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Anton P Porsteinsson - One of the best experts on this subject based on the ideXlab platform.
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memantine treatment in patients with mild to moderate Alzheimers Disease already receiving a cholinesterase inhibitor a randomized double blind placebo controlled trial
Current Alzheimer Research, 2008Co-Authors: Anton P Porsteinsson, George T Grossberg, Jacobo E Mintzer, Jason T OlinAbstract:Objective: To evaluate the efficacy and safety of memantine in patients with mild to moderate Alzheimers Disease (AD) receiving cholinesterase inhibitor (ChEI) treatment. Methods: Participants (N= 433) with probable AD, Mini-Mental State Exam (MMSE) scores between 10-22 (inclusive), and concurrent stable use of ChEIs (donepezil, rivastigmine, galantamine) were randomized to placebo or memantine (20 mg once daily) for 24 weeks. Primary outcomes were changes from baseline on the Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-cog) and on Clinicians Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) score. Secondary measures comprised the 23-item Alzheimer Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL23), Neuropsychiatric Inventory (NPI), and MMSE. Results: At the end of the trial, there were no statistically significant differences between the memantine- and placebo group on primary and secondary outcome measures. The incidence of adverse events (AEs) was similar between the two groups, with no AE occurring in more than 5% of memantine-treated patients and at a rate twice that of the placebo group. Conclusions: In this trial, memantine did not show an advantage over placebo based on protocol- specified primary or secondary analyses in patients with mild to moderate AD on stable ChEI regimens. There were no significant differences in tolerability and safety between the memantine- and placebo groups.
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a randomized double blind placebo controlled pilot trial of safety and tolerability of two doses of divalproex sodium in outpatients with probable Alzheimers Disease
Current Alzheimer Research, 2005Co-Authors: Louis A Profenno, Anton P Porsteinsson, Laura Jakimovich, Connie Holt, Pierre N TariotAbstract:OBJECTIVE: The Alzheimers Disease Cooperative Study (ADCS) is conducting a clinical trial to address whether chronic valproate treatment can delay emergence of behavioral symptoms in outpatients with AD. Since there were no data on the safety and tolerability of divalproex sodium in outpatients with dementia, we undertook a pilot study to inform the design of the ADCS study. METHODS: We recruited 20 outpatients with probable AD, MMSE 10-20, without history of agitation or psychosis. This was a 10-week randomized, double-blind, placebo-controlled study assessing the safety and tolerability of 1,000 mg/day and 1,500 mg/day of divalproex sodium delayed-release for 8 weeks followed by extended-release for 2 weeks. Other outcome measures addressed cognition, function, global status, side effects, and laboratory data. RESULTS: Participants assigned to active treatment ingested approximately 30% less of their prescribed study medication compared to those receiving placebo (p < .05 Wilcoxon Rank Sum test). The average tolerated dose for all participants at week 8 was 810 mg/day or 11.5 mg/kg/day, similar to the dose tolerated by nursing home patients. The most common side effects were sleepiness and tiredness, with worse cognitive performance in those assigned to 1500 mg/day. CONCLUSIONS: These results were used to design the multi-center ADCS trial. Doses of less than 1000 mg/day of divalproex sodium were the maximum tolerated by these outpatients with AD. A larger study of divalproex sodium dose tolerability is needed to define treatment in outpatients with Alzheimers Disease.
Pierre N Tariot - One of the best experts on this subject based on the ideXlab platform.
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a randomized double blind placebo controlled pilot trial of safety and tolerability of two doses of divalproex sodium in outpatients with probable Alzheimers Disease
Current Alzheimer Research, 2005Co-Authors: Louis A Profenno, Anton P Porsteinsson, Laura Jakimovich, Connie Holt, Pierre N TariotAbstract:OBJECTIVE: The Alzheimers Disease Cooperative Study (ADCS) is conducting a clinical trial to address whether chronic valproate treatment can delay emergence of behavioral symptoms in outpatients with AD. Since there were no data on the safety and tolerability of divalproex sodium in outpatients with dementia, we undertook a pilot study to inform the design of the ADCS study. METHODS: We recruited 20 outpatients with probable AD, MMSE 10-20, without history of agitation or psychosis. This was a 10-week randomized, double-blind, placebo-controlled study assessing the safety and tolerability of 1,000 mg/day and 1,500 mg/day of divalproex sodium delayed-release for 8 weeks followed by extended-release for 2 weeks. Other outcome measures addressed cognition, function, global status, side effects, and laboratory data. RESULTS: Participants assigned to active treatment ingested approximately 30% less of their prescribed study medication compared to those receiving placebo (p < .05 Wilcoxon Rank Sum test). The average tolerated dose for all participants at week 8 was 810 mg/day or 11.5 mg/kg/day, similar to the dose tolerated by nursing home patients. The most common side effects were sleepiness and tiredness, with worse cognitive performance in those assigned to 1500 mg/day. CONCLUSIONS: These results were used to design the multi-center ADCS trial. Doses of less than 1000 mg/day of divalproex sodium were the maximum tolerated by these outpatients with AD. A larger study of divalproex sodium dose tolerability is needed to define treatment in outpatients with Alzheimers Disease.
Jason T Olin - One of the best experts on this subject based on the ideXlab platform.
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memantine treatment in patients with mild to moderate Alzheimers Disease already receiving a cholinesterase inhibitor a randomized double blind placebo controlled trial
Current Alzheimer Research, 2008Co-Authors: Anton P Porsteinsson, George T Grossberg, Jacobo E Mintzer, Jason T OlinAbstract:Objective: To evaluate the efficacy and safety of memantine in patients with mild to moderate Alzheimers Disease (AD) receiving cholinesterase inhibitor (ChEI) treatment. Methods: Participants (N= 433) with probable AD, Mini-Mental State Exam (MMSE) scores between 10-22 (inclusive), and concurrent stable use of ChEIs (donepezil, rivastigmine, galantamine) were randomized to placebo or memantine (20 mg once daily) for 24 weeks. Primary outcomes were changes from baseline on the Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-cog) and on Clinicians Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) score. Secondary measures comprised the 23-item Alzheimer Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL23), Neuropsychiatric Inventory (NPI), and MMSE. Results: At the end of the trial, there were no statistically significant differences between the memantine- and placebo group on primary and secondary outcome measures. The incidence of adverse events (AEs) was similar between the two groups, with no AE occurring in more than 5% of memantine-treated patients and at a rate twice that of the placebo group. Conclusions: In this trial, memantine did not show an advantage over placebo based on protocol- specified primary or secondary analyses in patients with mild to moderate AD on stable ChEI regimens. There were no significant differences in tolerability and safety between the memantine- and placebo groups.
Mark A Sanner - One of the best experts on this subject based on the ideXlab platform.
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tau protein phosphorylation as a therapeutic target in Alzheimers Disease
Current Topics in Medicinal Chemistry, 2002Co-Authors: Litfui Lau, Joel B Schachter, Patricia A Seymour, Mark A SannerAbstract:Neurofibrillary tangles (NFTs) are a distinguishing neuropathological feature found in postmortem brains of Alzheimers Disease (AD) and tauopathy patients. The density of these lesions correlates with severity of AD and their distribution follows a characteristic pattern of expansion as the Disease progresses. The principle components of NFTs are highly phosphorylated forms of the microtubule-associated protein, tau. Tau phosphorylation is believed to initiate or facilitate dissociation from microtubules leading to microtubule destabilization, decay of cellular transport properties, and cell death. This review summarizes recent data and prevailing views on the roles of protein kinases and phosphatases in the regulation of tau phosphorylation in vitro and in vivo, taking into account data from human neurodegenerative Diseases and from transgenic rodent models. Small molecule inhibitors of tau phosphorylation that serve as important research tools and possibly the basis of potential new therapeutics, are also described. Key challenges in developing effective therapeutic agents include identification of the relevant kinase(s) responsible for aberrant tau phosphorylation in AD, synthesis of inhibitors selectively targeting those kinases and establishment of appropriate animal models.
Julia E Crook - One of the best experts on this subject based on the ideXlab platform.
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expression of sorl1 and a novel sorl1 splice variant in normal and Alzheimers Disease brain
Molecular Neurodegeneration, 2009Co-Authors: Karrie E Grear, Ifang Ling, James Simpson, Jennifer L Furman, Christopher R Simmons, Shawn Peterson, Frederick A Schmitt, William R Markesbery, Qiangqiang Liu, Julia E CrookAbstract:Background: Variations in sortilin-related receptor (SORL1) expression and function have been implicated in Alzheimers Disease (AD). Here, to gain insights into SORL1, we evaluated SORL1 expression and splicing as a function of AD and AD neuropathology, neural gene expression and a candidate single nucleotide polymorphism (SNP). Results: To identify SORL1 splice variants, we scanned each of the 46 internal SORL1 exons in human brain RNA samples and readily found SORL1 isoforms that lack exon 2 or exon 19. Quantification in a case-control series of the more abundant isoform lacking exon 2 (delta-2-SORL1), as well as the "full-length" SORL1 (FL-SORL1) isoform containing exon 2 showed that expression of FL-SORL1 was reduced in AD individuals. Moreover, FLSORL1 was reduced in cognitively intact individuals with significant AD-like neuropathology. In contrast, the expression of the delta-2-SORL1 isoform was similar in AD and non-AD brains. The expression of FL-SORL1 was significantly associated with synaptophysin expression while delta-2-SORL1 was modestly enriched in white matter. Lastly, FL-SORL1 expression was associated with rs661057, a SORL1 intron one SNP that has been associated with AD risk. A linear regression analysis found that rs661057, synaptophysin expression and AD neuropathology were each associated with FL-SORL1 expression. Conclusion: These results confirm that FL-SORL1 expression declines in AD and with AD-associated neuropathology, suggest that FL-SORL1 declines in cognitively-intact individuals with AD-associated neuropathology, identify a novel SORL1 splice variant that is expressed similarly in AD and non-AD individuals, and provide evidence that an AD-associated SNP is associated with SORL1 expression. Overall, these results contribute to our understanding of SORL1 expression in the human brain.