Alzheimer Disease: Mintzer JE

Faison WE, Schultz SK, Aerssens J, Alvidrez J, Anand R, Farrer LA, Jarvik L, Manly J, McRae T, Murphy GM, Olin JT, Regier D, Sano M, Mintzer JE. · Alzheimer's Research and Clinical Programs, Neurosciences Department, Medical University of South Carolina, Charleston, South Carolina 29406, USA. · Int Psychogeriatr. · Pubmed #17451614 No free full text.

Abstract: OBJECTIVE: Despite numerous clinical trials, it is unknown whether ethnicity affects treatment response to cognitive enhancers in Alzheimer's disease (AD). There is convincing evidence of ethnic and genetic variability in drug metabolism. This article reviews the available data on ethnicity in clinical trials for AD to answer two questions: (1) what are the challenges to diagnose and treat AD across different ethnic groups, and (2) are there differences in response to pharmacologic interventions for AD across these different ethnic groups? METHOD: Available data from Alzheimer's Disease Cooperative Study (ADCS) randomized controlled clinical trials and from randomized controlled industry-sponsored trials for four cognitive enhancers (donepezil, galantamine, rivastigmine and sabeluzole) were pooled to assess the numbers of non-Caucasian participants. RESULTS: The participation of ethnic minority subjects in clinical trials for AD was dependent on the funding source, although Caucasian participants were over-represented and non-Caucasian participants were under-represented in the clinical trials. Because of the low participation rate of ethnic minorities, there were insufficient data to assess any differences in treatment outcome among different ethnic groups. Strategies to improve diversity in clinical trials are discussed. CONCLUSION: Greater participation of ethnically diverse participants in clinical trials for AD would generate additional information on possible differences in metabolism, treatment response, adverse events to therapeutic agents, and could foster the investigation of genetic variability among ethnic groups.

Sambamurti K, Granholm AC, Kindy MS, Bhat NR, Greig NH, Lahiri DK, Mintzer JE. · Department of Physiology and Neuroscience, and Center on Aging, Medical University of South Carolina, 173 Ashley Avenue, BSB 403, Charleston, SC 29425, USA. · Curr Drug Targets. · Pubmed #15270198 No free full text.

Abstract: Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (Abeta) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Abeta precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Abeta deposition. Several biochemical and molecular studies using transfected cultured cells and transgenic animals point to mechanisms by which Abeta is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as 'secretases' participate in APP processing leading to the generation of either Abeta or non-amyloid proteins. However, the mechanisms of neurotoxicity of Abeta and the role of APP function in AD remain important unanswered questions. Although early studies recognized the loss of cholesterol and other lipids in the brain, these findings have been poorly connected with AD pathogenesis, despite the identification of the epsilon4 allele of APOE as a major risk factor in AD. The recent finding that cholesterol can modulate the yield of potentially toxic Abeta has boosted research on its role in AD. Consequently, several cholesterol-reducing drugs are currently being evaluated for the treatment of AD. The present review summarizes our current understanding of the relationship of AD pathogenesis with cholesterol, lipids and other genetic and environmental risk factors.

Mintzer JE. · Medical University of South Carolina and Ralph H. Johnson VA Medical Center, Charleston, SC, USA. · J Clin Psychiatry. · Pubmed #12934970 No free full text.

Abstract: Alzheimer's disease is a biological process that involves the disruption of multiple neurochemical pathways. Current treatments for Alzheimer's disease focus on deficits in the cholinergic neurochemical pathway. While newer generation cholinergic agents have a more favorable side effect profile, only a limited, but consistent, degree of efficacy is seen. Treatments are emerging that focus on other areas of neurochemical activity such as oxidative damage, inflammation, glutamatergic neurotransmissions, and serotonergic and dopaminergic pathways. These treatments, supplemented with current cholinergic therapies, may help to ease patients' suffering and caregiver distress.

Mintzer JE. · Department of Psychiatry, Medical University of South Carolina, Charleston, USA. · J Clin Psychiatry. · Pubmed #11584984 No free full text.

Abstract: It is well known that serotonergic function is related to aggression. Patients with Alzheimer's disease exhibit aggressive behavior, and alterations in their serotonergic function have been identified. Recent clinical trials involving new antipsychotic agents, such as risperidone, which has both serotonergic and dopaminergic activity, have demonstrated the efficacy and safety of these drugs in treating the psychosis and aggressive behavior associated with dementia.

Finkel SI, Mintzer JE, Dysken M, Krishnan KR, Burt T, McRae T. · Department of Psychiatry, University of Chicago Medical School, and the Leonard Schanfield Research Institute at Council for Jewish Elderly, Chicago, IL 60091, USA. · Int J Geriatr Psychiatry. · Pubmed #14716694 No free full text.

Abstract: OBJECTIVE: To examine the safety and efficacy of sertraline augmentation therapy in the treatment of behavioral manifestations of Alzheimer's disease (AD) in outpatients treated with donepezil. METHODS AND MATERIALS: Patients with probable or possible AD, and a Neuropsychiatric Inventory (NPI) total score >5 (with a severity score > or =2 in at least one domain), were treated with donepezil (5-10 mg) for 8 weeks, then randomly assigned to 12 weeks of double-blind augmentation therapy with either sertraline (50-200 mg) or placebo. Primary efficacy measures were the 12-item Neuropsychiatric Inventory (NPI) and the Clinical Global Impression Improvement (CGI-I) and Severity (CGI-S) scales. RESULTS: 24 patients were treated with donepezil+sertraline and 120 patients with donepezil+placebo. There were no statistically significant differences at endpoint on any of the three primary efficacy measures. However, a linear mixed model analysis found modest but statistically significantly greater improvements in the CGI-I score on donepezil+sertraline. Moreover, in a sub-group of patients with moderate-to-severe behavioral and psychological symptoms of dementia, 60% of patients on sertraline vs 40% on placebo (p = 0.006) achieved a response (defined as > or = 50% reduction in a four-item NPI-behavioral subscale). One adverse event (diarrhea) was significantly (p < 0.05) more common in the donepezil+sertraline group compared to the donepezil+placebo group. CONCLUSION: Sertraline augmentation was well-tolerated in this sample of AD outpatients. In addition, post hoc analyses demonstrated a modest but statistically significant advantage of sertraline over placebo augmentation in mixed model analyses and a clinically and statistically significant advantage in a subgroup of patients with moderate-to-severe behavioral and psychological symptoms of dementia.

Mintzer JE, Kershaw P. · Medical University of South Carolina, N Charleston, South Carolina, USA. · Int J Geriatr Psychiatry. · Pubmed #12673604 No free full text.

Abstract: BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) can provide benefits at the cognitive, behavioral, and functional levels to patients with Alzheimer's disease (AD). With more AChEIs now available, treatment considerations may include whether the patient has had prior exposure to an AChEI. OBJECTIVE: To compare the effects of galantamine in patients with AD who were previously exposed to AChEIs with its effects in patients with AD who had no previous exposure, using a post hoc analysis. RESULTS: Patients in groups treated with galantamine 16 mg/day and 24 mg/day achieved statistically significant improvements in ADAS-cog/11 scores in comparison with those who received placebo (naive: p = 0.003 and 0.005, respectively; prior exposure: p < 0.001 and 0.001, respectively). Similarly, a greater number of patients treated with galantamine 16 mg/day and 24 mg/day exhibited no change or improvement in their CIBIC-plus scores compared to patients who received placebo (naive: p < 0.001 and p = 0.077, respectively; prior exposure: p = 0.005 and p = 0.001, respectively). There were no significant differences in adverse events between naive patients and those with prior exposure to AChEIs. CONCLUSIONS: Galantamine is effective and safe in patients with AD, regardless of previous exposure to AChEIs.

Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M. · Department of Psychiatry, University of Pennsylvania Medical School, Philadelphia 19104, USA. · J Clin Psychiatry. · Pubmed #10084637 No free full text.

Abstract: BACKGROUND: We report the findings from the first large, double-blind, placebo-controlled study conducted to evaluate the efficacy and safety of risperidone in the treatment of psychotic and behavioral symptoms in institutionalized elderly patients with dementia. METHOD: 625 patients (67.8% women; mean age = 82.7 years) with DSM-IV diagnoses of Alzheimer's disease (73%), vascular dementia (15%), or mixed dementia (12%) and significant psychotic and behavioral symptoms were included. Each patient was randomly assigned to receive placebo or 0.5 mg/day, 1 mg/day, or 2 mg/day of risperidone for 12 weeks. The primary outcome measure was the Behavioral Pathology in Alzheimer's Disease rating scale (BEHAVE-AD). RESULTS: The study was completed by 70% of the patients. Baseline Functional Assessment Staging scores were 6 or 7 in more than 95% of the patients, indicating severe dementia. At endpoint, significantly greater reductions in BEHAVE-AD total scores and psychosis and aggressiveness subscale scores were seen in patients receiving 1 and 2 mg/day of risperidone than in placebo patients (p = .005 and p < .001, respectively). At week 12, 0.5 mg/day of risperidone was superior to placebo in reducing BEHAVE-AD aggression scores (p = .02). More adverse events were reported by patients receiving 2 mg/day of risperidone than 1 mg/day. The most common dose-related adverse events were extrapyramidal symptoms, somnolence, and mild peripheral edema. The frequency of extrapyramidal symptoms in patients receiving 1 mg/day of risperidone was not significantly greater than in placebo patients. CONCLUSION: Risperidone significantly improved symptoms of psychosis and aggressive behavior in patients with severe dementia. Results show that 1 mg/day of risperidone is an appropriate dose for most elderly patients with dementia.

Bachman DL, Stuckey M, Ebeling M, Wagner MT, Evans WJ, Hirth V, Walker A, Memon M, Joglekar R, Faison W, Mintzer JE. · Department of Neurosciences, Medical University of South Carolina, Charleston, S.C. 29425, USA. · Dement Geriatr Cogn Disord. · Pubmed #19276625 No free full text.

Abstract: BACKGROUND/AIMS: The recruitment of culturally diverse subject populations into research studies, particularly African-Americans (AA), has been the focus of intense interest by many groups. METHODS: In this paper, we present the methodology utilized to create a predominantly AA cohort for the longitudinal study of risk factors in Alzheimer's disease (AD). The underlying strategy was that of identifying geographically diverse clinical venues within South Carolina (SC) where large numbers of AA patients already come to seek medical care. RESULTS: This strategy was successful, although recruitment rates for AA subjects (43.4%) still fell below those for white subjects (70.3%; p = 0.0025). Subject characteristics of AA subjects that chose to enroll were not substantially different from those that declined to participate. The demographic characteristics of this cohort were largely similar to those of the SC Alzheimer Disease Registry, a population-based database. The problems of standardization of subject recruitment and assessment across diverse clinical venues are also addressed. CONCLUSION: The utilization of geographically diverse sites for research recruitment where minorities already receive medical care is one practical solution to the problem of minority participation in research. Multi-site recruitment to improve minority recruitment can be accomplished with acceptable standardization and inter-rater reliability.

Mintzer JE, Tune LE, Breder CD, Swanink R, Marcus RN, McQuade RD, Forbes A. · Alzheimer's Research & Clinical Programs, Medical University of South Carolina, North Charleston, SC 29406-6076, USA. · Am J Geriatr Psychiatry. · Pubmed #17974864 No free full text.

Abstract: OBJECTIVE: To assess the efficacy and safety of aripiprazole for psychosis associated with Alzheimer dementia (AD). METHODS: In this double-blind, multicenter study, 487 institutionalized patients with psychosis associated with AD were randomized to placebo or aripiprazole, 2, 5 or 10 mg/day. Primary efficacy assessment was the mean change from baseline to week 10 on the Neuropsychiatric Inventory-Nursing Home (NPI-NH) version Psychosis Subscale score. Secondary measures included NPI-NH Total, Clinical Global Impression-Severity of Illness (CGI-S), Brief Psychiatric Rating Scale (BPRS) Core and Total, and the Cohen-Mansfield Agitation Inventory (CMAI) scores. RESULTS: Aripiprazole 10 mg/day showed significantly greater improvements (mean change [2 x SD]) than placebo on the NPI-NH Psychosis Subscale (-6.87 [8.6] versus -5.13 [10.0]; F = 6.29, df = 1, 422, p = 0.013 by analysis of covariance [ANCOVA]); CGI-S (-0.72 [1.8] versus -0.46 [1.6]; F = 4.68, df = 1, 419, p = 0.031 [ANCOVA]); BPRS Total (-7.12 [18.4] versus -4.17 [21.6]; F = 4.72, df = 1, 399, p = 0.030 [ANCOVA]); BPRS Core (-3.07 [6.9] versus -1.74 [7.8]; F = 7.30, df = 1, 407, p = 0.007 [ANCOVA]); CMAI (-10.96 [22.6] versus -6.64 [28.6]; F = 5.23, df = 1, 410, p = 0.023 [ANCOVA]), and NPI-NH Psychosis response rate (65 versus 50%; chi(2) = 5.52, df = 1, p = 0.019 [CMH]). Aripiprazole 5 mg/day showed significant improvements versus placebo on BPRS and CMAI scores. Aripiprazole 2 mg/day was not efficacious. Cerebrovascular adverse events were reported: aripiprazole 2 mg/day, N = 1; 5 mg/day, N = 2; 10 mg/day, N = 4; placebo, N = 0. No deaths in any group (aripiprazole 2 mg/day, 3%; 5 mg/day, 2%; 10 mg/day, 7%; placebo, 3%) were considered to be treatment-related. CONCLUSION: Aripiprazole 10 mg/day was efficacious and safe for psychosis associated with AD, significantly improving psychotic symptoms, agitation, and clinical global impression. However, clinicians should be aware of the safety considerations of atypical antipsychotic uses in this population.

Martin BK, Frangakis CE, Rosenberg PB, Mintzer JE, Katz IR, Porsteinsson AP, Schneider LS, Rabins PV, Munro CA, Meinert CL, Niederehe G, Lyketsos CG. · Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. · Am J Geriatr Psychiatry. · Pubmed #17068314 No free full text.

Abstract: OBJECTIVE: Research on the efficacy of antidepressant therapy for depressive symptoms in Alzheimer disease has been hampered by lack of systematic diagnosis, small sample sizes, and short-term follow up. To address these issues, the authors present the design of the Depression in Alzheimer's Disease Study-2 (DIADS-2), a randomized, placebo-controlled multicenter trial to evaluate the efficacy and safety of the selective serotonin reuptake inhibitor sertraline for the treatment of depression in people with Alzheimer disease. METHODS: The authors present and discuss the following important aspects of the design: the inclusion of structured psychosocial therapy for the caregivers of all participants; the measurement not only of patient mood outcomes, but also of global and functional outcomes for patients and mood and burden outcomes for caregivers; the ongoing rating of multiple diagnostic criteria to allow nosologic study of depression in Alzheimer disease; the evaluation of both short-term efficacy and longer-term outcomes; the follow up of all patients regardless of whether they complete study treatment; and the unmasking of treatment assignment at the conclusion of each patient's treatment phase. CONCLUSIONS: The authors believe these design elements are important features to be included in trials of depression and other neuropsychiatric disturbances in Alzheimer disease.

Tariot PN, Schneider L, Katz IR, Mintzer JE, Street J, Copenhaver M, Williams-Hughes C. · Memory Disorders Center, Banner Alzheimer's Disease Institute, Phoenix, Arizona, USA. · Am J Geriatr Psychiatry. · Pubmed #16905684 No free full text.

Abstract: OBJECTIVES: The objectives of this study were to evaluate the efficacy, safety, and tolerability of quetiapine for treating psychosis in patients with probable/possible Alzheimer disease and assess its impact on other psychopathology and social and daily functioning. METHOD: The authors conducted a multicenter, double-blind, placebo-controlled, randomized trial of flexibly dosed quetiapine and haloperidol. Primary outcomes were change in total Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions-Severity of Illness (CGI-S) scores at week 10. Secondary outcomes included BPRS factors, Neuropsychiatric Inventory (NPI), Multidimensional Observation Scale for Elderly Subjects (MOSES), and Physical Self-Maintenance Scale (PSMS). RESULTS: Two hundred eighty-four participants (mean age: 83.2 years) were randomized; 63.4% completed; and mean Mini-Mental State Examination score was 12.8. Median of the mean daily dose was 96.9 mg for quetiapine and 1.9 mg for haloperidol. No differential benefit was seen on any psychosis measure. BPRS agitation factor scores improved with quetiapine versus placebo and not quetiapine versus haloperidol. BPRS anergia scores worsened with haloperidol versus quetiapine but not quetiapine versus placebo. No NPI factors showed change, including the agitation factor. MOSES Withdrawal Subscale and PSMS total scores worsened with haloperidol versus quetiapine. Somnolence occurred in 25.3%, 36.2%, and 4.1% of the quetiapine, haloperidol, and placebo groups, respectively; parkinsonism was most prevalent in the haloperidol group; other safety and tolerability measures differed little among groups. CONCLUSION: All treatment groups showed improvement in measures of psychosis without significant differences between them when planned comparisons were performed. Participants treated with quetiapine or haloperidol showed inconsistent evidence of improvement in agitation. Tolerability was better with quetiapine compared with haloperidol.

Cohen-Mansfield J, Mintzer JE. · Department of Health Care Sciences and of Prevention and Community Health, George Washington University Medical Center, Washington, DC, USA. · Alzheimer Dis Assoc Disord. · Pubmed #15764870 No free full text.

Abstract: This paper discusses the etiology of behavior problems in dementia and concludes that a substantial portion of such behaviors arise when care does not appropriately address the underlying causes. The needs of persons with dementia are frequently unrecognized and not addressed because of a combination of factors including communication problems, the multidimensional nature of etiologies and needs, the discounting of the needs of the patient with dementia, an environment that lacks knowledge and resources, and the improper allocation of resources on the part of policy makers, clinicians, and caregivers. The paper delineates some of the steps that are needed to move toward a more appropriate treatment of persons with dementia who manifest behavior problems.

Rosenberg PB, Onyike CU, Katz IR, Porsteinsson AP, Mintzer JE, Schneider LS, Rabins PV, Meinert CL, Martin BK, Lyketsos CG, Anonymous00389. · Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Int J Geriatr Psychiatry. · Pubmed #15660424 No free full text.

Abstract: OBJECTIVES: 'Depression of Alzheimer's Disease' (dAD) is a common complication of Alzheimer's disease and is increasingly recognized as a syndrome with a clinical presentation differing from major depression. Criteria for the diagnosis of dAD have been proposed previously. METHODS: This paper presents these criteria in operationalized format designed to be accessible for clinical use. Four cases are discussed that demonstrate the use of these criteria and illustrate important differences between dAD and major depression. RESULTS: The dAD criteria are broader than DSM-IV criteria for Major Depressive Episode and incorporate caregiver input. CONCLUSIONS: Given the differences between dAD and major depression diagnoses, it is important to assess the efficacy of treatments for dAD. Depression in Alzheimer's Disease-2 (DIADS-2) is a controlled trial of dAD treatments that will also assess the validity of these criteria.

Mintzer JE. · Medical University of Sourth Carolina, 5900 Core Road, Charleston, SC 29406, USA. · CNS Spectr. · Pubmed #15241295 No free full text.

Abstract: Alzheimer's disease (AD) is a debilitating condition affecting millions of elderly citizens. The quality of life for AD patients significantly deteriorates in the face of worsening cognitive deficits and disabling functional declines, both contributing to manifestations of difficult behaviors. Of the estimated 4 million individuals with AD, only 60% of probable AD cases are diagnosed, with little more than half of those receiving treatment. One of the possible reasons for this problem is the large role primary care physicians (PCPs) have in diagnosing and treating AD. The barriers that PCPs confront to adequately manage these patients will be discussed. Finally, the specific challenges that geriatric psychiatrists will face in addressing these issues in an environment where there is only a limited number of trained geriatric psychiatrists will be discussed, as well as the possible role that new technology could have in finding the solution to this difficult problem.

Mintzer JE. · Medical University of Sourth Carolina, Charleston, SC, USA. · CNS Spectr. · Pubmed #15241293 No free full text.

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