Mitochondrial DNA polymorphisms as risk factors for Parkinson’s disease and Parkinson’s disease dementia

The activity of complex I of the mitochondrial respiratory chain has been found to be decreased in patients with Parkinsons disease (PD), but no mutations have been identified in genes encoding complex I subunits. Recent studies have suggested that polymorphisms in mitochondrial DNA (mtDNA)-encoded complex I genes (MTND) modify susceptibility to PD. We hypothesize that the risk of PD is conveyed by the total number of nonsynonymous substitutions in the MTND genes in various mtDNA lineages rather than by single mutations. To test this possibility, we determined the number of nonsynonymous substitutions of the seven MTND genes from 183 Finns. The differences in the total number of nonsynonymous substitutions and the nonsynonymous to synonymous substitution rate ratio (K_a/K_s) of MTND genes between the European mtDNA haplogroup clusters (HV, JT, KU, IWX) were analysed by using a statistical approach. Patients with PD (n=238) underwent clinical examination together with mtDNA haplogroup analysis and the clinical features between patient groups defined by the number of nonsynonymous substitutions were compared. Our analysis revealed that the haplogroup clusters HV and KU had a lower average number of amino acid replacements and a lower K_a/K_s ratio in the MTND genes than clusters JT and IWX. Supercluster JTIWX with the highest number of amino acid replacements was more frequent among PD patients and even more frequent among patients with PD who developed dementia. Our results suggest that a relative excess of nonsynonymous mutations in MTND genes in supercluster JTWIX is associated with an increased risk of PD and the disease progression to dementia.     

Instruction prioritization in task-based balance training for individuals with idiopathic Parkinson’s disease

The objective of the study was to evaluate the effect of prioritization of instruction in balance training for individuals with Parkinson’s disease (PD). Thirty-six participants were evaluated before and after the training using the Berg Balance Scale, Dynamic Gait Index, and Geriatric Depression Scale. Results show that dual task training with variable priority instruction is as effective as single task training in improving the balance performance of individuals with idiopathic PD.     

Levodopa influences the regularity of the ankle joint kinematics in individuals with Parkinson’s disease

The aim of the investigation was to explore the influence of levodopa therapy on the regularity of the structural variations present in the lower extremity joints of individuals with Parkinson’s disease (PD). Ten participants with PD walked on a treadmill during the states of “off” and “on” levodopa. Approximate entropy was used to quantify the regularity of the structural variations present in the joint kinematics. Additionally, a pseudo-periodic surrogation analysis was used to evaluate if changes in the regularity of the joint’s movement were associated with a noisy or deterministic motor process. This investigation provided two key findings. The first was that the structural variations present in ankle joint were more regular with levodopa therapy. The second was that changes in the structural variations were related to a deterministic motor process. This indicated that the variations present in the walking patterns of individuals with PD most likely arose from higher-order neural couplings rather than noise in the motor process. Monitoring the regularity of the structural variations present in gait may help improve the management of PD.     

Prevention of progression in Parkinson’s disease

Environmental influences affecting genetically susceptible individuals seem to contribute significantly to the development of Parkinson’s disease (PD). Xenobiotic exposure including transitional metal deposition into vulnerable CNS regions appears to interact with PD genes. Such exposure together with mitochondrial dysfunction evokes a destructive cascade of biochemical events, including oxidative stress and degeneration of the sensitive dopamine (DA) production system in the basal ganglia. Recent research indicates that the substantia nigra degeneration can be decelerated by treatment with iron binding compounds such as deferiprone. Interestingly compounds known to decrease PD risk including caffeine, niacin, nicotine and salbutamol also possess iron binding properties. Adequate function of antioxidative mechanisms in the vulnerable brain cells can be restored by acetylcysteine supplementation to normalize intracellular glutathione activity. Other preventive measures to reduce deterioration of dopaminergic neurons may involve life-style changes such as intake of natural antioxidants and physical exercise. Further research is recommended to identify therapeutic targets of the proposed interventions, in particular protection of the DA biosynthesis by oxygen radical scavengers and iron binding agents.     

Chasing genes in Alzheimer’s and Parkinson’s disease

Alzheimers disease (AD), the most common type of dementia, and Parkinsons disease (PD), the most common movement disorder, are both neurodegenerative adult-onset diseases characterized by the progressive loss of specific neuronal populations and the accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies, sometimes performed on special isolated populations. A growing number of genes (and pathogenic mutations) is being identified that cause or increase susceptibility to AD and PD. This review discusses the way in which strategies of gene hunting have evolved during the last few years and the significance of finding genes such as the presenilins, -synuclein, parkin and DJ-1. In addition, we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of a few overlapping interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that need further intense investigation to find the missing links.     

Reproducibility and responsiveness of gait initiation in Parkinson’s disease

Persons with Parkinson’s disease (PD) have significant impairments in functional mobility, including the ability to initiate gait. Three-dimensional analysis of kinetic and kinematic outcomes has become one of the most powerful tools in evaluating abnormalities in gait initiation for persons with PD. Surprisingly however, the psychometric properties of spatial and temporal measures of gait initiation for persons with PD have not been established using force-platforms. The purposes of this study were to determine the reliability of kinetic and kinematic measures of gait initiation and to identify the minimal detectable change of these measures in persons with PD during On and Off medication conditions. Sixteen participants with idiopathic PD performed a series of 3 repeated trials of gait initiation by starting from a quiet stance position on 2 AMTI OR-6 force platforms, and walking forward across the floor following a signal from the investigators. Testing was performed first in the Off medication condition, after which participants took their medication and waited 60 min before repeating the gait initiation assessments. Relative test-retest reliability was good-to-excellent for most outcome measures (range 0.417–0.960). Bland-Altman analysis revealed no systematic variance in the majority of outcome measures when tested in distinct medication conditions (On vs. Off medication). Most outcome measures required low-to-moderate amounts of change (<50%) to indicate true change in individual participants. These results suggest that spatial and temporal measures of gait initiation using force-platforms are highly reliable and responsive to changes in performance for persons with PD, regardless of whether individuals are optimally medicated.     

Cognitive predictors of balance in Parkinson’s disease

Postural instability is one of the most incapacitating symptoms of Parkinson’s disease (PD) and appears to be related to cognitive deficits. This study aims to determine the cognitive factors that can predict deficits in static and dynamic balance in individuals with PD. A sociodemographic questionnaire characterized 52 individuals with PD for this work. The Trail Making Test, Rule Shift Cards Test, and Digit Span Test assessed the executive functions. The static balance was assessed using a plantar pressure platform, and dynamic balance was based on the Timed Up and Go Test. The results were statistically analysed using SPSS Statistics software through linear regression analysis. The results show that a statistically significant model based on cognitive outcomes was able to explain the variance of motor variables. Also, the explanatory value of the model tended to increase with the addition of individual and clinical variables, although the resulting model was not statistically significant The model explained 25–29% of the variability of the Timed Up and Go Test, while for the anteroposterior displacement it was 23–34%, and for the mediolateral displacement it was 24–39%. From the findings, we conclude that the cognitive performance, especially the executive functions, is a predictor of balance deficit in individuals with PD.     

Study protocol of “CHAPS”: a randomized controlled trial protocol of Care Coordination for Health Promotion and Activities in Parkinson’s Disease to improve the quality of care for individuals with Parkinson’s disease

Background

Parkinson’s disease, the second most common neurodegenerative disease, is diagnostically defined by motor impairments, but also includes often under-recognized impairments in cognition, mood, sleep, and the autonomic nervous system. These problems can severely affect individuals’ quality of life. In our prior research, we have developed indicators to measure the quality of care delivered to patients with Parkinson’s disease, and we identified gaps in delivering evidence-based treatments for this population. Effective strategies to close these gaps are needed to improve patient quality of life.

Methods/design

Building on prior research we developed a multi-faceted proactive implementation program called Care Coordination for Health Promotion and Activities in Parkinson’s Disease (CHAPS). To be eligible, patients had to have at least two visits with a primary diagnosis of idiopathic Parkinson’s disease (ICD-9 code: 332.0) at one of five Veterans Affairs Medical Centers in the southwestern United States from 2010 to 2014. The program consists of telephone assessments, evidence-based protocols, and tools to enhance patient self-management, care planning, and coordination of care across providers, including an electronic database to support and track coordination of care. Our mixed-methods study employs a randomized, controlled trial design to test whether the CHAPS intervention improves performance in 38 quality measures among an analytic sample of 346 patients. The 38 quality measures are categorized into overarching areas of communication, education, and continuity; regulatory reporting; diagnosis; periodic assessment; medication use; management of motor and non-motor symptoms; use of non-pharmacological approaches and therapies; palliative care; and health maintenance. Secondary outcomes are patient health-related quality of life, self-efficacy, and perceptions of care quality. We are also evaluating the extent of the CHAPS Program implementation and measuring program costs and impacts on health services utilization, in order to perform a analysis of the CHAPS program from the perspective of the Veterans Health Administration (VA). Outcomes are assessed by interviewer-administered surveys collected at baseline and at 6, 12, and 18 months, and by medical record chart abstractions. Analyses will be intention-to-treat.

Discussion

The CHAPS Program is poised for dissemination within the VA National Parkinson’s Disease Research, Education, and Clinical Center Consortium if demonstrated efficacious.

Trial Registration

ClinicalTrials.gov NCT01532986; registered on January 13, 2012.

     

Investigation of muscle tone in patients with Parkinson’s disease in unloading conditions

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, the main symptoms of which are hypertonicity and difficulties emerging during performance of stepping movements due to increased muscle stiffness. Biomechanical (stiffness) and electrophysiological (shortening reaction, SR) characteristics of hip and shank muscles were examined in 25 patients with mild and moderate stages of PD (1 to 3 of Hoehn and Yahr Rating Scale, 61 ± 9 years) and 22 age-matched healthy controls in unloading leg conditions during passive flexion/extension of hip, knee, and ankle joints, as well as the changes in the tonic state of muscles under the influence of levodopa. The data obtained were compared with similar findings in healthy subjects. Essentially greater stiffness in all leg muscle groups (except foot extensors) was observed in patients with PD as compared to the healthy subjects. In patients with PD, SR values in hip and shank extensors as well as in foot flexors and extensors were essentially greater then in the healthy subjects. The medicine essentially reduced the stiffness of hip flexors and knee flexors and extensors. The SR persisted, although the frequency of its occurrence decreased in half of studied muscles, and a significant decrease in the SR value was observed in foot extensors. The medicine had no marked effect on the SR in the proximal muscles. Thus, the increased muscle stiffness in patients with PD manifests itself as distorted reactions to external disturbances and increased reflectory reactions of muscles.     

Environmental toxins and α-synuclein in Parkinson’s disease

In recent years, environmental influences have been thought to play an important role in Parkinson’s disease (PD). Evidence from epidemiological investigations suggests that environmental factors might take part in the disease process. Intriguingly, most of environmental toxins share the common mechanism of causing mitochondria dysfunction by inhibiting complex I and promoting α-synuclein aggregation, a key factor in PD. Therefore, understanding the mechanism of interactions between α-synuclein and environmental factors could lead to new therapeutic approaches to PD.     

Origins and suppression of oscillations in a computational model of Parkinson’s disease

Efficacy of deep brain stimulation (DBS) for motor signs of Parkinson’s disease (PD) depends in part on post-operative programming of stimulus parameters. There is a need for a systematic approach to tuning parameters based on patient physiology. We used a physiologically realistic computational model of the basal ganglia network to investigate the emergence of a 34 Hz oscillation in the PD state and its optimal suppression with DBS. Discrete time transfer functions were fit to post-stimulus time histograms (PSTHs) collected in open-loop, by simulating the pharmacological block of synaptic connections, to describe the behavior of the basal ganglia nuclei. These functions were then connected to create a mean-field model of the closed-loop system, which was analyzed to determine the origin of the emergent 34 Hz pathological oscillation. This analysis determined that the oscillation could emerge from the coupling between the globus pallidus external (GPe) and subthalamic nucleus (STN). When coupled, the two resonate with each other in the PD state but not in the healthy state. By characterizing how this oscillation is affected by subthreshold DBS pulses, we hypothesize that it is possible to predict stimulus frequencies capable of suppressing this oscillation. To characterize the response to the stimulus, we developed a new method for estimating phase response curves (PRCs) from population data. Using the population PRC we were able to predict frequencies that enhance and suppress the 34 Hz pathological oscillation. This provides a systematic approach to tuning DBS frequencies and could enable closed-loop tuning of stimulation parameters.     

Altered joint kinetic strategies of healthy older adults and individuals with Parkinson’s disease to walk at faster speeds

Individuals with Parkinson’s disease (PD) exhibit poorer walking performance compared to healthy, age-matched adults. Lower extremity joint kinetics may provide insight into this performance deficit but are currently lacking in the PD literature, especially across multiple speeds. The primary purpose of this study was to compare joint kinetics between individuals with PD and healthy older adults at both comfortable and maximal walking speeds. Secondarily, we quantified relationships between joint kinetics and walking speeds within each group. Biomechanical gait analyses were conducted for 13 individuals with PD and 12 age-matched controls during comfortable (CWS) and maximal (MWS) speed walking. Relative contributions to total positive work from the hip, knee, and ankle were compared across groups and speeds. Within each group, relationships between relative joint work and CWS and MWS were also quantified. Significant group by speed interactions indicated that healthy older adults increased hip and decreased ankle relative work at MWS compared to CWS whereas relative work at all joints in PD group remained stable across speeds. In the older group, positive relationships were observed between relative hip work and MWS. In the PD group, negative relationships were observed between relative hip work and CWS and MWS. Healthy older adults disproportionately increased mechanical contributions from the hip at MWS compared to CWS. Individuals with PD did not exhibit similar disproportionate scaling of joint kinetics across speed conditions. Inability to appropriately scale joint kinetics in PD may represent an inflexible neuromuscular system in PD, which may limit walking performance in this population.     

151 Network inference and analysis of Parkinson’s disease

Based on existing literature and publicly available expression data-sets, a map of Parkinson’s disease (PD) has been inferred in collaborative effort with other teams in LCSB and Systems Biology Institute, Tokyo, Japan. However, due to the increased complexity of the map, human intuition is often insufficient in understanding the initiation, functional regulation, and progression of this disease. Hence, it is necessary to mine the information content of this network to make sense of this abundance complex information. To this end, current work aims to analyze the network topology and dynamics of the PD map, using Boolean modeling. Grounded on perturbation analysis, the work also aims to obtain a system level understanding of the genotype–phenotype relationships to identify key components in the disease regulation and to generate experimentally testable hypothesis for PD susceptibility and progression. Methodology includes using existing graph theoretical analysis tools, as well as to develop rigorous sophisticated analysis tools which could be vital for understanding the disease pathology and for successful quantitative modeling. In general, the major focus and contribution of this work aim at the fields of statistical inference, graph analysis, and dynamic modeling in systems biology.     

Predictive association of copper metabolism proteins with Alzheimer’s disease and Parkinson’s disease: a preliminary perspective

Neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD), constitute a major worldwide health problem. Several hypothesis have been put forth to elucidate the basis of onset and pathogenesis of AD and PD; however, till date, none of these seems to clearly elucidate the complex pathoetiology of these disorders. Notably, copper dyshomeostasis has been shown to underlie the pathophysiology of several neurodegenerative diseases including AD and PD. Numerous studies have concluded beyond doubt that imbalance in copper homeostatic mechanisms in conjunction with aging causes an acceleration in the copper toxicity elicited oxidative stress, which is detrimental to the central nervous system. Amyloid precursor protein and α-synuclein protein involved in AD and PD are copper binding proteins, respectively. In this review, we have discussed the possible association of copper metabolism proteins with AD and PD along with briefly outlining the expanding proportion of “copper interactome” in human biology. Using network biology, we found that copper metabolism proteins, superoxide dismutase 1 and ceruloplasmin may represent direct and indirect link with AD and PD, respectively.     

Emerging roles of epigenetic mechanisms in Parkinson’s disease

Epigenetic mechanisms have emerged as important components of a variety of human diseases, including cancer and central nervous system disorders. Despite recent studies highlighting the role of epigenetic mechanisms in several neurodegenerative and neuropsychiatric disorders, to date, there has been a paucity of studies exploring the role of epigenetic factors in Parkinson’s disease (PD). PD is a progressive neurological disorder with characteristic motor and non-motor symptoms, including a range of neuropsychiatric features, for which neither preventative nor effective long-term treatment strategies are available. It is one of the most common neurodegenerative disorders and the second most prevalent after Alzheimer’s disease. In this review, we present several lines of evidence suggesting that epigenetic factors may play an important role in the pathogenesis of PD and propose on this basis a framework to guide future investigations into epigenetic mechanisms and systems biology of PD. These notions, together with technical advances in the ability to perform genome-wide analysis of epigenomic states, and newly available small-molecule probes targeting chromatin-modifying enzymes, may help design new treatment strategies for PD and other human diseases involving epigenetic dysregulation.     

Tackling neurodegenerative diseases: animal models of Alzheimer’s disease and Parkinson’s disease

Our ageing society is confronted with a dramatic increase in incidence of age-related neurodegenerative diseases; biomedical research leading to novel therapeutic strategies is crucial to address this problem. Animal models of neurodegenerative conditions are invaluable in improving our understanding of the molecular basis of pathology, potentially revealing novel targets for intervention. Here, we review transgenic animal models of Alzheimer’s and Parkinson’s disease reported in mice, zebrafish, Caenorhabditis elegans and Drosophila melanogaster. This information will enable researchers to compare different animal models targeting disease-associated molecules by genomic engineering and to facilitate the development of novel animal models for any particular study, depending on the ultimate research goals.