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.     

Gene therapy in Parkinson’s disease

Gene therapy in Parkinsons disease appears to be at the brink of the clinical study phase. Future gene therapy protocols will be based on a substantial amount of preclinical data regarding the use of ex vivo and in vivo genetic modifications with the help of viral or non-viral vectors. To date, the supplementation of neurotrophic factors and substitution for the dopaminergic deficit have formed the focus of trials to achieve relief in animal models of Parkinsons disease. Newer approaches include attempts to influence detrimental cell signalling pathways and to inhibit overactive basal ganglia structures. Nevertheless, current models of Parkinsons disease do not mirror all aspects of the human disease, and important issues with respect to long-term protein expression, choice of target structures and transgenes and safety remain to be solved. Here, we thoroughly review available animal data of gene transfer in models of Parkinsons disease.     

Neuronal pathology in Parkinson’s disease

Parkinsons disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra leading to the major clinical and pharmacological abnormalities of PD. In order to establish causal or protective treatments for PD, it is necessary to identify the cascade of deleterious events that lead to the dysfunction and death of dopaminergic neurons. Based on genetic, neuropathological, and biochemical data in patients and experimental animal models, dysfunction of the ubiquitin-proteasome pathway, protein aggregation, mitochondrial dysfunction, oxidative stress, activation of the c-Jun N-terminal kinase pathway, and inflammation have all been identified as important pathways leading to excitotoxic and apoptotic death of dopaminergic neurons. Toxin-based and genetically engineered animal models allow (1) the study of the significance of these aspects and their interaction with each other and (2) the development of causal treatments to stop disease progression.     

Succinate dehydrogenase in Parkinson’s disease

Background

The prevalence of neurodegenerative disorders such as Parkinson’s disease (PD) is increased by age. Alleviation of their symptoms and protection of normal neurons against degeneration are the main aspects of the researches to establish novel therapeutic strategies. Many studies have shown that mitochondria as the most important organelles in the brain which show impairment in PD models. Succinate dehydrogenase (SDH) as a component of the oxidative phosphorylation system in mitochondria connects Krebs cycle to the electron transport chain. Dysfunction or inhibition of the SDH can trigger mitochondrial impairment and disruption in ATP generation. Excessive in lipid synthesis and induction of the excitotoxicity as inducers in PD are controlled by SDH activity directly and indirectly. On the other hand, mutation in subunits of the SDH correlates with the onset of neurodegenerative disorders. Therefore, SDH could behave as one of the main regulators in neuroprotection.

Objective

In this review we will consider contribution of the SDH and its related mechanisms in PD.

Methods

Pubmed search engine was used to find published studies from 1977 to 2016. “Succinate dehydrogenase”, “lipid and brain”, “mitochondria and Parkinson’s disease” were the main keywords for searching in the engine.

Results

Wide ranges of studies (59 articles) in neurodegenerative disorders especially Parkinson’s disease like genetics of the Parkinson’s disease, effects of the mutant SDH on cell activity and physiology and lipid alteration in neurodegenerative disorders have been used in this review.

Conclusion

Mitochondria as key organelles in the energy generation plays crucial roles in PD. ETC complex in this organelle consists four complexes which alteration in their activities cause ROS generation and ATP depletion. Most of complexes are encoded by mtDNA while complex II is the only part of the ETC which is encoded by nuclear genome. So, focusing on the SDH and related pathways which have important role in neuronal survival and SDH has a potential to further studies as a novel neuroprotective agent.

     

Calcium signaling in Parkinson’s disease

Calcium (Ca²⁺) is an almost universal second messenger that regulates important activities of all eukaryotic cells. It is of critical importance to neurons, which have developed extensive and intricate pathways to couple the Ca²⁺ signal to their biochemical machinery. In particular, Ca²⁺ participates in the transmission of the depolarizing signal and contributes to synaptic activity. During aging and in neurodegenerative disease processes, the ability of neurons to maintain an adequate energy level can be compromised, thus impacting on Ca²⁺ homeostasis. In Parkinson’s disease (PD), many signs of neurodegeneration result from compromised mitochondrial function attributable to specific effects of toxins on the mitochondrial respiratory chain and/or to genetic mutations. Despite these effects being present in almost all cell types, a distinguishing feature of PD is the extreme selectivity of cell loss, which is restricted to the dopaminergic neurons in the ventral portion of the substantia nigra pars compacta. Many hypotheses have been proposed to explain such selectivity, but only recently it has been convincingly shown that the innate autonomous activity of these neurons, which is sustained by their specific Cav1.3 L-type channel pore-forming subunit, is responsible for the generation of basal metabolic stress that, under physiological conditions, is compensated by mitochondrial buffering. However, when mitochondria function becomes even partially compromised (because of aging, exposure to environmental factors or genetic mutations), the metabolic stress overwhelms the protective mechanisms, and the process of neurodegeneration is engaged. The characteristics of Ca²⁺ handling in neurons of the substantia nigra pars compacta and the possible involvement of PD-related proteins in the control of Ca²⁺ homeostasis will be discussed in this review.     

Molecular genetics of Parkinson’s disease

The current views on the role of genetic factors in the pathogenesis of Parkinson’s disease are considered. The review is focused on monogenic forms of the disease, for which 11 loci are mapped and seven genes whose mutations cause the disease are identified. In addition, a number of candidate genes for sporadic Parkinson’s disease are described. The further development of studying genetic bases of Parkinson’s disease will follow two main directions: in-depth analysis of genes related to the monogenic form of the disease and more large-scale associative investigation of candidate genes for the sporadic form of Parkinson’s disease.     

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.     

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.     

Parkin-associated Parkinson’s disease

Mutations in the PARK2 gene coding for parkin cause autosomal recessive juvenile parkinsonism (AR-JP), a familial form of Parkinsons disease (PD). Parkin functions as an E3 ubiquitin ligase, and loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of AR-JP. Recently, the spectrum of genetic, clinical, and pathological findings on AR-JP has been significantly expanded. Moreover, a considerable number of parkin interactors and/or substrates have been identified and characterized, and animal models of parkin deficiency have been generated. In this review, we provide an overview of the most relevant findings and discuss their implications for the pathogenesis of AR-JP and sporadic PD.     

Peculiarities of L-DOPA treatment of Parkinson’s disease

Summary. L-Dihydroxyphenylalanine (L-DOPA), the anti-parkinsonian drug affording the greatest symptomatic relief of parkinsonian symptoms, is still misunderstood in terms of its neurotoxic potential and the mechanism by which generated dopamine (DA) is able to exert an effect despite the absence of DA innervation of target sites in basal ganglia. This review summaries important aspects and new developments on these themes. On the basis of L-DOPA therapy in animal models of Parkinsons disease, it appears that L-DOPA is actually neuroprotective, not neurotoxic, as indicated by L-DOPAs reducing striatal tissue content of the reactive oxygen species, hydroxyl radical (HO), and by leaving unaltered the extraneuronal in vivo microdialysate level of HO. In addition, the potential beneficial anti-parkinsonian effect of L-DOPA is actually increased because of the fact that the basal ganglia are largely DA-denervated. That is, from in vivo microdialysis studies it can be clearly demonstrated that extraneuronal in vivo microdialysate DA levels are actually higher in the DA-denervated vs. the intact striatum of rats – owing to the absence of DA transporter (i.e., uptake sites) on the absent DA nerve terminal fibers in parkinsonian brain. In essence, there are fewer pumps removing DA from the extraneuronal pool. Finally, the undesired motor dyskinesias that commonly accompany long-term L-DOPA therapy, can be viewed as an outcome of L-DOPAs sensitizing DA receptors (D₁–D₅), an effect easily replicated by repeated DA agonist treatments (especially agonist of the D₂ class) in animals, even if the brain is not DA-denervated. The newest findings demonstrate that L-DOPA induces BDNF release from corticostriatal fibers, which in-turn enhances the expression of D₃ receptors; and that this effect is associated with motor dyskinesias (and it is blocked by D₃ antagonists). The recent evidence on mechanisms and effects of L-DOPA increases our understanding of this benefical anti-parkinsonian drug, and can lead to improvements in L-DOPA effects while providing avenues for reducing or eliminating L-DOPAs deleterious effects.     

Exploring gene-environment interactions in Parkinson’s disease

The objective of this study was to explore combined effects of four candidate susceptibility genes and two exposures on Parkinson’s disease (PD) risk; namely, α-synuclein (SNCA) promoter polymorphism REP1, microtubule-associated protein tau (MAPT) H1/H2 haplotypes, apolipoprotein E (APOE) ε2/ε3/ε4 polymorphism, ubiquitin carboxy-terminal esterase L1 (UCHL1) S18Y variant, cigarette smoking and caffeinated coffee consumption. 932 PD patients and 664 control subjects from the NeuroGenetics Research Consortium, with complete data on all six factors, were studied. Uniform protocols were used for diagnosis, recruitment, data collection and genotyping. A logistic regression model which included gene-exposure interactions was applied. Likelihood ratio tests (LRTs) were used for significance testing and Bayesian inference was used to estimate odds ratios (ORs). MAPT (P = 0.007), SNCA REP1 (P = 0.012), smoking (P = 0.001), and coffee (P = 0.011) were associated with PD risk. Two novel interactions were detected: APOE with coffee (P = 0.005), and REP1 with smoking (P = 0.021). While the individual main effects were modest, each yielding OR < 1.6, the effects were cumulative, with some combinations reaching OR = 12.6 (95% CI: 5.9–26.8). This study provides evidence for the long-held notion that PD risk is modulated by cumulative and interactive effects of genes and exposures. Furthermore, the study demonstrates that while interaction studies are useful for exploring risk relationships that might otherwise go undetected, results should be interpreted with caution because of the inherent loss of power due to multiple testing. The novel findings of this study that warrant replication are the evidence for interaction of coffee with APOE, and of smoking with REP1 on PD risk. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Inventory of real world data sources in Parkinson’s disease

Background

Real world data have an important role to play in the evaluation of epidemiology and burden of disease; and in assisting health-care decision-makers, especially related to coverage and payment decisions. However, there is currently no overview of the existing longitudinal real world data sources in Parkinson’s disease (PD) in the USA. Such an assessment can be very helpful, to support a future effort to harmonize real world data collection and use the available resources in an optimal way.

Methods

The objective of this comprehensive literature review is to systematically identify and describe the longitudinal, real world data sources in PD in the USA, and to provide a summary of their measurements (categorized into 8 main dimensions: motor and neurological functions, cognition, psychiatry, activities of daily living, sleep, quality of life, autonomic symptoms and other). The literature search was performed using MEDLINE, EMBASE and internet key word search.

Results

Of the 53 data sources identified between May and August 2016, 16 were still ongoing. Current medications (81%) and comorbidities (79%) were frequently collected, in comparison to medical imaging (36%), genetic information (30%), caregiver burden (11%) and healthcare costs (2%). Many different measurements (n =?108) were performed and an interesting variability among used measurements was revealed.

Conclusions

Many longitudinal real world data sources on PD exist. Different types of measurements have been performed over time. To allow comparison and pooling of these multiple data sources, it will be essential to harmonize practices in terms of types of measurements.

     

MicroRNAs: Possible role in pathogenesis of Parkinson’s disease

Parkinson’s disease is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons from the substantia nigra pars compacta of human brain. However, causes and mechanisms of the progression of the disease are not yet fully clarified. To date, investigation of the role of miRNAs in norm and pathology is one of the most intriguing and actively developing areas in molecular biology. MiRNAs regulate expression of a variety of genes and can be implicated in pathogenesis of various diseases. Possible role of miRNAs in pathogenesis of Parkinson’s disease is discussed in this review.     

Investigation of EEG abnormalities in the early stage of Parkinson’s disease

The objective of the present study was to investigate brain activity abnormalities in the early stage of Parkinson’s disease (PD). To achieve this goal, eyes-closed resting state electroencephalography (EEG) signals were recorded from 15 early-stage PD patients and 15 age-matched healthy controls. The AR Burg method and the wavelet packet entropy (WPE) method were used to characterize EEG signals in different frequency bands between the groups, respectively. In the case of the AR Burg method, an increase of relative powers in the δ- and θ-band, and a decrease of relative powers in the α- and β-band were observed for patients compared with controls. For the WPE method, EEG signals from patients showed significant higher entropy over the global frequency domain. Furthermore, WPE in the γ-band of patients was higher than that of controls, while WPE in the δ-, θ-, α- and β-band were all lower. All of these changes in EEG dynamics may represent early signs of cortical dysfunction, which have potential use as biomarkers of PD in the early stage. Our findings may be further used for early intervention and early diagnosis of PD.     

Glutamate and Parkinson’s disease

Altered glutamatergic neurotransmission and neuronal metabolic dysfunction appear to be central to the pathophysiology of Parkinson’s disease (PD). The substantia nigra pars compacta—the area where the primary pathological lesion is located—is particularly exposed to oxidative stress and toxic and metabolic insults. A reduced capacity to cope with metabolic demands, possibly related to impaired mitochondrial function, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. In this way, glutamate may participate in the pathogenesis of PD. Degeneration of dopamine nigral neurons is followed by striatal dopaminergic denervation, which causes a cascade of functional modifications in the activity of basal ganglia nuclei. As an excitatory neurotransmitter, glutamate plays a pivotal role in normal basal ganglia circuitry. With nigrostriatal dopaminergic depletion, the glutamatergic projections from subthalamic nucleus to the basal ganglia output nuclei become overactive and there are regulatory changes in glutamate receptors in these regions. There is also evidence of increased glutamatergic activity in the striatum. In animal models, blockade of glutamate receptors ameliorates the motor manifestations of PD. Therefore, it appears that abnormal patterns of glutamatergic neurotransmission are important in the symptoms of PD. The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neuro-degenerative disorder.     

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.     

Uncomfortable and unpleasant sensations in the legs without an urge to move as the initial manifestation of Parkinson’s disease

Sleep and Biological Rhythms - A 74-year-old man presented with creepy, dull and restless sensation of the legs for a year. The abnormal leg sensation occurred predominantly during rest and...