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OBJECTIVE: Blepharospasm (BSP), focal dystonia with the highest risk of spread, lacks clear understanding of early spreading risk factors and objective prognostic indicators. We aimed to identify these risk factors through clinical and electrophysiological assessments, and to establish a predictive model for dystonic spread in BSP. METHODS: We prospectively followed BSP patients for 4 years, collecting data on dystonic spread, and conducting electrophysiological evaluations. The blink reflex, masseter inhibitory reflex, and trigeminal somatosensory evoked potential were assessed. Univariable and multivariable Cox proportional hazard regression models were used to assess clinical characteristics associated with BSP dystonic spread. A predictive model was constructed using a nomogram, and performance of the model was evaluated using the area under the receiver operating characteristic curve. RESULTS: A total of 136 enrolled participants (mean age 56.34 years) completed a 4-year follow-up. Among them, 62 patients (45.6%) showed spread to other body regions. Multivariable Cox regression analysis showed that a high Hamilton Anxiety Scale score (hazard ratio 1.19, 95% confidence interval 1.13-1.25, p < 0.001), prolonged trigeminal somatosensory evoked potential mandibular branch P1-N2 peak interval (hazard ratio 1.11, 95% confidence interval 1.02-1.21, p = 0.017), and elevated trigeminal somatosensory evoked potential mandibular branch P1-N2 peak amplitude (hazard ratio 1.26, 95% confidence interval 1.12-1.41, p < 0.001) were independent risk factors for BSP dystonic spread within 4 years. Combining these factors, the predictive models demonstrated excellent discriminative ability, with the receiver operating characteristic curve score being 0.797, 0.790, 0.847, and 0.820 at 1, 2, 3 and 4 years after enrollment, respectively. INTERPRETATION: We established a predictive model with significant value for anticipating dystonic spread in BSP, offering crucial evidence. These findings contribute essential insights into the early clinical identification of the development and evolution of BSP diseases. ANN NEUROL 2024.
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INTRODUCTION: Gait and posture abnormalities are the common disabling motor symptoms in Parkinson's disease (PD). This study aims to investigate the differential characteristics of gait and posture in early-onset PD (EOPD) and late-onset PD (LOPD) using the Kinect depth camera. METHODS: Eighty-eight participants, including two subgroups of 22 PD patients and two subgroups of 22 healthy controls (HC) matched for age, sex, and height, were enrolled. Gait and posture features were quantitatively assessed using a Kinect-based system. A two-way analysis of variance was used to compare the difference between different subgroups. RESULTS: EOPD had a significantly higher Gait score than LOPD (p = 0.031). Specifically, decreased swing phase (p = 0.034) was observed in the EOPD group. Although the Posture score was similar between the two groups, LOPD was characterized by an increased forward flexion angle of the trunk at the thorax (p = 0.042) and a decreased forward flexion angle of the head relative to the trunk (p = 0.009). Additionally, age-independent features were observed in both PD subgroups, and post hoc tests revealed that EOPD generally performed worse gait features. In comparison, LOPD was characterized by worse performance in posture features. CONCLUSIONS: EOPD and LOPD exhibit different profiles of gait and posture features. The phenotype-specific characteristics likely reflect the distinct neurodegenerative processes between them.
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Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Idade de Início , MarchaRESUMO
INTRODUCTION: The acute levodopa challenge test (ALCT) is an important and valuable examination but there are still some shortcomings with it. We aimed to objectively assess ALCT based on a depth camera and filter out the best indicators. METHODS: Fifty-nine individuals with parkinsonism completed ALCT and the improvement rate (IR, which indicates the change in value before and after levodopa administration) of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) was calculated. The kinematic features of the patients' movements in both the OFF and ON states were collected with an Azure Kinect depth camera. RESULTS: The IR of MDS-UPDRS III was significantly correlated with the IRs of many kinematic features for arising from a chair, pronation-supination movements of the hand, finger tapping, toe tapping, leg agility, and gait (rs = - 0.277 ~ - 0.672, P < 0.05). Moderate to high discriminative values were found in the selected features in identifying a clinically significant response to levodopa with sensitivity, specificity, and area under the curve (AUC) in the range of 50-100%, 47.22%-97.22%, and 0.673-0.915, respectively. The resulting classifier combining kinematic features of toe tapping showed an excellent performance with an AUC of 0.966 (95% CI = 0.922-1.000, P < 0.001). The optimal cut-off value was 21.24% with sensitivity and specificity of 94.44% and 87.18%, respectively. CONCLUSION: This study demonstrated the feasibility of measuring the effect of levodopa and objectively assessing ALCT based on kinematic data derived from an Azure Kinect-based system.
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Antiparkinsonianos , Estudos de Viabilidade , Levodopa , Transtornos Parkinsonianos , Humanos , Levodopa/administração & dosagem , Levodopa/uso terapêutico , Levodopa/farmacologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Antiparkinsonianos/uso terapêutico , Antiparkinsonianos/administração & dosagem , Fenômenos Biomecânicos/fisiologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/diagnóstico , Índice de Gravidade de DoençaRESUMO
Dystonia is a genetically and phenotypically heterogeneous disorder that occurs in isolation (isolated dystonia) or in combination with other movement disorders. To determine the genetic spectrum in isolated dystonia, we enrolled 88 patients with isolated dystonia for whole-exome sequencing (WES). Seventeen mutations, including nine novel ones, were identified in 19 of the 88 patients, providing a 21.59% positive molecular diagnostic rate. Eleven distinct genes were involved, of which TOR1A and THAP1 accounted for 47.37% (9/19) of the positive cases. A novel missense variant, p.S225R in TOR1A, was found in a patient with adolescence-onset generalized dystonia. Cellular experiments revealed that p.S255R results in the abnormal aggregation of Torsin-1A encoding by TOR1A. In addition, we reviewed the clinical and genetic features of the isolated dystonia patients carrying TOR1A, THAP1, ANO3, and GNAL mutations in the Chinese population. Our results expand the genetic spectrum and clinical profiles of patients with isolated dystonia and demonstrate WES as an effective strategy for the molecular diagnosis of isolated dystonia.
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Distonia , Distúrbios Distônicos , Humanos , Anoctaminas/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação a DNA/genética , Distonia/genética , Distúrbios Distônicos/genética , População do Leste Asiático , Chaperonas Moleculares/genética , Mutação , Proteínas Nucleares/genéticaRESUMO
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.
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Discinesia Induzida por Medicamentos , Doença de Parkinson , Parte Reticular da Substância Negra , Camundongos , Animais , Levodopa/efeitos adversos , Halorrodopsinas , Neurônios GABAérgicos , Substância NegraRESUMO
When spontaneous cervical spinal epidural hematoma (SCEH) presents with hemiparesis, it can be misdiagnosed with ischemic stroke (IS), and the treatment of IS such as thrombolysis may deteriorate the symptoms of patients with SCEH, leading to worse sequelae or even death. We reported 3 SCEH patients who were initially suspected as IS in our center between Jun 2020 and April 2022 and analyzed their clinical characteristics together with 48 patients reported in the literature from Jan 1995 to April 2022. Two of the 3 SCEH patients had neck symptoms, while none of them presented cranial nerve symptoms. Cranial computed tomography (CT) scans were negative; however, abnormal signals in the cervical spinal canal were observed during cranial computed tomography angiography (CTA) and subsequent cervical CT confirmed the diagnosis of SCEH. All of them avoid mistreatment with recombinant tissue plasminogen activator (rt-PA). Subsequently, we analyzed the clinical characteristics of a total of 51 patients. Thirteen of them developed symptoms during activity. Neck pain was an important sign of SCEH because 35 patients had neck pain or neck discomfort. Sensory impairment was reported in a small proportion of patients (11/51), which varied a lot in the patients. Some special manifestations highly suggested spinal cord lesions and provided evidence for the early differential diagnosis of SCEH and stroke, but the incidence of which was quite low: ipsilateral Horner syndrome in 2 patients, Brown-Séquard syndrome in 2 cases, and Lhermitte's sign in 1 case. Only a minority (8/51) of the patients were correctly diagnosed at the emergency unit using cervical CT. Six patients were correctly diagnosed when performing CTA. A large portion of the cases (21/51) were first misdiagnosed as IS, but no responsible lesions were found on cranial magnetic resonance imaging (MRI), and subsequent cervical MRI confirmed the diagnosis. Sixteen patients were diagnosed with SCEH after the deterioration of symptoms. A total of 13 patients received rt-PA, and 10 of them had symptoms aggravation after thrombolysis. For patients with acute onset of hemiparesis but without cranial nerve symptoms, especially those accompanied by clinical features such as neck pain, ipsilateral Horner syndrome, Brown-Séquard syndrome, and Lhermitte's sign, SCEH should be highly suspected rather than stroke. Careful differential diagnosis should be performed with a comprehensive medical history and thorough physical examination. Cervical CT scan is a reasonable choice for quick differential diagnosis prior to administering potentially harmful therapy, especially rt-PA.
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Hematoma Epidural Espinal , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Hematoma Epidural Espinal/diagnóstico , Hematoma Epidural Espinal/diagnóstico por imagem , AVC Isquêmico/tratamento farmacológico , Ativador de Plasminogênio Tecidual/efeitos adversos , Cervicalgia/complicações , Cervicalgia/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/complicações , Paresia/etiologia , Paresia/complicações , Imageamento por Ressonância Magnética/efeitos adversosRESUMO
BACKGROUND: Frailty is common in Parkinson's disease (PD) and increases vulnerability to adverse outcomes. Early detection of this syndrome aids in early intervention. AIMS: To objectively identify frailty at an early stage during routine motor tasks in PD patients using a Kinect-based system. METHODS: PD patients were recruited and assessed with the Fried criteria to determine their frailty status. Each participant was recorded performing the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) extremity tasks with a Kinect-based system. Statistically significant kinematic parameters were selected to discriminate the pre-frail from the non-frail group. RESULTS: Of the fifty-two participants, twenty were non-frail and thirty-two were pre-frail. Decreased frequency in finger tapping (P = 0.005), hand grasping (P = 0.002), toe tapping (P = 0.002), and leg agility (P = 0.019) alongside reduced hand grasping speed (P = 0.030), lifting (P < 0.001) and falling speed (P < 0.001) in leg agility were observed in the pre-frail group. Amplitude in leg agility (P = 0.048) and amplitude decrement rate (P = 0.046) in hand grasping showed marginally significant differences between two groups. Moderate discriminative values were found in frequency and speed of the extremity tasks to identify pre-frailty with sensitivity, specificity, and area under the curve (AUC) in the range of 45.00-85.00%, 68.75-100%, and 0.701-0.836, respectively. The combination of frequency and speed in extremity tasks showed moderate to high discriminatory ability, with AUC of 0.775 (95% CI 0.637-0.913, P < 0.001) for upper limb tasks and 0.909 (95% CI 0.832-0.987, P < 0.001) for lower limb tasks. When combining these features in both upper and lower limb tasks, the AUC increased to 0.942 (95% CI 0.886-0.999, P < 0.001). CONCLUSIONS: Our findings demonstrated the promise of utilizing Kinect-based kinematic data from MDS-UPDRS III tasks as early indicators of frailty in PD patients.
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Fragilidade , Doença de Parkinson , Humanos , Extremidade Inferior , Mãos , Extremidade SuperiorRESUMO
Parkinson's disease (PD) is characterized by dopaminergic neuronal loss and the presence of intra-neuronal Lewy body (LB) inclusions with aggregated α-synuclein (α-Syn) as the major component. MAOB, a crucial monoamine oxidase for dopamine metabolism, triggers oxidative stress in dopaminergic neurons and α-Syn aggregation. However, the key molecular mechanism that mediates PD pathogenesis remains elusive. Here we show that C/EBPß acts as an age-dependent transcription factor for both α-Syn and MAOB, and initiates the PD pathologies by upregulating these two pivotal players, in addition to escalating δ-secretase activity to cleave α-Syn and promotes its neurotoxicity. Overexpression of C/EBPß in human wild-type α-Syn transgenic mice facilitates PD pathologies and elicits motor disorders associated with augmentation of δ-secretase, α-Syn, and MAOB. In contrast, depletion of C/EBPß from human α-Syn Tg mice abolishes rotenone-elicited PD pathologies and motor impairments via downregulating the expression of these key factors. Hence, our study supports that C/EBPß/δ-secretase signaling mediates PD pathogenesis via regulating the expression and cleavage of α-Syn and MAOB.
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Doença de Parkinson , alfa-Sinucleína , Secretases da Proteína Precursora do Amiloide , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Neurônios Dopaminérgicos , Camundongos , Doença de Parkinson/genética , alfa-Sinucleína/genéticaRESUMO
Respiratory chain complex I deficiency elicits mitochondrial dysfunction and reactive oxidative species (ROS), which plays a crucial role in Parkinson's disease (PD) pathogenesis. However, it remains unclear whether the impairment in other complexes in the mitochondrial oxidative phosphorylation chain is also sufficient to trigger PD onset. Here we show that inhibition of Complex II or III in the electron transport chain (ETC) induces the motor disorder and PD pathologies in neuronal Thy1-C/EBPß transgenic mice. Through a cell-based screening of mitochondrial respiratory chain inhibitors, we identified TTFA (complex II inhibitor) and Atovaquone (complex III inhibitor), which robustly block the oxidative phosphorylation functions, strongly escalate ROS, and activate C/EBPß/AEP pathway that triggers dopaminergic neuronal cell death. Oral administration of these inhibitors to Thy1-C/EBPß mice elicits constipation and motor defects, associated with Lewy body-like inclusions. Deletion of SDHD (Succinate dehydrogenase) gene from the complex II in the Substantia Nigra of Thy1-C/EBPß mice triggers ROS and PD pathologies, resulting in motor disorders. Hence, our findings demonstrate that mitochondrial ETC inactivation triggers PD pathogenesis via activating C/EBPß/AEP pathway.
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Doença de Parkinson , Animais , Neurônios Dopaminérgicos/metabolismo , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Substância Negra/patologiaRESUMO
Torticaput is the most common primary form of cervical dystonia (CD). Obliquus capitis inferior (OCI) plays a major role in ipsilateral rotation of the head. The present study aimed to use single-photon emission computed tomography (SPECT/CT) to determine the involvement of OCI in torticaput and in torticaput associated with no-no tremor. We retrospectively analyzed the SPECT/CT images of 60 patients with torticaput as the main abnormal posture and ranked the affected muscles. The affected muscles in patients with no-no tremor were also ranked. The correlation between the radioactivity of OCI and the thickness of OCI measured by ultrasonography was analyzed. The agreement between SPECT/CT and electromyography in detecting OCI was also analyzed. After sternocleidomastoid muscle (81.7%), OCI was the second most affected muscle (70.0%) in torticaput, followed by splenius capitis (63.3%). In 23 patients with no-no tremor, OCI (78.3%) and sternocleidomastoid muscle (78.3%) were the most frequently affected muscles, followed by splenius capitis (69.6%). Furthermore, bilateral muscle involvement was commonly seen in patients with no-no tremor, especially for OCI (12/23) and sternocleidomastoid muscle (11/23). A positive correlation was found between the radioactivity and thickness of OCI (r = 0.330, P < 0.001). The total agreement rate between SPECT/CT and electromyography in the diagnosis of OCI excitement was 94.0%, with kappa value = 0.866 (P < 0.001). OCI plays a critical role in torticaput and no-no tremor. SPECT/CT could be a practical tool to help clinicians detect abnormally excited OCI.
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Torcicolo , Eletromiografia , Cabeça , Humanos , Músculos do Pescoço , Estudos Retrospectivos , Tomografia Computadorizada de Emissão de Fóton Único , Torcicolo/diagnóstico por imagem , TremorRESUMO
Abnormal movement of the head and neck is a typical symptom of Cervical Dystonia (CD). Accurate scoring on the severity scale is of great significance for treatment planning. The traditional scoring method is to use a protractor or contact sensors to calculate the angle of the movement, but this method is time-consuming, and it will interfere with the movement of the patient. In the recent outbreak of the coronavirus disease, the need for remote diagnosis and treatment of CD has become extremely urgent for clinical practice. To solve these problems, we propose a multi-view vision based CD severity scale scoring method, which detects the keypoint positions of the patient from the frontal and lateral images, and finally scores the severity scale by calculating head and neck motion angles. We compared the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) subscale scores calculated by our vision based method with the scores calculated by a neurologist trained in dyskinesia. An analysis of the correlation coefficient was then conducted. Intra-class correlation (ICC)(3,1) was used to measure absolute accuracy. Our multi-view vision based CD severity scale scoring method demonstrated sufficient validity and reliability. This low-cost and contactless method provides a new potential tool for remote diagnosis and treatment of CD.
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Torcicolo , Estudos de Viabilidade , Humanos , Reprodutibilidade dos Testes , Projetos de Pesquisa , Índice de Gravidade de Doença , Torcicolo/diagnóstico , Resultado do TratamentoRESUMO
Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.
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Toxinas Botulínicas Tipo A , Toxinas Botulínicas , Distonia , Distúrbios Distônicos , Algoritmos , Distonia/tratamento farmacológico , Distúrbios Distônicos/tratamento farmacológico , Humanos , Espasticidade Muscular/tratamento farmacológicoRESUMO
BACKGROUND: The relationship between brain abnormalities and phenotypic characteristics in cervical dystonia (CD) patients has not been fully established, and little is known about the neuroplastic changes induced by botulinum toxin type A (BoNT-A) treatment. METHODS: Ninety-two CD patients presenting with rotational torticollis and 45 healthy controls from our database were retrospectively screened. After clinical assessment, the 92 patients underwent baseline magnetic resonance imaging (MRI) followed by a single-dose injection of BoNT-A. Four weeks later, 76 out of the 92 patients were re-evaluated with the Tsui scale for dystonia severity, and 33 out of 76 patients completed post-treatment MRI scanning. Data-driven global brain connectivity and regional homogeneity in tandem with seed-based connectivity analyses were used to examine the functional abnormalities in CD and longitudinal circuit alterations that scaled with clinical response to BoNT-A. Multiple regression models were employed for the prediction analysis of treatment efficacy. RESULTS: Cervical dystonia patients exhibited elevated baseline connectivity of the right postcentral gyrus with the left dorsomedial prefrontal cortex and right caudate nucleus, which was associated with their symptom severity. BoNT-A reduced excessive functional connectivity between the sensorimotor cortex and right superior frontal gyrus, which was significantly correlated with changes in Tsui score. Moreover, pre-treatment regional homogeneity of the left middle frontal gyrus was linearly related to varied response to treatment. CONCLUSIONS: Our findings unravel dissociable connectivity of the sensorimotor cortex underlying the pathology of CD and central effects of BoNT-A therapy. Furthermore, baseline regional homogeneity with the left middle frontal gyrus may represent a potential evidence-based marker of patient stratification for BoNT-A therapy in CD.
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Toxinas Botulínicas Tipo A , Córtex Sensório-Motor , Torcicolo , Encéfalo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Torcicolo/diagnóstico por imagem , Torcicolo/tratamento farmacológicoRESUMO
Purpose: This study is aimed at exploring how soleus H-reflex change in poststroke patients with spasticity influenced by body position. Materials and Methods: Twenty-four stroke patients with spastic hemiplegia and twelve age-matched healthy controls were investigated. Maximal Hoffmann-reflex (Hmax) and motor potential (Mmax) were elicited at the popliteal fossa in both prone and standing positions, respectively, and the Hmax/Mmax ratio at each body position was determined. Compare changes in reflex behavior in both spastic and contralateral muscles of stroke survivors in prone and standing positions, and match healthy subjects in the same position. Results: In healthy subjects, Hmax and Hmax/Mmax ratios were significantly decreased in the standing position compared to the prone position (Hmax: p = 0.000, Hmax/Mmax: p = 0.016). However, Hmax/Mmax ratios were increased in standing position on both sides in poststroke patients with spasticity (unaffected side: p = 0.006, affected side: p = 0.095). The Hmax and Hmax/Mmax ratios were significantly more increased on the affected side than unaffected side irrespective of the position. Conclusions: The motor neuron excitability of both sides was not suppressed but instead upregulated in the standing position in subjects with spasticity, which may suggest that there was abnormal regulation of the Ia pathway on both sides.
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Reflexo H/fisiologia , Hemiplegia/fisiopatologia , Espasticidade Muscular/fisiopatologia , Postura/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Adulto , Idoso , Eletromiografia , Feminino , Hemiplegia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios Motores/fisiologia , Espasticidade Muscular/etiologia , Músculo Esquelético/fisiopatologia , Acidente Vascular Cerebral/complicaçõesRESUMO
Objectives: The present study is aimed at investigating the frequency and associated factors of asymmetrical prominent veins (APV) in patients with acute ischemic stroke (AIS). Methods: Consecutive patients with AIS admitted to the Comprehensive Stroke Center of Shanghai Fourth People's Hospital between January 2013 and December 2017 were enrolled. MRI including diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), and susceptibility-weighted imaging (SWI) was performed within 12 hours of symptom onset. The volume of asymmetrical prominent veins (APV) was evaluated using the Signal Processing In nuclear magnetic resonance software (SPIN, Detroit, Michigan, USA). Multivariate analysis was used to assess relationships between APV findings and medical history, clinical variables as well as cardio-metabolic indices. Results: Seventy-six patients met the inclusion criteria. The frequency of APV ≥ 10 mL was 46.05% (35/76). Multivariate analyses showed that proximal artery stenosis or occlusion (≥50%) (P < 0.001, adjusted odds ratio (OR) = 660.0, 95%CI = 57.28-7604.88) and history of atrial fibrillation (P < 0.001, adjusted OR = 10.48, 95%CI = 1.78-61.68) were independent factors associated with high APV (≥10 mL). Conclusion: Our findings suggest that the frequency of APV ≥ 10 mL is high in patients with AIS within 12 hours of symptom onset. History of atrial fibrillation and severe proximal artery stenosis or occlusion are strong predictors of high APV as calculated by SPIN on the SWI map.
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Isquemia Encefálica/diagnóstico por imagem , Veias Cerebrais/anormalidades , Veias Cerebrais/diagnóstico por imagem , AVC Isquêmico/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/terapia , China/epidemiologia , Estudos Transversais , Imagem de Difusão por Ressonância Magnética/tendências , Feminino , Humanos , AVC Isquêmico/epidemiologia , AVC Isquêmico/terapia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Automated and accurate assessment for postural abnormalities is necessary to monitor the clinical progress of Parkinson's disease (PD). The combination of depth camera and machine learning makes this purpose possible. METHODS: Kinect was used to collect the postural images from 70 PD patients. The collected images were processed to extract three-dimensional body joints, which were then converted to two-dimensional body joints to obtain eight quantified coronal and sagittal features (F1-F8) of the trunk. The decision tree classifier was carried out over a data set established by the collected features and the corresponding doctors' MDS-UPDRS-III 3.13 (the 13th item of the third part of Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale) scores. An objective function was implanted to further improve the human-machine consistency. RESULTS: The automated grading of postural abnormalities for PD patients was realized with only six selected features. The intraclass correlation coefficient (ICC) between the machine's and doctors' score was 0.940 (95%CI, 0.905-0.962), meaning the machine was highly consistent with the doctors' judgement. Besides, the decision tree classifier performed outstandingly, reaching 90.0% of accuracy, 95.7% of specificity and 89.1% of sensitivity in rating postural severity. CONCLUSIONS: We developed an intelligent evaluation system to provide accurate and automated assessment of trunk postural abnormalities in PD patients. This study demonstrates the practicability of our proposed method in the clinical scenario to help making the medical decision about PD.
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Doença de Parkinson , Humanos , Aprendizado de Máquina , Doença de Parkinson/complicações , Doença de Parkinson/diagnósticoRESUMO
Activation of cannabinoid receptor type II (CB2R) by AM1241 has been demonstrated to protect dopaminergic neurons in Parkinson's disease (PD) animals. However, the specific mechanisms of the action of the CB2R agonist AM1241 for PD treatment have not been characterized. Wild-type (WT), CB1R knockout (CB1-KO), and CB2R knockout (CB2-KO) mice were exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 1 week to obtain a PD mouse model. The therapeutic effects of AM1241 were evaluated in each group. Behavioral tests, analysis of neurotransmitters, and immunofluorescence results demonstrated that AM1241 ameliorated PD in WT animals and CB1-KO animals. However, AM1241 did not ameliorate PD symptoms in CB2-KO mice. RNA-seq analysis identified the lncRNA Xist as an important regulator of the protective actions of AM1241. Specifically, AM1241 allowed WT and CB1-KO animals treated with MPTP to maintain normal expression of Xist, which affected the expression of miR-133b-3p and Pitx3. In vitro, overexpression of Xist or AM1241 protected neuronal cells from death induced by 6-hydroxydopamine and increased Pitx3 expression. The CB2 receptor agonist AM1241 alleviated PD via regulation of the Xist/miR-133b-3p/Pitx3 axis, and revealed a new approach for PD treatment.
Assuntos
Proteínas de Homeodomínio/genética , MicroRNAs/genética , Degeneração Neural/genética , Doença de Parkinson/genética , Receptor CB2 de Canabinoide/genética , Fatores de Transcrição/genética , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Canabinoides/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Camundongos , Camundongos Knockout , Degeneração Neural/patologia , Doença de Parkinson/patologia , RNA Longo não Codificante/genética , Substância Negra/efeitos dos fármacos , Substância Negra/patologiaRESUMO
Although increasing evidence has suggested crosstalk between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM), the common mechanisms between the two diseases remain unclear. The aim of our study was to characterize the interconnection between T2DM and PD by exploring their shared biological pathways and convergent molecules. The intersections among the differentially expressed genes (DEGs) in the T2DM dataset GSE95849 and PD dataset GSE6613 from the Gene Expression Omnibus (GEO) database were identified as the communal DEGs between the two diseases. Then, an enrichment analysis, protein-protein interaction (PPI) network analysis, correlation analysis, and transcription factor-target regulatory network analysis were performed for the communal DEGs. As a result, 113 communal DEGs were found between PD and T2DM. They were enriched in lipid metabolism, including protein modifications that regulate metabolism, lipid synthesis and decomposition, and the biological effects of lipid products. All these pathways and their biological processes play important roles in both diseases. Fifteen hub genes identified from the PPI network could be core molecules. Their function annotations also focused on lipid metabolism. According to the correlation analysis and the regulatory network analysis based on the 15 hub genes, Sp1 transcription factor (SP1) could be a key molecule since it affected other hub genes that participate in the common mechanisms between PD and T2DM. In conclusion, our analyses reveal that changes in lipid metabolism could be a key intersection between PD and T2DM, and that SP1 could be a key molecule regulating these processes. Our findings provide novel points for the association between PD and T2DM.
Assuntos
Diabetes Mellitus Tipo 2/genética , Metabolismo dos Lipídeos/genética , Doença de Parkinson/genética , Fator de Transcrição Sp1/genética , Biologia Computacional , Diabetes Mellitus Tipo 2/patologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Humanos , Lipídeos/biossíntese , Lipídeos/genética , Doença de Parkinson/patologia , Mapas de Interação de Proteínas/genéticaRESUMO
The abnormal aggregation of fibrillar α-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating α-synuclein pathological effects are incompletely understood. Here we show that α-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. α-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn. A pleckstrin homology (PH) domain in PIKE-L directly binds α-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by 1-methyl-4-phenylpyridinium (MPP+), whereas PIKE-L knockdown elevates α-synuclein oligomerization and cell death. The overexpression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or α-synuclein induces greater dopaminergic cell loss and more severe motor defects in PIKE-KO and Fyn-KO mice than in wild-type mice, and these effects are attenuated by the expression of dominant-negative AMPK. Hence, our findings demonstrate that α-synuclein neutralizes PIKE-L's neuroprotective actions in synucleinopathies, triggering dopaminergic neuronal death by hyperactivating AMPK.
Assuntos
Adenilato Quinase/metabolismo , Neurônios Dopaminérgicos/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Corpos de Lewy/metabolismo , alfa-Sinucleína/metabolismo , 1-Metil-4-fenilpiridínio/toxicidade , Idoso , Idoso de 80 Anos ou mais , Animais , Morte Celular , Neurônios Dopaminérgicos/ultraestrutura , Ativação Enzimática , GTP Fosfo-Hidrolases/deficiência , Proteínas de Ligação ao GTP/química , Proteínas Ativadoras de GTPase/química , Humanos , Intoxicação por MPTP/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Fosforilação , Domínios de Homologia à Plecstrina , Agregação Patológica de Proteínas , Ligação Proteica , Mapeamento de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-fyn/deficiência , Proteínas Proto-Oncogênicas c-fyn/metabolismoRESUMO
LanbotulinumtoxinA (LAN) is manufactured and registered in China since 1994. Despite its widespread use in China and its increasing use in other Asian countries and in South America, it is not yet well known elsewhere. We wanted to compare its potency labelling using the mouse diaphragm assay (MDA), an isolated muscle model for botulinum toxin (BT) potency measurements, which is superior to clinical tests and which was recently refined as an alternative batch release assay for BT manufacturing. We also wanted to estimate LAN manufacturing quality by testing its inter-batch potency consistency. Potencies of 20, 60 and 100 MU of LAN, onabotulinumtoxinA (ONA) and incobotulinumtoxinA (INCO) were measured by the inversely related paresis time (PT) in the MDA. The PT (M ± SD) of all doses of LAN, ONA and INCO was 90.4 ± 27.0 min, 114.9 ± 46.5 min and 94.3 ± 29.9 min, respectively. Statistical analysis demonstrated indistinguishable potency labelling of LAN and INCO, but revealed a slightly lower potency of ONA compared to LAN and INCO. PT of LAN batch 1 and LAN batch 2 was 86.9 ± 21.2 min and 94.0 ± 32.8 min, respectively (no statistically significant difference), suggesting an adequate LAN manufacturing consistency. The MDA is an appropriate instrument for potency testing of BT drugs, including new ones currently under development. Our results allow comparing therapeutic effects, adverse effects and economics of LAN, ONA and INCO. They also suggest adequate manufacturing consistency of LAN.