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Cynthia A Munro,
Crystal Flynn Longmire,
Lea T Drye,
Barbara K Martin,
Constantine E Frangakis,
Curtis L Meinert, Jacobo E Mintzer,
Anton P Porsteinsson,
Peter V Rabins,
Paul B Rosenberg,
Lon S Schneider,
Daniel Weintraub,
Constantine G Lyketsos
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ABSTRACT: OBJECTIVES:: Although many depressed patients with Alzheimer disease (AD) are treated with antidepressants, the effect of such treatment on cognitive performance in these patients is not known. The authors report cognitive outcomes in patients with depression of AD (dAD) after a 24-week trial of sertraline or placebo. DESIGN:: Placebo-controlled, randomized, double-blind trial. SETTING:: Outpatient memory clinics at five academic medical centers in the United States. PARTICIPANTS:: A total of 131 patients with dAD (60 men) and Mini-Mental State Examination scores of 10-26. INTERVENTION:: Sertraline (n = 67), target dose of 100 mg daily or matching placebo (n = 64). Caregivers received standardized psychosocial intervention throughout the trial. MEASUREMENTS:: Mini-Mental State Examination, cognitive subscale of the Alzheimer's Disease Assessment Scale, letter fluency, backward digit span, Symbol Digit Modalities Test, and Finger Tapping Test, administered at baseline, and 8, 16, and 24 weeks following baseline. RESULTS:: A series of linear models indicated no effect of treatment or of depression remission on cognitive test performance at 24 weeks. Regardless of treatment condition, very little change in cognitive test performance was noted in general. CONCLUSIONS:: Treatment with sertraline in patients with dAD is not associated with greater improvement in cognition at week 24 than treatment with placebo.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 10/2012; · 3.35 Impact Factor
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ABSTRACT: BACKGROUND:: Research on efficacious treatments for apathy in Alzheimer disease has been hindered by a lack of consensus diagnosis, difficulties in measurement, and studies with small sample sizes. METHODS:: In designing the Apathy in Dementia Methylphenidate Trial (ADMET), a trial to evaluate the efficacy and safety of methylphenidate for the treatment of apathy in Alzheimer disease, we encountered the following issues: defining and measuring apathy, distinguishing apathy and depression, determining an appropriate test treatment, selecting relevant secondary outcomes, recruiting participants, and deciding on a suitable method for treatment unmasking. ADMET is a 6-week randomized, double-masked, placebo-controlled multicenter clinical trial with two parallel treatment groups assigned in a 1:1 ratio with randomization stratified by clinical center. The recruitment goal is 60 randomized participants over 2 years. The primary outcomes are change in apathy severity as measured by the Apathy Evaluation Scale and the Alzheimer Disease Cooperative Study-Clinical Global Impression of Change. CONCLUSION:: The design decisions made for ADMET are important elements to be considered in trials assessing the safety and efficacy of medications for clinically significant apathy in Alzheimer disease.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 04/2012; · 3.35 Impact Factor
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Lea T Drye,
Zahinoor Ismail,
Anton P Porsteinsson,
Paul B Rosenberg,
Daniel Weintraub,
Christopher Marano,
Gregory Pelton,
Constantine Frangakis,
Peter V Rabins,
Cynthia A Munro,
Curtis L Meinert,
D P Devanand,
Jerome Yesavage, Jacobo E Mintzer,
Lon S Schneider,
Bruce G Pollock,
Constantine G Lyketsos
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ABSTRACT: Agitation is one of the most common neuropsychiatric symptoms of Alzheimer's disease (AD), and is associated with serious adverse consequences for patients and caregivers. Evidence-supported treatment options for agitation are limited. The citalopram for agitation in Alzheimer's disease (CitAD) study was designed to evaluate the potential of citalopram to ameliorate these symptoms.
CitAD is a randomized, double-masked, placebo-controlled multicenter clinical trial, with two parallel treatment groups assigned in a 1:1 ratio and randomization stratified by clinical center. The study included eight recruiting clinical centers, a chair's office, and a coordinating center located in university settings in the United States and Canada. A total of 200 individuals having probable AD with clinically significant agitation and without major depression were recruited for this study. Patients were randomized to receive citalopram (target dose of 30 mg/d) or matching placebo. Caregivers of patients in both treatment groups received a structured psychosocial therapy. Agitation was compared between treatment groups using the NeuroBehavioral Rating Scale and the AD Cooperative Study- Clinical Global Impression of Change, which are the primary outcomes. Functional performance, cognition, caregiver distress, and rates of adverse and serious adverse events were also measured.
The authors believe the design elements in CitAD are important features to be included in trials assessing the safety and efficacy of psychotropic medications for clinically significant agitation in AD.
Alzheimer's & dementia: the journal of the Alzheimer's Association 02/2012; 8(2):121-30. · 5.90 Impact Factor
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Lea T Drye,
Barbara K Martin,
Constantine E Frangakis,
Curtis L Meinert, Jacobo E Mintzer,
Cynthia A Munro,
Anton P Porsteinsson,
Peter V Rabins,
Paul B Rosenberg,
Lon S Schneider,
Daniel Weintraub,
Constantine G Lyketsos
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ABSTRACT: To determine if the effect of sertraline in the depression in Alzheimer's disease study - 2 (DIADS-2) differed in subgroups of patients defined by baseline depression criteria.
DIADS-2 was a randomized, parallel, placebo-controlled, multicenter trial designed to evaluate the efficacy and safety of sertraline (target dose of 100 mg/day) for the treatment of depression in patients with Alzheimer's disease. DIADS-2 enrolled 131 patients who met criteria for the depression of Alzheimer's disease (dAD). Analyses reported here examined if the effect of sertraline differed in various subgroups, including those meeting criteria for major depressive episode (MaD), minor depressive episode (MiD), and Alzheimer's-associated affective disorder (AAAD) at baseline.
At baseline, 52 of 131 participants (39.7%) met criteria for MaD, 54 (41.2%) for MiD, and 90 (68.7%) for AAAD. For the primary outcome of modified Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (mADCS-CGIC) scores at 12 weeks of follow-up, the odds of being at or better than a given mADCS-CGIC category did not significantly differ between the two treatment groups for those patients with MaD at baseline (OR(sertraline) = 0.66 [95% CI: 0.24, 1.82], p = 0.42); tests for interactions between treatment group and baseline depression diagnostic subgroup were not significant for MaD versus MiD versus neither (χ(2) = 1.05 (2df), p = 0.59) or AAAD versus no AAAD (χ(2) = 0.06 (1df), p = 0.81).
There was no evidence that sertraline treatment was more efficacious in those patients meeting baseline criteria for MaD compared to MiD or to neither.
International Journal of Geriatric Psychiatry 06/2011; 26(6):573-83. · 2.42 Impact Factor
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ABSTRACT: To examine the influence of apoliprotein E ε4 allele (APOE4) carrier status on disease progression by evaluating the rate of regional gray matter (GM) volume loss and disease severity in patients with newly diagnosed Alzheimer disease (AD) and stable amnestic mild cognitive impairment (MCI).
This study was approved by the institutional review board and was HIPAA compliant. All subjects or their legal representatives gave informed consent for participation. Ninety-five subjects (63 male; average age, 77.1 years; age range, 58-91 years; 51 APOE4 carriers; 44 noncarriers) with either documented MCI to AD conversion or stable amnestic MCI underwent three yearly magnetic resonance imaging examinations. Voxel-based morphometry for image postprocessing and Clinical Dementia Rating (CDR) scale for cognitive assessment were used.
In APOE4 carriers, GM volume loss affected the hippocampi, temporal and parietal lobes, right caudate nucleus, and insulae in patients with MCI to AD conversion and the insular and temporal lobes in patients in whom MCI was stable. In subjects who were not APOE4 carriers, there was no significant GM volume change. There were no differences in CDR scores between APOE4 carriers and noncarriers.
APOE4 carriers with cognitive decline undergo faster GM atrophy than do noncarriers. The involvement of APOE4 in the progression of hippocampal atrophy, neocortical atrophy, or both has potential important implications for diagnosis and therapeutic approaches in patients with AD and should be considered in clinical trials. The present results and the results of prior studies indicate that the rate of hippocampal and neocortical atrophy is greater in association with APOE4 in nondemented elderly subjects, subjects with MCI, and those with AD.
Radiology 03/2011; 258(3):843-52. · 5.73 Impact Factor
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Paul B Rosenberg,
Lea T Drye,
Barbara K Martin,
Constantine Frangakis, Jacobo E Mintzer,
Daniel Weintraub,
Anton P Porsteinsson,
Lon S Schneider,
Peter V Rabins,
Cynthia A Munro,
Curtis L Meinert,
Constantine G Lyketsos
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ABSTRACT: Depression is common in Alzheimer disease (AD), and antidepressants are commonly used for its treatment, however, evidence for antidepressant efficacy in this population is lacking. The authors conducted a multicenter, randomized, placebo-controlled trial titled "Depression in Alzheimer's Disease-2" to assess the efficacy and tolerability of sertraline for depression in AD.
One hundred thirty-one participants from five U.S. medical centers with mild-to-moderate AD (Mini-Mental State Examination scores 10-26) and depression of AD were randomized to double-blinded treatment with sertraline (N = 67) or placebo (N = 64), with a target dosage of 100 mg daily. Efficacy was assessed using logistic regressions and mixed effects models in an intention-to-treat analysis with imputation of missing data. Principal outcome measures were modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC), change in Cornell Scale for Depression in Dementia (CSDD) scores, and remission defined by both mADCS-CGIC score <or=2 and CSDD score <or=6.
mADCS-CGIC ratings (odd ratio [OR = 1.01], 95% confidence interval [CI]: 0.52-1.97, p = 0.98), CSDD scores (median difference at 12 weeks 1.2, 95% CI: 1.65-4.05, p = 0.41), and remission at 12 weeks of follow-up (OR = 2.06, 95% CI: 0.84-5.04, p = 0.11) did not differ between sertraline (N = 67) and placebo (N = 64). Sertraline-treated patients experienced more adverse events, most notably gastrointestinal and respiratory, than placebo-treated patients.
Sertraline did not demonstrate efficacy for the treatment depression symptoms in patients with AD. In addition, its use was associated with an increased incidence of adverse events. Thus, selective serotonin reuptake inhibitors may be of limited value for treating depression in patients with AD.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 02/2010; 18(2):136-45. · 3.35 Impact Factor
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Daniel Weintraub,
Paul B Rosenberg,
Lea T Drye,
Barbara K Martin,
Constantine Frangakis, Jacobo E Mintzer,
Anton P Porsteinsson,
Lon S Schneider,
Peter V Rabins,
Cynthia A Munro,
Curtis L Meinert,
Constantine G Lyketsos
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ABSTRACT: Depression and antidepressant use are common in Alzheimer disease (AD), but the effect of antidepressant treatment for depression on longer term outcomes is unknown. The authors report the Week-24 outcomes of patients who participated in a 12-week efficacy study of sertraline for depression of AD.
One hundred thirty-one participants (sertraline = 67, placebo = 64) with mild-moderate AD and depression participated in the study. Patients who showed improvement on the modified Alzheimer's Disease Cooperative Study Clinical Global Impression-Change (mADCS-CGIC) after 12 weeks of randomized treatment with sertraline or placebo continued double-blinded treatment for an additional 12 weeks. Depression response and remission at 24 weeks were based on mADCS-CGIC score and change in Cornell Scale for Depression in Dementia (CSDD) score. Secondary outcome measures included time to remission, nonmood neuropsychiatric symptoms, global cognition, function, and quality of life.
One hundred seventeen (89.3%) participants completed all study assessments and 74 (56.5%; sertraline = 38, placebo = 36) completed all 24 weeks on randomized treatment. By 24 weeks, there were no between-group differences in depression response (sertraline = 44.8%, placebo = 35.9%; odds ratio [95% CI] = 1.23 [0.64-2.35]), change in CSDD score (median difference = 0.6 [95% CI: -2.26 to 3.46], chi2 [df = 2] = 1.03), remission rates (sertraline = 32.8%, placebo = 21.8%; odds ratio [95% CI] = 1.61 [0.70-3.68]), or secondary outcomes. Common selective serotonin reuptake inhibitor-associated adverse events, specifically diarrhea, dizziness, and dry mouth, and pulmonary serious adverse events were more frequent in sertraline-randomized patients than in placebo subjects.
Sertraline treatment is not associated with delayed improvement between 12 and 24 weeks of treatment and may not be indicated for the treatment of depression of AD.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 02/2010; 18(4):332-40. · 3.35 Impact Factor
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David L Bachman,
Marilyn Stuckey,
Myla Ebeling,
Mark T Wagner,
W James Evans,
Victor Hirth,
Aljoeson Walker,
Mohammed Memon,
Rajiv Joglekar,
Warachal Faison, Jacobo E Mintzer
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ABSTRACT: The recruitment of culturally diverse subject populations into research studies, particularly African-Americans (AA), has been the focus of intense interest by many groups.
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.
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.
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.
Dementia and Geriatric Cognitive Disorders 04/2009; 27(4):329-36. · 2.14 Impact Factor
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Jacobo E Mintzer
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 08/2008; 16(7):614. · 3.35 Impact Factor
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ABSTRACT: To assess the efficacy and safety of aripiprazole for psychosis associated with Alzheimer dementia (AD).
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.
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.
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.
American Journal of Geriatric Psychiatry 12/2007; 15(11):918-31. · 3.64 Impact Factor
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Warachal E Faison,
Susan K Schultz,
Jeroen Aerssens,
Jennifer Alvidrez,
Ravi Anand,
Lindsay A Farrer,
Lissy Jarvik,
Jennifer Manly,
Thomas McRae,
Greer M Murphy,
Jason T Olin,
Darrel Regier,
Mary Sano, Jacobo E Mintzer
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ABSTRACT: 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?
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.
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.
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.
International Psychogeriatrics 07/2007; 19(3):539-58. · 2.24 Impact Factor
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Barbara K Martin,
Constantine E Frangakis,
Paul B Rosenberg, Jacobo E Mintzer,
Ira R Katz,
Anton P Porsteinsson,
Lon S Schneider,
Peter V Rabins,
Cynthia A Munro,
Curtis L Meinert,
George Niederehe,
Constantine G Lyketsos
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ABSTRACT: 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.
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.
The authors believe these design elements are important features to be included in trials of depression and other neuropsychiatric disturbances in Alzheimer disease.
American Journal of Geriatric Psychiatry 12/2006; 14(11):920-30. · 3.64 Impact Factor
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ABSTRACT: 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.
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).
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.
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.
American Journal of Geriatric Psychiatry 10/2006; 14(9):767-76. · 3.64 Impact Factor
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Jacobo E Mintzer
The Journal of Clinical Psychiatry 02/2006; 67 Suppl 10:3-5. · 5.80 Impact Factor
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American Journal of Geriatric Psychiatry 08/2005; 13(7):541-4. · 3.64 Impact Factor
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ABSTRACT: '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.
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.
The dAD criteria are broader than DSM-IV criteria for Major Depressive Episode and incorporate caregiver input.
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.
International Journal of Geriatric Psychiatry 03/2005; 20(2):119-27. · 2.42 Impact Factor
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ABSTRACT: To compare the tolerability of quetiapine with risperidone in older outpatients.
Post hoc analysis of a subset of older patients (aged 60-80; n = 92) from a randomized, 4-month, multicenter, open-label trial comparing quetiapine and risperidone in an outpatient setting. Participants had various neuropsychiatric disorders associated with psychosis as defined by criteria from the Diagnostic and Statistical Manual of Mental Disorders (4th edn).
The main outcome measure was an extrapyramidal symptoms (EPS) checklist, used to assess motor symptoms, including parkinsonism, at baseline and after treatment. The Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression scale were used to assess therapeutic efficacy.
Substantial EPS (defined as EPS requiring a dosage adjustment or use of medication to reduce EPS) occurred less often with quetiapine (median dosage, 200 mg/day) than with risperidone (median dosage, 3 mg/day); odds ratio, 0.31 (P < 0.03). Quetiapine was also less likely than risperidone to cause akathisia or hypertonia. Both compounds produced comparable reductions in PANSS scores.
Interpretation of findings in this report is limited by the open-label design of the study and the post hoc nature of this analysis. However, the results suggest that quetiapine, when given within the recommended dosage range, has a benign EPS profile, with potentially greater tolerability and comparable efficacy to risperidone in older outpatients with psychotic disorders.
Current Medical Research and Opinion 10/2004; 20(9):1483-91. · 2.38 Impact Factor
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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.
Current Drug Targets 09/2004; 5(6):517-28. · 3.55 Impact Factor
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Jacobo E Mintzer
CNS spectrums 08/2004; 9(7 Suppl 5):5. · 2.20 Impact Factor
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Jacobo E Mintzer
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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.
CNS spectrums 08/2004; 9(7 Suppl 5):13-5. · 2.20 Impact Factor
