specific feeding inhibition.

The suppressive effect of insulin on food intake has been documented for decades. However, whether insulin signals can encode a certain type of nutrients to regulate nutrient-specific feeding behavior remains elusive. Here, we show that in female Drosophila, a pair of dopaminergic neurons, tritocerebrum 1-dopaminergic neurons (T1-DANs), are directly activated by a protein-intake-induced insulin signal from insulin-producing cells (IPCs). Intriguingly, opto-activating IPCs elicits feeding inhibition for both protein and sugar, while silencing T1-DANs blocks this inhibition only for protein food. Elevating insulin signaling in T1-DANs or opto-activating these neurons is sufficient to mimic protein satiety. Furthermore, this signal is conveyed to local neurons of the protocerebral bridge (PB-LNs) and specifically suppresses protein intake. Therefore, our findings reveal that a brain-derived insulin signal encodes protein satiety and suppresses feeding behavior in a nutrient-specific manner, shedding light on the functional specificity of brain insulin signals in regulating behaviors.

A subclass of evening cells promotes the switch from arousal to sleep at dusk.

Animals exhibit rhythmic patterns of behavior that are shaped by an internal circadian clock and the external environment. Although light intensity varies across the day, there are particularly robust differences at twilight (dawn/dusk). These periods are also associated with major changes in behavioral states, such as the transition from arousal to sleep. However, the neural mechanisms by which time and environmental conditions promote these behavioral transitions are poorly defined. Here, we show that the E1 subclass of Drosophila evening clock neurons promotes the transition from arousal to sleep at dusk. We first demonstrate that the cell-autonomous clocks of E2 neurons primarily drive and adjust the phase of evening anticipation, the canonical behavior associated with "evening" clock neurons. We next show that conditionally silencing E1 neurons causes a significant delay in sleep onset after dusk. However, rather than simply promoting sleep, activating E1 neurons produces time- and light-dependent effects on behavior. Activation of E1 neurons has no effect early in the day but then triggers arousal before dusk and induces sleep after dusk. Strikingly, these activation-induced phenotypes depend on the presence of light during the day. Despite their influence on behavior around dusk, in vivo voltage imaging of E1 neurons reveals that their spiking rate and pattern do not significantly change throughout the day. Moreover, E1-specific clock ablation has no effect on arousal or sleep. Thus, we suggest that, rather than specifying "evening" time, E1 neurons act, in concert with other rhythmic neurons, to promote behavioral transitions at dusk.

Tob Regulates the Timing of Sleep Onset at Night in Drosophila.

Sleep is regulated by homeostatic sleep drive and the circadian clock. While tremendous progress has been made in elucidating the molecular components of the core circadian oscillator, the output mechanisms by which this robust oscillator generates rhythmic sleep behavior remain poorly understood. At the cellular level, growing evidence suggests that subcircuits in the master circadian pacemaker suprachiasmatic nucleus (SCN) in mammals and in the clock network in Drosophila regulate distinct aspects of sleep. Thus, to identify novel molecules regulating the circadian timing of sleep, we conducted a large-scale screen of mouse SCN-enriched genes in Drosophila Here, we show that Tob (Transducer of ERB-B2) regulates the timing of sleep onset at night in female fruit flies. Knockdown of Tob pan-neuronally, either constitutively or conditionally, advances sleep onset at night. We show that Tob is specifically required in "evening neurons" (the LNds and the fifth s-LNv) of the clock network for proper timing of sleep onset. Tob levels cycle in a clock-dependent manner in these neurons. Silencing of these "evening" clock neurons results in an advanced sleep onset at night, similar to that seen with Tob knockdown. Finally, sharp intracellular recordings demonstrate that the amplitude and kinetics of LNd postsynaptic potentials (PSPs) cycle between day and night, and this cycling is attenuated with Tob knockdown in these cells. Our data suggest that Tob acts as a clock output molecule in a subset of clock neurons to potentiate their activity in the evening and enable the proper timing of sleep onset at night.

Sleep Duration Polygenic Risk and Phenotype: Associations with Biomarkers of Accelerated Aging in the Baltimore Longitudinal Study of Aging.

We sought to explore whether genetic risk for, and self-reported, short sleep are associated with biological aging and whether age and sex moderate these associations. Participants were a subset of individuals from the Baltimore Longitudinal Study of Aging who had complete data on self-reported sleep (n = 567) or genotype (n = 367). Outcomes included: Intrinsic Horvath age, Hannum age, PhenoAge, GrimAge, and DNAm-based estimates of plasminogen activator inhibitor-1 (PAI-1) and granulocyte count. Results demonstrated that polygenic risk for short sleep was positively associated with granulocyte count; compared to those reporting <6 hr sleep, those reporting >7 hr demonstrated faster PhenoAge and GrimAge acceleration and higher estimated PAI-1. Polygenic risk for short sleep and self-reported sleep duration interacted with age and sex in their associations with some of the outcomes. Findings highlight that polygenic risk for short sleep and self-reported long sleep is associated with variation in the epigenetic landscape and subsequently aging.

Evaluating a novel 24-hour rest/activity rhythm marker of preclinical ß-amyloid deposition.

STUDY OBJECTIVES: To compare sleep and 24-hour rest/activity rhythms (RARs) between cognitively normal older adults who are ß-amyloid-positive (Aß+) or Aß- and replicate a novel time-of-day-specific difference between these groups identified in a previous exploratory study. METHODS: We studied 82 cognitively normal participants from the Baltimore Longitudinal Study of Aging (aged 75.7 ±â€…8.5 years, 55% female, 76% white) with wrist actigraphy data and Aß+ versus Aß- status measured by [11C] Pittsburgh compound B positron emission tomography. RARs were calculated using epoch-level activity count data from actigraphy. We used novel, data-driven function-on-scalar regression analyses and standard RAR metrics to cross-sectionally compare RARs between 25 Aß+ and 57 Aß- participants. RESULTS: Compared to Aß- participants, Aß+ participants had higher mean activity from 1:00 p.m. to 3:30 p.m. when using less conservative pointwise confidence intervals (CIs) and from 1:30 p.m. to 2:30 p.m. using more conservative, simultaneous CIs. Furthermore, Aß+ participants had higher day-to-day variability in activity from 9:00 a.m. to 11:30 a.m. and lower variability from 1:30 p.m. to 4:00 p.m. and 7:30 p.m. to 10:30 p.m. according to pointwise CIs, and lower variability from 8:30 p.m. to 10:00 p.m. using simultaneous CIs. There were no Aß-related differences in standard sleep or RAR metrics. CONCLUSIONS: Findings suggest Aß+ older adults have higher, more stable day-to-day afternoon/evening activity than Aß- older adults, potentially reflecting circadian dysfunction. Studies are needed to replicate our findings and determine whether these or other time-of-day-specific RAR features have utility as markers of preclinical Aß deposition and if they predict clinical dementia and agitation in the afternoon/evening (i.e. "sundowning").

Outcome Disparities in Total Knee and Total Hip Arthroplasty among Native American Populations.

BACKGROUND: No prior racial disparities studies in total knee arthroplasty (TKA) and total hip arthroplasty (THA) have specifically evaluated outcomes among American Indian or Alaska Native (AIAN) patients. We hypothesized that AIAN patients have worse outcomes than White patients after controlling for demographics and comorbidities. METHODS: This was a retrospective cohort study comparing White and AIAN patients undergoing primary TKA/THA from 2012-2019 using the American College of Surgeons National Surgical Quality Improvement Program. Race, demographics, and comorbidities were analyzed for correlations with 30-day outcomes and complications using multivariable logistic and linear regression analyses. RESULTS: Comparing 422,215 White and 2,676 AIAN patients, AIAN patients had higher American Society of Anesthesiologist (ASA) classifications, body mass index (BMI), and were younger at the time of surgery. AIAN patients more often stayed inpatient > 2 days (49.4% vs 36.2%, p < 0.001), underwent reoperation (2.1% vs 1.4%, p < 0.01), and were discharged home (91.4% vs 81.7%, p < 0.01). Regression analyses controlling for age, BMI, sex, ASA classification, and functional status found that AIAN race was significantly positively correlated with a length of stay > 2 days (OR 1.6), reoperation (OR 1.4), and discharging home (OR 2.0). CONCLUSION: AIAN patients undergoing TKA/THA present with a greater comorbidity burden compared to White patients and experience multiple worse outcome metrics including increased hospital length of stay and reoperation rates. Interestingly, AIAN patients were more likely to discharge home, representing a unique racial disparity which warrants further study.

Assessing the Diagnostic Accuracy of Next-Generation Sequencing in Patients With Antibiotic Spacers Before Reimplantation.

Use of molecular sequencing modalities in periprosthetic joint infection diagnosis and organism identification has gained popularity recently. To date, there is no diagnostic test that reliably predicts infection eradication in patients with antibiotic spacers. The purpose of this study was to compare the diagnostic accuracy of next-generation sequencing (NGS), culture, the Musculoskeletal Infection Society (MSIS) criteria, and the criteria by Parvizi et al in patients with antibiotic spacers. In this retrospective study, aspirate or tissue samples were collected from 38 knee and 19 hip antibiotic spacers for routine diagnostic workup for the presence of persistent infection and sent to the laboratory for NGS. The kappa statistic along with statistical differences between diagnostic studies were calculated using the chi-square test for categorical data. The kappa coefficient for agreement between NGS and culture was 0.27 (fair agreement). The percentages of positive and negative agreement were 22.8% and 42.1%, respectively, with a total concordance of 64.9%. There were 12 samples that were culture positive and NGS negative. Eight samples were NGS positive but culture negative. The kappa coefficient was 0.42 (moderate agreement) when comparing NGS with MSIS criteria. In our series, NGS did not provide sufficient agreement compared with culture or MSIS criteria in the setting of an antibiotic spacer. A reliable diagnostic indicator for reimplantation has yet to be identified. [Orthopedics. 2024;47(1);46-51.].

Risk Factors for Early Readmission and Reoperation After Outpatient Total Hip Arthroplasty.

Outpatient total hip arthroplasty (THA) is a safe option for select patients. The purpose of this study was to analyze a national database and understand risk factors that lead to unplanned early readmission and reoperation after outpatient THA. The National Surgical Quality Improvement Program database was used to collect outpatient THAs performed from 2013 to 2020. The outpatient setting was defined as a reported hospital length of stay of 23 hours or less. Data variables collected included patient demographics, medical comorbidities, American Society of Anesthesiologists classification, functional status, preoperative laboratory values, National Surgical Quality Improvement Program morbidity probability, and 30-day readmissions and reoperations. A total of 15,055 patients underwent outpatient THA. Mean age was 62.6 years, and 52.1% of patients were men. Mean body mass index was 29.3 kg/m2. The overall rate of readmission was 1.8%, and the reoperation rate was 1.0%. Patients with a 30-day readmission were older (P<.01), with a higher incidence of hypertension (P<.01), steroid use (P<.01), and bleeding disorders (P=.01). Patients with a 30-day reoperation had higher body mass index (P<.01), hypertension (P<.01), and steroid use (P<.01). Regression analysis demonstrated that independent risk factors for readmission were age (P<.01) and steroid use (P<.01). Risk factors for 30-day reoperation were hypertension (P<.01) and steroid use (P<.01). There is a higher risk of early readmission after outpatient THA for older patients with hypertension, bleeding disorders, and steroid use. Patients with hypertension and steroid use have a higher risk for reoperation after outpatient THA. Modifiable risk factors should be addressed preoperatively, with proper patient selection for outpatient THA. [Orthopedics. 2024;47(1):e38-e44.].

Deep Phenotyping of Sleep in Drosophila.

Sleep is an evolutionarily conserved behavior, whose function is unknown. Here, we present a method for deep phenotyping of sleep in Drosophila, consisting of a high-resolution video imaging system, coupled with closed-loop laser perturbation to measure arousal threshold. To quantify sleep-associated microbehaviors, we trained a deep-learning network to annotate body parts in freely moving flies and developed a semi-supervised computational pipeline to classify behaviors. Quiescent flies exhibit a rich repertoire of microbehaviors, including proboscis pumping (PP) and haltere switches, which vary dynamically across the night. Using this system, we characterized the effects of optogenetically activating two putative sleep circuits. These data reveal that activating dFB neurons produces micromovements, inconsistent with sleep, while activating R5 neurons triggers PP followed by behavioral quiescence. Our findings suggest that sleep in Drosophila is polyphasic with different stages and set the stage for a rigorous analysis of sleep and other behaviors in this species.

A clock-dependent brake for rhythmic arousal in the dorsomedial hypothalamus.

Circadian clocks generate rhythms of arousal, but the underlying molecular and cellular mechanisms remain unclear. In Drosophila, the clock output molecule WIDE AWAKE (WAKE) labels rhythmic neural networks and cyclically regulates sleep and arousal. Here, we show, in a male mouse model, that mWAKE/ANKFN1 labels a subpopulation of dorsomedial hypothalamus (DMH) neurons involved in rhythmic arousal and acts in the DMH to reduce arousal at night. In vivo Ca2+ imaging reveals elevated DMHmWAKE activity during wakefulness and rapid eye movement (REM) sleep, while patch-clamp recordings show that DMHmWAKE neurons fire more frequently at night. Chemogenetic manipulations demonstrate that DMHmWAKE neurons are necessary and sufficient for arousal. Single-cell profiling coupled with optogenetic activation experiments suggest that GABAergic DMHmWAKE neurons promote arousal. Surprisingly, our data suggest that mWAKE acts as a clock-dependent brake on arousal during the night, when mice are normally active. mWAKE levels peak at night under clock control, and loss of mWAKE leads to hyperarousal and greater DMHmWAKE neuronal excitability specifically at night. These results suggest that the clock does not solely promote arousal during an animal's active period, but instead uses opposing processes to produce appropriate levels of arousal in a time-dependent manner.

A subclass of evening cells promotes the switch from arousal to sleep at dusk.

Animals exhibit rhythmic patterns of behavior that are shaped by an internal circadian clock and the external environment. While light intensity varies across the day, there are particularly robust differences at twilight (dawn/dusk). These periods are also associated with major changes in behavioral states, such as the transition from arousal to sleep. However, the neural mechanisms by which time and environmental conditions promote these behavioral transitions are poorly defined. Here, we show that the E1 subclass of Drosophila evening clock neurons promotes the transition from arousal to sleep at dusk. We first demonstrate that the cell-autonomous clocks of E2 neurons alone are required to drive and adjust the phase of evening anticipation, the canonical behavior associated with "evening" clock neurons. We next show that conditionally silencing E1 neurons causes a significant delay in sleep onset after dusk. However, rather than simply promoting sleep, activating E1 neurons produces time- and light- dependent effects on behavior. Activation of E1 neurons has no effect early in the day, but then triggers arousal before dusk and induces sleep after dusk. Strikingly, these phenotypes critically depend on the presence of light during the day. Despite their influence on behavior around dusk, in vivo voltage imaging of E1 neurons reveals that their spiking rate does not vary between dawn and dusk. Moreover, E1-specific clock ablation has no effect on arousal or sleep. Thus, we suggest that, rather than specifying "evening" time, E1 neurons act, in concert with other rhythmic neurons, to promote behavioral transitions at dusk.

24 h Rest/Activity Rhythms in Older Adults with Memory Impairment: Associations with Cognitive Performance and Depressive Symptomatology.

Little is known about links of circadian rhythm alterations with neuropsychiatric symptoms and cognition in memory impaired older adults. Associations of actigraphic rest/activity rhythms (RAR) with depressive symptoms and cognition are examined using function-on-scalar regression (FOSR). Forty-four older adults with memory impairment (mean: 76.84 ± 8.15 years; 40.9% female) completed 6.37 ± 0.93 days of actigraphy, the Beck depression inventory-II (BDI-II), mini-mental state examination (MMSE) and consortium to establish a registry for Alzheimer's disease (CERAD) delayed word recall. FOSR models with BDI-II, MMSE, or CERAD as individual predictors adjusted for demographics (Models A1-A3) and all three predictors and demographics (Model B). In Model B, higher BDI-II scores are associated with greater activity from 12:00-11:50 a.m., 2:10-5:50 p.m., 8:40-9:40 p.m., 11:20-12:00 a.m., higher CERAD scores with greater activity from 9:20-10:00 p.m., and higher MMSE scores with greater activity from 5:50-10:50 a.m. and 12:40-5:00 p.m. Greater depressive symptomatology is associated with greater activity in midafternoon, evening, and overnight into midday; better delayed recall with greater late evening activity; and higher global cognitive performance with greater morning and afternoon activity (Model B). Time-of-day specific RAR alterations may affect mood and cognitive performance in this population.

Does Order of Operation Matter in Patients Who Have Concomitant Hip and Spine Pathology?

BACKGROUND: In patients, who have coexisting lumbar spine and degenerative hip disease, there remains uncertainty regarding whether hip or spine surgery should be performed first. We hypothesized that undergoing total hip arthroplasty (THA) would protect against subsequent lumbar spine surgery (LSS) in patients who have 'hip-spine syndrome.' METHODS: A retrospective cohort study was performed from 2013 to 2021 on patients who had radiographically-confirmed hip osteoarthritis and degenerative lumbar spine pathology, evaluated separately in spine and arthroplasty clinics prior to surgical intervention. Included patients ultimately underwent THA and/or LSS. The primary outcome was survivorship free of LSS or THA after the other was initially performed. RESULTS: Of 256 patients, 206 (80.5%) underwent THA first. Only 14 of 206 (6.8%) who underwent THA required subsequent LSS, while 31 of 50 (62%) who underwent LSS required subsequent THA, (P < .001). At 5 years, there was 93.9% survivorship-free of LSS in the THA first group, compared to 44.7% survivorship-free of subsequent THA in the LSS group. Multivariate analyses showed that patients who had THA first had lower odds of undergoing subsequent surgery (odds ratio [OR]: 0.61, CI: 0.52-0.70, P < .001) compared to those who underwent LSS first. Additionally, those who have higher initial Kellgren-Lawrence grade hip osteoarthritis had lower odds (OR: 0.94, CI: 0.89-0.99, P = .04), and those who have progressive neurologic deficits (OR: 2.64, CI: 1.89-3.7, P < .001) and neurogenic claudication (OR: 1.15, CI: 1.06-1.24, P = .001) had increased odds of undergoing subsequent LSS. CONCLUSION: Patients with 'hip-spine syndrome' may receive more initial benefit from undergoing THA, potentially reducing the subsequent need for LSS. The exceptions were those patients who had lower-severity hip osteoarthritis and symptoms of major spinal stenosis.

An ACS-NSQIP Analysis of Unicompartmental Knee Arthroplasty Trends from 2013 to 2018.

Unicompartmental knee arthroplasty (UKA) volume has increased with advances in implant design, perioperative protocols, and patient selection. This study analyzed national trends of UKA from 2013 to 2018 and the relationship between patient demographics and postoperative outcomes. Data on UKA (CPT 27446) from 2013 to 2018 was collected from the National Surgical Quality Improvement Program (NSQIP). Variables collected included patient demographics, American Society of Anesthesiology classification, functional status, NSQIP morbidity probability, operative time, length of stay, 30-day reoperation, and readmission rates. There was an increase in outpatient UKAs performed (920 in 2013; 11,080 in 2018) (p < 0.0001). Analysis of variance from 2013 to 2018 revealed significant decrease in patient body mass index (BMI) (32.5 in 2013; 31.5 in 2018) (p < 0.01) and NSQIP morbidity probability (0.014 in 2013; 0.011 in 2018) (p < 0.0001). Operative time increased (79.1 minutes in 2013; 84.4 minutes in 2018) (p < 0.01), but length of stay decreased (0.9 days in 2013; 0.5 days in 2018) (p < 0.0001). The number of all-cause and related readmissions decreased significantly (p < 0.045; p < 0.01). Age, male gender, BMI >40 and chronic obstructive pulmonary disease (COPD) were significant predictors for 30-day readmission. BMI >40 was a significant predictor for discharge destination. UKA has seen a rise in incidence from 2013 to 2018 with an increasing number of outpatient UKAs. Operative times and 30-day readmissions have both decreased in this time. BMI > 40 is predictive for discharge destination after UKA, while age, male gender, BMI >40, and COPD are independent risk factors for 30-day readmission.

Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) Versus the Standard of Care Imaging in the Diagnosis of Peritoneal Carcinomatosis.

OBJECTIVE: To compare positron emission tomography (PET)/magnetic resonance imaging (MRI) to the standard of care imaging (SCI) for the diagnosis of peritoneal carcinomatosis (PC) in primary abdominopelvic malignancies. SUMMARY BACKGROUND DATA: Identifying PC impacts prognosis and management of multiple cancer types. METHODS: Adult subjects were prospectively and consecutively enrolled from April 2019 to January 2021. Inclusion criteria were: 1) acquisition of whole-body contrast-enhanced (CE) 18F-fluorodeoxyglucose PET/MRI, 2) pathologically confirmed primary abdominopelvic malignancies. Exclusion criteria were: 1) greater than 4 weeks interval between SCI and PET/MRI, 2) unavailable follow-up. SCI consisted of whole-body CE PET/computed tomography (CT) with diagnostic quality CT, and/or CE-CT of the abdomen and pelvis, and/or CE-MRI of the abdomen±pelvis. If available, pathology or surgical findings served as the reference standard, otherwise, imaging followup was used. When SCI and PET/MRI results disagreed, medical records were checked for management changes. Follow-up data were collected until August 2021. RESULTS: One hundred sixty-four subjects were included, 85 (52%) were female, and the median age was 60 years (interquartile range 50-69). At a subject level, PET/MRI had higher sensitivity (0.97, 95% CI 0.86-1.00) than SCI (0.54, 95% CI 0.37-0.71), P < 0.001, without a difference in specificity, of 0.95 (95% CI 0.90-0.98) for PET/MRI and 0.98 (95% CI 0.93-1.00) for SCI, P » 0.250. PET/MRI and SCI results disagreed in 19 cases. In 5/19 (26%) of the discordant cases, PET/MRI findings consistent with PC missed on SCI led to management changes. CONCLUSION: PET/MRI improves detection of PC compared with SCI which frequently changes management.

Does a fibula-sparing approach improve outcomes in tibiotalocalcaneal arthrodesis?

BACKGROUND: Tibiotalocalcaneal (TTC) arthrodesis is considered a salvage procedure for either complex deformity or arthritis about the hindfoot, and can be performed via fibula-resection (FR) or fibula-sparing (FS) approaches. The primary aim of this study was to investigate differences in outcomes in FR versus FS TTC arthrodeses. METHODS: This was a retrospective cohort study reviewing outcomes of TTC arthrodesis at a single institution. Patients who underwent a TTC arthrodesis from 2005 to 2017 and had minimum two-year follow-up were included. Preoperative diagnosis, pre- and post-operative radiographic coronal alignment, fixation methods, and complications were compared between groups. RESULTS: 107 patients (110 ankles) underwent TTC arthrodesis, with a mean age of 57.0 years (sd, 14.0 years). The mean clinical follow-up was 50.7 months (range, 24-146) and mean radiographic follow-up was 45.8 months (range, 6-146 months). Pre-operative diagnoses included arthritis (N = 40), prior non-union (N = 21), Charcot neuro-arthropathy (N = 15), failed total ankle arthroplasty (N = 15) and avascular necrosis of the talus (N = 19). Sixty-nine ankles comprised the FS group and 41 comprised the FR group. There was no significant difference in the non-union rate between groups (29% FR vs 38% FS, p = 0.37), complication rate (59% FR vs 64% FS, p = 0.59), or post-operative coronal standing radiographic alignment (89.6 degrees FR, 90.5 degrees FS, p = 0.26). Logistic regression analyses demonstrated a pre-operative diagnosis of failed TAA was associated with post-operative nonunion (OR:3.41,CI:1.13-11.04,p = 0.03). Pre-operative indication for TTC arthrodesis of arthritis alone was associated with a decreased risk of non-union (OR:0.27,CI:0.11-0.62,p = 0.002). CONCLUSION: TTC arthrodesis is a successful surgical option for complex hindfoot deformity, arthritis, and limb salvage regardless of surgical approach. We did not detect a difference in the union rate, incidence of complications, or coronal plane radiographic alignment in fibula-sparing versus fibula-resection constructs. Patients with a pre-operative indication for surgery of arthritis may be at decreased risk of developing non-union. LEVEL OF EVIDENCE: III - Retrospective cohort study.

Associations Between Objectively Measured Sleep and Cognition: Main Effects and Interactions With Race in Adults Aged ≥50 Years.

BACKGROUND: This study examined associations of actigraphy-estimated sleep parameters with concurrent and future cognitive performance in adults aged ≥ 50 years and explored interactions with race. METHODS: Participants were 435 cognitively normal adults in the Baltimore Longitudinal Study of Aging who completed wrist actigraphy at baseline (mean = 6.6 nights) and underwent longitudinal testing of memory, attention, executive function, language, and visuospatial ability. On average, participants with follow-up data were followed for 3.1 years. Primary predictors were baseline mean total sleep time, sleep onset latency, sleep efficiency (SE), and wake after sleep onset (WASO). Fully adjusted linear mixed-effects models included demographics, baseline health-related characteristics, smoking status, sleep medication use, APOE e4 carrier status, and interactions of each covariate with time. RESULTS: In adjusted models, higher SE (per 10%; B = 0.11, p = .012) and lower WASO (per 30 minutes; B = -0.12, p = .007) were associated with better memory cross-sectionally. In contrast, higher SE was associated with greater visuospatial ability decline longitudinally (B = -0.02, p = .004). Greater WASO was associated with poorer visuospatial ability cross-sectionally (B = -0.09, p = .019) but slower declines in visuospatial abilities longitudinally (B = 0.02, p = .002). Several sleep-cognition cross-sectional and longitudinal associations were stronger in, or limited to, Black participants (compared to White participants). CONCLUSIONS: This study suggests cross-sectional sleep-cognition associations differ across distinct objective sleep parameters and cognitive domains. This study also provides preliminary evidence for racial differences across some sleep-cognition relationships. Unexpected directions of associations between baseline sleep and cognitive performance over time may be attributable to the significant proportion of participants without follow-up data and require further investigation.

Sleep need-dependent changes in functional connectivity facilitate transmission of homeostatic sleep drive.

How the homeostatic drive for sleep accumulates over time and is released remains poorly understood. In Drosophila, we previously identified the R5 ellipsoid body (EB) neurons as putative sleep drive neurons1 and recently described a mechanism by which astrocytes signal to these cells to convey sleep need.2 Here, we examine the mechanisms acting downstream of the R5 neurons to promote sleep. EM connectome data demonstrate that R5 neurons project to EPG neurons.3 Broad thermogenetic activation of EPG neurons promotes sleep, whereas inhibiting these cells reduces homeostatic sleep rebound. Perforated patch-clamp recordings reveal that EPG neurons exhibit elevated spontaneous firing following sleep deprivation, which likely depends on an increase in extrinsic excitatory inputs. Our data suggest that cholinergic R5 neurons participate in the homeostatic regulation of sleep, and epistasis experiments indicate that the R5 neurons act upstream of EPG neurons to promote sleep. Finally, we show that the physical and functional connectivity between the R5 and EPG neurons increases with greater sleep need. Importantly, dual patch-clamp recordings demonstrate that activating R5 neurons induces cholinergic-dependent excitatory postsynaptic responses in EPG neurons. Moreover, sleep loss triggers an increase in the amplitude of these responses, as well as in the proportion of EPG neurons that respond. Together, our data support a model whereby sleep drive strengthens the functional connectivity between R5 and EPG neurons, triggering sleep when a sufficient number of EPG neurons are activated. This process could enable the proper timing of the accumulation and release of sleep drive.

Associations of circadian rest/activity rhythms with cognition in middle-aged and older adults: Demographic and genetic interactions.

Objectives: Wrist actigraphs (accelerometers) can record motor activity over multiple days and nights. The resulting data can be used to quantify 24-h activity profiles, known as circadian rest-activity rhythms (CRARs). Actigraphic CRARs have been tied to cognitive performance and decline in older adults; however, little is known about links between CRARs and performance or change in specific cognitive domains, or how individual differences may influence these associations. We investigated associations of actigraphic CRARs with cognitive performance and change in middle-aged and older adults, and explored whether age, sex/gender, race, and apolipoprotein E (APOE) e4 carrier status moderated these associations. Materials and methods: Participants (N = 422; 47% male) were cognitively healthy adults (i.e., without mild cognitive impairment or dementia) at baseline aged ≥ 50 years from the Baltimore Longitudinal Study of Aging who completed 5.6 ± 0.89 nights of wrist actigraphy and tests of memory, executive function, attention, language, and visuospatial ability at the same visit the actigraph was issued; 292 participants had repeat cognitive testing 3.12 (1.58) years later. Predictors included indices of rhythm strength [i.e., amplitude; relative amplitude (RA); interdaily stability (IS); mesor], delayed timing of the rhythm peak [i.e., later acrophase; midpoint of an individual's least active 5 h (L5 time); midpoint of an individual's most active 10 h (M10 time)], and fragmentation [i.e., intradaily variability (IV)]. Results: In main effects, later L5 time was cross sectionally associated with poorer memory, and greater IS predicted slower longitudinal memory decline. Associations of CRARs with cognition differed as a function of age, sex/gender, race, and APOE e4 carrier status. Conclusion: Among middle-aged and older adults, delayed circadian phase is associated with poorer memory performance, and greater day-to-day rhythm stability is associated with slower declines in memory. Significant interactions suggest that CRARs are generally more strongly associated with cognitive performance and rate of cognitive decline among women, Black adults, older individuals, and APOE e4 carriers. Replication in independent samples is needed.