Targets of antidementive therapy: drugs with a specific pharmacological mechanism of action

Diagnosis and therapy of dementia have made considerable progress in recent years. Drugs have been developed which improve cognitive performance, delay the loss of abilities of daily living and prevent early nursing home placement in a considerable number of patients. With the various pharmacological and non-pharmacological approaches, effective treatment options of AD are available at present and the therapeutic potential will even increase in future. Thus, the treatment of dementia should more focused and explicit in its goals for the doctor, the patient and the relatives. Therapeutic targets must be defined on the basis of the individual needs and deficits and with regard to different levels of the disease process. Ideally, treatment should always aim at an etiological and/or a pathophysiological level. At present, however, aiming at the neurotransmitter level, the core syndrome of cognitive deficits can be approached by treatment options. Further therapeutic targets can be defined on the level of activities of daily living, following a resource focused approach, as well as on the level of behavioral disturbances. Additional therapeutic targets should be seen under a humanitarian or palliative perspective. And finally, family members are also targets for therapy in dementia, even if such therapy is not directed towards the demented patient. All these treatment targets have to be evaluated and adapted under the perspective of time because prominent symptoms in AD change considerably with disease progression. Selection and adaptation of medication becomes easier if such targets are considered and if therapeutic effects are monitored target-specifically.     

The changing pattern of Kaposi sarcoma in patients with HIV, 1994-2003: the EuroSIDA Study

BACKGROUND: The introduction of highly active antiretroviral therapy (HAART) has radically changed the clinical course of human immunodeficiency virus (HIV) infection. The goals of the current study were to assess the change in the incidence of Kaposi sarcoma (KS) among European patients with HIV since the introduction of HAART and to identify the factors associated with the development of KS among patients receiving HAART. METHODS: The incidence of KS and the factors associated with the development of this malignancy in patients receiving HAART were evaluated using Poisson regression. Patients examined in the current study were among the 9803 individuals with HIV who were enrolled in the EuroSIDA study, a pan-European multicenter investigation. RESULTS: There was an estimated annual reduction of 39% (95% confidence interval [CI], 35-43%; P < 0.0001) in the incidence of KS between 1994 and 2003. The proportion of acquired immunodeficiency syndrome (AIDS) diagnoses made due to KS during prospective follow-up ranged from 4.1% to 7.5%, and there was no significant change over time in this figure (P = 0.97). Four thousand fourteen patients began receiving HAART during prospective follow-up; 41 of these 4014 were subsequently diagnosed with KS (1.0%). After adjustment in multivariate analyses, patients with higher current CD4 counts were found to have a decreased incidence of KS (incidence rate ratio [IRR], 0.60; 95% CI, 0.53-0.68; P < 0.0001), as were those for whom more time had elapsed since the initiation of HAART (IRR, 0.77; 95% CI, 0.60-0.98; P = 0.037). In contrast, homosexual men were found to have a significantly increased incidence of KS (IRR, 2.12; 95% CI, 1.00-4.54; P = 0.050) CONCLUSIONS: The current incidence of KS among patients with HIV is less than 10% of the incidence reported in 1994; the proportion of AIDS diagnoses made on the basis of KS diagnoses remains near 6%. Most individuals who developed KS while receiving HAART began treatment with low CD4 cell counts and developed KS within 6 months of the initiation of HAART. There continues to be an increased incidence of KS among homosexual men and a greatly reduced incidence of KS among patients with higher CD4 counts.     

Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up

BACKGROUND: Although the hippocampus has been found to be smaller in patients with depression, prospective longitudinal in vivo studies are necessary to investigate whether depression can result in a further diminution of hippocampal volumes or whether a smaller hippocampal volume predisposes an individual to the development of depression. METHOD: Thirty patients with DSM-IV major depressive disorder as well as 30 healthy control subjects matched for age, gender, and handedness were examined at admission to the hospital and 1 year later using a documentation of the medical history and high-resolution magnetic resonance imaging (MRI) for the presence of depression and to determine changes in hippocampal as well as amygdala volumes. Patients were enrolled from March 2000 to August 2002. RESULTS: No significant hippocampal and amygdala volume changes were observed in patients or controls between baseline and 1-year follow-up investigations. However, the subgroup of patients who were nonremitted at the time of the follow-up investigation showed significantly reduced left and right hippocampal volumes at both baseline and the 1-year follow-up compared with remitted patients. Moreover, the right hippocampal volumes of nonremitted patients were significantly smaller compared with matched healthy controls. CONCLUSION: These results do not support the hypothesis that hippocampal volumes diminish during the 1-year follow-up period. However, smaller hippocampal volumes may be related to a poor clinical outcome after 1 year.     

Use of brief depression screening tools in primary care: consideration of heterogeneity in performance in different patient groups

Heterogeneity of performance of screening tools in different patient groups has rarely been considered in the literature on depression screening in primary care. The objectives of the present study were to assess and to compare diagnostic accuracy of three screening questionnaires (Brief Patient Health Questionnaire, General Health Questionnaire-12, WHO-5) in identifying depression across various patient subpopulations and to assess the accuracy of the unaided clinical assessment of primary care physicians in the same subgroups. We conducted a cross-sectional validation study in 448 primary care patients. Two-by-two tables as well as receiver operating characteristics were applied. Results indicated that diagnostic accuracy (sensitivity, specificity) of the three screening instruments as well as of the clinical diagnoses differed in the various patient groups. Superiority of one screening tool over the other depends on the subgroup considered. Gender, age, form (subtype), and severity of depression influence the test characteristics of a screening tool. This should be considered if routine depression screening should be widely introduced. Of course, the benefit of routine screening also depends on efforts made for treatment and monitoring of patients in whom depression was diagnosed.     

Management of atherothrombosis with clopidogrel in high-risk patients with recent transient ischaemic attack or ischaemic stroke (MATCH): study design and baseline data

BACKGROUND: The CAPRIE study showed the superiority of clopidogrel over acetylsalicylic acid (ASA) for reducing the combined risk of major atherothrombotic events in patients with recent myocardial infarction (MI), recent ischaemic stroke (IS) or established peripheral arterial disease. The benefit of clopidogrel over ASA is amplified in high-risk patients. Proof of concept for the benefit of clopidogrel in addition to ASA in patients with coronary manifestations of atherothrombosis was provided by the CURE trial. METHODS: MATCH is a randomized, double-blind, placebo-controlled trial that compares clopidogrel and ASA versus clopidogrel alone in high-risk patients with recently symptomatic cerebrovascular disease. Eligible patients have experienced a transient ischaemic attack (TIA) or IS within the last 3 months and have evidence of at least 1 additional risk factor within the last 3 years (prior IS, MI, stable or unstable angina pectoris, diabetes or symptomatic peripheral arterial disease). Patients were randomized to receive ASA 75 mg once daily or placebo, with both groups receiving clopidogrel 75 mg once daily as part of standard therapy. The primary end point is the composite of IS, MI, vascular death and rehospitalization for an acute ischaemic event. The duration of treatment and follow-up is 18 months for each patient. RESULTS: Enrollment was completed in April 2002, with 7,599 patients randomized to receive the study medication. The mean age at randomization was 66 years, and the qualifying event was IS in 78.9% of patients and TIA in 21.1%. The baseline features of the study cohort indicate a population that is at a high risk for atherothrombotic recurrence. CONCLUSION: MATCH is a major ongoing trial that will provide important data on the benefit of clopidogrel and ASA compared with clopidogrel alone for reduction of vascular ischaemic events in patients with recent TIA or IS who are at high risk of atherothrombotic event recurrence.     

Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression

BACKGROUND: Substantial evidence supports a role for dysfunction of the serotonin transporter in the pathogenesis of major depression. Several studies have found reciprocal interactions between the serotonergic system and both brain-derived neurotrophic factor and glutamate, which are known to modulate or affect hippocampal morphologic characteristics. OBJECTIVE: To examine the influence of a polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene on hippocampal volumes in patients with major depression and healthy controls. DESIGN: Baseline investigation of a prospective magnetic resonance imaging study with a 4-year follow-up period. PATIENTS: We examined 40 inpatients with major depression as well as 40 healthy controls matched for age, sex, and handedness. MAIN OUTCOME MEASURES: Subjects underwent high-resolution magnetic resonance imaging. Furthermore, genotyping for the 5-HTTLPR biallelic polymorphism was performed, which consists of a 44-base pair insertion (L allele) or deletion (S allele). RESULTS: Patients with the L/L homozygous genotype had significantly smaller hippocampal gray matter (left hemisphere: P=.003; right hemisphere: P=.01) and white matter volumes (left hemisphere: P=.001; right hemisphere: P=.002) than controls with this genotype. No significant differences were found between patients and controls with the L/S or S/S genotype. Moreover, patients with the L/L genotype had significantly smaller hippocampal white matter volumes than those with the L/S or S/S genotype (P=.03). CONCLUSIONS: These findings suggest that homozygosity for the L allele is associated with decreased hippocampal volumes in patients with major depression but not in healthy controls. A possible explanation is that the interaction between the serotonergic system and neurotrophic factors as well as excitatory amino acid neurotransmission may affect hippocampal morphologic characteristics.     

Heat shock protein-27 is upregulated in the temporal cortex of patients with epilepsy

PURPOSE: Heat shock protein-27 (HSP-27) belongs to the group of small heat shock proteins that become induced in response to various pathologic conditions. HSP-27 has been shown to protect cells and subcellular structures, particularly mitochondria, and serves as a carrier for estradiol. It is a reliable marker for tissues affected by oxidative stress. Oxidative stress and related cellular defence mechanisms are currently thought to play a major role during experimentally induced epileptic neuropathology. We addressed the question whether HSP-27 becomes induced in the neocortex resected from patients with pharmacoresistant epilepsy. METHODS: Human epileptic temporal neocortex was obtained during neurosurgery, and control tissue was obtained at autopsy from subjects without known neurologic diseases. The tissues were either frozen for Western blot analysis or fixed in Zamboni's fixative for the topographic detection of HSP-27 at the cellular level by means of immunohistochemistry. RESULTS: HSP-27 was highly expressed in all epilepsy specimens and in the cortex of a patient who died in the final stage of multiple sclerosis (positive control), whereas only low amounts of HSP-27 were detectable in control brains. In epilepsy patients, HSP-27 was present in astrocytes and in the walls of blood vessels. The intracortical distribution patterns varied strongly among the epilepsy specimens. CONCLUSIONS: These results demonstrate that HSP-27 becomes induced in response to epileptic pathology. Although the functional aspects of HSP-27 induction during human epilepsy have yet to be elucidated, it can be concluded that HSP-27 is a marker for cortical regions in which a stress response has been caused by seizures.