Alzheimer Disease: Dodel R

Schmidt R, Neff F, Lampl C, Benke T, Anditsch M, Bancher C, Dal-Bianco P, Reisecker F, Marksteiner J, Rainer M, Kapeller P, Dodel R. · Universitätsklinik für Neurologie, Medizinische Universität Graz. · Neuropsychiatr. · Pubmed #18826870 No free full text.

Abstract: Cholinesterase inhibitors and memantine can slow the course of Alzheimer's disease. In Austria the frequency of treatment is in the upper third among countries of the EU. Yet, the majority of Alzheimer patients does not receive adequate medication. Compliance to treatment is low. Studies on cholinesterase inhibitors show that only one third and one fifth of patients adhere to medication after 3 months and 12 months, respectively. Causes for low compliance are only partly patient-related, many factors are system-inherent. Knowledge of these factors is a pre-requisite for the treating physician to improve current unfavourable situation. Present treatment strategies are symptomatic, causal disease-modifying therapies are urgently needed. Research activity in the field is high and dominated by the amyloid hypothesis. We here review the basis and recent studies on secretase-inhibitors, immunization, aggregation of Abeta, statins and PPARgamma-agonists. Research towards strategies against tau-pathology is less dominant and focuses on inhibition of kinases and increase of activity of phosphatases. Causal therapies would have great effects on a population basis even if efficacy is only moderate. A disease-modifying therapy which delays the onset of Alzheimer disease by 5 years, will probably reduce the number of patients by nearly 50% during the next 50 years.

Neff F, Wei X, Nölker C, Bacher M, Du Y, Dodel R. · Department of Neurology, Philipps-University Marburg, Germany. · Autoimmun Rev. · Pubmed #18558370 No free full text.

Abstract: Parkinson's disease, Alzheimer's disease and other neurodegenerative disorders share a common pathologic pathway with aggregation and deposition of misfolded proteins causing a disruption of particular neuronal networks. Several mechanisms have been implicated in the down-stream events following deposition of misfolded proteins including failure of cellular defenses among many others. Recently, naturally occurring autoantibodies against ss-amyloid and alpha-synuclein have been detected in healthy persons and altered levels in patients were associated with particular neurodegenerative disorders. In this review the current knowledge on the role of naturally occurring autoantibodies is discussed in respect to neurodegenerative disorders.

Dodel R, Bacher M. · Arbeitsgruppe Neurologische Therapieforschung, Neurologische Klinik, Philipps-Universität Marburg, Rudolf-Bultmann-Strasse 8, 35039, Marburg. · Nervenarzt. · Pubmed #19212743 No free full text.

Abstract: Immunotherapeutic approaches for treating Alzheimer's disease were first described in 1999. A clinical trial using an active immunization with Abeta1-42 was initiated shortly thereafter, but it was halted early because of serious safety issues (acute meningoencephalitis in 6% of the treated patients). Despite this drawback, encouraging data from preclinical and clinical data were available, prompting researchers to seek alternative approaches for safer active and passive immunization. Currently, several passive and active immunotherapeutic approaches are being tested in clinical trials. However, our understanding of the mechanisms behind immunization in neurodegenerative disorders is still incomplete. In this review we present the current status of the different approaches in relation to Alzheimer's disease as well as to other neurodegenerative disorders.

Popp J, Bacher M, Kölsch H, Noelker C, Deuster O, Dodel R, Jessen F. · University of Bonn, Department of Psychiatry, Bonn, Germany. · J Psychiatr Res. · Pubmed #19038405 No free full text.

Abstract: Inflammatory processes may substantially contribute to the cerebral pathology in Alzheimer's disease (AD) and accelerate the disease progression. The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine which promotes the production of several inflammatory mediators such as TNF-alpha, IL-6 and IFN-gamma, and plays a central regulatory role in the pathogenesis of several inflammatory and autoimmune diseases. There is now first evidence that MIF may be involved in the neuroinflammation in AD. To determine whether MIF production is up-regulated early in the course of AD, we compared the levels of MIF assessed by ELISA in the cerebrospinal fluid (CSF) of 31 patients with AD, 28 patients with amnestic mild cognitive impairment (MCI), and 19 subjects without cognitive deficits. Additionally, we measured the CSF concentrations of the inflammatory mediators TNF-alpha, IL-6 and IFN-gamma, which are thought to be both up-regulated by MIF and involved in the pathophysiology of AD. CSF MIF concentrations were significantly increased in AD (p=0.003) and MCI patients (p<0.001) compared to controls. The levels of TNF-alpha, IL-6 and IFN-gamma did not differ significantly between the groups. There was a correlation only between the concentrations of MIF and of TNF-alpha in the AD group (r=0.407; p=0.023). These results demonstrate increased MIF production in AD and MCI suggesting that MIF may be involved in the occurring neuroinflammatory process at a clinical pre-dementia disease stage.

Bacher M, Depboylu C, Du Y, Noelker C, Oertel WH, Behr T, Henriksen G, Behe M, Dodel R. · Department of Neurology, Philipps University, Rudolf-Bultmann-Str. 8, 35033 Marburg, Germany. · Neurosci Lett. · Pubmed #18786612 No free full text.

Abstract: Active as well as passive immunization against beta-amlyoid (Abeta) has been proposed as a treatment to lower cerebral amyloid burden and stabilize cognitive decline in Alzheimer's disease (AD). To clarify the mechanism of action underlying passive immunization, the in vivo distribution (and sites of degradation) of peripherally administered radiolabeled human and mouse anti-Abeta antibodies were analyzed in a transgenic mouse model of AD. In APP23 mice, a model in which mutated human amyloid precursor protein is overexpressed, the biodistribution of intravenously applicated (111)indium-conjugated affinity-purified human polyclonal autoantibodies (NAbs-Abeta) was compared to that of monoclonal anti-Abeta(1-17) (6E10), anti-Abeta(17-24) antibodies (4G8) and anti-CD-20 (Rituximab), a non-Abeta targeting control. Blood clearance half-lives were 50+/-6h for Rituximab, 20-30h for NAbs-Abeta, 29+/-5h for 4G8 and 27+/-3h for 6E10. Blood activity was higher for 6E10 at 4h as compared to 4G8, Rituximab and NAbs-Abeta. At the 96h time point, Rituximab had the highest blood activity among the antibodies tested. As expected, all antibodies displayed hepatobiliary clearance. Additionally, NAbs-Abeta was excreted in the urinary tract. Liver and kidney uptake of NAbs-Abeta increased over time and was higher than in the monoclonal antibodies at 48h/96h. The brain-to-blood radioactivity ratio for NAbs-Abeta at later time points (>48h) was higher than that of 6E10, 4G8 and Rituximab. In addition, the distribution varied, with highest values found in the hippocampus. Our data indicate a cerebral accumulation of human NAbs-Abeta in the APP23 model. Further studies with human immunoglobulins and particularly with those that recognize different Abeta-epitopes are required in order to delineate in more detail the mode of action of NAbs-Abeta.

Bacher M, Dodel R, Aljabari B, Keyvani K, Marambaud P, Kayed R, Glabe C, Goertz N, Hoppmann A, Sachser N, Klotsche J, Schnell S, Lewejohann L, Al-Abed Y. · Department of Neurology, Philipps-University Marburg, 35039 Marburg, Germany. · J Exp Med. · Pubmed #18573905 links to  free full text

Abstract: Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid beta protein (Abeta) peptide "oligomers" and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. We show that CNI-1493, a tetravalent guanylhydrazone with established antiinflammatory properties, interferes with Abeta assembly and protects neuronal cells from the toxic effect of soluble Abeta oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Abeta deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87% reduction in the hippocampus of these animals. Administration of CNI-1493 significantly improved memory performance in a cognition task compared with vehicle-treated mice. In vitro analysis of CNI-1493 on APP processing in an APP-overexpressing cell line revealed a significant dose-dependent decrease of total Abeta accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD.

Wei X, Chen X, Fontanilla C, Zhao L, Liang Z, Dodel R, Hampel H, Farlow M, Du Y. · Department of Neurology, Indiana University School of Medicine, 975 West Walnut Street, IB457, Indianapolis, IN 46202, USA. · Life Sci. · Pubmed #17257626 links to  free full text

Abstract: Recently, association of an interleukin-1A promoter polymorphism (-889, thymine/thymine (T/T)) with Alzheimer's disease was reported, suggesting that this cytokine may play an important role in disease development. To understand the mechanism underlying the interleukin-1A promoter's role in Alzheimer's disease, a study comparing promoter function of an interleukin-1A polymorphism was performed in the SVG astroglia cell line. The effects of thymine and cytosine on transcriptional activity of the interleukin-1A promoter were analyzed by testing luciferase-reporter activity in transfected SVG cells. Our results demonstrate that cytosine/thymine conversion increases activity of the interleukin-1A promoter in SVG cells. Both sodium salicylate and lovastatin are able to block induced promoter activities in astroglial cells. Induced promoter activity by the polymorphism (T/T) may result in the upregulation of interleukin-1alpha protein and "cytokine cycle" amplification, which may promote disease development.

Brettschneider S, Morgenthaler NG, Teipel SJ, Fischer-Schulz C, Bürger K, Dodel R, Du Y, Möller HJ, Bergmann A, Hampel H. · Department of Psychiatry, Ludwig-Maximilian University Munich, Munich, Germany. · Biol Psychiatry. · Pubmed #15820240 No free full text.

Abstract: BACKGROUND: Autoantibodies against amyloid beta (A beta) peptide found in patients with Alzheimer's disease (AD) also occur naturally in the general population independently of the cognitive status. METHODS: We compared serum A beta(1-42) autoantibody levels (A beta(1-42)-AL) of 96 AD patients and 30 healthy elderly control subjects (HC), assessing their diagnostic value for AD with a newly developed immunoprecipitation assay with radiolabeled A beta(1-42) peptide. RESULTS: We found a highly significant decrease of A beta(1-42)-AL in AD patients (p = .001) independently of age, cognitive status, and apolipoprotein E epsilon4 carrier status. Amyloid beta(1-42) autoantibody levels were correlated with gender in AD, with a higher level occurring in women. When A beta(1-42) autoantibody sensitivity (specificity) was set >80%, specificity (sensitivity) was below 50% to correctly allocate patients and healthy control subjects. CONCLUSIONS: Our data indicate a potentially pathophysiologic decrease of serum A beta(1-42) antibodies in AD. Amyloid beta(1-42) antibodies in the serum alone, however, seem not to be useful as a diagnostic marker of AD.

Hampel H, Teipel SJ, Fuchsberger T, Andreasen N, Wiltfang J, Otto M, Shen Y, Dodel R, Du Y, Farlow M, Möller HJ, Blennow K, Buerger K. · Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Dementia Research Section and Memory Clinic, Ludwig-Maximilian University, Nussbaumstrasse 7, 80336 Munich, Germany. · Mol Psychiatry. · Pubmed #14699432 No free full text.

Abstract: Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) beta-amyloid(1-42) (Abeta(1-42)) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Abeta(1-42) and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Abeta(1-42) and CSF tau. The levels of CSF tau were increased, whereas levels of Abeta(1-42) were decreased in MCI subjects. Abeta(1-42) predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Abeta(1-42), but not other predictor variables (tau protein, gender, age, apolipoprotein E epsilon4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (P<0.05). Our findings support the notion that CSF tau and Abeta(1-42) may be useful biomarkers in the early identification of AD in MCI subjects.

Dodel R, Hampel H, Depboylu C, Lin S, Gao F, Schock S, Jäckel S, Wei X, Buerger K, Höft C, Hemmer B, Möller HJ, Farlow M, Oertel WH, Sommer N, Du Y. · Department of Neurology, Philipps University Marburg, Germany. · Ann Neurol. · Pubmed #12210803 No free full text.

Abstract: Naturally occurring antibodies directed against beta-amyloid (Abeta) were detected in intravenous immunoglobulin preparations. After intravenous immunoglobulin treatment in patients with different neurological diseases, total Abeta and Abeta(1-42) in the cerebrospinal fluid was reduced significantly compared with baseline values. In the serum, total Abeta levels increased after intravenous immunoglobulin treatment, whereas no significant change was observed in Abeta(1-42) levels. Antibodies against Abeta were found to be increased in the serum and cerebrospinal fluid after intravenous immunoglobulin treatment. This study provides evidence that intravenous immunoglobulin or purified Abeta antibodies may modify Abeta and Abeta(1-42) levels, suggesting potential utility as a therapy for Alzheimer disease.

Du Y, Dodel R, Hampel H, Buerger K, Lin S, Eastwood B, Bales K, Gao F, Moeller HJ, Oertel W, Farlow M, Paul S. · Department of Pharmacology, Indiana University School of Medicine, Indianapolis 46285, USA. · Neurology. · Pubmed #11552007 No free full text.

Abstract: OBJECTIVE: To investigate whether it was possible to detect the presence and different levels of naturally occurring anti-beta-amyloid (Abeta) antibodies in the CSF of patients with AD and age-matched controls by employing a sensitive ELISA. BACKGROUND: Immunization with preaggregated amyloid beta-peptide (Abeta(1-42)) and administration of antibodies against Abeta into amyloid precursor protein APP(V717F)- transgenic mice (an animal model of AD) have recently been reported to dramatically reduce amyloid plaque deposition, neuritic dystrophy, and astrogliosis, most likely by enhancing Abeta clearance from brain. METHODS: A sensitive ELISA was performed to detect levels of naturally occurring anti-Abeta antibodies in the CSF of patients with AD and age-matched controls. Additionally, an immunoprecipitation assay was performed to confirm that naturally occurring anti-Abeta antibodies also exist in the human blood. RESULT: - Naturally occurring antibodies directed against Abeta were found in the CSF and plasma of patients with AD and healthy control subjects. Moreover, CSF anti-Abeta antibody titers are significantly lower in patients with AD compared with healthy control subjects. CONCLUSION: Naturally occurring antibodies directed against Abeta exist in human CSF and plasma. The CSF anti-Abeta antibody titers may be helpful in better understanding the effects of future immunologic therapies for AD.