Victoria A Nelson

Psychological and Behavioral Interventions for Managing Insomnia Disorder: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians

Sleep difficulties, including the inability to initiate or maintain sleep, are common in adults. Sleep difficulties are typically transient; however, when they become chronic and cause distress or daytime dysfunction, insomnia disorder may be present. The American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, defines insomnia disorder as a predominant symptom of difficulty with sleep initiation, difficulty maintaining sleep, or early-morning waking with inability to return to sleep causing clinically significant distress or impairment in activities, occurring at least 3 nights per week for 3 months or more (1). Furthermore, individuals must have adequate opportunity for sleep and the symptoms cannot be better explained by medical or mental conditions, including another sleep disorder (such as breathing-related sleep disorder), or medication or substance use. The term previously used for insomnia disorder is chronic insomnia (14), for which diagnostic criteria required sleep problems lasting from weeks to months. These criteria are empirically similar to current criteria for insomnia disorder. We use the term insomnia disorder even though much of the primary research has used other terminology (such as chronic insomnia and persistent insomnia). Between 6% and 10% of adults meet the diagnostic criteria for insomnia disorder (4). Duration ranges from 1 to 20 years across longitudinal studies (5). Insomnia disorder is more common in female patients and older adults (6, 7). Older adults typically report difficulty maintaining sleep as opposed to initiating sleep, which is common in younger adults (8). Many treatment types are available once insomnia disorder is accurately diagnosed by using established diagnostic criteria (4, 9). These include psychological and behavioral treatments, pharmacologic therapies, and complementary and alternative medicine. The American Academy of Sleep Medicine recommends psychological and behavioral interventions and supports short-term supplementary medication (9, 10). Psychological and behavioral interventions include cognitive behavioral therapy for insomnia (CBT-I), multicomponent behavioral therapy (brief behavioral therapy for insomnia), and single-component interventions (such as sleep hygiene and education, stimulus control, sleep restriction, and relaxation) (Table). Cognitive behavioral therapy for insomnia most commonly includes behavioral therapies (sleep restriction, stimulus control, relaxation training), cognitive therapy (cognitive restructuring) to change dysfunctional beliefs about sleep, as well as sleep hygiene education (3). Multicomponent behavioral therapies combine several behavioral therapies and do not include a cognitive component. Table. Psychological and Behavioral Interventions for Insomnia Disorder* Treatment goals include improving quality and quantity of sleep and associated impairments (10). Ideally, meaningful improvements in global outcomes measuring sleep and associated distress and dysfunction are realized. The Insomnia Severity Index (ISI) and the Pittsburgh Sleep Quality Index (PSQI) are commonly used for measuring global outcomes. Sleep outcomes include specific sleep variables (sleep-onset latency [SOL], wake time after sleep onset [WASO], total sleep time [TST], sleep efficiency (sleep time/time in bed), and sleep quality. Sleep variables can be measured objectively (with polysomnography or actigraphy) or subjectively (sleep diaries). Guidelines suggest monitoring symptoms with sleep diaries and polysomography is not indicated (10). We conducted a systematic review on the management of insomnia disorder for the Agency for Healthcare Research and Quality (11). This article reports evidence on psychological and behavioral interventions. Another article reports on the evidence on pharmacologic interventions and the comparison of pharmacologic interventions with psychological and behavioral interventions (12), and the full report provides evidence on complementary and alternative interventions. This evidence was used by the American College of Physicians to develop the guideline on the treatment of insomnia disorder in primary care. Evidence summarized here enhances previous reports (1315) by providing a comprehensive evaluation of psychological and behavioral interventions across all delivery modes with a primary emphasis on global outcomes. Methods Data Sources and Searches We searched bibliographic databases, including MEDLINE, Embase, and PsycINFO via Ovid, as well as the Cochrane Library, to identify randomized, controlled trials published from 2004 through September 2015 (Supplement). We identified studies published before 2004 by searching the citations in relevant systematic reviews. Supplement. Supplementary Material Study Selection Two investigators independently reviewed titles and abstracts of search results to identify potentially eligible references. Two investigators independently screened full texts of those references to determine whether inclusion criteria were met. We included randomized, controlled trials of psychological and behavioral interventions if they enrolled adults, provided at least 4 weeks of treatment, reported global or sleep outcomes, and were published in English. We excluded trials enrolling pure subgroups of patients with major medical conditions or conditions that may explain the sleep problems (such as menopause, pregnancy, and neurologic conditions). Data Extraction and Quality Assessment Risk of bias was independently assessed by two investigators using an instrument developed using Agency for Healthcare Research and Quality guidance (16) and was summarized as low, medium, or high on the basis of summary risk of bias and confidence that results were believable given limitations. Study, participant, and treatment characteristics; outcomes; and adverse events were extracted from eligible trials with low or moderate risk of bias. Data Synthesis and Analysis We used RevMan 5.2 (Nordic Cochrane Center) for pooling when adequate data were provided and populations, interventions, and outcomes were similar (17). DerSimonian and Laird random-effects estimates of risk ratios and absolute risk differences with 95% CIs were calculated for categorical outcomes, and weighted mean differences (WMDs) and/or standardized mean differences with 95% CIs were calculated for continuous outcomes. We assessed heterogeneity with the Cochran Q test and I 2 statistic (75% indicates substantial heterogeneity) (18). We analyzed the general adult population and older adults separately because sleep measures vary. We used established minimum important differences (MIDs) to capture clinical significance in global outcomes. The MID for the ISI is a 6-point change from baseline (19). Trials that conducted remitter or responder analysis on the basis of established MID offer simplistic interpretation. When trials provided mean scores, we interpreted WMDs in relation to MID by using the method of Johnson and colleagues (20). Weighted mean differences equal to or greater than the MID suggest that many patients gain important benefits, WMDs greater than half the MID but less than the MID suggest that an appreciable number of patients benefit, and WMDs less than half of the MID suggest that patients do not achieve important benefits (20). One investigator assessed strength of evidence for unique comparisons as high, moderate, low, or insufficient (21); assessments were confirmed through consensus. Role of Funding Source This topic was nominated to and funded by the Agency for Healthcare Research and Quality Effective Health Care Program. Key informants representing various perspectives offered suggestions as refined the review scope. Our draft protocol was shared with a technical expert panel that had the opportunity to review the draft report. The American College of Physicians provided support for this manuscript preparation. The authors are solely responsible for its contents. Results We identified 3572 citations; 559 required full-text review after title and abstract screening (Appendix Figure 1). Seventy-six articles (2297) reporting on 70 trials that compared psychological and behavioral interventions with inactive controls or other psychological and behavioral interventions were eligible. We extracted data and analyzed results for 60 trials with low to moderate risk of bias. We grouped trials by intervention type and comparison. Interventions for CBT-I had cognitive and behavioral components; multicomponent behavioral therapy interventions had several behavioral components and no cognitive component; and single-component interventions included sleep restriction, stimulus control, and relaxation. Appendix Figure 1. Summary of evidence search and selection. Intervention type totals do not equal total references because several trials were used in the analysis for 2 different types of interventions. RCT = randomized, controlled trial. Eligible trials (Tables 1 and 2 of the Supplement) enrolled individuals most commonly diagnosed with chronic insomnia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, with mean durations of several years. Participants were predominantly female and white. Trials were conducted in the United States, Canada, the United Kingdom, Sweden, Australia, Norway, Scotland, the Netherlands, and China. Mean age was mid-40s in general adult populations and lower 70s in older adults. Baseline ISI scores were approximately 17, indicating moderate severity, and baseline SOL was more than 45 minutes. Comparisons varied across trials. Inactive controls included information (such as sleep hygiene education) or waitlist; trials infrequently used sham treatments. Adverse effects were rarely reported. Withdrawals were not always reported by group. Evidence on adverse effects and withdrawals was insufficient for all comparisons. We assessed strength of

Physical Activity Interventions in Preventing Cognitive Decline and Alzheimer-Type Dementia: A Systematic Review

Forty-seven million people worldwide live with dementia (1), and this number is expected to triple by 2050 (2). Despite evidence that the overall incidence of dementia has declined in the United States (3, 4), the number of U.S. adults older than 70 years with dementia or mild cognitive impairment (MCI) increases as our population ages (5, 6). Dementia severely erodes functioning and quality of life, creates burden and stress on families, and leads to institutionalization. Dementia-related costs exceed those of heart disease and cancer and often are paid directly by families (7). Therefore, preventing dementia is an urgent public health priority. Many believe that an active lifestyle may prevent cognitive decline and dementia. Findings of several reviews, primarily those looking at cohort studies, suggest that physical activity may reduce or delay the development of potential modifiable risk factors for cognitive decline, such as obesity, diabetes, and hypertension (813). However, the relationships among physical activity, other risk factors, and cognitive decline are complex and interrelated. Findings of associations from cohort studies alone cannot clarify whether physical activity affects cognitive decline directly, indirectly through the reduction of medical risk factors, or both. Previous systematic reviews of randomized controlled trials report some cognitive benefits of physical activity interventions, although the certainty and clinical importance of these findings have not always been clear (14, 15). This systematic review reports a synthesis of the evidence assessing the effectiveness of physical activity interventions in slowing cognitive decline and delaying the onset of cognitive impairment and dementia in adults without diagnosed cognitive impairments. Methods We developed and followed a standard protocol (16). Our full technical report (17) contains details on methods and findings, an analysis of studies addressing secondary prevention in adults with MCI, and an evaluation of comparative effectiveness. Data Sources and Searches We searched bibliographic databases, including MEDLINE, EMBASE, and PsycINFO via Ovid, as well as the Cochrane Library, to identify controlled trials published in any language from January 2009 through July 2017. (See Part A of the Supplement, for search strategies.) We identified studies published before 2009 by citation searching relevant systematic reviews. Supplement. Data Supplement Study Selection Two investigators independently reviewed titles and abstracts of search results and screened the full text of potentially eligible references. Disagreements about eligibility were resolved by consensus. We included randomized controlled trials of physical activity interventions with any sample size and large (n > 500) prospective quasi-experimental cohort studies with comparator groups if they enrolled adults without diagnosed cognitive impairments, had follow-up of at least 6 months, were published in English, and reported 1 of our preselected primary or intermediate outcomes. We excluded trials enrolling pure subgroups of patients with major medical conditions or conditions that may explain changes in cognitive function (namely stroke, Parkinson disease, cancer, and traumatic brain injury). Our main outcomes of interest were MCI or dementia. Intermediate outcomes included measures of cognitive function assessed by instruments that tested cognition across several domains or those that specifically tested executive function, attention, and processing speed, or memory. Intermediate outcomes were categorized as follows: broad measures intended to capture several cognitive domains that were either brief cognitive tests (category 1) or more comprehensive multidomain neuropsychological tests (category 2) and domain-specific neuropsychological tests or subscales of broader instruments that assessed executive function, attention, and processing speed (category 3) or memory (category 4). Part B of the Supplement shows a list of the intermediate outcomes reported from the studies and our categorization of those outcomes. Data Extraction and Quality Assessment One reviewer extracted the study population, treatment characteristics, and funding source from all eligible studies. Risk of bias was assessed independently by 2 investigators using an instrument developed with guidance from the Agency for Healthcare Research and Quality (AHRQ) (18). Risk of bias for each reported outcome was rated as low, medium, or high on the basis of adequacy of randomization and allocation concealment, masking, attrition, use of intention-to-treat analyses, selectiveness of outcome reporting, and confidence that results were believable given limitations. Outcomes and adverse effects were extracted from eligible trials with low or moderate risk of bias, and a second investigator checked the extraction. Data Synthesis and Analysis We grouped studies by type of physical activity intervention and analyzed results by direction of effect and statistical significance. We found it impossible to assess the clinical significance of findings of the intermediate outcomes across all studies, because many different instruments were used and we did not always find information on the degree of change in specific instrument scores or subscores that would indicate clinical importance. (Part B of the Supplement shows the information we did find about clinically important changes in specific instrument scores.) In addition, results were measured, analyzed, and reported in many different ways. When sufficient data were available (from more than 1 study or 1 study with 500 participants), 1 investigator assessed the strength of evidence for unique comparisons. These assessments were confirmed through consensus. We assessed strength of evidence by using 5 required domains: study limitations (risk of bias of eligible studies for a given comparison), directness (single, direct link between intervention and outcome), consistency (similarity of effect direction and size), precision (degree of certainty around an estimate that includes attention to small sample sizes with power to detect only large differences), and reporting bias (19). On the basis of these factors, the overall strength of evidence for each outcome from a given intervention was rated as high, moderate, low, or insufficient. Role of the Funding Source This review was funded by the National Institute on Aging and AHRQ. These agencies and members of the National Academies Committee on Preventing Dementia and Cognitive Impairment helped refine the scope and reviewed a draft report of findings. The authors are solely responsible for the content preparation, writing of the manuscript, and decision to submit the manuscript for publication. Results Of 32 eligible studies that compared interventions using physical activity components with an inactive control in adults without a cognitive impairment diagnosis (2051), 16all of which were randomized trialswere considered to have low to medium risk of bias (20, 23, 25, 29, 30, 33, 3537, 39, 40, 43, 45, 46, 48, 50). Inactive controls in the trials with low to medium risk of bias included waitlist, usual care, no-intervention, and attention (that is, education and information) groups. Most trials were government funded. Most studies enrolled older adults; some limited enrollment to men or women. Total sample sizes ranged from 42 to 1635 participants. Trials rarely reported adverse effects; those that did showed no differences between groups, with 1 exception. Intervention components, frequency, and duration varied. (Part C of the Supplement contains the literature flow diagram; part D contains evidence tables.) The Table shows overall conclusions and strength-of-evidence ratings. Details of studies considered to have low to medium risk of bias are described later. For any cognitive outcome, evidence was insufficient to draw conclusions about most interventions (aerobic training, resistance training, tai chi, physical activity with diet, and physical activity with a cognitive component). Low-strength evidence showed that multicomponent physical activity interventions of 1 to 2 years did not improve multidomain neurologic performance; executive function, attention, and processing speed; or memory compared with an attention control. Low-strength evidence showed that an intervention combining physical activity, diet, and cognitive training benefited multidomain neuropsychological test performance and executive function, attention, and processing speed compared with an attention control; however, evidence was insufficient to draw conclusions about the efficacy of this intervention on memory. Moderate-strength evidence showed that more participants in the intervention than the control groups had musculoskeletal pain. Table. Conclusions: Physical Activity Versus Inactive Comparisons in Adults Physical Activity Interventions Multicomponent Physical Activity Four trials (n= 1885) with low to medium risk of bias examined multicomponent physical activity interventions. Components included flexibility, strength, balance, endurance, and aerobic training (36, 45, 46, 50). Enrollment criteria varied by trial. Sink and colleagues (45) and Williamson and colleagues (50) enrolled sedentary adults older than 70 years, most of whom were white women. Mean Modified Mini-Mental State Examination (MMSE) scores were higher than 90 points (on a scale of 0 to 100 points). Taylor-Piliae and colleagues (46) enrolled adults, mostly white college-educated women, older than 60 years. Napoli and colleagues (36) enrolled frail, obese older adults, most of whom were white women; mean Modified MMSE score was 96 points. Interventions during the trials lasted from 6 months to 2 years. Sink and colleagues (45) (n= 1635) reported diagnostic outcomes that showed no difference in the incidence of MCI (odds ratio, 1.14 [95% CI, 0.79 to 1.62]) or dementia (odds ratio, 0.9

Over-the-Counter Supplement Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review

Fear of losing cognitive ability to Alzheimer disease and related dementias drives a growing industry of over-the-counter (OTC) supplements intended to boost brain health and prevent or slow cognitive decline. The Alzheimers Research and Prevention Foundation recommends that people be sure to take [their] vitamins and memory-specific nutrients and suggests optimal dosages for an array of vitamins and nutrients (1). An estimated 63% of older adults use OTC supplements (2). In 2015, Americans spent

Does Cognitive Training Prevent Cognitive Decline?: A Systematic Review

37 billion on OTC supplements and

Efficacy of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: a systematic review

91 million on ginkgo bilobajust one of a growing number of supplements marketed to boost memory (3). Whether any dietary or herbal supplement or specific food can prevent or delay cognitive decline is unclear. This review summarizes the evidence on efficacy and harms of OTC supplements to prevent or delay cognitive decline, mild cognitive impairment (MCI), or clinical Alzheimer-type dementia. Methods We developed and followed a standard protocol (https://effectivehealthcare.ahrq.gov/topics/cognitive-decline/research-protocol). Data Sources and Searches We searched Ovid MEDLINE, PsycINFO, EMBASE, and the Cochrane Central Register of Controlled Trials for relevant literature published between 2009 and July 2017 (see Part A of the Supplement for search strategies). We identified studies published before 2009 by searching citations in systematic reviews and pertinent studies (48). Supplement. Supplementary Material Study Selection Two investigators independently reviewed titles and abstracts and screened the full text of potentially eligible references. We included randomized and nonrandomized controlled trials of any OTC supplements that enrolled adults with normal cognition or MCI. Because the review focused on prevention, we excluded studies of adults with dementia. We included only studies that followed participants for at least 6 months, reported incident MCI or dementia (our main outcome of interest) or cognitive performance outcomes, and were published in English. There were no restrictions on sample size or comparator type. Disagreements about eligibility were resolved by consensus. Data Extraction and Quality Assessment One reviewer extracted information on study design, population, intervention, comparator, setting, and funding source from eligible studies. For each study, 2 reviewers read the full text and independently rated risk of bias for the overall study and for each outcome and time point as low, medium, or high according to Agency for Healthcare Research and Quality (AHRQ) guidance (9). Outcomes and adverse events were extracted from studies with low to medium risk of bias. A second reviewer checked the quality of all data. Data Synthesis and Analysis We summarized results for studies with low to medium risk of bias by intervention, baseline cognitive status (presumed normal cognition or MCI), and outcome. Because studies used highly variable outcome measures, neuropsychological tests were categorized according to the following 4 specific cognitive domains to facilitate analysis: executive function, attention, and processing speed; memory; language; and visuospatial abilities (see Supplement Table A1 for the list of cognitive outcomes that were used and Supplement Table A2 for measurement properties, including change indices, of neuropsychological tests that were used). We grouped executive function, attention, and processing speed because a large number of cognitive tests frequently measure all 3 of these related domains. Our preliminary work found that studies analyzed and reported cognitive test results in widely varying ways, frequently making it impossible to determine effect size or assess whether between-group differences in scores or subscores were clinically meaningful. We instead analyzed and report cognitive test results by direction of effect and statistical significance. When there were at least 2 studies or 1 large study (>500 participants) for a treatment comparison, 2 reviewers graded strength of evidence for each outcome on the basis of study limitations, directness, consistency, and precision; otherwise, strength of evidence was graded as insufficient (10). Assessments were confirmed by consensus. Role of the Funding Source This review was funded by the National Institute on Aging and the AHRQ. These agencies and members of the National Academies Committee on Preventing Dementia and Cognitive Impairment helped refine the scope and reviewed a draft report of findings. The authors are solely responsible for the content, preparation, and writing of the manuscript and the decision to submit it for publication. Results We identified 63 publications of 56 unique studies covering 13 categories of OTC treatments (Appendix Figure). A third of the studies were at least partially funded by industry. Eighteen were assessed as having high risk of bias and were not further analyzed. Table 1 depicts the interventions and populations of the 38 studies judged as having low or medium risk of bias. Detailed evidence tables and risk-of-bias assessments are presented for studies involving adults with normal cognition in Part B of the Supplement and for studies involving adults with MCI in Part C of the Supplement; these tables are also available in the parent technical report (11). Table 2 summarizes the strength of evidence for the findings. Appendix Figure. Evidence search and selection. Table 1. Number of Studies With Low or Moderate Risk of Bias, by Intervention Type and Population Table 2. Effect of OTC Supplement Interventions Versus Control on Cognitive Outcomes in Adults With Normal Cognition and MCI* Table. Continued. -3 Fatty Acids Normal Cognition Seven randomized trials with low to medium risk of bias (n= 21027) that enrolled adults with presumed normal cognition compared -3 fatty acids with placebo (1218). Interventions lasted from 6 months to more than 6 years. Five trials reported cognitive exclusion criteria, including a Mini-Mental State Examination (MMSE) score less than 22 (14, 15), less than 24 (13), or less than 26 (16, 17) out of a possible 30 points. One study used only docosahexaenoic acid (DHA) (17); all others used some combination of eicosapentaenoic acid (EPA) plus DHA. The largest study (n= 15077) allowed participation of adults who were already using -3 supplementation (18). Populations varied in baseline health and risk for cognitive decline. Participants included patients with diabetes or impaired glucose tolerance (18), patients with a history of ischemic heart disease (12) or coronary artery disease (14), and healthy adults (13, 1517). None of the studies reported on incident Alzheimer-type dementia or MCI. A large multinational study of adults with diabetes or impaired glucose tolerance (n= 15077) used a combination of clinical diagnosis or an MMSE score less than 24 and found no difference in probable dementia incidence between the EPA/DHA group and the placebo group at a median follow-up of 6.2 years (hazard ratio [HR], 0.93 [95% CI, 0.86 to 1.0]) (18). Overall, studies provided low-strength evidence suggesting that -3 fatty acids do not improve cognitive performance in adults with normal cognition compared with placebo. Of 67 reported cognitive testsincluding 9 brief cognitive tests (12, 14, 17, 18); 1 test of multidomain neuropsychological performance (13); 32 tests of executive function, attention, and processing speed (13, 1518); and 25 memory tests (13, 1517)only 5 showed scores that were statistically significantly better in -3treated groups than in control groups. These 5 tests were administered in 2 studies that had relatively short follow-up (6 months) and included fewer than 5% of the total participants in the 7 studies (16, 17). Four studies did not report adverse events, and no studies reported statistically significant differences in adverse events between the -3 and placebo groups. The parent technical report provides details on adverse events (11). Subgroups were examined in 4 studies. No statistically significant differences in effect were found by age (12, 14, 15, 18), sex (14, 15, 18), time since myocardial infarction (14), or diabetes status (18). One study (n= 884) with 4-year follow-up examined the comparative effectiveness of -3 fatty acids and B vitamins on cognition (12). No between-group differences were found for any cognitive outcome between -3 fatty acids (alone or in combination with B vitamins) and B vitamins alone. Adverse events were not reported. MCI Evidence was insufficient for benefits of -3 fatty acids on cognitive outcomes compared with placebo after 1 year in the single small study of adults with MCI that we identified (n= 36) (19). No serious adverse events were reported. Soy Normal Cognition Five randomized trials with low to medium risk of bias that enrolled 35 to 350 participants (n= 829) and lasted 6 months to 2.5 years compared soy supplementation with placebo (2025). Populations included older adults without dementia (20) and generally healthy postmenopausal women (21, 2325). Baseline testing excluded persons with cognitive impairment in 2 of the studies (20, 21). Mean reported baseline MMSE scores ranged from 28 to 29 (2023). None of the trials reported MCI or Alzheimer-type dementia outcomes. Evidence was deemed insufficient to determine soys effect on brief cognitive test performance (21, 25) and multidomain neuropsychological test performance (21, 24) and low-strength for soy having no effect on executive function, attention, and processing speed (20, 21, 2325) or memory (2025) for up to 2.5 years. Two studies reported no serious adverse events and no statistically significant differences in adverse events between the soy and placebo groups (21, 25). MCI Evidence was insufficient to determine any beneficial effect on cognitive outcomes from soybean-derived phosphatidylserine at 2 doses (100 and 300 mg daily) compared with placebo after 9 months in a single small study of adults with

Comparative Effectiveness of Newer Medications for Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: A Systematic Review and Meta-analysis

Fear of losing ones cognitive ability to Alzheimer disease and related dementias (ADRD) and ultimately declining to a state considered by many to be worse than death (1) is driving a growing brain-training industry. Cognitive training programs, marketed to otherwise healthy adults and persons with a recent diagnosis of mild cognitive impairment (MCI), make bold claims for reversing brain aging. Such claims include the ability to boost cognitive reserve in midlife (with cognitive reserve referring to both the mismatch between clinical symptoms of dementia and pathologic brain lesion load at death and the repeatedly demonstrated association between educational achievement and dementia risk). However, few studies have evaluated the effect of cognitive training programs on cognitive decline or the onset of dementia, which is the outcome of interest for most people who buy these programs. This review systematically evaluates the existing literature on the effectiveness of cognitive training in preventing cognitive decline and ADRD. It is part of a larger systematic review commissioned by the National Institute on Aging to address a range of potential interventions to slow cognitive decline and prevent or delay dementia. Methods We developed and followed a standard protocol that was posted on the Agency for Healthcare Research and Quality (AHRQ) Web site (www.effectivehealthcare.ahrq.gov). Full details of the methods, including literature searches, findings, and evidence tables, are available in the final report (2). Data Sources and Searches We searched Ovid MEDLINE, PsycINFO, EMBASE, and the Cochrane Central Register of Controlled Trials for relevant literature published between January 2009 and July 2017 (see Part A of the Supplement, for searches) and hand-searched reference lists of selected articles. We identified studies published before 2009 by reviewing studies included and excluded from the 2010 AHRQ review on preventing Alzheimer disease and cognitive decline (3). Supplement. Cognitive Training Supplement Study Selection Two investigators independently reviewed titles and abstracts of search results and screened the full text of potentially eligible references. We included randomized trials of cognitive training interventions enrolling adults with either normal cognition or MCI if the studies followed participants for at least 6 months, provided cognitive performance or incident dementia outcomes, and were published in English. We excluded studies that enrolled only persons diagnosed with dementia. The final health outcome of interest was incident ADRD. Intermediate health outcomes of interest included performance on cognitive testing, biomarker protein levels, brain matter volume, and brain cell activity level. No restrictions were placed on sample size or comparator type. Data Extraction and Quality Assessment One reviewer extracted study, population, intervention, comparator, and setting characteristics as well as the funding source from all eligible studies. Risk of bias was assessed independently from full texts by 2 investigators using an instrument based on AHRQ guidance (4). Risk of bias was individually reviewed overall and for each outcome and time point, and was summarized as low, medium, or high on the basis of a summary of bias risk across risk-of-bias domains and confidence that results were credible given the studys limitations. Outcomes and adverse events were extracted from studies with low to medium risk of bias. A second reviewer checked the quality of all data. Data Synthesis and Analysis Only studies with low or medium risk of bias were summarized, because we judged findings from studies with high risk of bias to lack validity, have little meaning, or be easily misinterpreted. Because studies used a highly varied set of outcome measures, neuropsychological tests were categorized by the following specific cognitive domains to facilitate analysis: executive function, attention, and processing speed; memory; language; and visuospatial abilities (Supplement Table A1). The domains of executive function, attention, and processing speed were grouped together because cognitive tests frequently measure all 3 of these related domains. Because studies analyzed and reported cognitive test results in many different ways, making it difficult or impossible to determine effect size or to assess whether between-group differences in scores or subscores were clinically meaningful (Supplement Table A2), we analyzed and reported cognitive test results by direction of effect and statistical significance. When we identified at least 2 studies or 1 large study (>500 participants) for a treatment comparison, 2 reviewers graded strength of evidence for each outcome on the basis of study limitations, directness, consistency, and precision; otherwise, strength of evidence was graded as insufficient. Assessments were confirmed by consensus. Role of the Funding Source The National Institute on Aging of the National Institutes of Health requested this report from the AHRQ Evidence-based Practice Center Program. The funding agencies provided comments on draft reports but had no role in data collection, analysis, interpretation, or manuscript development. Results We identified 35 publications of 34 unique randomized controlled trials of cognitive training interventions, 11 of which had medium or low risk of bias (516). Only 1 trial was industry funded (8), whereas in 3 cases, trial funding was not reported (9, 15, 16). (See the Supplement Figure and Supplement Tables C1 to C4 for the literature flow diagram, evidence tables, and risk-of-bias assessments.) The Table summarizes the overall strength-of-evidence findings. For cognitively normal adults, moderate-strength evidence suggests that cognitive training in a particular domain improves performance in that domain compared with inactive or attention control populations. These results are driven largely by the results from the ACTIVE (Advanced Cognitive Training for Independent and Vital Elderly) trial. Low-strength evidence suggests that for persons with MCI, cognitive training in a particular domain does not improve performance in that domain compared with controls. The MCI trials have more limitations and are less precise than the studies conducted with cognitively normal participants. Evidence is insufficient for incident MCI or ADRD outcomes. Table. Summary of Conclusions and Strength of Evidence for Cognitive Training in Adults With Normal Cognition or MCI* Studies in Cognitively Normal Populations Six trials with low to medium risk of bias tested training interventions in cognitively normal older adults (510). Sample sizes for the selected studies ranged from 40 to 2832 participants. Interventions lasted from 2 weeks to 6 months; follow-up ranged from 6 months to 2 years. Three of the 6 trials used only computer-based interventions (68), 2 used a combination of computer and noncomputer (paper-and-pencil) interventions (5, 9), and 1 used group-based competition to increase divergent thinking (10). Three of the computer-based interventions were designed to increase performance on a specific cognitive domain (such as processing speed) (5, 6, 9), 1 used computers for cognitive stimulation more generally (7), and 1 used a computer program designed to train several cognitive domains (8). Comparators included both inactive (5, 7, 8, 10) and attention controls (6, 9). No studies reported adverse effects. The largest trial of cognitive training, ACTIVE, randomly assigned 2832 older adults (mean age, 74 years) without clinically significant cognitive impairment to 1 of 3 training groups or a no-contact control group (5). In each training group, a different cognitive domain was targeted: memory, reasoning, or processing speed. Participants in the intervention groups received 10 trainings of 60 to 70 minutes over 6 weeks. Cognitive testing outcomes included measuring changes in domain-specific test performance. Patient-centered cognitive outcomes included measuring changes in everyday problem solving (such as the ability to identify information on medication bottles), everyday speed (such as the time required to find food items on a grocery shelf), driving, and degree of dependency in completing activities of daily living and instrumental activities of daily living. Incident MCI or ADRD was not a prespecified outcome. Although 5- and 10-year outcomes from the ACTIVE trial have been published (17, 18), only the results from the 2-year study had a medium risk of bias (5). At 2 years, ACTIVE participants showed improvement in the cognitive domains in which they were trained (for example, those who received memory training improved on memory-related tasks compared with control participants), but no statistically significant differences were found among groups with regard to other cognitive outcomes (for example, persons who received training in memory did not do better than control participants on reasoning tasks). Intervention and control groups did not differ in other patient-centered cognitive outcomes at 2-year follow-up. Modeled on the visual process and speed training group of the ACTIVE trial, IHAMS (the Iowa Healthy and Active Minds Study) (n= 681) (6) randomly assigned adults by age group (50 to 64 years vs. 65 years) to visual processing speed training at the study center, visual processing speed training on the participants home computer, or computerized crossword puzzles (attention control group). Two-hour training sessions were held once a week for 5 weeks. Participants assigned to the intervention at the training center also received a booster training at 11 months. One year after training, both intervention groups showed statistically significant improvement in the primary outcome of the Useful Field of View test compared with the attention control group. The IHAMS participants also were administered 8 secondary cognitive tests on which they had not been tr

Nonpharmacologic Interventions for Agitation and Aggression in Dementia

Abstract We conducted a systematic review to evaluate the efficacy and adverse effects of newer drugs used to treat lower urinary tract symptoms (LUTS). The drugs were either Food and Drug Administration (FDA) approved for benign prostatic hyperplasia (BPH) or not FDA approved for BPH but have been evaluated for treatment of BPH since 2008. We searched bibliographic databases through September 2017. We included randomized controlled trials (RCTs) lasting one month or longer published in English. Outcomes of interest were LUTS assessed by validated measures. Efficacy was interpreted using established thresholds indicating clinical significance that identified the minimal detectable difference. Twenty-three unique, generally short-term, RCTs evaluating over 9000 participants were identified. Alpha-blocker silodosin and phosphodiesterase type 5 inhibitor tadalafil were more effective than placebo in improving LUTS (moderate strength evidence) but these drugs had more adverse effects, including abnormal ejaculation (silodosin). Anticholinergics were only effective versus placebo when combined with an alpha-blocker. Evidence was generally low strength or insufficient for other drugs. Evidence was insufficient to assess long-term efficacy, prevention of symptom progression, need for surgical intervention, or long-term adverse effects. Longer trials are needed to assess the effect of these therapies on response rates using established minimal detectable difference thresholds, disease progression, and harms.