The neuroprotective role of microglial cells against amyloid beta-mediated toxicity in organotypic hippocampal slice cultures

During Alzheimer’s disease (AD) progression, microglial cells play complex roles and have potentially detrimental as well as beneficial effects. The use of appropriate model systems is essential for characterizing and understanding the roles of microglia in AD pathology. Here, we used organotypic hippocampal slice cultures (OHSCs) to investigate the impact of microglia on amyloid beta (Aβ)-mediated toxicity. Neurons in OHSCs containing microglia were not vulnerable to cell death after 7 days of repeated treatment with Aβ1-42 oligomer-enriched preparations. However, when clodronate was used to remove microglia, treatment with Aβ1-42 resulted in significant neuronal death. Further investigations indicated signs of endoplasmic reticulum stress and caspase activation after Aβ1-42 challenge only when microglia were absent. Interestingly, microglia provided protection without displaying any classic signs of activation, such as an amoeboid morphology or the release of pro-inflammatory mediators (e.g., IL-6, TNF-α, NO). Furthermore, depleting microglia or inhibiting microglial uptake mechanisms resulted in significant more Aβ deposition compared to that observed in OHSCs containing functional microglia, suggesting that microglia efficiently cleared Aβ. Because inhibiting microglial uptake increased neuronal cell death, the ability of microglia to engulf Aβ is thought to contribute to its protective properties. Our study argues for a beneficial role of functional ramified microglia whereby they act against the accumulation of neurotoxic forms of Aβ and support neuronal resilience in an in situ model of AD pathology

IVIG Delays Onset in a Mouse Model of Gerstmann-Sträussler-Scheinker Disease

Our previous studies showed that intravenous immunoglobulin (IVIG) contained anti-Aβ autoantibodies that might be able to treat Alzheimer's disease (AD). Recently, we identified and characterized naturally occurring autoantibodies against PrP from IVIG. Although autoantibodies in IVIG blocked PrP fibril formation and PrP neurotoxicity in vitro, it remained unknown whether IVIG could reduce amyloid plaque pathology in vivo and be used to effectively treat animals with prion diseases. In this study, we used Gerstmann-Sträussler-Scheinker (GSS)-Tg (PrP-A116V) transgenic mice to test IVIG efficacy since amyloid plaque formation played an important role in GSS pathogenesis. Here, we provided strong evidence that demonstrates how IVIG could significantly delay disease onset, elongate survival, and improve clinical phenotype in Tg (PrP-A116V) mice. Additionally, in treated animals, IVIG could markedly inhibit PrP amyloid plaque formation and attenuate neuronal apoptosis at the age of 120 days in mice. Our results indicate that IVIG may be a potential, effective therapeutic treatment for GSS and other prion diseases

Die Genetik des Lipidstoffwechsels als Risikofaktor für kognitive Defizite bei der Parkinson-Krankheit

Die Parkinson-Krankheit gehört zu den Basalganglienerkrankungen und ist nach der Alzheimer-Krankheit die zweithäufigste neurodegenerative Erkrankung. Von den typischen motorischen Leitsymptomen sind kognitive Defizite, auch Parkinson-Demenz genannt, abzugrenzen. Etwa 75% der Parkinson-Syndrome sind idiopathisch und treten sporadisch auf. Bei dieser großen Mehrheit der Erkrankten gibt es bislang kein identifizierbares Vererbungsmuster. Für eine intakte Hirnfunktion ist der zerebrale Cholesterinmetabolismus von hoher Bedeutung, sodass kodierende Gene des Cholesterinstoffwechsels in die Pathogenese neurodegenerativer Erkrankungen, insbesondere der Alzheimer-Krankheit, involviert sind. Ausgehend von der bekannten pathophysiologischen Überschneidung der Alzheimer- und Parkinson-Krankheit, dient diese Arbeit einer systematischen Untersuchung ausgewählter Gene des Lipidstoffwechsels im Zusammenhang mit der Parkinson-Demenz. Das Kollektiv aus 94 Parkinson-Erkrankten entstammte der Datenbank der longitudinalen LANDSCAPE Studie, wobei 2 Gruppen von Parkinson-Patienten mit Demenz und unbeeinträchtigter Kognition gebildet wurden. Im Vorfeld wurde ein Matching zwecks höherer Vergleichbarkeit der Fall- und Kontrollgruppe anhand der Kriterien Geschlecht, ≥ 6 Jahre Erkrankungsdauer und ± 7 Jahre Altersdifferenz durchgeführt. Als Ausgangsmaterial der laborchemischen Versuche lag isolierte Desoxyribonukleinsäure vor, wobei mittels Polymerase-Kettenreaktion bestimmte Gen-Loci zwecks weiterer Aufschlüsselung amplifiziert wurden. Im Sinne eines genetischen Screenings wurden alle kodierenden Abschnitte der Apolipoproteine E, A1 und J sequenziert, wobei es sich um etablierte Risikogene der Alzheimer-Krankheit handelt. Zusätzlich wurden ausgewählte Exone von Adenosine Triphosphate-binding Cassette Transporter A1 (Exon 7, 18, 35) und Very-Low-Density-Lipoprotein Receptor (Exon 15) untersucht, bei denen bereits im Vorfeld kritische Mutationen beschrieben wurden. Im Fokus stand dabei die Identifikation von Einzelnukleotid-Polymorphismen, die möglicherweise mit der Ausprägung einer Demenz bei der Parkinson-Krankheit zusammenhängen. Im Rahmen der Sequenzierung mit Hilfe der Kettenabbruchmethode nach Sanger wurden insgesamt 8 Einzelnukleotid-Polymorphismen identifiziert, darunter 7 missense Mutationen und eine synonyme Variante. Apolipoprotein A1 und Very-Low-Density-Lipoprotein Receptor wiesen keine Mutation auf. Eine statistische Signifikanz konnte für keinen Einzelnukleotid-Polymorphismus gezeigt werden. Dementsprechend konnte kein eindeutiger Zusammenhang zwischen dem Vorhandensein einer Mutation und der Ausbildung einer Parkinson-Demenz in der vorliegenden Stichprobe abgeleitet werden. In der Tendenz waren jedoch 2 Mutationen hervorzuheben: rs7982 (Apolipoprotein J Exon 5) mit einer Odds ratio von 1.575 (95% Konfidenzintervall=0.680~3.646, p=0.288) sowie rs2066714/ rs4149313 (Adenosine Triphosphate-binding Cassette Transporter A1 Exon 18) mit einer Odds Ratio von 1.4 (95% Konfidenzintervall=0.551~3.554, p=0.478). Apolipoprotein J und Adenosine Triphosphate-binding Cassette Transporter A1 stellen somit als mögliche Risikogene der Parkinson-Demenz das Ziel weiterer Analysen dar. Als Limitation der Arbeit war die geringe Fallzahl bei initial zu hoch geschätzter Effektgröße zu betrachten, sodass die fokussierte Untersuchung in Bezug auf oben genannte Mutationen an weiteren Patienten der LANDSCAPE Studie sinnvoll und in Zukunft geplant ist

Costs of Parkinson's Disease and Antiparkinsonian Pharmacotherapy: An Italian Cohort Study

Objective: Antiparkinsonian pharmacotherapy is costly and the determinants of drug costs in Parkinson's disease (PD) have been poorly investigated. The objective of this study was to investigate the costs of PD and antiparkinsonian drugs in an Italian cohort of patients and identify cost-driving factors of drug therapy. Methods: Seventy outpatients with idiopathic PD were recruited in the Department of Neurology, Napoli University, Italy. Data on resource utilization were collected for 6 months using a bottom-up approach. Clinical status was evaluated using the Unified Parkinson's Disease Rating Scale. Direct and indirect costs were calculated from the societal perspective (figures of year 2009). Independent determinants of total costs and costs of antiparkinsonian drugs were identified using multivariate regression analysis. Results: The total costs of PD were EUR 8,640 (95% CI: EUR 6,700-11,240) per patient over a 6-month period. Direct costs accounted for 70% of the total costs. Antiparkinsonian drugs (EUR 1,450; 95% CI: EUR 1,220-1,760) were the primary component of costs paid by the health insurance (39.6%) and one of the most expensive components of the direct costs (24.0%). The highest copayments made by patients were for antiparkinsonian drugs and medical equipment (58%). Independent determinants of the increased costs of antiparkinsonian pharmacotherapy were younger age and occurrence of motor fluctuations. Conclusions: Antiparkinsonian pharmacotherapy is one of the major cost components of PD-related costs for health insurance. It imposes a considerable economic burden on patients and their families as well. Copyright (C) 2010 S. Karger AG, Base

Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder primarily affecting regions of the brain responsible for higher cognitive functions. Immunization against β-amyloid (Aβ) in animal models of AD has been shown to be effective on the molecular level but also on the behavioral level. Recently, we reported naturally occurring autoantibodies against Aβ (NAbs-Aβ) being reduced in Alzheimer's disease patients. Here, we further investigated their physiological role: in epitope mapping studies, NAbs-Aβ recognized the mid-/C-terminal end of Aβ and preferentially bound to oligomers but failed to bind to monomers/fibrils. NAbs-Aβ were able to interfere with Aβ peptide toxicity, but NAbs-Aβ did not readily clear senile plaques although early fleecy-like plaques were reduced. Administration of NAbs-Aβ in transgenic mice improved the object location memory significantly, almost reaching performance levels of wild-type control mice. These findings suggest a novel physiological mechanism involving NAbs-Aβ to dispose of proteins or peptides that are prone to forming toxic aggregates

Factors associated with long-term impact on informal caregivers during Alzheimer's disease dementia progression: 36-month results from GERAS

OBJECTIVE: To identify, in caregivers of patients with Alzheimer's disease (AD) dementia, factors associated with subjective (personal, physical, emotional, and social) and objective (informal caregiver time and costs) caregiver burden. DESIGN: Prospective longitudinal European observational study: post-hoc analysis. SETTING: Clinic. PARTICIPANTS: Community-dwelling patients in France and Germany aged ≥ 55 years (n = 969) with probable AD and their informal caregivers. MEASUREMENTS: Mini-Mental State Examination (MMSE), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), 12-item Neuropsychiatric Inventory (NPI-12), Zarit Burden Interview (ZBI), informal caregiver basic and instrumental ADL hours (Resource Utilization in Dementia instrument), and informal caregiver costs. Mixed-effect models of repeated measures (MMRM) were run, including baseline and time-dependent covariates (change from baseline [CFB] to 18 months in MMSE, ADCS-ADL, and NPI-12 scores) associated with CFB in ZBI score/informal caregiver time over 36 months (analyzed using linear regression models) and informal caregiver costs over 36 months (analyzed using generalized linear models). RESULTS: Greater decline in patient function (ADCS-ADL) over 18 months was associated with increased subjective caregiver burden (ZBI), hours, and costs over 36 months. Increased behavioral problems (NPI-12) over 18 months also negatively impacted ZBI. Cognitive decline (MMSE) over 18 months did not affect change in caregiver burden. CONCLUSIONS: Long-term informal caregiver burden was driven by worsening functional abilities and behavioral symptoms but not cognitive decline, over 18 months in community-dwelling patients with AD dementia. Identifying the drivers of caregiver burden could highlight areas in which interventions may benefit both caregivers and patients

Плазменное получение тепловой энергии из сульфатного лигнина

This article shows an overview and analysis of the literature on methods of using sludge lignin. This product obtained after treatment of pulp. As a result of calculating the optimum composition of water, organic materials with mechanical impurities from the adiabatic combustion temperature of about 1200 K were determined. Using the obtained results of experimental studies have been carried out in a plasma reactor of the catalytic reactor and has been optimized. The obtained results can be used to create industrial enterprises based on plasma catalytic reactors for waste sludge lignin for the purpose of obtaining heat

Cost-Utility of Using Alzheimer's Disease Biomarkers in Cerebrospinal Fluid to Predict Progression from Mild Cognitive Impairment to Dementia

Background: Diagnostic research criteria for Alzheimer's disease support the use of biomarkers in the cerebrospinal fluid (CSF) to improve the accuracy of the prognosis regarding progression to dementia for people with mild cognitive impairment (MCI). Objective: The aim of this study was to estimate the potential incremental cost-effectiveness ratio of adding CSF biomarker testing to the standard diagnostic workup to determine the prognosis for patients with MCI. Methods: In an early technology assessment, a mathematical simulation model was built, using available evidence on added prognostic value as well as expert opinion to estimate the incremental costs and quality-adjusted life years (QALYs) of 20,000 virtual MCI patients with (intervention strategy) and without (control strategy) relying on CSF, from a health-care sector perspective and with a 5-year time horizon. Results: Adding the CSF test improved the accuracy of prognosis by 11%. This resulted in an average QALY gain of 0.046 and € 432 additional costs per patient, representing an incremental cost-effectiveness ratio of € 9,416. Conclusion: The results show the potential of CSF biomarkers in current practice from a health-economics perspective. This result was, however, marked by a high degree of uncertainty, and empirical research is required into the impact of a prognosis on worrying, false-positive/negative prognosis, and stigmatization