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Martin R Farlow

Publications and source records attributed to Martin R Farlow.

At least 19 recordsLinked to original sources
PubMed2025

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

Humans↗
PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition.

BACKGROUND: Decreased cerebrospinal fluid (CSF) beta-amyloid 42 (A beta 42) concentration, but not A beta 40 concentration, is a biomarker for Alzheimer disease. This A beta 42 concentration decrease in CSF likely reflects precipitation of A beta 42 in amyloid plaques in brain parenchyma. This pathogenic plaque deposition begins years before the clinical expression of dementia in Alzheimer disease. Normal aging and the presence of the apolipoprotein E (APOE*4) allele are the most important known risk factors for Alzheimer disease. OBJECTIVE: To estimate the interactive effects of normal aging and presence of the APOE*4 allele on CSF A beta 42 concentration in adults with normal cognition across the life span. DESIGN: The CSF was collected in the morning after an overnight fast using Sprotte 24-g atraumatic spinal needles. The CSF A beta 42 and A beta 40 concentrations were measured in the 10th milliliter of CSF collected by sandwich enzyme-linked immunosorbent assay. The APOE genotype was determined by a restriction digest method. Subjects One hundred eighty-four community volunteers with normal cognition aged 21 to 88 years. RESULTS: The CSF A beta 42, but not the A beta 40, concentration decreased significantly with age. There was a sharp decrease in CSF A beta 42 concentration beginning in the sixth decade in subjects with the APOE*4 allele. This age-associated decrease in CSF A beta 42 concentration was significantly and substantially greater in subjects with the APOE*4 allele compared with those without the APOE*4 allele. CONCLUSION: These CSF A beta 42 findings are consistent with acceleration by the APOE*4 allele of pathogenic A beta 42 brain deposition starting in later middle age in persons with normal cognition.

Adult↗
PubMed2006

Quantitative analysis of amyloid beta peptides in cerebrospinal fluid of Alzheimer's disease patients by immunoaffinity purification and stable isotope dilution liquid chromatography/negative electrospray ionization tandem mass spectrometry.

The 40 and 42 amino-acid residue forms of amyloid beta (Abeta(1-40) and Abeta(1-42)) in cerebrospinal fluid (CSF) have been proposed as potential biomarkers of Alzheimer's disease (AD). Quantitative analyses of Abeta peptides in CSF have relied almost exclusively on the use of immunoassay-based assays such as the enzyme-linked immunosorbent assay (ELISA) procedure. However, due to the ability of the Abeta peptides to readily self-aggregate or bind to other proteins and glassware, such analyses are extremely challenging. Analyses are further complicated by the potential of the peptides to undergo post-translational modifications and the possibilities for cross-reaction in the ELISA assays with endogenous components of the CSF. An approach based on liquid chromatography/tandem mass spectrometry (LC/MS/MS) has now been developed which overcomes these methodological issues. The key steps in implementing this new approach involved immunoaffinity purification coupled with the use of [15N]-labeled Abeta peptides as internal standards, a basic LC mobile phase, negative ion electrospray ionization, and a basic solvent for dissolving the peptides and washing the injection needle to prevent carryover of analytes during multiple injections on the LC/MS system. The validated method had limits of quantitation of 44 fmol/mL (200 pg/mL) for Abeta(1-42) and 92 fmol/mL (400 pg/mL) for Abeta(1-40). An excellent correlation was found between the LC/MS/MS assay and an ELISA assay for Abeta(1-42) in human CSF (r2 = 0.915), although less correlation was observed for Abeta(1-40) (r2 = 0.644). Mean CSF Abeta(1-42) concentrations for samples collected 2 weeks apart from a limited number of AD patients provided additional confidence in the reproducibility of the LC/MS/MS assay. Concentrations for duplicate samples from AD patients were slightly higher than most previously reported values (mean 1.06 +/- 0.25 ng/mL; n = 7). Abeta(1-40) concentrations in duplicate samples obtained from AD patients were also reproducible but were found to be slightly lower than most previously reported values (mean 6.36 +/- 3.07 ng/mL; n = 7). Consistent with literature reports, mean Abeta(1-42) concentrations were found to be lower in AD patients compared with the normal subjects (mean 1.49 +/- 0.59 ng/mL; n = 7), whereas there was no difference in Abeta(1-40) concentrations between AD patients and normal subjects (mean 5.88 +/- 3.03 ng/mL; n = 7). The accuracy and precision of the LC/MS assay mean that it will be a useful complement to existing ELISA assays for monitoring therapeutic interventions designed to modulate CSF Abeta(1-42) concentrations in individual AD patients. Moreover, the introduction of stable isotope labeled internal standards offers the potential to achieve a more rigorous account of the influence of methodological effects related to sample collection and processing.

Alzheimer Disease↗
PubMed2006

Recommendations for best practices in the treatment of Alzheimer's disease in managed care.

BACKGROUND: Alzheimer's disease and related dementias (ADRDs) are increasingly recognized as important causes of impaired cognition, function, and quality of life, as well as excess medical care utilization and costs in the elderly Medicare managed care population. Evidence-based clinical practice guidelines for ADRDs were published in 2001. More recent studies have resulted in the approval of new agents and demonstrated an expanded role for antidementia therapy in various types of dementia, settings of care, stages of disease, and the use of combination therapy. However, these clinical guidelines have not been updated in the past few years. OBJECTIVE: The goal of this article was to provide practical recommendations developed by a panel of experts that address issues of early diagnosis, treatment, and care management of ADRDs. The panel also addressed the societal and managed care implications. METHODS: A panel of leading experts was convened to develop consensus recommendations for the treatment and management of dementia based on currently available evidence and the panel's informed expert opinion. The panel comprised 12 leading experts, including clinical investigators and practitioners in geriatric medicine, neurology, psychiatry, and psychology; managed care medical and pharmacy directors; a health systems medical director; and a health policy expert. In addition, articles were collected based on PubMed searches (2000-2005) that were relevant to the key issues identified. Search terms included Alzheimer's disease, dementia, clinical practice guidelines, clinical trials, screening and assessment, and managed care. RESULTS: ADRDs represent a significant clinical and economic burden to individuals and society, including Medicare managed care organizations (MCOs). Appropriate utilization of antidementia therapy and care management is vitally important to achieving quality of life and care for dementia patients and their caregivers, and for managing the excess costs of Alzheimer's disease. The recommendations address relevant, practical, and timely concerns that are faced on a daily basis by practitioners and by Medicare MCO medical management programs in the care of dementia patients. These consensus recommendations attempt to describe a reasonable current standard for the provision of quality care for patients with dementia. The panel recommendations support the use of screening for cognitive impairment and the use of antidementia therapy for ADRDs in different stages of disease and types of dementia in all clinical settings. The panel members evaluated the use of the 3 marketed cholinesterase inhibitors-donepezil, galantamine, and rivastigmine-as well as the N-methyl-D-aspartate antagonist memantine. Recommendations for using these medications are made with an appreciation of the difficulties in translating the results from investigational clinical trials into clinical practice. CONCLUSIONS: The recommendations of the expert panel represent a clear consensus that nihilism in the diagnosis, treatment, and management of ADRDs is unwarranted, impairs quality of care, and is ultimately not costeffective.

Aged↗
PubMed2006

High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression.

Autism is characterized by restricted, repetitive behaviors and impairment in socialization and communication. Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor (BDNF) in neuropathologic and blood studies favor an anabolic state. We examined acetylcholinesterase, plasma neuronal proteins, secreted beta-amyloid precursor protein (APP), and amyloid-beta 40 and amyloid-beta 42 peptides in children with and without autism. Children with severe autism and aggression expressed secreted beta-amyloid precursor protein at two or more times the levels of children without autism and up to four times more than children with mild autism. There was a trend for children with autism to show higher levels of secreted beta-amyloid precursor protein and nonamyloidogenic secreted beta-amyloid precursor protein and lower levels of amyloid-beta 40 compared with controls. This favors an increased alpha-secretase pathway in autism (anabolic), opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found.

Acetylcholinesterase↗
PubMed2006

Use of antidementia agents in vascular dementia: beyond Alzheimer disease.

Vascular dementia (VaD) is the second leading cause of dementia and is often underdiagnosed. Stroke is the leading cause of VaD, although it may also develop secondary to a variety of other cerebrovascular or cardiovascular conditions. Currently, no drugs are approved for the treatment of VaD. However, because cholinergic deficits have been found in patients with VaD, similar to those found in patients with Alzheimer disease (AD), it is believed that cholinesterase inhibitors, which are indicated for the treatment of mild to moderate AD, may also provide benefit for patients with VaD. Clinical trials of donepezil, galantamine, and rivastigmine have supported this idea, although as yet, large-scale, prospective studies in VaD have only been reported for donepezil. Donepezil was shown to provide benefits in cognition, global function, and activities of daily living compared with placebo. The N-methyl-D-aspartate receptor antagonist memantine may also provide some cognitive benefit in VaD, particularly in patients with more advanced disease. These data suggest that antidementia drugs currently used for treatment of AD should be considered for treatment of VaD as well.

Cholinesterase Inhibitors↗
PubMed2005

Efficacy of rivastigmine in Alzheimer's disease patients with rapid disease progression: results of a meta-analysis.

BACKGROUND: Alzheimer's disease (AD) patients experiencing more rapid symptom progression are likely to have a poorer prognosis than those experiencing slow symptom progression. In a recent retrospective analysis, treatment effects of rivastigmine were more pronounced in AD patients with rapid cognitive decline than in those with slow cognitive decline. This warranted further investigation. METHODS: Rapidly and slowly progressing patients were identified by rates of cognitive decline [>/=4 points and <4 points, respectively, on the Alzheimer's Disease Assessment Scale -- cognitive subscale (ADAS-cog)] during 26 weeks of placebo treatment in four randomized controlled trials (weeks 0--26). This meta-analysis evaluated rates of cognitive decline in both subgroups during subsequent open-label rivastigmine 26-week extension studies (weeks 26--52). A longitudinal mixed effects model compared cognitive decline in rapidly and slowly progressing patients, including correction for possible regression to the mean. RESULTS: 180 (75%) rapidly and 337 (78%) slowly progressing patients provided ADAS-cog data after 26 weeks of open-label rivastigmine treatment. Improvements in cognitive symptoms were observed during the first 12 weeks, which were more pronounced in patients with rapid progression than in those with slow progression. Rapidly progressing patients experienced significantly greater cognitive benefits than slowly progressing patients (p=0.029), who experienced a modest decline in cognitive symptoms at the end of the study. COMMENT: Patients experiencing rapid symptom progression may receive greater benefit from rivastigmine than those with slow progression. In this study, cholinesterase inhibition appeared to be of particular utility in the management of AD patients whose symptoms were rapidly worsening.

Alzheimer Disease↗
PubMed2005

NF-(kappa)B mediates amyloid beta peptide-stimulated activity of the human apolipoprotein E gene promoter in human astroglial cells.

The apolipoprotein E gene (APOE) plays an important role in the pathogenesis of Alzheimer's disease (AD), and amyloid plaque comprised mostly of the amyloid-beta peptide (A(beta)) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A(beta) treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-(kappa)B in APOE gene regulation. To delineate NF-(kappa)B's role, we have characterized a 1098 nucleotide (nt) segment containing the 5'-flanking region of the human APOE gene (-1054/+44, +1 transcription start site). Sequence analysis of this region suggests the presence of two potential NF-(kappa)B elements. To demonstrate promoter activity, the region was cloned upstream of a promoterless luciferase (reporter) gene. This segment was able to drive expression of luciferase in transient transfections of human fetal glial cells. Promoter activity was stimulated twofold by A(beta)(1-40) (25 microM, 24 h) treatment. Pretreatment with double-stranded DNA decoy oligonucleotides against NF-(kappa)B (2 microM) reduced A(beta) stimulation. Deletion and mutagenetic analyses demonstrated that the distal NF-(kappa)B element was functional and showed a strong DNA-protein complex band in gel shift analysis, similar to that from control NF-(kappa)B consensus element. An anti-inflammatory and anti-NF-(kappa)B drug, sodium salicylate, significantly blocked A(beta)-induced APOE promoter function. Our data provide evidence that upregulation of APOE by A(beta) in astroglial cells is mediated by an NF-(kappa)B-element present in the 5'-flanking region of the APOE gene.

Amyloid beta-Peptides↗
PubMed2005

Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease.

Extracellular amyloid plaques, intracellular neurofibrillary tangles, and loss of basal forebrain cholinergic neurons in the brains of Alzheimer's disease (AD) patients may be the end result of abnormalities in lipid metabolism and peroxidation that may be caused, or exacerbated, by beta-amyloid peptide (Abeta). Apolipoprotein E (apoE) is a major apolipoprotein in the brain, mediating the transport and clearance of lipids and Abeta. ApoE-dependent dendritic and synaptic regeneration may be less efficient with apoE4, and this may result in, or unmask, age-related neurodegenerative changes. The increased risk of AD associated with apoE4 may be modulated by diet, vascular risk factors, and genetic polymorphisms that affect the function of other transporter proteins and enzymes involved in brain lipid homeostasis. Diet and apoE lipoproteins influence membrane lipid raft composition and the properties of enzymes, transporter proteins, and receptors mediating Abeta production and degradation, tau phosphorylation, glutamate and glucose uptake, and neuronal signal transduction. The level and isoform of apoE may influence whether Abeta is likely to be metabolized or deposited. This review examines the current evidence for diet, lipid homeostasis, and apoE in the pathogenesis of AD. Effects on the cholinergic system and response to cholinesterase inhibitors by APOE allele carrier status are discussed briefly.

Alzheimer Disease↗
PubMed2005

Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer's disease for up to 5 years.

BACKGROUND: Rivastigmine, a butyl- and acetylcholinesterase inhibitor, is approved for symptomatic treatment of Alzheimer's disease (AD). Data supporting the safety and efficacy of second-generation cholinesterase inhibitors, such as rivastigmine, are available for treatment up to 1 year, with limited data up to 2 1/2 years. The purpose of this report is to present safety and effectiveness data for rivastigmine therapy in patients with mild to moderately severe AD receiving treatment for up to 5 years. METHODS: An observational approach was used to study 37 patients with originally mild to moderate AD receiving rivastigmine as a therapy for AD in an open-label extension (ENA713, B352 Study Group, 1998). RESULTS: The initial trial demonstrated rivastigmine was well-tolerated and effective in terms of cognition, global functioning and activities of daily living. In this open label extension, high-dose rivastigmine therapy was safe and well tolerated over a 5-year period. Two thirds of the participants still enrolled at week 234 were in the original high-dose rivastigmine group during the double-blind phase, suggesting that early therapy may confer some benefit in delaying long-term progression of symptoms. CONCLUSIONS: Long-term cholinesterase inhibition therapy with rivastigmine was well tolerated, with no dropouts due to adverse effects past the initial titration period. Early initiation of treatment, with titration to high-dose therapy, may have an advantage in delaying progression of the illness.

Aged↗
PubMed2005

Caffeic acid phenethyl ester possesses potent cardioprotective effects in a rabbit model of acute myocardial ischemia-reperfusion injury.

Although great achievements have been made in elucidating the molecular mechanisms contributing to acute myocardial ischemia/reperfusion (I/R) injury, an effective pharmacological therapy to protect cardiac tissues from serious damage associated with acute myocardial infarction, coronary arterial bypass grafting surgery, or acute coronary syndromes has not been developed. We examined the in vivo cardioprotective effects of caffeic acid phenethyl ester (CAPE), a natural product with potent anti-inflammatory, antitumor, and antioxidant activities. CAPE was systemically delivered to rabbits either 60 min before or 30 min after surgically inducing I/R injury. Infarct dimensions in the area at risk were reduced by >2-fold (P < 0.01) with CAPE treatment at either period. Accordingly, serum levels of normally cytosolic enzymes lactate dehydrogenase, creatine kinase (CK), MB isoenzyme of CK, and cardiac-specific troponin I were markedly reduced in both CAPE treatment groups (P < 0.05) compared with the vehicle-treated control group. CAPE-treated tissues displayed significantly less cell death (P < 0.05), which was in part due to inhibition of p38 mitogen-activated protein kinase activation and reduced DNA fragmentation often associated with caspase 3 activation (P < 0.05). In addition, CAPE directly blocked calcium-induced cytochrome c release from mitochondria. Finally, the levels of inflammatory proteins IL-1beta and TNF-alpha expressed in the area at risk were significantly reduced with CAPE treatment (P < 0.05). These data demonstrate that CAPE has potent cardioprotective effects against I/R injury, which are mediated, at least in part, by the inhibition of inflammatory and cell death responses. Importantly, protection is conferred when CAPE is systemically administered after the onset of ischemia, thus demonstrating potential efficacy in the clinical scenario.

Acute Disease↗
PubMed2005

A randomized, double-blind, placebo-controlled trial of two doses of Ginkgo biloba extract in dementia of the Alzheimer's type.

CONTEXT: Previous studies of Ginkgo biloba extract (GbE) in patients with various forms of cognitive impairment or dementia have shown promising results. OBJECTIVE: To determine the clinical efficacy of GbE in mild to moderate dementia of the Alzheimer type. DESIGN: Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial. SETTING: Outpatient clinics of universities and private research centers specialized in dementia. PATIENTS: 513 outpatients with uncomplicated dementia of the Alzheimer's type scoring 10 to 24 on the Mini-Mental State Examination and less than 4 on the modified Hachinski Ischemic Score, free of other serious illnesses and not requiring continuous treatment with any psychoactive drug. INTERVENTION: 26-week treatment with GbE at daily doses of 120 mg or 240 mg or placebo. MAIN OUTCOMES: Cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC). RESULTS: There were no significant between-group differences for the whole sample. There was little cognitive and functional decline of the placebo-treated patients, however. For a subgroup of patients with neuropsychiatric symptoms there was a greater decline of placebo-treated patients and significantly better cognitive performance and global assessment scores for the patients on GbE. CONCLUSION: The trial did not show efficacy of GbE, however, the lack of decline of the placebo patients may have compromised the sensitivity of the trial to detect a treatment effect. Thus, the study remains inconclusive with respect to the efficacy of GbE.

Aged↗
PubMed2005

The use of memantine in dementia with Lewy bodies.

OBJECTIVE: To determine the effect of memantine in the treatment of Dementia with Lewy Bodies (DLB). BACKGROUND: While memantine has been used to successfully treat moderate-to-severe Alzheimer's disease (AD) and some non AD dementias, no reports are available regarding the effect of the drug on DLB. METHODS: We reviewed the charts of 11 subjects with DLB by McKeith Criteria that were prospectively evaluated and treated with memantine (with or without cholinesterase inhibitors (ChEIs)) for varying lengths of time. RESULTS: 9 of 11 DLB subjects on memantine were also on ChEIs. Seven of eleven were stable or improved with memantine while the remaining four worsened or responded adversely when exposed to the drug. No adverse effects on motor function were observed. CONCLUSIONS: Memantine can be used safely in patients with DLB, but its symptomatic effects may be variable.

Aged↗
PubMed2005

Switching From Donepezil to Rivastigmine Is Well Tolerated: Results of an Open-Label Safety and Tolerability Study.

Background: Transitioning patients between cholinesterase inhibitors was thought to require a washout period to avoid cholinergic toxicity; however, evidence suggests that abrupt discontinuation of donepezil may lead to cognitive decline. We evaluated the safety and tolerability of an immediate switch from donepezil to rivastigmine.Method: This is an analysis of the safety and tolerability data from the first 28 days of an open-label, multicenter, prospective trial, conducted from August 2002 to August 2003, in which patients satisfying NINCDS-ADRDA criteria for probable Alzheimer's disease were administered rivastigmine 1.5 mg b.i.d. within 24 to 36 hours of donepezil discontinuation. Results are compared with adverse event rates from a retrospective analysis of a pivotal, placebo-controlled trial examining patients not previously treated with a cholinesterase inhibitor.Results: Fifty-eight of 61 patients completed the first 28 days, with no suspected drug-related discontinuations during this period. Incidence of overall gastrointestinal adverse events at day 7 was 8.2%, and at day 28 was 11.5%. The corresponding rate for rivastigmine-treated patients in the retrospective analysis of the pivotal trial for day 7 was 3.3%.Conclusion: These study results suggest that transitioning patients from donepezil to rivastigmine without a washout period is safe and well tolerated.

Journal Article↗
PubMed2004

Caffeic acid phenethyl ester prevents neonatal hypoxic-ischaemic brain injury.

Neonatal hypoxic-ischaemic (HI) brain injury resulting in encephalopathy is a leading cause of morbidity and mortality with no effective treatment. Here we show that caffeic acid phenethyl ester (CAPE), an active component of propolis, administered either before or after an HI insult, significantly prevents HI-induced neonatal rat brain damage in the cortex, hippocampus and thalamus. In addition to blocking HI-induced caspase 3 activation, CAPE also inhibits HI-mediated expression of inducible nitric oxide synthase and caspase 1 in vivo and potently blocks nitric oxide-induced neurotoxicity in vitro. Furthermore, CAPE directly inhibits Ca2+-induced cytochrome c release from isolated brain mitochondria. Thus, CAPE induces neuroprotection against HI-induced neuronal death, possibly by blocking HI-induced inflammation and/or directly inhibiting the HI-induced neuronal death pathway. CAPE may therefore be a novel effective therapy for preventing neonatal HI injury.

Animals↗
PubMed2004

Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial.

CONTEXT: Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled trials have demonstrated the safety and efficacy of memantine monotherapy for patients with moderate to severe Alzheimer disease (AD) but no controlled trials of memantine in patients receiving a cholinesterase inhibitor have been performed. OBJECTIVE: To compare the efficacy and safety of memantine vs placebo in patients with moderate to severe AD already receiving stable treatment with donepezil. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled clinical trial of 404 patients with moderate to severe AD and Mini-Mental State Examination scores of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed the trial. INTERVENTIONS: Participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks. MAIN OUTCOME MEASURES: Change from baseline on the Severe Impairment Battery (SIB), a measure of cognition, and on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale). RESULTS: The change in total mean (SE) scores favored memantine vs placebo treatment for SIB (possible score range, 0-100), 0.9 (0.67) vs -2.5 (0.69), respectively (P<.001); ADCS-ADL19 (possible score range, 0-54), -2.0 (0.50) vs -3.4 (0.51), respectively (P =.03); and the CIBIC-Plus (possible score range, 1-7), 4.41 (0.074) vs 4.66 (0.075), respectively (P =.03). All other secondary measures showed significant benefits of memantine treatment. Treatment discontinuations because of adverse events for memantine vs placebo were 15 (7.4%) vs 25 (12.4%), respectively. CONCLUSIONS: In patients with moderate to severe AD receiving stable doses of donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. These results, together with previous studies, suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD.

Aged↗