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Background Inflammatory bowel disease (IBD) is associated with a reduced quality of life. Minority patients with IBD specifically report more impairing symptoms compared with nonminority patients. Sleep quality, a key component of quality of life, is significantly compromised in minority patients compared with nonminority patients. Nevertheless, subjective and objective sleep assessments in minority patients with IBD have not explicitly been assessed. The purpose of this prospective cohort study is to assess and compare objective sleep parameters utilizing wrist actigraphy between minority and nonminority IBD patients. Methods In this institutional review board approved study, 74 patients with IBD were recruited and stratified into 2 cohorts by self-identification: white nonminority patients and minority patients. Patients in the minority cohort included black and Hispanic individuals (black and nonblack). Exclusion criteria included significant comorbidity, a history of an underlying sleep disorder, or patients who did not self-identify into categorized cohorts. Sleep was measured not only through wrist-based actigraphy but also with sleep surveys. Sleep parameters were compared between minority and nonminority cohorts. Regression analyses were performed to assess for factors independently associated with parameters of poor sleep quality. Results Sixty-four patients (86.4%) were included in the final analysis. Thirty-one individuals (48.4%) were categorized into the nonminority cohort, and 33 (51.6%) patients were in the minority cohort. A significantly higher number of minority patients had poorer sleep efficiency and fragmented sleep compared with nonminority patients (90.9% vs 67.7%; P = 0.03 and 87.8% vs 61.3%; P = 0.02). In the adjusted analysis, minority status was independently associated with poor sleep efficiency (odds ratio = 6.41; 95% confidence interval, 1.48-28.17; P = 0.0139) and fragmented sleep (odds ratio = 4.98; 95% confidence interval, 1.09-22.89; P = 0.0389). Conclusions Minority patients with IBD were shown to have poorer objective measures of sleep as assessed through wrist actigraphy compared to nonminority patients. Cultural competency in the care of minority patients with IBD, specifically focusing on the management of psychosocial issues, is needed to address these disparities in sleep. The inclusion of minority patients with IBD in studies investigating sleep and other psychosocial issues are warranted not only to assess potential disparities in disease course but also to determine the etiologies of poor sleep in minority patients with IBD.

Qiu et al. present a novel deep learning strategy to generate high-resolution visualizations of Alzheimer’s disease risk in humans that are highly interpretable and can accurately predict Alzheimer’s disease status. They then test the model by comparing its performance to that of neurologists and neuropathological data., Alzheimer’s disease is the primary cause of dementia worldwide, with an increasing morbidity burden that may outstrip diagnosis and management capacity as the population ages. Current methods integrate patient history, neuropsychological testing and MRI to identify likely cases, yet effective practices remain variably applied and lacking in sensitivity and specificity. Here we report an interpretable deep learning strategy that delineates unique Alzheimer’s disease signatures from multimodal inputs of MRI, age, gender, and Mini-Mental State Examination score. Our framework linked a fully convolutional network, which constructs high resolution maps of disease probability from local brain structure to a multilayer perceptron and generates precise, intuitive visualization of individual Alzheimer’s disease risk en route to accurate diagnosis. The model was trained using clinically diagnosed Alzheimer’s disease and cognitively normal subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (n = 417) and validated on three independent cohorts: the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) (n = 382), the Framingham Heart Study (n = 102), and the National Alzheimer’s Coordinating Center (NACC) (n = 582). Performance of the model that used the multimodal inputs was consistent across datasets, with mean area under curve values of 0.996, 0.974, 0.876 and 0.954 for the ADNI study, AIBL, Framingham Heart Study and NACC datasets, respectively. Moreover, our approach exceeded the diagnostic performance of a multi-institutional team of practicing neurologists (n = 11), and high-risk cerebral regions predicted by the model closely tracked post-mortem histopathological findings. This framework provides a clinically adaptable strategy for using routinely available imaging techniques such as MRI to generate nuanced neuroimaging signatures for Alzheimer’s disease diagnosis, as well as a generalizable approach for linking deep learning to pathophysiological processes in human disease.

Sleep disordered breathing (SDB) is highly prevalent, but frequently unrecognized among stroke patients. Polysomnography (PSG) is difficult to perform soon after a stroke. We evaluated the use of screening questionnaires and portable sleep testing (PST) for patients with acute stroke, subarachnoid hemorrhage, or transient ischemic attack to expedite SDB diagnosis and management. We performed a single-center retrospective analysis of a quality improvement study on SDB screening of consecutive daytime, weekday, adult admissions to a stroke unit. We excluded patients who were unable to communicate and lacked available family members. Patients were screened with the Epworth Sleepiness Scale, Berlin Questionnaire, and STOP-BANG Questionnaire and underwent overnight PST and/or outpatient PSG. The 4-item STOP Questionnaire was derived from STOP-BANG for a secondary analysis. We compared the sensitivity and specificity of the questionnaires for the diagnosis of at least mild SDB (apnea hypopnea index (AHI) ≥5) on PST and correlated AHI measurements between PST and PSG using the Spearman correlation. Out of sixty-eight patients included in the study, 54 (80%) were diagnosed with SDB. Only one (1.5%) had a previous SDB diagnosis. Thirty-three patients completed all questionnaires and a PST. The STOP-BANG questionnaire had the highest sensitivity for at least mild SDB (0.81, 95% CI (confidence interval): 0.65–0.92) but a low specificity (0.33, 95% CI 0.10, 0.65). The discrimination of all questionnaires was overall poor (C statistic range 0.502–0.640). There was a strong correlation (r = 0.71) between the AHI results estimated using PST and outpatient PSG among 28 patients. The 4-item STOP Questionnaire was the easiest to administer and had a comparable or better sensitivity than the other questionnaires. Inpatient PSTs were useful for screening in the acute setting to facilitate an early diagnosis of SDB and to establish further outpatient evaluations with sleep medicine.

Introduction Despite the availability of age- and education-adjusted standardized scores for most neuropsychological tests, there is a lack of objective rules in how to interpret multiple concurrent neuropsychological test scores that characterize the heterogeneity of Alzheimer's disease. Methods Using neuropsychological test scores of 2091 participants from the Framingham Heart Study, we devised an automated algorithm that follows general diagnostic criteria and explores the heterogeneity of Alzheimer's disease. Results We developed a series of stepwise diagnosis rules that evaluate information from multiple neuropsychological tests to produce an intuitive and objective Alzheimer's disease dementia diagnosis with more than 80% accuracy. Discussion A data-driven stepwise diagnosis system is useful for diagnosis of Alzheimer's disease from neuropsychological tests. It demonstrated better performance than the traditional dichotomization of individuals' performance into satisfactory and unsatisfactory outcomes, making it more reflective of dementia as a spectrum disorder. This algorithm can be applied to both within clinic and outside-of-clinic settings., Highlights • Stepwise diagnosis rules for Alzheimer's disease (AD) dementia diagnosis. • Heterogeneous AD profiles based on specific AD risk factors identified. • Selection of important neuropsychological tests aid differential diagnoses. • Grading system more reflective of dementia as a spectrum disorder. • Automated diagnosis rules applicable to both within clinic and outside-of-clinic settings.

Background The Clock Drawing Test (CDT) has been widely used in clinic for cognitive assessment. Recently, a digital Clock Drawing Text (dCDT) that is able to capture the entire sequence of clock drawing behaviors was introduced. While a variety of domain-specific features can be derived from the dCDT, it has not yet been evaluated in a large community-based population whether the features derived from the dCDT correlate with cognitive function. Objective We aimed to investigate the association between dCDT features and cognitive performance across multiple domains. Methods Participants from the Framingham Heart Study, a large community-based cohort with longitudinal cognitive surveillance, who did not have dementia were included. Participants were administered both the dCDT and a standard protocol of neuropsychological tests that measured a wide range of cognitive functions. A total of 105 features were derived from the dCDT, and their associations with 18 neuropsychological tests were assessed with linear regression models adjusted for age and sex. Associations between a composite score from dCDT features were also assessed for associations with each neuropsychological test and cognitive status (clinically diagnosed mild cognitive impairment compared to normal cognition). Results The study included 2062 participants (age: mean 62, SD 13 years, 51.6% women), among whom 36 were diagnosed with mild cognitive impairment. Each neuropsychological test was associated with an average of 50 dCDT features. The composite scores derived from dCDT features were significantly associated with both neuropsychological tests and mild cognitive impairment. Conclusions The dCDT can potentially be used as a tool for cognitive assessment in large community-based populations.

The relationship between body mass index (BMI) and health outcomes of older adults, including dementia, remains controversial. Many studies find inverse associations between BMI and dementia among older adults, while in other studies high BMI in midlife is associated with increased dementia risk. In this issue, Li et al. (Am J Epidemiol. 2021;190(12):2503–2510) examine BMI from mid- to late life and risk of dementia using the extensive follow-up of the Framingham Offspring Study. They found changing trends in the association between BMI and dementia from a positive association for midlife (ages 40–49) to an inverse trend in late life. Their work demonstrates the importance of studying dementia risk factors across the life course. Midlife obesity might be an important modifiable risk factor for dementia. However, because incipient dementia can lead to weight loss, reverse causation remains a key source of bias that could explain an inverse trend between BMI and dementia in older ages. The extent of other biases, including unmeasured confounding, inaccuracy of BMI as a measure for adiposity, or selective survival, are also unclear. Triangulating evidence on body composition and dementia risk could lead to better targets for dementia intervention, but future work will need to evaluate specific pathways.

The continuous, longitudinal nature of accelerometry monitoring is well-suited to capturing the regular 24-hour oscillations in human activity across the day, the cumulative effect of our circadian rhythm and behavior. Disruption of the circadian rhythm in turn disrupts rest-activity rhythms. Although circadian disruption is a major feature of Parkinson's disease (PD), rest-activity rhythms and their relationship with disease severity have not been well characterized in PD. 13 PD participants (Hoehn & Yahr Stage [HY significant associations between MDS-UPDRS scores and activity levels were observed only in the unadjusted model. These findings demonstrate that continuous actigraphy is capable of detecting rest-activity disruption in PD, and provides preliminary evidence that rest-activity rhythms are associated with motor symptom severity and H&Y Stage.

STUDY OBJECTIVES: Sleep-disordered breathing (SDB) is highly prevalent in patients with acute stroke. SDB is often underdiagnosed and associated with neurological deterioration and stroke recurrence. Polysomnography or home sleep apnea testing (HSAT) is typically used as the diagnostic modality; however, it may not be feasible to use regularly in patients with acute stroke. We investigated the predictive performance of pulse oximetry, a simpler alternative, to identify SDB. METHODS: The records of 254 patients, who were admitted to Boston Medical Center for acute stroke and underwent HSAT, were retrospectively reviewed. Oxygen desaturation index (ODI) from pulse oximetry channel were compared to respiratory event index (REI) obtained from HSAT devices. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ODI were calculated, and different ODI cutoff values to predict SDB were proposed. RESULTS: ODI had a strong correlation (r = .902) and agreement with REI. ODI was accurate in predicting SDB at different REI thresholds (REI ≥ 5, REI ≥ 15, and REI ≥ 30 events/h) with the area under the curve (AUC) of .965, .974, and .951, respectively. An ODI ≥ 5 events/h rules in the presence of SDB (specificity 91.7%, PPV 96.3%). An ODI ≥ 15 events/h rules in moderate to severe SDB (specificity 96.4%, PPV 95%) and an ODI < 5 events/h rules out moderate to severe SDB (sensitivity 100%, NPV 100%). CONCLUSIONS: Nocturnal pulse oximetry has a high diagnostic accuracy in predicting moderate to severe SDB in patients with acute stroke. Oximetry can be a simple modality to rapidly recognize patients with more severe SDB and facilitate the referral to the confirmation sleep study. CITATION: Lin SH, Branson C, Park L, Leung J, Doshi N, Auerbach SH. Oximetry as an accurate tool for identifying moderate to severe sleep apnea in patients with acute stroke.J Clin Sleep Med. 2018;14(12):2065–2073.

Enuresis, or "bedwetting," in children is associated with obstructive sleep apnea (OSA), and often resolves with treatment of OSA. However, it is poorly understood whether a similar relationship exists in adults. We describe a case series of 5 adult patients in whom OSA was diagnosed by laboratory polysomnography, who presented with enuresis that resolved after treatment with continuous positive airway pressure (CPAP). All cases occurred in the setting of obesity, in addition to other known risk factors for urinary incontinence and enuresis. OSA was diagnosed as severe in all but one case, which was mild. One patient noted recurrence of enuresis that coincided with malfunction of his CPAP machine. There is growing evidence that CPAP therapy may alleviate OSA and enuresis in adults with both conditions. Clinicians should routinely ask about enuresis in patients suspected of having OSA. A systematic study of the association between enuresis and OSA in adults is warranted.

Introduction With a rapidly aging population, general practitioners are confronting the challenge of how to determine those who are at greatest risk for dementia and potentially need more specialized follow-up to mitigate symptoms early in its course. We created a practical dementia risk score and provided individualized estimates of future dementia risk. Methods Using the Framingham Heart Study data, we built our prediction model using Cox proportional hazard models and developed a point system for the risk score and risk estimates. Results The score system used total points ranging from −1 to 31 and stratifies individuals into different levels of risk. We estimated 5-, 10-, and 20-year dementia risk prediction and incorporated these into the points system. Discussion This risk score system provides a practical tool because all included predictors are easy to assess by practitioners. It can be used to estimate future probabilities of dementia for individuals.

Alzheimer’s disease (AD) is the primary cause of dementia worldwide (1), with an increasing morbidity burden that may outstrip diagnosis and management capacity as the population ages. Current methods integrate patient history, neuropsychological testing and magnetic resonance imaging (MRI) to identify likely cases, yet effective practices remain variably-applied and lacking in sensitivity and specificity (2). Here we report an explainable deep learning strategy that delineates unique AD signatures from multimodal inputs of MRI, age, gender, and mini-mental state examination (MMSE) score. Our framework linked a fully convolutional network (FCN) to a multilayer perceptron (MLP) to construct high resolution maps of disease probability from local brain structure. This enabled precise, intuitive visualization of individual AD risk en route to accurate diagnosis. The model was trained using clinically-diagnosed AD and cognitively normal (NC) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (n=417) (3), and validated on three independent cohorts: the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL, n=382) (4), the Framingham Heart Study (FHS, n=102) (5), and the National Alzheimer’s Coordinating Center (NACC, n=582) (6). Model performance was consistent across datasets, with mean accuracy values of 0.966, 0.948, 0.815, and 0.916 for ADNI, AIBL, FHS and NACC, respectively. Moreover, our approach exceeded the diagnostic performance of a multi-institutional team of practicing neurologists (n=11), and high-risk cerebral regions predicted by the model closely tracked postmortem histopathological findings. This framework provides a clinically-adaptable strategy for using routinely available imaging techniques such as MRI to generate nuanced neuroimaging signatures for AD diagnosis, as well as a generalizable approach for linking deep learning to pathophysiological processes in human disease.

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have β-amyloid deposition, dementia, and parkinsonism than CTE alone (p 8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5–25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.

Introduction:Nightmare disorder affects approximately 4% of adults, occurring in isolation or as part of other disorders such as posttraumatic stress disorder (PTSD), and can significantly impair q...

Author(s): Tan, Zaldy S; Spartano, Nicole L; Beiser, Alexa S; DeCarli, Charles; Auerbach, Sanford H; Vasan, Ramachandran S; Seshadri, Sudha | Abstract: BackgroundSeveral longitudinal studies found an inverse relationship between levels of physical activity and cognitive decline, dementia, and/or Alzheimer's disease (AD), but results have been inconsistent. We followed an older, community-based cohort for over a decade to examine the association of physical activity with the risk of incident dementia and subclinical brain MRI markers of dementia.MethodsThe physical activity index (PAI) was assessed in the Framingham Study Original and Offspring cohorts, aged 60 years or older. We examined the association between PAI and risk of incident all-cause dementia and AD in participants of both cohorts who were cognitively intact and had available PAI (n = 3,714; 54% women; mean age = 70±7 years). We additionally examined the association between PAI and brain MRI in the Offspring cohort (n = 1,987).ResultsOver a decade of follow-up, 236 participants developed dementia (188 AD). Participants in the lowest quintile of PAI had an increased risk of incident dementia compared with those in higher quintiles (hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.04-1.97, p = .028) in a multivariable-adjusted model. Secondary analysis revealed that this relation was limited to participants who were apolipoprotein (APO)E e4 allele noncarriers (HR = 1.58, 95% CI = 1.08-2.32; p = .018) and strongest in participants aged 75 years or older. PAI was also linearly related to total brain and hippocampal volumes (β ± SE = 0.24±0.06; p l .01 and 0.004±0.001; p = .003, respectively).ConclusionLow physical activity is associated with a higher risk for dementia in older individuals, suggesting that a reduced risk of dementia and higher brain volumes may be additional health benefits of maintaining physical activity into old age.

Objective:To evaluate the association between sleep duration and the risk of incident dementia and brain aging.Methods:Self-reported total hours of sleep were examined in the Framingham Heart Study (n = 2,457, mean age 72 ± 6 years, 57% women) as a 3-level variable: 9 hours (long), and was related to the risk of incident dementia over 10 years, and cross-sectionally to total cerebral brain volume (TCBV) and cognitive performance.Results:We observed 234 cases of all-cause dementia over 10 years of follow-up. In multivariable analyses, prolonged sleep duration was associated with an increased risk of incident dementia (hazard ratio [HR] 2.01; 95% confidence interval [CI] 1.24–3.26). These findings were driven by persons with baseline mild cognitive impairment (HR 2.83; 95% CI 1.06–7.55) and persons without a high school degree (HR 6.05; 95% CI 3.00–12.18). Transitioning to sleeping >9 hours over a mean period of 13 years before baseline was associated with an increased risk of all-cause dementia (HR 2.43; 95% CI 1.44–4.11) and clinical Alzheimer disease (HR 2.20; 95% CI 1.17–4.13). Relative to sleeping 6–9 hours, long sleep duration was also associated cross-sectionally with smaller TCBV (β ± SE, −1.08 ± 0.41 mean units of TCBV difference) and poorer executive function (β ± SE, −0.41 ± 0.13 SD units of Trail Making Test B minus A score difference).Conclusions:Prolonged sleep duration may be a marker of early neurodegeneration and hence a useful clinical tool to identify those at a higher risk of progressing to clinical dementia within 10 years.

Study Objectives:To report at a population level the prevalence of restless legs syndrome, insomnia, and the risk of obstructive sleep apnea in multiple sclerosis patients. Sleep patterns and assoc...

Studies of clinical and community cohorts have shown that antemortem imaging measures of hippocampal volume have correlated with postmortem Alzheimer's pathology. Fewer studies have examined the relationship between both Alzheimer's and cerebrovascular pathology, and antemortem brain imaging. The aim of this study was to correlate antemortem brain magnetic resonance imaging (MRI) volumes with postmortem brain pathology (both Alzheimer-related and cerebrovascular) in a community-derived cohort from the Framingham Heart Study (FHS). Participants (n=59) from the FHS were included if they were enrolled in the brain autopsy program and underwent antemortem clinical evaluation, neuropsychological testing and brain MRI. Cortical neurofibrillary tangle pathology correlated with lower total cerebral brain (beta±SE=−0.04±0.01, p=0.004) and hippocampal volumes (beta±SE=−0.03±0.02, p=0.044) and larger temporal horns (log-transformed, beta±SE=0.05±0.01, p=0.001). Similar findings were seen between total/cortical neuritic plaques and total cerebral brain and temporal horn volume. White matter hyperintensities (also log-transformed) were best predicted by the presence of deep nuclei microinfarcts (beta±SE=0.53±0.21, p=0.016), whereas hippocampal volume was significantly decreased in the presence of hippocampal sclerosis (beta±SE =−1.23±0.30, p

This cohort study uses data from second-generation participants in the Framingham Heart Study to analyze the association of plasma amylin concentration with Alzheimer disease risk and brain structure., Key Points Question Is plasma amylin concentration associated with Alzheimer disease (AD) risk in humans? Findings In this cohort study of 3061 participants in the Framingham Heart Study, the association between plasma amylin concentrations with AD onset and the brain volume was nonlinear and U-shaped. Compared with participants with a low concentration of plasma amylin, participants with a high concentration of plasma amylin had a lower rate of AD incidence but participants with an extremely high concentration of plasma amylin had a higher rate of AD incidence, and a high, but not extremely high, concentration of plasma amylin was positively associated with temporal lobe volumes. Meaning Amylin is a neuropeptide that may be beneficial for the aging brain, but an extremely high concentration of plasma amylin, which may lead to amylin aggregation and loss of its protective function for the brain, may be a risk factor for AD., Importance Preclinical studies suggest that amylin has a U-shaped dose-response association with risk of Alzheimer disease (AD). The association of plasma amylin with AD in humans is unknown. Objectives To measure amylin concentration in plasma by using enzyme-linked immunosorbent assay and to study the association between plasma amylin, incidence of AD, and brain structure in humans. Design, Setting, and Participants This cohort study used data from the Framingham Heart Study offspring cohort from 1998 to 2015. Using a Monte Carlo approach, participants were divided into 3 plasma amylin concentration groups: (1) low (

We examined the progression of lexical-retrieval deficits in individuals with neuropathologically determined Alzheimer's disease (AD; n = 23) and a comparison group without criteria for AD (n = 24) to determine whether linguistic changes were a significant marker of the disease. Our participants underwent multiple administrations of a neuropsychological battery, with initial administration occurring on average 16 years prior to death. The battery included the Boston Naming Test (BNT), a letter fluency task (FAS) and written description of the Cookie Theft Picture (CTP). Repeated measures analysis revealed that the AD-group showed progressively greater decline in FAS and CTP lexical performance than the comparison group. Cross-sectional time-specific group comparisons indicated that the CTP differentiated performance between the two groups at 7-9 years prior to death and FAS and BNT only at 2-4 years. These results suggest that lexical-retrieval deficits in written discourse serve as an early indicator of AD.

Purpose: The primary objective of this study is to determine how the phases of the menstrual cycle influence the results of polysomnography (PSG). Methods: Twenty-eight adult subjects who reported regular menstrual periods, last menstrual period (LMP) within 26 days of their PSG, no exogenous hormone use, no history of polycystic ovarian syndrome, and who were scheduled for diagnostic PSG at Boston Medical satisfied inclusion criteria for the study. These subjects were divided into a Follicular Cohort (days 0-13 of the cycle) or Luteal Cohort (days 14-26 of the cycle), and a one-way analysis using a t-test was performed to test the hypothesis that the follicular phase confers protection against obstructive sleep apnea (OSA). A likelihood-ratio chi-square test was also applied to assess for a statistically significant association between menstrual stage and the presence of moderate-to-severe sleep apnea (apnea-hypopnea index (AHI) > 15/h). Thus, the statistical analysis was performed using AHI as both a continuous and a categorical outcome. Results: The mean AHI for patients in the Follicular Cohort (6.1/h) was significantly lower than the Luteal Cohort (14.3/h, p = 0.033). In the Follicular Cohort, 12% of patients had moderate to severe OSA. In the Luteal Cohort, 46% of patients had moderate to severe OSA (p = 0.045). Conclusions: Subjects undergoing PSG during the follicular phase have significantly lower AHIs than those in the luteal phase. Thus, the timing of PSG acquisition for regularly menstruating women should be considered when interpreting results.

Background: Despite high prevalence in the stroke population, sleep apnea is underdiagnosed. Obstructive sleep apnea is associated with poor cardiovascular outcomes and treatment with continuous positive airway pressure has been shown to lower blood pressure. No standard exists for screening patients who present to the hospital with acute stroke. We assessed three screening tools, the Epworth Sleepiness Scale (ESS), Berlin Questionnaire (BQ), and STOP-BANG Questionnaire (STOP-BANG), along with the use of a portable sleep study device for evaluation of sleep apnea. Overnight polysomnography (PSG) was performed on a subset of patients on outpatient follow up. Methods: Patients admitted to the stroke unit at our hospital, over nine months, were screened for sleep apnea using the three instruments, ESS, BQ, and STOP-BANG. The patients were evaluated with a portable sleep study device, ApneaLink Air (ResMed, USA), prior to discharge. Respiratory effort, respiratory flow, pulse oximetry, and oxygen saturation were recorded and sleep apnea was determined by apnea-hypopnea index (AHI) ≥ 5. Predictions from the screening tools were compared to the portable sleep study and overnight PSG results. Sensitivity and specificity testing were used to assess the validity and reliability of the tools. Results: Sleep questionnaires were administered on 37 patients who underwent an overnight sleep study. Portable studies were used to evaluate 33 patients, and 13 PSGs were performed. Obstructive sleep apnea was diagnosed in 20 (69%) and central sleep apnea in 9 (31%). Cheyne-Stokes pattern breathing was observed in 2 (5%). Mean AHI was 18.3 + 21.8/hr and maximum AHI was 105.8/hr. Sensitivity for the ESS, BQ, and STOP-BANG were 0.39, 0.66, and 0.83 and specificity for these tools were 0.26, 0.33, and 0.29, respectively. In patients who underwent the portable sleep study and overnight PSG, 9/10 (90%) of the studies were concordant. Conclusions: The STOP-BANG questionnaire, administered to hospitalized stroke patients, had high sensitivity and low-moderate specificity in our study, compared to two other commonly used screening tools. Further, the feasibility of using an unattended inpatient portable sleep study on stroke inpatients is demonstrated.

In patients with epilepsy, improvement in seizure control with treatment of coexisting obstructive sleep apnea (OSA) has been reported, but there is lack of data on the effect of continuous positive airway pressure (CPAP) compliance on seizure control in these patients. We examined the variability in seizure frequency in patients who were CPAP compliant and those who were not CPAP compliant. We undertook a retrospective review of clinical and polysomnographic data of adult patients with OSA and epilepsy seen at the Boston University Medical Center Epilepsy and Sleep Clinics between 2000 and 2010. Data were reviewed for CPAP compliance and seizure frequency after at least 6 months of CPAP use. Only patients with no changes in antiepileptic drug regimens during CPAP trial were included. Of the 660 patients identified, 41 fulfilled inclusion criteria, of whom 28 were CPAP compliant and 13 were not CPAP compliant. In the compliant group, CPAP use led to decreased seizure frequency from 1.8 per month to 1 per month (p = 0.01). In the noncompliant group, no significant difference in seizure frequency was noted between baseline (2.1 per month) and at follow-up (1.8 per month, p = 0.36). Sixteen of 28 CPAP-compliant subjects were seizure free, whereas only 3 of 13 non-CPAP compliant subjects were seizure free [relative risk (RR) 1.54, p = 0.05]. Patients with epilepsy and OSA not compliant with CPAP treatment are at higher risk of seizures than are CPAP-compliant patients. To validate this observation, further prospective studies are warranted.

Importance The association between peripheral inflammatory biomarkers and Alzheimer disease (AD) is not consistent in the literature. It is possible that chronic inflammation, rather than 1 episode of inflammation, interacts with genetic vulnerability to increase the risk for AD. Objective To study the interaction between the apolipoprotein E (ApoE) genotype and chronic low-grade inflammation and its association with the incidence of AD. Design, Setting, and Participants In this cohort study, data from 2656 members of the Framingham Heart Study offspring cohort (Generation 2; August 13, 1971-November 27, 2017) were evaluated, including longitudinal measures of serum C-reactive protein (CRP), diagnoses of incident dementia including AD, and brain volume. Chronic low-grade inflammation was defined as having CRP at a high cutoff level at a minimum of 2 time points. Statistical analysis was performed from December 1, 1979, to December 31, 2015. Main Outcomes and Measures Development of AD and brain volumes. Results Of the 3130 eligible participants, 2656 (84.9%; 1227 men and 1429 women; mean [SD] age at last CRP measurement, 61.6 [9.5] years) with both ApoE status and longitudinal CRP measurements were included in this study analysis. Median (interquartile range) CRP levels increased with mean (SD) age (43.3 [9.6] years, 0.95 mg/L [0.40-2.35 mg/L] vs 59.1 [9.6] years, 2.04 mg/L [0.93-4.75 mg/L] vs 61.6 [9.5] years, 2.21 mg/L [1.05-5.12 mg/L]; P, This population-based cohort study uses data from the Framingham Heart Study offspring cohort to study the interaction between the apolipoprotein E genotype and chronic low-grade inflammation and its association with the incidence of Alzheimer disease., Key Points Question Is interaction of chronic low-grade inflammation and the apolipoprotein E genotype associated with development of Alzheimer disease? Findings In this population-based cohort study, chronic low-grade inflammation, assessed by longitudinal C-reactive protein measurements, was associated with an increased risk of Alzheimer disease only in ApoE4 carriers. Meaning Clinical follow-up and treatment of high levels of C-reactive protein may be beneficial for prevention of Alzheimer disease in ApoE4 carriers.

Prazosin is recommended for treatment of Posttraumatic Stress Disorder (PTSD)-associated nightmares. Level A. Image Rehearsal Therapy (IRT) is recommended for treatment of nightmare disorder. Level A. Systematic Desensitization and Progressive Deep Muscle Relaxation training are suggested for treatment of idiopathic nightmares. Level B. Venlafaxine is not suggested for treatment of PTSD-associated nightmares. Level B. Clonidine may be considered for treatment of PTSD-associated nightmares. Level C. The following medications may be considered for treatment of PTSD-associated nightmares, but the data are low grade and sparse: trazodone, atypical antipsychotic medications, topiramate, low dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, cyproheptadine, and tricyclic antidepressants. Nefazodone is not recommended as first line therapy for nightmare disorder because of the increased risk of hepatotoxicity. Level C. The following behavioral therapies may be considered for treatment of PTSD-associated nightmares based on low-grade evidence: Exposure, Relaxation, and Rescripting Therapy (ERRT); Sleep Dynamic Therapy; Hypnosis; Eye-Movement Desensitization and Reprocessing (EMDR); and the Testimony Method. Level C. The following behavioral therapies may be considered for treatment of nightmare disorder based on low-grade evidence: Lucid Dreaming Therapy and Self-Exposure Therapy. Level C No recommendation is made regarding clonazepam and individual psychotherapy because of sparse data.

At present, eszopiclone and zolpidem are the most commonly prescribed drugs for treating insomnia. Despite the established relationship between sleep disturbance and anxiety, it remains unknown whether targeted treatment for insomnia may affect acute anxiety. Therefore, the objective of this study was to examine the effects of three different doses (1, 3, and 10 mg/kg) of eszopiclone and zolpidem on the states of sleep and wakefulness, levels of anxiety-like behavior, and long-term contextual memory in footshock-induced anxious rats. The results of this study demonstrated that the administration of eszopiclone and zolpidem both were equally effective in attenuating footshock stressor-induced suppression of slow-wave sleep (SWS). The administration of eszopiclone at 1 mg/kg or zolpidem at 1 and 3 mg/kg doses showed a tendency for attenuating stressor-induced suppression of REM sleep. However, the REM sleep attenuating effects of these drugs disappeared when they were administered at higher doses. The administration of eszopiclone at 3 and 10 mg/kg doses and zolpidem at all three doses reduced the power of electroencephalographic theta band frequencies during wakefulness. In addition, the administration of eszopiclone at 1 and 3 mg/kg doses suppressed stressor-induced anxiety-like behavior. The administration of zolpidem at 1, 3, or 10 mg/kg doses was not effective in attenuating stressor-induced anxiety-like behavior. Contextual memory after administration of eszopiclone at 1 mg/kg dose had no effects, but was reduced significantly with increased dosage. Contextual memory after administration of zolpidem, at all three doses, was severely disrupted. The results of this study suggest that eszopiclone at a low dose could be used effectively to control anxiety and anxiety-induced insomnia.

Patients with multiple sclerosis (MS) often have unrecognized sleep disorders at higher frequency than the general population. Sleep disorders such as sleep disordered breathing, insomnia, REM sleep behavior disorder, narcolepsy and restless legs syndrome have all been reported in the MS population. Notably, the most common symptom of MS is "fatigue," which itself has been correlated with sleep disturbances. Sleep disorders may impact the quality of life of the MS patient population. This paper reviews the association of sleep disorders with MS, and discusses the association of sleep disruption with MS fatigue.

We thank Dr. Kim for the letter regarding our article.1 In this important first step, we demonstrated an association between lower REM sleep percentage and an increased risk of dementia. It is now important for future studies to explore why REM sleep is related to dementia risk. We concur with Dr. Kim that it would be interesting to examine whether the suppression of REM sleep through exposure to antidepressants is associated with dementia incidence. However, as only 11 (3%) of our patients were taking antidepressants, such a study would require a much larger sample. It would also be challenging to overcome indication bias given that depression may also increase risk of dementia.2 Focusing on antidepressants with nonpsychiatric indications is one potential approach to help limit such bias. We agree with the sentiments of Dr. Kim in that the intriguing relationships between sleep and dementia require further study.

Summary of Recommendations: Modifying the sleep environment is recommended for the treatment of patients with RBD who have sleep-related injury. Level A Clonazepam is suggested for the treatment of RBD but should be used with caution in patients with dementia, gait disorders, or concomitant OSA. Its use should be monitored carefully over time as RBD appears to be a precursor to neurodegenerative disorders with dementia in some patients. Level B Clonazepam is suggested to decrease the occurrence of sleep-related injury caused by RBD in patients for whom pharmacologic therapy is deemed necessary. It should be used in caution in patients with dementia, gait disorders, or concomitant OSA, and its use should be monitored carefully over time. Level B Melatonin is suggested for the treatment of RBD with the advantage that there are few side effects. Level B Pramipexole may be considered to treat RBD, but efficacy studies have shown contradictory results. There is little evidence to support the use of paroxetine or L-DOPA to treat RBD, and some studies have suggested that these drugs may actually induce or exacerbate RBD. There are limited data regarding the efficacy of acetylcholinesterase inhibitors, but they may be considered to treat RBD in patients with a concomitant synucleinopathy. Level C The following medications may be considered for treatment of RBD, but evidence is very limited with only a few subjects having been studied for each medication: zopiclone, benzodiazepines other than clonazepam, Yi-Gan San, desipramine, clozapine, carbamazepine, and sodium oxybate. Level C

A number of behavioral studies have emphasized the importance of interactions between the pontine-wave (P-wave) generator and the dorsal hippocampus (DH) in two-way active avoidance (TWAA) memory processing; however, the direct involvement of the P-wave generator in the TWAA training trial-induced molecular events in the DH and amygdala has not been systematically evaluated. Here we demonstrate that the TWAA learning training trials activate P-wave generator, and increase phosphorylation of CREB (pCREB) and expression of activity-regulated cytoskeletal-associated (Arc) protein, as well as messenger ribonucleic acid (mRNAs) of Arc, brain-derived nerve growth factor (BDNF) and early growth response-1 (Egr-1) in the DH and amygdala. Selective elimination of P-wave-generating cells abolished P-wave activity and suppressed TWAA learning training trial-induced expression of pCREB and Arc proteins and Arc, BDNF and Egr-1 mRNAs in the DH and amygdala. Following a session of TWAA training, all rats were equal in terms of time spent in wakefulness, slow-wave sleep and rapid eye movement (REM) sleep irrespective of P-wave lesions. The second set of experiments demonstrated that localized cholinergic stimulation of the P-wave generator increased expression of Arc, BDNF and Egr-1 mRNAs in the DH. Together, these findings provide the first direct evidence that activation of P-wave-generating cells is critically involved in the TWAA training trial-induced expression of plasticity-related genes in the DH and amygdala. These findings are discussed in relation to the role of P-wave generator activation for the REM sleep-dependent development and cognitive functions of the brain.

To evaluate the effect of continuing medical education (CME) activities on patient reported outcomes with regard to (1) screening for excessive sleepiness (ES) and obstructive sleep apnea (OSA) and (2) appropriate referral and treatment.A total of 725 patients were recruited from 75 providers who either participated or did not participate in Transtheoretical Model (TTM)-based OSA CME activities. Patient reported outcomes from participating (n = 36) and non-participating providers (n = 39) were compared using generalized estimating equations examining random effects of provider as unit of assignment.Patients' reports demonstrate that participating physicians were 1.7 times more likely to initiate discussion of sleep problems than non-participating physicians (t1,411 = 3.71, p = 0.05) and 2.25-2.86 times more likely to administer validated measures for OSA (Epworth Sleepiness Scale and STOP-BANG). Patient reports also indicated that participating clinicians (79.9%) were significantly more likely to recommend seeing a sleep specialist compared to non-participating clinicians (60.7%; t1,348 = 9.1, p0.01, OR = 2.6). Furthermore, while 89.4% of participating clinicians recommended a sleep study, only 73.2% of the non-participating physicians recommended one (t1,363 = 11.46, p0.001, OR = 3.1).Participation in TTM-based OSA CME activities was associated with improved patient reported outcomes compared to the non-participating clinicians.

Nightmares are frightening dreams that most often occur during rapid eye movement (REM) sleep. Up to 50% of children between 3 and 6 years of age and 20% between 6 and 12 years of age experience frequent nightmares, and 2-6% of the American adult population experiences nightmares at least once a week. Nightmares typically appear during one of the late REM episodes that occur during the early morning period between 4 and 7 a.m., and these episodes are associated with heightened activation levels in the amygdala. Nightmare content typically involves extreme anxiety, fear, or terror and simulates physical threat to the dreamer by animals, strangers, or supernatural beings or monsters. Recurrent nightmares occur frequently in recurrent nightmare disorder, posttraumatic stress disorder, REM behavior disorder, and other neuropsychiatric syndromes. Nightmares may be due, in part, to dysfunction in the normal mood regulatory functions of REM sleep.

We theorise that in some cases Attention Deficit Hyperactivity Disorder (ADHD) predisposes to narcolepsy and hypersomnia, and that there may be a shared pathophysiology with various addictions [Reward Deficiency Syndrome (RDS)]. Reticence to acknowledge such connections may be due to a narrow nosological framework. Additionally, we theorise that the development of narcolepsy on a baseline of ADHD/RDS leads to an additional assault on the dopaminergic reward system in such individuals. In this study, we propose to test these hypotheses by using a combination of broad genetic screening, and neuroimaging with and without pharmacological intervention, in those with pure ADHD, pure narcolepsy, and the combined ADHD-narcolepsy phenotype. Results of this proposed study may reveal a common pathophysiology of ADHD, narcolepsy and RDS, and perhaps an additional compromise to the reward system in those with combined ADHD-narcolepsy. If the evidence supports the hypothesis that indeed there is a shared pathophysiology for narcolepsy with RDS and thus its subtype ADHD, early intervention/preventative treatment amongst those with ADHD may be beneficial with the putative dopaminergic compound KB220Z™.

Sleep disruption and cognitive impairments are not uncommon in the aging adult (affecting up to 50%) and there has been growing information to suggest a link between these conditions, which may lead to new opportunities in clinical care. In this issue of Neurology ®, Haba-Rubio et al.1 highlight the association between sleep-disordered breathing (SDB) and cognitive impairment in the elderly. Such findings are consistent with recent studies.2–4 Identification of this relationship must be considered in the context of efforts to identify potentially treatable and modifiable factors that may contribute to the development of cognitive impairment in the older adult. Does this study suggest that we should become more aggressive in the management of SDB in elderly? Furthermore, should we be more thorough in our assessment of cognitive impairments in the elderly with SDB?

Study objective: We obtain preliminary information on the neuropsychological performance of house officers at the beginning and end of a shift while they worked consecutive night shifts in the emergency department. Methods: We prospectively studied interns working 12-hour consecutive night shifts in an urban Level I trauma center ED. All consecutive non–emergency medicine interns rotating for 1 month were eligible except those older than 40 years and those with sleep disorders or depression (identified by using the Profile of Mood Scale, Sleep Diagnostic Questionnaire). We tested research subjects at the beginning of a day shift and at the beginning and end of night shifts 1 and 3 of 4 consecutive night shifts at times of estimated baseline wakefulness (10 PM) and maximum fatigue (3 AM). We used 3 standardized neuropsychological tests: (1) Delayed Recognition Span Test (visual memory capacity); (2) Continuous Performance Test (attentional function, vigilance); and (3) Santa Ana Form Board Test (psychomotor speed, coordination). We analyzed data with mixed-model analysis, with research subject as a random effect. Results: Thirteen interns were eligible, and 1 declined. Twelve interns (6 men and 6 women; age range 25 to 35 years) were enrolled. The Delayed Recognition Span Test (number correct before first error) revealed significant deterioration from the beginning of the shift to the end of the shift (mean difference –2.2; 95% confidence interval –3.1 to –1.3). This represents an 18.5% decrease in visual memory capacity. There were no significant differences found for the other tests. Conclusion: Interns working nights demonstrated a significant reduction in visual memory capacity across the night shift. Research involving neuropsychological performance during night shifts in the ED is important. It might provide valuable insights into ways to improve our performance during night shifts.

A 67-year-old man with a history of epilepsy, cardiac failure, alcohol dependence, and hypercholesterolemia underwent a polysomnogram (PSG) study because of snoring and observed apnea during sleep. Body mass index was recorded at 25.9 kg/m2. Medications included metoprolol, valsartan, simvastatin, phenytoin, valproate, and levetiracetam. Prior echocardiogram had shown an ejection fraction of 35%. PSG showed an overall Central Apnea Index (CAI) of 18, with 18 central apneas/hour, 7 hypopneas/hour, 0 mixed apneas/hour, and 0 obstructive apneas/hour (figure 1). Central apneas displayed a crescendo-decrescendo pattern, consistent with CSB. Because of recurrent seizures, topiramate was added to the medication regimen, with a titration schedule to 100 mg twice per day. After 5 months, a second PSG for titration with adaptive servo-ventilation was obtained. Baseline portion of the study (about 90 minutes) showed a significant decrease in number of central apneas, with an overall CAI of 0, with 0 central apneas/hour, 12 hypopneas/hour, 0 mixed apneas/hour, 0 obstructive apneas per hour of sleep, and …

We hypothesize that rapid eye movement or REM sleep evolved, in part, to mediate sexual/reproductive behaviors and strategies. Because development of sexual and mating strategies depends crucially on early attachment experiences, we further hypothesize that REM functions to mediate attachment processes early in life. Evidence for these hypotheses comes from (1) the correlation of REM variables with both attachment and sexual/reproductive variables; (2) attachment-related and sex-related hormonal release during REM; (3) selective activation during REM of brain sites implicated in attachment and sexual processes; (4) effects of maternal deprivation on REM; (5) effects of REM deprivation on sexual behaviors; and (6) the REM-associated sexual excitation. To explain why we find associations among REM sleep, attachment, and adult reproductive strategies, we rely on recent extensions of parent-offspring conflict theory. Using data from recent findings on genomic imprinting, Haig (2000) and others suggest that paternally expressed genes are selected to promote growth of the developing fetus/child at the expense of the mother, while maternally expressed genes counter these effects. Because developmental REM facilitates attachment-related outcomes in the child, developmental REM may be regulated by paternally expressed genes. In that case, REM may have evolved to support the "aims" of paternal genes at the expense of maternal genes.

We thank Liguori et al. for the interest in our article, which demonstrated an association between long sleep duration and incident dementia.1 We did not examine the underlying mechanisms; these require investigation.

Dr. Cranston and colleagues should be commended for the thorough job they did expanding upon the foundation of the article, “Best Practice Guide for the Treatment of Nightmare Disorder in Adults.”1 The authors have 3 criticisms of the article: (1) the methodology was used inconsistently at updated time points; (2) the article was missing references that were within the search criteria and therefore not reported; and (3) the search database used was insufficient. In the following sections, these concerns are addressed.

We describe a case series of 4 patients with varying degrees of obstructive sleep apnea who incidentally had a history of nocturnal leg cramps. None of the patients had periodic limb movements during the study and denied symptoms consistent with restless legs syndrome. In 3 of the 4 patients, nocturnal leg cramps resolved with CPAP treatment for OSA, while the fourth patient noted near-resolution of cramping after starting CPAP. In patients presenting with muscle cramps, obstructive sleep apnea should be considered.

Objectives: It has been suggested in some studies that head injury is a risk factor for AD, and that this risk is heightened among carriers of the APOE -e4 allele. We examined the effects of head injury and APOE genotype on AD risk in a large family study. Subjects: A total of 2,233 probands who met criteria for probable or definite AD and their 14,668 first-degree family members (4,465 parents, 7,694 siblings, and 2,509 spouses) were ascertained at 13 centers in the United States, Canada, and Germany participating in the MIRAGE (Multi-Institutional Research in Alzheimer Genetic Epidemiology) project. Information on head injury was collected by interview of multiple informants and review of medical records. Nondemented relatives and spouses served as control subjects for this study. Methods: Odds of AD for head trauma with or without loss of consciousness were computed by comparing probands with unaffected spouses using conditional logistic regression analysis. To account for the unique biologic relationship between probands and their parents and siblings, odds of AD were computed using a generalized estimating equation (GEE) Poisson regression approach. GEE logistic regression was used to examine the joint effects of APOE genotype and head injury on the odds of AD in probands and a control group comprised of unaffected siblings and spouses. Results: Comparison of probands with their unaffected spouses yielded odds ratios for AD of 9.9 (95% CI, 6.5 to 15.1) for head injury with loss of consciousness and 3.1 (2.3 to 4.0) for head injury without loss of consciousness. The corresponding odds derived from the comparison of probands with their parents and sibs were 4.0 (2.9 to 5.5) for head injury with loss of consciousness and 2.0 (1.5 to 2.7) for head injury without loss of consciousness. Head injury without loss of consciousness did not significantly increase the risk of AD in spouses (OR = 1.3; 95% CI, 0.4 to 4.1). The joint effects of head injury and APOE genotype were evaluated in a subsample of 942 probands and 327 controls (spouses and siblings). Head injury increased the odds of AD to a greater extent among those lacking e4 (OR = 3.3) than among e4 heterozygotes (OR = 1.8) or homozygotes (OR = 1.3). Conclusion: Head injury is a risk factor for AD. The magnitude of the risk is proportional to severity and heightened among first-degree relatives of AD patients. The influence of head injury on the risk of AD appears to be greater among persons lacking APOE -e4 compared with those having one or two e4 alleles, suggesting that these risk factors may have a common biologic underpinning.

Although disturbed sleep has been frequently reported in patients with seizures, little is known about insomnia and epilepsy. The aims of this study were (1) to analyze the prevalence and degree of insomnia in patients with epilepsy, (2) to examine the clinical features and correlates of insomnia in these patients, and (3) to evaluate the impact of poor sleep on their quality of life.One hundred-fifty-two patients with epilepsy (mean age 46 years) completed the following questionnaires: Insomnia Severity Index, Pittsburgh Sleep Quality Index, Beck Depression Inventory-II, Quality of Life in Epilepsy Inventory-31. Patients with other known sleep disorders, including obstructive sleep apnea, were excluded from the study. Regression analysis was conducted for adjusting for age, years since epilepsy onset, number of antiepileptic drugs, comorbidities, and depression scores.More than half of the participants (55%) suffered from insomnia and more than 70% were "poor sleepers." Insomnia and poor sleep quality were significantly correlated with the number of antiepileptic medications and scores of depressive symptoms. After controlling for covariates, insomnia and poor sleep quality were significant predictors of lower quality of life.These results suggest that insomnia and poor sleep are common in patients with epilepsy and may adversely impact quality of life. Further studies should examine whether improvements in sleep can improve seizure control and quality of life of these patients.

We sought to examine the prevalence of central sleep apnea (CSA) and complex sleep apnea (CompSA) in patients with epilepsy and to examine their clinical profile, with respect to epilepsy type, etiology, medication use, and EEG abnormalities. We undertook a retrospective analysis of 719 consecutive patients with epilepsy who underwent polysomnography (PSG) at our institution between 2004 and 2011. Of the 458 patients with complete data, we excluded 42 patients with congestive heart failure or left ventricular ejection fraction