Alzheimer Disease: Farlow MR

Fillit HM, Doody RS, Binaso K, Crooks GM, Ferris SH, Farlow MR, Leifer B, Mills C, Minkoff N, Orland B, Reichman WE, Salloway S. · Alzheimer's Drug Discovery Foundation and Institute for the Study of Aging New York, New York 10019, USA. · Am J Geriatr Pharmacother. · Pubmed #17157793 No free full text.

Abstract: 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.

Farlow MR. · No affiliation provided · Geriatrics. · Pubmed #15948660 No free full text.

This publication has no abstract.

Farlow MR, Miller ML, Pejovic V. · Indiana University School of Medicine, Indianapolis, Ind. 46202-5111, USA. · Dement Geriatr Cogn Disord. · Pubmed #18391487 No free full text.

Abstract: Alzheimer's disease (AD) is becoming an increasingly heavy burden on the society of developed countries, and physicians now face the challenge of providing efficient treatment regimens to an ever-higher number of individuals affected by the disease. Currently approved anti-AD therapies - the cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine - offer modest symptomatic relief, which can be enhanced using combination therapy with both classes of drugs. Additionally, alternative therapies such as nonsteroidal anti-inflammatory drugs, vitamin E, selegiline, Ginkgo biloba extracts, estrogens, and statins, as well as behavioral and lifestyle changes, have been explored as therapeutic options. Until a therapy is developed that can prevent or reverse the disease, the optimal goal for effective AD management is to develop a treatment regimen that will yield maximum benefits for individual patients across multiple domains, including cognition, daily functioning, and behavior, and to provide realistic expectations for patients and caregivers throughout the course of the disease. This review provides a basic overview of approved AD therapies, discusses some pharmacologic and nonpharmacologic treatment strategies that are currently being investigated, and offers suggestions for optimizing treatment to fit the needs of individual patients.

Farlow MR, Cummings J. · Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Dement Geriatr Cogn Disord. · Pubmed #18311077 No free full text.

Abstract: BACKGROUND/AIMS: Parkinson's disease dementia (PDD) is common, but its neuropathological basis has been controversial. The aim of this review was to survey the recent literature on the pathology of PDD and compare the pathology of PDD to that of Alzheimer's disease (AD). METHODS: A literature search was performed to identify relevant research published since 2001. RESULTS: There is widespread Lewy body pathology in the neocortex and subcortical regions in PDD, and Lewy neurites in the CA2 region of the hippocampus that correlate with cognitive decline. Genetic forms of PD, which frequently lead to dementia, are associated with deposition of alpha-synuclein; PDD is not related to the apolipoprotein E epsilon 4 genotype. Compared with AD, central cholinergic deficits occur earlier, are greater and more widespread in PDD, but PDD can occur without the abundant senile plaques and neurofibrillary tangles indicative of AD. CONCLUSION: Epidemiological investigations, neuroimaging, as well as genetic and neuropathological studies increasingly support PDD as distinct from AD.

Farlow MR, Cummings JL. · Department of Neurology, Indiana University School of Medicine, Indianapolis 46202-5111, USA. · Am J Med. · Pubmed #17466645 No free full text.

Abstract: In order to assist physicians in the effective pharmacologic management of this challenging population, evidence-based pharmacologic treatment algorithms for the different stages of Alzheimer's disease have been developed. Evidence-based guidelines outlining pharmacotherapeutic strategies can be systematically implemented to optimize outcomes for patients in different stages of Alzheimer's disease. The first step toward the best possible long-term management is early diagnosis of Alzheimer's disease, thereby facilitating early initiation of cholinesterase inhibitor treatment, which may stabilize/reduce the rate of symptomatic cognitive and functional decline. Cholinesterase inhibitor therapy with rivastigmine, donepezil, or galantamine is endorsed as standard first-line therapy in patients with mild-to-moderate Alzheimer's disease. The N-methyl-D-aspartate receptor-antagonist, memantine, may be used as monotherapy or in combination with a cholinesterase inhibitor for patients with moderate Alzheimer's disease, and as monotherapy for patients with severe Alzheimer's disease. During treatment, cognitive and functional status should be monitored over 6-month intervals, and pharmacologic therapy should ideally be continued until there are no meaningful social interactions and quality of life has irreversibly deteriorated.

Farlow MR. · Department of Neurology, Indiana University School of Medicine, CL 299, 541 Clinical Dr, Indianapolis, IN 46202, USA. · Mayo Clin Proc. · Pubmed #17036561 links to  free full text

Abstract: 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.

Farlow MR. · Department of Neurology, Indiana University School of Medicine, CL 299, 541 Clinical Drive, Indianapolis, IN 46202 5111, USA. · Expert Rev Neurother. · Pubmed #15853507 No free full text.

Abstract: Alzheimer's disease may not yet be curable, but it is treatable. Two classes of drugs with differing mechanisms of action have received Food and Drug Administration approval for the treatment of Alzheimer's disease: the cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine (Ebixa, Lundbeck; Namenda, Forest Laboratories). Alzheimer's disease research directed at increasing the understanding of the underlying disease process has led to the identification of several other potential targets for drug development strategies. Due to the complexity of the disease, it is possible that combination therapy -- concomitant use of agents with nonoverlapping or even synergistic mechanisms of action -- may represent the best means available to enhance treatment effectiveness. This review evaluates the available data on combination therapy in Alzheimer's disease and provides an expert opinion on the use and implementation of combination therapy in clinical practice.

Lane RM, Farlow MR. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. · J Lipid Res. · Pubmed #15716586 links to  free full text

Abstract: 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.

Farlow MR. · Department of Neurology, Indiana University School of Medicine, Indianapolis, USA. · Geriatrics. · Pubmed #15224791 No free full text.

Abstract: Research into Alzheimer's disease (AD) pathology has identified several underlying disease processes that are potential targets for drug discovery and development. One strategy targets glutamatergic neurotransmission mediated by the N-methyl-D-aspartate (NMDA) receptor. Therapeutic intervention with high-affinity NMDA receptor antagonists, such as phencyclidine (PCP) and MK-801, is not practical due to adverse side effects; however, a low-moderate affinity, uncompetitive and strongly voltage-dependent NMDA receptor antagonist, memantine (NamendaTM), is well tolerated and recently has been approved by the U.S. Food and Drug Administration for the treatment of moderate to severe AD. Clinical results support NMDA receptor antagonism as a viable therapeutic strategy for AD and suggest that this novel pharmacologic approach, either alone or in combination with other drugs, is likely to significantly impact the current AD treatment paradigm.

Gauthier S, Emre M, Farlow MR, Bullock R, Grossberg GT, Potkin SG. · McGill Centre for Studies in Aging, Verdun, Quebec, Canada. · Curr Med Res Opin. · Pubmed #14687441 No free full text.

Abstract: Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.

Farlow MR. · Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5111, USA. · Clin Pharmacokinet. · Pubmed #14674789 No free full text.

Abstract: Galantamine is the most recently approved cholinergic drug for the treatment of Alzheimer's disease, the most common type of dementia. Vascular dementia and Alzheimer's disease with cerebrovascular disease are also common in older patients. Dementia affects cognition, causes losses in ability to perform activities of daily living and often results in the emergence of psychiatric and abnormal behavioural symptoms. Dementia also results in an ever-increasing burden and a decreased quality of life for caregivers. Treatments for dementia, particularly Alzheimer's disease, have focused on improving function in the cholinergic system. Vascular dementia and diffuse Lewy body dementia are also associated with significant defects in cholinergic function. Galantamine works by inhibiting acetylcholinesterase and by allosterically modulating nicotinic receptors. In clinical trials, galantamine has shown benefits in the domains of cognition, function in activities of daily living, and behaviour. Galantamine is about 90% bioavailable and displays linear pharmacokinetics. It has a relatively large volume of distribution and low protein binding. Metabolism is primarily through the cytochrome P450 system, specifically the CYP2D6 and CYP3A4 isoenzymes. Population pharmacokinetic modelling with galantamine has shown that the variables affecting clearance are age, sex, and bodyweight. Model simulations demonstrate the importance of a slower dose-escalation schedule in patients with moderate hepatic impairment. In several large trials, galantamine has been shown to be well tolerated, with most adverse events being mild-to-moderate and gastrointestinal in nature. Based on the literature and clinical trial experience, galantamine appears to be an excellent treatment option for patients with Alzheimer's disease, vascular dementia or Alzheimer's disease with cerebrovascular disease.

Farlow MR. · Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202-5111, USA. · Neurologist. · Pubmed #14587496 No free full text.

Abstract: BACKGROUND: Rivastigmine is a carbamate drug designed to inhibit both acetylcholinesterase and butyrylcholinesterase by reversibly covalently bonding to these enzymes. Butyrylcholinesterase in-creases as Alzheimer disease progresses, so its inhibition may become more important as the disease worsens. Metabolism of rivastigmine occurs at the synapse rather than at the liver and previous studies have demonstrated no drug-drug interactions. Rivastigmine has a half-life at the synapse of 9 hours allowing for bid dosing. REVIEW SUMMARY: Effective therapy requires up-titration from initial dosage of 3 mg/d to 6 mg/d with additional increases to 9 mg or 12 mg/d giving additional benefits in some patients. Beneficial effects with rivastigmine therapy in the functioning of activities of daily living, behavior, cognition, and global functioning have been demonstrated in patients with mild to moderate Alzheimer disease in 4 large double-blind, placebo-controlled multicenter clinical trials. Potential adverse effects of nausea, vomiting, or diarrhea in these original Alzheimer trials with rapid (every week) dosage increases occurred in up to 34% of patients and can be minimized by slower monthly up-titrations. Rivastigmine also was proven effective in decreasing psychiatric symptoms and cognitive deficits in a large double-blind, placebo-controlled trial in patients with diffuse Lewy body disease. Other studies have suggested that rivastigmine improves symptoms in nursing home patients with more severe stage Alzheimer disease, Parkinson dementia, and subcortical dementia. Follow-up studies have suggested that rivastigmine may delay disease progression and, in patients discontinuing the drug, no withdrawal effects were seen. CONCLUSION: Rivastigmine is an effective therapeutic agent for treating cognitive and behavioral symptoms in Alzheimer disease and diffuse Lewy body disease and may also have beneficial effects in vascular and Parkinson dementias.

Lahiri DK, Farlow MR, Sambamurti K, Greig NH, Giacobini E, Schneider LS. · Department of Psychiatry and Neurology, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202-4887, USA. · Curr Drug Targets. · Pubmed #12558063 No free full text.

Abstract: Alzheimer's disease (AD), a progressive, degenerative disorder of the brain, is believed to be the most common cause of dementia amongst the elderly. AD is characterized by the presence of amyloid deposits and neurofibrillary tangles in the brain of afflicted individuals. AD is associated with a loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning. AD appears to have a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in one of several genes, such as the beta-amyloid precursor protein (APP) and presenilins (PS1, PS2). These proteins along with tau, secretases, such as beta-amyloid cleaving enzyme (BACE), and apolipoprotein E play important roles in the pathology of AD. On therapeutic fronts, there is significant research underway in the development of new inhibitors for BACE, PS-1 and gamma-secretase as targets for treatment of AD. There is also a remarkable advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. The development of vaccination strategies, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy are examples of new approaches for treating or slowing the progression of AD. In addition, nutritional, genetic and environmental factors highlight more effective preventive strategies for AD. Developments of early diagnostic tools and of quantitative markers are critical to better follow the course of the disease and to evaluate different therapeutic strategies. In this review, we attempt to critically examine recent trends in AD research from molecular, genetic to clinical areas. We discuss various neurobiological mechanisms that provide the basis of new targets for AD drug development. All these current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain in order to effectively diagnose and prevent their occurrence.

Farlow MR. · Indiana University School of Medicine, Indianapolis, USA. · Int J Clin Pract Suppl. · Pubmed #12139366 No free full text.

Abstract: In the absence of a cure for Alzheimer's disease (AD), treatment has focused on therapy to provide symptomatic benefits and to slow progression of the disease, so that patients can maintain their independence for as long as possible. New research suggests that rivastigmine, a potent, pseudo-irreversible inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase that shows preferential selectivity for the G1 form of AChE, may provide symptomatic and disease progression slowing effects. The drug's pharmacological properties may help to slow the conversion of diffuse, benign amyloid plaques to neuritic plaques associated with clinical dementia. In 'delayed-start' paradigms--open-label extensions of placebo-controlled studies involving mild to moderate AD patients--the treatment effects of rivastigmine on cognitive and non-cognitive outcomes at 52 weeks were even greater than those observed at 26 weeks, and patients who received rivastigmine for the entire 52 weeks had better outcomes than those who received rivastigmine only for the latter 26 weeks (having received placebo for the first 26 weeks during the placebo-controlled phase). These treatment effects were even more robust in patients with moderately severe disease, indicating that the sustained long-term benefits of rivastigmine apply across the continuum of disease severity. The results seen in those patients with mild and moderately severe AD suggest that the progression of AD was being slowed in treated patients and that a disease-modifying effect may have been taking place. The effects of rivastigmine on cognition remain clinically relevant for at least 2 years, with benefits over projected placebo increasing over time. The long-term benefits of rivastigmine have also been reported in behavioural domains of patients with mild to moderate AD for 104 weeks and in patients with the Lewy body variant of AD for 96 weeks. Rivastigmine may slow AD progression, allowing patients to maintain autonomy for longer.

Farlow MR. · Indiana University School of Medicine, Indianapolis, USA. · Int J Clin Pract Suppl. · Pubmed #12139364 No free full text.

This publication has no abstract.

Hake AM, Farlow MR. · Indiana University School of Medicine, Department of Neurology, Indianapolis, IN 46202, USA. · Expert Opin Pharmacother. · Pubmed #11825329 No free full text.

Abstract: There are currently four compounds approved for use in the treatment of Alzheimer's disease (AD). These drugs are all cholinesterase (ChE) inhibitors, which are thought to provide predominantly symptomatic benefits by increasing the level of acetylcholine (ACh) in the synapse. Although there are slight differences in the mechanisms of action of these compounds, it remains to be determined whether any one of them has a significant therapeutic advantage over the others. Several other drugs have also been investigated for their potential use as either symptomatic or disease-modifying agents in the treatment of AD, with mixed results. Current therapeutic research is focused on addressing the underlying pathology of AD, in the hope of arresting or reversing the course of the disease. This review will provide an overview of the ChE inhibitors and other drugs used for treating the symptoms of AD, summarise the results of recent therapeutic trials, discuss directions of future research and outline the current treatment recommendations for AD.

Kawas CH, Clark CM, Farlow MR, Knopman DS, Marson D, Morris JC, Thal LJ, Whitehouse PJ. · Department of Neurology and Alzheimer's Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10485569 No free full text.

Abstract: During the past 10 years, there has been a rapidly growing number of pharmaceutical industry-sponsored drug trials for treatment of Alzheimer disease (AD) and other neurodegenerative diseases. As public awareness and concerns about AD have grown, so has interest in developing drug therapies for retarding symptom progression, delaying onset, and ultimately curing the disease. Ethical debate on the use of placebo control trials in AD research has come of age in the United States with the availability of treatments approved by the Food and Drug Administration. The experts and the public agree that more effective therapies are necessary, and new therapeutic options are being developed as rapidly as possible. The arguments on each side of the debate are provocative and important but do not provide unequivocal justification for either the abandonment or the maintenance of placebo-controlled trials in all AD research. Clinical trials differ with respect to scientific and practical goals, and these factors inherently affect the ethical priorities of each study. We present these contrasting points of view to delineate some of the issues rather than to make specific recommendations other than to urge that all clinical trials in AD should be designed with careful consideration of the ethical issues surrounding the use of placebo controls. As new and more effective treatments emerge, the ethical framework for placebo use in AD studies will require frequent re-examination. To make wise choices, patients, caregivers, physicians, and ethicists (among others) must have a voice in this continuing discussion.

Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, Galvin JE, Peskind ER, Quinn JF, Sherzai A, Sowell BB, Aisen PS, Thal LJ. · University of California, San Diego, La Jolla, CA 92037, USA. · Arch Neurol. · Pubmed #18695053 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN: Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING: Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES: Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS: Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS: LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.

Siemers ER, Dean RA, Friedrich S, Ferguson-Sells L, Gonzales C, Farlow MR, May PC. · Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, · Clin Neuropharmacol. · Pubmed #18090456 No free full text.

Abstract: OBJECTIVES: gamma-Secretase inhibitors may be useful as disease-modifying drugs for the treatment of Alzheimer disease. LY450139 is a gamma-secretase inhibitor currently in clinical development, with doses being optimized through the use of biomarkers. METHODS: To further characterize biomarker responses to LY450139, single oral doses of 60, 100, or 140 mg were administered to volunteers without neuropsychiatric disease. Extensive safety assessments were obtained along with measures of changes in amyloid-beta (Abeta) in plasma and cerebrospinal fluid (CSF). A measure of the change in plasma Abeta1-40 was derived (area above the curve), which was determined by both the magnitude and duration of Abeta1-40 reduction. RESULTS: A total of 31 subjects (ages 49-53 years, 19 men) were enrolled. With the possible exception of headache, no clinically significant adverse events or laboratory changes were observed. A dose-proportional increase in drug exposure was present in plasma and in CSF. A dose-dependent change in plasma Abeta1-40 area above the curve was also demonstrated. Using the 140-mg dose, a maximum 72.6% reduction in plasma Abeta1-40 was demonstrated that did not return to baseline for more than 12 hours. Cerebrospinal fluid concentrations of Abeta were unchanged 4 hours after drug administration. CONCLUSIONS: These data show that single doses of LY450139 up to 140 mg are accompanied by a dose-dependent plasma Abeta response. No response in CSF Abeta was apparent 4 hours after dosing.

Evans RM, Hui S, Perkins A, Lahiri DK, Poirier J, Farlow MR. · Department of Neurology, Indiana University School of Medicine, Indianapolis, USA. · Neurology. · Pubmed #15159498 No free full text.

Abstract: In this retrospective analysis of 443 Alzheimer disease (AD) patients from a 30-week tacrine trial, change in Alzheimer's Disease Assessment Scale score from baseline to final value was significantly associated with a total serum cholesterol/APOE genotype interaction. Disease progression in the no-APOE epsilon4 allele/high-cholesterol subgroup was greater than in the normal-cholesterol subgroups with or without epsilon4. Cholesterol levels and APOE genotype may interact to affect AD progression. The results are consistent with preclinical data on cholesterol's effects in AD.

Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I, Anonymous00181. · Department of Psychiatry, University of Rochester Medical Center, Monroe Community Hospital, Rochester, NY 14620, USA. · JAMA. · Pubmed #14734594 links to  free full text

Abstract: 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.

Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ, Anonymous00135. · Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. · JAMA. · Pubmed #12783912 links to  free full text

Abstract: CONTEXT: Laboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease. OBJECTIVE: To determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications. SETTING: Forty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium. PARTICIPANTS: Participants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled. INTERVENTIONS: Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo. MAIN OUTCOME MEASURES: The primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death). RESULTS: The 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group. CONCLUSION: The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.

Farlow MR, Hake A, Messina J, Hartman R, Veach J, Anand R. · Department of Neurology, Indiana University School of Medicine, CL583, 541 Clinical Dr., Indianapolis, IN 46202-5111, USA. · Arch Neurol. · Pubmed #11255445 links to  free full text

Abstract: BACKGROUND: Evidence suggests that disease severity predicts the response of patients with Alzheimer disease (AD) to cholinesterase inhibitor treatment, raising the question of whether disease progression also predicts response to this treatment. OBJECTIVE: To evaluate retrospectively whether rate of disease progression during placebo treatment affects response to subsequent rivastigmine tartrate therapy for patients with mild to moderately severe AD. DESIGN: A 26-week, open-label extension study following a 26-week, double-blind, randomized, placebo-controlled trial. SETTING: Outpatient research centers at 22 sites in the United States. PATIENTS: We studied 187 of 235 patients originally randomized to receive placebo treatment in the double-blind phase of the trial who continued with open-label (rivastigmine) extension therapy. INTERVENTION: Placebo treatment for 26 weeks followed by rivastigmine treatment, 2 to 12 mg/d, for 26 weeks. MAIN OUTCOME MEASURES: Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), Progressive Deterioration Scale, Mini-Mental State Examination, and Global Deterioration Scale scores. RESULTS: Rivastigmine administration during open-label extension therapy benefited patients who had progressed slowly and those who had progressed rapidly during initial double-blind placebo treatment. Slowly progressive patients responded with a mean 1.03-point improvement in the week 26 (ie, start of open-label rivastigmine treatment) ADAS-Cog score at 12 weeks of rivastigmine treatment (week 38 of treatment; P =.02 vs week 26). However, more rapidly progressive patients had a significantly larger mean 4.97-point improvement from the week 26 ADAS-Cog score at 12 weeks (with respect to week 26 of treatment and slowly progressive patient scores, P<.001 for both). Thus, a more rapid disease progression rate while receiving placebo treatment was predictive of a significantly stronger patient response to rivastigmine therapy. This relation also was observed with the other 3 outcome measures and was still apparent when accounting for disease severity. CONCLUSIONS: Rate of disease progression for patients with mild to moderate AD seems to predict response to rivastigmine treatment. Patients with more rapidly progressive disease might be particularly likely to benefit from rivastigmine therapy.

Kareken DA, Doty RL, Moberg PJ, Mosnik D, Chen SH, Farlow MR, Hutchins GD. · Department of Neurology, Indiana University School of Medicine, Indianapolis 46202, USA. · Neuropsychology. · Pubmed #11216885 No free full text.

Abstract: Olfaction is impaired in Alzheimer's disease (AD). It was hypothesized that AD would reduce olfactory-evoked perfusion in mesial temporal olfactory (piriform) cortex, where neuropathology begins. Seven AD patients and 8 elderly controls (ECs) underwent olfactory threshold and identification tests and olfactory stimulation during positron emission tomography. Odor identification was impaired in AD, but threshold was not. Olfactory stimulation in ECs activated right and left piriform areas and right anterior ventral temporal cortex. AD patients had less activation in right piriform and anterior ventral temporal cortex but not in the left piriform area. Although orbital cortex did not activate in ECs, there was a significant between-groups difference in this area. Right piriform activation correlated with odor identification. Impaired odor identification likely reflects sensory cortex dysfunction rather than cognitive impairment. Given olfactory bulb projections to the mesial temporal lobe, olfactory stimulation during functional imaging might detect early dysfunction in this region.

Aisen PS, Davis KL, Berg JD, Schafer K, Campbell K, Thomas RG, Weiner MF, Farlow MR, Sano M, Grundman M, Thal LJ. · Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA. · Neurology. · Pubmed #10680787 No free full text.

Abstract: BACKGROUND: Laboratory and epidemiologic studies suggest that anti-inflammatory/immunosuppressive therapy may be useful in the treatment of AD. In preliminary studies, a regimen of low to moderate dose prednisone was found to suppress peripheral inflammatory markers without adverse effects in subjects with AD. METHODS: We conducted a randomized, placebo-controlled multicenter trial to determine whether prednisone treatment slowed the rate of cognitive decline in AD. The active treatment regimen consisted of an initial dose of 20 mg of prednisone daily for 4 weeks tapered to a maintenance dose of 10 mg daily for 1 year, followed by gradual withdrawal during an additional 16 weeks. The primary outcome measure was the 1-year change in the cognitive subscale of the AD Assessment Scale. RESULTS: A total of 138 subjects were randomized to the drug and placebo groups. There was no difference in cognitive decline between the prednisone and placebo treatment groups in the primary intent-to-treat analysis, or in a secondary analysis considering completers only. Subjects treated with prednisone showed behavioral decline compared with those in the placebo group. CONCLUSION: A low-dose regimen of prednisone is not useful in the treatment of AD.