Parallel relationship between microglial activation and substantia nigra damage in a rotenone-induced Parkinson's disease rat model

BACKGROUND:Inflammatory injury induced by microglial activation plays an important role in the occurrence and development of Parkinson’s disease (PD). However, few studies have examined the relationship between microglia and substantia nigra damage or dopaminergic neuron loss in animals with rotenone-induced PD. OBJECTIVE: To explore the relationship between activated microglia and loss of the substantia nigra, and the changes in concentration and dose of rotenone in the brain of rats with rotenone-induced ...     

Regional alterations of brain microstructure in Parkinson's disease using diffusion tensor imaging

This study tested the hypothesis that diffusion tensor imaging can detect alteration in microscopic integrity of white matter and basal ganglia regions known to be involved in Parkinson's disease (PD) pathology. It was also hypothesized that there is an association between diffusion abnormality and PD severity and subtype. Diffusion tensor imaging at 4 Tesla was obtained in 12 PD and 20 control subjects, and measures of fractional anisotropy and mean diffusivity were evaluated using both region‐of‐interest and voxel‐based methods. Movement deficits and subtypes in PD subjects were assessed using the Motor Subscale (Part III) of the Unified Parkinson's Disease Rating Scale. Reduced fractional anisotropy (P < .05, corrected) was found in PD subjects in regions related to the precentral gyrus, substantia nigra, putamen, posterior striatum, frontal lobe, and the supplementary motor areas. Reduced fractional anisotropy in the substantia nigra correlated (P < .05, corrected) with the increased rating scale motor scores. Significant spatial correlations between fractional anisotropy alterations in the putamen and other PD‐affected regions were also found in the context of PD subtypes index analysis. Our data suggest that microstructural alterations detected with diffusion tensor might serve as a potential biomarker for PD. © 2011 Movement Disorder Society     

Combined R2* and Diffusion Tensor Imaging Changes in the Substantia Nigra in Parkinson's Disease

Recent magnetic resonance imaging studies suggest an increased transverse relaxation rate and reduced diffusion tensor imaging fractional anisotropy values in the substantia nigra in Parkinson's disease. The transverse relaxation rate and fractional anisotropy changes may reflect different aspects of Parkinson's disease‐related pathological processes (ie, tissue iron deposition and microstructure disorganization). This study investigated the combined changes of transverse relaxation rate and fractional anisotropy in the substantia nigra in Parkinson's disease. High‐resolution magnetic resonance imaging (T2‐weighted, T2*, and diffusion tensor imaging) were obtained from 16 Parkinson's disease patients and 16 controls. Bilateral substantia nigras were delineated manually on T2‐weighted images and coregistered to transverse relaxation rate and fractional anisotropy maps. The mean transverse relaxation rate and fractional anisotropy values in each substantia nigra were then calculated and compared between Parkinson's disease subjects and controls. Logistic regression, followed by receiver operating characteristic curve analysis, was employed to investigate the sensitivity and specificity of the combined measures for differentiating Parkinson's disease subjects from controls. Compared with controls, Parkinson's disease subjects demonstrated increased transverse relaxation rate (P < .0001) and reduced fractional anisotropy (P = .0365) in the substantia nigra. There was no significant correlation between transverse relaxation rate and fractional anisotropy values. Logistic regression analyses indicated that the combined use of transverse relaxation rate and fractional anisotropy values provides excellent discrimination between Parkinson's disease subjects and controls (c‐statistic = 0.996) compared with transverse relaxation rate (c‐statistic = 0.930) or fractional anisotropy (c‐statistic = 0.742) alone. This study shows that the combined use of transverse relaxation rate and fractional anisotropy measures in the substantia nigra of Parkinson's disease enhances sensitivity and specificity in differentiating Parkinson's disease from controls. Further studies are warranted to evaluate the pathophysiological correlations of these magnetic resonance imaging measurements and their effectiveness in assisting in diagnosing Parkinson's disease and following its progression. © 2011 Movement Disorder Society     

Microstructural abnormalities of substantia nigra in Parkinson's disease: A neuromelanin sensitive MRI atlas based study

Microstructural changes associated with degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) have been studied using Diffusion Tensor Imaging (DTI). However, these studies show inconsistent results, mainly due to methodological variations in delineation of SNc. To mitigate this, our work aims to construct a probabilistic atlas of SNc based on a 3D Neuromelanin Sensitive MRI (NMS‐MRI) sequence and demonstrate its applicability to investigate microstructural changes on a large dataset of PD. Using manual segmentation and deformable registration we created a novel SNc atlas in the MNI space using NMS‐MRI sequences of 27 healthy controls (HC). We first quantitatively evaluated this atlas and then employed it to investigate the micro‐structural abnormalities in SNc using diffusion MRI from 133 patients with PD and 99 HCs. Our results demonstrated significant increase in diffusivity with no changes in anisotropy. In addition, we also observed an asymmetry of the diffusion metrics with a higher diffusivity and lower anisotropy in the left SNc than the right. Finally, a multivariate classifier based on SNc diffusion features could delineate patients with PD with an average accuracy of 71.7%. Overall, from this work we establish a normative baseline for the SNc region of interest using NMS‐MRI while the application on PD data emphasizes on the contribution of diffusivity measures rather than anisotropy of white matter in PD.     

Dopamine D₁ and D₂ receptor subtypes functional regulation in cerebral cortex of unilateral rotenone lesioned Parkinson's rat model: Effect of serotonin, dopamine and norepinephrine

Parkinson's disease is a progressive neurodegenerative disorder characterized by selective degeneration of dopaminergic neurons in substantia nigra pars compacta leading to marked reduction of dopamine levels in the cerebral cortex. The present study analysed the effect of serotonin, dopamine and norepinephrine as treatment on rotenone induced Hemi-Parkinson's disease in rats and its role in the regulation of dopamine receptor subtypes in the cerebral cortex of the experimental rats. Unilateral stereotaxic single dose infusions of rotenone were administered to the substantia nigra of adult male Wistar rats. Neurotransmitters--serotonin, dopamine and norepinephrine treatments--were given to rotenone induced Hemi-Parkinson's rats. Scatchard analysis of Dopamine D? and D? receptor showed a significant increase (p < 0.001) in the cerebral cortex of the Parkinson's rats compared to control. These altered parameters were reversed to near control in the serotonin and norepinephrine treated Parkinson's disease rats and no change was observed in dopamine treated Parkinson's rats. Real-time PCR results confirmed the receptor data. Our results showed serotonin and norepinephrine functionally reversed the dopamine receptors significantly in rotenone induced Hemi-Parkinson's rat. This has clinical significance in the therapeutic management of Parkinson's disease.     

Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson's disease

We carried out an investigation to identify neuromelanin-containing noradrenergic and dopaminergic neurons in the locus ceruleus and substantia nigra pars compacta of healthy volunteers and patients with Parkinson's disease using a newly developed magnetic resonance imaging technique that can demonstrate neuromelanin-related contrast. The high-resolution neuromelanin images obtained by a 3-T scanner revealed high signal areas in the brain stem and these corresponded well with the location of the locus ceruleus and substantia nigra pars compacta in gross specimens. In Parkinson's disease patients, the signal intensity in the locus ceruleus and substantia nigra pars compacta was greatly reduced, suggesting depletion of neuromelanin-containing neurons. We conclude that neuromelanin magnetic resonance imaging can be used for direct visualization of the locus ceruleus and substantia nigra pars compacta, and may help in detecting pathological changes in Parkinson's disease and related disorders.     

Quantitative diffusion tensor imaging detects dopaminergic neuronal degeneration in a murine model of Parkinson's disease

Early diagnosis of Parkinson's disease (PD) is required to improve therapeutic responses. Indeed, a clinical diagnosis of resting tremor, rigidity, movement and postural deficiencies usually reflect >50% loss of the nigrostriatal system in disease. In a step to address this, quantitative diffusion tensor magnetic resonance imaging (DTI) was used to assess nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication model of dopaminergic nigral degeneration. We now demonstrate increased average diffusion (p<0.005) and decreased fractional anisotropy (p<0.03) in the substantia nigra (SN) of 5- to 7-day MPTP-treated animals when compared to saline controls. Transverse diffusivity demonstrated the most significant differences (p < or = 0.002) and correlated with the numbers of SN dopaminergic neurons (r=-0.75, p=0.012). No differences were found in the striatum, corpus callosum, cerebral cortex, or ventricles. These results demonstrate that DTI may be used as a surrogate biomarker of nigral dopaminergic neuronal degeneration.     

In vivo magnetic resonance imaging characterization of bilateral structural changes in experimental Parkinson's disease: a T2 relaxometry study combined with longitudinal diffusion tensor imaging and manganese-enhanced magnetic resonance imaging in the 6-hydroxydopamine rat model

The neuropathological hallmark of Parkinson's disease is the loss of dopaminergic neurons in the pars compacta of the substantia nigra (SNc). The degenerative process starts unilaterally and spreads to the dopaminergic system of both hemispheres. However, the complete characterization of the nigra lesion and the subsequent changes in basal ganglia nuclei activity has not yet been achieved in vivo. The aim of this study was to characterize the time course of the nigral lesion in vivo, using longitudinal T2 relaxometry and diffusion tensor imaging, and the changes in basal ganglia nuclei activity, using manganese-enhanced magnetic resonance imaging, in 6-hydroxydopamine (6-OHDA)-lesioned rats. Our results showed that a unilateral SNc lesion induces bilateral alterations, as indicated by the enhancement of magnetic resonance imaging T2 relaxation times in both the ipsilateral and contralateral SNc. Moreover, axial and radial diffusivities demonstrated bilateral changes at 3 and 14 days after 6-OHDA injection in the pars reticulata of the substantia nigra and cortex, respectively, in comparison to the sham group, suggesting bilateral microstructural alterations in these regions. Unexpectedly, manganese-enhanced magnetic resonance imaging showed decreased axonal transport from the ipsilateral subthalamic nucleus to the ventral pallidum in 6-OHDA-lesioned animals compared with the sham group. These findings demonstrate, for the first time in vivo, the temporal pattern of bilateral alteration induced by the 6-OHDA model of Parkinson's disease, and indicate decreased axonal transport in the ipsilateral hemisphere.     

Early pathological changes in the parkinsonian brain demonstrated by diffusion tensor MRI

OBJECTIVE: To determine whether the fractional anisotropy (FA) of magnetic resonance diffusion tensor imaging is decreased in the nigrostriatal projection in parkinsonian patients. METHODS: FA values were compared in the extrapyramidal system of 12 patients with Parkinson's disease and eight age matched normal controls. RESULTS: Patients with Parkinson's disease had significantly decreased FA in the region of interest along a line between the substantia nigra and the lower part of the putamen/caudate complex, in which most of the nigrostriatal dopaminergic neurones are included. Loss of FA in this region was obvious even during the early clinical stages of Parkinson's disease. CONCLUSIONS: Assuming that the loss of FA parallels the neuronal change in the brain, the results are consistent with the view that more than half the dopaminergic neurones in the nigrostriatal projection are lost before the onset of Parkinson's disease. Close comparison of FA in the basal ganglia may contribute to the early diagnosis of Parkinson's disease.     

黑质FA值对早期诊断帕金森病的临床研究

目的 探讨帕金森病(PD)黑质各向异性分数(FA)值的变化特点。方法 对PD患者单侧症状组10例,PD双侧症状组20例和20例健康对照组行常规MRI和DTI扫描,描绘并测量黑质头部(SNr)、黑质体部(SNm)、黑质尾部(SNc)各感兴趣区(ROI)的FA值。结果 PD单侧症状组黑质体部(0.363±177;0.036,0.371±177;0.035)、尾部(0.454±177;0.027,0.464±177;0.038)FA值和PD双侧症状组黑质头部(0.380±177;0.031)、体部(0.352±177;0.031)、尾部(0.431±177;0.033)FA值均较对照组(0.440±177;0.047,0.384±177;0.033,0.481±177;0.042)明显降低(P<0.05)。结论 黑质FA值下降对早期帕金森病的诊断有一定价值。     

Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson''s disease

BACKGROUND:Parkinson's disease (PD) is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor (BDNF) mRNA (20%) than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.     

Future perfect? Presymptomatic diagnosis, neural transplantation, and trophic factors.

Parkinson's disease has served as the prototype for study of degenerative neurologic diseases, perhaps because in patients with Parkinson's disease a set of conspicuous symptoms is due to loss of neurons in a single nucleus, the substantia nigra pars compacta. The restricted pathology enabled researchers to understand the salient biochemical abnormalities of and to develop effective drug therapies for Parkinson's disease. Our understanding of Parkinson's disease may enable identification of markers for presymptomatic diagnosis of the disease. Trophic factors and transplantation enabled researchers to begin to develop and implement strategies to protect remaining dopaminergic neurons in the substantia nigra pars compacta and to restore dopaminergic innervation in the striatum.     

COX-2-deficient mice are less prone to MPTP-neurotoxicity than wild-type mice

The primary lesion in Parkinson's disease is the death of dopaminergic neurons in the substantia nigra. The role of cyclooxygenase (COX)-2 in the etiology of Parkinson's disease was explored using COX-2 gene knockout mice. Mortality after injection of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP, a chemical known to cause parkinsonism in humans) in heterozygous COX-2-deficient mice was lower than that in wild-type mice. The number of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta of MPTP-treated wild-type mice declined to a greater extent than in heterozygous mice. Inhibition of COX-2 protein expression decreased the lesion caused by MPTP and protected the dopaminergic neurons in substantia nigra pars compacta. This result suggested that inhibition of COX-2 has potential therapeutic implications.     

Inhibiting BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons

Brain derived neurotrophic factor (BDNF) expression is significantly reduced in the Parkinson's disease substantia nigra. This neurotrophin has potent affects on dopaminergic neuron survival protecting them from the neurotoxins MPTP and 6-hydroxydopamine (6-OHDA) commonly used to create animal models of Parkinson's disease and also promoting dopaminergic axonal sprouting. In this study, we demonstrate that an antisense oligonucleotide infusion (200 nM for 28 days) to prevent BDNF production in the substantia nigra of rats mimics many features of the classical animal models of Parkinson's disease. 62% of antisense treated rats rotate (P < or = 0.05) in response to dopaminergic receptor stimulation by apomorphine. 40% of substantia nigra pars compacta tyrosine hydroxylase immunoreactive neurons are lost (P < or = 0.00001) and dopamine uptake site density measured by (3)H-mazindol autoradiography is reduced by 34% (P < or = 0.005). Loss of haematoxylin and eosin stained nigral neurons is significant (P < or = 0.0001) but less extensive (34%). These observations indicate that loss of BDNF expression leads both to down regulation of the dopaminergic phenotype and to dopaminergic neuronal death. Therefore, reduced BDNF mRNA expression in Parkinson's disease substantia nigra may contribute directly to the death of nigral dopaminergic neurons and the development of Parkinson's disease.     

Electrophysiological characterization of substantia nigra dopaminergic neurons in partially lesioned rats: effects of subthalamotomy and levodopa treatment

Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta is the main histopathological characteristic of Parkinson's disease. We studied the electrophysiological characteristics of the spontaneous activity of substantia nigra pars compacta dopaminergic neurons in rats with a partial, unilateral, 6-hydroxydopamine lesion of the nigrostriatal pathway. In addition, the effects of subthalamotomy and prolonged levodopa treatment on the activity of dopaminergic neurons were investigated. As a result of the lesion ( approximately 50% neuronal loss), the number of spontaneously active neurons was significantly reduced. Basal firing rate, burst firing and responsiveness to intravenously administered apomorphine remained unchanged. In contrast, the variation coefficient, a measure of interspike interval regularity, was significantly increased. Ibotenic acid (10 microg) lesion of the ipsilateral subthalamic nucleus in lesioned rats did not modify the electrophysiological parameters. However, prolonged levodopa treatment (100 mg/kg/day + benserazide 25 mg/kg/day, 14 days) reversed the irregularity observed in cells from lesioned rats, while it induced an irregular firing pattern in cells from intact rats. Our results using an experimental model of moderate Parkinson's disease indicate that surviving substantia nigra pars compacta dopaminergic neurons fire irregularly. In this model, subthalamotomy does not modify the firing pattern while levodopa treatment efficiently restores normal firing of SNpc neurons and does not appear to be toxic to them.     

Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons

Dysfunction of the ubiquitin-proteasomal system (UPS) has been implicated in the pathogenesis of Parkinson's disease. The systemic administration of UPS inhibitors has been reported to induce nigrostriatal cell death and model Parkinson's disease pathology in rodents. We administered a synthetic, specific UPS inhibitor (PSI) subcutaneously to rats and quantified substantia nigral tyrosine hydroxylase-positive dopaminergic neurons by stereology. PSI caused a 15% decrease in UPS activity at 2 weeks and a 42% reduction in substantia nigra pars compacta tyrosine hydroxylase-positive neurons at 8 weeks. Systemic inhibition of the UPS warrants further evaluation as a means to model Parkinson's disease.     

酪氨酸羟化酶cDNA移植治疗帕金森病的实验研究

帕金森病(PD)的主要病因是黑质多巴胺能神经元损伤,表达的酪氨酸羟化酶(TH)减少。本文在应用6-羟多巴胺(6-OHDA)制备偏侧PD大鼠模型的前提下,首次将TH cDNA移植到PD大鼠纹状体内,模型动物的旋转行为明显改善,用免疫组化法及PCR法证实了外源性THcDNA可以进入脑细胞内,并表达出有生物活性的TH。     

光学相干断层扫描技术评估帕金森病患者视网膜改变的研究进展

帕金森病(PD)患者在黑质多巴胺能神经元变性丢失的同时,视网膜的多巴胺能神经元也同样受到影响,使视网膜的结构和功能发生改变。光学相干断层扫描(OCT)是一种近10年来发展迅速的生物组织活体成像技术,可以通过弱相干光干涉仪原理对人体组织进行显微结构断层成像。研究显示,通过OCT评估PD患者视网膜厚度变化可能对PD的早期诊断以及病情监测具有重要意义。文中就近年来OCT应用于PD诊断及评估中的研究进展进行介绍。     

鱼藤酮致大鼠脑内α-突触核蛋白的表达分布变化

目的 研究鱼藤酮所致的帕金森病大鼠的脑内α-突触核蛋白（α—synuclein,ASN）分布。方法 Wistar大鼠随机分成两组,分别给予鱼藤酮和／或溶剂（对照组）皮下注射,4周后取脑组织,对黑质部位HE染色,光镜下观察Lewy小体形态;对黑质、海马、纹状体等脑区进行酪氨酸羟化酶（tyrosine hydroxylase,TH）、ASN免疫组织化学染色。结果 在对照组大鼠脑内,ASN广泛分布于各脑区,尤其在皮质、纹状体、海马等纤维投射丰富的区域。鱼藤酮处理的大鼠脑中,黑质TH阳性多巴胺能神经元数目减少、纹状体区TH阳性纤维脱失,黑质部位可见Lewy小体样结构;ASN阳性染色在各个脑区均有增强但各个脑区增强程度不一,黑质部位神经元胞浆和胞核内均有ASN明显聚集,纹状体可见ASN聚集围绕在细胞周围。海马部位偶见ASN在胞浆中点状聚集,胞核中无明显改变。结论 在鱼藤酮皮下注射导致的帕金森病大鼠的脑内,ASN在多个脑区中表达增加,而在黑质纹状体部位聚集最为明显,蛋白分布由多巴胺能神经元的突触末端向胞浆和胞核扩展。     

Investigation of MS normal-appearing brain using diffusion tensor MRI with clinical correlations

OBJECTIVE: To quantitatively investigate water diffusion changes in normal-appearing white matter (NAWM) and gray matter in patients with MS, and to evaluate whether these changes are correlated with clinical disability and disease duration. BACKGROUND: Diffusion tensor imaging provides quantitative information about the magnitude and directionality (anisotropy) of water diffusion in vivo and detects pathologic changes in MS brain tissue. METHODS: Diffusion tensor imaging was performed in 39 patients with MS and in 21 age-matched control subjects. Quantitative indices, including fractional anisotropy, volume ratio, and mean diffusivity, were obtained in 30 regions of interest located in normal-appearing basal ganglia, cerebellar gray matter, and supratentorial and infratentorial NAWM. RESULTS: Patients with MS showed significantly reduced anisotropy and a trend toward increased diffusivity in the infratentorial and supratentorial NAWM, and significantly increased anisotropy in the basal ganglia. In all patients with MS, both fractional anisotropy and mean diffusivity in the cerebral peduncles were inversely correlated with the Expanded Disability Status Scale and pyramidal functional scores. In patients with relapsing-remitting MS, there was a strong correlation between Expanded Disability Status Scale score and fractional anisotropy in both supratentorial and infratentorial NAWM. In primary and secondary progressive MS, disease duration correlated strongly with mean diffusivity in infratentorial NAWM and fractional anisotropy in the cerebral peduncles, respectively. CONCLUSION: The most striking finding of decreased fractional anisotropy in supratentorial and infratentorial NAWM and increased fractional anisotropy in basal ganglia may result from axonal degeneration due to fiber transection in remote focal lesions. Diffusion tensor imaging indices, in particular fractional anisotropy, appear sensitive to structural damage in NAWM that is associated with disability and progression in MS.