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This study characterized person-specific rates of change of total daily physical activity (TDPA) and identified correlates of this change. TDPA metrics were extracted from multiday wrist-sensor recordings from 1083 older adults (average age 81 years; 76% female). Thirty-two covariates were collected at baseline. A series of linear mixed-effect models were used to identify covariates independently associated with the level and annual rate of change of TDPA. Though, person-specific rates of change varied during a mean follow-up of 5 years, 1079 of 1083 showed declining TDPA. The average decline was 16%/year, with a 4% increased rate of decline for every 10 years of age older at baseline. Following variable selection using multivariate modeling with forward and then backward elimination, age, sex, education, and 3 of 27 non-demographic covariates including motor abilities, a fractal metric, and IADL disability remained significantly associated with declining TDPA accounting for 21% of its variance (9% non-demographic and 12% demographics covariates). These results show that declining TDPA occurs in many very old adults. Few covariates remained correlated with this decline and the majority of its variance remained unexplained. Further work is needed to elucidate the biology underlying TDPA and to identify other factors that account for its decline.
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Envejecimiento , Personas con Discapacidad , Humanos , Femenino , Anciano , Anciano de 80 o más Años , Masculino , Ejercicio Físico , Actividades Cotidianas , Estudios LongitudinalesRESUMEN
INTRODUCTION: Sleep disruption is associated with astrocyte activation and impaired cognition in model organisms. However, the relationship among sleep, astrocyte activation, and cognition in humans is uncertain. METHODS: We used RNA-seq to quantify the prefrontal cortex expression of a panel of human activated astrocyte marker genes in 1076 older adults in the Religious Orders Study and Rush Memory and Aging Project, 411 of whom had multi-day actigraphy prior to death. We related this to rest fragmentation, a proxy for sleep fragmentation, and to longitudinal cognitive function. RESULTS: Fragmentation of rest periods was associated with higher expression of activated astrocyte marker genes, which was associated with a lower level and faster decline of cognitive function. DISCUSSION: Astrocyte activation and fragmented rest are associated with each other and with accelerated cognitive decline. If experimental studies confirm a causal relationship, targeting sleep fragmentation and astrocyte activation may benefit cognition in older adults. HIGHLIGHTS: Greater fragmentation of rest periods, a proxy for sleep fragmentation, is associated with higher composite expression of a panel of genes characteristic of activated astrocytes. Increased expression of genes characteristic of activated astrocytes was associated with a lower level and more rapid decline of cognitive function, beyond that accounted for by the burden of amyloid and neurofibrillary tangle pathology. Longitudinal and experimental studies are needed to delineate the causal relationships among sleep, astrocyte activation, and cognition.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/patología , Privación de Sueño , Astrocitos/patología , Sueño/fisiología , Disfunción Cognitiva/genética , Cognición/fisiologíaRESUMEN
INTRODUCTION: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples. METHODS: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately. RESULTS: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010). DISCUSSION: In NHW adults, APOE ε2 may protect men but not women against cognitive decline. HIGHLIGHTS: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.
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Apolipoproteína E2 , Disfunción Cognitiva , Caracteres Sexuales , Adulto , Femenino , Humanos , Masculino , Apolipoproteína E2/genética , Apolipoproteína E3/genética , Apolipoproteínas E/genética , Disfunción Cognitiva/genética , GenotipoRESUMEN
BACKGROUND AND PURPOSE: The pathogenesis of cerebral small vessel disease remains incompletely understood. The relationship between circadian rhythm disturbances and histopathologic measures of cerebral small vessel disease has not been studied. We hypothesized that disrupted circadian rest-activity rhythms would be associated with a higher burden of cerebral small vessel disease pathology. METHODS: We studied 561 community-dwelling older adults (mean age at death, 91.2, 27.4% male) from the Rush Memory and Aging Project. We used actigraphy to quantify several measures of 24-hour rest-activity rhythmicity, including interdaily stability, intradaily variability, and amplitude, and used ordinal logistic regression models to relate these measures to the severity of cerebral arteriolosclerosis, atherosclerosis, macroinfarcts, and microinfarcts, assessed at autopsy. RESULTS: Lower interdaily stability was associated with a higher burden of arteriolosclerosis, higher intradaily variability was associated with a higher burden of atherosclerosis and subcortical infarcts, and lower amplitude was associated with a higher burden of arteriosclerosis, atherosclerosis and subcortical macroinfarcts. Moreover, the associations between interdaily stability and arteriolosclerosis and intradaily variability and subcortical infarcts were independent of cardiovascular risk factors, sleep fragmentation, and medical comorbidities. CONCLUSIONS: Disrupted rest-activity rhythms are associated with a greater burden of cerebral small vessel disease in older adults.
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Envejecimiento/patología , Envejecimiento/fisiología , Enfermedades de los Pequeños Vasos Cerebrales/patología , Enfermedades de los Pequeños Vasos Cerebrales/fisiopatología , Ritmo Circadiano/fisiología , Descanso/fisiología , Actigrafía/métodos , Actigrafía/tendencias , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Vida Independiente/tendencias , MasculinoRESUMEN
BACKGROUND: Sleep problems are both symptoms of and modifiable risk factors for many psychiatric disorders. Wrist-worn accelerometers enable objective measurement of sleep at scale. Here, we aimed to examine the association of accelerometer-derived sleep measures with psychiatric diagnoses and polygenic risk scores in a large community-based cohort. METHODS AND FINDINGS: In this post hoc cross-sectional analysis of the UK Biobank cohort, 10 interpretable sleep measures-bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration-were derived from 7-day accelerometry recordings across 89,205 participants (aged 43 to 79, 56% female, 97% self-reported white) taken between 2013 and 2015. These measures were examined for association with lifetime inpatient diagnoses of major depressive disorder, anxiety disorders, bipolar disorder/mania, and schizophrenia spectrum disorders from any time before the date of accelerometry, as well as polygenic risk scores for major depression, bipolar disorder, and schizophrenia. Covariates consisted of age and season at the time of the accelerometry recording, sex, Townsend deprivation index (an indicator of socioeconomic status), and the top 10 genotype principal components. We found that sleep pattern differences were ubiquitous across diagnoses: each diagnosis was associated with a median of 8.5 of the 10 accelerometer-derived sleep measures, with measures of sleep quality (for instance, sleep efficiency) generally more affected than mere sleep duration. Effect sizes were generally small: for instance, the largest magnitude effect size across the 4 diagnoses was ß = -0.11 (95% confidence interval -0.13 to -0.10, p = 3 × 10-56, FDR = 6 × 10-55) for the association between lifetime inpatient major depressive disorder diagnosis and sleep efficiency. Associations largely replicated across ancestries and sexes, and accelerometry-derived measures were concordant with self-reported sleep properties. Limitations include the use of accelerometer-based sleep measurement and the time lag between psychiatric diagnoses and accelerometry. CONCLUSIONS: In this study, we observed that sleep pattern differences are a transdiagnostic feature of individuals with lifetime mental illness, suggesting that they should be considered regardless of diagnosis. Accelerometry provides a scalable way to objectively measure sleep properties in psychiatric clinical research and practice, even across tens of thousands of individuals.
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Acelerometría/instrumentación , Bancos de Muestras Biológicas , Trastornos Mentales/fisiopatología , Sueño/fisiología , Adulto , Anciano , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Herencia Multifactorial , Reproducibilidad de los Resultados , Factores de Riesgo , Autoinforme , Reino UnidoRESUMEN
BACKGROUND: There are few data concerning the association between season and cognition and its neurobiological correlates in older persons-effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects. METHODS AND FINDINGS: We analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07-0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07-0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years' difference in age (95% CI 2.1-8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10-1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aß 42 level (amplitude 0.30 SD [95% CI 0.10-0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21-0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27-0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24-0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20-0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere. CONCLUSIONS: Season has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD.
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Enfermedad de Alzheimer/psicología , Cognición , Estaciones del Año , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Biomarcadores/líquido cefalorraquídeo , Encéfalo/patología , Estudios de Cohortes , Estudios Transversales , Femenino , Expresión Génica , Humanos , Modelos Lineales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Corteza Prefrontal/metabolismoRESUMEN
INTRODUCTION: Healthy physiological systems exhibit fractal regulation (FR), generating similar fluctuation patterns in physiological outputs across different time scales. FR in motor activity is degraded in dementia, and the degradation correlates to cognitive decline. We tested whether degraded FR predicts Alzheimer's dementia. METHODS: FR in motor activity was assessed in 1097 nondemented older adults at baseline. Cognition was assessed annually for up to 11 years. RESULTS: Participants with an FR metric at the 10th percentile in this cohort had a 1.8-fold Alzheimer's disease risk (equivalent to the effect of being â¼5.2 years older) and 1.3-fold risk for mild cognitive impairment (equivalent to the effect of being â¼3.0 years older) than those at the 90th percentile. Consistently, degraded FR predicted faster cognitive decline. These associations were independent of physical activity, sleep fragmentation, and stability of daily activity rhythms. DISCUSSION: FR may be a useful tool for predicting Alzheimer's dementia.
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Enfermedad de Alzheimer/diagnóstico , Trastornos del Conocimiento/diagnóstico , Actividad Motora , Actigrafía , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/fisiopatología , Cognición , Trastornos del Conocimiento/fisiopatología , Femenino , Fractales , Humanos , Estudios Longitudinales , Masculino , Pruebas Neuropsicológicas , PronósticoRESUMEN
INTRODUCTION: Patients with Parkinson's disease (PD) frequently experience disrupted sleep, and several sleep abnormalities are associated with an increased risk of incident PD. However, there are few data concerning the relationship between objectively quantified sleep disruption and the cardinal histopathological features of PD, especially in individuals without clinical PD. METHODS: We studied 269 older adults without PD who had participated in the Rush Memory and Aging Project and undergone uniform structured neuropathologic evaluations upon death. Sleep fragmentation was measured using actigraphy. Logistic regression models examined the associations of sleep fragmentation proximate to death with the burden of Lewy body pathology and substantia nigra neuron loss. RESULTS: Greater sleep fragmentation was associated with the presence of Lewy body pathology (odds ratio 1.40; 95% confidence interval 1.05-1.86; P = .02) and substantia nigra neuron loss (odds ratio 1.43; 95% confidence interval 1.10-1.88; P = .008) and a higher odds of a pathological diagnosis of PD (odds ratio 2.04; 95% confidence interval 1.34-3.16; P = .0009). These associations were independent of motor features of parkinsonism, demographic characteristics, and a wide range of medical co-morbidities. CONCLUSIONS: Sleep fragmentation is associated with PD pathology in older adults without PD. These results suggest that sleep fragmentation may be a marker of or risk factor for PD pathology in older adults without PD. © 2017 International Parkinson and Movement Disorder Society.
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Envejecimiento/patología , Encéfalo/patología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/patología , Trastornos del Sueño-Vigilia/etiología , Anciano de 80 o más Años , Encéfalo/metabolismo , Estudios de Cohortes , Femenino , Humanos , Cuerpos de Lewy/patología , Modelos Logísticos , Masculino , Índice de Severidad de la Enfermedad , alfa-Sinucleína/metabolismoRESUMEN
Circadian rhythms modulate the biology of many human tissues, including brain tissues, and are driven by a near 24-hour transcriptional feedback loop. These rhythms are paralleled by 24-hour rhythms of large portions of the transcriptome. The role of dynamic DNA methylation in influencing these rhythms is uncertain. While recent work in Neurospora suggests that dynamic site-specific circadian rhythms of DNA methylation may play a role in modulating the fungal molecular clock, such rhythms and their relationship to RNA expression have not, to our knowledge, been elucidated in mammalian tissues, including human brain tissues. We hypothesized that 24-hour rhythms of DNA methylation exist in the human brain, and play a role in driving 24-hour rhythms of RNA expression. We analyzed DNA methylation levels in post-mortem human dorsolateral prefrontal cortex samples from 738 subjects. We assessed for 24-hour rhythmicity of 420,132 DNA methylation sites throughout the genome by considering methylation levels as a function of clock time of death and parameterizing these data using cosine functions. We determined global statistical significance by permutation. We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing. We found evidence of significant 24-hour rhythmicity of DNA methylation. Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1-3 hours. Weak ante-mortem rest-activity rhythms were associated with lower amplitude DNA methylation rhythms as were older age and the presence of Alzheimer's disease. These findings support the hypothesis that 24-hour rhythms of DNA methylation, particularly near transcription start sites, may play a role in driving 24-hour rhythms of gene expression in the human dorsolateral prefrontal cortex, and may be affected by age and Alzheimer's disease.
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Enfermedad de Alzheimer/genética , Ritmo Circadiano/genética , Ritmo Circadiano/fisiología , Metilación de ADN/genética , Transcripción Genética , Enfermedad de Alzheimer/fisiopatología , Animales , Metilación de ADN/fisiología , Regulación de la Expresión Génica , Humanos , Intrones/genética , Corteza Prefrontal/fisiopatología , ARN Mensajero/genética , Análisis de Secuencia de ARN , Sitio de Iniciación de la TranscripciónRESUMEN
INTRODUCTION: Circadian alterations are prevalent in Alzheimer's disease (AD) and may contribute to cognitive impairment, behavioral symptoms, and neurodegeneration. Epigenetic mechanisms regulate the circadian clock, and changes in DNA methylation have been reported in AD brains, but the pathways that mediate circadian deregulation in AD are incompletely understood. We hypothesized that aberrant DNA methylation may affect circadian rhythms in AD. METHODS: We investigated DNA methylation, transcription, and expression of BMAL1, a positive regulator of the circadian clock, in cultured fibroblasts and brain samples from two independent cohorts of aging and AD. RESULTS: DNA methylation modulated rhythmic expression of clock genes in cultured fibroblasts. Moreover, rhythmic methylation of BMAL1 was altered in AD brains and fibroblasts and correlated with transcription cycles. DISCUSSION: Our results indicate that cycles of DNA methylation contribute to the regulation of BMAL1 rhythms in the brain. Hence, aberrant epigenetic patterns may be linked to circadian alterations in AD.
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Factores de Transcripción ARNTL/metabolismo , Enfermedad de Alzheimer/metabolismo , Ritmo Circadiano/fisiología , Metilación de ADN , Factores de Transcripción ARNTL/genética , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Estudios de Casos y Controles , Células Cultivadas , Ritmo Circadiano/genética , Femenino , Fibroblastos/metabolismo , Lóbulo Frontal/metabolismo , Expresión Génica , Humanos , Masculino , Transcripción GenéticaRESUMEN
BACKGROUND AND PURPOSE: Although several forms of sleep disruption are associated with stroke, few studies have examined the relationship between sleep and histopathologic measures of cerebrovascular disease. We tested the hypothesis that greater sleep fragmentation is associated with a higher burden of cerebral vessel and infarct pathology at autopsy. METHODS: We used ordinal logistic regression models to relate sleep fragmentation measured by actigraphy to the severity of arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy, and the number of macroscopic and microscopic infarcts assessed by structured brain autopsy in 315 participants from the Rush Memory and Aging Project. RESULTS: Greater sleep fragmentation was associated with more severe arteriolosclerosis (odds ratio, 1.27; 95% confidence interval, 1.02-1.59; P=0.03 per 1 SD greater sleep fragmentation) and more subcortical macroscopic infarcts (odds ratio, 1.31; 95% confidence interval, 1.01-1.68; P=0.04). These associations were independent of established cardiovascular risk factors and diseases, and several medical comorbidities. CONCLUSIONS: Sleep fragmentation is associated with arteriolosclerosis and subcortical infarcts in older adults.
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Arterioloesclerosis/epidemiología , Angiopatía Amiloide Cerebral/epidemiología , Infarto Cerebral/epidemiología , Arteriosclerosis Intracraneal/epidemiología , Privación de Sueño/epidemiología , Actigrafía , Anciano de 80 o más Años , Arterioloesclerosis/patología , Autopsia , Infarto Encefálico/epidemiología , Infarto Encefálico/patología , Angiopatía Amiloide Cerebral/patología , Infarto Cerebral/patología , Femenino , Humanos , Vida Independiente , Arteriosclerosis Intracraneal/patología , Modelos Logísticos , Masculino , Oportunidad Relativa , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: The aim of this study was to assess medication prescribing and patient-reported outcomes among people with epilepsy (PWE) in Bhutan and introduce criteria for evaluating unmet epilepsy care needs, particularly in resource-limited settings. METHODS: People with epilepsy in Bhutan (National Referral Hospital, 2014-2015) completed a questionnaire, the Quality of Life in Epilepsy Inventory (QOLIE-31), and an electroencephalogram (EEG). Management gap was the proportion of participants meeting any of six prespecified criteria based on best practices and the National Institute for Health and Care Excellence (NICE) guidelines. RESULTS: Among 253 participants (53% female, median: 24years), 93% (n=235) were treated with antiepileptic drugs (AEDs). Seventy-two percent (n=183) had active epilepsy (≥1 seizure in the prior year). At least one criterion was met by 55% (n=138) of participants, whereas the treatment gap encompassed only 5% (n=13). The criteria were the following: 1. Among 18 participants taking no AED, 72% (n=13) had active epilepsy. 2. Among 26 adults on subtherapeutic monotherapy, 46% (n=12) had active epilepsy. 3. Among 48 participants reporting staring spells, 56% (n=27) were treated with carbamazepine or phenytoin. 4. Among 101 female participants aged 14-40years, 23% (n=23) were treated with sodium valproate. 5. Among 67 participants reporting seizure-related injuries, 87% (n=58) had active epilepsy. 6. Among 111 participants with a QOLIE-31 score below 50/100, 77% (n=86) had active epilepsy. Years since first AED treatment (odds ratio: 1.07, 95% CI: 1.03, 1.12) and epileptiform discharges on EEG (odds ratio: 1.95, 95% CI: 1.15, 3.29) were significantly associated with more criteria met. CONCLUSIONS: By defining the management gap, subpopulations at greatest need for targeted interventions may be prioritized, including those already taking AEDs.
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Anticonvulsivantes/uso terapéutico , Prescripciones de Medicamentos , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Medición de Resultados Informados por el Paciente , Adulto , Anciano , Bután/epidemiología , Carbamazepina/uso terapéutico , Electroencefalografía/métodos , Epilepsia/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenitoína/uso terapéutico , Calidad de Vida/psicología , Encuestas y Cuestionarios , Ácido Valproico/uso terapéuticoRESUMEN
Fragmented sleep is a common and troubling symptom in ageing and Alzheimer's disease; however, its neurobiological basis in many patients is unknown. In rodents, lesions of the hypothalamic ventrolateral preoptic nucleus cause fragmented sleep. We previously proposed that the intermediate nucleus in the human hypothalamus, which has a similar location and neurotransmitter profile, is the homologue of the ventrolateral preoptic nucleus, but physiological data in humans were lacking. We hypothesized that if the intermediate nucleus is important for human sleep, then intermediate nucleus cell loss may contribute to fragmentation and loss of sleep in ageing and Alzheimer's disease. We studied 45 older adults (mean age at death 89.2 years; 71% female; 12 with Alzheimer's disease) from the Rush Memory and Aging Project, a community-based study of ageing and dementia, who had at least 1 week of wrist actigraphy proximate to death. Upon death a median of 15.5 months later, we used immunohistochemistry and stereology to quantify the number of galanin-immunoreactive intermediate nucleus neurons in each individual, and related this to ante-mortem sleep fragmentation. Individuals with Alzheimer's disease had fewer galaninergic intermediate nucleus neurons than those without (estimate -2872, standard error = 829, P = 0.001). Individuals with more galanin-immunoreactive intermediate nucleus neurons had less fragmented sleep, after adjusting for age and sex, and this association was strongest in those for whom the lag between actigraphy and death was <1 year (estimate -0.0013, standard error = 0.0005, P = 0.023). This association did not differ between individuals with and without Alzheimer's disease, and similar associations were not seen for two other cell populations near the intermediate nucleus. These data are consistent with the intermediate nucleus being the human homologue of the ventrolateral preoptic nucleus. Moreover, they demonstrate that a paucity of galanin-immunoreactive intermediate nucleus neurons is accompanied by sleep fragmentation in older adults with and without Alzheimer's disease.
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Enfermedad de Alzheimer/patología , Neuronas/patología , Área Preóptica/patología , Trastornos del Sueño-Vigilia/patología , Sueño/fisiología , Actigrafía , Anciano de 80 o más Años , Envejecimiento/fisiología , Enfermedad de Alzheimer/fisiopatología , Recuento de Células , Estudios de Cohortes , Interpretación Estadística de Datos , Femenino , Galanina/metabolismo , Humanos , Inmunohistoquímica , Masculino , Área Preóptica/fisiopatología , Descanso/fisiología , Privación de Sueño/patología , Privación de Sueño/fisiopatología , Trastornos del Sueño-Vigilia/fisiopatología , Núcleo Supraquiasmático/crecimiento & desarrollo , Núcleo Supraquiasmático/patologíaRESUMEN
OBJECTIVE: Sleep complaints are associated with adverse health consequences. We hypothesized that non-disabled older persons with more sleep complaints have an increased risk of developing disability. METHODS: Subjects included 908 older clergy participating in the Religious Order Study without clinical dementia, history of stroke, or Parkinson disease. At baseline, participants rated their difficulty falling asleep, frequency of nocturnal awakenings, sleep efficacy, and napping frequency, from which a summary dyssomnia measure was derived. Self-report assessment of disability included instrumental activities of daily living (IADLs), basic activities of daily living (ADLs), and Rosow-Breslau mobility disability at baseline and at annual evaluations. RESULTS: Mean follow-up was 9.6 (SD: 4.2) years. At baseline, more than 60% had one or more sleep complaints. In a series of Cox proportional hazards models controlling for age, sex, and education, a one-point higher dyssomnia score at baseline was associated with about 20% increased risk of IADL disability (hazard ratio: 1.20; 95% confidence interval [CI]: 1.04-1.39; χ(2)1 = 7.62; p <0.05), about 27% increased risk of ADL disability (hazard ratio: 1.27; 95% CI: 1.10-1.47; χ(2)1 = 12.15; p <0.01), and about 27% increased risk of mobility disability (hazard ratio: 1.27; 95% CI: 1.09-1.48; χ(2)1 = 11.04; p <0.01). These associations did not vary by age, sex, or education and remained significant after controlling for potential confounders including body mass index, chronic medical conditions, and several common medications. Controlling for depressive symptoms attenuated the association between sleep complaints and incident IADL and ADL disabilities but the association between sleep complaints and incident mobility disability remained significant. CONCLUSION: Non-disabled older adults with more sleep complaints have an increased risk of developing disability.
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Envejecimiento/psicología , Evaluación de la Discapacidad , Disomnias/epidemiología , Actividades Cotidianas , Anciano , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Modelos de Riesgos Proporcionales , Autoinforme , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: Circadian rhythms influence the timing of behavior, neurological diseases, and even death. Rare mutations in homologs of evolutionarily conserved clock genes are found in select pedigrees with extreme sleep timing, and there is suggestive evidence that certain common polymorphisms may be associated with self-reported day/night preference. However, no common polymorphism has been associated with the timing of directly observed human behavioral rhythms or other physiological markers of circadian timing at the population level. METHODS: We performed a candidate gene association study with replication, evaluating associations between polymorphisms in homologs of evolutionarily conserved clock genes and the timing of behavioral rhythms measured by actigraphy. For validated polymorphisms, we evaluated associations with transcript expression and time of death in additional cohorts. RESULTS: rs7221412, a common polymorphism near period homolog 1 (PER1), was associated with the timing of activity rhythms in both the discovery and replication cohorts (joint p = 2.1 × 10(-7) ). Mean activity timing was delayed by 67 minutes in rs7221412(GG) versus rs7221412(AA) homozygotes. rs7221412 also showed a suggestive time-dependent relationship with both cerebral cortex (p = 0.05) and CD14+ CD16- monocyte (p = 0.02) PER1 expression and an interesting association with time of death (p = 0.015) in which rs7221412(GG) individuals had a mean time of death nearly 7 hours later than rs7221412(AA/AG) . INTERPRETATION: A common polymorphism near PER1 is associated with the timing of human behavioral rhythms, and shows evidence of association with time of death. This may be mediated by differential PER1 expression. These results may facilitate individualized scheduling of shift work, medical treatments, or monitoring of vulnerable patient populations.
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Ritmo Circadiano/genética , Actividad Motora/genética , Proteínas Circadianas Period/genética , Polimorfismo Genético/genética , Percepción del Tiempo/fisiología , Actigrafía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Receptores de Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Monocitos/patología , Fenotipo , Receptores de IgG/metabolismo , Estudios Retrospectivos , Adulto JovenRESUMEN
STUDY OBJECTIVES: To characterize the impact of CPAP use on cognition in a clinical cohort with obstructive sleep apnea (OSA) and cognitive impairment due to neurodegenerative or vascular etiologies after controlling for baseline sleepiness. METHODS: We retrospectively analyzed data from 171 patients with cognitive impairment and an OSA diagnosis confirmed with in-laboratory polysomnography or home sleep apnea testing (mean age 69.8 ± 10.6; 66% male) who were eligible to use CPAP. Baseline and follow-up Epworth Sleepiness Score (ESS), Montreal Cognitive Assessment (MoCA), and Mini-Mental Status Examination (MMSE) were obtained from clinical and research visits conducted before and after CPAP initiation. Good CPAP adherence was defined as CPAP use ≥4 h/night, for 7 days/week at follow-up. Associations between CPAP adherence and follow-up cognitive scores were analyzed using multivariable linear mixed-effects models. RESULTS: After adjusting for age, sex, body mass index, baseline ESS, duration of CPAP therapy, relevant comorbidities and the random effect of research study cohort, good CPAP adherence (compared to poor CPAP adherence or no use of CPAP) for a duration of 2-12 months was associated with a 2.3-point (1.2-3.3 95% CI) higher follow-up MoCA score (p < 0.001) and a 1.2-point (0.3-2.3 95% CI) higher follow-up MMSE score (p = 0.01). CONCLUSIONS: In patients with OSA and cognitive impairment due to a neurodegenerative or vascular etiology, use of CPAP is associated with improved cognitive outcomes. The findings of this study may aid in motivating patients to use CPAP and support future randomized controlled trials in this area.
Asunto(s)
Disfunción Cognitiva , Demencia , Apnea Obstructiva del Sueño , Humanos , Masculino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Lactante , Femenino , Estudios Retrospectivos , Somnolencia , Presión de las Vías Aéreas Positiva Contínua , Disfunción Cognitiva/complicaciones , Cognición , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/terapia , Demencia/complicacionesRESUMEN
Previous work has showed that nigral neuron density is related to the severity of parkinsonism proximate to death in older persons without a clinical diagnosis of Parkinson's disease (PD). We tested the hypothesis that neuron density in other brain stem aminergic nuclei is also related to the severity of parkinsonism. We studied brain autopsies from 125 deceased older adults without PD enrolled in the Memory and Aging Project, a clinicopathologic investigation. Parkinsonism was assessed with a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). We measured neuron density in the substantia nigra, ventral tegmental area, locus coeruleus, and dorsal raphe, along with postmortem indices of Lewy body disease, Alzheimer's disease and cerebrovascular pathologies. Mean age at death was 88.0 years, and global parkinsonism was 14.8 (SD, 9.50). In a series of regression models that controlled for demographics and neuron density in the substantia nigra, neuron density in the locus coeruleus (estimate, -0.261; SE, 0.117; P = .028) but not in the ventral tegmental area or dorsal raphe was associated with severity of global parkinsonism proximate to death. These findings were unchanged in models that controlled for postmortem interval, whole-brain weight, and other common neuropathologies including Alzheimer's disease and Lewy body pathology and cerebrovascular vascular pathologies. In older adults without a clinical diagnosis of PD, neuron density in locus coeruleus nuclei is associated with the severity of parkinsonism and may contribute to late-life motor impairments.
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Envejecimiento/patología , Locus Coeruleus/patología , Neuronas/patología , Trastornos Parkinsonianos/patología , Anciano , Anciano de 80 o más Años , Amiloide/metabolismo , Recuento de Células , Femenino , Humanos , Cuerpos de Lewy/patología , Masculino , Neuronas/ultraestructura , Cambios Post Mortem , Escalas de Valoración PsiquiátricaAsunto(s)
Arterioloesclerosis , Privación de Sueño , Encéfalo , Humanos , Vida Independiente , SueñoRESUMEN
Diurnal and seasonal rhythms influence many aspects of human physiology including brain function. Moreover, altered diurnal and seasonal behavioral and physiological rhythms have been linked to Alzheimer's disease and related dementias (ADRD). Understanding the molecular basis for these links may lead to identification of novel targets to mitigate the negative impact of normal and abnormal diurnal and seasonal rhythms on ADRD or to alleviate the adverse consequences of ADRD on normal diurnal and seasonal rhythms. Diurnally and seasonally rhythmic gene expression and epigenetic modification in the human neocortex may be a key mechanism underlying these links. This chapter will first review the observed epidemiological links between normal and abnormal diurnal and seasonal rhythmicity, cognitive impairment, and ADRD. Then it will review normal diurnal and seasonal rhythms of brain epigenetic modification and gene expression in model organisms. Finally, it will review evidence for diurnal and seasonal rhythms of epigenetic modification and gene expression the human brain in aging, Alzheimer's disease, and other brain disorders.