Hanna Kaduszkiewicz

Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials

Abstract Objectives Pharmacological treatment of Alzheimers disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents. Data sources The terms “donepezil”, “rivastigmine”, and “galantamine”, limited by “randomized-controlled-trials” were searched in Medline (1989-November 2004), Embase (1989-November 2004), and the Cochrane Database of Systematic Reviews without restriction for language. Study selection All published, double blind, randomised controlled trials examining efficacy on the basis of clinical outcomes, in which treatment with donepezil, rivastigmine, or galantamine was compared with placebo in patients with Alzheimers disease, were included. Each study was assessed independently, following a predefined checklist of criteria of methodological quality. Results 22 trials met the inclusion criteria. Follow-up ranged from six weeks to three years. 12 of 14 studies measuring the cognitive outcome by means of the 70 point Alzheimers disease assessment scale—cognitive subscale showed differences ranging from 1.5 points to 3.9 points in favour of the respective cholinesterase inhibitors. Benefits were also reported from all 12 trials that used the clinicians interview based impression of change scale with input from caregivers. Methodological assessment of all studies found considerable flaws—for example, multiple testing without correction for multiplicity or exclusion of patients after randomisation. Conclusion Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimers disease is questionable.

Prediction of Dementia by Subjective Memory Impairment Effects of Severity and Temporal Association With Cognitive Impairment

CONTEXT Subjective memory impairment (SMI) is receiving increasing attention as a pre-mild cognitive impairment (MCI) condition in the course of the clinical manifestation of Alzheimer disease (AD). OBJECTIVES To determine the risk for conversion to any dementia, dementia in AD, or vascular dementia by SMI, graded by the level of SMI-related worry and by the temporal association of SMI and subsequent MCI. DESIGN Longitudinal cohort study with follow-up examinations at 1(1/2) and 3 years after baseline. SETTING Primary care medical record registry sample. PARTICIPANTS A total of 2415 subjects without cognitive impairment 75 years or older in the German Study on Aging, Cognition and Dementia in Primary Care Patients. MAIN OUTCOME MEASURES Conversion to any dementia, dementia in AD, or vascular dementia at follow-up 1 or follow-up 2 predicted by SMI with or without worry at baseline and at follow-up 2 predicted by different courses of SMI at baseline and MCI at follow-up 1. RESULTS In the first analysis, SMI with worry at baseline was associated with greatest risk for conversion to any dementia (hazard ratio [HR], 3.53; 95% confidence interval [CI], 2.07-6.03) or dementia in AD (6.54; 2.82-15.20) at follow-up 1 or follow-up 2. The sensitivity was 69.0% and the specificity was 74.3% conversion to dementia in AD. In the second analysis, SMI at baseline and MCI at follow-up 1 were associated with greatest risk for conversion to any dementia (odds ratio [OR], 8.92; 95% CI, 3.69-21.60) or dementia in AD (19.33; 5.29-70.81) at follow-up 2. Furthermore, SMI at baseline and amnestic MCI at follow-up 1 increased the risk for conversion to any dementia (OR, 29.24; 95% CI, 8.75-97.78) or dementia in AD (60.28; 12.23-297.10), with a sensitivity of 66.7% and a specificity of 98.3% for conversion to dementia in AD. CONCLUSION The prediction of dementia in AD by SMI with subsequent amnestic MCI supports the model of a consecutive 3-stage clinical manifestation of AD from SMI via MCI to dementia.

AD dementia risk in late MCI, in early MCI, and in subjective memory impairment

To compare the risk of developing Alzheimers disease (AD) dementia in late mild cognitive impairment (LMCI), early MCI (EMCI), and subjective memory impairment (SMI) with normal test performance.

Mild Cognitive Impairment in General Practice: Age-Specific Prevalence and Correlate Results from the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe)

Background: Although mild cognitive impairment (MCI) represents a high-risk factor for developing dementia, little is known about the prevalence of MCI among patients of general practitioners (GPs). Aims: Estimation of age-specific prevalence for original and modified concepts of MCI and their association with sociodemographic, medical and genetic (apoE Ε4 genotype) factors among patients of GPs. Methods: A GP practice sample of 3,327 individuals aged 75+ was assessed by structured clinical interviews. Results: Prevalence was 15.4% (95% CI = 14.1–16.6) for original and 25.2% (95% CI = 23.7–26.7) for modified MCI. Rates increased significantly with older age. Positive associations were found for apoE Ε4 allele, vascular diseases and depressive symptoms. Conclusion: MCI is frequent in elderly patients of GPs. GPs have a key position in secondary prevention and care of incipient cognitive deterioration up to the diagnosis of dementia.

Prevalence and risk factors for depression in non-demented primary care attenders aged 75 years and older

BACKGROUND Depression among the elderly is an important public health issue. The aims of this study were to report the prevalence of depression and to determine the impact of socio-demographic variables, functional impairment and medical diagnoses, lifestyle factors, and mild cognitive impairment on depression as part of the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe Study). METHODS Included in the cross-sectional survey were 3327 non-demented subjects aged 75 and over attending general practitioners (GPs) (n=138) in an urban area of Germany. The GDS-15 Geriatric Depression Scale was used to measure depression with a threshold of <6/6+. Associations with social and clinical risk factors were assessed by means of multiple logistic regression models. RESULTS The prevalence of depression was 9.7% (95% confidence interval 8.7-10.7). In a univariate analysis, the following variables were significantly associated with depression: female gender, increasing age, living alone, divorce, lower educational status, functional impairment, comorbid somatic disorder, mild cognitive impairment, smoking, and abstinence from alcohol. After full adjustment for confounding variables, odds ratios for depression were significantly higher only for functional impairment, smoking, and multi-domain mild cognitive impairment. LIMITATIONS Recruitment procedures might have led to an underestimation of current prevalence. The cross-sectional data did not allow us to analyze the temporal relationship between risk factors and depression. CONCLUSIONS The prevalence of depression in the elderly is high and remains high into old age. In designing prevention programs, it is important to call more attention to the impact of functional and cognitive impairment on depression.

Prediction of dementia in primary care patients.

Background Current approaches for AD prediction are based on biomarkers, which are however of restricted availability in primary care. AD prediction tools for primary care are therefore needed. We present a prediction score based on information that can be obtained in the primary care setting. Methodology/Principal Findings We performed a longitudinal cohort study in 3.055 non-demented individuals above 75 years recruited via primary care chart registries (Study on Aging, Cognition and Dementia, AgeCoDe). After the baseline investigation we performed three follow-up investigations at 18 months intervals with incident dementia as the primary outcome. The best set of predictors was extracted from the baseline variables in one randomly selected half of the sample. This set included age, subjective memory impairment, performance on delayed verbal recall and verbal fluency, on the Mini-Mental-State-Examination, and on an instrumental activities of daily living scale. These variables were aggregated to a prediction score, which achieved a prediction accuracy of 0.84 for AD. The score was applied to the second half of the sample (test cohort). Here, the prediction accuracy was 0.79. With a cut-off of at least 80% sensitivity in the first cohort, 79.6% sensitivity, 66.4% specificity, 14.7% positive predictive value (PPV) and 97.8% negative predictive value of (NPV) for AD were achieved in the test cohort. At a cut-off for a high risk population (5% of individuals with the highest risk score in the first cohort) the PPV for AD was 39.1% (52% for any dementia) in the test cohort. Conclusions The prediction score has useful prediction accuracy. It can define individuals (1) sensitively for low cost-low risk interventions, or (2) more specific and with increased PPV for measures of prevention with greater costs or risks. As it is independent of technical aids, it may be used within large scale prevention programs.

Risk factors for incident mild cognitive impairment – results from the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe)

Luck T, Riedel‐Heller SG, Luppa M, Wiese B, Wollny A, Wagner M, Bickel H, Weyerer S, Pentzek M, Haller F, Moesch E, Werle J, Eisele M, Maier W, van den Bussche H, Kaduszkiewicz H for the AgeCoDe Study Group. Risk factors for incident mild cognitive impairment – results from the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe).

Self-reported competence, attitude and approach of physicians towards patients with dementia in ambulatory care: Results of a postal survey

BackgroundCaring for patients with dementia is a demanding task. Little is known as to whether physicians feel competent enough to perform this task or whether a lack of self-perceived competence influences attitudes and professional approach. Even less is known with respect to potential differences between general practitioners (GPs) and specialists. The purpose of this study was to investigate the interrelationship between the self-perceived competence, attitude and professional approach of physicians in ambulatory care in Germany. A further aim was to compare GPs and specialists with regard to differences in these areas.MethodsA standardised postal survey was sent to 389 GPs and 239 neurologists and psychiatrists in six metropolitan areas in Germany. The 49-item questionnaire consisted of attitudinal statements to be rated on a Likert-type scale. Return rates were 54 percent for GPs and 40 percent for specialists. Statistical methods used to analyze data included correlation analysis, cluster analysis and ordinal regression analysis.ResultsNo differences were found between GPs and specialists with regard to their general attitude towards caring for patients with dementia. Approximately 15 percent of both disciplines showed a clearly negative attitude. Self-reported competence was strongly associated with general attitude. In particular among GPs, and less so among specialists, a strong positive association was found between self-reported competence, general attitude and professional approach (e.g. early detection, active case finding and cooperation with caregivers). Differences between GPs and specialists were smaller than expected and appear to predominantly reflect task differences within the German health care system.ConclusionTraining opportunities which enable in particular GPs to enhance not only their competence but also their general attitude towards dementia care would appear to be beneficial and might carry positive consequences for patients and their caregivers.

Impact of safety warnings on antipsychotic prescriptions in dementia: Nothing has changed but the years and the substances

Dementia patients suffering from behavioral and psychological symptoms (BPSD) are often treated with antipsychotics. Trial results document an increased risk for serious adverse events and mortality in dementia patients taking these agents. Furthermore, the efficacy of treating BPSD with antipsychotics seems to be only modest. Using data of a German statutory health insurance company, we examined prescription trends of antipsychotics in prevalent dementia patients in the context of official warnings. The study period is 2004-2009. We studied trends in demographics, age and sex, as well as need of care and the intake of typical and atypical antipsychotics. Seeking for linear trends adjusted for age, sex and level of care between 2004 and 2009, we obtained p-values from a multivariate logistic regression. Prescription volumes were calculated by number of packages as well as defined daily doses (DDDs) using multiple linear regressions for trends in prescriptions amount. We included 3460-8042 patients per year (mean age 80 years). The prescription prevalence of antipsychotics decreased from 35.5% in 2004 to 32.5% in 2009 (multivariate analysis for linear trend: p=0.1645). Overall prescriptions for typical antipsychotics decreased (from 27.2% in 2004 to 23.0% in 2009, p<0.0001) and prescriptions for atypical antipsychotics increased from 17.1% to 18.9% (p<0.0001). The mean DDD per treated patient increased from 80.5 to 91.2 (2004-2009; p=0.0047). Our findings imply that warnings of international drug authorities and manufacturers against adverse drug events in dementia patients receiving antipsychotics did not impact overall prescription behavior.

Prognosis of Mild Cognitive Impairment in General Practice: Results of the German AgeCoDe Study

PURPOSE The concept of mild cognitive impairment (MCI) has recently been introduced into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as mild neurocognitive disorder, making it a formal diagnosis. We investigated the prognostic value of such a diagnosis and analyzed the determinants of the future course of MCI in the AgeCoDe study (German Study on Ageing, Cognition, and Dementia in Primary Care Patients). METHODS We recruited 357 patients with MCI aged 75 years or older from primary care practices and conducted follow-up with interviews for 3 years. Depending on the course of impairment over time, the patients were retrospectively split into 4 groups representing remittent, fluctuating, stable, and progressive courses of MCI. We performed ordinal logistic regression analysis and classification and regression tree (CART) analysis. RESULTS Overall, 41.5% of the patients had remission of symptoms with normal cognitive function 1.5 and 3 years later, 21.3% showed a fluctuating course, 14.8% had stable symptoms, and 22.4% had progression to dementia. Patients were at higher risk for advancing from one course to the next along this spectrum if they had symptoms of depression, impairment in more than 1 cognitive domain, or more severe cognitive impairment, or were older. The result on a test of the ability to learn and reproduce new material 10 minutes later was the best indicator at baseline for differentiating between remittent and progressive MCI. Symptoms of depression modified the prognosis. CONCLUSIONS In primary care, about one-quarter of patients with MCI have progression to dementia within the next 3 years. Assessments of memory function and depressive symptoms are helpful in predicting a progressive vs a remittent course. When transferring the concept of MCI into clinical diagnostic algorithms (eg, DSM-5), however, we should not forget that three-quarters of patients with MCI stayed cognitively stable or even improved within 3 years. They should not be alarmed unnecessarily by receiving such a diagnosis.