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Ageing Research Reviews Dec 2022Dementia prevention research has progressed rapidly in recent years, with publication of several large lifestyle intervention trials, and renewed interest in... (Review)
Review
Dementia prevention research has progressed rapidly in recent years, with publication of several large lifestyle intervention trials, and renewed interest in pharmacological interventions, notably for individuals with Alzheimer's disease biomarkers, warranting an updated review of results and methodology. We identified 112 completed trials testing the efficacy of single-domain pharmacological (n = 33, 29%), nutritional (n = 27, 24%), physical activity (n = 18, 16%) and cognitive stimulation (n = 13, 12%), or multidomain (n = 22, 20%) interventions on incident dementia, or a relevant intermediate marker (e.g. cognitive function, biomarkers or dementia risk scores) in people without dementia. The earliest trials tested pharmacological interventions or nutritional supplements, but lifestyle interventions predominated in the last decade. In total, 21 (19%) trials demonstrated a clear beneficial effect on the pre-specified primary outcome (or all co-primary outcomes), but only two (10%) were large-scale (testing blood pressure lowering (Syst-Eur) or multidomain (FINGER) interventions on incident dementia and cognitive change in cognitive function, respectively). Of the 116 ongoing trials, 40% (n = 46) are testing multidomain interventions. Recent methodological shifts concern target populations, primary outcome measures, and intervention design, but study design remains constant (parallel group randomised controlled trial). Future trials may consider using adaptive trials or interventions, and more targeted approaches, since certain interventions may be more effective in certain subgroups of the population, and at specific times in the life-course. Efforts should also be made to increase the representativeness and diversity of prevention trial populations.
Topics: Humans; Cognitive Dysfunction; Cognition; Alzheimer Disease; Cognitive Behavioral Therapy; Life Style; Randomized Controlled Trials as Topic
PubMed: 36336171
DOI: 10.1016/j.arr.2022.101777 -
Translational Psychiatry Apr 2022Polysomnography (PSG) studies of sleep changes in Alzheimer's disease (AD) have reported but not fully established the relationship between sleep disturbances and AD. To... (Meta-Analysis)
Meta-Analysis
Polysomnography (PSG) studies of sleep changes in Alzheimer's disease (AD) have reported but not fully established the relationship between sleep disturbances and AD. To better detail this relationship, we conducted a systematic review and meta-analysis of reported PSG differences between AD patients and healthy controls. An electronic literature search was conducted in EMBASE, MEDLINE, All EBM databases, CINAHL, and PsycINFO inception to Mar 2021. Twenty-eight studies were identified for systematic review, 24 of which were used for meta-analysis. Meta-analyses revealed significant reductions in total sleep time, sleep efficiency, and percentage of slow-wave sleep (SWS) and rapid eye movement (REM) sleep, and increases in sleep latency, wake time after sleep onset, number of awakenings, and REM latency in AD compared to controls. Importantly, both decreased SWS and REM were significantly associated with the severity of cognitive impairment in AD patients. Alterations in electroencephalogram (EEG) frequency components and sleep spindles were also observed in AD, although the supporting evidence for these changes was limited. Sleep in AD is compromised with increased measures of wake and decreased TST, SWS, and REM sleep relative to controls. AD-related reductions in SWS and REM sleep correlate with the degree of cognitive impairment. Alterations in sleep EEG frequency components such as sleep spindles may be possible biomarkers with relevance for diagnosing AD although their sensitivity and specificity remain to be clearly delineated. AD-related sleep changes are potential targets for early therapeutic intervention aimed at improving sleep and slowing cognitive decline.
Topics: Alzheimer Disease; Humans; Polysomnography; Sleep; Sleep Wake Disorders; Sleep, REM
PubMed: 35365609
DOI: 10.1038/s41398-022-01897-y -
Neuroscience and Biobehavioral Reviews Aug 2021Endogenous melatonin levels are inversely associated with age and cognitive deficits. Although melatonin can improve psychopathological behavior disturbances in clinical... (Meta-Analysis)
Meta-Analysis Review
Neurocognitive effects of melatonin treatment in healthy adults and individuals with Alzheimer's disease and insomnia: A systematic review and meta-analysis of randomized controlled trials.
Endogenous melatonin levels are inversely associated with age and cognitive deficits. Although melatonin can improve psychopathological behavior disturbances in clinical trials, whether melatonin may also enhance cognitive function remains elusive. This study examined cognitive outcomes from randomized trials of melatonin treatment for Alzheimer's disease (AD), insomnia, and healthy-subjects. Twenty-two studies met the inclusion criteria (AD = 9, insomnia = 2, healthy-subjects = 11). AD patients receiving >12 weeks of melatonin treatment improved mini-mental state examination (MMSE) score [MD: 1.82 (1.01; 2.63) p < 0.0001]. Importantly, melatonin significantly improved MMSE score in mild stage of AD [MD: 1.89 (0.96; 2.82) p < 0.0001]. In healthy-subjects, although daytime melatonin treatment notably decreased in accuracy by correct responses [SMD: -0.74 (-1.03; -0.45) p < 0.00001], the reaction-time score on different stimuli (p = 0.37) did not increased. Additionally, by pooling of short-term, spatial, and visual memory scores, melatonin did not reduce memory function (p = 0.08). Meta-analysis of MMSE score suggested that melatonin is effective in treatment for mild stage of AD. Additionally, we propose that melatonin may be preferable to traditional hypnotics in management of insomnia.
Topics: Adult; Alzheimer Disease; Cognition Disorders; Humans; Melatonin; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders
PubMed: 33957167
DOI: 10.1016/j.neubiorev.2021.04.034 -
The Cochrane Database of Systematic... Jul 2021Dementia is a progressive syndrome of global cognitive impairment with significant health and social care costs. Global prevalence is projected to increase, particularly...
BACKGROUND
Dementia is a progressive syndrome of global cognitive impairment with significant health and social care costs. Global prevalence is projected to increase, particularly in resource-limited settings. Recent policy changes in Western countries to increase detection mandates a careful examination of the diagnostic accuracy of neuropsychological tests for dementia.
OBJECTIVES
To determine the accuracy of the Montreal Cognitive Assessment (MoCA) for the detection of dementia.
SEARCH METHODS
We searched MEDLINE, EMBASE, BIOSIS Previews, Science Citation Index, PsycINFO and LILACS databases to August 2012. In addition, we searched specialised sources containing diagnostic studies and reviews, including MEDION (Meta-analyses van Diagnostisch Onderzoek), DARE (Database of Abstracts of Reviews of Effects), HTA (Health Technology Assessment Database), ARIF (Aggressive Research Intelligence Facility) and C-EBLM (International Federation of Clinical Chemistry and Laboratory Medicine Committee for Evidence-based Laboratory Medicine) databases. We also searched ALOIS (Cochrane Dementia and Cognitive Improvement Group specialized register of diagnostic and intervention studies). We identified further relevant studies from the PubMed 'related articles' feature and by tracking key studies in Science Citation Index and Scopus. We also searched for relevant grey literature from the Web of Science Core Collection, including Science Citation Index and Conference Proceedings Citation Index (Thomson Reuters Web of Science), PhD theses and contacted researchers with potential relevant data.
SELECTION CRITERIA
Cross-sectional designs where all participants were recruited from the same sample were sought; case-control studies were excluded due to high chance of bias. We searched for studies from memory clinics, hospital clinics, primary care and community populations. We excluded studies of early onset dementia, dementia from a secondary cause, or studies where participants were selected on the basis of a specific disease type such as Parkinson's disease or specific settings such as nursing homes.
DATA COLLECTION AND ANALYSIS
We extracted dementia study prevalence and dichotomised test positive/test negative results with thresholds used to diagnose dementia. This allowed calculation of sensitivity and specificity if not already reported in the study. Study authors were contacted where there was insufficient information to complete the 2x2 tables. We performed quality assessment according to the QUADAS-2 criteria. Methodological variation in selected studies precluded quantitative meta-analysis, therefore results from individual studies were presented with a narrative synthesis.
MAIN RESULTS
Seven studies were selected: three in memory clinics, two in hospital clinics, none in primary care and two in population-derived samples. There were 9422 participants in total, but most of studies recruited only small samples, with only one having more than 350 participants. The prevalence of dementia was 22% to 54% in the clinic-based studies, and 5% to 10% in population samples. In the four studies that used the recommended threshold score of 26 or over indicating normal cognition, the MoCA had high sensitivity of 0.94 or more but low specificity of 0.60 or less.
AUTHORS' CONCLUSIONS
The overall quality and quantity of information is insufficient to make recommendations on the clinical utility of MoCA for detecting dementia in different settings. Further studies that do not recruit participants based on diagnoses already present (case-control design) but apply diagnostic tests and reference standards prospectively are required. Methodological clarity could be improved in subsequent DTA studies of MoCA by reporting findings using recommended guidelines (e.g. STARDdem). Thresholds lower than 26 are likely to be more useful for optimal diagnostic accuracy of MoCA in dementia, but this requires confirmation in further studies.
Topics: Aged; Alzheimer Disease; Cognitive Dysfunction; Cross-Sectional Studies; Dementia; Executive Function; Humans; Memory, Short-Term; Mental Status and Dementia Tests; Neuropsychological Tests; Orientation; Reference Standards; Sensitivity and Specificity
PubMed: 34255351
DOI: 10.1002/14651858.CD010775.pub3 -
Brain and Behavior Jan 2023In recent years, longitudinal studies of Alzheimer's disease (AD) have been successively concluded. Our aim is to determine the efficacy of amyloid-β (Aβ) PET in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In recent years, longitudinal studies of Alzheimer's disease (AD) have been successively concluded. Our aim is to determine the efficacy of amyloid-β (Aβ) PET in diagnosing AD and early prediction of mild cognitive impairment (MCI) converting to AD. By pooling studies from different centers to explore in-depth whether diagnostic performance varies by population type, radiotracer type, and diagnostic approach, thus providing a more comprehensive theoretical basis for the subsequent widespread application of Aβ PET in the clinical setting.
METHODS
Relevant studies were searched through PubMed. The pooled sensitivities, specificities, DOR, and the summary ROC curve were obtained based on a Bayesian random-effects model.
RESULTS
Forty-eight studies, including 5967 patients, were included. Overall, the pooled sensitivity, specificity, DOR, and AUC of Aβ PET for diagnosing AD were 0.90, 0.80, 35.68, and 0.91, respectively. Subgroup analysis showed that Aβ PET had high sensitivity (0.91) and specificity (0.81) for differentiating AD from normal controls but very poor specificity (0.49) for determining AD from MCI. The pooled sensitivity and specificity were 0.84 and 0.62, respectively, for predicting the conversion of MCI to AD. The differences in diagnostic efficacy between visual assessment and quantitative analysis and between C-PIB PET and F-florbetapir PET were insignificant.
CONCLUSIONS
The overall performance of Aβ PET in diagnosing AD is favorable, but the differentiation between MCI and AD patients should consider that some MCI may be at risk of conversion to AD and may be misdiagnosed. A multimodal diagnostic approach and machine learning analysis may be effective in improving diagnostic accuracy.
Topics: Humans; Alzheimer Disease; Bayes Theorem; Amyloid beta-Peptides; Cognitive Dysfunction; Sensitivity and Specificity; Positron-Emission Tomography
PubMed: 36573329
DOI: 10.1002/brb3.2850 -
Annals of Family Medicine 2024We conducted a meta-analysis to evaluate clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid in patients with Alzheimer dementia. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
We conducted a meta-analysis to evaluate clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid in patients with Alzheimer dementia.
METHODS
We searched PubMed, Cochrane CENTRAL, and 5 trial registries, as well as the reference lists of identified studies. We included randomized controlled trials comparing a monoclonal antibody with placebo at a dose consistent with that used in phase 3 trials or for Food and Drug Administration approval. Studies had to report at least 1 clinically relevant benefit or harm. Data were extracted independently by at least 2 researchers for random effects meta-analysis. Changes in cognitive and functional scales were compared between groups, and each difference was assessed to determine if it met the minimal clinically important difference (MCID).
RESULTS
We identified 19 publications with 23,202 total participants that evaluated 8 anti-amyloid antibodies. There were small improvements over placebo in the Alzheimer's Disease Assessment Scale (ADAS)-Cog-11 to -14 score (standardized mean difference = -0.07; 95% CI, -0.10 to -0.04), Mini Mental State Examination score (0.32 points; 95% CI, 0.13 to 0.50), and Clinical Dementia Rating-Sum of Boxes scale score (mean difference =-0.18 points; 95% CI, -0.34 to -0.03), and the combined functional scores (standardized mean difference = 0.09; 95% CI, 0.05 to 0.13). None of the changes, including those for lecanemab, aducanumab, and donanemab, exceeded the MCID. Harms included significantly increased risks of amyloid-related imaging abnormalities (ARIA)-edema (relative risk [RR] = 10.29; number needed to harm [NNH] = 9), ARIA-hemorrhage (RR = 1.74; NNH = 13), and symptomatic ARIA-edema (RR = 24.3; NNH = 86).
CONCLUSIONS
Although monoclonal antibodies targeting amyloid provide small benefits on cognitive and functional scales in patients with Alzheimer dementia, these improvements are far below the MCID for each outcome and are accompanied by clinically meaningful harms.
Topics: United States; Humans; Alzheimer Disease; Antibodies, Monoclonal; Mental Status and Dementia Tests; Edema; Antibodies, Monoclonal, Humanized
PubMed: 38253509
DOI: 10.1370/afm.3050 -
JAMA Neurology Mar 2022After more than a decade of research and development of clinical trials testing anti-β-amyloid monoclonal antibodies (mAbs), extensive experience has been gained... (Review)
Review
IMPORTANCE
After more than a decade of research and development of clinical trials testing anti-β-amyloid monoclonal antibodies (mAbs), extensive experience has been gained regarding the effects of these treatments in patients with Alzheimer disease (AD). On the verge of an expected large-scale introduction in the clinical setting after the recent US Food and Drug Administration approval of aducanumab, shared knowledge regarding amyloid-related imaging abnormalities (ARIAs) is of paramount importance.
OBJECTIVE
To summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti-β-amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment.
EVIDENCE REVIEW
In this systematic review, a literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence-Based Medicine.
FINDINGS
Twenty-two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid-attenuated inversion recovery and T2-weighted sequences were termed ARIA-E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA-H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA-E incidence was further associated with treatment dose, affecting the 55% of ApoE ε4 carriers in the high-dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3% of ARIA-E cases at higher treatment doses across RCTs, whereas ARIA-H cases were generally asymptomatic. Most ARIA-E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA-E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6% across RCTs.
CONCLUSIONS AND RELEVANCE
Evidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid-modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real-world clinical settings.
Topics: Aged; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidogenic Proteins; Amyloidosis; Apolipoprotein E4; Female; Humans; Male
PubMed: 35099507
DOI: 10.1001/jamaneurol.2021.5205 -
BMC Psychiatry Sep 2019Dementia represents a mental and economic burden for both patients and their caregivers. Therefore, the aim of this study is to explore the effectiveness of animal...
BACKGROUND
Dementia represents a mental and economic burden for both patients and their caregivers. Therefore, the aim of this study is to explore the effectiveness of animal assisted therapy (AAT) with special focus on canis therapy among people with dementia, specifically Alzheimer's disease.
METHODS
The key method of this review study is a systematic review of the research studies detected in the Web of Science, Scopus and PubMed. The search was conducted for the studies dating from 2016 till 31 August 2018 because several review studies were published before. Eventually, only six studies were involved into the final analysis.
RESULTS
The findings of this review, based on significant effect sizes, reveal that AAT may work as a beneficial and effective complementary treatment, especially in the area of behavioral and psychological symptoms, for patients with different degree of dementia severity if AAT is targeted at their specific needs and interests.
CONCLUSIONS
More research in the area of methodology for the implementation of AAT is necessary, and more research should be conducted with respect to the use of AAT for the improvement of cognitive functions in people with dementia.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Animal Assisted Therapy; Animals; Caregivers; Dementia; Dogs; Female; Humans; Male; Middle Aged; Treatment Outcome
PubMed: 31492131
DOI: 10.1186/s12888-019-2245-x -
Ageing Research Reviews Feb 2024The comparative clinical utility of the disease-modifying treatments for mild cognitive impairment and Alzheimer's disease that are approved or under review by the Food... (Meta-Analysis)
Meta-Analysis Review
Comparative efficacy, tolerability and acceptability of donanemab, lecanemab, aducanumab and lithium on cognitive function in mild cognitive impairment and Alzheimer's disease: A systematic review and network meta-analysis.
BACKGROUND
The comparative clinical utility of the disease-modifying treatments for mild cognitive impairment and Alzheimer's disease that are approved or under review by the Food and Drug Administration (i.e., donanemab, lecanemab and aducanumab), and lithium, which is a potential disease-modifying agent for this condition, remains elusive.
OBJECTIVE
We aimed to compare the efficacy on cognitive decline, tolerability and acceptability of these drugs in this condition.
METHODS
We systematically searched in MEDLINE, CENTRAL, CINHAL and ClinicalTrials,gov for randomized controlled trials from their inception to 7 November 2023, and then performed a random-effect network meta-analysis.
RESULTS
The analysis included 8 randomized placebo-controlled trials with 6547 participants. On the Mini-Mental State Examination, lithium significantly outperformed donanemab, aducanumab and placebo. On the Alzheimer's Disease Assessment Scale-cognitive subscale, the efficacy of all active drugs was significantly higher than placebo. In addition, in the Clinical Dementia Rating sum of boxes, the efficacy of donanemab and lecanemab was significantly higher than placebo. Compared to placebo, donanemab and lecanemab were significantly less acceptable and tolerable. Aducanumab was also less well tolerated compared to placebo. There were no significant differences in the other comparisons.
CONCLUSION
Although it is yet to be determined which is more effective between lithium or lecanemab or donanemab, lithium may be more effective than aducanumab. Aducanumab, lecanemab and donanemab do not appear to differ in their effectiveness on cognitive function. Low-dose lithium may be safer than aducanumab, lecanemab and donanemab.
Topics: Humans; Alzheimer Disease; Lithium; Network Meta-Analysis; Cognitive Dysfunction; Cognition; Antibodies, Monoclonal, Humanized
PubMed: 38253184
DOI: 10.1016/j.arr.2024.102203 -
International Journal of Environmental... Jan 2022The purpose of this meta-analysis was to examine the effects of physical activity (PA) on cognition and activities of daily living in adults with Alzheimer's Disease... (Meta-Analysis)
Meta-Analysis Review
Physical Activity Improves Cognition and Activities of Daily Living in Adults with Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
OBJECTIVE
The purpose of this meta-analysis was to examine the effects of physical activity (PA) on cognition and activities of daily living in adults with Alzheimer's Disease (AD).
METHODS
Six electronic databases (MEDLINE, CINAHL, PsycArticles, SPORTDiscus, EMBASE and CNKI) were used to search for potential studies from inception until October 2021. Randomized controlled trials (RCTs) investigating the effect of physical activity (PA) on cognition and activities of daily living in AD patients compared to a control condition were included. The effect sizes were synthesized using a random effects model with a 95% confidence interval (CI).
RESULTS
Sixteen articles including 945 participants (aged 70 to 88 years, 34.6% male) met the inclusion criteria. The pooled effect sizes demonstrated that PA intervention was associated with significant improvements in global cognition (Standard Mean Difference (SMD) = 0.41, 95% CI [0.24, 0.58], < 0.01) and activities of daily living (SMD = 0.56, 95% CI [0.32, 0.79], < 0.01) in AD patients. Subgroup analyses suggested that PA for 3-4 times per week for 30-45 min for more than 12 weeks had a relatively strong effect on improving global cognition in AD patients. The sensitivity analysis showed robust results.
CONCLUSIONS
The findings from the current meta-analysis suggested that AD patients can improve their global cognition and Activities of Daily Living (ADL) through engaging in aerobic and mixed exercise (aerobic and anaerobic exercise).
Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Exercise; Female; Humans; Male; Randomized Controlled Trials as Topic
PubMed: 35162238
DOI: 10.3390/ijerph19031216