bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic distributed flow scheduling for effective link utilization in data center networks
Authors: Bharti Sourabh , Pattanaik K.K.
Published: December 2019

Current static flow scheduling techniques such as Equal Cost Multi Path (ECMP) and Valiant Load Balancing (VLB) use randomization and hash based techniques to schedule the flow in Data Center Networks (DCN). In such flow scheduling techniques, the probability of allotment of the same path for different flows at a time is high. This causes collision of flows and at times can lead to unfair link utilization. On other hand, Dynamic flow scheduling techniques such as Global first fit use a centralized mechanism to schedule flows. Global first fit can introduce the problem of unfair link utilization and also vulnerable to a single point of failure. Effective flow scheduling is the key problem in fat-tree topology based DCNs mainly due to the bandwidth over-subscription ratio and bursty nature of traffic. In this paper, we propose a dynamic distributed flow scheduling mechanism for effective link utilization and load balancing. Moreover our proposed mechanism prevents the core switch saturation scenario by taking flow scheduling decisions at lower layers. Load measurement performed on aggregate switches for various data center traffic flow patterns reveals that the load factors across all the aggregate switches vary by at most 0.11 when dynamic distributed flow scheduling is applied without flowlet splitting. Further with flowlet splitting our dynamic distributed flow scheduling mechanism improved the load factor variation to 0.08. The load factor values signify there is considerable improvement in link utilization and the switches are fairly load balanced. The experiment scenario is simulated using Colored Petri Nets.
Efficient source mobility support in content-centric networking
Authors: Tang Jianqiang , Zhou Huachun , Liu Ying , Zhang Hongke
Published: December 2019

With the development of wireless network technology, the number of mobile devices that access to contents on Internet increases rapidly. It is impressively popular for mobile users to use their mobile devices anytime and anywhere to generate, access and share contents on the Internet. To comply with this tendency, a new network paradigm called content-centric networking (CCN) emerges. With extensive research and demonstration, CCN is gradually widely recognized as a promising next generation Internet architecture, but remains an open issue on how to support source mobility in CCN. In this paper, we take full advantage of the locator/identifier separation along with control and data plane separation into supporting efficient source mobility in CCN. We decouple the content name from both routing of content requests and content identifying. We split the control and data plane by handling handover signaling and data traffic separately. We also divide the network into many rendezvous domains and design the handover processes of intra-domain and inter-domain movements. We then propose a method to allocate a rendezvous point for a mobile source according to its history roaming behavior in a rendezvous domain. Finally, we present numerical results to demonstrate the performance of the proposed approaches.
Lightweight coordinated checkpointing in cloud computing
Authors: Meroufel Bakhta , Belalem Ghalem
Published: December 2019

Fault tolerance is actually an essential issue in cloud computing to face failures and minimize their damages. The checkpointing is a powerful fault tolerance technique that consists of saving the transient state of a computation system on a persistent storage from which the execution state can be restarted in case of failure. The coordinated checkpointing is an efficient checkpointing strategy because it is domino effect-free and it needs only the last stored checkpoint to ensure a consistent state. In this paper we propose a lightweight coordinated checkpointing for cloud computing that minimizes the overload of classical coordinated checkpointing by minimizing the number of the participating virtual machines (VMs) in each checkpointing interval. The experimental results prove that our proposal reduces the overload and improves the system performances.
Extended High Speed Networks Employing Hippi Switches, High Speed WANs, and FDDI Rings
Authors: Franta W. R. , Hughes J. P.
Published: December 2019

Computational and storage “power” is increasing at alarmingly well documented rates. As everything that's connected to data transmission network becomes more capable so must data networks.

To truly unleash the genie stored in these “power” increases, information (data) must flow more rapidly into and out of these devices. Channel and backplane speeds commensurate with these increasing computational and storage “powers” are beginning to appear. The data transfer equation is then balanced only if network speeds follow suit.

Our focus in this paper is to concentrate on LAN/WAN networks currently within reach that attempt to “follow suit”, concentrating specifically on FDDI- and HIPPI-based LAN networks, new WAN offerings, and concluding with speculations on next generation high speed networking capabilities. Along the way we enumerate certain observations relevant to the acquisition and use of extended high-speed networks.
A Dynamic Multi-Path Routing Algorithm for ATM Networks
Authors: Bahk Saewoong , El Zarki Magda
Published: December 2019

In this paper we describe briefly a dynamic multi-path routing scheme that has been considered for connection oriented homogeneous high-speed wide area Asynchronous Transfer Mode (ATM) networks. The fundamental objective of the scheme is to bridge the gap between routing and congestion control as the network becomes congested. Because propagation delay far out shadows queueing and transmission delay in high-speed networks, the proposed routing scheme works as a shortest path (minimum hop) first algorithm under light traffic conditions. However as the shortest path becomes congested, the source node uses multiple paths when and if available in order to distribute the load and reduce packet loss. The scheme is a cross between Alternate Path Routing and Trunk Reservation.

We compare the performance of the proposed scheme with the Shortest Path Only Algorithm, the Alternate Path Routing Algorithm, the Random Routing Algorithm, and the Trunk Reservation Scheme. The throughput and packet loss performance are compared via simulations. These have been carried out concentrating on a five-node network, each with varying traffic patterns, the intention being to gain insight into the strengths and weaknesses of the various schemes.
Realization of a Multimedia Traffic Generator Based on (μ,σ) Buffer Occupancy Analysis
Authors: Kowtha Sitaram , Vaman Dhadesugoor R. , Djuknic Goran
Published: December 2019

Carefully selected traffic generators enable accurate simulation of integrated broad-band networks. Simulation tools are crucial in analysis of traditional as well as new protocols and algorithms designed for optimum network management in the era of high-speed integrated ATM-based networks. In this paper, we survey proposed ATM traffic models and traffic generators derived from them for the purposes of representing voice, data, and video traffic. We then compare (μ, σ) buffer occupancy levels at a statistical multiplexer due to traffic generated from various traffic generators and show that the generator based on K-superposition of identical On/Off sources (K-ON-OFF model) possesses desirable characteristics as a general multimedia traffic model. The K-ON-OFF generator has been implemented and used to represent voice, data, or video sources as well as aggregated traffic behavior.
Analysis of the Leaky Bucket Algorithm for ON-OFF Data Sources
Authors: Yin Nanying , Hluchyj Michael G.
Published: December 2019

The leaky bucket algorithm has been proposed as an important element in the rate-based management of bandwidth in high-performance, integrated packet communication networks. In this paper, the leaky bucket algorithm is analyzed for ON-OFF data sources, which may be characterized by their average data rate, peak data rate, and average number of bits generated during an ON period. A fictitious queue is used to model the behavior of the leaky bucket algorithm, and a two-state Markov-modulated rate process is used to model the ON-OFF data source. The analysis applies to buffered and unbuffered leaky buckets with rejecting or marking of violating data. Simple, closed-form expressions are derived that relate the leaky bucket parameters (bucket size and rate) and the ON-OFF source characteristics to the loss and mark probabilities and the leaky bucket queueing delay. The required bucket size is shown to increase linearly with the average number of bits generated during an ON period, and increase logarithmically with the decrease in loss or mark probability. For a buffered leaky bucket, we also show that the bucket size increases logarithmically with the decrease in the average delay in the leaky bucket queue.
Architecture and Analysis of Fast Packet Switches Based on Time-Multiplexed Photonic Fabrics
Authors: Aly Khaled A. , Dowdt Patrick W.
Published: December 2019

This paper proposes and evaluates two fast packet switching architectures based on time-division multiplexed integrated photonic fabrics. The architectures are targeted towards low-latency inter-node switching and intra-node routing in high-speed networks. The inter-node switch achieves output packet queueing via asynchronous time-division multiplexing a strictly-nonblocking photonic fabric. Buffer behavior is analyzed at both input and output stages to .determine the effect of varying the switching bandwidth on the performance metrics (delay, throughput, and packet loss probability). Analysis is performed for finite switch dimensions by obtaining upper and lower bounds on the packet loss at input. The dependence of finite output buffer latency and overflow probability on the normalized switching bandwidth is examined. The intra-node trunk traffic router consists of a passive optical coupler followed by an active routing stage. For this architecture, both synchronous and asynchronous time-division multiplexing modes are modeled and analyzed to obtain expressions for corresponding packet buffering delay and total switching latency. The router is shown to saturate at the waiting time singularity of its input (or output) buffers, given by the ratio of the switching bandwidth to the dimension.
Minimizing delay and packet loss in single-hop lightwave WDM networks using TDMA schedules
Authors: Rouskas George N. , Ammar Mostafa H.
Published: December 2019

We consider packet-switched lightwave WDM networks with stations equipped with tunable transmitters and fixed receivers. Access to each of the available channels is controlled by a weighted TDMA scheme, whereby the channels are not necessarily shared equally among the various sources. In this paper we study the problem of designing TDMA frames to minimize the mean packet delay, as well as the mean packet loss probability given a finite buffer capacity. We develop optimization methods which, for non-uniform communication patterns common to parallel and distributed computations, represent a significant improvement over 1-TDMA*. Furthermore, the margin of improvement increases with the size of the network. Our main contribution is to present relatively simple media access control schemes which, in the general case (i.e., non-uniform traffic), achieve good performance in terms of delay, throughput, and packet loss.
An ATM multimedia architecture: Design, implementation, and performance
Authors: Zeadally Sherali
Published: December 2019

This paper describes the design, implementation, and performance of an ATM multimedia architecture for the UNIX environment. An ATM card has been designed for the EISA bus and provides host connectivity to an ATM network. The network architecture has been built from scratch and supports applications that use standard protocols such as TCP/IP as well as other applications that require a raw AAL5 service. To support continuous media applications such as digital video/audio, a kernel module has been implemented and incorporated into the UNIX operating system. The kernel module improves application performance by providing an in-kernel data path which allows direct streaming of digital video/audio between an ATM network adapter and the display device.
Analysis of an ATM statistical multiplexer with heterogeneous Markovian on/off sources and applications to call admission control
Authors: Elsayed Khaled M. , Perros Harry G.
Published: December 2019

A computationally efficient algorithm for characterizing the superposition process of N heterogeneous and independent Interrupted Bernoulli Processes is first introduced. The algorithm is then used to analyze a statistical multiplexer with a finite buffer. Numerical examples highlighting the accuracy of algorithm are given. Finally, we use the algorithm to test two popular schemes for call admission control in an ATM network, namely the equivalent capacity and the heavy traffic approximation methods.
Center selection and migration for wide-area multicast routing
Authors: Donahoo Michael J. , Calvert Kenneth L. , Zegura Ellen W.
Published: December 2019

Interdomain multicast routing is a challenge, requiring a scalable solution that is suitable for diverse application characteristics. Center-based routing trees overcome some of the limitations associated with traditional shortest-path tree routing, however, they present a new set of routing problems. Specifically, the choice of the center router can be critical in determining the multicast routing performance. We present and assess algorithms to solve two problems: selection of an initial center router, and migration of the center router in response to dynamic chauges in the group membership during the application lifetime. These two problems, and our proposed solutions, may have more general applicability in wide-area networking, e.g., in placing shared resources in the network or estimating bandwidth utilization for multicast distribution.
A survey and new results in renegotiated service
Authors: Zegura Ellen W. , McFarland Scott , Parekh Ojas
Published: December 2019

To use a network service class, an application must determine which service is suitable and provide a concise description of traffic characteristics required by the service class. Applications may find it difficult to do this if accurate a priori knowledge of traffic is not available or if the traffic characteristics will change over time. Both of these difficulties can be addressed by a renegotiated service that supports changes in the traffic contract over time.

We focus in this paper on applications that have known, but changing, service requirements, thus they can use off-line processing. We survey existing work and present new algorithms for determining when to renegotiate the service and what new traffic contract to supply. We evaluate the performance of our work and the work of others using a common set of application streams.
A scheme for QoS control in ATM switching systems
Authors: Chen Wen-Tsuen , Huang Chun-Fu , Ding Sheng-Chuan
Published: December 2019

This paper concerns with the problem of supporting multiple QoS classes for BISDN services. To support multiple QoS classes, the cell loss rate and cell delay must be able to be controlled. We propose a scheme that can effectively control the cell loss rate and cell delay for each QoS class in an output queueing system. The proposed scheme combines the partial sharing scheme with a static service controller to support multiple QoS classes. Services are categorized into several QoS classes and each class is assigned with a loss-priority and a delay-priority. The buffer space at each output port is logically divided into several nested regions, and higher loss-priority cells can access a larger region to ensure a smaller cell loss probability. Also, the buffer space is physically divided into several queues, and cells of the same delay-priority are stored in the same queue. Higher delay-priOlity cells are served with a higher service rate to ensure a shorter delay. Four traffic classes of combining two different delay and two different loss requirements are considered in the performance evaluation. We have analyzed both the cell loss rates due to buffer overflow and the cell loss rates due to violating the cell delay requirements for all four traffic classes. We have also compared the proposed scheme with the priority assignment control (PAC) scheme which provides a separate queue for each QoS class. These evaluation results show that the proposed scheme is more efficient than the PAC scheme. Moreover, it is even simpler than the PAC scheme, since a less number of queues are needed to be maintained.
Effect of seasonal temperature fluctuations on performance of 160 Gbps transmission with adjustable chromatic dispersion compensation
Authors: Bourdoucen Hadj
Published: December 2019

In this paper, effect of seasonal temperature fluctuations on performance of chromatic dispersion compensated 160 Gbps optical fiber networks is investigated. Compensation of temperature dispersion effects on single mode fiber (SMF) is obtained by adjusting the length of the dispersion compensation fiber (DCF) as compensation and compensation slope factors of SMF fiber vary with temperature. Based on temperature dependence models and measurements, simulation studies have been carried out and the obtained results show expected quantitative compensation requirements for seasonal thermal effects. The range of temperatures considered corresponds to seasonal ones for Muscat area with changes from −10°C to 60°C. This has been done for typical optical fiber spans of SMF and DCF fibers for 160 Gbps rates. In addition to this, the results that the NRZ coding format is more tolerant to temperature changes than the RZ format.
Modified TCP startup procedure for large bandwidth-delay networks
Authors: Cheng Rung-Shiang , Lin Hui-Tang
Published: December 2019

This paper proposes an improvement to the TCP startup procedure in large bandwidth-delay networks. Current TCP congestion control algorithms may lead to the premature termination of the slow-start phase, resulting in an under-utilization of network resources and a corresponding degradation of the network performance. Consequently, this paper develops an algorithm which estimates the network conditions during the startup phase and rapidly expands the congestion window to match the available bandwidth. The simulation results confirm that the proposed TCP startup procedure improves the throughput of the modified TCP connection while remaining fair to other active TCP implementations in terms of bandwidth consumption.
Modeling and analysis of a hybrid optical switching system with delay buffer and wavelengths classification
Authors: Jia Peng , Zhang Jie , Gu Wanyi
Published: December 2019

Optical Circuit Switching (OCS) provides a good support for the services requiring high bandwidth and Quality of Service (QoS). When the character of network traffic changes from voice-oriented to data-oriented, OCS must cooperate with new switching mechanisms such as Optical Burst Switching (OBS) to improve performance. So a Hybrid Optical Switching (HOS) system is proposed. In HOS, different traffics are classified and both OBS and OCS can be processed. At the same time, delay buffer mechanisms, which are Fiber Delay Line (FDL) and electronic buffering, are introduced in HOS to solve the contention of OBS bursts. And a wavelengths classification mechanism, which assigns some wavelengths dedicated to OCS traffics, is provided to guarantee the QoS of OCS. To analyze the performance in theory, models based on Markovian theory and iterative method are provided. The results got by theory are accurate compared with simulations. The use of delay buffer can decrease the blocking probability of OBS and increase resource utilization. Wavelength classification mechanism benefits to improve OCS's performance.
Secure group re-keying using key inverses
Authors: El-Zoghdy Said Fathy , Asem Yasser Mohammed
Published: December 2019

The Internet multicast capabilities have been used in enormous number of groups through the Internet. However, IP multicast does not deploy any mechanisms to secure the multicast messages in these groups. A lot of research efforts have been done to secure multicast messages. The idea behind the multicast security is to share a symmetric key between group members to encrypt/decrypt the multicast messages and to change this key after any membership change. The main re-keying problem is how to exchange the new group key between the group members in a scalable and secure way. In this paper we present a new multicast re-keying approach that is based on dividing the whole group into smaller subgroups. Each subgroup in turn is organized in a logical key hierarchy tree, and each subgroup member has the inverse key values of the other members in his subgroup in order to make the subgroup re-keying in a scalable and secure way. This decomposition, the proposed approach, which is named as Key Inverse Re-keying (KIR), reduces the multicast complexity from O(n) to O(log 2m) where n is the total number of the whole group members and m is the number of members in each subgroup. The performance of KIR is compared with that of other group re-keying approaches to prove its effectiveness. The comparison is undertaken according to the computational overhead, communication overhead, storage overhead, and message size. The results show that KIR enhances the group performance in terms of computational overhead and communication overhead especially at the leave operation which represents a big problem for most of the previous group re-keying protocols.
Performance analysis of downlink traffic in WiMAX networks by considering a shadowing radio propagation model
Authors: Kaddour Mejdi , Tandjaoui Amel Faiza
Published: December 2019

We investigate in this paper the implications of scheduling and adaptive modulation and coding (AMC) on the performance of downlink traffic in OFDMA-based IEEE 802.16 cells. To this end, we model the downlink traffic as a discrete-time Markov chain by assuming exponential interarrival times of packets at the upstream of the unidirectional unbuffered connection maintained by the base station with each associated subscriber station (SS). Various performance metrics are derived by considering two usual scheduling policies: equal-slot sharing (ESS) and equal-throughput sharing (ETS). In particular, the estimated packet access delays provide a lower bound on the achieved delays in case of buffering. Besides, our model considers the adaptivity of the modulation and coding schemes (MCSs) used by the base station. By assuming uniform distribution of the SSs over the cell and shadowing log-normal radio propagation, we derive the probability density function of the signal-to-noise ratios measured at the level of the SSs. Albeit defined in the context of WiMAX networks, this second contribution can be exploited in more generic wireless settings. Several numerical results are presented and discussed to expose the effects of system parameters and scheduling policies on performance.
Energy aware based fault tolerance approach for topology control in distributed sensor networks
Authors: Bhajantri Lokesh B. , Nalini N.
Published: December 2019

A Distributed Sensor Networks (DSNs) can provide access to information anytime, anywhere by collecting, processing, analyzing and disseminating data. Thus, the network actively participates in creating a smart environment. DSNs promise to revolutionize sensing in a wide range of application domains. This is because of their reliability, accuracy, flexibility, cost effectiveness and ease of deployment of nodes in topology of DSN. Smart sensors can offer vigilant surveillance and can detect and collect data concerning any sign of machines failure, earthquakes, floods and even a terrorist attack. Energy efficiency, topology control and fault-tolerance are the most important issues in the development of next-generation DSNs. Fault tolerance is the ability of a system to deliver a desired level of functionality in presence of faults in the topology. Topology control as a low level service governs communication among all nodes and is hence the primary target for increasing connectivity and saving energy.

In this work, we have proposed two models for fault detection and fault recovery to achieve fault tolerance in topology. The proposed fault detection model is used to detect faults at node level (checking nodes energy) and network level faults (link failure and packet error). The proposed fault recovery model is used to achieve fault tolerance by adjusting the topology of the randomly deployed sensor nodes based on energy aware of nodes. Finally, we have evaluated the performance parameters for the proposed scheme.
“Skeletal Muscle MicroRNAs: Their Diagnostic and Therapeutic Potential in Human Muscle Diseases”
Authors: Alexander Matthew S. , Kunkel Louis M.
Published: December 2019

MicroRNAs (miRNAs) are small 21–24 nucleotide RNAs that are capable of regulating multiple signaling pathways across multiple tissues. MicroRNAs are dynamically regulated and change in expression levels during periods of early development, tissue regeneration, cancer, and various other disease states. Recently, microRNAs have been isolated from whole serum and muscle biopsies to identify unique diagnostic signatures for specific neuromuscular disease states. Functional studies of microRNAs in cell lines and animal models of neuromuscular diseases have elucidated their importance in contributing to neuromuscular disease progression and pathologies. The ability of microRNAs to alter the expression of an entire signaling pathway opens up their unique ability to be used as potential therapeutic entry points for the treatment of disease. Here, we will review the recent findings of key microRNAs and their dysregulation in various neuromuscular diseases. Additionally, we will highlight the current strategies being used to regulate the expression of key microRNAs as they have become important players in the clinical treatment of some of the neuromuscular diseases.
Impact of Falls and Fear of Falling on Health-Related Quality of Life in Patients with Parkinson's Disease
Authors: Grimbergen Yvette A.M. , Schrag Annette , Mazibrada Gordon , Borm George F. , Bloem Bastiaan R.
Published: December 2019

Postural instability, recurrent falls and fear of falling are common in advanced Parkinson's disease (PD). We examined the impact of fall frequency, fear of falling, balance confidence and objectively measured balance impairment (using Tinetti's Mobility Index) on health-related quality of life (HrQoL) in PD. In 74 subjects HrQoL was assessed using the 39-item Parkinson's disease Quality of Life Questionnaire [PDQ-39]. Patients were interviewed using a validated falls questionnaire, addressing fall history, consequences of falls and fear of falling. Neurological examination included Hoehn and Yahr scale, the Unified Parkinson's disease Rating Scale and Tinetti's Mobility Index. Disease severity, age and gender explained 43% of the differences in HrQoL across patients (R2 = 0.43). The combination of these factors and each of the factors fear of falling, balance confidence and fall frequency lead to 55%, 50% and 45% of explained variation, respectively. The standardised regression coefficients of these risk factors were 0.34 (fear of falling), 0.28 (balance confidence) and 0.13 (fall frequency). This suggests that fear of falling is a more important determinant of HrQoL than actual falling. These results emphasise the importance of addressing fear of falling in the clinical management of PD, and the need for development of strategies to reduce fear of falling in intervention programs.
Parkinson's Disease – the Debate on the Clinical Phenomenology, Aetiology, Pathology and Pathogenesis
Authors: Jenner Peter , Morris Huw R. , Robbins Trevor W. , Goedert Michel , Hardy John , Ben-Shlomo Yoav , Bolam Paul , Burn David , Hindle John V. , Brooks David ,   For The Parkinson's UK Discussion Group
Published: December 2019

The definition of Parkinson's disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article - widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic perspective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include - Parkinson's syndrome, Parkinson's syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA).
Dopamine Agonists Rather than Deep Brain Stimulation Cause Reflection Impulsivity in Parkinson's Disease
Authors: Djamshidian Atbin , O'Sullivan Sean S. , Foltynie Thomas , Aviles-Olmos Iciar , Limousin Patricia , Noyce Alastair , Zrinzo Ludvic , Lees Andrew J. , Averbeck Bruno B.
Published: December 2019

Background: Dopamine agonist therapy is the main risk factor for impulse control disorders in Parkinson's disease (PD). However, it is unclear whether bilateral deep brain stimulation of the subthalamic nucleus also causes impairment in decision making. Objectives: To assess the role of dopamine agonist therapy and deep brain stimulation on reflection impulsivity in non-demented patients with PD. Methods: We recruited 61 PD patients, 20 treated with L-dopa in combination with a dopamine agonist, 14 taking L-dopa monotherapy, a further 16 PD patients with bilateral subthalamic nucleus deep brain stimulation treated with L-dopa in combination with a dopamine agonist, and 11 PD patients with bilateral subthalamic nucleus deep brain stimulation taking L-dopa but not a dopamine agonist. Results were compared with 18 healthy controls. Patients who had evidence of impulsive compulsive behaviour were excluded. Reflection impulsivity was assessed with the beads task, which is a validated information sampling task. Results: All patients treated with a dopamine agonist gathered significantly less information and made more irrational decisions than all other groups regardless of whether they had surgical treatment. Conclusions: Our results imply that dopamine agonist therapy but not deep brain stimulation leads to “reflection impulsivity” in PD.
Comparison of Handheld Video Camera and GAITRite® Measurement of Gait Impairment in People with Early Stage Parkinson's Disease: A Pilot Study
Authors: Beijer Tim R. , Lord Stephen R. , Brodie Matthew A. D.
Published: December 2019

In this pilot study, we investigated the validity and reliability of low-cost handheld video camera recordings for measuring gait in people with early stage Parkinson's disease (PD). Five participants with PD, Hoehn & Yahr stage I–II, mean age 66.2 years and five healthy age-matched controls were recruited. Participants walked across a GAITRite® electronic walkway at self-selected pace while video was simultaneously recorded. Data from both systems were analyzed and compared. Step time variability, measured from handheld video recordings, revealed significant (p ≤ 0.05) differences between the gait of early stage PD and controls. Concurrent validity between video analyses and GAITRite were good (ICC(2,1) ≥ 0.86) for mean step time and mean dual support duration. However, the inter-assessor reliability for the video analysis was poor for step time variability (ICC(2,1) = 0.18). More reliable measurement of step time variability may require a system to measure extended periods of walking. Further research involving longer walks and more participants with higher stages of PD is required to investigate if step time variability can be measured with acceptable reliability using video recordings. If this could be demonstrated, this simple technology could be adapted to run on a tablet or smart phone, providing low cost gait assessments without the need for specialized equipment and expensive infrastructure.
Daytime Sleepiness is Associated with Falls in Parkinson's Disease
Authors: Spindler Meredith , Gooneratne Nalaka S. , Siderowf Andrew , Duda John E. , Cantor Charles , Dahodwala Nabila
Published: December 2019

Falls are frequent in Parkinson's disease (PD), and may be influenced by daytime sleepiness. We reviewed the records of 120 men with PD. Mean Epworth Sleepiness Scale (ESS) values were significantly different between non-fallers and fallers (6.0 vs. 9.7, p < 0.01). In multivariate analysis, ESS remained significantly associated with falls (OR 1.2, 95% CI 1.1–1.4, p = 0.02), along with cognitive impairment (OR 4.4 95% CI 1.0–18.7, p = 0.04) and postural instability/gait dysfunction (OR 1.6 95% CI 1.0–2.4, p = 0.03) in non-depressed patients. In conclusion, non-depressed PD patients are 20% more likely to fall for every one unit increase in the ESS measure of sleepiness.
Levodopa in the Treatment of Parkinson's Disease: Current Status and New Developments
Authors: Salat David , Tolosa Eduardo
Published: December 2019

Levodopa, a dopamine precursor, is an effective and well-tolerated dopamine replacement agent used to treat Parkinson's disease (PD). Oral levodopa has been widely used for over 40 years, often in combination with a dopa-decarboxylase inhibitor (DDCI), which reduces many treatment complications, extending its half-life and increasing levodopa availability to the brain. Entacapone, a catechol-O-methyltransferase inhibitor, can also be used to improve the bioavailability of levodopa, especially when used in conjunction with a DDCI. During early-stage PD, treatment will depend on the severity of symptoms; if greater symptomatic effect is required then levodopa or dopamine agonists are usually the drugs of choice. The ability to remain employable or physically active is an important goal in younger patients, therefore, in some instances levodopa initiation should be considered early on, either as a monotherapy or in combination with other drugs. The clinical use of levodopa may eventually be limited by the development of various treatment-related complications, including response fluctuations, dyskinesia and psychiatric problems. Motor complications are related to the intermittent delivery of dopamine-replacing drugs to the brain. Triple combination of levodopa/carbidopa/entacapone available in a single tablet in multiple levodopa dose strengths offers flexibility and helps control response fluctuations. Recent developments in treatment with levodopa try to obtain continuous delivery with levodopa and include duodenal infusion of a levodopa/carbidopa, transdermal levodopa patch, and oral pro-levodopa. Levodopa remains the most potent dopaminergic therapy for PD.
Continuous Real-Time in vivo Measurement of Cerebral Nitric Oxide Supports Theoretical Predictions of an Irreversible Switching in Cerebral ROS after Sufficient Exposure to External Toxins
Authors: Finnerty Niall J. , O'Riordan Saidhbhe L. , Lowry John P. , Cloutier Mathieu , Wellstead Peter
Published: December 2019

Background: Mathematical models of the interactions between alphasynuclein (αS) and reactive oxygen species (ROS) predict a systematic and irreversible switching to damagingly high levels of ROS after sufficient exposure to risk factors associated with Parkinson's disease (PD). Objectives: We tested this prediction by continuously monitoring real-time changes in neurochemical levels over periods of several days in animals exposed to a toxin known to cause Parkinsonian symptoms. Methods: Nitric oxide (NO) sensors were implanted in the brains of freely moving rats and the NO levels continuously recorded while the animals were exposed to paraquat (PQ) injections of various amounts and frequencies. Results: Long-term, real-time measurement of NO in a cohort of animals showed systematic switching in levels when PQ injections of sufficient size and frequency were administered. The experimental observations of changes in NO imply a corresponding switching in endogenous ROS levels and support theoretical predictions of an irreversible change to damagingly high levels of endogenous ROS when PD risks are sufficiently large. Conclusions: Our current results only consider one form of PD risk, however, we are sufficiently confident in them to conclude that: (i) continuous long-term measurement of neurochemical dynamics provide a novel way to measure the temporal change and system dynamics which determine Parkinsonian damage, and (ii) the bistable feedback switching predicted by mathematical modelling seems to exist and that a deeper analysis of its characteristics would provide a way of understanding the pathogenic mechanisms that initiate Parkinsonian cell damage.
Memory, Mood, and Vitamin D in Persons with Parkinson's Disease
Authors: Peterson Amie L. , Murchison Charles , Zabetian Cyrus , Leverenz James B. , Watson G. Stennis , Montine Thomas , Carney Natasha , Bowman Gene L. , Edwards Karen , Quinn Joseph F.
Published: December 2019

Background: Research in recent years has suggested a role of vitamin D in the central nervous system. The final converting enzyme and the vitamin D receptor are found throughout the human brain. From animal studies vitamin D appears important in neurodevelopment, up-regulation of neurotrophic factors, stabilization of mitochondrial function, and antioxidation. Objective: To examine the relationship between serum vitamin D and neuropsychiatric function in persons with Parkinson's disease (PD). Methods: This is an add-on study to a longitudinal study following neuropsychiatric function in persons with PD. Baseline neuropsychiatric performance and serum 25-hydroxyvitamin D were examined for 286 participants with PD. Measures of global cognitive function (MMSE, MOCA, Mattis Dementia Scale), verbal memory (Hopkins Verbal Learning Test), fluency (animals, vegetables, and FAS words), visuospatial function (Benton Line Orientation), executive function (Trails Making Test and Digit-Symbol Substitution), PD severity (Hoehn & Yahr and Unified Parkinson's Disease Rating Scale) and depression (Geriatric Depression Scale (GDS)) were administered. Multivariate linear regression assessed the association between vitamin D concentration and neuropsychiatric function, in the entire cohort as well as the non-demented and demented subsets. Results: Using a multivariate model, higher vitamin D concentrations were associated with better performance on numerous neuropsychiatric tests in the non-demented subset of the cohort. Significant associations were specifically found between vitamin D concentration and verbal fluency and verbal memory (t = 4.31, p < 0.001 and t = 3.04, p = 0.0083). Vitamin D concentrations also correlated with depression scores (t = −3.08, p = 0.0083) in the non-demented subset. Conclusions: Higher plasma vitamin D is associated with better cognition and better mood in this sample of PD patients without dementia. Determination of causation will require a vitamin D intervention study.
Phenotypic Screening of the Prestwick Library for Treatment of Parkinson's Tremor Symptoms using a Humanized Quantitative Systems Pharmacology Platform
Authors: Spiros Athan , Roberts Patrick , Geerts Hugo
Published: December 2019

Background: Possible solutions for the low success rate in CNS Drug discovery and development in CNS diseases include drug repurposing. Objectives: As a possible alternative to prohibitively expensive systematic testing in animal models, we propose to use a humanized quantitative systems pharmacology (QSP) platform as an example of a well-validated phenotypic assay in Parkinson's disease (PD) tremor for filtering out possible interesting molecules that then can be tested in preclinical animal models. This will significantly reduce discovery time and costs, while at the same time providing a better predictability to the human clinical outcome. The method will be applied to the Prestwick library, a library of FDA approved and off-patent medications. Methods: The platform contains 30 CNS physiologically implemented targets and simulates biophysically realistic neuronal network interactions between supplemental motor cortex and motor striatum based on preclinical neurophysiology and human electrophysiology data. Importantly, the platform is further calibrated using retrospective clinical data on Parkinsonian side-effects with antipsychotics. Results: We use this QSP platform to screen pharmacological profiles of serotonergic drugs in the Prestwick library. We identified five interesting multi-pharmacology agents, including trazodone that in a previously reported study improved clinical PD scales as augmentation strategy. Conclusion: The Quantitative Systems Pharmacology platform is a powerful modeling and simulation tool with a relevant human clinical scale as output, where multi-target drugs effect can be simulated and promising candidates for further study in pharmacological profiling or animal models can be identified.
The Role of Innate and Adaptive Immunity in Parkinson's Disease
Authors: Kannarkat George T. , Boss Jeremy M. , Tansey Malú G.
Published: December 2019

In recent years, inflammation has become implicated as a major pathogenic factor in the onset and progression of Parkinson's disease. Understanding the precise role for inflammation in PD will likely lead to understanding of how sporadic disease arises. In vivo evidence for inflammation in PD includes microglial activation, increased expression of inflammatory genes in the periphery and in the central nervous system (CNS), infiltration of peripheral immune cells into the CNS, and altered composition and phenotype of peripheral immune cells. These findings are recapitulated in various animal models of PD and are reviewed herein. Furthermore, we examine the potential relevance of PD-linked genetic mutations to altered immune function and the extent to which environmental exposures that recapitulate these phenotypes, which may lead to sporadic PD through similar mechanisms. Given the implications of immune system involvement on disease progression, we conclude by reviewing the evidence supporting the potential efficacy of immunomodulatory therapies in PD prevention or treatment. There is a clear need for additional research to clarify the role of immunity and inflammation in this chronic, neurodegenerative disease.
Can Intrabodies Serve as Neuroprotective Therapies for Parkinson's Disease? Beginning Thoughts
Authors: Bhatt Mansi A. , Messer Anne , Kordower Jeffrey H.
Published: December 2019

Misfolded proteins and subsequent protein aggregation appears to underlie a significant fraction of neurodegenerative diseases including Parkinson's disease. One of the neuropathological hallmarks of Parkinson's disease is the presence of α-syn containing intracellular inclusions known as Lewy bodies and Lewy neurites. Intrabodies are antibody fragments that have been engineered to be expressed intracellularly. They can be directed towards specific target antigens present in various subcellular locations, and have shown promise in cancer, HIV, autoimmune diseases, and Huntington's disease. More recently they have been shown to modulate abnormalities caused by aggregated α-syn in cell culture. This mini-review mainly focuses on summarizing structural and cellular effects of intrabodies shown to have affinity for different forms of α-synuclein (monomeric, oligomeric and fibrillar), as well as those exhibiting affinity for particular residues of α-synuclein (e.g., the NAC region, C terminal region).
Decline in Verbal Fluency After Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A Microlesion Effect of the Electrode Trajectory?
Authors: Le Goff Floriane , Derrey Stéphane , Lefaucheur Romain , Borden Alaina , Fetter Damien , Jan Maryvonne , Wallon David , Maltête David
Published: December 2019

Background: Decline in verbal fluency (VF) is frequently reported after chronic deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson disease (PD). Objective: We investigated whether the trajectory of the implanted electrode correlate with the VF decline 6 months after surgery. Methods: We retrospectively analysed 59 PD patients (mean age, 61.9 ± 7; mean disease duration, 13 ± 4.6) who underwent bilateral STN-DBS. The percentage of VF decline 6 months after STN-DBS in the on-drug/on-stimulation condition was determined in respect of the preoperative on-drug condition. The patients were categorised into two groups (decline and stable) for each VF. Cortical entry angles, intersection with deep grey nuclei (caudate, thalamic or pallidum), and anatomical extent of the STN affected by the electrode pathway, were compared between groups. Results: A significant decline of both semantic and phonemic VF was found after surgery, respectively 14.9% ± 22.1 (P < 0.05) and 14.2% ± 30.3 (P < 0.05). Patients who declined in semantic VF (n = 44) had a left trajectory with a more anterior cortical entry point (56 ± 53 versus 60 ± 55 degree, P = 0.01) passing less frequently trough the thalamus (P = 0.03). Conclusions: Microlesion of left brain regions may contribute to subtle cognitive impairment following STN-DBS in PD.
Fatty Acid Composition of the Anterior Cingulate Cortex Indicates a High Susceptibility to Lipid Peroxidation in Parkinson's Disease
Authors: Abbott Sarah K. , Jenner Andrew M. , Spiro Adena S. , Batterham Marijka , Halliday Glenda M. , Garner Brett
Published: December 2019

Background: Oxidative stress contributes to Parkinson's disease (PD) etiology. Although previous studies have focused on sources of free radical formation in brain regions affected by PD, less is known regarding changes in lipid composition and the implications for susceptibility to peroxidation. Objective: To assess fatty acid profiles from control and PD tissues that are susceptible to PD pathology but devoid of severe destruction. Methods: We used gas chromatography methods to assess fatty acid profiles from control (n = 10) and PD (n = 9) postmortem tissues. We focused on the anterior cingulate cortex (ACC), a region that accumulates alpha-synuclein, but does not undergo severe destruction, and compared this to the occipital cortex, a region that is pathologically spared. Results: Our data indicate a significant 33% increase in the proportion of polyunsaturated fatty acids (mol%) present in the PD ACC as compared to control ACC. Increases in highly unsaturated 22:5n-6 and 22:6n-3 fatty acids were particularly pronounced (109% and 73%, respectively). Calculation of a peroxidation index (accounting for total fatty acyl double bounds) indicated a 44% increase in susceptibility of the PD ACC to lipid peroxidation compared to control ACC. Such differences were not detected in the occipital cortex from the same donors. Assessment of F2-isprostane levels confirmed that PD tissue lipids were more oxidized than controls. Conclusions: The global composition of fatty acids in the PD ACC is altered in a way that increases susceptibility to peroxidation in a region-specific manner. This has important implications for PD, supporting the oxidative stress hypothesis of PD pathogenesis.