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Early Detection of Mild Cognitive Impairment (MCI) in an At-Home Setting.
Sabbagh, MN, Boada, M, Borson, S, Doraiswamy, PM, Dubois, B, Ingram, J, Iwata, A, Porsteinsson, AP, Possin, KL, Rabinovici, GD, et al
The journal of prevention of Alzheimer's disease. 2020;(3):171-178
Abstract
Emerging digital tools have the potential to enable a new generation of qualitative and quantitative assessment of cognitive performance. Moreover, the ubiquity of consumer electronics, such as smartphones and tablets, can be harnessed to support large-scale self-assessed cognitive screening with benefit to healthcare systems and consumers. A wide variety of apps, wearables, and new digital technologies are either available or in development for the detection of mild cognitive impairment (MCI), a risk factor for dementia. Two categories of novel methodologies may be considered: passive technologies (which monitor a user's behavior without active user input) and interactive assessments (which require active user input). Such examinations can be self-administered, supervised by a caregiver, or conducted by an informant at home or outside of a clinical setting. These direct-to-consumer tools have the potential to sidestep barriers associated with cognitive evaluation in primary care, thus improving access to cognitive assessments. Although direct-to-consumer cognitive assessment is associated with its own barriers, including test validation, user experience, and technological concerns, it is conceivable that these issues can be addressed so that a large-scale, self-assessed cognitive evaluation that would represent an initial cognitive screen may be feasible in the future.
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Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials.
Wessels, AM, Tariot, PN, Zimmer, JA, Selzler, KJ, Bragg, SM, Andersen, SW, Landry, J, Krull, JH, Downing, AM, Willis, BA, et al
JAMA neurology. 2020;(2):199-209
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IMPORTANCE Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression. OBJECTIVE To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia. DESIGN, SETTING, AND PARTICIPANTS AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging-Alzheimer's Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study. INTERVENTIONS Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo. MAIN OUTCOMES AND MEASURES The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale-cognitive subscale. Secondary outcomes included Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population. RESULTS Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo. CONCLUSIONS AND RELEVANCE Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT02245737 and NCT02783573.
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Preserving Cognition, Preventing Dementia.
Cleveland, ML
Clinics in geriatric medicine. 2020;(4):585-599
Abstract
Dementia incidence continues to rise in the United States and around the world. Although age is the single biggest risk factor for the development of dementia, it is not considered normal sequelae of aging. Although there has been little to no progress made in the past couple of decades in the treatment or cure of Alzheimer disease, there has been significant progress made in prevention. Single factors, such as hearing loss or cardiovascular risk factors, may increase the risk for cognitive decline. The opportunity to mitigate these risk factors provides an exciting new healthy aging approach to dementia prevention.
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Unique Role of Caffeine Compared to Other Methylxanthines (Theobromine, Theophylline, Pentoxifylline, Propentofylline) in Regulation of AD Relevant Genes in Neuroblastoma SH-SY5Y Wild Type Cells.
Janitschke, D, Lauer, AA, Bachmann, CM, Seyfried, M, Grimm, HS, Hartmann, T, Grimm, MOW
International journal of molecular sciences. 2020;(23)
Abstract
Methylxanthines are a group of substances derived from the purine base xanthine with a methyl group at the nitrogen on position 3 and different residues at the nitrogen on position 1 and 7. They are widely consumed in nutrition and used as pharmaceuticals. Here we investigate the transcriptional regulation of 83 genes linked to Alzheimer's disease in the presence of five methylxanthines, including the most prominent naturally occurring methylxanthines-caffeine, theophylline and theobromine-and the synthetic methylxanthines pentoxifylline and propentofylline. Methylxanthine-regulated genes were found in pathways involved in processes including oxidative stress, lipid homeostasis, signal transduction, transcriptional regulation, as well as pathways involved in neuronal function. Interestingly, multivariate analysis revealed different or inverse effects on gene regulation for caffeine compared to the other methylxanthines, which was further substantiated by multiple comparison analysis, pointing out a distinct role for caffeine in gene regulation. Our results not only underline the beneficial effects of methylxanthines in the regulation of genes in neuroblastoma wild-type cells linked to neurodegenerative diseases in general, but also demonstrate that individual methylxanthines like caffeine mediate unique or inverse expression patterns. This suggests that the replacement of single methylxanthines by others could result in unexpected effects, which could not be anticipated by the comparison to other substances in this substance class.
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Effect of desalted Salicornia europaea L. ethanol extract (PM-EE) on the subjects complaining memory dysfunction without dementia: a 12 week, randomized, double-blind, placebo-controlled clinical trial.
Lee, WJ, Shin, YW, Kim, DE, Kweon, MH, Kim, M
Scientific reports. 2020;(1):19914
Abstract
Desalted Salicornia europaea L. (SE) inhibits acetylcholine esterase, attenuates oxidative stress and inflammatory cytokines, and activates neurotrophic pathway. We performed 12-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy of PhytoMeal(a desalted SE)-ethanol extract (PM-EE), in improving the cognitive performance in patients with subjective memory impairment. 63 participants complaining memory dysfunction without dementia (Korean Mini-Mental State Examination [K-MMSE] score ≥ 23) were assigned to PM-EE 600 mg/day or placebo. The cognitive domain of the Alzheimer's disease assessment scale-Korean version (ADAS-K) was set as the primary outcome. After 12 weeks, there was no differences in the changes in the primary outcome or the frequency of adverse events between the groups. In the subgroup analysis for the 30 subjects with mild cognitive impairment (MCI, baseline K-MMSE scores ≤ 28), PM-EE significantly improved the color-reading score of the Korean color-word stroop test (8.2 ± 25.0 vs. - 4.7 ± 13.2, P = 0.018). Our findings suggest that PM-EE is safe but might not be effective in this setting of this study. However, PM-EE may improve the frontal executive function in the patients with MCI. Further large-sized studies with longer follow-up period is warranted (trial registration number KCT0003418).
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Education Research: Online Alzheimer education for high school and college students: A randomized controlled trial.
Saif, N, Niotis, K, Dominguez, M, Hodes, JF, Woodbury, M, Amini, Y, Sadek, G, Scheyer, O, Caesar, E, Hristov, H, et al
Neurology. 2020;(16):e2305-e2313
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OBJECTIVE Alzheimer disease (AD) risk factors are present throughout the lifespan. This randomized controlled trial evaluated the effectiveness of various online education strategies concerning AD risk reduction and brain health in younger populations. METHOD High school and college students were recruited via social media (Facebook and Instagram) to join AlzU.org, an evidence-based education portal, and were randomized to 1 of 4 courses: highly interactive webinar lessons narrated by actor Seth Rogen (celebrity webinar) or a physician (doctor webinar), minimally interactive video lessons with Seth Rogen (celebrity video), or minimally interactive video lessons (control). Surveys were administered at baseline and postcourse. The primary outcome was change in knowledge of AD risk reduction assessed by pre vs post lesson quiz scores. Secondary outcomes included change in awareness of AD research, hopefulness about AD, interest in pursuing health care, willingness to volunteer, and likelihood of recommending AlzU.org. RESULT A total of 721 participants joined. A total of 281 (38.9%) completed the course. Among college students, quiz score improvements were greater in celebrity webinar and celebrity video vs doctor webinar and control. Among high school students, no differences were found in quiz scores. In both groups, celebrity webinar, celebrity video, and doctor webinar resulted in greater improvements in awareness that nutrition and exercise may reduce AD risk vs controls. Among college students, celebrity webinar and celebrity video group participants felt more hopeful about the future of AD and more likely to recommend AlzU.org vs doctor webinar and control participants. Among college students, celebrity webinar, celebrity video, and doctor webinar participants were more willing to volunteer for AD causes and pursue health care careers vs controls. CONCLUSION Online education involving a celebrity may be an effective strategy for educating college students about AD risk reduction strategies. Further studies are warranted in high school students.
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Half a century of amyloids: past, present and future.
Ke, PC, Zhou, R, Serpell, LC, Riek, R, Knowles, TPJ, Lashuel, HA, Gazit, E, Hamley, IW, Davis, TP, Fändrich, M, et al
Chemical Society reviews. 2020;(15):5473-5509
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Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-β architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids, and realizing that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing. At the conclusion of a half century since Eanes and Glenner's seminal study of amyloids in humans, this review commemorates the occasion by documenting the major milestones in amyloid research to date, from the perspectives of structural biology, biophysics, medicine, microbiology, engineering and nanotechnology. We also discuss new challenges and opportunities to drive this interdisciplinary field moving forward.
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Short and medium-term effects of a multicomponent physical exercise program with a Mediterranean diet on bone mineral density, gait, balance, and fall risk for patients with Alzheimer disease: Randomized controlled clinical trial study protocol.
Puente-González, AS, Sánchez-González, F, Hernández-Xumet, JE, Sánchez-Sánchez, MC, Barbero-Iglesias, FJ, Méndez-Sánchez, R
Medicine. 2020;(38):e22385
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INTRODUCTION Reduced bone mineral density and increased risk of falls are related with Alzheimer disease, and these increase likelihood of bone osteoporotic fractures causing serious complications such as disability, fear of falling, loss autonomy, decreased quality of life, and anticipated mortality in elderly patients. Gait and balance disturb are 2 factors to favor falls in elderly, and in patients with cognitive impairment, the risk of falls increases to double. Exercise and Mediterranean diet produce beneficial effects for aging, cognitive decline, and are widely recommended to reduce the effects of osteoporosis, fall risk, and related fragility fractures. The primary objective of this study is to evaluate the short and medium-term effects during 6 months, of a multicomponent physical exercise program with a Mediterranean diet on bone mineral density, fall risk, balance, and gait by a controlled clinical trial in patients with Alzheimer disease. METHODS The study is a 6-month, randomized controlled parallel-group, single-blinded clinical trial. Institutionalized patients with Alzheimer disease will be included. The intervention group will perform a multicomponent physical exercise program in reduced groups, with a frequency of 3 sessions per week, associated with a Mediterranean diet. This program includes strength, balance, and aerobic resistance exercises, and in the main part of the session, also ludic exercises to improve agility, coordination, and balance. The control group will receive usual care. The outcomes to assess are the change of physical functions, such as gait and balance, and the change of bone mineral density by calcaneal quantitative ultrasound, during the study follow-up at 1, 3, and 6 months. This clinical trial will generate more and new evidence on the effects of a multicomponent physical exercise program and Mediterranean diet in patients with Alzheimer disease on risk of falls and osteoporotic fractures, the relation of these with bone mineral density, gait and balance, and the correlations between them. ETHICS AND DISSEMINATION This study protocol has been approved by the Ethics Committee of the University of Salamanca. The results will be published in peer-reviewed journals and disseminated in national and international conferences, to the participants and their families, and the general public through the associations of people with AD. TRIAL REGISTRATION ID ClínicalTrials.gov ID: NCT04439097.
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Lipid lowering and Alzheimer disease risk: A mendelian randomization study.
Williams, DM, Finan, C, Schmidt, AF, Burgess, S, Hingorani, AD
Annals of neurology. 2020;(1):30-39
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OBJECTIVE To examine whether genetic variation affecting the expression or function of lipid-lowering drug targets is associated with Alzheimer disease (AD) risk, to evaluate the potential impact of long-term exposure to corresponding therapeutics. METHODS We conducted Mendelian randomization analyses using variants in genes that encode the protein targets of several approved lipid-lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encoding the target of mipomersen). Variants were weighted by associations with low-density lipoprotein cholesterol (LDL-C) using data from lipid genetics consortia (n up to 295,826). We meta-analyzed Mendelian randomization estimates for regional variants weighted by LDL-C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls). RESULTS Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid-lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug target = 1.45, 95% confidence interval = 1.23-1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition. INTERPRETATION We did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for AD prevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9 inhibitors may be warranted. ANN NEUROL 2020;87:30-39.
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Lifestyle Risk Factors and Cognitive Outcomes from the Multidomain Dementia Risk Reduction Randomized Controlled Trial, Body Brain Life for Cognitive Decline (BBL-CD).
McMaster, M, Kim, S, Clare, L, Torres, SJ, Cherbuin, N, DʼEste, C, Anstey, KJ
Journal of the American Geriatrics Society. 2020;(11):2629-2637
Abstract
BACKGROUND/OBJECTIVES To evaluate the efficacy of a multidomain intervention to reduce lifestyle risk factors for Alzheimer's disease (AD) and improve cognition in individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). DESIGN The study was an 8-week two-arm single-blind proof-of-concept randomized controlled trial. SETTING Community-dwelling individuals living in Canberra, Australia, and surrounding areas. PARTICIPANTS Participants were 119 individuals (intervention n = 57; control n = 62) experiencing SCD or MCI. INTERVENTION The control condition involved four educational modules covering dementia and lifestyle risk factors, Mediterranean diet, physical activity, and cognitive engagement. Participants were instructed to implement this information into their own lifestyle. The intervention condition included the same educational modules and additional active components to assist with the implementation of this information into participants' lifestyles: dietitian sessions, an exercise physiologist session, and online brain training. MEASUREMENTS Lifestyle risk factors for AD were assessed using the Australian National University-Alzheimer's Disease Risk Index (ANU-ADRI), and cognition was assessed using Alzheimer's Disease Assessment Scale-Cognitive subscale, Pfeffer Functional Activities Questionnaire, Symbol Digit Modalities Test (SDMT), Trail Making Test-B, and Category Fluency. RESULTS The primary analysis showed that the intervention group had a significantly lower ANU-ADRI score (χ2 = 10.84; df = 3; P = .013) and a significantly higher cognition score (χ2 = 7.28; df = 2; P = .026) than the control group. A secondary analysis demonstrated that the changes in lifestyle were driven by increases in protective lifestyle factors (χ2 = 12.02; df = 3; P = .007), rather than a reduction in risk factors (χ2 = 2.93; df = 3; P = .403), and cognitive changes were only apparent for the SDMT (χ2 = 6.46; df = 2; P = .040). Results were robust to intention-to-treat analysis controlling for missing data. CONCLUSION Results support the hypothesis that improvements in lifestyle risk factors for dementia can lead to improvements in cognition over a short time frame with a population experiencing cognitive decline. Outcomes from this trial support the conduct of a larger and longer trial with this participant group.