Efficacy and safety of insomnia treatment with lemborexant in older adults: analyses from three clinical trials.

BACKGROUND: Insomnia is more common as people age. Several common hypnotics used to treat insomnia often do not adequately alleviate sleep issues in older adults and may be associated with negative residual effects such as an increased risk of falls, cognitive impairment, automobile accidents, and lack of response to auditory stimuli. The objective of these analyses of three clinical studies was to investigate the efficacy and safety of the dual orexin-receptor antagonist lemborexant (LEM) in older adults. METHODS: Study E2006-G000-304 (Study 304; NCT02783729) was a randomized, double-blind, placebo (PBO)-controlled, active-comparator trial where subjects with insomnia disorder received LEM 5 mg (LEM5), LEM 10 mg (LEM10), zolpidem tartrate extended-release 6.25 mg (ZOL), or PBO for 30 days. In crossover Study E2006-E044-106 (Study 106; NCT02583451), healthy subjects (good sleepers) received LEM 2.5 mg, LEM5, LEM10, or PBO for eight nights or zopiclone on days 1 and 8 (and PBO on days 2-7). In crossover Study E2006-A001-108 (Study 108; NCT03008447), healthy subjects received a single dose of LEM5, LEM10, PBO, or ZOL. Sleep assessments included polysomnography-based latency to persistent sleep (LPS), wake after sleep onset (WASO), WASO in the second half of the night (WASO2H), sleep efficiency, postural stability, middle-of-the-night and next-day cognitive performance, middle-of-the-night auditory awakening threshold and return-to-sleep latency, and driving performance. RESULTS: Overall, 453 of 1006 (45%; Study 304), 24 of 48 (50%; Study 106), and 28 of 56 (50%; Study 108) subjects were aged ≥ 65 years. In Study 304, LEM decreased (improved) LPS, WASO, and WASO2H from baseline more than ZOL and PBO; subjects treated with LEM had greater increases in sleep efficiency (improved) than with ZOL or PBO. In both Studies 304 and 108, postural stability was not impaired at waketime in subjects who received LEM compared with PBO. At waketime, LEM did not impair memory compared with PBO. In Study 108, following middle-of-the-night awakening, LEM and ZOL did not affect subjects' ability to awaken to auditory stimuli; LEM did not affect tests of memory and attention. In Study 106, LEM did not impair next-day driving performance in healthy elderly compared with PBO. LEM was well tolerated in subjects aged ≥ 65 years. CONCLUSIONS: LEM provided benefits on sleep variables without next-morning residual effects in subjects aged ≥ 65 years, supporting LEM as a treatment option for older adults with insomnia. TRIAL REGISTRATION NUMBERS AND DATES OF REGISTRATION: Study 304: ClinicalTrials.gov identifier, NCT02783729, date of registration, 26 May 2016. Study 106: ClinicalTrials.gov identifier, NCT02583451, date of registration, 22 October 2015. Study 108: ClinicalTrials.gov identifier, NCT03008447, date of registration, 2 January 2017.

The prevalence of insomnia increases with age; however, some hypnotics used for treating insomnia do not adequately resolve sleep problems in older adults and may be associated with adverse residual effects. Specifically, some hypnotics pose safety concerns in this population of patients who are generally more vulnerable to treatment-related effects, including increasing the risk of falls, risks of cognitive impairment, automobile accidents, and unresponsiveness to auditory stimuli. Safer and more effective insomnia medications are needed to reduce sleep problems with improved side-effect profiles. This analysis of lemborexant clinical studies conducted in adult subjects at least 65 years old found the drug to be effective without impairing memory, attention or balance the following day compared with placebo. These subjects were normal sleepers (for age) or had insomnia disorder. Furthermore, lemborexant was not associated with impaired ability to drive the next morning or awaken to loud middle-of-the-night sounds. Lemborexant was well tolerated in these older adults, similar to findings for adults aged at least 18 years. These findings indicate that lemborexant may be an appropriate treatment option for insomnia in older adults.

Subjective Cognitive Decline Plus and Longitudinal Assessment and Risk for Cognitive Impairment.

Importance: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting. Objective: To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults. Design, Setting, and Participants: The Framingham Heart Study, a community-based prospective cohort study, assessed SCD between 2005 and 2019, with up to 12 years of follow-up. Participants 60 years and older with normal cognition at analytic baseline were included. Cox proportional hazards (CPH) models were adjusted for baseline age, sex, education, APOE ε4 status, and tertiles of AD polygenic risk score (PRS), excluding the APOE region. Data were analyzed from May 2021 to November 2023. Exposure: SCD was assessed longitudinally using a single question and considered present if endorsed at the last cognitively normal visit. It was treated as a time-varying variable, beginning at the first of consecutive, cognitively normal visits, including the last, at which it was endorsed. Main Outcomes and Measures: Consensus-diagnosed MCI, AD, and all-cause dementia. Results: This study included 3585 participants (mean [SD] baseline age, 68.0 [7.7] years; 1975 female [55.1%]). A total of 1596 participants (44.5%) had SCD, and 770 (21.5%) were carriers of APOE ε4. APOE ε4 and tertiles of AD PRS status did not significantly differ between the SCD and non-SCD groups. MCI, AD, and all-cause dementia were diagnosed in 236 participants (6.6%), 73 participants (2.0%), and 89 participants (2.5%), respectively, during follow-up. On average, SCD preceded MCI by 4.4 years, AD by 6.8 years, and all-cause dementia by 6.9 years. SCD was significantly associated with survival time to MCI (hazard ratio [HR], 1.57; 95% CI, 1.22-2.03; P <.001), AD (HR, 2.98; 95% CI, 1.89-4.70; P <.001), and all-cause dementia (HR, 2.14; 95% CI, 1.44-3.18; P <.001). After adjustment for APOE and AD PRS, the hazards of SCD were largely unchanged. Conclusions and Relevance: Results of this cohort study suggest that in a community setting, SCD reflecting SCD+ features was associated with an increased risk of future MCI, AD, and all-cause dementia with similar hazards estimated in clinic-based settings. SCD may be an independent risk factor for AD and other dementias beyond the risk incurred by APOE ε4 and AD PRS.

Monitoring Gait and Physical Activity of Elderly Frail Individuals in Free-Living Environment: A Feasibility Study.

INTRODUCTION: Frailty is conventionally diagnosed using clinical tests and self-reported assessments. However, digital health technologies (DHTs), such as wearable accelerometers, can capture physical activity and gait during daily life, enabling more objective assessments. In this study, we assess the feasibility of deploying DHTs in community-dwelling older individuals, and investigate the relationship between digital measurements of physical activity and gait in naturalistic environments and participants' frailty status, as measured by conventional assessments. METHODS: Fried Frailty Score (FFS) was used to classify fifty healthy individuals as non-frail (FFS = 0, n/female = 21/11, mean ± SD age: 71.10 ± 3.59 years), pre-frail (FFS = 1-2, n/female = 23/9, age: 73.74 ± 5.52 years), or frail (FFS = 3+, n/female = 6/6, age: 70.70 ± 6.53 years). Participants wore wrist-worn and lumbar-worn GENEActiv accelerometers (Activinsights Ltd., Kimbolton, UK) during three in-laboratory visits, and at-home for 2 weeks, to measure physical activity and gait. After this period, they completed a comfort and usability questionnaire. Compliant days at-home were defined as follows: those with ≥18 h of wear time, for the wrist-worn accelerometer, and those with ≥1 detected walking bout, for the lumbar-worn accelerometer. For each at-home measurement, a group analysis was performed using a linear regression model followed by ANOVA, to investigate the effect of frailty on physical activity and gait. Correlation between at-home digital measurements and conventional in-laboratory assessments was also investigated. RESULTS: Participants were highly compliant in wearing the accelerometers, as 94% indicated willingness to wear the wrist device, and 66% the lumbar device, for at least 1 week. Time spent in sedentary activity and time spent in moderate activity as measured from the wrist device, as well as average gait speed and its 95th percentile from the lumbar device were significantly different between frailty groups. Moderate correlations between digital measurements and self-reported physical activity were found. CONCLUSIONS: This work highlights the feasibility of deploying DHTs in studies involving older individuals. The potential of digital measurements in distinguishing frailty phenotypes, while unobtrusively collecting unbiased data, thus minimizing participants' travels to sites, will be further assessed in a follow-up study.

Is dietary choline intake related to dementia and Alzheimer's disease risks? Results from the Framingham Heart Study.

BACKGROUND: The positive association of choline for cognition has been reported in both animal and human studies, yet the associations of choline with the risks of incident dementia or Alzheimer's disease (AD) in humans is unclear. OBJECTIVES: Our objective was to test the hypothesis that lower or higher dietary choline intake is associated with increased or decreased, respectively, risks of incident dementia and AD. METHODS: Data from the Framingham Heart Study Offspring Cohort exam 5 to exam 9 were used. Participants were free of dementia and stroke, with a valid self-reported 126-item Harvard FFQ at exam 5. The intakes of total choline, its contributing compounds, and betaine were estimated based on a published nutrient database. The intakes were updated at each exam to represent the cumulative average intake across the 5 exams. The associations between dietary choline intakes and incident dementia and AD were examined in mixed-effect Cox proportional hazard models, adjusting for covariates. RESULTS: A total of 3224 participants (53.8% female; mean ± SD age, 54.5 ± 9.7 y) were followed up for a mean ± SD of 16.1 ± 5.1 y (1991-2011). There were 247 incident dementia cases, of which 177 were AD. Dietary choline intake showed nonlinear relationships with incident dementia and AD. After adjusting for covariates, low choline intake (defined as ≤ 219 and ≤ 215 mg/d for dementia and AD, respectively) was significantly associated with incident dementia and incident AD. CONCLUSIONS: Low choline intake was associated with increased risks of incident dementia and AD.

Association Between the Digital Clock Drawing Test and Neuropsychological Test Performance: Large Community-Based Prospective Cohort (Framingham Heart Study).

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.

Development and validation of an interpretable deep learning framework for Alzheimer's disease classification.

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.

Exploring the Hierarchical Influence of Cognitive Functions for Alzheimer Disease: The Framingham Heart Study.

BACKGROUND: Although some neuropsychological (NP) tests are considered more central for the diagnosis of Alzheimer disease (AD), there is a lack of understanding about the interaction between different cognitive tests. OBJECTIVE: This study aimed to demonstrate a global view of hierarchical probabilistic dependencies between NP tests and the likelihood of cognitive impairment to assist physicians in recognizing AD precursors. METHODS: Our study included 2091 participants from the Framingham Heart Study. These participants had undergone a variety of NP tests, including Wechsler Memory Scale, Wechsler Adult Intelligence Scale, and Boston Naming Test. Heterogeneous cognitive Bayesian networks were developed to understand the relationship between NP tests and the cognitive status. The performance of probabilistic inference was evaluated by the 10-fold cross validation. RESULTS: A total of 4512 NP tests were used to build the Bayesian network for the dementia diagnosis. The network demonstrated conditional dependency between different cognitive functions that precede the development of dementia. The prediction model reached an accuracy of 82.24%, with sensitivity of 63.98% and specificity of 92.74%. This probabilistic diagnostic system can also be applied to participants that exhibit more heterogeneous profiles or with missing responses for some NP tests. CONCLUSIONS: We developed a probabilistic dependency network for AD diagnosis from 11 NP tests. Our study revealed important psychological functional segregations and precursor evidence of AD development and heterogeneity.

Association of Plasma Amylin Concentration With Alzheimer Disease and Brain Structure in Older Adults.

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 (<75 pmol/L), (2) high (75-2800 pmol/L), and (3) extremely high (≥2800 pmol/L). Data analyses were conducted October 5, 2017, to December 18, 2018. Exposures: Baseline plasma amylin concentrations at examination 7. Main Outcomes and Measures: Incidence of dementia or AD and brain volumetric measures from structural magnetic resonance imaging data. Results: From the Framingham Heart Study offspring cohort, 3061 participants (mean [SD] age at baseline, 61.0 [9.5] years; 1653 [54.0%] women) who had plasma amylin measurements, dementia incidence, and brain volume measurements on record were included in this study. The distribution of plasma amylin concentrations was highly skewed (median [interquartile range], 7.5 [4.6-18.9] pmol/L; mean [SD], 302.3 [1941.0] pmol/L; range, 0.03-44 623.7 pmol/L). Compared with the low plasma amylin concentration group, the high plasma amylin concentration group had a lower rate of AD incidence (2.3% vs 5.6%; P = .04), but the extremely high plasma amylin concentration group had a higher rate of AD incidence (14.3%; P < .001). After adjusting for age, sex, education, body mass index, diabetes, cardiovascular disease, high-density lipoprotein level, and APOE4, high plasma amylin was not associated with decreased AD risk (hazard ratio, 0.42 [95% CI, 0.16-1.14]; P = .09) but was positively associated with volume of gray matter in the temporal lobe (ß = 0.17 [SE, 0.05]; P < .001). In contrast, extremely high plasma amylin concentration was associated with a higher AD risk (hazard ratio, 2.51 [95% CI, 1.38-4.57]; P = .003) but not associated with temporal lobe volume (ß = 0.02 [SE, 0.07]; P = .82). Conclusions and Relevance: This study found that plasma amylin concentration was associated with AD incidence and brain structure with a U-shaped pattern. These findings are consistent with preclinical findings that suggest amylin is a neuropeptide that is physiological; however, at extremely high concentrations, it may lead to amylin aggregation and therefore may be a risk factor for AD.

Using data science to diagnose and characterize heterogeneity of Alzheimer's disease.

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.

Oximetry as an Accurate Tool for Identifying Moderate to Severe Sleep Apnea in Patients With Acute Stroke.

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.

Association of Chronic Low-grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers.

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 < .001), but less so among those with ApoE4 alleles, followed by ApoE3 then ApoE2 genotypes. During the 17 years of follow-up, 194 individuals (7.3%) developed dementia, 152 (78.4%) of whom had AD. ApoE4 coupled with chronic low-grade inflammation, defined as a CRP level of 8 mg/L or higher, was associated with an increased risk of AD, especially in the absence of cardiovascular diseases (hazard ratio, 6.63; 95% CI, 1.80-24.50; P = .005), as well as an increased risk of earlier disease onset compared with ApoE4 carriers without chronic inflammation (hazard ratio, 3.52; 95% CI, 1.27-9.75; P = .009). This phenomenon was not observed among ApoE3 and ApoE2 carriers with chronic low-grade inflammation. Finally, a subset of 1761 individuals (66.3%) underwent brain magnetic resonance imaging, and the interaction between ApoE4 and chronic low-grade inflammation was associated with brain atrophy in the temporal lobe (ß = -0.88, SE = 0.22; P < .001) and hippocampus (ß = -0.04, SE = 0.01; P = .005), after adjusting for confounders. Conclusions and Relevance: In this study, peripheral chronic low-grade inflammation in participants with ApoE4 was associated with shortened latency for onset of AD. Rigorously treating chronic systemic inflammation based on genetic risk could be effective for the prevention and intervention of AD.

Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia.

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: <6 hours (short), 6-9 hours (reference), and >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 (ß ± SE, -1.08 ± 0.41 mean units of TCBV difference) and poorer executive function (ß ± 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.

Physical Activity, Brain Volume, and Dementia Risk: The Framingham Study.

BACKGROUND: Several 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. METHODS: The 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). RESULTS: Over 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 ε4 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 (ß ± SE = 0.24±0.06; p < .01 and 0.004±0.001; p = .003, respectively). CONCLUSION: Low 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.

The Influence of the Menstrual Phases on Polysomnography.

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.

Reward Deficiency Syndrome: Attentional/Arousal Subtypes, Limitations of Current Diagnostic Nosology, and Future Research.

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™.

CPAP treats muscle cramps in patients with obstructive sleep apnea.

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.

Central sleep apnea and complex sleep apnea in patients with epilepsy.

PURPOSE: 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. METHODS: 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 <40 %. Comparison of clinical and PSG variables between the three groups were conducted with Fisher exact test and analysis of variance. RESULTS: Out of 416 patients tested, 315 (75 %) had obstructive sleep apnea (OSA), 16 (3.7 %) had CSA, 33 (7.9 %) had CompSA. There were more males in the CSA and CompSA groups than in the OSA group (81.2, 81.8, and 59.6 %, respectively, p=0.04). Focal seizures were more prevalent in patients with CSA than in patients OSA or CompSA (62.5, 265, and 21.1 %, respectively, p=0.02). CONCLUSION: About 11 % of epilepsy patients have sleep-breathing disorders with central apneas, which is not higher than that in a general population. These data should be expanded with future research investigating the role of interictal, ictal, and postictal central apneas in epileptogenesis and epilepsy.

Insomnia and epilepsy: a questionnaire-based study.

STUDY OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.