Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer’s Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study

Gold, Michael; Alderton, Claire; Zvartau-Hind, Marina; Egginton, Sally; Saunders, Ann M.; Irizarry, Michael C.; Craft, Suzanne; Landreth, Gary E.; Linnamägi, Ülla; Sawchak, Sharon

doi:10.1159/000318845

Cited by 309 publications

(228 citation statements)

References 104 publications

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“…The majority of trials (n = 94) used at least one cognitive outcome, 25,27-29, 51,52,55,57,64,66,68,75,78,[86][87][88][89][90][91][92][93]97,104,106,107,110,112,115,118,119,121,123,125,126,130,131,133,134,[137][138][139][140]143,145,146 with a variety of 16 measures used. ADLs were measured in 55 trials, using 12 measures.…”

Section: Published Trialsmentioning

confidence: 99%

“…ADLs were measured in 55 trials, using 12 measures. 27,28,33,37,41,45,46,49,51,52,54,55,57,59,61,63,64,66,68,77,78,81,[85][86][87][88][89][90]92,97,104,[106][107][108][110][111][112]114,115,118,119,[121][122][123][124][125]128,134,135,137,138,[142][143][144][145] Biological markers were measured in 51 trials using a variety of nine biological t...…”

Section: Published Trialsmentioning

confidence: 99%

“…29,31,33,37,40,43,47,[53][54][55]59,63,66,[68][69][70][71]73,77,78,81,85,86,89,93,95,96,98,101,[103][104][105][109][110][111][112][113]115,116,121,122,[129][130][131][132]137,[139][140][141]144,145 Eleven of the published trials measured quality of life, using one of three outcomes. 28,33,66,68,78,…”

Section: Published Trialsmentioning

confidence: 99%

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Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Webster

Groskreutz

Grinbergs-Saull

et al. 2017

Health Technol Assess

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Background: There is currently no disease-modifying treatment available to halt or delay the progression of the disease pathology in dementia. An agreed core set of the best-available and most appropriate outcomes for disease modification would facilitate the design of trials and ensure consistency across disease modification trials, as well as making results comparable and meta-analysable in future trials. Objectives: To agree a set of core outcomes for disease modification trials for mild to moderate dementia with the UK dementia research community and patient and public involvement (PPI). Data sources: We included disease modification trials with quantitative outcomes of efficacy from (1) references from related systematic reviews in workstream 1; (2) searches of the Cochrane Dementia and Cognitive Improvement Group study register, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Latin American and Caribbean Health Sciences Literature and PsycINFO on 11 December 2015, and clinical trial registries [International Standard Randomised Controlled Trial Number (ISRCTN) and clinicaltrials.gov] on 22 and 29 January 2016; and (3) hand-searches of reference lists of relevant systematic reviews from database searches. Review methods: The project consisted of four workstreams. (1) We obtained related core outcome sets and work from co-applicants. (2) We systematically reviewed published and ongoing disease modification trials to identify the outcomes used in different domains. We extracted outcomes used in each trial, recording how many used each outcome and with how many participants. We divided outcomes into the domains measured and searched for validation data. (3) We consulted with PPI participants about recommended outcomes. (4) We presented all the synthesised information at a conference attended by the wider body of National Institute for Health Research (NIHR) dementia researchers to reach consensus on a core set of outcomes. Results: We included 149 papers from the 22,918 papers screened, referring to 125 individual trials. Eighty-one outcomes were used across trials, including 72 scales [31 cognitive, 12 activities of daily living (ADLs), 10 global, 16 neuropsychiatric and three quality of life] and nine biological techniques. We consulted with 18 people for PPI. The conference decided that only cognition and biological markers are core measures of disease modification. Cognition should be measured by the Mini Mental State Examination (MMSE) or the Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog), and brain changes through structural magnetic resonance imaging (MRI) in a subset of participants. All other domains are important but not core. We recommend using the Neuropsychiatric Inventory for neuropsychiatric symptoms: the Disability Assessment for Dementia for ADLs, the Dementia Quality of Life Measure for quality of life and the Clinical Dementia Rating scale to measure dementia globally. Limitations: Most of the trials inclu...

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Section: Published Trialsmentioning

confidence: 99%

Section: Published Trialsmentioning

confidence: 99%

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Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Webster

Groskreutz

Grinbergs-Saull

et al. 2017

Health Technol Assess

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“…Anti-diabetic agent rosiglitazone which is a PPAR agonist was used in a Phase III clinical trial because it reduces ϐ-amyloid pathology and inflammation in animal models of AD [37]. In diabetes 2 rats and streptozotocin injected diabetic mice, rosiglitazone (RSG) reduced tau phosphorylation and also is associated with reduction of JNK activity and not of GSK3ϐ activity [38].…”

Section: Tau Hyperphosphorylation and Insulin Resistance Via Pparsmentioning

confidence: 99%

Hyperphosphorylation of Tau Protein in Down ’s Dementia and Alzheimer’s Disease: Methylation and Implications in Prevention and Therapy

Nichols¹

2014

J Alzheimers Dis Parkinsonism

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The changes of insulin signaling, calcium signaling, mitochondrial decline and oxidative stress have been implicated in the hyperphosphorylation of tau protein found in Downs syndrome dementia. Such pathogenic etiologies have clear implications in the prevention and therapy of Down's syndrome (DS) dementia. The occurrence of methylation defects in DS is discussed and though controversial, more recent studies do show significance. Kinases such as DYK1A and GlcNA cylation are discussed as well as a Cdk5 inhibitory peptide (CIP). Even sleep medicine has been demonstrated in that seniors, who have better sleep, suffer less cognitive decline than those with sleep problems with enhanced clearance of β amyloid and tau neurofibrillary tangles. Studies have reported a high incidence of sleep problems in Down's. Environmental toxin arsenite and low dose methyl mercury have been speculated to induce tau phosphorylation. Dietary changes to low glycemic carbohydrate and gluten avoidance should be made. Adding B vitamins may be equally important to prevent brain atrophy especially in those with MTHFR and MTRR gene defects. The therapeutic strategy of reducing insulin resistance by up regulation of PPARS alpha with glitazones and decreasing calcium influx into the mitochondria is mentioned. Protecting mitochondrial decline from oxidative stress with antioxidants, and treatment with CBD, polyphenols, ellagic acid, resveratrol and other grape bioflavinoids and moderate magnetic fields is discussed.

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“…However, subgroup analyses stratified by ApoE genotype in clinical trials of TZD have not fully determined whether ApoE gene polymorphisms affect therapeutic response because the results of previous reports were contradictory and inconclusive. [21][22][23] Therefore, we conducted a systematic re-view and meta-analysis on previous clinical studies to examine whether ApoE gene polymorphisms affect the efficacy of TZD for AD.…”

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confidence: 99%

Apolipoprotein E Gene Polymorphisms Affect the Efficacy of Thiazolidinediones for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Iketani

Ohno

Kawasaki

et al. 2018

Biological & Pharmaceutical Bulletin

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Although several studies have evaluated the efficacy of thiazolidinediones (TZD) for the treatment of Alzheimer's disease (AD), investigation of the impact of apolipoprotein E (ApoE) gene polymorphisms on the efficacy of TZD remains insufficient. We investigated the impact by conducting a systematic review and meta-analysis. MEDLINE, Cochrane Library, and Japana Centra Revuo Medicina were searched to identify relevant studies based on eligibility criteria. Mean differences (MD) of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score with 95% confidence intervals (CI) were calculated for subgroups stratified by ApoE genotype. To evaluate the impact of ApoE gene polymorphisms, meta-regression analysis was also conducted to calculate the regression coefficient (Coef) of ApoE expression status with 95% CI. Three randomized controlled studies comparing rosiglitazone and placebo, with a total of 2381 subjects met the eligibility criteria. Key words Alzheimer's disease; meta-analysis; meta-regression analysis; rosiglitazone; systematic review; thiazolidinedione Dementia affects an estimated 47.5 million individuals worldwide, 60-70% of whom have Alzheimer's disease (AD). 1) Currently, although some drugs such as choline esterase inhibitors and memantine are used for treating AD, their efficacy is limited to delaying disease progression or relieving symptoms. 2) One reason for these limitations may be the fact that AD pathogenesis remains unclear. Therefore, despite the lack of established treatment, drug development has faced difficulties. 3) Several recent studies have reported an association between AD and diabetes mellitus (DM). [4][5][6] These studies demonstrated insulin resistance in the central nervous system (CNS) in some AD patients, which contributed to impaired cognitive functions. This association has been termed type 3 DM. 5,7) Based on this hypothesis, some studies were conducted to investigate the efficacy of anti-diabetic agents for the treatment of AD. 8-11) Among these agents, thiazolidinediones (TZD) exhibited various favorable effects in in vitro and in vivo studies. [10][11][12][13][14] These agents contributed to clearing of amyloid beta protein through apolipoprotein E (ApoE) function. 14) Some reports of clinical trials indicate that TZD improved cognitive function in AD patients. [15][16][17] Additionally, a systematic review and meta-analysis concluded that the efficacy of TZD was significant. 18) Although the efficacy of TZD has been demonstrated, the clinical relevance is limited because the efficacy is lower than that of choline esterase inhibitors.ApoE is a lipoprotein that has genetic polymorphisms (ApoE2, ApoE3, and ApoE4). 19,20) The wild-type ApoE3 constitutes 50-90% of individuals, whereas ApoE4 that constitutes 5-35% of individuals is known to be a genetic risk factor of AD. 19) A clinical trial using intranasal insulin for AD showed improved cognitive function in ApoE4-negative AD patients following short-term intranasal insulin treatment, 8) suggesting tha...

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Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer’s Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study

Cited by 309 publications

References 104 publications

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Hyperphosphorylation of Tau Protein in Down ’s Dementia and Alzheimer’s Disease: Methylation and Implications in Prevention and Therapy

Apolipoprotein E Gene Polymorphisms Affect the Efficacy of Thiazolidinediones for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

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