P1‐112: Effects of 12 months of treatment with the PPARγ agonist rosiglitazone on brain glucose metabolism in Alzheimer's Disease: A <sup>18</sup>F‐FDG PET study

Rabiner, Eugenii A.; Tzimopoulou, Sofia; Cunningham, Vincent J.; Jeter, Barbara; Zvartau-Hind, Marina; Castiglia, Mary; Mistry, Praful; Bird, Nick; Matthews, Julian C.; Whitcher, Brandon; Nichols, Thomas E.; Lai, Robert; Lotay, Narinder; Saunders, Ann M.; Reiman, Eric M.; Chen, Kewei; Gold, Mike; Matthews, Paul M.

doi:10.1016/j.jalz.2009.04.117

Cited by 7 publications

(5 citation statements)

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“…However a recent phase III trial of rosiglitazone (NCT00428090) in mild to moderate LOAD failed to show a benefit. (38). It is possible however that the use of thiazolidinediones in mild cognitive impairment could improve the risk of dementia.…”

Section: Implications Of the Relation Between T2d And Dementiamentioning

confidence: 99%

Diabetes, related conditions, and dementia

Luchsinger

2010

Journal of the Neurological Sciences

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This manuscript provides a brief review of the epidemiologic evidence linking type 2 diabetes (T2D) and its precursor conditions, elevated adiposity and hyperinsulinemia, to dementia. Elevated adiposity in middle age is related to a higher risk of dementia but the data on this association in old age is conflicting. Hyperinsulinemia, a consequence of higher adiposity and insulin resistance is also related to a higher risk of dementia, including late onset Alzheimer's disease (LOAD). Studies have consistently shown a relation of T2D with higher dementia risk, but the associations are stronger for vascular dementia compared to LOAD. One implication of these associations is that strategies used to prevent T2D can be used to prevent dementia. Several studies in the prevention and treatment of T2D are currently measuring cognitive outcomes and will provide information on whether T2D treatment and prevention can prevent cognitive decline and dementia.

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Section: Implications Of the Relation Between T2d And Dementiamentioning

confidence: 99%

Diabetes, related conditions, and dementia

Luchsinger

2010

Journal of the Neurological Sciences

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“…In the case of rosiglitazone, APOE allowed the identification of a potentially responsive subset of participants, thus enabling Phase III trials with patient subpopulations stratified by ε4 status [133,134]. Although the Phase III trial was negative, pharmacogenomic strategies are likely to continue to be explored in AD treatment and prevention trials [135]. Broad support of genomic-based approaches, including from research funders and advocacy groups, will be necessary to accelerate discovery of effective prevention strategies in this area.…”

Section: Future Perspective On Ad Risk Assessmentmentioning

confidence: 99%

Estimating and disclosing the risk of developing Alzheimer‘s disease: challenges, controversies and future directions

Roberts

Tersegno

2010

Future Neurol.

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With Alzheimer’s disease increasing in prevalence and public awareness, more people are becoming interested in learning their chances of developing this condition. Disclosing Alzheimer’s disease risk has been discouraged because of the limited predictive value of available tests, lack of prevention and treatment options, and concerns regarding potential psychological and social harms. However, challenges to this status quo include the availability of direct-to-consumer health risk information (e.g., genetic susceptibility tests), as well as a growing literature suggesting that people seeking risk information for Alzheimer’s disease through formal education and counseling protocols generally find it useful and do not experience adverse effects. This paper reviews current and potential methods of risk assessment for Alzheimer’s disease, discusses the process and impact of disclosing risk to interested patients and consumers, and considers the practical and ethical challenges in this emerging area. Anticipated future directions are addressed.

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“…[25][26][27][28][29][30] Recently, a phase III clinical study with the brain-impermeable PPARγ agonist rosiglitazone failed to demonstrate efficacy in patients with established AD. 31 However, PPARγ agonists might be able to counteract the increased AD risk in patients with type 2 diabetes, and in fact, ongoing treatment and prevention trials for type 2 diabetes include cognition ancillary studies. 24 In this respect, a pilot study with the PPARγ agonist pioglitazone has provided evidence for cognitive stabilization in AD patients with concurrent type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, a recent cross of an AD mouse model to leptin-deficient diabetic mice revealed accelerated learning deficits and severe cerebrovascular amyloid deposition . Importantly, individuals with type 2 diabetes appear to have a 2-fold increased risk of developing AD. , Potential direct effects of PPARγ agonists on brain pathology in AD include lowering of Aβ levels, suppression of toxic proinflammatory mediators, and reduction of cerebrovascular impairment. − Recently, a phase III clinical study with the brain-impermeable PPARγ agonist rosiglitazone failed to demonstrate efficacy in patients with established AD . However, PPARγ agonists might be able to counteract the increased AD risk in patients with type 2 diabetes, and in fact, ongoing treatment and prevention trials for type 2 diabetes include cognition ancillary studies .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity

et al. 2010

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We present a novel class of dual modulators of gamma-secretase and peroxisome proliferator-activated receptor gamma (PPARgamma) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC(50)(Abeta42) = 22.8 microM, EC(50)(PPARgamma) = 8.3 microM). The modulation of both targets with approved drugs (i.e., amyloid-beta 42 (Abeta42)-lowering NSAIDs for gamma-secretase and glitazones for PPARgamma) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer's disease (AD). However, although NSAIDs and PPARgamma agonists share similar structural features, no druglike compounds with dual activities as gamma-secretase modulators (GSMs) and PPARgamma agonists have been designed so far. On the basis of our initial lead structure 8, we present the structure-activity relationships (SARs) of broad structural variations. A significant improvement was reached by the introduction of p-trifluoromethyl substituents at the phenyl residues yielding compound 16 (IC(50)(Abeta42) = 6.0 microM, EC(50)(PPARgamma) = 11.0 microM) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC(50)(Abeta42) = 5.1 microM, EC(50)(PPARgamma) = 6.6 microM).

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P1‐112: Effects of 12 months of treatment with the PPARγ agonist rosiglitazone on brain glucose metabolism in Alzheimer's Disease: A ¹⁸F‐FDG PET study

Cited by 7 publications

References 1 publication

Diabetes, related conditions, and dementia

Diabetes, related conditions, and dementia

Estimating and disclosing the risk of developing Alzheimer‘s disease: challenges, controversies and future directions

Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity

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P1‐112: Effects of 12 months of treatment with the PPARγ agonist rosiglitazone on brain glucose metabolism in Alzheimer's Disease: A 18F‐FDG PET study

Cited by 7 publications

References 1 publication

Diabetes, related conditions, and dementia

Diabetes, related conditions, and dementia

Estimating and disclosing the risk of developing Alzheimer‘s disease: challenges, controversies and future directions

Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity

Contact Info

Product

Resources

About

P1‐112: Effects of 12 months of treatment with the PPARγ agonist rosiglitazone on brain glucose metabolism in Alzheimer's Disease: A ¹⁸F‐FDG PET study