Hypoxemia during rapid eye movement sleep mediates memory impairment in older adults at risk for dementia via CA1 hippocampal volume loss.

BACKGROUND AND PURPOSE: Obstructive sleep apnea is associated with increased dementia risk. Nocturnal hypoxemia, which can be more severe during rapid eye movement (REM) sleep, may be a key mechanism. This study examines how REM hypoxemia affects memory and explores whether hippocampal vulnerability to hypoxemia mediates this effect in older adults at risk for dementia. METHODS: Older adults aged ≥50 years (N = 338) with subjective or mild cognitive impairment (i.e., objective impairment) underwent neuropsychological, mood, and medical assessment, magnetic resonance imaging scanning (n = 135), and overnight polysomnography. Verbal learning and memory were assessed with the Rey Auditory Verbal Learning Test. REM sleep hypoxemia was measured using the Oxygen Desaturation Index-3% (REM-ODI). Hippocampal subfield (CA1, CA3, subiculum, and dentate gyrus) volumes were derived from T1 and high-resolution hippocampus T2 scans. We determined whether the relationship between REM-ODI and learning and memory was mediated by hippocampal subfield volume. Analyses were repeated in non-REM sleep to determine whether the effects were REM-specific. RESULTS: Although there was not a direct effect of REM-ODI on verbal learning (p > 0.05) or memory (p > 0.05), mediation analyses showed a significant indirect effect of high REM-ODI on poorer verbal learning (ß = -0.09, 95% confidence interval [CI] = -0.238 to -0.005) and memory (ß = -0.100, 95% CI = -0.255 to -0.005), which was mediated by CA1 volume. These associations were absent in non-REM sleep (p > 0.05). CONCLUSIONS: Hypoxemia during REM sleep may impair memory in people at risk for dementia by reducing CA1 hippocampal volume. Research is needed to explore whether interventions targeting REM sleep hypoxemia are protective against memory decline.

Different heart rate variability profile during sleep in mid-later life adults with remitted early-onset versus late-onset depression.

BACKGROUND: In mid-later life adults, early-onset and late-onset (i.e., onset ≥50 years) depression appear to be underpinned by different pathophysiology yet have not been examined in relation to autonomic function. Sleep provides an opportunity to examine the autonomic nervous system as the physiology changes across the night. Hence, we aimed to explore if autonomic profile is altered in mid-later life adults with remitted early-onset, late-onset and no history of lifetime depression. METHODS: Participants aged 50-90 years (n = 188) from a specialised clinic underwent a comprehensive clinical assessment and completed an overnight polysomnography study. General Linear Models were used to examine the heart rate variability differences among the three groups for four distinct sleep stages and the wake after sleep onset. All analyses controlled for potential confounders - age, sex, current depressive symptoms and antidepressant usage. RESULTS: For the wake after sleep onset, mid-later life adults with remitted early-onset depression had reduced standard deviation of Normal to Normal intervals (SDNN; p = .014, d = -0.64) and Shannon Entropy (p = .004, d = -0.46,) than those with no history of lifetime depression. Further, the late-onset group showed a reduction in high-frequency heart rate variability (HFn.u.) during non-rapid eye movement sleep stage 2 (N2; p = .005, d = -0.53) and non-rapid eye movement sleep stage 3 (N3; p = .009, d = -0.55) when compared to those with no lifetime history. LIMITATIONS: Causality between heart rate variability and depression cannot be derived in this cross-sectional study. Longitudinal studies are needed to examine the effects remitted depressive episodes on autonomic function. CONCLUSION: The findings suggest differential autonomic profile for remitted early-onset and late-onset mid-later life adults during sleep stages and wake periods. The differences could potentially serve as peripheral biomarkers in conjunction with more disease-specific markers of depression to improve diagnosis and prognosis.

Assessing sleep architecture and cognition in older adults with depressive symptoms attending a memory clinic.

BACKGROUND: While depression is intrinsically and bidirectionally linked with both sleep disturbance and cognition, the inter-relationships between sleep, cognition, and brain integrity in older people with depression, especially those with late-onset depression are undefined. METHODS: One hundred and seventy-two older adults (mean age 64.3 ± 6.9 years, Depression: n = 66, Control: n = 106) attending a memory clinic underwent a neuropsychological battery of declarative memory, executive function tasks, cerebral magnetic resonance imaging and overnight polysomnography with quantitative electroencephalography. RESULTS: The time spent in slow-wave sleep (SWS) and rapid eye movement (REM) sleep, slow-wave activity, sleep spindles, hippocampal volume and prefrontal cortex thickness did not differ between depression and control and depression onset groups. However, sleep onset latency (p = 0.005) and REM onset latency (p = 0.02) were later in the Depression group compared to controls. Less SWS was associated with poorer memory (r = 0.31, p = 0.023) in the depression group, and less SWS was related to better memory in the control group (r = -0.20, p = 0.043; Fishers r-to-z = -3.19). LIMITATIONS: Longitudinal studies are needed to determine if changes in sleep in those with depressive symptoms predict cognitive decline and illness trajectory. CONCLUSION: Older participants with depressive symptoms had delayed sleep initiation, suggestive of delayed sleep phase. The association between SWS and memory suggests SWS may be a useful target for cognitive intervention in older adults with depression symptoms. Reduced hippocampal volumes did not mediate this relationship, indicating a broader distributed neural network may underpin these associations.

Sleep spindle architecture associated with distinct clinical phenotypes in older adults at risk for dementia.

Sleep spindles are a hallmark of non-REM sleep and play a fundamental role in memory consolidation. Alterations in these spindles are emerging as sensitive biomarkers for neurodegenerative diseases of ageing. Understanding the clinical presentations associated with spindle alterations may help to elucidate the functional role of these distinct electroencephalographic oscillations and the pathophysiology of sleep and neurodegenerative disorders. Here, we use a data-driven approach to examine the sleep, memory and default mode network connectivity phenotypes associated with sleep spindle architecture in older adults (mean age = 66 years). Participants were recruited from a specialist clinic for early diagnosis and intervention for cognitive decline, with a proportion showing mild cognitive deficits on neuropsychological testing. In a sample of 88 people who underwent memory assessment, overnight polysomnography and resting-state fMRI, a k-means cluster analysis was applied to spindle measures of interest: fast spindle density, spindle duration and spindle amplitude. This resulted in three clusters, characterised by preserved spindle architecture with higher fast spindle density and longer spindle duration (Cluster 1), and alterations in spindle architecture (Clusters 2 and 3). These clusters were further characterised by reduced memory (Clusters 2 and 3) and nocturnal hypoxemia, associated with sleep apnea (Cluster 3). Resting-state fMRI analysis confirmed that default mode connectivity was related to spindle architecture, although directionality of this relationship differed across the cluster groups. Together, these results confirm a diversity in spindle architecture in older adults, associated with clinically meaningful phenotypes, including memory function and sleep apnea. They suggest that resting-state default mode connectivity during the awake state can be associated with sleep spindle architecture; however, this is highly dependent on clinical phenotype. Establishing relationships between clinical and neuroimaging features and sleep spindle alterations will advance our understanding of the bidirectional relationships between sleep changes and neurodegenerative diseases of ageing.

Heart rate variability during slow wave sleep is linked to functional connectivity in the central autonomic network.

Reduced heart rate variability can be an early sign of autonomic dysfunction in neurodegenerative diseases and may be related to brain dysfunction in the central autonomic network. As yet, such autonomic dysfunction has not been examined during sleep-which is an ideal physiological state to study brain-heart interaction as both the central and peripheral nervous systems behave differently compared to during wakefulness. Therefore, the primary aim of the current study was to examine whether heart rate variability during nocturnal sleep, specifically slow wave (deep) sleep, is associated with central autonomic network functional connectivity in older adults 'at-risk' of dementia. Older adults (n = 78; age range = 50-88 years; 64% female) attending a memory clinic for cognitive concerns underwent resting-state functional magnetic resonance imaging and an overnight polysomnography. From these, central autonomic network functional connectivity strength and heart rate variability data during sleep were derived, respectively. High-frequency heart rate variability was extracted to index parasympathetic activity during distinct periods of sleep, including slow wave sleep as well as secondary outcomes of non-rapid eye movement sleep, wake after sleep onset, and rapid eye movement sleep. General linear models were used to examine associations between central autonomic network functional connectivity and high-frequency heart rate variability. Analyses revealed that increased high-frequency heart rate variability during slow wave sleep was associated with stronger functional connectivity (F = 3.98, P = 0.022) in two core brain regions within the central autonomic network, the right anterior insular and posterior midcingulate cortex, as well as stronger functional connectivity (F = 6.21, P = 0.005) between broader central autonomic network brain regions-the right amygdala with three sub-nuclei of the thalamus. There were no significant associations between high-frequency heart rate variability and central autonomic network connectivity during wake after sleep onset or rapid eye movement sleep. These findings show that in older adults 'at-risk' of dementia, parasympathetic regulation during slow wave sleep is uniquely linked to differential functional connectivity within both core and broader central autonomic network brain regions. It is possible that dysfunctional brain-heart interactions manifest primarily during this specific period of sleep known for its role in memory and metabolic clearance. Further studies elucidating the pathophysiology and directionality of this relationship should be conducted to determine if heart rate variability drives neurodegeneration, or if brain degeneration within the central autonomic network promotes aberrant heart rate variability.

Multi-institutional distributed data networks for real-world evidence about medical devices: building unique device identifiers into longitudinal data (BUILD).

Objectives: To support development of a robust postmarket device evaluation system using real-world data (RWD) from electronic health records (EHRs) and other sources, employing unique device identifiers (UDIs) to link to device information. Methods: To create consistent device-related EHR RWD across 3 institutions, we established a distributed data network and created UDI-enriched research databases (UDIRs) employing a common data model comprised of 24 tables and 472 fields. To test the system, patients receiving coronary stents between 2010 and 2019 were loaded into each institution's UDIR to support distributed queries without sharing identifiable patient information. The ability of the system to execute queries was tested with 3 quality assurance checks. To demonstrate face validity of the data, a retrospective survival study of patients receiving zotarolimus or everolimus stents from 2012 to 2017 was performed using distributed analysis. Propensity score matching was used to compare risk of 6 cardiovascular outcomes within 12 months postimplantation. Results: The test queries established network functionality. In the analysis, we identified 9141 patients (Mercy = 4905, Geisinger = 4109, Intermountain = 127); mean age 65 ± 12 years, 69% males, 23% zotarolimus. Separate matched analyses at the 3 institutions showed hazard ratio estimates (zotarolimus vs everolimus) of 0.85-1.59 for subsequent percutaneous coronary intervention (P = .14-.52), 1.06-2.03 for death (P = .16-.78) and 0.94-1.40 for the composite endpoint (P = .16-.62). Discussion: The analysis results are consistent with clinical studies comparing these devices. Conclusion: This project shows that multi-institutional data networks can provide clinically relevant real-world evidence via distributed analysis while maintaining data privacy.

Thalamic abnormalities in older adults with remitted early-onset depression using structural magnetic resonance imaging.

BACKGROUND: The thalamus is a key diencephalic structure involved in major depressive disorder (MDD). Studies have consistently revealed abnormalities in thalamic volumes in older adults with late-onset depression (LOD), however abnormalities in older adults with early-onset depression (EOD) have not yet been well-studied. METHODS: Fifty-nine euthymic participants with a history of EOD and fifty-nine matched comparison participants without a lifetime history of depression underwent neuroimaging, medical and neuropsychological assessments. Thalamic volumes were compared between groups. To investigate the previously-proposed right hemispheric (RH) dominance theory of MDD, we explored the bilateral, right and left hemispheric (LH) thalamic volumes. Multiple regression analyses were used to evaluate between-group and within-group effects. Correlational analyses examined associations between group and cognitive performance. RESULTS: Relative to the comparison group, those with EOD had significantly larger bilateral, LH and RH thalamic volumes. Those with EOD, those who were younger, and those who had fewer years of education demonstrated larger bilateral and LH thalamic volumes. For RH thalamic volumes, those with EOD and those who were younger demonstrated larger RH thalamic volumes. EOD within-group models were also run to assess associations between relevant depression variables. The results showed that only age was significant for bilateral and RH thalamic volumes. For the LH thalamic volumes, the model was not significant. No significant correlations were found between cognitive performance and EOD groups. CONCLUSION: Older adults with a history of EOD showed significantly larger bilateral, RH and LH thalamic volumes. Further research is needed to delineate potential underlying mechanisms of this change.

Safety of higher doses of melatonin in adults: A systematic review and meta-analysis.

Melatonin is commonly used for sleep and jetlag at low doses. However, there is less documentation on the safety of higher doses, which are being increasingly used for a wide variety of conditions, including more recently COVID-19 prevention and treatment. The aim of this review was to investigate the safety of higher doses of melatonin in adults. Medline, Scopus, Embase and PsycINFO databases from inception until December 2019 with convenience searches until October 2020. Randomised controlled trials investigating high-dose melatonin (≥10 mg) in human adults over 30 years of age were included. Two investigators independently abstracted articles using PRISMA guidelines. Risk of bias was assessed by a committee of three investigators. 79 studies were identified with a total of 3861 participants. Studies included a large range of medical conditions. The meta-analysis was pooled data using a random effects model. The outcomes examined were the number of adverse events (AEs), serious adverse events (SAEs) and withdrawals due to AEs. A total of 29 studies (37%) made no mention of the presence or absence of AEs. Overall, only four studies met the pre-specified low risk of bias criteria for meta-analysis. In that small subset, melatonin did not cause a detectable increase in SAEs (Rate Ratio = 0.88 [0.52, 1.50], p = .64) or withdrawals due to AEs (0.93 [0.24, 3.56], p = .92), but did appear to increase the risk of AEs such as drowsiness, headache and dizziness (1.40 [1.15, 1.69], p < .001). Overall, there has been limited AE reporting from high-dose melatonin studies. Based on this limited evidence, melatonin appears to have a good safety profile. Better safety reporting in future long-term trials is needed to confirm this as our confidence limits were very wide due to the paucity of suitable data.

Poorer Theory of Mind in Amnestic Mild Cognitive Impairment Is Associated with Decreased Functional Connectivity in the Default Mode Network.

BACKGROUND: Older adults living with amnestic mild cognitive impairment (aMCI) not only demonstrate impairments in Theory of Mind (ToM), relative to adults with non-amnestic MCI (naMCI), but are also at a higher risk of developing dementia. OBJECTIVE: Our primary objective was to ascertain whether default mode network (DMN) functional connectivity was differentially associated with ToM abilities between MCI subgroups. METHODS: Using functional magnetic resonance imaging, we investigated alterations in resting-state functional connectivity within the brain's DMN in a sample of 43 older adults with aMCI (n = 19) and naMCI (n = 24), previously reported to demonstrate poorer ToM abilities. RESULTS: Compared to naMCI, the aMCI subgroup revealed a significant association between poorer ToM performance and reduced functional connectivity between the bilateral temporal pole (TempP) and the left lateral temporal cortex (LTC) (LTC_L-TempP_L: b = -0.06, t(33) = -3.53, p = 0.02; LTC_L-TempP_R: b = -0.07,t(33) = -3.20, p = 0.03); between the right TempP and the dorsal medial prefrontal cortex (dMPFC) (b = -0.04, t(33) = -3.02, p = 0.03) and between the left and right TempP (b = -0.05, t(33) = -3.26, p = 0.03). In the naMCI subgroup, the opposite relationship was present between the bilateral TempP and the left LTC (Combined correlation: r = -0.47, p = 0.02), however, not between the right TempP and the dMPFC (r = -0.14, p = 0.51) or the left and right TempP (r = -0.31, p = 0.14). CONCLUSION: Our findings suggest that alterations in functional connectivity within the DMN involving temporal and frontal lobe regions are associated with ToM deficits in aMCI.

Apolipoprotein E ε4 Allele-Based Differences in Brain Volumes Are Largely Uniform Across Late Middle Aged and Older Hispanic/Latino- and Non-Hispanic/Latino Whites Without Dementia.

Hispanics/Latinos are at an equal or a greater risk for Alzheimer's disease (AD), yet risk factors remain more poorly characterized as compared to non-Hispanic/Latino Whites. Among non-Hispanic/Latino White cohorts, the apolipoprotein E (APOE) ε4 allele is one of the strongest risk factors for AD with subtle declines in episodic memory and brain volumes detectable in the preclinical stages. We examined whether the APOE ε4 status had a differential impact on cognition and brain volumes among cognitively healthy and mild cognitively impaired Hispanics/Latinos (n = 86; ε4 n = 23) compared to a well-matched group of non-Hispanic/Latino Whites (n = 92; ε4 n = 29). Neither the APOE ε4 status nor the interaction between the ε4 status and ethnicity was associated with cognitive performance. The APOE ε4 status was associated with white matter and not with gray matter volumes. APOE ε4 carriers had a significantly smaller total brain white matter volumes, as well as smaller right middle temporal and left superior temporal volumes. The Hispanics/Latinos had significantly smaller left middle frontal gray matter volumes, yet marginally larger overall white matter volumes, than the non-Hispanic/Latino Whites. Exploratory analysis within the Hispanic/Latino sample found that those people whose primary language was Spanish had larger total brain white matter volumes compared primarily to the English speakers. Importantly, primary language differences only held for Hispanic/Latino ε4 carriers and did not differentiate Hispanic/Latino non-carriers, underscoring the need for further investigation into the impacts of language and acculturation on cognitive aging among the fastest growing ethnic minority group in the United States.

Cardiovascular risk factors and APOE-ε4 status affect memory functioning in aging via changes to temporal stem diffusion.

Prior research investigating associations between hypertension, obesity, and apolipoprotein (APOE) genotype status with memory performance among older adults has yielded inconsistent results. This may reflect, in part, a lack of first accounting for the effects these variables have on structural brain changes, that in turn contribute to age-related memory impairment. The current study sought to clarify the relationships between these factors via path modeling. We hypothesized that higher body mass index (BMI), hypertension, and being an APOE-ε4 allele carrier would predict poorer memory scores, with much of these effects accounted for by indirect effects operating via differences in the integrity of temporal stem white matter. Participants included 125 healthy older adults who underwent neuropsychological assessment and diffusion-weighted MRI scanning. Direct effects were found for hypertension and demographic variables including age, sex, and education. Importantly, indirect effects were found for BMI, hypertension, APOE-ε4 status, age, and sex, where these factors predicted memory scores via their impact on temporal stem diffusion measures. There was also a dual effect of sex, with a direct effect indicating that females had better memory performance overall, and an indirect effect indicating that females with greater temporal stem diffusion had poorer memory performance. Results suggest that changes to the integrity of temporal white matter in aging may underpin reduced memory performance. These results highlight that accounting for variables that not only directly impact cognition, but also for those that indirectly impact cognition via structural brain changes, is crucial for understanding the impact of risk factors on cognition.

Altered heart rate variability during sleep in mild cognitive impairment.

STUDY OBJECTIVES: Cardiovascular autonomic dysfunction, as measured by short-term diurnal heart rate variability (HRV), has been reported in older adults with mild cognitive impairment (MCI). However, it is unclear whether this impairment also exists during sleep in this group. We, therefore, compared overnight HRV during sleep in older adults with MCI and those with subjective cognitive impairment (SCI). METHODS: Older adults (n = 210) underwent overnight polysomnography. Eligible participants were characterized as multi-domain MCI or SCI. The multi-domain MCI group was comprised of amnestic and non-amnestic subtypes. Power spectral analysis of HRV was conducted on the overnight electrocardiogram during non-rapid eye movement (NREM), rapid eye movement (REM), N1, N2, N3 sleep stages, and wake periods. High-frequency HRV (HF-HRV) was employed as the primary measure to estimate parasympathetic function. RESULTS: The MCI group showed reduced HF-HRV during NREM sleep (p = 0.018), but not during wake or REM sleep (p > 0.05) compared to the SCI group. Participants with aMCI compared to SCI had the most pronounced reduction in HF-HRV across all NREM sleep stages-N1, N2, and N3, but not during wake or REM sleep. The naMCI sub-group did not show any significant differences in HF-HRV during any sleep stage compared to SCI. CONCLUSIONS: Our study showed that amnestic MCI participants had greater reductions in HF-HRV during NREM sleep, relative to those with SCI, suggesting potential vulnerability to sleep-related parasympathetic dysfunction. HF-HRV, especially during NREM sleep, may be an early biomarker for dementia detection.

Nocturnal Hypoxemia Is Associated with Altered Parahippocampal Functional Brain Connectivity in Older Adults at Risk for Dementia.

BACKGROUND: Obstructive sleep apnea is associated with an increased risk of developing mild cognitive impairment and dementia. Intermittent nocturnal hypoxemia in obstructive sleep apnea is associated with brain changes in key regions that underpin memory. OBJECTIVE: To determine whether older adults with severe nocturnal hypoxemia would exhibit reduced functional connectivity within these regions, with associated deficits in memory. METHODS: Seventy-two participants 51 years and over underwent polysomnography with continuous blood oxygen saturation recorded via oximetry. The oxygen desaturation index (ODI, 3% dips in oxygen levels per hour) was the primary outcome measure. ODI was split into tertiles, with analyses comparing the lowest and highest tertiles (N = 48). Thirty-five of the 48 participants from these two tertiles had mild cognitive impairment. Participants also underwent resting-state fMRI and comprehensive neuropsychological, medical, and psychiatric assessment. RESULTS: The highest ODI tertile group demonstrated significantly reduced connectivity between the left and right parahippocampal cortex, relative to the lowest ODI tertile group (t(42) = -3.26, p = 0.041, beta = -1.99).The highest ODI tertile group also had poorer working memory performance. In the highest ODI tertile group only, higher left-right parahippocampal functional connectivity was associated with poorer visual memory recall (between-groups z = -2.93, p = 0.0034). CONCLUSIONS: Older adults with severe nocturnal hypoxemia demonstrate impaired functional connectivity in medial temporal structures, key regions involved in sleep memory processing and implicated in dementia pathophysiology. Oxygen desaturation and functional connectivity in these individuals each relate to cognitive performance. Research is now required to further elucidate these findings.

The impact of cardiovascular risk factors on cognition in Hispanics and non-Hispanic whites.

Among non-Hispanic whites, cardiovascular risk factors are associated with increased mortality and poorer cognition. Prevalence of cardiovascular risk factors among aging Hispanics is also high and Hispanics generally have poorer access to healthcare, yet they tend to have advantageous cardiovascular disease rates and outcomes and live longer than non-Hispanic whites, an epidemiological phenomenon commonly referred to as the Hispanic or Latino health paradox. Although robust data support these ethnic benefits on physical health and mortality, it is unknown if it extends to include cognition resilience advantages in older adulthood. The present study compared relationships between cardiovascular risk and cognition (executive functions and episodic memory) in late middle age and older Hispanics (n = 87) and non-Hispanic whites (n = 81). Participants were selected from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases. Hispanics and non-Hispanic white groups were matched on age (50-94 yr, mean age = 72 yr), education, gender, cognitive status (i.e., cognitively healthy versus mildly cognitively impaired), and apolipoprotein E4 status. History of hypertension and higher body mass index were both associated with poorer executive functions among Hispanics but not non-Hispanic whites. Our findings suggest greater vulnerability to impairments in executive functions among Hispanics with hypertension and obesity, contrary to the notion of a Hispanic health paradox for cognitive aging.

Relationships between sleep quality, depressive symptoms and MCI diagnosis: A path analysis.

BACKGROUND: This study examined the complex relationships between sleep quality, depressive symptoms, and cognitive decline in older adults. We hypothesised that older age, lower education and greater medical comorbidities would each be associated with increased mild cognitive impairment (MCI) diagnosis risk through indirect effects via poorer sleep quality, and greater depressive symptomology. METHODS: 540 adults 44 years and over were recruited at the Brain and Mind Centre, Sydney, Australia. Participants underwent comprehensive psychiatric, neuropsychological, and medical assessment. Subjective sleep quality, current depressive symptomatology, and current medical burden were assessed. RESULTS: There were significant indirect effects of each of age, comorbidities and education, that operated via both sleep and depression. Younger age, greater comorbidities and fewer years' education each predicted greater chance of MCI diagnosis via poorer sleep and in turn higher depressive symptomatology. Additionally, there was a significant direct effect of older age on MCI. LIMITATIONS: The current study is cross-sectional and cannot determine whether poorer sleep quality and greater depressive symptomatology precede or arise as a result of the onset of cognitive decline in later-life. A longitudinal design may allow further explication of these relationships. CONCLUSIONS: Both sleep and depression are linked with cognitive decline in older adults, with sleep disturbance appearing to predict depressive symptoms. These findings have implications for the management of MCI. Both greater depression symptomatology and sleep disturbance were shown to predict the risk of MCI diagnosis, with this effect strongest in those that are younger. Improved early detection and treatment of sleep problems in older adults may help prevent depressive symptom manifestation or exacerbation, in turn potentially reducing the risk of subsequent cognitive decline.

Anti-Tumour Necrosis Factor Therapy for Inflammatory Bowel Diseases Do Not Impact Serious Infections after Arthroplasty.

BACKGROUND AND AIMS: There is a paucity of data on the safety of joint replacement surgery in patients with inflammatory bowel disease [IBD], including those on tumour necrosis factor-alpha inhibitors [anti-TNF]. We explored the risk of serious infections in this population. METHODS: A retrospective case-control study [2006-2014] was performed using the MarketScan Database. All patients aged 18-64 years with an International Classification of Diseases code for IBD and an IBD-specific medication, with ≥ 6 months of enrollment prior to hip, knee or shoulder replacement surgery, were included. Ten non-IBD controls were frequency-matched to each case on length of enrollment, year and the joint replaced. Primary outcome was serious infection [composite of joint infection, surgical site infection, pneumonia, sepsis] within 90 days of the operation. Cox proportional hazards models were used to assess the association of IBD and IBD medications with serious infection. RESULTS: More patients with IBD [N = 1455] had serious infections than controls [3.2% vs 2.3%, p = 0.04], but not after controlling for comorbidities (hazard ratio [HR], 1.3; 95% confidence interval [CI], 0.95-1.76). Among IBD patients, corticosteroids were associated with increased risk of serious infection [HR, 4.6; 95% CI, 2.2-9.8; p < 0.01] while anti-TNFs were not. Opioids were also associated with increased risk of infection [HR, 1.5; 95% CI, 1.2-1.8; p < 0.01]. CONCLUSIONS: After controlling for comorbidities, IBD patients were not at increased risk of serious infection following joint replacement. Corticosteroids, but not anti-TNFs or immunomodulators, were associated with increased risk of serious infections in IBD patients.

Predictors of mortality for preterm infants with intraventricular hemorrhage: a population-based study.

PURPOSE: The goal of this longitudinal, population-level study was to examine factors affecting mortality in preterm infants with intraventricular hemorrhage (IVH). METHODS: The study examined patients who were born at 36 weeks estimated gestational age (EGA) or less with a diagnosis of IVH between the years 2005 and 2014 using data from the New York and Nebraska State Inpatient Databases. Potential predictors for mortality were investigated with multivariable survival analysis. RESULTS: The cohort included 7437 preterm infants with IVH. All-cause inpatient mortality occurred in 746 (10.0%). The majority of deaths were in infants born at less than 25 weeks EGA (378 or 50.7%) and with birthweight less than 750 g (459 or 61.5%). Mortality was highest for children with grade IV IVH (306/848 or 36.1%), followed by grades III (203/955 or 21.3%), II (103/1328 or 7.8%), and I (134/4306 or 3.1%). Hydrocephalus was diagnosed within 6 months in 627 (8.4%) patients, with cerebrospinal fluid shunts required in 237 (3.2%). Shunts were eventually revised in 122 (51.5% of shunts), and 43 (18.1%) had infections. Multivariable Cox survival analyses found male sex (HR 1.3 [95% CI 1.1-1.5]), Asian race (HR 1.5 [1.1-2.2]), lower EGA (HR 9.9 [6.3-15.5] for < 25 weeks), higher IVH grade (HR 6.1 [4.9-7.6] for grade IV), gastrostomy (HR 4.0 [2.0-7.7]), tracheostomy (HR 3.5 [1.7-7.1]), and shunt infection (HR 3.2 [1.0-9.9]) to be independently associated with increased mortality risk. CONCLUSIONS: This database is the first of its kind assembled for population-based investigations of long-term neurosurgical outcomes in preterm infants with IVH.

Current sleep disturbance in older people with a lifetime history of depression is associated with increased connectivity in the Default Mode Network.

BACKGROUND: The present study investigated Default Mode Network (DMN) functional connectivity in subjects with a lifetime history of major depression, comparing those with and without current sleep disturbance. Controls were included to assess DMN abnormalities specific to depression. METHODS: A total of 93 adults aged 50 years and over were recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney, Australia. The sample comprised two groups, including 22 controls and 71 participants with a lifetime history of DSM-IV major depression (with depressive episode current or remitted). 52 of those with a lifetime history of depression also met criteria for Mild Cognitive Impairment (MCI). Participants underwent resting-state fMRI along with comprehensive psychiatric, neuropsychological, and medical assessment. Subjective sleep quality was assessed via the Pittsburgh Sleep Quality Index (PSQI). Sleep disturbance was defined as a PSQI score > 5. A total of 68% (n = 48) of cases with a lifetime history of depression met criteria for sleep-disturbance. DMN functional connectivity was assessed via ROI-to-ROI analyses. RESULTS: Relative to controls, those with lifetime major depression demonstrated significantly increased functional connectivity between the ventromedial prefrontal cortex and the temporal pole. Within the depression group (n = 48), those with current sleep disturbance had significantly increased connectivity between the anterior medial prefrontal cortex and both the parahippocampal cortex and the hippocampal formation, relative to those without sleep disturbance (n = 23). These results were present after controlling for MCI diagnosis. CONCLUSIONS: Current sleep disturbance together with depression is associated with distinct abnormalities in DMN functioning incorporating regions responsible for self-reflection and declarative memory processes. Impaired sleep is associated with increased connectivity between these regions. Future studies may augment these findings with complementary imaging techniques including cortical thickness and diffusion tensor imaging, as well as high density electroencephalogram recording.

Functional Connectivity in the Default Mode Network is Reduced in Association with Nocturnal Awakening in Mild Cognitive Impairment.

BACKGROUND: Sleep disturbance is prevalent in MCI, and is a risk factor for cognitive deterioration. OBJECTIVE: To identify functional connectivity deficits in the default mode network (DMN) in patients with mild cognitive impairment (MCI) and sleep disturbance, relative to MCIs with intact sleep. METHODS: Participants comprised 47 adults aged 55 years and over, recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney, Australia. This sample contained 15 controls and 32 participants meeting criteria for MCI. Participants underwent resting-state fMRI and actigraphy, along with comprehensive neuropsychological, medical and psychiatric assessment. MCIs were split into two groups according to average wake after sleep onset (WASO) per night. WASO equal to or greater than 1 standard deviation (SD) above the control mean was deemed to reflect disturbed sleep. There were 11 patients in the MCI sleep-disturbed group, and 21 in the MCI sleep-intact group. RESULTS: Relative to controls, MCIs demonstrated significant connectivity reductions between parietal and temporoparietal regions, and between temporal regions. Relative to MCIs with intact sleep, MCIs with sleep disturbance demonstrated reductions in functional connectivity between temporal and parietal regions, and between temporal and temporoparietal regions. CONCLUSIONS: MCIs with nocturnal awakenings demonstrate reductions in DMN connectivity. These reductions comprise brain regions that are crucially involved in sleep and memory processes. These results strengthen our previous findings, which found reduced connectivity in MCIs with self-reported sleep disturbances. Future studies may build on these findings through incorporating complementary neuroimaging techniques and experimental manipulations of sleep.

Sleep disturbance in mild cognitive impairment is associated with alterations in the brain's default mode network.

This study aimed to identify default mode network (DMN) functional connectivity deficits in patients with mild cognitive impairment (MCI) and sleep disturbance, relative to those with MCI and no sleep disturbance. A control group was included to aid in identifying DMN changes specific to MCI. A cross-sectional, single-center study was performed at the Brain and Mind Research Centre in Sydney, Australia. Participants (95 adults over the age of 65: 38 controls and 57 meeting criteria for MCI) underwent resting-state functional MRI along with comprehensive neuropsychological, medical, and psychiatric assessment. Self-report data were collected including sleep quality assessment via the Pittsburgh Sleep Quality Index. A total score of greater than 5 on the Pittsburgh Sleep Quality Index was used to signify the presence of significant sleep disturbance, as per commonly used methodology. Using this criterion, 53% (n = 30) of our MCI group were classified as sleep-disturbed. Whereas the total group of MCI subjects and controls demonstrated no significant differences, sleep-disturbed MCIs demonstrated increased connectivity between temporal and parietal regions, and decreased connectivity between the prefrontal cortex and the temporoparietal junction relative to sleep-disturbed controls. Relative to those MCIs without sleep disturbance, sleep-disturbed MCI participants demonstrated significantly diminished DMN connectivity between temporal and parietal regions, a finding that was particularly pronounced in amnestic MCI. Sleep disturbance in MCI is associated with distinct alterations in DMN functional connectivity in brain regions underpinning salient memory and sleep systems. Future studies may build on these results via experimental manipulation and objective measurement of sleep. (PsycINFO Database Record