Sequence variation in the proximity of IDE may impact age at onset of both Parkinson disease and Alzheimer disease

We recently reported that a linkage disequilibrium (LD) block on chromosome 10q encompassing the gene encoding insulin-degrading enzyme (IDE) harbors sequence variants that associate with Alzheimer disease (AD). Evidence also indicated effects upon a number of quantitative indices of AD severity, including age-at-onset (AAO). Since linkage of this immediate region to AAO has been shown in both AD and Parkinson disease (PD), we have explored the possibility that polymorphism within this LD block might also influence PD. Utilizing single nucleotide polymorphisms that delineate common haplotypes from this region, we observed significant evidence of association with AAO in an Australian PD case-control sample. Analyses were complemented with AAO data from two independent Swedish AD case samples, for which previously reported findings were replicated. Results were consistent between AD and PD, suggesting the presence of equivalent detrimental and protective alleles. These data highlight a genomic region in the proximity of IDE that may contribute to AD and PD in a similar manner.

Selective loss of synaptic proteins in Alzheimer's disease: Evidence for an increased severity with APOE epsilon 4

A pathological feature of Alzheimer's disease (AD) is an area-specific neuronal loss that may be caused by excitotoxicity-related synaptic dysfunction. Relative expression levels of synaptopbysin, dynamin I, complexins I and II, N-cadherin, and alpha CaMKII were analysed in human brain tissue from AD cases and controls in hippocampus, and inferior temporal and occipital cortices. Synaptophysin and dynamin I are presynaptic terminal proteins not specific to any neurotransmitter system whereas complexin II, N-cadherin, and alpha CaMKII are specific for excitatory synapses. Complexin I is a presynaptic protein localised to inhibitory synapses. There were no significant differences in synaptophysin, dynamin I, N-cadherin, or alpha CaMKII protein levels between AD cases and controls. The complexin proteins were both markedly lower in AD cases than in controls (P < 0.01). Cases were also categorised by APOE genotype. Averaged across areas there was a 36% lowering of presynaptic proteins in AD cases carrying at least one epsilon 4 allele compared with in AD cases lacking the epsilon 4 allele. We infer that synaptic protein level is not indicative of neuronal loss, but the synaptic dysfunction may result from the marked relative loss of the complexins in AD, and lower levels of presynaptic proteins in AD cases with the APOE epsilon 4 allele. (c) 2006 Elsevier Ltd. All rights reserved.

Dementia with Lewy bodies:Clustering of Lewy bodies in human patients

Clustering of Lewy bodies (LB) was studied in four regions of the medial temporal lobe in 12 cases of dementia with LB (DLB). LB exhibited clustering in 67/70 (96%) brain areas analysed. In 34/70 (49%) analyses, LB were present in a single large cluster ≤6400 μm in diameter, in 33/70 (47%) LB occurred in smaller clusters 200-3200 μm in diameter which exhibited a regular periodicity relative to the tissue boundary and in 3/70 (4%), LB were randomly distributed. A regular pattern of LB clusters was observed equally frequently in the cortex and hippocampus, in upper and lower cortical laminae and in 'pure' cases of DLB with negligible Alzheimer's disease (AD) pathology compared with cases of AD with DLB. In cortical regions, there was no significant correlation between LB cluster size in the upper and lower cortical laminae. The regular periodicity of LB clusters suggests that LB develop in relation to the cells of origin of specific cortico-cortical and cortico-hippocampal projections.

The levels of neopterin, biopterin and the neopterin/biopterin ratio in urine from control subjects and patients with Alzheimer’s disease and Down’s syndrome

The levels of neopterin, biopterin and the neopterin/biopterin ratio (N/B) were measured in urine samples taken from normal young and elderly control subjects, exceptionally healthy elderly control subjects classified according to the ‘Senieur’ protocol and patients with Down’s syndrome (DS) or Alzheimer’s disease (AD). The N/B ratio was approximately unity in control groups with the exception of the normal elderly controls. The levels of neopterin and biopterin declined with age in the exceptionally healthy ‘Senieur’ control group. The N/B ratio was elevated in young and old DS patients as a result of the significant increase in neopterin. Neopterin levels were significantly elevated in AD patients compared with the healthy elderly controls, but this did not result in a significant increase in the N/B ratio in these patients. The N/B ratio increased with age in AD patients as a result of a decline in biopterin. These results suggested that there is a cellular immune reponse in DS and AD patients which in DS, may precede the formation of beta-amyloid deposits in the brain. In addition, there may be a deficiency in tetrahydrobiopterin biosynthesis in AD which becomes more marked with age.

Analysis of β-amyloid (Aβ) deposition in the temporal lobe in Alzheimer's disease using Fourier (spectral) analysis

To determine the spatial pattern of ß-amyloid (Aß) deposition throughout the temporal lobe in Alzheimer's disease (AD). Methods: Sections of the complete temporal lobe from six cases of sporadic AD were immunolabelled with antibody against Aß. Fourier (spectral) analysis was used to identify sinusoidal patterns in the fluctuation of Aß deposition in a direction parallel to the pia mater or alveus. Results: Significant sinusoidal fluctuations in density were evident in 81/99 (82%) analyses. In 64% of analyses, two frequency components were present with density peaks of Aß deposits repeating every 500–1000 µm and at distances greater than 1000 µm. In 25% of analyses, three or more frequency components were present. The estimated period or wavelength (number of sample units to complete one full cycle) of the first and second frequency components did not vary significantly between gyri of the temporal lobe, but there was evidence that the fluctuations of the classic deposits had longer periods than the diffuse and primitive deposits. Conclusions: (i) Aß deposits exhibit complex sinusoidal fluctuations in density in the temporal lobe in AD; (ii) fluctuations in Aß deposition may reflect the formation of Aß deposits in relation to the modular and vascular structure of the cortex; and (iii) Fourier analysis may be a useful statistical method for studying the patterns of Aß deposition both in AD and in transgenic models of disease.

The visual cortex in Alzheimer disease:laminar distribution of the pathological changes in visual areas V1 and V2

Alzheimer’s disease (AD) is an important neurodegenerative disorder causing visual problems in the elderly population. The pathology of AD includes the deposition in the brain of abnormal aggregates of ?-amyloid (A?) in the form of senile plaques (SP) and abnormally phosphorylated tau in the form of neurofibrillary tangles (NFT). A variety of visual problems have been reported in patients with AD including loss of visual acuity (VA), colour vision and visual fields; changes in pupillary responses to mydriatics, defects in fixation and in smooth and saccadic eye movements; changes in contrast sensitivity and in visual evoked potentials (VEP); and disturbances in complex visual tasks such as reading, visuospatial function, and in the naming and identification of objects. In addition, pathological changes have been observed to affect the eye, visual pathway, and visual cortex in AD. To better understand degeneration of the visual cortex in AD, the laminar distribution of the SP and NFT was studied in visual areas V1 and V2 in 18 cases of AD which varied in disease onset and duration. In area V1, the mean density of SP and NFT reached a maximum in lamina III and in laminae II and III respectively. In V2, mean SP density was maximal in laminae III and IV and NFT density in laminae II and III. The densities of SP in laminae I of V1 and NFT in lamina IV of V2 were negatively correlated with patient age. No significant correlations were observed in any cortical lamina between the density of NFT and disease onset or duration. However, in area V2, the densities of SP in lamina II and lamina V were negatively correlated with disease duration and disease onset respectively. In addition, there were several positive correlations between the densities of SP and NFT in V1 with those in area V2. The data suggest: (1) NFT pathology is greater in area V2 than V1, (2) laminae II/III of V1 and V2 are most affected by the pathology, (3) the formation of SP and NFT in V1 and V2 are interconnected, and (4) the pathology may spread between visual areas via the feed-forward short cortico-cortical connections.

RELAX:a language to address uncertainty in self-adaptive systems requirement

Self-adaptive systems have the capability to autonomously modify their behavior at run-time in response to changes in their environment. Self-adaptation is particularly necessary for applications that must run continuously, even under adverse conditions and changing requirements; sample domains include automotive systems, telecommunications, and environmental monitoring systems. While a few techniques have been developed to support the monitoring and analysis of requirements for adaptive systems, limited attention has been paid to the actual creation and specification of requirements of self-adaptive systems. As a result, self-adaptivity is often constructed in an ad-hoc manner. In order to support the rigorous specification of adaptive systems requirements, this paper introduces RELAX, a new requirements language for self-adaptive systems that explicitly addresses uncertainty inherent in adaptive systems. We present the formal semantics for RELAX in terms of fuzzy logic, thus enabling a rigorous treatment of requirements that include uncertainty. RELAX enables developers to identify uncertainty in the requirements, thereby facilitating the design of systems that are, by definition, more flexible and amenable to adaptation in a systematic fashion. We illustrate the use of RELAX on smart home applications, including an adaptive assisted living system.

The visual cortex in alzheimer's disease:laminar distribution of the pathological changes in visual areas V1 and V2

Alzheimer's disease (AD) is an important neurodegenerative disorder causing visual problems in the elderly population. The pathology of AD includes the deposition in the brain of abnormal aggregates of β-amyloid (Aβ) in the form of senile plaques (SP) and abnormally phosphorylated tau in the form of neurofibrillary tangles (NFT). A variety of visual problems have been reported in patients with AD including loss of visual acuity (VA), colour vision and visual fields; changes in pupillary responses to mydriatics, defects in fixation and in smooth and saccadic eye movements; changes in contrast sensitivity and in visual evoked potentials (VEP); and disturbances in complex visual tasks such as reading, visuospatial function, and in the naming and identification of objects. In addition, pathological changes have been observed to affect the eye, visual pathway, and visual cortex in AD. To better understand degeneration of the visual cortex in AD, the laminar distribution of the SP and NFT was studied in visual areas V1 and V2 in 18 cases of AD which varied in disease onset and duration. In area V1, the mean density of SP and NFT reached a maximum in lamina III and in laminae II and III respectively. In V2, mean SP density was maximal in laminae III and IV and NFT density in laminae II and III. The densities of SP in laminae I of V1 and NFT in lamina IV of V2 were negatively correlated with patient age. No significant correlations were observed in any cortical lamina between the density of NFT and disease onset or duration. However, in area V2, the densities of SP in lamina II and lamina V were negatively correlated with disease duration and disease onset respectively. In addition, there were several positive correlations between the densities of SP and NFT in V1 with those in area V2. The data suggest: (1) NFT pathology is greater in area V2 than V1, (2) laminae II/III of V1 and V2 are most affected by the pathology, (3) the formation of SP and NFT in V1 and V2 are interconnected, and (4) the pathology may spread between visual areas via the feed-forward short cortico-cortical connections. © 2012 by Nova Science Publishers, Inc. All rights reserved.

Who speaks up for Inés Fonseca? Representing violence against vulnerable subjects and the ethics of care in fictional narrative about Alzheimer’s disease:Ahora tocad música de baile (2004) by Andrés Barba

This paper studies the Spanish fictional novel by Andrés Barba, Ahora tocad música de baile (2004), one of the first cultural texts dealing entirely with Alzheimer’s disease (AD) to appear in Spain. It argues that the significance of Barba’s fictional novel rests on two important issues: the ethics of representation of violence against vulnerable subjects and the ethics of care. The paper analyses how these two issues allow Barba to create a story in which the verbal and physical abuse to which the person living with Alzheimer’s disease is subjected places the reader, on the one hand, as voyeur/witness of the abuse; and, on the other, as interpreter, and ultimately judge, of the fine line that separates euthanasia, assisted suicide, and murder. The open ending of the novel defers all ethical and moral judgment to the reader. It examines how the novel offers a monolithic perspective about AD, in which care is presented as a burden. In fact, this study shows that the novel’s multi-layered structure and polyphonic nature places the emphasis on stigmas, stereotypes and negative metaphors around AD, as found in contemporary social discourses.

Performance analysis of IEEE 802.11 cognitive radio ad hoc networks

IEEE 802.11 standard is the dominant technology for wireless local area networks (WLANs). In the last two decades, the Distributed coordination function (DCF) of IEEE 802.11 standard has become the one of the most important media access control (MAC) protocols for mobile ad hoc networks (MANETs). The DCF protocol can also be combined with cognitive radio, thus the IEEE 802.11 cognitive radio ad hoc networks (CRAHNs) come into being. There were several literatures which focus on the modeling of IEEE 802.11 CRAHNs, however, there is still no thorough and scalable analytical models for IEEE 802.11 CRAHNs whose cognitive node (i.e., secondary user, SU) has spectrum sensing and possible channel silence process before the MAC contention process. This paper develops a unified analytical model for IEEE 802.11 CRAHNs for comprehensive MAC layer queuing analysis. In the proposed model, the SUs are modeled by a hyper generalized 2D Markov chain model with an M/G/1/K model while the primary users (PUs) are modeled by a generalized 2D Markov chain and an M/G/1/K model. The performance evaluation results show that the quality-of-service (QoS) of both the PUs and SUs can be statistically guaranteed with the suitable settings of duration of channel sensing and silence phase in the case of under loading.

Secure routing and trust computation in multihop infrastructureless networks

Today's wireless networks rely mostly on infrastructural support for their operation. With the concept of ubiquitous computing growing more popular, research on infrastructureless networks have been rapidly growing. However, such types of networks face serious security challenges when deployed. This dissertation focuses on designing a secure routing solution and trust modeling for these infrastructureless networks. ^ The dissertation presents a trusted routing protocol that is capable of finding a secure end-to-end route in the presence of malicious nodes acting either independently or in collusion, The solution protects the network from active internal attacks, known to be the most severe types of attacks in an ad hoc application. Route discovery is based on trust levels of the nodes, which need to be dynamically computed to reflect the malicious behavior in the network. As such, we have developed a trust computational model in conjunction with the secure routing protocol that analyzes the different malicious behavior and quantifies them in the model itself. Our work is the first step towards protecting an ad hoc network from colluding internal attack. To demonstrate the feasibility of the approach, extensive simulation has been carried out to evaluate the protocol efficiency and scalability with both network size and mobility. ^ This research has laid the foundation for developing a variety of techniques that will permit people to justifiably trust the use of ad hoc networks to perform critical functions, as well as to process sensitive information without depending on any infrastructural support and hence will enhance the use of ad hoc applications in both military and civilian domains. ^

Directionality based preventive link maintenance scheme for mobile ad hoc networks

The purpose of this study was to design a preventive scheme using directional antennas to improve the performance of mobile ad hoc networks. In this dissertation, a novel Directionality based Preventive Link Maintenance (DPLM) Scheme is proposed to characterize the performance gain [JaY06a, JaY06b, JCY06] by extending the life of link. In order to maintain the link and take preventive action, signal strength of data packets is measured. Moreover, location information or angle of arrival information is collected during communication and saved in the table. When measured signal strength is below orientation threshold , an orientation warning is generated towards the previous hop node. Once orientation warning is received by previous hop (adjacent) node, it verifies the correctness of orientation warning with few hello pings and initiates high quality directional link (a link above the threshold) and immediately switches to it, avoiding a link break altogether. The location information is utilized to create a directional link by orienting neighboring nodes antennas towards each other. We call this operation an orientation handoff, which is similar to soft-handoff in cellular networks. ^ Signal strength is the indicating factor, which represents the health of the link and helps to predict the link failure. In other words, link breakage happens due to node movement and subsequently reducing signal strength of receiving packets. DPLM scheme helps ad hoc networks to avoid or postpone costly operation of route rediscovery in on-demand routing protocols by taking above-mentioned preventive action. ^ This dissertation advocates close but simple collaboration between the routing, medium access control and physical layers. In order to extend the link, the Dynamic Source Routing (DSR) and IEEE 802.11 MAC protocols were modified to use the ability of directional antennas to transmit over longer distance. A directional antenna module is implemented in OPNET simulator with two separate modes of operations: omnidirectional and directional. The antenna module has been incorporated in wireless node model and simulations are performed to characterize the performance improvement of mobile ad hoc networks. Extensive simulations have shown that without affecting the behavior of the routing protocol noticeably, aggregate throughput, packet delivery ratio, end-to-end delay (latency), routing overhead, number of data packets dropped, and number of path breaks are improved considerably. We have done the analysis of the results in different scenarios to evaluate that the use of directional antennas with proposed DPLM scheme has been found promising to improve the performance of mobile ad hoc networks. ^

Simulazione della bradicinesia in soggetti parkinsoniani attraverso modello neurale

I Gangli della Base svolgono un ruolo molto importante nel movimento volontario, ovvero nel meccanismo di azione-selezione, e la loro influenza è evidente soprattutto in alcune patologie che ancora ad oggi sono in fase di studio: una di queste è il Morbo di Parkinson. I Gangli della Base comprendono quattro formazioni nervose: lo striato, il globus pallidus, la substantia nigra e il nucleo subtalamico: essi ricevono le principali afferenze dalla corteccia cerebrale ed inviano le principali efferenze al tronco dell’encefalo, e, per mezzo del talamo, alle corteccia prefrontale, premotoria e motrice. A differenza della maggior parte delle altre componenti dei sistemi motori, i Gangli della Base non stabiliscono direttamente né connessioni afferenti, né efferenti con il midollo spinale. Il compito principale svolto dai Gangli dDella Base è la selezione di un’azione: esso permette ad un’azione di essere selezionata rispetto ad un’altra, che in questo modo viene inibita. La descrizione dell’anatomia, dei meccanismi fisiologici e del Morbo di Parkinson è trattata nel Capitolo 1. In questo elaborato è utilizzato il modello computazionale di Mauro Ursino e Chiara Baston, che sarà illustrato dettagliatamente nel Capitolo 2, riguardante il meccanismo di azione-selezione svolto dai Gangli della Base. E’ descritto un sistema di valutazione di un paziente parkinsoniano, il tapping test: esso consiste in un movimento alternato del dito e ad oggi risulta essere uno dei metodi più semplici per ottenere informazioni sulla gravità della bradicinesia. L’obiettivo di questo lavoro è quello di comprendere, tramite l’analisi di simulazioni effettuate per mezzo del modello computazionale di Mauro Ursino e Chiara Baston, come la frequenza di tapping dipenda dal variare di alcuni parametri delle equazioni del modello: gli effetti dovuti alla variazione di un singolo parametro o più di uno, saranno mostrati nel Capitolo 3.

Data on the biogeochemical cycle of methane in the ocean

Geological, mineralogical and microbiological aspects of the methane cycle in water and sediments of different areas in the oceans are under consideration in the monograph. Original and published estimations of formation- and oxidation rates of methane with use of radioisotope and isotopic methods are given. The role of aerobic and anaerobic microbial oxidation of methane in production of organic matter and in formation of authigenic carbonates is considered. Particular attention is paid to processes of methane transformation in areas of its intensive input to the water column from deep-sea hydrothermal sources, mud volcanoes, and cold methane seeps.

miRNAs as therapeutic agents in neurodegeneration, a pilot study

L’échec des différents essais cliniques souligne la nécessité de développer des nouvelles thérapies pour la maladie d’Alzheimer (MA), la cause la plus commune de démence. Les microARNs (miARNs) sont les ARNs non-codants les plus étudiés et ils jouent un rôle important dans la modulation de l’expression des gènes et de multiples voies de signalisation. Des études antérieures, dont celles de mon laboratoire d’accueil, ont permis de développer l’hypothèse que certains membres de la famille miR-15/107 (c.-à-d. miR-15ab, miR-16, miR-195, miR-424, and miR-497) pourraient être utilisés comme agents thérapeutiques dans MA. En effet, cette famille avait le potentiel de réguler de multiples gènes associés à MA, tels que la protéine précurseur de l’amyloïde (APP), la β-secrétase (BACE1), et la protéine Tau. Tel que démontré dans ce projet de thèse, j’ai choisi miR-16 comme cible thérapeutique potentielle pour MA parmi tous les membres de la famille. L’essai luciférase dans ce projet confirme que miR-16 peut réguler simultanément APP et BACE1, directement par une interaction avec la région non-codante en 3’ de l’ARNm). Notamment, nous observons aussi une réduction de la production des peptides amyloïdes et de la phosphorylation de Tau après une augmentation de miR-16 en cellule. J’ai ensuite validé mes résultats in vivo dans la souris en utilisant une méthode de livraison de miR-16 via une pompe osmotique implanté dans le cerveau. Dans ce cas, l’expression des protéines d’intérêts (APP, BACE1, Tau) a été mesurée par immunobuvardage et PCR à temps réel. Après validation, ces résultats ont été complémentés par une étude protéomique (iTRAQ) du tronc cérébral et de l’hippocampe, deux régions associées à la maladie. Ces données m’ont permis d’identifier d’autres protéines régulées par miR-16 in vivo, incluant α-Synucléine, Transferrine receptor1, et SRm300. Une autre observation intéressante : les voies régulées par miR-16 in vivo sont directement en lien avec le stress oxydatif et la neurodégénération. En résumé, ce travail démontre l’efficacité et la faisabilité d’utiliser un miARN comme outil thérapeutique pour la maladie d’Alzheimer. Ces résultats rentrent dans un cadre plus vaste de découvrir de nouvelles cibles pour MA, et en particulier la forme sporadique de la maladie qui représente plus de 95% de tous les cas. Évidemment, la découverte d’une molécule pouvant cibler simultanément les deux pathologies de la maladie (plaques amyloïdes et hyper phosphorylation de tau) est nouvelle et intéressante, et ce domaine de recherche ouvre la porte aux autres petits ARNs non-codants dans MA et les maladies neurodégénératives connexes.