Does Certainty of Genuine Treatment Increase the Drug Response in Alzheimer’s Disease Patients: A Meta-Analysis and Critical Discussion

2021 ◽  
pp. 1-12
Author(s):  
Susan Tomczak Matthiesen ◽  
Sophie Rosenkjær ◽  
Moa Pontén ◽  
Karin B. Jensen ◽  
Hanne Gottrup ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Effects ◽  
Meta Analysis ◽  
Specific Treatment ◽  
Critical Discussion ◽  
Pharmacological Treatments ◽  
Open Label ◽  
Significant Difference ◽  
Pre Treatment

Background: Non-specific treatment effects, such as expectations, contribute to the effectiveness of pharmacological treatments across diseases. However, the contribution of expectancy, i.e., certainty of receiving treatment, in patients with Alzheimer’s disease (AD) is unknown. Objective: The aim is to investigate whether certainty of receiving a genuine treatment influences the response to active treatment in AD patients. Methods: The efficacy of active treatments in open-label trials, where patients are certain of receiving treatment (100%certainty), was compared to the same active treatments in randomized controlled trials (RCT), where patients are uncertain of receiving treatment or placebo (50%certainty). Results: In the seven open-label trials, there was no significant difference between post- and pre-treatment scores (difference in means = 0.14, 95%CI [–0.51; 0.81], p = 0.66). In the eight RCT trials, there was a significant difference between post- and pre-treatment (difference in means = –0.91, 95%CI [–1.43; –0.41], p <  0.001). There was a statistically significant difference between open-label and RCT trials (difference = 1.06, 95%CI [0.23; 1.90], p = 0.001). Conclusion: Patients with AD did not benefit from certainty of receiving genuine treatment. This could be due to the nature/progression of the disease, but it could also be related to an order effect in the practice of running AD trials, where RCTs are conducted prior to open label. These findings have implications for the understanding of non-specific treatment effects in AD patients as well as for the design of clinical trials that test pharmacological treatments in AD.

Characteristics of Insulin-degrading Enzyme in Alzheimer's Disease: A Meta-Analysis

2018 ◽  
Vol 15 (7) ◽  
pp. 610-617 ◽  
Author(s):  
Huifeng Zhang ◽  
Dan Liu ◽  
Huanhuan Huang ◽  
Yujia Zhao ◽  
Hui Zhou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Enzyme Activity ◽  
Protein Level ◽  
Senile Plaque ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Significant Difference

Background: β-amyloid (Aβ) accumulates abnormally to senile plaque which is the initiator of Alzheimer's disease (AD). As one of the Aβ-degrading enzymes, Insulin-degrading enzyme (IDE) remains controversial for its protein level and activity in Alzheimer's brain. Methods: The electronic databases PubMed, EMBASE, The Cochrane Library, OVID and Sinomed were systemically searched up to Sep. 20th, 2017. And the published case-control or cohort studies were retrieved to perform the meta-analysis. Results: Seven studies for IDE protein level (AD cases = 293; controls = 126), three for mRNA level (AD cases = 138; controls = 81), and three for enzyme activity (AD cases = 123; controls = 75) were pooling together. The IDE protein level was significantly lower in AD cases than in controls (SMD = - 0.47, 95% CI [-0.69, -0.24], p < 0.001), but IDE mRNA and enzyme activity had no significant difference (SMD = 0.02, 95% CI [-0.40, 0.43] and SMD = 0.06, 95% CI [-0.41, 0.53] respectively). Subgroup analyses found that IDE protein level was decreased in both cortex and hippocampus of AD cases (SMD = -0.43, 95% CI [-0.71, -0.16], p = 0.002 and SMD = -0.53, 95% CI [-0.91, -0.15], p = 0.006 respectively). However, IDE mRNA was higher in cortex of AD cases (SMD = 0.71, 95% CI [0.14, 1.29], p = 0.01), not in hippocampus (SMD = -0.26, 95% CI [-0.58, 0.06]). Conclusions: Our results indicate that AD patients may have lower IDE protease level. Further relevant studies are still needed to verify whether IDE is one of the factors affecting Aβ abnormal accumulation and throw new insights for AD detection or therapy.

Acupuncture plus Herbal Medicine for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

2017 ◽  
Vol 45 (07) ◽  
pp. 1327-1344 ◽  
Author(s):  
Simin Zhou ◽  
Lanlan Dong ◽  
Yuan He ◽  
Hong Xiao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chinese Medicine ◽  
Herbal Medicine ◽  
Traditional Chinese Medicine ◽  
Chinese Herbal Medicine ◽  
Meta Analysis ◽  
World Population ◽  
Chinese Herbal ◽  
Significant Difference

Alzheimer’s disease (AD) is associated with the unprecedented aging tendency in our world population and has become a significant health issue. The use of Traditional Chinese Medicine to treat AD has been increasing in recent years. The objective of this meta-analysis is to evaluate the effectiveness of combining acupuncture with herbal medicine to treat AD. Randomized controlled trials (RCTs) of acupuncture plus herbals versus treatment with western drugs for AD were retrieved from 11 databases. The data were extracted by two authors; dichotomous data were expressed as odds ratio (ORs) and 95% confidence intervals (CIs), while continuous data were calculated by mean differences (MDs) with 95% CIs. Although the combined analysis of the score of Activity of Daily Life (ADL) scale MD was [Formula: see text]3.59 (95% CI [Formula: see text]7.18–0.01, [Formula: see text]), which indicates there was no statistically significant difference between the two treatments at reducing the ADL scale score, the pooled results of 12 trials indicated that acupuncture plus Chinese herbal medicine was better than western drugs at improving the effectiveness rate (OR 2.24, 95% CI 1.40–3.56), the combined evidence of 11 articles showed that acupuncture plus Chinese herbal medicine was more effective than western drugs at improving the scores for the Mini Mental State Examination (MMSE) scale (2.10, 95% CI 0.69–3.51, [Formula: see text]) and the traditional Chinese medicine symptom (MD 5.07, 95% CI 3.90–6.25, [Formula: see text]). From the current research results, acupuncture plus herbal medicine may have advantages over western drugs for treating AD. Nevertheless, well-designed RCTs with a larger sample size are required in the future.

scholarly journals Measuring serum oestradiol in women with Alzheimer's disease: the importance of the sensitivity of the assay method

2003 ◽  
pp. 67-72 ◽  
Author(s):  
E Hogervorst ◽  
J Williams ◽  
M Combrinck ◽  
A David Smith
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Robust Regression ◽  
Meta Analysis ◽  
Hormone Replacement ◽  
Assay Method ◽  
Sensitive Assay ◽  
Significant Difference ◽  
Low Levels ◽  
The Difference

OBJECTIVE: Oestrogens could be protective against the development of Alzheimer's disease (AD) but reports on oestrogen levels in AD have been conflicting. DESIGN AND METHODS: A meta-analysis using robust regression was carried out to assess whether the sensitivity of the assays of past studies had affected the reported level of total oestradiol. We had also measured total oestradiol in women with AD (n=66) and controls (n=62) not using hormone replacement therapy. We used two assays for total oestradiol to assess the difference between sensitive (radioimmunoassay with a specific rabbit antibody: 3 pmol/l) and relatively insensitive (immunoassay: 37 pmol/l) assays. RESULTS: Meta-analysis using robust regression indicated that insensitive assays gave higher levels of total oestradiol when many samples fall below the level of sensitivity of the method. Earlier reports of low levels of total oestradiol in AD might be explained by this phenomenon, since total oestradiol levels (using the sensitive assay) in our controls were one third of those reported in the earlier studies. Using the sensitive assay we found that women with AD had significantly (P<0.01) higher levels (26+/-13 pmol/l) of total oestradiol than controls (21+/-13 pmol/l). Using the insensitive assay, there was no significant difference in the levels of total oestradiol. CONCLUSIONS: The sensitivity of the assay determines the reported value of the oestradiol levels. Studies using a sensitive assay do not report significantly lower levels of total oestradiol in women with AD. This weighs against the hypothesis that low levels of total oestradiol are a risk factor for AD.

The Effectiveness and Safety of Chemical Drugs Combined with Acupuncture for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

2021 ◽  
Author(s):  
Shenghua Yu ◽  
Hongjie Liu ◽  
Li Xu ◽  
Yan Zhang ◽  
Yan Ma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Small Sample Size ◽  
Meta Analysis ◽  
Small Sample ◽  
Risk Of Bias ◽  
Disease Assessment ◽  
High Quality ◽  
Significant Difference

Introduction: Acupuncture has been applied with chemical drugs to treat Alzheimer’s disease (AD) in the clinic. Whether such combination is effective and safe should be studied although it is recommended by some researchers.Methods: To explore the effectiveness and safety of acupuncture combined with the chemical drugs for AD, databases like PubMed, Web of Science were searched to retrieve randomized controlled trials (RCTs) on AD treated with acupuncture and chemical drugs to perform meta-analysis. The risk of bias in each study was assessed using the Cochrane Risk of Bias scale. Meta-analysis was performed using RevMan 5.3.Results: Five studies were included in which only donepezil combined with acupuncture was evaluated. Acupuncture combined with donepezil showed a significant difference in effectiveness rate [RR=1.45, 95% CI (1.19, 1.77), P=0.0002] compared with donepezil. On the comparison of mini-mental state examination (MMSE) score and Alzheimer's disease assessment scale cognitive subscale (ADAS-Cog) score there was no difference. However, after one trial with severe AD patients was removed, acupuncture combined with donepezil showed better effect than donepezil alone. Conclusion: Acupuncture combined with donepezil could work on AD at the early stage or with mild AD, implying that acupuncture could be a complementary therapy for AD at early stage or with mild condition. Besides, scalp acupuncture seems to be more effective on improving cognitive function. However, this conclusion must be considered cautiously, given the small sample size and lack of trials of high quality. Therefore, more high-quality, multicenter, prospective, RCTs with large sample sizes are needed to further clarify the effect of acupuncture combined with chemical drugs for AD.

Use of CSF α-synuclein in the differential diagnosis between Alzheimer's disease and other neurodegenerative disorders

2015 ◽  
Vol 27 (9) ◽  
pp. 1429-1438 ◽  
Author(s):  
Zheng-Yu Wang ◽  
Zhen-Min Han ◽  
Qi-Fei Liu ◽  
Wei Tang ◽  
Kui Ye ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Differential Diagnosis ◽  
Neurodegenerative Disorders ◽  
Meta Analysis ◽  
Lewy Bodies ◽  
Cochrane Library ◽  
Random Effects Models ◽  
Significant Difference ◽  
Meta Analyses

ABSTRACTBackground:The etiology and pathogenesis of neurodegenerative disorders has yet to be elucidated, so their differential diagnosis is a challenge. This is especially true in differentiating Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson disease (PD), and multiple system atrophy (MSA).Methods:A total of 11 eligible articles were identified by search of electronic databases including PubMed, Springer Link, Elsevier, and the Cochrane Library, up to June 2014. In meta-analyses, standardized mean differences (SMD), with 95% confidence intervals (CI), comparing cerebrospinal fluid (CSF) measures of α-synuclein between the above conditions were calculated using random-effects models.Results:CSF α-synuclein concentrations were significantly higher in AD compared to DLB [SMD: 0.32, 95% CI: (0.02, 0.62), z = 2.07, P = 0.038]; PD [SMD: 0.87, 95% CI: (0.15, 1.58), z = 2.38, P = 0.017]; or MSA [SMD: 1.14, 95% CI: (0.15, 2.14), z = 2.25, P = 0.025]. However, no significant difference was found between patients with AD and neurological cognitively normal controls [SMD: 0.02, 95% CI: (−0.21, 0.24), z = 0.13, P = 0.894].Conclusions:Results of these meta-analysis suggest that quantification of CSF α-synuclein could help distinguish AD from other neurodegenerative disorders such as DLB, PD, or MSA.

Effect of Apolipoprotein E ɛ4 Carrier Status on Cognitive Response to Acetylcholinesterase Inhibitors in Patients with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

2018 ◽  
Vol 45 (5-6) ◽  
pp. 335-352 ◽  
Author(s):  
Ying-Chih Cheng ◽  
Yu-Chen Huang ◽  
Hsing-Cheng Liu
Keyword(s):  
Systematic Review ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Meta Analysis ◽  
Acetylcholinesterase Inhibitors ◽  
Cognitive Outcomes ◽  
Carrier Status ◽  
Apoe Ε4 ◽  
Significant Difference

Background: The apolipoprotein E ɛ4 (APOE ɛ4) genotype is the major genetic risk factor for Alzheimer’s disease (AD). However, its effect on an individual’s response to treatment is less well understood. Many studies have reported that the presence or absence of APOE ɛ4 may have influence on the therapeutic response for acetylcholinesterase inhibitors (AChEIs), but the results were inconsistent. This study performed a systematic review and meta-analysis to evaluate the association between response of treatment with AChEIs and the APOE ɛ4 carrier status. Methods: Clinical studies with AD patients reporting APOE ɛ4 genotype were included in the analysis. Cognitive outcome was measured by the change in Mini-Mental State Examination (MMSE), cognition subscales of the Alzheimer’s Disease Assessment Scale (ADAS-cog), or Cognitive Abilities Screening Instrument (CASI). A random effects model was employed to calculate the standardized mean difference (SMD) and odds ratio (OR). Results: Of the 284 screened abstracts, 38 studies were identified, 30 of which were included for meta-analysis. Continuous data for assessing the association between APOE ε4 and cognitive outcomes of AChEIs were available from 18 studies. The cognitive outcomes showed no significant difference between APOE ε4 carriers and APOE ε4 non-carriers (SMD = 0.022, 95% CI: –0.089∼0.133, p = 0.702, I2 = 55.3%). Twelve studies with binary data were included, also revealing insignificant difference between the two groups (OR = 1.164, 95% CI: 0.928∼1.459, p = 0.189, I2 = 16.4%). Subgroup analysis indicated that AChEIs were significantly more effective than placebo in both groups. Conclusions: APOE ɛ4 carrier status had no significant influence on the treatment response to AChEIs in patients with AD. AChEIs had a positive therapeutic effect compared with placebo regardless of APOE ε4 carrier status.

Efficacy and safety of idalopirdine for Alzheimer’s disease: a systematic review and meta-analysis

2018 ◽  
Vol 31 (11) ◽  
pp. 1627-1633 ◽  
Author(s):  
Shinji Matsunaga ◽  
Hiroshige Fujishiro ◽  
Hajime Takechi
Keyword(s):  
Systematic Review ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Effect Size ◽  
Meta Analysis ◽  
Disease Assessment ◽  
High Dose ◽  
Significant Heterogeneity ◽  
Elevated Liver Enzymes ◽  
Significant Difference

ABSTRACTObjective:The efficacy and tolerability of idalopirdine, a selective 5-hydroxytryptamine6 receptor antagonist, in patients with Alzheimer’s disease (AD) is uncertain. A systematic review and meta-analysis of randomized controlled trials (RCTs) testing idalopirdine for patients with AD was performed.Methods:We included RCTs of idalopirdine for patients with AD and used Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores as a primary measure.Results:Four RCTs with 2,803 patients with AD were included. There was no significant difference in ADAS-cog between the idalopirdine and placebo groups [mean difference (MD) = −0.41,P= 0.32,I2= 62%]. However, significant heterogeneity remained. Sensitivity analysis revealed that idalopirdine was more effective than placebo for ADAS-cog in the high dose and moderate AD subgroups (high dose subgroup: MD = −2.15,P= 0.005, moderate AD subgroup: MD = −2.15,P= 0.005). Moreover, meta-regression analysis showed that idalopirdine effect size for ADAS-cog was associated with mean dose (coefficient, −0.0289), ADAS-cog at baseline (coefficient, −0.9519), and proportion of male participants (coefficient, 0.2214). For safety outcomes, idalopirdine was associated with a higher incidence of at least one adverse event and increased γ-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase, and vomiting than placebo. There were no significant differences in other secondary outcomes between both treatments.Conclusions:Idalopirdine is not effective for AD patients and is associated with a risk of elevated liver enzymes and vomiting. Although idalopirdine might be more effective at high doses and in moderate AD subgroups, the effect size is small and may be limited.

scholarly journals Improving Drug Trials for Mild to Moderate Alzheimer's Disease

2007 ◽  
Vol 34 (S1) ◽  
pp. S97-S102 ◽  
Author(s):  
David B. Hogan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Significance ◽  
Treatment Effects ◽  
Controlled Trials ◽  
Drug Trials ◽  
Open Label ◽  
Regulatory Authorities ◽  
Open Label Extension

Over the last two decades, numerous studies have been conducted on subjects with mild to moderate Alzheimer's disease. The objective of this paper was to review concerns raised in the literature about the design and methodology of these clinical trials and to make recommendations to deal with the limitations identified. Concerns raised in the literature include the following: undue focus on statistical rather than clinical significance; the need for further pharmacoeconomic evaluations; the nonrepresentativeness of the study populations; perceived inadequacies in the direct-comparison studies conducted to date; the limitations of open-label extension studies; the inability of standard psychometric tools to document all the relevant treatment effects; the ethics of placebo-controlled trials; and, problems caused by the actions of the regulatory authorities. Recommendations are made to deal with the issues raised.

scholarly journals The Effectiveness and Tolerability of the High Dose Donepezil at 23 mg Tablet per Day for Alzheimer’s Disease: A Meta-analysis of Randomized Controlled Trials

2020 ◽  
Vol 54 (3) ◽  
Author(s):  
Adrian I. Espiritu ◽  
Alvin Rae F. Cenina
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Clinical Status ◽  
Controlled Trials ◽  
High Dose ◽  
Randomized Controlled ◽  
Significant Difference

Objective. To assess the effectiveness and tolerability of the 23 mg tablet donepezil in patients with Alzheimer’s disease (AD) using meta-analysis of randomized controlled trials. Methods. Major healthcare databases were searched from May to September 2016. Evaluation of relevant trials, assessment of risk of bias, collection and analyses of data were performed. Results. A total of 1,774 adult participants with AD were pooled from the two trials included. Pooled data showed that after 24 weeks of treatment, no significant difference was noted between Donepezil 23 mg/day and Donepezil 10 mg/day in terms of cognitive function (1.06 SIB points [-0.13, 2.26]; 1704 participants) and in terms of global clinical assessment (-0.02 CIBIC+ points [-0.13, 0.09]; 1705 participants). The participants who took the higher dose were at higher risk to experience “any adverse event” than those who received the lower dose (1.17 RR [1.09, 1.26]; 1785 participants). Conclusion. Current evidences do not support the routine use of Donepezil 23 mg tablet for the improvement of cognitive function and global clinical status of patients with AD. The higher dose is also marked with an increased incidence of adverse events compared to the lower dose.

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