Effectiveness of Existing Insomnia Therapies for Patients Undergoing Hemodialysis : A Randomized Clinical Trial.

BACKGROUND: Chronic insomnia is common in patients undergoing in-center hemodialysis, yet there is limited evidence on effective treatments for this population. OBJECTIVE: To compare the effectiveness of cognitive behavioral therapy for insomnia (CBT-I), trazodone, and placebo for insomnia in patients undergoing long-term hemodialysis. DESIGN: Randomized, multicenter, double-blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT03534284). SETTING: 26 dialysis units in Albuquerque, New Mexico, and Seattle, Washington. PARTICIPANTS: Patients with Insomnia Severity Index (ISI) score of 10 or greater, with sleep disturbances on 3 or more nights per week for 3 or more months. INTERVENTION: Participants were randomly assigned to 6 weeks of CBT-I, trazodone, or placebo. MEASUREMENTS: The primary outcome was the ISI score at 7 and 25 weeks from randomization. RESULTS: A total of 923 patients were prescreened, and of the 411 patients with chronic insomnia, 126 were randomly assigned to CBT-I (n = 43), trazodone (n = 42), or placebo (n = 41). The change in ISI scores from baseline to 7 weeks with CBT-I or trazodone was no different from placebo: CBT-I, -3.7 (95% CI, -5.5 to -1.9); trazodone, -4.2 (CI, -5.9 to -2.4); and placebo, -3.1 (CI, -4.9 to -1.3). There was no meaningful change in ISI scores from baseline to 25 weeks: CBT-I, -4.8 (CI, -7.0 to -2.7); trazodone, -4.0 (CI, -6.0 to -1.9); and placebo, -4.3 (CI, -6.4 to -2.2). Serious adverse events (SAEs), particularly serious cardiovascular events, were more frequent with trazodone (annualized cardiovascular SAE incidence rates: CBT-I, 0.05 [CI, 0.00 to 0.29]; trazodone, 0.64 [CI, 0.34 to 1.10]; and placebo, 0.21 [CI, 0.06 to 0.53]). LIMITATION: Modest sample size and most participants had mild or moderate insomnia. CONCLUSION: In patients undergoing hemodialysis with mild or moderate chronic insomnia, there was no difference in the effectiveness of 6 weeks of CBT-I or trazodone compared with placebo. The incidence of SAEs was higher with trazodone. PRIMARY FUNDING SOURCE: National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.

Daily sleep, well-being, and adult day services use among dementia care dyads.

OBJECTIVES: The study aimed to describe daily sleep characteristics for dementia care dyads in the context of adult day services (ADS) use and examine the associations with sleep quality and daytime functioning (fatigue, affect, and behavior problems). METHODS: Caregivers (CG; N = 173) reported daily bedtime, wake time, and sleep quality for themselves and the persons living with dementia (PLWD) across 8 consecutive days (N = 1359), where PLWD attended ADS at least 2 days of the week. On each day, caregivers also reported their own fatigue and affect and PLWD's daytime behavior problems and nighttime sleep problems. Considering the context of ADS use, we compared mean differences in bedtime, wake time, and total time in bed on nights before versus after ADS use. We estimated multilevel models to examine daily sleep-well-being associations. RESULTS: On nights before an upcoming ADS day, care dyads went to bed and woke up earlier, and spent less time in bed. Further, PLWD had better sleep quality the night before an upcoming ADS day. Using ADS during the day buffered the negative impact of PLWD's sleep problems in the previous night, reducing daytime negative affect for caregivers. For caregivers, using ADS yesterday attenuated the association between shorter than typical time in bed and daytime fatigue; it also attenuated the association between PLWD's nighttime sleep problems and lowered daytime positive affect. CONCLUSIONS: Regular ADS use may promote earlier sleep timing and protect against the adverse impact of sleep disturbances on daytime functioning for dementia care dyads.

Correction: Genetic data and cognitively defined late-onset Alzheimer's disease subgroups.

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Genetic data and cognitively defined late-onset Alzheimer's disease subgroups.

Categorizing people with late-onset Alzheimer's disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer's disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10-5 and odds ratios more extreme than those previously reported for Alzheimer's disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10-27). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10-5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.

Sleep Disruption Due to Stress in Women Veterans: A Comparison between Caregivers and Noncaregivers.

Objective/Background: Sleep problems are common in women and caregiving for an adult is a common role among women. However, the effects of caregiving on sleep and related daytime impairment are poorly understood among women veterans. This study compared stress-related sleep disturbances, insomnia symptoms, and sleep-related daytime impairment between women veterans who were caregivers and those who did not have a caregiving role. Participants: Of 12,225 women veterans who received care in one Veterans Administration Healthcare System, 1,457 completed data on a postal survey (mean age = 51.7 ± 15.9 years). Two hundred forty three (17%) respondents (mean age 53.8 ± 12.7 years) were caregivers for an adult, predominantly for a parent, providing transportation. Methods: The survey included items that addressed insomnia symptoms, total sleep time, sleep-related daytime impairments, caregiving characteristics, self-rated health, pain, stress, body mass index, and demographic information. Results: In adjusted analyses, caregiver status did not directly predict sleep complaints alone. However, in multiple regression analyses, being a caregiver (odds ratio 1.7, p = .001) significantly predicted stress-related sleep disturbance, even after adjusting for age, pain, self-rated health, and other characteristics. Furthermore, being a caregiver (ß = 3.9, p = .031) significantly predicted more symptoms of sleep-related daytime impairment after adjusting for age, pain, self-rated health, and other factors. Conclusions: Compared to noncaregivers, women veterans who were caregivers for an adult were more likely to report stress causing poor sleep, and more daytime impairment due to poor sleep. These findings suggest the need to target stress and other factors when addressing sleep disturbance among women veterans who are caregivers.

Theoretical impact of the AT(N) framework on dementia using a community autopsy sample.

The AT(N) research framework categorizes eight biomarker profiles using amyloid (A), tauopathy (T), and neurodegeneration (N), regardless of dementia status. We evaluated associations with dementia risk in a community-based cohort by approximating AT(N) profiles using autopsy-based neuropathology correlates, and considered cost implications for clinical trials for secondary prevention of dementia based on AT(N) profiles. We used Consortium to Establish a Registry for Alzheimer's Disease (moderate/frequent) to approximate A+, Braak stage (IV-VI) for T+, and temporal pole lateral ventricular dilation for (N)+. Outcomes included dementia prevalence at death and incidence in the last 5 years of life. A+T+(N)+ was the most common profile (31%). Dementia prevalence ranged from 14% (A-T-[N]-) to 79% (A+T+[N]+). Between 8% (A+T-[N]-) and 68% (A+T+[N]-) of decedents developed incident dementia in the last 5 years of life. Clinical trials would incur substantial expense to characterize AT(N). Many people with biomarker-defined preclinical Alzheimer's disease will never develop clinical dementia during life, highlighting resilience to clinical expression of AD neuropathologic changes and the need for improved tools for prediction beyond current AT(N) biomarkers.

Toward a theory-based specification of non-pharmacological treatments in aging and dementia: Focused reviews and methodological recommendations.

INTRODUCTION: Non-pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological rigor and continues to produce mixed results. METHODS: In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System. RESULTS: Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols. DISCUSSION: We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area.

Sleep-HD trial: short and long-term effectiveness of existing insomnia therapies for patients undergoing hemodialysis.

BACKGROUND: Patients with end-stage kidney disease (ESKD) treated with hemodialysis (HD) experience many distressing symptoms. One frequently reported symptom is insomnia. There are unique issues about HD treatments and schedules that disrupt regular sleep/wake routines and possibly contribute to the high severity of insomnia. Despite evidence for broad-ranging health effects of insomnia, very few clinical trials have tested the efficacy of treatments for HD patients. Cognitive-behavioral therapy for insomnia (CBT-I) is a recommended first-line therapy but largely inaccessible to HD patients in the United States, partly because they commit considerable amounts of time to thrice-weekly dialysis treatments. Another important reason could be the logistical and reimbursement challenges associated with providing behavioral health care at the dialysis center. CBT-I delivered by telehealth can overcome barriers to access, but its efficacy has never been rigorously tested for these patients. Pharmacotherapy is the most widely used treatment for insomnia; however, some drugs presently used are unsafe as they are associated with a higher risk for death for HD patients (benzodiazepines and zolpidem-like drugs). The efficacy and safety of other medications (trazodone) for the treatment of insomnia has never been tested for patients treated with HD. METHODS: This trial tests the short- and long-term comparative effectiveness of 6-week treatment with telehealth CBT-I, trazodone, or medication placebo. This will be accomplished with a randomized controlled trial (RCT) in which 126 participants treated with HD in community-based dialysis facilities with chronic insomnia will be assigned 1:1:1 to telehealth CBT-I, trazodone, or medication placebo, respectively; short-term effectiveness of each treatment arm will be determined at the end of 6-weeks of treatment and long-term effectiveness at 25-weeks. The primary and secondary patient-reported outcomes will be assessed with computer-based telephone interviewing by research scientists blinded to treatment assignment; additional secondary outcomes will be assessed by participant interview and actigraphy. DISCUSSION: This clinical RCT will provide the first evidence for the comparative effectiveness of two distinct approaches for treating chronic insomnia and other patient-reported outcomes for patients receiving maintenance HD. TRIAL REGISTRATION: NCT03534284 May 23, 2018. SLEEP-HD Protocol Version: 1.3.4 (7/22/2020).

Characterizing Behavioral Activity Rhythms in Older Adults Using Actigraphy.

Wrist actigraphy has been used to assess sleep in older adult populations for nearly half a century. Over the years, the continuous raw activity data derived from actigraphy has been used for the characterization of factors beyond sleep/wake such as physical activity patterns and circadian rhythms. Behavioral activity rhythms (BAR) are useful to describe individual daily behavioral patterns beyond sleep and wake, which represent important and meaningful clinical outcomes. This paper reviews common rhythmometric approaches and summarizes the available data from the use of these different approaches in older adult populations. We further consider a new approach developed in our laboratory designed to provide graphical characterization of BAR for the observed behavioral phenomenon of activity patterns across time. We illustrate the application of this new approach using actigraphy data collected from a well-characterized sample of older adults (age 60+) with osteoarthritis (OA) pain and insomnia. Generalized additive models (GAM) were implemented to fit smoothed nonlinear curves to log-transformed aggregated actigraphy-derived activity measurements. This approach demonstrated an overall strong model fit (R2 = 0.82, SD = 0.09) and was able to provide meaningful outcome measures allowing for graphical and parameterized characterization of the observed activity patterns within this sample.

Associations between recent and established ophthalmic conditions and risk of Alzheimer's disease.

INTRODUCTION: Identifying ophthalmic diseases associated with increased risk of Alzheimer's disease (AD) may enable better screening and understanding of those at risk of AD. METHODS: Diagnoses of glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR) were based on International Classification of Diseases, 9th revision, codes for 3877 participants from the Adult Changes in Thought study. The adjusted hazard ratio for developing probable or possible AD for recent (within 5 years) and established (>5 years) diagnoses were assessed. RESULTS: Over 31,142 person-years of follow-up, 792 AD cases occurred. The recent and established hazard ratio were 1.46 (P = .01) and 0.87 (P = .19) for glaucoma, 1.20 (P = .12) and 1.50 (P < .001) for AMD, and 1.50 (P = .045) and 1.50 (P = .03) for DR. DISCUSSION: Increased AD risk was found for recent glaucoma diagnoses, established AMD diagnoses, and both recent and established DR. People with certain ophthalmic conditions may have increased AD risk.

Effects of Pain, Insomnia, and Depression on Psychoactive Medication Supply in Older Adults With Osteoarthritis.

BACKGROUND: Determinants of prescribing psychoactive medications for symptom management in older adults remain underexamined despite known risks and cautions concerning these medications. OBJECTIVE: To examine independent and combined effects of pain, concurrent insomnia and depression symptoms on psychoactive medications supplied to older adults with osteoarthritis (OA). RESEARCH DESIGN: Survey data on pain, insomnia, and depression obtained from OA patients screened for a randomized controlled trial were used to identify predictors of psychoactive medication supply [opioids, sedatives, tricyclic antidepressants (TCAs), and non-TCAs] over a 4-year period. SUBJECTS: Group Health Cooperative patients with a diagnosis of OA (N=2976). MEASURES: Survey data on pain (Graded Chronic Pain Scale), insomnia (Insomnia Severity Index), and depression (Patient Health Questionnaire-8); and medications supply assessed from electronic medical records. RESULTS: In negative binomial models, pain [incidence rate ratio (IRR), 2.8-3.5; P<0.001], insomnia (IRR, 2.0; P<0.001), and depression (IRR, 1.5; P<0.05) each independently predicted opioid supply. Insomnia (IRR, 3.2; P<0.001) and depression (IRR, 3.0; P<0.001) each independently predicted sedative supply. Pain (IRR, 2.1; P<0.05) and insomnia (IRR, 2.0; P<0.05) independently predicted TCA supply, whereas only depression (IRR, 2.2; P<0.001) independently predicted non-TCA supply. Combined effects of pain and insomnia/depression on these medications were additive and increased the rate of medication supply 1.5-7.5 times. Combined effects increased with insomnia or depression severity. CONCLUSIONS: Concurrent insomnia and depressive symptoms predicted increased supply of opioids, sedatives, and antidepressants after accounting for pain, indicating the importance of sleep and mood disorders as factors increasing supply of these medications.

Brief Behavioral Treatment for Insomnia in Persons Living with HIV.

This study examined the feasibility and preliminary efficacy of brief behavioral treatment for insomnia (BBTI) for persons living with HIV (PLWH). Of the 22 persons enrolled, 9 were lost before starting treatment, and one dropped out after starting BBTI. Acceptability was rated favorably by those completing the treatment (n = 12). The most common problems pertained to sleep hygiene: variable bedtimes and rise times, watching television, or consuming caffeine. Improvements on sleep outcomes at posttreatment were clinically and statistically significant on questionnaire and sleep diary outcomes. This study supports the overall feasibility of BBTI in PLWH, and the preliminary evidence supports further research on this treatment for PLWH who have insomnia, but dropouts indicate that some individuals may have difficulty initiating treatment.

Caregiving-Related Sleep Problems and Their Relationship to Mental Health and Daytime Function in Female Veterans.

OBJECTIVE/BACKGROUND: To identify caregiving-related sleep problems and their relationship to mental health and daytime function in female Veterans. PARTICIPANTS: Female Veterans (N = 1,477) from cross-sectional, nationwide, postal survey data. METHODS: The survey respondent characteristics included demographics, comorbidity, physical activity, health, use of sleep medications, and history of sleep apnea. They self-identified caregiving- related sleep problems (i.e., those who had trouble sleeping because of caring for a sick adult, an infant/child, or other respondents). Patient Health Questionnaire (PHQ-4) was used to assess mental health, and daytime function was measured using 11 items of International Classification of Sleep Disorders-2 (ICSD-2). RESULTS: Female Veterans with self-identified sleep problems due to caring for a sick adult (n = 59) experienced significantly more symptoms of depression and anxiety (p < 0.001) and impairment in daytime function (e.g., fatigue, daytime sleepiness, loss of concentration, p < 0.001) than those with self-identified sleep problems due to caring for an infant or child (n = 95) or all other respondents (n = 1,323) after controlling for the respondent characteristics. CONCLUSIONS: Healthcare providers should pay attention to assessing sleep characteristics of female Veterans with caregiving responsibilities, particularly those caregiving for a sick adult.

Sleep and Caregiving Experiences among Caregivers of Veterans in an Adult Day Health Care Program: A Pilot Study.

OBJECTIVES: This pilot study explored caregivers' attitudes toward core elements of a behavioral sleep intervention for managing sleep problems of older veteran care recipients and the caregivers, as an initial step for developing a dyadic sleep intervention program. METHODS: Five caregivers (all women; age range, 66-75 years) participated in a focus group discussion. Data were collected at one Veterans Affairs, adult day health care program. RESULTS: Caregivers' poor sleep was not necessarily explained by their caregiving responsibility. Caregivers felt that behavioral recommendations regarding sleep compression scheduling, increased indoor physical activity, and outdoor light exposure would be acceptable sleep interventions for themselves and the care recipients. Some challenges to the sleep recommendation were identified and they included limiting naptime of care recipients and change of their current sleep schedule. CONCLUSIONS: Caregivers are receptive to some key components of behavioral approaches to improving sleep. Tailored sleep recommendation strategy is needed to address potential challenges. CLINICAL IMPLICATIONS: If available within clinical care settings or delivered at the patient's home, caregivers of older veterans are likely to engage in behavioral sleep intervention programs.

Training Area Agencies on Aging Case Managers to Improve Physical Function, Mood, and Behavior in Persons With Dementia and Caregivers: Examples from the RDAD-Northwest Study.

The Reducing Disability in Alzheimer's Disease (RDAD) program has been shown to be an effective tool for teaching caregivers strategies to improve mood, behavior, and physical function in persons with dementia. This paper describes how RDAD has been translated and implemented for use by Area Agencies on Aging (AAA) case managers across Washington and Oregon. Modifications to the original RDAD program as part of its community translation included decreasing the number of in-person sessions while preserving all educational content; involving caregivers in exercise activities for themselves as well as acting as exercise coaches for care-receivers; and enrolling persons with cognitive impairment due to mixed etiologies. This paper describes these changes and their rationale, the challenges faced by community agencies recruiting for and delivering evidence-based programs, and illustrates the actual RDAD implementation process through several brief case examples. Case examples also illustrate how RDAD-Northwest can be useful with care-receivers with a range of cognitive impairment severity, family caregiving situations, and levels of mood and behavioral challenges.

Impact of home visit capacity on genetic association studies of late-onset Alzheimer's disease.

INTRODUCTION: Findings for genetic correlates of late-onset Alzheimer's disease (LOAD) in studies that rely solely on clinic visits may differ from those with capacity to follow participants unable to attend clinic visits. METHODS: We evaluated previously identified LOAD-risk single nucleotide variants in the prospective Adult Changes in Thought study, comparing hazard ratios (HRs) estimated using the full data set of both in-home and clinic visits (n = 1697) to HRs estimated using only data that were obtained from clinic visits (n = 1308). Models were adjusted for age, sex, principal components to account for ancestry, and additional health indicators. RESULTS: LOAD associations nominally differed for 4 of 21 variants; CR1 and APOE variants were significant after Bonferroni correction. DISCUSSION: Estimates of genetic associations may differ for studies limited to clinic-only designs. Home visit capacity should be explored as a possible source of heterogeneity and potential bias in genetic studies.

Incidence of cognitively defined late-onset Alzheimer's dementia subgroups from a prospective cohort study.

INTRODUCTION: There may be biologically relevant heterogeneity within typical late-onset Alzheimer's dementia. METHODS: We analyzed cognitive data from people with incident late-onset Alzheimer's dementia from a prospective cohort study. We determined individual averages across memory, visuospatial functioning, language, and executive functioning. We identified domains with substantial impairments relative to that average. We compared demographic, neuropathology, and genetic findings across groups defined by relative impairments. RESULTS: During 32,286 person-years of follow-up, 869 people developed Alzheimer's dementia. There were 393 (48%) with no domain with substantial relative impairments. Some participants had isolated relative impairments in memory (148, 18%), visuospatial functioning (117, 14%), language (71, 9%), and executive functioning (66, 8%). The group with isolated relative memory impairments had higher proportions with ≥ APOE ε4 allele, more extensive Alzheimer's-related neuropathology, and higher proportions with other Alzheimer's dementia genetic risk variants. DISCUSSION: A cognitive subgrouping strategy may identify biologically distinct subsets of people with Alzheimer's dementia.

Glucose levels and risk of dementia.

BACKGROUND: Diabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes. METHODS: We used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension. RESULTS: During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P=0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P=0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76). CONCLUSIONS: Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes. (Funded by the National Institutes of Health.)

Information without Implementation: A Practical Example for Developing a Best Practice Education Control Group.

This article considers methodology for developing an education-only control group and proposes a simple approach to designing rigorous and well-accepted control groups. This approach is demonstrated in a large randomized trial. The Lifestyles trial (n = 367) compared three group interventions: (a) cognitive-behavioral treatment (CBT) for osteoarthritis pain, (b) CBT for osteoarthritis pain and insomnia, and (c) education-only control (EOC). EOC emulated the interventions excluding hypothesized treatment components and controlling for nonspecific treatment effects. Results showed this approach resulted in a control group that was highly credible and acceptable to patients. This approach can be an effective and practical guide for developing high-quality control groups in trials of behavioral interventions.

Open-Loop Audio-Visual Stimulation (AVS): A Useful Tool for Management of Insomnia?

Audio Visual Stimulation (AVS), a form of neurofeedback, is a non-pharmacological intervention that has been used for both performance enhancement and symptom management. We review the history of AVS, its two sub-types (close- and open-loop), and discuss its clinical implications. We also describe a promising new application of AVS to improve sleep, and potentially decrease pain. AVS research can be traced back to the late 1800s. AVS's efficacy has been demonstrated for both performance enhancement and symptom management. Although AVS is commonly used in clinical settings, there is limited literature evaluating clinical outcomes and mechanisms of action. One of the challenges to AVS research is the lack of standardized terms, which makes systematic review and literature consolidation difficult. Future studies using AVS as an intervention should; (1) use operational definitions that are consistent with the existing literature, such as AVS, Audio-visual Entrainment, or Light and Sound Stimulation, (2) provide a clear rationale for the chosen training frequency modality, (3) use a randomized controlled design, and (4) follow the Consolidated Standards of Reporting Trials and/or related guidelines when disseminating results.