Alzheimer Disease: Lyketsos CG

Lyketsos CG, Colenda CC, Beck C, Blank K, Doraiswamy MP, Kalunian DA, Yaffe K, Anonymous00013. · No affiliation provided · Am J Geriatr Psychiatry. · Pubmed #16816009 No free full text.

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Rabins PV, Lyketsos CG. · No affiliation provided · Nat Clin Pract Neurol. · Pubmed #17479071 No free full text.

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Martin BK, Breitner JC, Evans D, Lyketsos CG, Meinert CL. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md, USA. · Am J Med. · Pubmed #17349436 No free full text.

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Lyketsos CG, Szekely CA, Mielke MM, Rosenberg PB, Zandi PP. · Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland, U.S.A. · Int Psychogeriatr. · Pubmed #18498669 No free full text.

Abstract: This synthetic review presents an approach to the use of biomarkers for the development of new treatments for Alzheimer's disease (AD). After reviewing the process of translation as applied to AD, the paper provides a general update on what is known about the biology of the disease, and highlights currently available treatments. This is followed by a discussion of future drug development for AD emphasizing the roles that biomarkers are likely to play in this process: (1) define patients who are going to progress rapidly for the purpose of trial enrichment; (2) differentiate disease and therapeutically relevant AD subtypes; (3) assess the potential activity of specific therapies in vivo or ex vivo; and (4) measure the underlying disease state, so as to (a) detect disease and assess drug response in asymptomatic patients, (b) serve as a secondary outcome measure in clinical trials of symptomatic patients, and (c) decide if further development of a treatment should be stopped if not likely to be effective. Several examples are used to illustrate each biomarker utility in the AD context.

Mielke MM, Lyketsos CG. · Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry, and the Alzheimer's Disease Research Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA. · Int Rev Psychiatry. · Pubmed #16777671 No free full text.

Abstract: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder characterized pathologically by amyloid-beta plaques, neurofibrillary tangles and neuronal loss. Its fundamental cause(s) and the pathological cascades leading to clinical symptoms remain unknown. Lipids and lipid peroxidation products have important roles in the homeostasis of the central nervous system. As well, lipid transport genes and vascular changes associated with peripheral dyslipidemia have been associated with an increased risk of AD. The present review discusses ways in which lipids may be involved in the pathogenesis of AD-associated neurodegeneration through their roles as neuronal structural components, cell modulators, or second messengers. Given the many possibilities through which lipids may be directly involved in or contribute to the pathogenesis of AD, the use of lipids as biomarkers for disease progression is discussed, as are other avenues for future research.

Lyketsos CG, Lee HB. · Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287-5371, USA. · Dement Geriatr Cogn Disord. · Pubmed #14564126 No free full text.

Abstract: Over 80% of patients with Alzheimer's disease (AD) develop 'noncognitive' neuropsychiatric symptoms at some point during the course of their illness. Depression is among the most frequent of such comorbidities. Affecting up to 50% of AD patients, depression is associated with severe negative consequences for patients and caregivers. Despite having a presentation in the context of AD that differs from typical 'geriatric' depression, it can be detected and quantified reliably, and can be differentiated from the other neuropsychiatric symptoms of AD. Several effective treatment modalities for depression in AD are available. In many cases, these reduce its adverse impact on patients and caregivers. This paper provides an overview of current knowledge regarding depression in AD for the clinician. It is followed by a practical discussion of the detection, evaluation, quantification, differential diagnosis and treatment of depression in AD.

Bassiony MM, Lyketsos CG. · Faculty of Medicine, Zagazig University, Sharkia, Zagazig, Egypt. · Psychosomatics. · Pubmed #12954913 links to  free full text

Abstract: The authors reviewed studies published from 1990 to 2001 that address the epidemiology, phenomenology, course, etiology, assessment, and treatment of delusions and hallucinations in Alzheimer's disease. The prevalence of delusions in Alzheimer's disease patients ranged from 16% to 70% (median=36.5%) in the reviewed reports, and the prevalence of hallucinations ranged from 4% to 76% (median=23%). Delusions and hallucinations tended to persist over time, tended to recur often during the course of Alzheimer's disease, and were associated with sociodemographic and clinical correlates that differed from one study to another and with substantial consequences such as functional impairment and aggression. Psychosocial methods and both typical and atypical antipsychotics are effective in the treatment of delusions and hallucinations in Alzheimer's disease.

Lee HB, Lyketsos CG. · Geriatric Psychiatry and Neuropsychiatry Service, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · Biol Psychiatry. · Pubmed #12893110 No free full text.

Abstract: Several studies have demonstrated that the great majority of Alzheimer's disease (AD) patients suffer "noncognitive" neuropsychiatric symptoms. Depression is one of the most frequent neuropsychiatric comorbidities of AD. Affecting up to 50% of AD patients, depression in AD is associated with serious negative consequences for patients and their caregivers. Yet available studies on the natural course, etiology, and treatment of depression in AD have been few and equivocal. Heterogeneity in research methodology and etiology of depression in AD might have contributed to inconsistent findings across studies. Recently, the National Institute of Mental Health (NIMH) convened the Depression of Alzheimer's Disease Workgroup, which proposed provisional diagnostic criteria for depression of Alzheimer's Disease (NIMH-dAD). These criteria may provide a framework for future studies to clarify the unresolved issues in nosology, etiology, and treatment of depression in AD. A longitudinal cohort study of depression in incident AD cases may provide further syndrome refinement that would facilitate investigation of the etiology and treatment of depression in AD.

Lyketsos CG, Olin J. · Neuropsychiatry Service (CGL), Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA. · Biol Psychiatry. · Pubmed #12182930 No free full text.

Abstract: Psychiatric disturbances affect as many as 90% of patients with Alzheimer's disease (AD) and are a major focus of treatment. Depression is one of the most frequent psychiatric complications of AD, affecting as many as 50% of patients. In this context, depression is a significant public health problem that has a series of serious adverse consequences for patients and their caregivers. There has been little research into the course or treatment of depression associated with AD. This is in part due to the absence of validated operational criteria for defining depression in AD. Recently, the National Institute of Mental Health (NIMH) convened an expert consensus panel to develop draft criteria for depression of Alzheimer's disease (NIMH-dAD) and to establish research priorities in this area. This article provides an overview of recent knowledge with regard to depression in AD with a special emphasis on its treatment. We conclude with recommendations for further research in this area.

Khachaturian AS, Zandi PP, Lyketsos CG, Hayden KM, Skoog I, Norton MC, Tschanz JT, Mayer LS, Welsh-Bohmer KA, Breitner JC. · Khachaturian and Associates Inc., Potomac, MD, USA. · Arch Neurol. · Pubmed #16533956 links to  free full text

Abstract: BACKGROUND: Recent reports suggest that antihypertensive (AH) medications may reduce the risk of dementing illnesses. OBJECTIVES: To examine the relationship of AH medication use with incidence of Alzheimer disease (AD) among the elderly population (aged 65 years and older) of Cache County, Utah, and to examine whether the relationship varies with different classes of AH medications. METHODS: After an initial (wave 1) multistage assessment (1995 through 1997) to identify prevalent cases of dementia, we used similar methods 3 years later (wave 2) to identify 104 incident cases of AD among the 3308 survivors. At the baseline assessment, we obtained a detailed drug inventory from the study participants. We carried out discrete time survival analyses to examine the association between the use of AH medications (including angiotensin converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics) at baseline with subsequent risk of AD. RESULTS: Use of any AH medication at baseline was associated with lower incidence of AD (adjusted hazard ratio, 0.64; 95% confidence interval, 0.41-0.98). Examination of medication subclasses showed that use of diuretics (adjusted hazard ratio, 0.57; 95% confidence interval, 0.33-0.94), and specifically potassium-sparing diuretics (adjusted hazard ratio, 0.26; 95% confidence interval, 0.08-0.64), was associated with the greatest reduction in risk of AD. Corresponding analysis with a fully examined subsample controlling for blood pressure measurements did not substantially change our findings. CONCLUSIONS: These data suggest that AH medications, and specifically potassium-sparing diuretics, are associated with reduced incidence of AD. Because the latter association is a new finding, it requires confirmation in further study.

Rao V, Spiro JR, Rosenberg PB, Lee HB, Rosenblatt A, Lyketsos CG. · Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry & Behavioral Sciences, The Johns Hopkins School of Medicine, Baltimore, MD, USA. · Int J Geriatr Psychiatry. · Pubmed #16477587 No free full text.

Abstract: BACKGROUND: Depression is a frequent neuropsychiatric complication of Alzheimer's Disease. METHODS: This study investigated the safety and effectiveness of escitalopram (LEXAPRO) for depression in AD (dAD) as defined by the NIMH consensus criteria in an 8-week, open-label treatment study. CONCLUSION: Escitalopram was efficacious and safe for the treatment of dAD in this study. Larger, controlled studies are warranted to further assess the efficacy for mood and behavioral disturbances in this medically fragile population.

Politis AM, Vozzella S, Mayer LS, Onyike CU, Baker AS, Lyketsos CG. · The Johns Hopkins University, Baltimore, MD 21287, USA. · Int J Geriatr Psychiatry. · Pubmed #15481065 No free full text.

Abstract: BACKGROUND: Apathy is a common symptom in patients with dementia and has adverse consequences for patients and caregivers. Most treatments for apathy, particularly non-pharmacologic interventions, have not been evaluated in controlled trials. OBJECTIVES: This study evaluated the efficacy of a kit-based activity intervention, compared to a time and attention control (one-on-one meetings with an activity therapist) in reducing apathy and improving quality of life in 37 patients with dementia. METHODS: The design was a randomized, controlled, partially masked clinical trial. All outcome measures were administered at baseline and follow-up. The primary outcome measure was the apathy score of the Neuropsychiatric Inventory (NPI). Other outcome measures were the NPI total score, the Alzheimer Disease Related Quality of Life scale(ADQRL), and the Copper Ridge Activity Index (CRAI). RESULTS: There was a significant reduction in NPI apathy scores in both treatment groups. The only significant difference between the two treatment groups was a modest advantage for the control intervention on the CRAI cueing subscale (p = 0.027), but not on the other CRAI subscales. There was also a greater within group improvement in quality of life ratings in the control intervention (p=0.03). CONCLUSIONS: Despite the substantial improvement in apathy scores during the course of the study, there was no clear advantage to the reminiscence-based intervention over the time and attention, one-on-one control intervention. More research is needed to develop specific behavioral interventions for apathy in patients with dementia.

Munro CA, Brandt J, Sheppard JM, Steele CD, Samus QM, Steinberg M, Rabins PV, Lyketsos CG. · Division of Medical Psychology, Department of Psychiatry and Behavioral Sciences, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA. · Am J Geriatr Psychiatry. · Pubmed #15353387 No free full text.

Abstract: OBJECTIVE: The authors assessed the cognitive effects of depression treatment with sertraline in patients with Alzheimer disease (AD) and major depression. METHODS: Forty-four patients with probable AD and major depression were enrolled in a double-blind, placebo-controlled clinical trial of sertraline. Cognitive testing was done at baseline and at 3-week intervals throughout the 12-week study. At the 12th week, subjects were categorized by treatment response (full, partial, or no response). Cognitive data from 41 participants who completed three or more testing sessions and 36 who completed all five study visits were included in the analyses. RESULTS: Neither improved mood nor use of sertraline was associated with cognitive change over time in AD patients. Post-hoc exploration of the data, however, suggested a sex difference in cognitive response to sertraline such that women treated with sertraline demonstrated improved cognition compared with women on placebo, whereas men treated with sertraline worsened significantly in cognition compared with men on placebo. CONCLUSIONS: In this study, among depressed AD patients after treatment with sertraline or placebo, there was no evidence that improved mood was associated with cognitive improvement. Future studies aimed at increasing power to detect mood as well as medication effects will be valuable in determining the relationship between cognition and treatment of depression in AD patients.

Lyketsos CG, Reichman WE, Kershaw P, Zhu Y. · Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Osler 320, 600 North Wolfe Street, Baltimore, MD 21287, USA. · Am J Geriatr Psychiatry. · Pubmed #15353385 No free full text.

Abstract: OBJECTIVE: The authors evaluated the long-term safety, efficacy, and tolerability of galantamine 24 mg/day in the treatment of Alzheimer disease by means of a 12-month, open-label extension of an earlier 5-month, double-blind, placebo-controlled trial with a 6-week withdrawal phase. METHODS: Patients completing two double-blind, placebo-controlled trials (N=699) were escalated to a 24-mg dose (12 mg bid) of galantamine during a period of 2 weeks and treated for 12 months beyond the initial 6.5-month, double-blind period (total treatment duration: 18.5 months). The primary efficacy measure was the change from baseline in the Alzheimer's Disease Assessment Scale (ADAS-Cog/11) score at 18.5 months; secondary endpoints included total scores on the Alzheimer's Disease Cooperative Study of Activities of Daily Living and the Neuropsychiatric Inventory. Standard safety evaluations, including adverse-event monitoring, were performed. RESULTS: Patients taking galantamine continuously throughout the double-blind and open-label studies (N=288) showed sustained cognitive benefits on ADAS-Cog/11 scores at 18.5 months. Patients were maintained close to baseline cognitive ability for 12 months, and safety was as expected and documented in other large studies of galantamine. Analysis of the subgroup of patients (N=113) who completed the entire 18.5 months of galantamine treatment showed that cognitive function was maintained up to 14 months. CONCLUSIONS: Results of this open-label extension support the findings from previous galantamine studies and demonstrate the safety and tolerability of galantamine for up to 18.5 months.

Steinberg M, Munro CA, Samus Q, V Rabins P, Brandt J, Lyketsos CG. · Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Int J Geriatr Psychiatry. · Pubmed #14758580 No free full text.

Abstract: OBJECTIVE: To investigate patient predictors of response to treatment of Major Depressive Episode (MDE) in Alzheimer's disease (AD). METHODS: Forty-four outpatients with AD and MDE were randomized to receive either sertraline or placebo in a 12-week placebo-controlled, flexible-dose clinical trial after a one week single-blind placebo phase. All participants were evaluated for depression at entry using the 21-item Hamilton Depression Rating Scale (HDRS) and the Cornell Scale for Depression in Dementia (CSDD). All subjects completed baseline neuropsychological testing. Caregiver burden and depression were also measured. The forty-two subjects who completed at least one post-enrollment follow-up visit were included in the analysis. RESULTS: No baseline demographic, mood, neuropsychiatric, neuropsychological, or caregiver variable was a statistically significant predictor of response to treatment. There were trends for African-American patients (p=0.07) and those with milder baseline agitation/aggression (p=0.08) to respond better. CONCLUSION: No baseline characteristic assessed clearly predicts response to treatment of MDE in AD. A diverse population of depressed AD patients may thus respond similarly to the same treatment.

Lyketsos CG, DelCampo L, Steinberg M, Miles Q, Steele CD, Munro C, Baker AS, Sheppard JM, Frangakis C, Brandt J, Rabins PV. · Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA. · Arch Gen Psychiatry. · Pubmed #12860778 links to  free full text

Abstract: CONTEXT: Major depression affects about 25% of the patients who have Alzheimer disease and has serious adverse consequences for patients and caregivers. Results of prior antidepressant treatment studies have produced contradictory findings and have not fully assessed the benefits of depression reduction. OBJECTIVES: To assess the efficacy and safety of sertraline hydrochloride for the treatment of major depression in Alzheimer disease, and to evaluate the effect of depression reduction on activities of daily living, cognition, and nonmood behavioral disturbance. DESIGN: Randomized, placebo-controlled, parallel, 12-week, flexible-dose clinical trial with a 1-week, single-blind placebo phase. The study was conducted between January 1, 1998, and July 19, 2001. SETTING: University outpatient clinic. PARTICIPANTS: Forty-four outpatients who have probable Alzheimer disease and major depressive episodes. INTERVENTION: Sertraline hydrochloride, mean dosage of 95 mg/d, or identical placebo, randomly assigned. MAIN OUTCOME MEASURES: Response rate, Cornell Scale for Depression in Dementia, Hamilton Depression Rating Scale, Mini-Mental State Examination, Psychogeriatric Depression Rating Scale-activities of daily living subscale, and Neuropsychiatric Inventory to quantify patient behavior disturbance and caregiver distress. RESULTS: In the sertraline-treated group 9 patients (38%) were full responders and 11 (46%) were partial responders compared with 3 (20%) and 4 (15%), respectively, in the placebo-treated group (P =.007). The sertraline-treated group had greater improvements in the scores for the Cornell Scale for Depression in Dementia (P =.002) and Hamilton Depression Rating Scale (P =.01), and a statistical trend toward less decline in activities of daily living on the Psychogeriatric Depression Rating Scale-activities of daily living subscale (P =.07). There was no difference between the treatment groups in Mini-Mental State Examination (P =.22) or Neuropsychiatric Inventory (P =.32) ratings over time. When full responders, partial responders, and nonresponders were compared, full responders only, or full and partial responders had significantly better ratings on activities of daily living (P =.04), behavioral disturbance (P =.01), and caregiver distress (P =.006), but not on the Mini-Mental State Examination (P =.76). Safety monitoring indicated few differences in adverse effects between the 2 treatment groups. CONCLUSIONS: Sertraline is superior to placebo for the treatment of major depression in Alzheimer disease. Depression reduction is accompanied by lessened behavior disturbance and improved activities of daily living, but not improved cognition.

Schneider LS, Tariot PN, Lyketsos CG, Dagerman KS, Davis KL, Davis S, Hsiao JK, Jeste DV, Katz IR, Olin JT, Pollock BG, Rabins PV, Rosenheck RA, Small GW, Lebowitz B, Lieberman JA. · Clinical Antipsychotic Trials of Intervention Effectiveness Program of the National Institute of Mental Health at the University of North Carolina, Chapel Hill, NC, USA. · Am J Geriatr Psychiatry. · Pubmed #11739062 No free full text.

Abstract: The authors describe the development of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) protocol for Alzheimer disease (AD), a trial developed in collaboration with the National Institute of Mental Health (NIMH), assessing the effectiveness of atypical antipsychotics for psychosis and agitation occurring in AD outpatients. They provide an overview of the methodology utilized in the trial as well as the clinical-outcomes and effectiveness measures that were implemented.

Lyketsos CG, Sheppard JM, Steele CD, Kopunek S, Steinberg M, Baker AS, Brandt J, Rabins PV. · Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, USA. · Am J Psychiatry. · Pubmed #11007727 links to  free full text

Abstract: OBJECTIVE: This study evaluated the efficacy and safety of sertraline in the treatment of major depression in 22 outpatients with Alzheimer's disease. METHOD: Twelve of the 22 patients were given sertraline and 10 were given placebo by random group assignment for 12 weeks. Response to treatment was measured by using the Cornell Scale for Depression in Dementia. The patients were also assessed with the Hamilton Depression Rating Scale, the activities of daily living subscale of the Psychogeriatric Dependency Rating Scales, and the Mini-Mental State. RESULTS: After 12 weeks of double-blind, placebo-controlled treatment, nine of the patients given sertraline and two of those given placebo were at least partial responders. Patients given sertraline had significantly greater mean declines from baseline in Cornell Scale for Depression in Dementia scores; the bulk of antidepressant response occurred by the third week of treatment. CONCLUSIONS: Sertraline is superior to placebo in reducing depression in patients with Alzheimer's disease who also suffer from major depression.

Lyketsos CG, Lindell Veiel L, Baker A, Steele C. · Department of Psychiatry and Behavioral Sciences, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21287, USA. · Int J Geriatr Psychiatry. · Pubmed #10440971 No free full text.

Abstract: BACKGROUND: Agitated behaviors are common in dementia patients residing in chronic care settings. Their occurrence may be associated with lack of adequate exposure to sunlight and with circadian rhythm disturbances.OBJECTIVE: Prior research has suggested that bright light therapy (BLT) may reduce agitated behaviors in dementia patients. The aim of this study was to test the efficacy of BLT in a randomized, controlled, crossover clinical trial. METHOD: Fifteen patients with dementia and agitated behaviors residing in a chronic care facility were randomized in a crossover design to morning BLT for 1 hour per day or to a control condition with dim light exposure. Patients were treated in either condition for 4 weeks, followed by 1 week on no treatment, prior to being crossed over to the other condition. RESULTS: Eight out of 15 patients completed the entire study. The rest completed at least 2 weeks of study. Patients randomized to the BLT condition exhibited a statistically significant improvement in nocturnal sleep from a mean of 6.4 hours/night to 8.1 hours/night 4 weeks later (p<0.05). The sleep of patients in the control condition did not improve significantly. There were no other significant differences between baseline and follow-up, nor between BLT and control treated patients on the other outcome measures, which included the Behavioral Pathology in Alzheimer Disease scale (Behave-AD) and the Cornell Scale for Depression in Dementia. CONCLUSION: Patients with dementia in chronic care who exhibit agitated behaviors sleep more hours at night when administered morning BLT. However, BLT does not lead to improvements in agitated behaviors in institutionalized patients with dementia with non-disturbed sleep-wake cycles.

Ballard CG, Gauthier S, Cummings JL, Brodaty H, Grossberg GT, Robert P, Lyketsos CG. · King's College London, London, UK. · Nat Rev Neurol. · Pubmed #19488082 No free full text.

Abstract: Agitation and aggression are frequently occurring and distressing behavioral and psychological symptoms of dementia (BPSD). These symptoms are disturbing for individuals with Alzheimer disease, commonly confer risk to the patient and others, and present a major management challenge for clinicians. The most widely prescribed pharmacological treatments for these symptoms-atypical antipsychotics-have a modest but significant beneficial effect in the short-term treatment (over 6-12 weeks) of aggression but limited benefits in longer term therapy. Benefits are less well established for other symptoms of agitation. In addition, concerns are growing over the potential for serious adverse outcomes with these treatments, including stroke and death. A detailed consideration of other pharmacological and nonpharmacological approaches to agitation and aggression in patients with Alzheimer disease is, therefore, imperative. This article reviews the increasing evidence in support of psychological interventions or alternative therapies (such as aromatherapy) as a first-line management strategy for agitation, as well as the potential pharmacological alternatives to atypical antipsychotics-preliminary evidence for memantine, carbamazepine, and citalopram is encouraging.

Oishi K, Faria A, Jiang H, Li X, Akhter K, Zhang J, Hsu JT, Miller MI, van Zijl PC, Albert M, Lyketsos CG, Woods R, Toga AW, Pike GB, Rosa-Neto P, Evans A, Mazziotta J, Mori S. · The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neuroimage. · Pubmed #19385016 No free full text.

Abstract: The purpose of this paper is to establish single-participant white matter atlases based on diffusion tensor imaging. As one of the applications of the atlas, automated brain segmentation was performed and the accuracy was measured using Large Deformation Diffeomorphic Metric Mapping (LDDMM). High-quality diffusion tensor imaging (DTI) data from a single-participant were B0-distortion-corrected and transformed to the ICBM-152 atlas or to Talairach coordinates. The deep white matter structures, which have been previously well documented and clearly identified by DTI, were manually segmented. The superficial white matter areas beneath the cortex were defined, based on a population-averaged white matter probability map. The white matter was parcellated into 176 regions based on the anatomical labeling in the ICBM-DTI-81 atlas. The automated parcellation was achieved by warping this parcellation map to normal controls and to Alzheimer's disease patients with severe anatomical atrophy. The parcellation accuracy was measured by a kappa analysis between the automated and manual parcellation at 11 anatomical regions. The kappa values were 0.70 for both normal controls and patients while the inter-rater reproducibility was 0.81 (controls) and 0.82 (patients), suggesting "almost perfect" agreement. A power analysis suggested that the proposed method is suitable for detecting FA and size abnormalities of the white matter in clinical studies.

Zheng L, Mack WJ, Dagerman KS, Hsiao JK, Lebowitz BD, Lyketsos CG, Stroup TS, Sultzer DL, Tariot PN, Vigen C, Schneider LS. · Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, USA. · Am J Psychiatry. · Pubmed #19369318 No free full text.

Abstract: OBJECTIVE: The second-generation antipsychotics are associated with metabolic abnormalities in patients with schizophrenia. Elderly patients with Alzheimer's disease are frequently treated with these antipsychotics, but limited data are available on their metabolic effects. METHOD: The authors assessed 186 male and 235 female Alzheimer's disease outpatients from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) for changes in weight, waist circumference, blood pressure, fasting glucose, and lipids in relation to duration of second-generation antipsychotic use (i.e., olanzapine, quetiapine, and risperidone) throughout the 36-week trial, using logistic regression and mixed-effects models. RESULTS: Women showed significant weight gain (0.14 lb/week of use) while change was nonsignificant in men. Clinically significant weight gain (i.e., > or = 7% of body weight) was seen among patients with antipsychotic use < or = 12 weeks (odds ratio [OR]=1.56, 95% CI=0.53 to 4.58), between 12 and 24 weeks (OR=2.89, 95% CI=0.97 to 8.64), and > 24 weeks (OR=3.38, 95% CI=1.24 to 9.23) relative to patients who did not use antipsychotics during the trial. Olanzapine and quetiapine treatments were significantly associated with weight gain (0.12 and 0.14 lb/week, respectively). In addition, olanzapine was significantly associated with decreases in HDL cholesterol (-0.19 mg/dl/week) and increased girth (0.07 inches/week) relative to the placebo group. No treatment effects were noted for changes in blood pressure, glucose, and triglycerides. CONCLUSION: Second-generation antipsychotic use was associated with weight gain in women, with olanzapine and quetiapine in particular, and with unfavorable change in HDL cholesterol and girth with olanzapine. The potential consequences of these effects suggest that patients with Alzheimer's disease treated with second-generation antipsychotics should be monitored closely.

Rosenberg PB, Mielke MM, Tschanz J, Cook L, Corcoran C, Hayden KM, Norton M, Rabins PV, Green RC, Welsh-Bohmer KA, Breitner JC, Munger R, Lyketsos CG. · Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA. · Am J Geriatr Psychiatry. · Pubmed #18978249 links to  free full text

Abstract: BACKGROUND: Evidence suggests that cardiovascular medications, including statins and antihypertensive medications, may delay cognitive decline in patients with Alzheimer dementia (AD). We examined the association of cardiovascular medication use and rate of functional decline in a population-based cohort of individuals with incident AD. METHODS: In the Dementia Progression Study of the Cache County Study on Memory, Health, and Aging, 216 individuals with incident AD were identified and followed longitudinally with in-home visits for a mean of 3.0 years and 2.1 follow-up visits. The Clinical Dementia Rating (CDR) was completed at each follow-up. Medication use was inventoried during in-home visits. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) as the outcome and cardiovascular medication use as the major predictors. RESULTS: CDR-Sum increased an average of 1.69 points annually, indicating a steady decline in functioning. After adjustment for demographic variables and the baseline presence of cardiovascular conditions, use of statins (p = 0.03) and beta-blockers (p = 0.04) was associated with a slower annual rate of increase in CDR-Sum (slower rate of functional decline) of 0.75 and 0.68 points respectively, while diuretic use was associated with a faster rate of increase in CDR-Sum (p = 0.01; 0.96 points annually). Use of calcium-channel blockers, angiotensin-converting enzyme inhibitors, digoxin, or nitrates did not affect the rate of functional decline. CONCLUSIONS: In this population-based study of individuals with incident AD, use of statins and beta-blockers was associated with delay of functional decline. Further studies are needed to confirm these results and to determine whether treatment with these medications may help delay AD progression.

Sultzer DL, Davis SM, Tariot PN, Dagerman KS, Lebowitz BD, Lyketsos CG, Rosenheck RA, Hsiao JK, Lieberman JA, Schneider LS, Anonymous00049. · Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. · Am J Psychiatry. · Pubmed #18519523 links to  free full text

Abstract: OBJECTIVE: The study measured the effects of atypical antipsychotics on psychiatric and behavioral symptoms in patients with Alzheimer's disease and psychosis or agitated behavior. METHOD: The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Alzheimer's disease effectiveness study included 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behavior. Patients were assigned randomly to masked, flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks. Patients could be randomly reassigned to a different medication at the clinician's discretion, which ended phase 1. Psychiatric and behavioral symptoms, functioning, cognition, care needs, and quality of life were measured at regular intervals. RESULTS: In relation to placebo, the last observation in phase 1 showed greater improvement with olanzapine or risperidone on the Neuropsychiatric Inventory total score, risperidone on the Clinical Global Impression of Changes, olanzapine and risperidone on the Brief Psychiatric Rating Scale (BPRS) hostile suspiciousness factor, and risperidone on the BPRS psychosis factor. There was worsening with olanzapine on the BPRS withdrawn depression factor. Among patients continuing phase 1 treatment at 12 weeks, there were no significant differences between antipsychotics and placebo on cognition, functioning, care needs, or quality of life, except for worsened functioning with olanzapine compared to placebo. CONCLUSION: In this descriptive analysis of outpatients with Alzheimer's disease in usual care settings, some clinical symptoms improved with atypical antipsychotics. Antipsychotics may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. They do not appear to improve functioning, care needs, or quality of life.

Treiber KA, Lyketsos CG, Corcoran C, Steinberg M, Norton M, Green RC, Rabins P, Stein DM, Welsh-Bohmer KA, Breitner JC, Tschanz JT. · Department of Psychology, Utah State University, Logan, U.S.A. · Int Psychogeriatr. · Pubmed #18289451 links to  free full text

Abstract: OBJECTIVE: To examine, in an exploratory analysis, the association between vascular conditions and the occurrence of neuropsychiatric symptoms (NPS) in a population-based sample of incident Alzheimer's disease (AD). METHODS: The sample consisted of 254 participants, identified through two waves of assessment. NPS were assessed using the Neuropsychiatric Inventory. Prior to the onset of AD, data regarding a history of stroke, hypertension, hyperlipidemia, heart attack or coronary artery bypass graft (CABG), and diabetes were recorded. Logistic regression procedures were used to examine the relationship of each vascular condition to individual neuropsychiatric symptoms. Covariates considered were age, gender, education, APOE genotype, dementia severity, and overall health status. RESULTS: One or more NPS were observed in 51% of participants. Depression was most common (25.8%), followed by apathy (18.6%), and irritability (17.7%). Least common were elation (0.8%), hallucinations (5.6%), and disinhibition (6.0%). Stroke prior to the onset of AD was associated with increased risk of delusions (OR = 4.76, p = 0.02), depression (OR = 3.87, p = 0.03), and apathy (OR = 4.48, p = 0.02). Hypertension was associated with increased risk of delusions (OR = 2.34, p = 0.02), anxiety (OR = 4.10, p = 0.002), and agitation/aggression (OR = 2.82, p = 0.01). No associations were observed between NPS and diabetes, hyperlipidemia, heart attack or CABG, or overall health. CONCLUSIONS: Results suggest that a history of stroke and hypertension increase the risk of specific NPS in patients with AD. These conditions may disrupt neural circuitry in brain areas involved in NPS. Findings may provide an avenue for reduction in occurrence of NPS through the treatment or prevention of vascular risk conditions.