Potential ethnic modifiers in the assessment and treatment of Alzheimer's disease: challenges for the future

2007 ◽  
Vol 19 (3) ◽  
pp. 539-558 ◽  
Author(s):  
Warachal E. Faison ◽  
Susan K. Schultz ◽  
Jeroen Aerssens ◽  
Jennifer Alvidrez ◽  
Ravi Anand ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Genetic Variability ◽  
Treatment Response ◽  
Ethnic Groups ◽  
Participation Rate ◽  
Convincing Evidence ◽  
Cognitive Enhancers ◽  
Randomized Controlled

Objective: Despite numerous clinical trials, it is unknown whether ethnicity affects treatment response to cognitive enhancers in Alzheimer's disease (AD). There is convincing evidence of ethnic and genetic variability in drug metabolism. This article reviews the available data on ethnicity in clinical trials for AD to answer two questions: (1) what are the challenges to diagnose and treat AD across different ethnic groups, and (2) are there differences in response to pharmacologic interventions for AD across these different ethnic groups?Method: Available data from Alzheimer's Disease Cooperative Study (ADCS) randomized controlled clinical trials and from randomized controlled industry-sponsored trials for four cognitive enhancers (donepezil, galantamine, rivastigmine and sabeluzole) were pooled to assess the numbers of non-Caucasian participants.Results: The participation of ethnic minority subjects in clinical trials for AD was dependent on the funding source, although Caucasian participants were over-represented and non-Caucasian participants were under-represented in the clinical trials. Because of the low participation rate of ethnic minorities, there were insufficient data to assess any differences in treatment outcome among different ethnic groups. Strategies to improve diversity in clinical trials are discussed.Conclusion: Greater participation of ethnically diverse participants in clinical trials for AD would generate additional information on possible differences in metabolism, treatment response, adverse events to therapeutic agents, and could foster the investigation of genetic variability among ethnic groups.

scholarly journals Cerebrolysin in Mild-to-Moderate Alzheimer's Disease: A Meta-Analysis of Randomized Controlled Clinical Trials

2015 ◽  
Vol 39 (5-6) ◽  
pp. 332-347 ◽  
Author(s):  
Serge Gauthier ◽  
Jefferson Voltaire Proaño ◽  
Jianping Jia ◽  
Lutz Froelich ◽  
Johannes Christophe Vester ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Function ◽  
Meta Analysis ◽  
Controlled Clinical Trials ◽  
Clinical Change ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Randomized Controlled

Objective: The aim of this study was to provide a systematic and quantitative summary of benefit and risk of Cerebrolysin in patients with mild-to-moderate Alzheimer's disease (AD) and to avoid major deficiencies of an earlier meta-analysis. Design: This is a meta-analysis of randomized double-blind placebo-controlled clinical trials. Data Sources: Trials were identified with the help of PubMed, the Cochrane Dementia Group database, the Center for Collaborative Neurosciences, and references from reviews; no language restrictions were applied. Study Selection: All randomized double-blind placebo-controlled studies on 30 ml/day of Cerebrolysin in mild-to-moderate AD were included. Results: There were 6 eligible randomized controlled trials comparing Cerebrolysin with placebo. For all studies, either individual patient data and/or published data (aggregate data) were available. Analyses were based on the odds ratio (OR) for dichotomized global clinical change and for safety criteria, on the standardized mean difference (SMD) for pooling of cognitive function, and on the Mann-Whitney statistic (MW) for multivariate analysis of ‘global benefit' (combined effect of global clinical change and cognitive function). Cerebrolysin was significantly more effective than placebo at 4 weeks regarding cognitive function (4 weeks: SMD -0.40 points; 95% CI -0.66 to -0.13; p = 0.0031; 6 months: SMD -0.37 points; 95% CI -0.90 to 0.16; p = 0.1710), at 4 weeks and 6 months regarding global clinical change (4 weeks: OR 3.32; 95% CI 1.20-9.21; p = 0.0212; 6 months: OR 4.98; 95% CI 1.37-18.13; p = 0.0150), and at 4 weeks and 6 months regarding ‘global benefit' (combined efficacy criteria; 4 weeks: MW 0.57, 95% CI 0.53-0.61; p = 0.0006; 6 months: MW 0.57; 95% CI 0.53-0.61; p = 0.0010). The safety aspects of Cerebrolysin were comparable to placebo. Conclusion: This meta-analysis provides evidence that Cerebrolysin has an overall beneficial effect and a favorable benefit-risk ratio in patients with mild-to-moderate AD. Cerebrolysin as a therapeutic agent should be considered by clinicians seeking treatment options for mild-to-moderate AD.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials

2018 ◽  
Vol 15 (5) ◽  
pp. 429-442 ◽  
Author(s):  
Nishant Verma ◽  
S. Natasha Beretvas ◽  
Belen Pascual ◽  
Joseph C. Masdeu ◽  
Mia K. Markey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Latent Variable ◽  
Brain Regions ◽  
Disease Assessment ◽  
Latent Variable Analysis ◽  
The Relationship ◽  
Selection Of

Background: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Method: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Results: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. Conclusion: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer’s disease.

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

scholarly journals On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

2021 ◽  
pp. 174077452110344
Author(s):  
Michelle M Nuño ◽  
Joshua D Grill ◽  
Daniel L Gillen ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cerebrospinal Fluid ◽  
Phosphorylated Tau ◽  
Inclusion Criteria ◽  
Eligibility Criteria ◽  
Total Tau ◽  
Prodromal Alzheimer’S Disease ◽  
Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

scholarly journals Virtual Reality-Based Cognitive Stimulation on People with Mild to Moderate Dementia due to Alzheimer’s Disease: A Pilot Randomized Controlled Trial

2021 ◽  
Vol 18 (10) ◽  
pp. 5290
Author(s):  
Jorge Oliveira ◽  
Pedro Gamito ◽  
Teresa Souto ◽  
Rita Conde ◽  
Maria Ferreira ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Randomized Controlled Trial ◽  
Virtual Reality ◽  
Cognitive Function ◽  
Controlled Trial ◽  
Cognitive Stimulation ◽  
Randomized Controlled ◽  
Moderate Dementia ◽  
Pilot Randomized Controlled Trial

The use of ecologically oriented approaches with virtual reality (VR) depicting instrumental activities of daily living (IADL) is a promising approach for interventions on acquired brain injuries. However, the results of such an approach on dementia caused by Alzheimer’s disease (AD) are still lacking. This research reports on a pilot randomized controlled trial that aimed to explore the effect of a cognitive stimulation reproducing several IADL in VR on people with mild-to-moderate dementia caused by AD. Patients were recruited from residential care homes of Santa Casa da Misericórdia da Amadora (SCMA), which is a relevant nonprofit social and healthcare provider in Portugal. This intervention lasted two months, with a total of 10 sessions (two sessions/week). A neuropsychological assessment was carried out at the baseline and follow-up using established neuropsychological instruments for assessing memory, attention, and executive functions. The sample consisted of 17 patients of both genders randomly assigned to the experimental and control groups. The preliminary results suggested an improvement in overall cognitive function in the experimental group, with an effect size corresponding to a large effect in global cognition, which suggests that this approach is effective for neurocognitive stimulation in older adults with dementia, contributing to maintaining cognitive function in AD.

scholarly journals Cognitive Effects of Aerobic Exercise in Alzheimer’s Disease: A Pilot Randomized Controlled Trial

2021 ◽  
pp. 1-12
Author(s):  
Fang Yu ◽  
David M. Vock ◽  
Lin Zhang ◽  
Dereck Salisbury ◽  
Nathaniel W. Nelson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Randomized Controlled Trial ◽  
Aerobic Exercise ◽  
Controlled Trial ◽  
Moderate Intensity ◽  
Cognitive Effects ◽  
Data Set ◽  
Randomized Controlled

Background: Aerobic exercise has shown inconsistent cognitive effects in older adults with Alzheimer’s disease (AD) dementia. Objective: To examine the immediate and longitudinal effects of 6-month cycling on cognition in older adults with AD dementia. Methods: This randomized controlled trial randomized 96 participants (64 to cycling and 32 to stretching for six months) and followed them for another six months. The intervention was supervised, moderate-intensity cycling for 20–50 minutes, 3 times a week for six months. The control was light-intensity stretching. Cognition was assessed at baseline, 3, 6, 9, and 12 months using the AD Assessment Scale-Cognition (ADAS-Cog). Discrete cognitive domains were measured using the AD Uniform Data Set battery. Results: The participants were 77.4±6.8 years old with 15.6±2.9 years of education, and 55%were male. The 6-month change in ADAS-Cog was 1.0±4.6 (cycling) and 0.1±4.1 (stretching), which were both significantly less than the natural 3.2±6.3-point increase observed naturally with disease progression. The 12-month change was 2.4±5.2 (cycling) and 2.2±5.7 (control). ADAS-Cog did not differ between groups at 6 (p = 0.386) and 12 months (p = 0.856). There were no differences in the 12-month rate of change in ADAS-Cog (0.192 versus 0.197, p = 0.967), memory (–0.012 versus –0.019, p = 0.373), executive function (–0.020 versus –0.012, p = 0.383), attention (–0.035 versus –0.033, p = 0.908), or language (–0.028 versus –0.026, p = 0.756). Conclusion: Exercise may reduce decline in global cognition in older adults with mild-to-moderate AD dementia. Aerobic exercise did not show superior cognitive effects to stretching in our pilot trial, possibly due to the lack of power.

scholarly journals Saffron for mild cognitive impairment and dementia: a systematic review and meta-analysis of randomised clinical trials

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zahra Ayati ◽  
Guoyan Yang ◽  
Mohammad Hossein Ayati ◽  
Seyed Ahmad Emami ◽  
Dennis Chang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Function ◽  
Daily Living ◽  
Randomised Clinical Trials ◽  
Disease Assessment ◽  
Significant Difference

Abstract Background Saffron (stigma of Crocus sativus L.) from Iridaceae family is a well-known traditional herbal medicine that has been used for hundreds of years to treat several diseases such as depressive mood, cancer and cardiovascular disorders. Recently, anti-dementia property of saffron has been indicated. However, the effects of saffron for the management of dementia remain controversial. The aim of the present study is to explore the effectiveness and safety of saffron in treating mild cognitive impairment and dementia. Methods An electronic database search of some major English and Chinese databases was conducted until 31st May 2019 to identify relevant randomised clinical trials (RCT). The primary outcome was cognitive function and the secondary outcomes included daily living function, global clinical assessment, quality of life (QoL), psychiatric assessment and safety. Rev-Man 5.3 software was applied to perform the meta-analyses. Results A total of four RCTs were included in this review. The analysis revealed that saffron significantly improves cognitive function measured by the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating Scale-Sums of Boxes (CDR-SB), compared to placebo groups. In addition, there was no significant difference between saffron and conventional medicine, as measured by cognitive scales such as ADAS-cog and CDR-SB. Saffron improved daily living function, but the changes were not statistically significant. No serious adverse events were reported in the included studies. Conclusions Saffron may have the potential to improve cognitive function and activities of daily living in patients with Alzheimer’s disease and mild cognitive impairment (MCI). However, due to limited high-quality studies there is insufficient evidence to make any recommendations for clinical use. Further clinical trials on larger sample sizes are warranted to shed more light on its efficacy and safety.

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