NPJ Parkinson's Disease最新文献

{"title":"Increased mean diffusivity of the caudal motor SNc identifies patients with REM sleep behaviour disorder and Parkinson's disease.","authors":"Erind Alushaj, Dimuthu Hemachandra, Hooman Ganjavi, Ken N Seergobin, Manas Sharma, Alia Kashgari, Jennifer Barr, William Reisman, Ali R Khan, Penny A MacDonald","doi":"10.1038/s41531-024-00731-0","DOIUrl":"10.1038/s41531-024-00731-0","url":null,"abstract":"<p><p>Idiopathic rapid eye movement sleep behaviour disorder (iRBD)-a Parkinson's disease (PD) prodrome-might exhibit neural changes similar to those in PD. Substantia nigra pars compacta (SNc) degeneration underlies motor symptoms of PD. In iRBD and early PD (ePD), we measured diffusion MRI (dMRI) in the caudal motor SNc, which overlaps the nigrosome-1-the earliest-degenerating dopaminergic neurons in PD-and in the striatum. Nineteen iRBD, 26 ePD (1.7 ± 0.03 years), and 46 age-matched healthy controls (HCs) were scanned at Western University, and 47 iRBD, 115 ePD (0.9 ± 0.01 years), and 56 HCs were scanned through the Parkinson's Progression Markers Initiative, using 3T MRI. We segmented the SNc and striatum into subregions using automated probabilistic tractography to the cortex. We measured mean diffusivity (MD) and fractional anisotropy (FA) along white-matter bundles and subregional surfaces. We performed group-level and classification analyses. Increased caudal motor SNc surface MD was the only iRBD-HCs and ePD-HCs difference replicating across datasets (p_adj < 0.05). No iRBD-ePD differences emerged. Caudal motor SNc surface MD classified patient groups from HCs at the single-subject level with good-to-excellent balanced accuracy in an independent sample (0.91 iRBD and 0.86 iRBD and ePD combined), compared to fair performance for total SNc surface MD (0.72 iRBD and ePD). Caudal motor SNc surface MD correlated significantly with MDS-UPDRS-III scores in ePD patients. Using dMRI and automated segmentation, we detected changes suggesting altered microstructural integrity in iRBD and ePD in the nigrostriatal subregion known to degenerate first in PD. Surface MD of the caudal motor SNc presents a potential measure for inclusion in neuroimaging biomarkers of iRBD and PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11217278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A retrospective study of the MDS criteria for prodromal Parkinson's disease in the general population.","authors":"Gijs W de Klerk, Teus van Laar, Sanne K Meles","doi":"10.1038/s41531-024-00739-6","DOIUrl":"10.1038/s41531-024-00739-6","url":null,"abstract":"<p><p>The Movement Disorder Society developed research criteria for the detection of the prodromal phase of Parkinson's disease (PD). Accurate identification of this phase is essential for early interventions. Therefore, we investigated the diagnostic value of these research criteria in the general population. Lifelines is an ongoing cohort study of 167,000 participants from the general population of the Northern Netherlands. 160 participants self-reported to have developed PD during three rounds of follow-up of five years each. Data were available to infer six out of eleven risk markers, and six out of twelve prodromal markers. We retrospectively compared the criteria in the prodromal stage of a group of 160 'converters' with 320 age- and sex-matched controls. The overall incidence rate of PD was 0.20 per 1.000 person-years (95% CI: 0.049-0.36), increasing with age and rates were higher in men. The median probability for prodromal PD in PD-converters was 1.29% (interquartile range: 0.46-2.9), compared to 0.83% (0.39-1.8) for controls (P = 0.014). The MDS set of criteria for prodromal PD had an ROC-AUC of 0.577, and was therefore not sufficient to adequately predict conversion to PD. We were unable to predict conversion to PD in the general population using a selection of the prodromal PD research criteria. Ancillary investigations are required to improve the diagnostic accuracy of the criteria, but most are precluded from large-scale use. Strategies, including olfactory tests or alpha-synuclein seeding amplification assays may improve the detection of prodromal PD in the general population.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of striatal connectivity corresponding to striosomes and matrix in de novo Parkinson's disease and isolated REM behavior disorder.","authors":"S Marecek, T Krajca, R Krupicka, P Sojka, J Nepozitek, Z Varga, C Mala, J Keller, J L Waugh, D Zogala, J Trnka, K Sonka, E Ruzicka, P Dusek","doi":"10.1038/s41531-024-00736-9","DOIUrl":"10.1038/s41531-024-00736-9","url":null,"abstract":"<p><p>Striosomes and matrix are two compartments that comprise the striatum, each having its own distinct immunohistochemical properties, function, and connectivity. It is currently not clear whether prodromal or early manifest Parkinson's disease (PD) is associated with any striatal matrix or striosomal abnormality. Recently, a method of striatal parcellation using probabilistic tractography has been described and validated, using the distinct connectivity of these two compartments to identify voxels with striosome- and matrix-like connectivity. The goal of this study was to use this approach in tandem with DAT-SPECT, a method used to quantify the level of nigrostriatal denervation, to analyze the striatum in populations of de novo diagnosed, treatment-naïve patients with PD, isolated REM behavioral disorder (iRBD) patients, and healthy controls. We discovered a shift in striatal connectivity, which showed correlation with nigrostriatal denervation. Patients with PD exhibited a significantly higher matrix-like volume and associated connectivity than healthy controls and higher matrix-associated connectivity than iRBD patients. In contrast, the side with less pronounced nigrostriatal denervation in PD and iRBD patients showed a decrease in striosome-like volume and associated connectivity indices. These findings could point to a compensatory neuroplastic mechanism in the context of nigrostriatal denervation and open a new avenue in the investigation of the pathophysiology of Parkinson's disease.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of motor and non-motor Parkinson's disease symptoms using serum lipidomics and machine learning: a 2-year study.","authors":"Jasmin Galper, Giorgia Mori, Gordon McDonald, Diba Ahmadi Rastegar, Russell Pickford, Simon J G Lewis, Glenda M Halliday, Woojin S Kim, Nicolas Dzamko","doi":"10.1038/s41531-024-00741-y","DOIUrl":"10.1038/s41531-024-00741-y","url":null,"abstract":"<p><p>Identifying biological factors which contribute to the clinical progression of heterogeneous motor and non-motor phenotypes in Parkinson's disease may help to better understand the disease process. Several lipid-related genetic risk factors for Parkinson's disease have been identified, and the serum lipid signature of Parkinson's disease patients is significantly distinguishable from controls. However, the extent to which lipid profiles are associated with clinical outcomes remains unclear. Untargeted high-performance liquid chromatography-tandem mass spectrometry identified >900 serum lipids in Parkinson's disease subjects at baseline (n = 122), and the potential for machine learning models using these lipids to predict motor and non-motor clinical scores after 2 years (n = 67) was assessed. Machine learning models performed best when baseline serum lipids were used to predict the 2-year future Unified Parkinson's disease rating scale part three (UPDRS III) and Geriatric Depression Scale scores (both normalised root mean square error = 0.7). Feature analysis of machine learning models indicated that species of lysophosphatidylethanolamine, phosphatidylcholine, platelet-activating factor, sphingomyelin, diacylglycerol and triacylglycerol were top predictors of both motor and non-motor scores. Serum lipids were overall more important predictors of clinical outcomes than subject sex, age and mutation status of the Parkinson's disease risk gene LRRK2. Furthermore, lipids were found to better predict clinical scales than a panel of 27 serum cytokines previously measured in this cohort (The Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium). These results suggest that lipid changes may be associated with clinical phenotypes in Parkinson's disease.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interpretable video-based tracking and quantification of parkinsonism clinical motor states.","authors":"Daniel Deng, Jill L Ostrem, Vy Nguyen, Daniel D Cummins, Julia Sun, Anupam Pathak, Simon Little, Reza Abbasi-Asl","doi":"10.1038/s41531-024-00742-x","DOIUrl":"10.1038/s41531-024-00742-x","url":null,"abstract":"<p><p>Quantification of motor symptom progression in Parkinson's disease (PD) patients is crucial for assessing disease progression and for optimizing therapeutic interventions, such as dopaminergic medications and deep brain stimulation. Cumulative and heuristic clinical experience has identified various clinical signs associated with PD severity, but these are neither objectively quantifiable nor robustly validated. Video-based objective symptom quantification enabled by machine learning (ML) introduces a potential solution. However, video-based diagnostic tools often have implementation challenges due to expensive and inaccessible technology, and typical \"black-box\" ML implementations are not tailored to be clinically interpretable. Here, we address these needs by releasing a comprehensive kinematic dataset and developing an interpretable video-based framework that predicts high versus low PD motor symptom severity according to MDS-UPDRS Part III metrics. This data driven approach validated and robustly quantified canonical movement features and identified new clinical insights, not previously appreciated as related to clinical severity, including pinkie finger movements and lower limb and axial features of gait. Our framework is enabled by retrospective, single-view, seconds-long videos recorded on consumer-grade devices such as smartphones, tablets, and digital cameras, thereby eliminating the requirement for specialized equipment. Following interpretable ML principles, our framework enforces robustness and interpretability by integrating (1) automatic, data-driven kinematic metric evaluation guided by pre-defined digital features of movement, (2) combination of bi-domain (body and hand) kinematic features, and (3) sparsity-inducing and stability-driven ML analysis with simple-to-interpret models. These elements ensure that the proposed framework quantifies clinically meaningful motor features useful for both ML predictions and clinical analysis.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid of de novo Parkinson's disease.","authors":"Michael Bartl, Johanna Nilsson, Mohammed Dakna, Sandrina Weber, Sebastian Schade, Mary Xylaki, Bárbara Fernandes Gomes, Marielle Ernst, Maria-Lucia Muntean, Friederike Sixel-Döring, Claudia Trenkwalder, Henrik Zetterberg, Ann Brinkmalm, Brit Mollenhauer","doi":"10.1038/s41531-024-00726-x","DOIUrl":"10.1038/s41531-024-00726-x","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity.","authors":"Xi Zhang, Linhao Ruan, Hu Wang, Jin Zhu, Taibo Li, Gordon Sun, Yi Dong, Yuhao Wang, Gil Berreby, Ashley Shay, Rong Chen, Sreekumar Ramachandran, Valina L Dawson, Ted M Dawson, Rong Li","doi":"10.1038/s41531-024-00733-y","DOIUrl":"10.1038/s41531-024-00733-y","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11192938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the role of cerebellum in early Parkinson’s disease: a structural and functional MRI study","authors":"S. Pietracupa, A. Ojha, D. Belvisi, C. Piervincenzi, S. Tommasin, N. Petsas, M. I. De Bartolo, M. Costanzo, A. Fabbrini, A. Conte, A. Berardelli, P. Pantano","doi":"10.1038/s41531-024-00727-w","DOIUrl":"https://doi.org/10.1038/s41531-024-00727-w","url":null,"abstract":"<p>Increasing evidence suggests that the cerebellum may have a role in the pathophysiology of Parkinson’s disease (PD). Hence, the scope of this study was to investigate whether there are structural and functional alterations of the cerebellum and whether they correlate with motor and non-motor symptoms in early PD patients. Seventy-six patients with early PD and thirty-one age and sex-matched healthy subjects (HS) were enrolled and underwent a 3 T magnetic resonance imaging (MRI) protocol. The following MRI analyses were performed: (1) volumes of 5 cerebellar regions of interest (sensorimotor and cognitive cerebellum, dentate, interposed, and fastigial nuclei); (2) microstructural integrity of the cerebellar white matter connections (inferior, middle, and superior cerebellar peduncles); (3) functional connectivity at rest of the 5 regions of interest already described in point 1 with the rest of brain. Compared to controls, early PD patients showed a significant decrease in gray matter volume of the dentate, interposed and fastigial nuclei, bilaterally. They also showed abnormal, bilateral white matter microstructural integrity in all 3 cerebellar peduncles. Functional connectivity of the 5 cerebellar regions of interest with several areas in the midbrain, basal ganglia and cerebral cortex was altered. Finally, there was a positive correlation between abnormal functional connectivity of the fastigial nucleus with the volume of the nucleus itself and a negative correlation with axial symptoms severity. Our results showed that structural and functional alterations of the cerebellum are present in PD patients and these changes contribute to the pathophysiology of PD in the early phase.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurovascular and immune factors of vulnerability of substantia nigra dopaminergic neurons in non-human primates","authors":"Tiziano Balzano, Natalia López-González del Rey, Noelia Esteban-García, Alejandro Reinares-Sebastián, José A. Pineda-Pardo, Inés Trigo-Damas, José A. Obeso, Javier Blesa","doi":"10.1038/s41531-024-00735-w","DOIUrl":"https://doi.org/10.1038/s41531-024-00735-w","url":null,"abstract":"<p>Dopaminergic neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson’s disease (PD), while those in the dorsal tier and ventral tegmental area are relatively spared. The factors determining why these neurons are more vulnerable than others are still unrevealed. Neuroinflammation and immune cell infiltration have been demonstrated to be a key feature of neurodegeneration in PD. However, the link between selective dopaminergic neuron vulnerability, glial and immune cell response, and vascularization and their interactions has not been deciphered. We aimed to investigate the contribution of glial cell activation and immune cell infiltration in the selective vulnerability of ventral dopaminergic neurons within the midbrain in a non-human primate model of PD. Structural characteristics of the vasculature within specific regions of the midbrain were also evaluated. Parkinsonian monkeys exhibited significant microglial and astroglial activation in the whole midbrain, but no major sub-regional differences were observed. Remarkably, the ventral substantia nigra was found to be typically more vascularized compared to other regions. This feature might play some role in making this region more susceptible to immune cell infiltration under pathological conditions, as greater infiltration of both T- and B- lymphocytes was observed in parkinsonian monkeys. Higher vascular density within the ventral region of the SNc may be a relevant factor for differential vulnerability of dopaminergic neurons in the midbrain. The increased infiltration of T- and B- cells in this region, alongside other molecules or toxins, may also contribute to the susceptibility of dopaminergic neurons in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141333723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subthalamic nucleus input-output dynamics are correlated with Parkinson's burden and treatment efficacy.","authors":"Xiaowei Liu, Jing Guang, Stefanie Glowinsky, Hodaya Abadi, David Arkadir, Eduard Linetsky, Muneer Abu Snineh, Juan F León, Zvi Israel, Wei Wang, Hagai Bergman","doi":"10.1038/s41531-024-00737-8","DOIUrl":"10.1038/s41531-024-00737-8","url":null,"abstract":"<p><p>The subthalamic nucleus (STN) is pivotal in basal ganglia function in health and disease. Micro-electrode recordings of >25,000 recording sites from 146 Parkinson's patients undergoing deep brain stimulation (DBS) allowed differentiation between subthalamic input, represented by local field potential (LFP), and output, reflected in spike discharge rate (SPK). As with many natural systems, STN neuronal activity exhibits power-law dynamics characterized by the exponent α. We, therefore, dissected STN data into aperiodic and periodic components using the Fitting Oscillations & One Over F (FOOOF) tool. STN LFP showed significantly higher aperiodic exponents than SPK. Additionally, SPK beta oscillations demonstrated a downward frequency shift compared to LFP. Finally, the STN aperiodic and spiking parameters explained a significant fraction of the variance of the burden and treatment efficacy of Parkinson's disease. The unique STN input-output dynamics may clarify its role in Parkinson's physiology and can be utilized in closed-loop DBS therapy.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11180194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}