低频电刺激大鼠脚桥核对丘脑腹外侧核神经元自发放电的影响及其机制

本文旨在观察低频电刺激脚桥核(pedunculopontine nucleus,PPN)对帕金森病(Parkinson’s disease,PD)模型大鼠丘脑腹外侧核(ventrolateral thalamic nucleus,VL)神经元自发放电活动的影响,以探讨低频电刺激PPN改善PD症状的作用机制。通过纹状体内注射6-羟多巴胺制备PD大鼠模型。采用在体细胞外记录、电刺激及微电泳方法,观察低频电刺激PPN、微电泳乙酰胆碱(acetylcholine,ACh)及其M型受体阻断剂阿托品(atropine,ATR)、γ-氨基丁酸(γ-aminobutyric acid,GABA)及其A型受体阻断剂荷包牡丹碱(bicuculline,BIC)对大鼠VL神经元放电频率的影响。结果显示,低频电刺激PPN可使正常大鼠和PD大鼠VL神经元自发放电频率增加。微电泳ACh对VL神经元具有兴奋和抑制两种作用,而微电泳ATR则主要抑制VL神经元,即使对被ACh抑制的神经元也产生抑制作用。微电泳GABA抑制VL神经元,而微电泳BIC则兴奋VL神经元。另外,在微电泳ACh的过程中微电泳GABA,被ACh兴奋或抑制的VL神经元放电频...     

Basal ganglia oscillations and pathophysiology of movement disorders

Low frequency rest tremor is one of the cardinal signs of Parkinson's disease and some of its animal models. Current physiological studies and models of the basal ganglia differ as to which aspects of neuronal activity are crucial to the pathophysiology of Parkinson's disease. There is evidence that neural oscillations and synchronization play a central role in the generation of the disease. However, parkinsonian tremor is not strictly correlated with the synchronous oscillations in the basal ganglia networks. Rather, abnormal basal ganglia output enforces abnormal thalamo-cortical processing leading to akinesia, the main negative symptom of Parkinson's disease. Parkinsonian tremor has probably evolved as a downstream compensatory mechanism.     

On the origin of tremor in Parkinson's disease

The exact origin of tremor in Parkinson's disease remains unknown. We explain why the existing data converge on the basal ganglia-thalamo-cortical loop as a tremor generator and consider a conductance-based model of subthalamo-pallidal circuits embedded into a simplified representation of the basal ganglia-thalamo-cortical circuit to investigate the dynamics of this loop. We show how variation of the strength of dopamine-modulated connections in the basal ganglia-thalamo-cortical loop (representing the decreasing dopamine level in Parkinson's disease) leads to the occurrence of tremor-like burst firing. These tremor-like oscillations are suppressed when the connections are modulated back to represent a higher dopamine level (as it would be the case in dopaminergic therapy), as well as when the basal ganglia-thalamo-cortical loop is broken (as would be the case for ablative anti-parkinsonian surgeries). Thus, the proposed model provides an explanation for the basal ganglia-thalamo-cortical loop mechanism of tremor generation. The strengthening of the loop leads to tremor oscillations, while the weakening or disconnection of the loop suppresses them. The loop origin of parkinsonian tremor also suggests that new tremor-suppression therapies may have anatomical targets in different cortical and subcortical areas as long as they are within the basal ganglia-thalamo-cortical loop.     

单侧帕金森病猴模型的行为、神经递质、多巴胺受体、病理及局部脑血流研究

经右侧颈总动脉注射甲基-苯基-四氢吡啶(MPTP)使猴产生左侧肢体动作减少、行动迟缓、震颤及向右侧缓慢旋转。应用美多巴和阿朴吗啡显著地改善单侧帕金森病(PD)症状,同时引起向左侧快速旋转,并呈明显的剂量依赖性;应用苯丙胺引起向右侧快速旋转。连续应用美多巴诱致单侧PD猴产生舞蹈手足徐动症。高效液相色谱测定显示右侧壳核、尾状核和黑质多巴胺(DA)含量显著降低。光镜发现右侧黑质神经元变性。SPECT活体显像发现病损侧纹状体D_2DA受体活性在病损初期无改变,病损严重时超敏,以及病损侧脑血流灌注减低。实验表明MPTP可建成理想的能形象地模拟人类PD的单侧PD猴模型。SPECT是活体研究PD病理生理的有效检测手段。     

Contribution of Noradrenergic Neurons to the Regulation of Dopaminergic (D1) Receptor Denervation Supersensitivity in Rat Prefrontal Cortex

3,4-Dihydroxyphenylethylamine (DA, dopamine) levels in the rat prefrontal cortex were selectively decreased by 52%, leaving noradrenaline (NA) levels unaffected, 4 weeks following restricted bilateral electrolytic lesions of the ventral mesencephalic tegmentum (VMT). These lesions also induced a significant increase in DA-sensitive, but not isoproterenol-sensitive, adenylate cyclase activity in tissue homogenates (+38%). We had shown previously that chemical (6-hydroxydopamine, 6-OHDA) lesions of the VMT destroy both ascending DA and NA fibers but do not alter the D1-receptor density in the prefrontal cortex. In this study, electrolytic lesions of the VMT were combined with bilateral injections of 6-OHDA made laterally in the pedunculus cerebellaris superior to assess the role of NA fibers in the development of D1-receptor supersensitivity. This combined treatment produces a large decrease of cortical NA levels (-95%), an increase in beta-adrenergic-sensitive adenylate cyclase activity (+110%), and a decrease in DA levels (-60%), but does not alter D1-receptor density in the prefrontal cortex. These results indicate that the development of D1-receptor supersensitivity in the prefrontal cortex following electrolytic lesion of the VMT depends on the presence of an intact NA innervation.     

快速眼动睡眠期行为障碍(RBD)的帕金森病临床特征分析

目的:探究合并不同发作形式的快速眼动睡眠期行为障碍(RBD)与帕金森病的临床特点及自主神经功能障碍变化。方法:采用快速眼动期睡眠行为障碍筛查量表及帕金森综合评分量表(Unified Parkinson's disease rating scale),对20例合并简单型(RBD)的帕金森病患者(RBD-简单组)与20例合并复杂型(RBD)的帕金森病患者(RBD-复杂组)进行研究。结果:两组帕金森病患者的一般情况、左旋多巴药物日剂量、疾病病程等无统计学差异(P>0.05)。合并复杂型(RBD)的帕金森病患者运动部分评分高于合并简单型(RBD)的帕金森病患者(P<0.05)。两组患者之间在非震颤、强直、运动减少症状均存在统计学差异(P<0.05),(RBD)复杂组评分均高于(RBD)简单组。多因素logistics回归显示,复杂型(RBD)的存在与UPDRS-Ш部分评分相关,而与年龄、病程、教育年限、左旋多巴药物日剂量等无显著相关,与运动减少症状最为相关,与震颤、非震颤、强直症状无相关性。两组患者运动障碍类型与(RBD)发作形式无明显相关性(P=0.108)。结论:合并复杂型(RBD)的帕金森病患者运动症状更重,并且累及运动障碍的诸多方面。帕金森病患者存在复杂型(RBD)症状主要与UPDRS-Ш评分相关,其中与运动减少方面显著相关。     

Human vastus lateralis and soleus muscles display divergent cellular contractile properties

The purpose of this study was to investigate potential differences in single-fiber contractile physiology of fibers with the same myosin heavy chain isoform (MHC I and MHC IIa) originating from different muscles. Vastus lateralis (VL) and soleus biopsies were obtained from 27 recreationally active females (31 +/- 1 yr, 59 +/- 1 kg). A total of 943 single fibers (MHC I = 562; MHC IIa = 301) were isolated and examined for diameter, peak tension (Po), shortening velocity (Vo), and power. The soleus had larger (P < 0.05) fibers (MHC I +18%; MHC IIa +19%), higher MHC I Vo (+13%), and higher MHC I Po (+18%) compared with fibers from the VL. In contrast, fibers from the VL had higher (P < 0.05) specific tension (MHC I +18%; MHC IIa +20%), and MHC I normalized power (+25%) compared with the soleus. There was a trend for MHC IIa soleus fibers to have higher Vo [MHC IIa +13% (P = 0.058)], whereas VL MHC IIa fibers showed a trend for higher normalized power compared with soleus fibers [MHC IIa +33% (P = 0.079)]. No differences in absolute power were detected between muscles. These data highlight muscle-specific differences in single-fiber contractile function that should serve as a scientific basis for consideration when extending observations of skeletal muscle tissue from one muscle of interest to other muscles of origin. This is important when examining skeletal muscle adaptation to physical states such as aging, unloading, and training.     

H1-MAPT and the Risk for Familial Essential Tremor

The most frequent MAPT H1 haplotype is associated with the risk for developing progressive supranuclear palsy and other neurodegenerative diseases such as Parkinson's disease. A recent report suggests that the MAPT H1 is associated with the risk for developing essential tremor. We wanted to confirm this association in a different population. We analyzed the distribution of allelic and genotype frequencies of rs1052553, which is an H1/H2 SNP, in 200 subjects with familial ET and 291 healthy controls. rs1052553 genotype and allelic frequencies did not differ significantly between subjects with ET and controls and were unrelated with the age at onset of tremor or gender, and with the presence of head, voice, chin, and tongue tremor. Our study suggests that the MAPT H1 rs1052553 is not associated with the risk for developing familial ET in the Spanish population.     

Recovery of chronic parkinsonian monkeys by autotransplants of carotid body cell aggregates into putamen

We have studied the effect of unilateral autografts of carotid body cell aggregates into the putamen of MPTP-treated monkeys with chronic parkinsonism. Two to four weeks after transplantation, the monkeys initiated a progressive recovery of mobility with reduction of tremor and bradykinesia and restoration of fine motor abilities on the contralateral side. Apomorphine injections induced rotations toward the side of the transplant. Functional recovery was accompanied by the survival of tyrosine hydroxylase-positive (TH-positive) grafted glomus cells. A high density of TH-immunoreactive fibers was seen reinnervating broad regions of the ipsilateral putamen and caudate nucleus. The nongrafted, contralateral striatum remained deafferented. Intrastriatal autografting of carotid body tissue is a feasible technique with beneficial effects on parkinsonian monkeys; thus, this therapeutic approach could also be applied to treat patients with Parkinson's disease.     

Fiber type-specific distribution of parvalbumin in rabbit skeletal muscle. A quantitative microbiochemical and immunohistochemical study.

A highly sensitive sandwich ELISA for parvalbumin (PA), based on a fluorometric detection system, was developed. This assay detected PA concentrations as low as 20 pg/ml (2 pg per assay) and was used for measuring PA contents in fragments of single muscle fibers isolated from freeze-dried 100-150 microns thick cross sections. The fibers were typed according to their histochemically assessed mATPase in parallel cross sections. Type I fibers from rabbit tibialis anterior (TA) and vastus lateralis (VL) muscles contained extremely low PA concentrations (2-5 micrograms/g w.wt.). Type IIA fibers displayed slightly higher values with mean values of 17 and 29 micrograms/g w.wt. (range 5-65) in TA and VL, respectively. Much higher PA concentrations were found in type IIB fibers with wide ranges from 75-1150 micrograms/g w.wt. in TA and 440-1370 micrograms/g w.wt. in VL. Whereas the IIB fibers of the TA displayed a continuum, two subgroups were distinguishable according to their PA contents (means of 590 and 1230 micrograms/g w.wt.) in VL. Possibly, the population with the lower PA content which was histochemically defined as type IIB in the present study, corresponds to fiber type IID. The finding that PA is predominantly present in type IIB fibers was also confirmed by the parallel decay of PA and type IIB fibers during chronic low-frequency stimulation. The use of freeze substitution, or alternatively, of freeze-drying, made it possible to demonstrate PA immunohistochemically without artifacts and to evaluate the staining intensity by microphotometry.(ABSTRACT TRUNCATED AT 250 WORDS)     

Unloaded shortening of skinned muscle fibers from rabbit activated with and without Ca2+.

Unloaded shortening velocity (VUS) was determined by the slack method and measured at both maximal and submaximal levels of activation in glycerinated fibers from rabbit psoas muscle. Graded activation was achieved by two methods. First, [Ca2+] was varied in fibers with endogenous skeletal troponin C (sTnC) and after replacement of endogenous TnC with either purified cardiac troponin C (cTnC) or sTnC. Alternatively, fibers were either partially or fully reconstituted with a modified form of cTnC (aTnC) that enables force generation and shortening in the absence of Ca2+. Uniformity of the distribution of reconstituted TnC across the fiber radius was evaluated using fluorescently labeled sTnC and laser scanning fluorescence confocal microscopy. Fiber shortening was nonlinear under all conditions tested and was characterized by an early rapid phase (VE) followed by a slower late phase (VL). In fibers with endogenous sTnC, both VE and VL varied with [Ca2+], but VE was less affected than VL. Similar results were obtained after extraction of TnC and reconstitution with either sTnC or cTnC, except for a small increase in the apparent activation dependence of VE. Partial activation with aTnC was obtained by fully extracting endogenous sTnC followed by reconstitution with a mixture of aTnC and cTnC (aTnC:cTnC molar ratio 1:8.5). At pCa 9.2, VE and VL were similar to those obtained in fibers reconstituted with sTnC or cTnC at equivalent force levels. In these fibers, which contained aTnC and cTnC, VE and VL increased with isometric force when [Ca2+] was increased from pCa 9.2 to 4.0. Fibers that contained a mixture of a TnC and cTnC were then extracted a second time to selectively remove cTnC. In fibers containing aTnC only, VE and VL were proportional to the resulting submaximal isometric force compared with maximum Ca(2+)-activated control. With aTnC alone, force, VE, and VL were not affected by changes in [Ca2+]. The similarity of activation dependence of VUS whether fibers were activated in a Ca(2+)-sensitive or -insensitive manners implies that VUS is determined by the average level of thin filament activation and that, with sTnC or cTnC, VUS is affected by Ca2+ binding to TnC only.     

Aerobic performance capacity in athletes

Maximal oxygen uptake (max VO2) in leg and arm work, succinate dehydrogenase activity (SDH) and percentage of slow twitch fibers (%ST fibers) in M. vastus lateralis (VL), M. gastrocnemius c.l. (GL) and M. deltoideus (D) were studied in 89 athletes practising 11 different sport events. It was found that maximal oxygen uptake correlated positively with %ST fibers and SDH activity in M. VL. The SDH activity and %ST fibers in M. VL correlated also with one another. The results suggest that oxidative capacity of the muscles is not the limiting factor for maximal oxygen uptake. The role of the oxidative capacity of the muscles might be important during submaximal work of long duration and when a relatively small muscle mass is activated (long-distance running). MaxVO2 might be the most important determinant of performance when large muscle mass is activated during maximal work of a duration from several minutes up to 1 h (cross-country skiing).     

Somatosensory evoked potentials in the ventrolateral thalamus

Within the target area (VL) used for the stereotactic treatment of parkinsonian tremor and spasmodic torticollis, electrical stimulation as well as recording of somatosensory evoked potential (SEP) was performed. The effects of stimulation in the target area are facilitation of muscle tone showing some degree of somatotopic distribution. The recorded SEPs indicate a projection of an afferent system (probably of muscle afferents) to the target area. We assume that the target area is a relay station involved in the control of muscle tone. The interruption of muscle afferents in combination with the correct somatotopic localization of the lesion is important for the therapeutic efficacy in parkinsonian tremor and spasmodic torticollis.     

Contributions of functional imaging to understanding parkinsonian symptoms

Brain imaging experiments identify plausible circuits involved in the genesis of the cardinal symptoms of Parkinson's disease. Akinesia is linked to hypoactivation of the supplementary motor area secondary to insufficient thalamocortical facilitation. Overactivation in other areas such as the lateral premotor and parietal cortex probably represents a compensatory mechanism. Bradykinesia is associated with abnormal functioning within intrinsic basal ganglia circuitry for scaling movements to appropriate magnitude. Parkinson's disease tremor is localized to pontine- and mesencephalic-cerebellar-thalamic circuits, with abnormalities of both dopamine and serotonin neurotransmission. There is a need to understand the anatomic intersections where information is shared across these circuits.     

Loss of alpha-conotoxinMII- and A85380-sensitive nicotinic receptors in Parkinson's disease striatum

Multiple nicotinic receptors are present in rodent and monkey striatum, with a selective localization of alpha-conotoxinMII-sensitive sites in the striatum and preferential declines in their numbers after nigrostriatal damage. Here we report the presence of 125I-alpha-conotoxinMII and alpha-conotoxinMII-sensitive 125I-epibatidine nicotinic receptors in human control and Parkinson's disease striatum. 125I-alpha-ConotoxinMII bound to control striatum with the characteristics of a nicotinic receptor ligand although the number of sites was approximately fivefold lower than in rodent and monkey. Competition analyses of alpha-conotoxinMII with 125I-epibatidine showed that toxin-sensitive sites comprised approximately 15% of nicotinic receptors in human striatum. In Parkinson's disease caudate, there was a approximately 50% decline in 125I-alpha-conotoxinMII sites with a similar decline in the dopamine transporter. In putamen, there were substantially greater losses of the dopamine transporter (80-90%) but only 50-60% decreases in 125I-alpha-conotoxinMII sites with corresponding declines in alpha-conotoxinMII-sensitive 125I-epibatidine sites, 125I-epibatidine (multiple) sites and 125I-A85380 (beta2-containing) nicotinic receptors. The greater loss of the transporter compared with nicotinic sites suggests that only a subpopulation of nicotinic receptors is located pre-synaptically on striatal dopaminergic neurons in man. Correlation analyses between changes in nicotinic receptors and the dopamine transporter in Parkinson's disease striatum suggest that alpha-conotoxinMII-sensitive 125I-epibatidine sites (low-affinity sites), 125I-A85380 and 125I-epibatidine sites are localized in part to dopaminergic terminals. In summary, these results show that alpha-conotoxinMII-sensitive sites are present in human striatum and that there are high- and low-affinity subtypes which are both decreased in Parkinson's disease.     

Gln --> Arg 191 polymorphism of paraoxonase and Parkinson's disease.

We investigated the Gln --> Arg 191 polymorphism in paraoxonase (PON1) in St. Petersburg population, in three clinically differentiated groups of patients with Parkinson's disease (PD) and in the symptomatic tremor group. A new approach for Gln --> Arg 191 PON1 polymorphism genotyping is suggested. No significant differences in the groups studies as compared to the controls was observed.     

Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease

Parkinson's disease (PD; OMIM #168600) is the second most common neurodegenerative disorder in the Western world and presents as a progressive movement disorder. The hallmark pathological features of PD are loss of dopaminergic neurons from the substantia nigra and neuronal intracellular Lewy body inclusions. Parkinsonism is typically sporadic in nature; however, several rare familial forms are linked to genetic loci, and the identification of causal mutations has provided insight into the disease process. PARK8, identified in 2002 by Funayama and colleagues, appears to be a common cause of familial PD. We describe here the cloning of a novel gene that contains missense mutations segregating with PARK8-linked PD in five families from England and Spain. Because of the tremor observed in PD and because a number of the families are of Basque descent, we have named this protein dardarin, derived from the Basque word dardara, meaning tremor.     

Finite dimensional structure of the GPI discharge in patients with Parkinson's disease

Stochastic systems are infinitely dimensional and deterministic systems are low dimensional, while real systems lie somewhere between these two limit cases. If the calculation of a low (finite) dimension is in fact possible, one could conclude that the system under study is not purely random. In the present work we calculate the maximal Lyapunov exponent from interspike intervals time series recorded from the internal segment of the Globus Pallidusfrom patients with Parkinson's disease. We show the convergence of the maximal Lyapunov exponent at a dimension equal to 7 or 8, which is therefore our estimation of the embedding dimension for the system. For dimensions below 7 the observed behavior is what would be expected from a stochastic system or a complex system projecting onto lower dimensional spaces. The maximal Lyapunov exponent did not show any differences between tremor and akineto-rigid forms of the disease. However, it did decay with the value of motor Unified Parkinson's Disease Rating Scale -OFF scores. Patients with a more severe disease (higher UPDRS-OFF score) showed a lower value of the maximal Lyapunov exponent. Taken together, both indexes (the maximal Lyapunov exponent and the embedding dimension) remark the importance of taking into consideration the system's non-linear properties for a better understanding of the information transmission in the basal ganglia.     

Phenotypic adaptations in human muscle fibers 6 and 24 wk after spinal cord injury.

The effects of spinal cord injury (SCI) on the profile of sarco(endo) plasmic reticulum calcium-ATPase (SERCA) and myosin heavy chain (MHC) isoforms in individual vastus lateralis (VL) muscle fibers were determined. Biopsies from the VL were obtained from SCI subjects 6 and 24 wk postinjury (n = 6). Biopsies from nondisabled (ND) subjects were obtained at two time points 18 wk apart (n = 4). In ND subjects, the proportions of VL fibers containing MHC I, MHC IIa, and MHC IIx were 46 +/- 3, 53 +/- 3, and 1 +/- 1%, respectively. Most MHC I fibers contained SERCA2. Most MHC IIa fibers contained SERCA1. All MHC IIx fibers contained SERCA1 exclusively. SCI resulted in significant increases in fibers with MHC IIx (14 +/- 4% at 6 wk and 16 +/- 2% at 24 wk). In addition, SCI resulted in high proportions of MHC I and MHC IIa fibers with both SERCA isoforms (29% at 6 wk and 54% at 24 wk for MHC I fibers and 16% at 6 wk and 38% at 24 wk for MHC IIa fibers). Thus high proportions of VL fibers were mismatched for SERCA and MHC isoforms after SCI (19 +/- 3% at 6 wk and 36 +/- 9% at 24 wk) compared with only ~5% in ND subjects. These data suggest that, in the early time period following SCI, fast fiber isoforms of both SERCA and MHC are elevated disproportionately, resulting in fibers that are mismatched for SERCA and MHC isoforms. Thus the adaptations in SERCA and MHC isoforms appear to occur independently.     

High prevalence of extrapyramidal signs and symptoms in a group of Italian dental technicians

Background  

Occupational and chronic exposure to solvents and metals is considered a possible risk factor for Parkinson's disease and essential tremor. While manufacturing dental prostheses, dental technicians are exposed to numerous chemicals that contain toxins known to affect the central nervous system, such as solvents (which contain n-hexane in particular) and metals (which contain mercury, iron, chromium, cobalt and nickel).