Biomedical subjects

Richard C Dodel

Publications and source records attributed to Richard C Dodel.

12 recordsLinked to original sources

PubMed2006

Alpha2-macroglobulin, lipoprotein receptor-related protein and lipoprotein receptor-associated protein and the genetic risk for developing Alzheimer's disease.

Alpha2-macroglobulin (alpha2M) as well as its receptor, the low-density lipoprotein receptor-related (LRP) and the receptor-associated protein (RAP) are involved in the clearance of cerebral A beta. Current evidence suggests that polymorphisms in the genes of alpha2M, LRP and RAP may have functional effects on the proteins. Two independent association samples of 271 AD patients and 280 representative controls were investigated whether the risk for developing AD is altered in carriers of polymorphisms in the alpha2M-gene (Va1000Ile), in the LRP-gene (Ala216Val) and in the RAP-gene (Val311Met). Genotypes were determined by standard PCR and restriction fragment length polymorphism. The results were adjusted for age, gender and apolipoprotein E-epsilon4 (APOE) polymorphism. Inheritance of alpha2M conferred a small increased risk for sporadic AD with an estimated Mantel-Haenszel odds ratio of 1.47. There was no age- or gender-dependent increase in alpha2M Val1000Ile allele frequencies in AD patients compared to controls. There was no significant difference in the allele frequencies among control and AD subjects for the LRP and RAP polymorphisms. We found no evidence of an interaction between the alpha2M and RAP or LRP with regard to conferred risk. Our data suggest that the alpha2M Val1000Ile polymorphism is weakly associated with AD. Although LRP as well as RAP seem to play an essential role in the metabolism of alpha2M and APOE, there is no increase in the genetic risk for AD in patients carrying the investigated polymorphisms.

Aged↗

PubMed2004

Caffeic acid phenethyl ester prevents neonatal hypoxic-ischaemic brain injury.

Neonatal hypoxic-ischaemic (HI) brain injury resulting in encephalopathy is a leading cause of morbidity and mortality with no effective treatment. Here we show that caffeic acid phenethyl ester (CAPE), an active component of propolis, administered either before or after an HI insult, significantly prevents HI-induced neonatal rat brain damage in the cortex, hippocampus and thalamus. In addition to blocking HI-induced caspase 3 activation, CAPE also inhibits HI-mediated expression of inducible nitric oxide synthase and caspase 1 in vivo and potently blocks nitric oxide-induced neurotoxicity in vitro. Furthermore, CAPE directly inhibits Ca2+-induced cytochrome c release from isolated brain mitochondria. Thus, CAPE induces neuroprotection against HI-induced neuronal death, possibly by blocking HI-induced inflammation and/or directly inhibiting the HI-induced neuronal death pathway. CAPE may therefore be a novel effective therapy for preventing neonatal HI injury.

Animals↗

PubMed2004

Lack of association between the interleukin-1 alpha (-889) polymorphism and early-onset Parkinson's disease.

An increasing number of studies have shown that an inflammatory process is part of Parkinson's disease (PD) brain pathology. Interleukin-1 (IL-1) is a multifunctional cytokine and is considered to contribute to several inflammatory diseases. Recently, we detected an associated risk in a subgroup of PD patients with a disease onset < 50 years and a C to T transition in the IL-1alpha promoter (-889). One-hundred-seventy-six German PD patients (42.1 +/- 6.4 years; 42.4% male) and 170 unrelated age-matched control individuals (40.4 +/- 8.7 years; 57.6% male) were investigated for the presence of the IL-1alpha (-889C/T) polymorphism. No significant difference in the allelic distribution of the analyzed IL-1alpha polymorphism has been found between PD and controls. We conclude that the C/T polymorphism in the IL-1alpha promoter region at -889 does not increase the risk to develop PD.

Adult↗

PubMed2004

An interleukin-6 promoter variant is not associated with an increased risk for Alzheimer's disease.

Recent studies have implicated interleukin-6 (IL-6) in the pathogenesis of Alzheimer's disease (AD). Neuro-inflammatory processes surrounding the amyloid plaques contribute to the progression of AD-related neurodegeneration. IL-6 is a multifunctional inflammatory cytokine which possibly acts as a mediator in the local immune response in the brain of AD patients. In this study we investigated whether the risk of developing AD is altered in carriers of the C allele of a G/C polymorphism at position -174. 113 AD patients and 108 age- and gender-matched nondemented control subjects were analysed. Genotyping of IL-6 was performed using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender and apolipoprotein E epsilon4 status. There was no evidence for an association between the polymorphism and the risk of developing AD. No evidence of an earlier age at onset for carriers of the C allele was evaluated. We conclude that IL-6 (-174) polymorphism does not influence the risk of developing AD in our cohort.

Aged↗

PubMed2003

Lack of association of interleukin-10 promoter region polymorphisms with Alzheimer's disease.

There is increasing evidence that immune mechanisms are involved in the pathogenesis of Alzheimer's disease (AD). Recently, polymorphisms of the interleukin (IL)-1 and IL-6 genes were found to be associated with late-onset AD. The immunoregulatory IL-10 downregulates synthesis of pro-inflammatory cytokines such as IL-1. Current evidence suggests that some polymorphisms in the IL-10 promoter may have functional effects on IL-10 transcription. A total of 406 German AD patients (mean age 70.2+/-10.0 years, range 50-95 years, 42% female) and 251 unrelated non-demented control subjects (mean age 66.8+/-10.6 years, range 50-93 years, 38% female) were investigated for the presence of three polymorphisms in the IL-10 promoter region (-1087A/G, -824C/T, -597C/A). No significant differences in the allelic distribution of the analyzed IL-10 polymorphisms have been found between AD patients and controls. We conclude that polymorphisms in the IL-10 promoter region do not increase the risk of developing AD.

Aged↗

PubMed2003

Cabergoline versus levodopa monotherapy: a decision analysis.

We evaluated the incremental cost-effectiveness of cabergoline compared with levodopa monotherapy in patients with early Parkinson's disease (PD) in the German healthcare system. The study design was based on cost-effectiveness analysis using a Markov model with a 10-year time horizon. Model input data was based on a clinical trial "Early Treatment of PD with Cabergoline" as well as on cost data of a German hospital/office-based PD network. Direct and indirect medical and nonmedical costs were included. Outcomes were costs, disease stage, cumulative complication incidence, and mortality. An annual discount rate of 5% was applied and the societal perspective was chosen. The target population included patients in Hoehn and Yahr Stages I to III. It was found that the occurrence of motor complications was significantly lower in patients on cabergoline monotherapy. For patients aged >/=60 years of age, cabergoline monotherapy was cost effective when considering costs per decreased UPDRS score. Each point decrease in the UPDRS (I-IV) resulted in costs of euro;1,031. Incremental costs per additional motor complication-free patient were euro;104,400 for patients <60 years of age and euro;57,900 for patients >/=60 years of age. In conclusion, this decision-analytic model calculation for PD was based almost entirely on clinical and observed data with a limited number of assumptions. Although costs were higher in patients on cabergoline, the corresponding cost-effectiveness ratio for cabergoline was at least as favourable as the ratios for many commonly accepted therapies.

Antiparkinson Agents↗

PubMed2003

Role of dopamine transporter SPECT for the practitioner and the general neurologist.

The accurate clinical diagnosis of parkinsonism may be impeded by atypical presentations and confounding comorbidity. The presence of parkinsonism is misdiagnosed in up to a quarter of cases in general practice. Movement disorder specialists misdiagnose parkinsonian syndromes using histopathological findings as the "gold standard" in up to 10% of cases. Dopamine transporter SPECT represents a simple and fast method to confirm nigrostriatal degeneration in a given patient. This study provides several case reports to illustrate when dopamine transporter SPECT might be carried out and discusses whether dopamine transporter SPECT should be used in primary health care practice or by general neurologists in uncertain cases. Ideally, all possible cases of parkinsonism should be referred to a neurologist experienced in the field of movement disorders. If this could be achieved then the role of dopamine transporter SPECT in the general practitioner's or local neurologist's practice would be extremely limited. Future studies must clarify whether it is cost effective to generously perform dopamine transporter SPECTs to minimize the time until parkinsonism can be diagnosed.

Adult↗

PubMed2003

Dopamine transporter imaging and SPECT in diagnostic work-up of Parkinson's disease: a decision-analytic approach.

As a diagnostic test for patients with suspected Parkinson's disease (PD), single photon emission computed tomography (SPECT) using [(123)I]FP-CIT tracer has better sensitivity but is more expensive than regular clinical examination (CE). Our objective was to evaluate the clinical and economic impacts of different diagnostic strategies involving [(123)I]FP-CIT SPECT. We developed a decision tree model to predict adequate treatment-month equivalents (ATME), costs, and incremental cost-effectiveness ratio (ICER) during a 12-month time horizon in patients with suspected PD referred to a specialized movement disorder outpatient clinic. In our cost- effectiveness analysis, we adopted the perspective of the German health care system and used data from a German prospective health care utilization study (n = 142) and published diagnostic studies. Compared strategies were CE only (EXAM+), SPECT only (SPECT+), SPECT following negative CE (SINGLE+), and SPECT following positive CE (DOUBLE+). Costs of SPECT amounted to euro;789 per investigation. Based on our model, expected costs (and ATME) were euro;946 (52.85 ATME) for EXAM+, euro;1352 (53.40 ATME) for DOUBLE+, euro;1731 (32.82 ATME) for SINGLE+, and euro;2003 (32.96 ATME) for SPECT+; performance of SPECT was induced in 0%, 54%, 56%, and 100% of the patients, respectively. DOUBLE+ was more effective and less expensive than SINGLE+ or SPECT+; thus these two do not offer reasonable choices. The ICER of DOUBLE+ compared to EXAM+ was euro;733 per ATME gained. In sensitivity analyses, the ICER of DOUBLE+ versus EXAM+ ranged from euro;63 to euro;2411 per ATME gained. Whether the diagnostic work-up of patients referred to a specialized movement disorder clinic with a high prevalence of PD should include [(123)I]FP-CIT SPECT depends on patient preferences and the decision maker's willingness to pay for adequate early treatment. SPECT should be used as a confirmatory test before treatment initiation and limited to patients with a positive test result in the clinical examination. These results should be adjusted to the specific setting and individual patient preferences.

Ambulatory Care Facilities↗

PubMed2003

Immunotherapy for Alzheimer's disease.

Recent studies in murine models of Alzheimer's disease (AD) have found that active immunisation with amyloid-beta peptide (Abeta) or passive immunisation with Abeta antibodies can lessen the severity of Abeta-induced neuritic plaque pathology through the activation of microglia. These antibodies can be detected in the serum and CSF. Whether they slow down or speed up the development and progression of AD has not been determined. Furthermore, the conditions that induce formation of such antibodies are unknown, or how specific they are to AD. However, the evidence suggests at least a potential beneficial role for some features of neuroinflammation in AD. A clinical phase II study of an active immunisation approach with AN1792 was started in 2001, but was recently suspended after some patients developed serious adverse events. These were most likely caused by the activation of the proinflammatory cascade. Immunotherapy approaches represent fascinating ways to test the amyloid hypothesis and may offer genuine opportunities to modify disease progression. This review focuses on immunisation strategies and details of the pathways involved in antibody clearance of Abeta.

Alzheimer Disease↗

PubMed2002

NF-kappaB mediates IL-1beta-induced synthesis/release of alpha2-macroglobulin in a human glial cell line.

Increasingly, inflammatory responses in localized areas of brain parenchyma in response to the extracellular deposition of the Abeta peptides are thought to play a causative role in Alzheimer's disease (AD) progression. Anti-inflammatory agents, in particular non-steroid anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, have been shown to be associated with a delayed onset or slowed rate of disease progression in several epidemiological studies. Activation of glial cells and the subsequent expression of a number of proteins including alpha(2)-macroglobulin (alpha(2)M) are associated with the induction of brain tissue inflammation. Additionally cytokines, such as interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) are co-localized to senile plaques, a neuropathological hallmark of AD. Alpha(2)M binds various cytokines, including IL-1beta, as well as Abeta. In this study, we demonstrate that IL-1beta induces alpha(2)M synthesis/release from a human astroglial cell line (U373) via the activation of the nuclear transcription factor NF-kappaB. Our data suggest that attenuation of IL-1beta-induced alpha(2)M synthesis/release by blocking NF-kappaB activation may potentially be 'protective' against the development of late-onset AD.

Alzheimer Disease↗

PubMedDate not supplied

Resource utilization and costs of stroke unit care in Germany.

OBJECTIVES: Stroke imposes a considerable economic burden on the individual and society. Recently, the concept of an integrated stroke unit has been established in several countries to improve the outcome of patients. This study evaluates the costs of acute care of the different cerebrovascular insults in a stroke unit. METHODS: The study population included 340 patients who were consecutively admitted to the Department of Neurology, Philipps University Marburg, with the diagnosis of stroke or transient ischemic attack (TIA) between January 1 and June 30, 2000. Clinical status and course were evaluated by using the Barthel index and the modified Rankin scale. Employing a "bottom-up" approach, we calculated the costs from the perspective of the hospital and the third-party payer using data from provider departments and other published sources. RESULTS: Inpatient costs were 3020 euros (3290 US dollars) for TIA, 3480 euros (3790 US dollars) for ischemic stroke (IS), and 5080 euros (5540 US dollars) for intracerebral hemorrhage (ICH) and differed significantly among these subgroups (P < .05). Patient subgroups ranked in the same order for average length of stay at 9.4 days for TIA, 10.2 days for IS, and 11.9 days for ICH (P > .05). Approximately 30% of the hospital costs are due to physician charges and care. Imaging amounted to 10% and lab investigations to 14% of total costs, independent of the diagnosis. Postacute treatment, including inpatient rehabilitation, cost 9880 euros per patient. Across all diagnostic groups, a mean clinical improvement was observed at time of discharge. CONCLUSIONS: Care of patients with cerebrovascular events in a stroke unit causes a high demand of resources and has a considerable impact on health-care expenditure. Therefore, investigations comparing the stroke unit concept with other strategies in stroke care are necessary to evaluate the stroke unit concept for a rational use of available resources in patients with cerebrovascular events.

Aged↗

PubMedDate not supplied

Systematic assessment of decision models in Parkinson's disease.

OBJECTIVE: To give an insight into the structural and methodological approaches used in published decision-analytic models evaluating interventions in Parkinson's disease (PD) and to derive recommendations for future comprehensive PD decision models. METHODS: A systematic literature review was performed to identify studies that evaluated PD interventions using mathematical decision models. Using a standardized assessment form, information on the study design, methodological framework, and data sources was extracted from each publication and systematically reported. Strengths and limitations were assessed. RESULTS: We identified eight studies that used mathematical models to evaluate different pharmaceutical (n=7) and surgical (n=1) treatment options in PD. All models included economic evaluations. Modeling approaches comprised mathematical equations, decision trees, and Markov models with a time horizon ranging from 5 years to lifetime. All based progression on the evolution of clinical surrogate endpoints. Treatment effects were either modeled via reduction of symptomatic progression and/or initial symptomatic improvement or via reduction of adverse effect rates. No model is currently available that encompasses both the underlying biologic disease progression and the spectrum of all relevant complications and also links them to patient preferences and economic outcomes. CONCLUSIONS: Models have been successfully applied to evaluate PD treatments. However, currently available models have substantial limitations. We recommend that a comprehensive, generic, and flexible decision model for PD that can be applied to different treatment strategies should consider a large spectrum of clinically relevant outcomes and complications of the disease during a sufficiently long time horizon, include PD-specific mortality, systematically evaluate uncertainty including heterogeneity effects, and should be validated by independent data or other models. Approaches to model treatment effects included reduction of symptomatic progression, initial symptomatic improvement, or reduction of adverse effects. We believe that structural bias could be avoided if underlying disease progression and treatment effects on symptoms are modeled separately.

Cost-Benefit Analysis↗