Multimodal Imaging of Substantia Nigra in Parkinson's Disease with Levodopa-Induced Dyskinesia

Background

Degeneration of the substantia nigra (SN) may contribute to levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), but the exact characteristics of SN in LID remain unclear.

Objective

To further understand the pathogenesis of patients with PD with LID (PD-LID), we explored the structural and functional characteristics of SN in PD-LID using multimodal magnetic resonance imaging (MRI).

Methods

Twenty-nine patients with PD-LID, 37 patients with PD without LID (PD-nLID), and 28 healthy control subjects underwent T1-weighted MRI, quantitative susceptibility mapping, neuromelanin-sensitive MRI, multishell diffusion MRI, and resting-state functional MRI. Different measures characterizing the SN were obtained using a region of interest–based approach.

Results

Compared with patients with PD-nLID and healthy control subjects, the quantitative susceptibility mapping values of SN pars compacta (SNpc) were significantly higher (P = 0.049 and P = 0.00002), and the neuromelanin contrast-to-noise ratio values in SNpc were significantly lower (P = 0.012 and P = 0.000002) in PD-LID. The intracellular volume fraction of the posterior SN in PD-LID was significantly higher compared with PD-nLID (P = 0.037). Resting-state fMRI indicated that PD-LID in the medication off state showed higher functional connectivity between the SNpc and putamen compared with PD-nLID (P = 0.031), and the functional connectivity changes in PD-LID were positively correlated with Unified Dyskinesia Rating Scale total scores (R = 0.427, P = 0.042).

Conclusions

Our multimodal imaging findings highlight greater neurodegeneration in SN and the altered nigrostriatal connectivity in PD-LID. These characteristics provide a new perspective into the role of SN in the pathophysiological mechanisms underlying PD-LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Monitoring Substantia Nigra Degeneration Using Free Water Imaging across Prodromal and Clinical Parkinson's Disease

Background

Substantia nigra (SN) free water has been suggested as a good surrogate marker in Parkinson's disease (PD). However, its usefulness for diagnosing prodromal PD (pPD) and monitoring disease progression warrants further validation.

Objective

The aim was to investigate SN free water values across prodromal and clinical stages of PD.

Methods

Four groups were enrolled in this study: 48 healthy controls (HC), 43 pPD patients, 50 de novo PD (dnPD) patients, and 49 medicated PD (mPD) patients. Based on diffusion tensor images, free water maps were calculated, and SN free water values were extracted from the anterior SN (ASN) and posterior SN (PSN). The SN free water values were compared among the four groups, and associations between free water and clinical symptoms were explored. The distinguishing power of PSN free water was evaluated using the receiver operating characteristic curve analysis. Follow-up was performed for 14 pPD patients.

Results

PSN free water in the pPD group was significantly higher than that in the HC group and significantly lower than that in the dnPD group. Surprisingly, the mPD group showed decreased PSN free water compared to the dnPD group. There was a positive correlation between motor symptoms and PSN free water in the pPD and dnPD groups. Longitudinal analysis showed a significant increase in PSN free water in pPD patients over time.

Conclusions

The PSN free water increased from prodromal to early clinical stages, but the trend might be reversed in late disease stages. This biphasic trend should be considered when applying this marker in future studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

磁共振测量帕金森病患者基底节区、黑质体积的研究

目的:探讨MR体积测量技术评价帕金森病(Parkinson’sdiseasePD)患者基底节区(尾状核,壳核,苍白球)、黑质体积改变的价值。方法:采用3·0TMR测量早、晚期PD患者和年龄匹配正常人对照组全脑体积、尾状核、壳核、苍白球、黑质体积。对患者进行PD统一评分量表(UPDRS)第Ⅱ、Ⅲ、Ⅴ部分评分。评分结果与患者基底节区、黑质体积行相关性分析。结果:早、晚期PD患者壳核体积较正常人分别下降12·5%(P=0·004)和26·5%(P<0·001),晚期患者较早期患者下降16·0%(P=0·002)。晚期患者苍白球体积较正常人下降19·2%(P=0·023)。PD患者壳核体积与Hoehn&Yahr分级呈负相关(r=-0·741,P<0·001)。结论:MR体积测量技术是评价PD患者基底节区、黑质体积改变的一种可靠的方法,能为PD辅助诊断提供有效的影像学指标。     

Emotion recognition in patients with idiopathic Parkinson's disease.

Emotion recognition (ER) was examined in 64 patients with idiopathic Parkinson's disease (PD; 56 bilateral and 8 right-sided) and 64 matched healthy volunteers. Participants were administered an ER battery, consisting of the following subscores: overall ER (OER), overall facial ER, facial emotion identification (FEI) and discrimination, overall prosodic ER, and prosodic emotion identification (PEI) and discrimination. Measures of visuospatial functions, auditory attention, and depression were also administered. After controlling for visuospatial functions, auditory attention and depression, results indicated that patients with bilateral PD had poorer performance on all ER subscores, regardless of the modality and type of experimental task involved, relative to healthy volunteers. However, patients with right-sided PD had difficulty on FEI and PEI only. Whereas none of the clinical variables examined in this study predicted any of the ER subscores, visual organization and auditory attention positively predicted OER in patients with PD. In addition, visual organization also positively predicted FEI in these patients. Implications are discussed in terms of the neural substrates underlying ER.     

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     

Nigral Pathology Contributes to Microstructural Integrity of Striatal and Frontal Tracts in Parkinson's Disease

Background

Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood.

Objective

To unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD.

Methods

Combining post-mortem in situ MRI and histopathology, T1-weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively.

Results

Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased MD of the SN and FA of SN-caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load.

Conclusions

In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

磁共振测量基底节区、黑质体积在帕金森病及其相关疾病诊断中的意义

磁共振体积测量是一项能够测量活体组织结构体积的影像学方法。本文对基底节区、黑质磁共振成像及磁共振测量基底节区、黑质体积在帕金森病及其相关疾病诊断中的意义作一综述。     

Functional Imaging of Working Memory in Parkinson's Disease: Compensations and Deficits

BACKGROUND AND PURPOSE: Over and above typical motor alterations, executive and working memory (WM) impairment can also occur in early idiopathic Parkinson's disease (PD). We aimed to investigate the compensatory neural processes involved in WM performance, as well as the networks involved in the long-term memory transfer from short-term stores in PD. METHODS: Relative cerebral blood flow (rCBF) was mapped with H2O(15)-PET in eight treated nondemented PD patients while performing a WM verbal double-task (Brown-Peterson paradigm) using both short (6-second) and long (18-second) delays. RESULTS: As compared to nine age-matched healthy subjects, performance of the PD group was only slightly reduced on the short-delay but markedly impaired on the long-delay task. Underlying the relatively preserved short-delay performance, the PD group exhibited overactivation of prefrontal and parietal areas involved in attention-demanding processes, suggestive of efficient compensatory processes. Further supporting this, significant positive correlations were found between short-delay performance and rCBF in the bilateral inferior parietal cortex. In contrast, the lack of overactivation with the long-delay task together with posterior cingulate hypoactivation would support the idea of functional disconnection impairing transfer of information from prefrontal onto (para)limbic areas. These findings suggest novel areas of investigation into early cognitive impairments in PD.     

Insights into Neurodegeneration in Parkinson's Disease from Single-Cell and Spatial Genomics

Parkinson's disease (PD) is pathologically defined by the death of dopaminergic (DA) neurons within the pars compacta of the substantia nigra. To date, the cause of this multifaceted disease remains largely unclear, which may contribute in part to a current lack of disease-modifying therapies. Recent advances in single-cell and spatial genomic profiling tools have provided powerful new ways to measure cellular state changes in brain diseases. Here, we describe how these tools have offered insight into these complex disorders and highlight a recently performed comprehensive study of DA neuron susceptibility in PD. The data generated by this recent work provide evidence for the role of specific pathways and common genetic variants resulting in the loss of a critical DA subtype in PD. We conclude by outlining a set of basic and translational opportunities that arise from those data and insights gathered from this work. © 2023 International Parkinson and Movement Disorder Society.     

Substantia nigra lesions in viral encephalitis.

Post-encephalitic parkinsonism is a well-known entity, but involvement of the basal ganglia is rarely documented. We describe a 21-year-old man who developed parkinsonism following encephalitic illness presumed to be of viral origin with substantia nigra lesions evident on magnetic resonance imaging scan.     

Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia

Background

Long-term use of levodopa for Parkinson's disease (PD) treatment is often hindered by development of motor complications, including levodopa-induced dyskinesia (LID). The substantia nigra pars reticulata (SNr) and globus pallidus internal segment (GPi) are the output nuclei of the basal ganglia. Dysregulation of SNr and GPi activity contributes to PD pathophysiology and LID.

Objective

The objective of this study was to determine whether direct modulation of SNr GABAergic neurons and SNr projections to the pedunculopontine nucleus (PPN) regulates PD symptoms and LID in a mouse model.

Methods

We expressed Cre-recombinase activated channelrhodopsin-2 (ChR2) or halorhodopsin adeno-associated virus-2 (AAV2) vectors selectively in SNr GABAergic neurons of Vgat-IRES-Cre mice in a 6-hydroxydopamine model of PD to investigate whether direct optogenetic modulation of SNr neurons or their projections to the PPN regulates PD symptoms and LID expression. The forepaw stepping task, mouse LID rating scale, and open-field locomotion were used to assess akinesia and LID to test the effect of SNr modulation.

Results

Akinesia was improved by suppressing SNr neuron activity with halorhodopsin. LID was significantly reduced by increasing SNr neuronal activity with ChR2, which did not interfere with the antiakinetic effect of levodopa. Optical stimulation of ChR2 in SNr projections to the PPN recapitulated direct SNr stimulation.

Conclusions

Modulation of SNr GABAergic neurons alters akinesia and LID expression in a manner consistent with the rate model of basal ganglia circuitry. Moreover, the projections from SNr to PPN likely mediate the antidyskinetic effect of increasing SNr neuronal activity, identifying a potential novel role for the PPN in LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Hyperechogenicity of the Substantia Nigra in Parkinson''s Disease

Substantia nigra (SN) was assessed by transcranial sonography (TCS) in 47 Parkinson's disease (PD) patients and in 39 healthy volunteers. A semiquantitative echogenicity scale was created with arbitrary values ranging from 1 to 5, zones with grade >or=3 and larger than 0.19 cm(2) were recorded as hyperechogenic SN. TCS examination of SN as a diagnostic test for PD in our study showed 87.2% sensitivity and 94.9% specificity.