Sitting movement in elderly subjects with and without Parkinson’s disease: A biomechanical study

The aim of the present study was to compare kinetic, kinematic, and electromyographic variables during the sitting movement between healthy elderly and in those with Parkinson’s disease (PD) with moderate involvement. We hypothesized that subjects with PD would show difficulty in selecting the muscles for the task and that this could be related to the co-activation pattern and would be reflected in the behavior of some biomechanical variables. Fifteen subjects participated in this study, seven healthy subjects (NN group) and eight with Parkinson’s disease. Electromyography (EMG) activity of the tibialis anterior (TA), soleus (SO), vastus medialis oblique (VMO), biceps femoris (BF), and erector spinae (ES) were recorded, and biomechanical variables were calculated, during four phases of the sitting movement. Compared to healthy subjects, the subjects with PD showed more flexion at the ankle, knee, and hip joints in the initial position and lower joint velocity. However, the EMG activity and hip, knee, and ankle joint torques were not different during all phases of movement. The sitting movement in PD subjects with moderate involvement generates EMG activity and joint torques similar to healthy elderly subjects. Only a reduced movement velocity was found in PD patients during the sitting task.     

Age-related changes in saccadic eye movements in healthy subjects and patients with Parkinson’s disease

The age-related changes in saccadic eye movements (the latency, the duration of single saccades and the percentage of multistep saccades) were compared in healthy subjects and patients with Parkinson’s disease. Healthy volunteers without neurological symptoms were divided into six age groups: (17–20, 21–30, 31–40, 41–50, 51–60, and 61–75 years of age); and parkinsonian patients, into three groups (41–50, 51–60, and 61–75 years of age). According to the data obtained, the saccade characteristics depend on the age in both the subjects without neurological symptoms and parkinsonian patients. In healthy volunteers, the percentage of multistep saccades and the mean saccade latency increase significantly after the age of 60 years. These parameters in patients with Parkinson’s disease significantly exceed the values in healthy subjects from the age-matched groups. The “disease” factor has a greater influence on the saccade latency and the percentage of multistep saccades than the “age” factor. The duration of single saccades depends on age to a lesser degree and does not change in patients with Parkinson’s disease. The peculiarities of the development of neurodegenerative processes in cases of normal aging and in idiopathic parkinsonism are discussed.     

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.

     

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.     

Mitochondrial dysfunction in Parkinson’s disease

The review highlights mitochondrial structural and functional abnormalities in Parkinson’s disease and experimental animal models of this pathology. Special attention is paid to the inactivation of mitochondrial enzymes, mutations in mitochondrial and nuclear DNA, and genomic and proteomic studies of mitochondrial proteins in Parkinson’s disease and experimental parkinsonism in animals.     

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.     

Parkinson’s disease: clinical aspects

Parkinsonism is a clinical syndrome characterized by akinesia, muscular rigidity, and resting tremor. The most frequent cause of parkinsonism is Parkinsons disease (PD). Progressive loss of substantia nigra neurons together with the occurrence of Lewy bodies are considered essential neuropathological features of PD. Recent neuropathological studies suggest that nigral degeneration is only part of a more extended brain degeneration that starts in the medulla oblongata and then spreads to the mesencephalon and cerebral cortex. Correspondingly, the clinical symptoms occurring in PD go far beyond parkinsonism. Depending on the disease stage, autonomic dysfunction, olfactory disturbances, depression, and dementia are frequently encountered in PD. These neuropathological and clinical observations have major implications for future research in PD. In particular, the analysis of the properties that the neuronal cell types involved in PD have in common and that might make them susceptible to degeneration is essential.     

Effects of subthalamic deep brain stimulation on fixational eye movements in Parkinson’s disease

Journal of Computational Neuroscience - Miniature yoked eye movements, fixational saccades, are critical to counteract visual fading. Fixational saccades are followed by a return saccades forming...     

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.     

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.     

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.     

PARK2 gene variants in Korean patients with Parkinson’s disease

Mutations in PARK2 are considered a common cause of Parkinson’s disease (PD). To assess the frequency of PARK2 mutations in the Korean population, we screened the PARK2 gene in 83 Korean PD patients: two young onset (YO, ≤ 49), 32 middle onset (MO, 50–69) and 49 late onset (LO, ≥ 70). Detection of the point mutations was performed by direct sequencing of the PARK2 exons, and exonic rearrangements were analyzed using multiplex ligation-dependent probe amplification. Five known PARK2 variants were identified in 53 (63.9 %) of the Korean PD patients: two missense mutations (Y267H and M458L) and three polymorphisms (S167N, L272I and V380L). We also found an increased frequency of PARK2 variants in PD patients and a lowered PD age at onset (AAO) in those having two variants, suggesting that the genetic variation in PARK2 gene might be a genetic risk factor of PD in Korean population.     

Electromyographic activity of sternocleidomastoid muscle in patients with Parkinson’s disease

The aim of this study was to evaluate the effect of administration of levo–dopa, which means without effect-off state and under effect-on state, on the sternocleidomastoid muscle electromyographic activity (SCM-EA) in patients with Parkinson’s disease (PD) at rest and to compare it to asymptomatic subjects. Ten patients with PD, mean age 64.6 ± 6.2 (SD) years and nine asymptomatic subjects, mean age 61.4 ± 5.9 (SD) years were studied. The SCM-EA was evaluated during maximal inspiratory pressure and breathing at rest through surface electromyography. Statistical analysis was performed with t-test (anthropometric data and SCM-EA of patients in off state to asymptomatic), Mann–Whitney (SCM-EA of patients in on state to asymptomatic) and Wilcoxon test (SCM-EA off and on states). The effect size index (d) was calculated for statistically significant differences. There were no significant differences in SCM electromyographic activity between patients with PD comparing off to on (p = 0.13) or among on state to asymptomatic subjects (p = 0.06). However, when subjects with PD in off where compared to asymptomatic there was a significantly higher SCM electromyographic activity (p = 0.03, d = 1.09). These patients, without levo–dopa effect, when compared with asymptomatic subjects, present a significantly higher electromyographic activity of SCM, the main accessory respiratory muscle, which could be related to an increased work of breathing.     

Variations in rest-activity rhythm are associated with clinically measured disease severity in Parkinson’s disease

ABSTRACT

The continuous, longitudinal nature of accelerometry monitoring is well-suited to capturing the regular 24-hour oscillations in human activity across the day, the cumulative effect of our circadian rhythm and behavior. Disruption of the circadian rhythm in turn disrupts rest-activity rhythms. Although circadian disruption is a major feature of Parkinson’s disease (PD), rest-activity rhythms and their relationship with disease severity have not been well characterized in PD. 13 PD participants (Hoehn & Yahr Stage [H&Y] 1–3) wore a Philips Actiwatch Spectrum PRO continuously for two separate weeks. Rest-activity rhythms were quantified by fitting an oscillating 24-hour cosinor model to each participant-day of activity data. One-way ANOVAs adjusted for demographics revealed significant variation in the amount (MESOR, F = 12.76, p < .01), range (Amplitude, F = 9.62, p < .01), and timing (Acrophase, F = 2.7, p = .05) of activity across H&Y Stages. Those with higher H&Y Stages were significantly more likely to be active later in the day, where-as those who shifted between H&Y Stages during the study were significantly more active than those who did not change H&Y Stage. Being active later in the day was also significantly associated with higher scores on the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Section III (motor symptom severity, p = .02), Section II (self-reported impact of motor symptoms on daily living, p = .01), and Total Score (p = .01) in an adjusted linear regression model; significant associations between MDS-UPDRS scores and activity levels were observed only in the unadjusted model. These findings demonstrate that continuous actigraphy is capable of detecting rest-activity disruption in PD, and provides preliminary evidence that rest-activity rhythms are associated with motor symptom severity and H&Y Stage.     

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.     

NADPH oxidases in Parkinson’s disease: a systematic review

Parkinson’s disease (PD) is a progressive movement neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, is thought to play an important role in dopaminergic neurotoxicity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are multi-subunit enzymatic complexes that generate reactive oxygen species as their primary function. Increased immunoreactivities for the NADPH oxidases catalytic subunits Nox1, Nox2 and Nox4 have been reported in the brain of PD patients. Furthermore, knockout or genetic inactivation of NADPH oxidases exert a neuroprotective effect and reduce detrimental aspects of pathology in experimental models of the disease. However, the connections between NADPH oxidases and the biological processes believed to contribute to neuronal death are not well known. This review provides a comprehensive summary of our current understanding about expression and physiological function of NADPH oxidases in neurons, microglia and astrocytes and their pathophysiological roles in PD. It summarizes the findings supporting the role of both microglial and neuronal NADPH oxidases in cellular disturbances associated with PD such as neuroinflammation, alpha-synuclein accumulation, mitochondrial and synaptic dysfunction or disruption of the autophagy-lysosome system. Furthermore, this review highlights different steps that are essential for NADPH oxidases enzymatic activity and pinpoints major obstacles to overcome for the development of effective NADPH oxidases inhibitors for PD.