Changes in Parkinsonian gait kinematics with self-generated and externally-generated cues: a comparison of responders and non-responders

Abstract

Purpose: Rhythmic auditory stimulation such as listening to music can alleviate gait bradykinesia in people with Parkinson disease (PD) by increasing spatiotemporal gait features. However, evidence about what specific kinematic alterations lead to these improvements is limited, and differences in responsiveness to cueing likely affect individual motor strategies. Self-generated cueing techniques, such as singing or mental singing, provide similar benefits but no evidence exists about how these techniques affect lower limb joint movement. In this study, we assessed immediate effects of external and self-generated cueing on lower limb movement trajectories during gait.

Methods: Using 3D motion capture, we assessed sagittal plane joint angles at the hip, knee, and ankle across 35 participants with PD, divided into responders (n?=?23) and non-responders (n?=?12) based on a clinically meaningful change in gait speed. Joint motion was assessed as overall range of motion as well as at two key time points during the gait cycle: initial contact and toe-off.

Results: Responders used both cue types to increase gait speed and induce increases in overall joint ROM at the hip while only self-generated cues also increased ROM at the ankle. Increased joint excursions for responders were also evident at initial contact and toe-off.

Conclusions: Our results indicate that self-generated rhythmic cues can induce similar increases in joint excursions as externally-generated cues and that some people may respond more positively than others. These results provide important insight into how self-generated cueing techniques may be tailored to meet the varied individual needs of people with PD.     

The Parkinson disease gene LRRK2: evolutionary and structural insights

Mutations in the human leucine-rich repeat kinase 2 (LRRK2) gene are associated with both familial and sporadic Parkinson disease (PD). LRRK2 belongs to a gene family known as Roco. Roco genes encode for large proteins with several protein domains. Particularly, all Roco proteins have a characteristic GTPase domain, named Roc, plus a domain of unknown function called COR. In addition, LRRK2 and several other Roco proteins also contain a protein kinase domain. In this study, I use a combination of phylogenetic and structural analyses of the COR, Roc, and kinase domains present in Roco proteins to describe the origin and evolutionary history of LRRK2. Phylogenetic analyses using these domains demonstrate that LRRK2 emerged from a duplication that occurred after the protostome-deuterostome split. The duplication was followed by the acquisition by LRRK2 proteins of a specific type of N-terminal repeat, described here for the first time. This repeat is absent in the proteins encoded by the paralogs of LRRK2, called LRRK1 or in protostome LRRK proteins. These results suggest that Drosophila or Caenorhabditis LRRK genes may not be good models to understand human LRRK2 function. Genes in the slime mold Dictyostelium discoideum with structures very similar to those found in animal LRRK genes, including the protein kinase domain, have been described. However, phylogenetic analyses suggest that this structural similarity is due to independent acquisitions of distantly related protein kinase domains. Finally, I confirm in an extensive sequence analysis that the Roc GTPase domain is related but still substantially different from small GTPases, such as Rab, Ras, or Rho. Modeling based on known kinase structures suggests that mutations in LRRK2 that cause familiar PD may alter the local 3-dimensional folding of the LRRK2 protein without affecting its overall structure.     

Distinctive patterns of DNA methylation associated with Parkinson disease

Parkinson disease (PD) is a multifactorial neurodegenerative disorder with high incidence in the elderly, where environmental and genetic factors are involved in etiology. In addition, epigenetic mechanisms, including deregulation of DNA methylation have been recently associated to PD. As accurate diagnosis cannot be achieved pre-mortem, identification of early pathological changes is crucial to enable therapeutic interventions before major neuropathological damage occurs. Here we investigated genome-wide DNA methylation in brain and blood samples from PD patients and observed a distinctive pattern of methylation involving many genes previously associated to PD, therefore supporting the role of epigenetic alterations as a molecular mechanism in neurodegeneration. Importantly, we identified concordant methylation alterations in brain and blood, suggesting that blood might hold promise as a surrogate for brain tissue to detect DNA methylation in PD and as a source for biomarker discovery.     

Effect of sitting postures and shoulder position on the cervicocephalic kinesthesia in healthy young males

Information about head orientation, position, and movement with respect to the trunk relies on the visual, vestibular, extensive muscular, and articular proprioceptive system of the neck. Various factors can affect proprioception since it is the function of afferent integration, and tuning of muscular and articular receptors. Pain, muscle fatigue, and joint position have been shown to affect proprioceptive capacity. Thus, it can be speculated that changes in body posture can alter the neck proprioception. This study was undertaken to investigate the effect of body posture on cervicocephalic kinesthetic sense in healthy subjects. Cervicocephalic kinesthetic sensibility was measured by the kinesthetic sensibility test in healthy young adults while in (a) habitual slouched sitting position with arms hanging by the side (SS), (b) habitual slouched sitting position with arms unloaded (supported) (SS-AS), and (c) upright sitting position with arms hanging by the side (US) during maximum and 30 degree right, left rotations, flexion, and extension. Thirty healthy male adults (mean age 27.83; SD 3.41) volunteered for this study. The least mean error was found for the SS-AS position (0.48; SD 0.24), followed by SS (0.60; SD 0.43) and US (0.96; SD 0.71), respectively. For all test conditions, there was significant difference in mean absolute error while head repositioning from maximum and 30 degree rotation during SS and SS-AS positions (p?相似文献   

慢性间断性缺氧对帕金森病模型小鼠行为学及纹状体多巴胺含量的影响

目的:探讨慢性间断性缺氧(chronic episodic hypoxia,EHYP)对帕金森病(Parkinson disease,PD)模型小鼠行为学及纹状体多巴胺(DA)含量的影响。方法:44只雄性6周龄C57BL/6小鼠随机分为百草枯 EHYP组、EHYP组、百草枯组和对照组,观察小鼠自发行为活动及悬挂实验、游泳实验、步态实验进行行为学检测,高效液相色谱分析(HPLC)测定纹状体DA含量。结果:百草枯 EHYP组小鼠出现PD综合征表现,悬挂实验及游泳实验结果与其它各组间有显著性差异(P<0.05或P<0.01),纹状体DA含量较其它各组小鼠出现明显下降(均P<0.01),余各组行为学实验结果及纹状体DA含量差异无显著性(P>0.05)。结论:EHYP联合百草枯暴露可使小鼠出现PD综合征表现及纹状体DA含量的明显下降。     

Spread of neuronal degeneration in a dopaminergic,Lrrk-G2019S model of Parkinson disease

Flies expressing the most common Parkinson disease (PD)-related mutation, LRRK2-G2019S, in their dopaminergic neurons show loss of visual function and degeneration of the retina, including mitochondrial abnormalities, apoptosis and autophagy. Since the photoreceptors that degenerate are not dopaminergic, this demonstrates nonautonomous degeneration, and a spread of pathology. This provides a model consistent with Braak’s hypothesis on progressive PD. The loss of visual function is specific for the G2019S mutation, implying the cause is its increased kinase activity, and is enhanced by increased neuronal activity. These data suggest novel explanations for the variability in animal models of PD. The specificity of visual loss to G2019S, coupled with the differences in neural firing rate, provide an explanation for the variability between people with PD in visual tests.     

Progress and potential of non-inhibitory small molecule chaperones for the treatment of Gaucher disease and its implications for Parkinson disease

Gaucher disease, caused by pathological mutations GBA1, encodes the lysosome-resident enzyme glucocerebrosidase, which cleaves glucosylceramide into glucose and ceramide. In Gaucher disease, glucocerebrosidase deficiency leads to lysosomal accumulation of substrate, primarily in cells of the reticulo-endothelial system. Gaucher disease has broad clinical heterogeneity, and mutations in GBA1 are a risk factor for the development of different synucleinopathies. Insights into the cell biology and biochemistry of glucocerebrosidase have led to new therapeutic approaches for Gaucher disease including small chemical chaperones. Such chaperones facilitate proper enzyme folding and translocation to lysosomes, thereby preventing premature breakdown of the enzyme in the proteasome. This review discusses recent progress in developing chemical chaperones as a therapy for Gaucher disease, with implications for the treatment of synucleinopathies. It focuses on the development of non-inhibitory glucocerebrosidase chaperones and their therapeutic advantages over inhibitory chaperones, as well as the challenges involved in identifying and validating chemical chaperones.     

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

Parkinson disease (PD), once considered as a prototype of a sporadic disease, is now known to be considerably affected by various genetic factors, which interact with environmental factors and the normal process of aging, leading to PD. Large studies determined that the hereditary component of PD is at least 27%, and in some populations, single genetic factors are responsible for more than 33% of PD patients. Interestingly, many of these genetic factors, such as LRRK2, GBA, SMPD1, SNCA, PARK2, PINK1, PARK7, SCARB2, and others, are involved in the autophagy-lysosome pathway (ALP). Some of these genes encode lysosomal enzymes, whereas others correspond to proteins that are involved in transport to the lysosome, mitophagy, or other autophagic-related functions. Is it possible that all these factors converge into a single pathway that causes PD? In this review, we will discuss these genetic findings and the role of the ALP in the pathogenesis of PD and will try to answer this question. We will suggest a novel hypothesis for the pathogenic mechanism of PD that involves the lysosome and the different autophagy pathways.     

Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease and is caused by genetics, environmental factors and aging, with few treatments currently available. Apoptosis and macroautophagy/autophagy play critical roles in PD pathogenesis; as such, modulating their balance is a potential treatment strategy. BCL2 (B cell leukemia/lymphoma 2) is a key molecule regulating this balance. Piperlongumine (PLG) is an alkaloid extracted from Piper longum L. that has antiinflammatory and anticancer effects. The present study investigated the protective effects of PLG in rotenone-induced PD cell and mouse models. We found that PLG administration (2 and 4 mg/kg) for 4 wk attenuated motor deficits in mice and prevented the loss of dopaminergic neurons in the substantia nigra induced by oral administration of rotenone (10 mg/kg) for 6 wk. PLG improved cell viability and enhanced mitochondrial function in primary neurons and SK-N-SH cells. These protective effects were exerted via inhibition of apoptosis and induction of autophagy through enhancement of BCL2 phosphorylation at Ser70. These results demonstrate that PLG exerts therapeutic effects in a rotenone-induced PD models by restoring the balance between apoptosis and autophagy.

Abbreviations: 6-OHDA, 6-hydroxydopamine; ACTB, actin, beta; BafA1, bafilomycin A₁; BAK1, BCL2-antagonist/killer 1; BAX, BCL2-associated X protein; BCL2, B cell leukemia/lymphoma2; BECN1, Beclin 1, autophagy related; CoQ10, coenzyme Q₁₀; COX4I1/COX IV, cytochrome c oxidase subunit 4I1; CsA, cyclosporine A; ED50, 50% effective dose; FITC, fluorescein isothiocyanate; GFP, green fluorescent protein; HPLC, high-performance liquid chromatography; JC-1, tetraethylbenz-imidazolylcarbocyanine iodide; LC3, microtubule-associated protein 1 light chain3; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LDH, lactate dehydrogenase; l-dopa, 3, 4-dihydroxyphenyl-l-alanine; MAPK8/JNK1, mitogen-activated protein kinase 8; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mRFP, monomeric red fluorescent protein; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NFE2L2/NRF2, nuclear factor, erythroid derived 2, like 2; PD, Parkinson disease; PLG, piperlongumine; pNA, p-nitroanilide; PI, propidium iodide; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PTX, paclitaxel; Rap, rapamycin; SQSTM1/p62, sequestosome 1; TH, tyrosine hydroxylase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; WIPI2, WD repeat domain, phosphoinositide interacting 2; ZFYVE1/DFCP1, zinc finger, FYVE domain containing 1.     

Systematic analysis of gut microbiome reveals the role of bacterial folate and homocysteine metabolism in Parkinson’s disease

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Impact of motor activity and antennal mechanosensory input on the intensity of proctolin-like immunoreactivity in antennal motoneurons of crickets (Gryllus bimaculatus)

The change of the intensity of proctolin immunolabeling of 2 of 17 proctolinergic antennal motoneurons [one adductor (Ad3), and one depressor (D5)] was quantitatively studied in crickets in relation to flight and antennal deafferentation. During flight, the maintained forward position of the antennae is supported by high frequency tonic firing of Ad3 but probably all motoneurons are activated. In animals sacrificed immediately after the last of five consecutive flight periods the intensity of proctolin-like immunolabeling showed a significant decrease in the Ad3 soma in comparison to the Ad3 of non-flyers. The identical result was observed in the D5 soma. In animals sacrificed 40 h after flight, no difference in the intensity of proctolin immunolabeling between the Ad3 soma of flyers and non-flyers was evident. Thus, at high motoneuron activity, the production of proctolin may not be able to keep pace with its transport from the soma. Deletion of all proprioceptors of one antenna which respond to horizontal movements only led to a significant decrease of the intensity of proctolin immunolabeling in the Ad3 soma on the operated side, but not in the soma of D5. This indicates that selected afferent input has an impact on proctolin expression in distinct motoneuron pools. Accepted: 7 February 1997     

G/A polymorphism in intronic sequence affects the processing of MAO-B gene in patients with Parkinson disease

Monoamine oxidase B (MAO-B) plays an important role in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. Increased levels of MAO-B mRNA and enzymatic activity have been reported in platelets from patients with Parkinson’s and Alzheimer’s diseases, however the triggers of enhanced mRNA levels are unknown. Our results demonstrate for the first time that G/A dimorphism in intron 13 sequence creates splicing enhancer thus stimulating intron 13 removal efficiency. The increased MAO-B protein levels might serve as a surrogate marker for - Parkinson disease.     

Neuronal NOS and cyclooxygenase-2 contribute to DNA damage in a mouse model of Parkinson disease

DNA damage is a proposed pathogenic factor in neurodegenerative disorders such as Parkinson disease. To probe the underpinning mechanism of such neuronal perturbation, we sought to produce an experimental model of DNA damage. We thus first assessed DNA damage by in situ nick translation and emulsion autoradiography in the mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 × 20 mg/kg, ip, every 2 h), a neurotoxin known to produce a model of Parkinson disease. Here we show that DNA strand breaks occur in vivo in this mouse model of Parkinson disease with kinetics and a topography that parallel the degeneration of substantia nigra neurons, as assessed by FluoroJade labeling. Previously, nitric oxide synthase and cyclooxygenase-2 (Cox-2) were found to modulate MPTP-induced dopaminergic neuronal death. We thus assessed the contribution of these enzymes to DNA damage in mice lacking neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), or Cox-2. We found that the lack of Cox-2 and nNOS activities but not of iNOS activity attenuated MPTP-related DNA damage. We also found that not only nuclear, but also mitochondrial, DNA is a target for the MPTP insult. These results suggest that the loss of genomic integrity can be triggered by the concerted actions of nNOS and Cox-2 and provide further support to the view that DNA damage may contribute to the neurodegenerative process in Parkinson disease.     

普拉克索治疗帕金森病合并抑郁的系统评价

目的:评价普拉克索治疗帕金森病合并抑郁的疗效和安全性。方法:通过电子检索和手工检索,运用Cochrance协作网系统评价的方法对纳入所有应用普拉克索治疗帕金森病合并抑郁的随机对照试验(RCT)进行系统评价。结果:共检出5个RCT,其中3个(454例)符合纳入标准,三项研究随访时间为3-57个月。Meta分析结果显示:1)抑郁改善情况:3项研究随访结束后,应用量表进行评分,普拉克索治疗组抑郁症状改善率明显对照组,两组差异有统计学意义[RR=0.63,95%CI(0.48,0.83),P<0.001];2)UPDRS评分变化:2项研究在治疗末应用UPDRS进行评分,UPDRSⅢ和Ⅱ相对于基线评分,普拉克索组均较对照组明显下降,两组之间差别有统计学意义;3)不良反应:与普拉克索组相比,对照组中因药物不良反应而终止试验研究的病例增多,两组相比有统计学差异[RR=0.48,95%CI(0.34,0.69),p<0.0001]。结论:现有的临床研究证据表明,与对照组相比,普拉克索能够改善帕金森病伴发抑郁病人的抑郁症状,并减轻帕金森病的运动症状,提高病人日常生活活动能力,且安全性较高。但因研究样本局限性,尚需进行大样本长期...     

Vitamin E concentrations in human brain of patients with Alzheimer's disease,fetuses with Down's syndrome,centenarians, and controls

The concentration of vitamin E (alpha-tocopherol) was measured in samples of cortex from patients with Alzheimer's disease (AD), fetuses with Down's syndrome (DS), and also in a group of centenarians. The mean tocopherol concentrations in the two patient groups did not differ significantly from appropriate controls. When expressed per lipid the mean tocopherol concentration of the centenarians was greater than that of the controls but this reflected a significant decrease in the lipid concentration of the former group. These results indicate that neither the normal aging processes, Alzheimer's disease, nor the increased in vitro lipid peroxidation reported in fetuses with Down's syndrome result from a gross lack of alpha-tocopherol, or cause a significant depletion of the vitamin.     

Effects of altitude on exercise level and heart rate in patients with coronary artery disease and healthy controls

Background. To evaluate the safety and effects of high altitude on exercise level and heart rate in patients with coronary artery disease compared with healthy controls. Methods. Eight patients with a history of an acute myocardial infarction (ejection fraction >5%) with a low-risk score were compared with seven healthy subjects during the Dutch Heart Expedition at the Aconcagua in Argentina in March 2007. All subjects underwent a maximum exercise test with a cycle ergometer at sea level and base camp, after ten days of acclimatisation, at an altitude of 4200 m. Exercise capacity and maximum heart rate were compared between groups and within subjects. Results. There was a significant decrease in maximum heart rate at high altitude compared with sea level in both the patient and the control group (166 vs. 139 beats/min, p<0.001 and 181 vs. 150 beats/min, p<0.001). There was no significant difference in the decrease of the exercise level and maximum heart rate between patients and healthy controls (-31 vs. -30%, p=0.673). Conclusion. Both patients and healthy controls showed a similar decrease in exercise capacity and maximum heart rate at 4200 m compared with sea level, suggesting that patients with a history of coronary artery disease may tolerate stay and exercise at high altitude similarly to healthy controls. (Neth Heart J 2010;18:118-21.)     

Effects of general fatigue induced by incremental maximal exercise test on gait stability and variability of healthy young subjects

The purpose of this study was to determine whether general fatigue induced by incremental maximal exercise test (IMET) affects gait stability and variability in healthy subjects. Twenty-two young healthy male subjects walked in a treadmill at preferred walking speed for 4 min prior (PreT) the test, which was followed by three series of 4 min of walking with 4 min of rest among them. Gait variability was assessed using walk ratio (WR), calculated as step length normalized by step frequency, root mean square (RMS_ratio) of trunk acceleration, standard deviation of medial-lateral trunk acceleration between strides (VAR_ML), coefficient of variation of step frequency (SFCV), length (SLCV) and width (SWCV). Gait stability was assessed using margin of stability (MoS) and local dynamic stability (λ_s). VAR_ML, SFCV, SLCV and SWCV increased after the test indicating an increase in gait variability. MoS decreased and λ_s increased after the test, indicating a decrease in gait stability. All variables showed a trend to return to PreT values, but the 20-min post-test interval appears not to be enough for a complete recovery. The results showed that general fatigue induced by IMET alters negatively the gait, and an interval of at least 20 min should be considered for injury prevention in tasks with similar demands.     

Microtubule affinity-regulating kinase 2 (MARK2) turns on phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) at Thr-313, a mutation site in Parkinson disease: effects on mitochondrial transport

The kinase MARK2/Par-1 plays key roles in several cell processes, including neurodegeneration such as Alzheimer disease by phosphorylating tau and detaching it from microtubules. In search of interaction partners of MARK2, we identified phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), which is important for the survival of neurons and whose mutations are linked to familial Parkinson disease (PD). MARK2 phosphorylated and activated the cleaved form of PINK1 (ΔN-PINK1; amino acids 156-581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD. Mutation of Thr-313 to Met or Glu in PINK1 showed toxic effects with abnormal mitochondrial distribution in neurons. MARK2 and PINK1 were found to colocalize with mitochondria and regulate their transport. ΔN-PINK1 promoted anterograde transport and increased the fraction of stationary mitochondria, whereas full-length PINK1 promoted retrograde transport. In both cases, MARK2 enhanced the effects. The results identify MARK2 as an upstream regulator of PINK1 and ΔN-PINK1 and provide insights into the regulation of mitochondrial trafficking in neurons and neurodegeneration in PD.     

An overview on the correlation of neurological disorders with cardiovascular disease

Neurological disorders (NDs) are one of the leading causes of death especially in the developed countries. Among those NDs, Alzheimer’s disease (AD) and Parkinson disease (PD) are heading the table. There have been several reports in the scientific literatures which suggest the linkage between cardiovascular disorders (CVDs) and NDs. In the present communication, we have tried to compile NDs (AD and PD) association with CVDs reported in the literature. Based on the available scientific literature, we believe that further comprehensive study needs to be done to elucidate the molecular linking points associated with the above mentioned disorders.Abbreviations: AD, Alzheimer’s disease, Aβ, β amyloid, PD, Parkinson disease, l-DOPA, l-dihydroxyphenylalanine, LBs, Lewy bodies, DA, dopamine, APP, amyloid precursor protein, CVD, cardiovascular disease     

Decreased alpha-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson's disease

There is ample biochemical, pathological, and genetic evidence that the metabolism of alpha-synuclein (alpha-syn) plays a crucial role in the pathogenesis of Parkinson disease (PD). To examine whether quantification of alpha-syn in cerebrospinal fluid (CSF) is potentially informative in the diagnosis of PD, we developed a specific ELISA system and measured the concentration of alpha-syn in CSF from 33 patients with PD (diagnosed according to UK PD Society Brain Bank criteria) and 38 control subjects including 9 neurologically healthy individuals. We found that PD patients had significantly lower alpha-syn levels in their CSF than the control groups (p<0.0001) even after adjusting for gender and age. Age was independently associated with lower alpha-syn levels. Logistic regression analysis showed that reduction in CSF alpha-syn served as a significant predictor of PD beyond age and gender alone (area under ROC curve, c=0.882). Furthermore, we observed a close inverse correlation between alpha-syn levels in CSF and assigned Hoehn and Yahr score in this cohort of 71 living subjects (p<0.0001), even after adjusting for age. These findings identify in the quantification of alpha-syn from CSF a potential laboratory marker to aid the clinical diagnosis of PD.