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The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.
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Ataxia Cerebelosa , Enfermedades Cerebelosas , Temblor Esencial , Humanos , Ataxia de la Marcha/etiología , Temblor , Consenso , Ataxia Cerebelosa/complicaciones , Ataxia/complicaciones , Enfermedades Cerebelosas/complicaciones , Marcha/fisiologíaRESUMEN
BACKGROUND: The hippocampus (HP) plays a critical role in memory and orientational functions and is functionally heterogeneous along the longitudinal anterior-posterior axis. Although the previous study has reported volumetric atrophy in hippocampal subfields of patients with poststroke dementia (PSD), how the functional connectivity (FC) is altered in these subfields remains unclear. PURPOSE: To examine the FC changes of the HP subfields in patients with PSD. STUDY TYPE: Prospective. POPULATION: Seventeen normal controls, 20 PSD, and 24 nondemented poststroke (PSND) patients. FIELD STRENGTH/SEQUENCE: A 3.0 T/ T1-weighted imaging, resting-state functional and diffusion tensor imaging. ASSESSMENT: We first segmented the HP using independent component analysis, and then used granger causality analysis to calculate the directed FCs (dFCs) between the subfields and the whole brain, and compared the dFCs among PSD, PSND, and controls. STATISTICAL TESTS: Student's t-test, chi-square test, one-way ANCOVA, multiple regression, support vector machine, multiple comparison correction, and reproducibility analysis. A P value < 0.05 was considered statistically significant. RESULTS: Our results showed HP was functionally divided into HPhead , HPbody , and HPtail bilaterally along the longitudinal axis. PSD patients showed significant dementia-specific decreases in the inward information flow and increases in the outward information flow associated with the bilateral entire HP/HPhead and left HPbody (P < 0.05). Moreover, we observed significant correlations (P < 0.05) between the cognition score and the dFCs related to the bilateral entire HP and left HPhead in the PSD group. Furthermore, dFCs of the HP and its subfields improved the classification between the PSD and PSND patients (accuracy/sensitivity/specificity: 94%/95%/93%) compared to the clinical and demographic parameters alone. DATA CONCLUSION: These findings suggest that altered transmission and reception of information in the HP. These alternations were specific to individual subfields in PSD patients and may offer insight into the neurophysiological mechanisms underlying PSD. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.
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Demencia , Imagen de Difusión Tensora , Demencia/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
Although many neuroimaging studies have reported structural and functional abnormalities in the brains of patients with cognitive impairments following stroke, little is known about the pattern of such brain reorganization in poststroke dementia (PSD). The present study was aimed at investigating alterations in spontaneous brain activity and gray matter volume (GMV) in PSD patients. We collected T1-weighted and resting-state functional magnetic resonance imaging data from 20 PSD patients, 24 poststroke nondementia (PSND) patients, and 21 well-matched normal controls (NCs). We compared the differences among the groups in GMV and the fractional amplitude of low-frequency fluctuations (fALFF). Then, we evaluated the relationship between these brain measures and cognitive assessments and explored the possible distinguisher for PSD by receiver operating characteristic (ROC) curve analysis. PSD patients showed smaller GMV in the right superior temporal gyrus and lower fALFF values in the right inferior frontal gyrus than both PSND patients and NCs, but such differences were not observed between PSND patients and NCs. Moreover, GMV in the left medial prefrontal cortex showed a significant positive correlation with the Mini-Cog assessment in PSD patients, and GMV in the left CPL displayed the highest area under the ROC curve among all the features for classifying PSD versus PSND patients. Our findings suggest that PSD patients show dementia-specific structural and functional alteration patterns, which may help elucidate the pathophysiological mechanisms underlying PSD.
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Escalas de Valoración Psiquiátrica Breve , Demencia/diagnóstico por imagen , Demencia/psicología , Imagen por Resonancia Magnética/métodos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/psicología , Anciano , Demencia/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Accidente Cerebrovascular/complicacionesRESUMEN
Cerebral venous thrombosis is an important etiology of stroke in young patients. Its clinical manifestations are variable and based on different involved venous or sinus processes. Cerebral venous thrombosis could mimic ischemic infarction and is easy to misdiagnose. Although many patients have favorable outcomes, delayed or incorrect diagnosis due to atypical symptoms may lead to a poor prognosis. Here we present a case of a 33-year-old woman with transient headache and recurrent right extremity weakness whose symptoms progressed and were sustained in the hospital. She was diagnosed with ischemic infarction and recombinant tissue plasminogen activator (rtPA) thrombolysis was performed. However, her symptoms progressed, and intracranial hematoma was found on a computed tomography scan. Ruling out other hemorrhage etiology, we confirmed the presence of cerebral venous thrombosis using magnetic resonance venography. She underwent mechanical thrombectomy and her condition improved thereafter. This case raises the awareness that in young woman patients on oral contraceptives with neurological deficits and headache, cerebral venous thrombosis is a considerable diagnosis. A contrast CT or MRI scan should be ordered in the early course of evaluation, which can help the physician to make the right clinical decision.
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Angiografía de Substracción Digital , Infarto Encefálico/diagnóstico por imagen , Angiografía Cerebral/métodos , Trombosis Intracraneal/diagnóstico por imagen , Trombosis Intracraneal/terapia , Angiografía por Resonancia Magnética , Flebografía , Trombectomía/métodos , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/terapia , Adulto , Anticoagulantes/administración & dosificación , Infarto Encefálico/tratamiento farmacológico , Infarto Encefálico/etiología , Errores Diagnósticos , Femenino , Cefalea/etiología , Humanos , Hemorragias Intracraneales/inducido químicamente , Trombosis Intracraneal/etiología , Debilidad Muscular/etiología , Valor Predictivo de las Pruebas , Terapia Trombolítica/efectos adversos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Trombosis de la Vena/etiologíaRESUMEN
BACKGROUND: Unsafe injection practices significantly increase the risk of human immunodeficiency virus (HIV) infection among injection drug users (IDUs). Little is known about how demographic characteristics of IDUs are linked to HIV-related risk behaviors in the central regions of China. METHODS: A cross-sectional survey was conducted at Mandatory Detoxification Centers (MDCs) and the community in Maanshan, China. RESULTS: Of the 916 IDUs, 96.4 % reported a history of heroin use during the past year, 93.4 % had HIV/AIDS knowledge, 16.8 % reported receptive syringe sharing and 12.2 % reported inconsistent condom use in commercial sex in the past year. Unsafe injection practice was associated with increased odds of minority ethnicity, lower level of education, and no peer education in the past year. Unsafe sex practice was associated with increased odds of being single, 18-30 years of age, non-local residence, and history of methamphetamine use in the past year. CONCLUSIONS: Integrated interventions to promote safe injection and protected commercial sex practices targeting IDUs must also consider individual and socio-environmental factors.
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Síndrome de Inmunodeficiencia Adquirida/psicología , Conocimientos, Actitudes y Práctica en Salud , Compartición de Agujas/estadística & datos numéricos , Asunción de Riesgos , Abuso de Sustancias por Vía Intravenosa/epidemiología , Síndrome de Inmunodeficiencia Adquirida/epidemiología , China/epidemiología , Estudios Transversales , Consumidores de Drogas , Femenino , Infecciones por VIH/epidemiología , Humanos , Masculino , Trabajo Sexual , Abuso de Sustancias por Vía Intravenosa/psicología , Sexo Inseguro/estadística & datos numéricosRESUMEN
INTRODUCTION: Molecular studies have revealed that some patients with myopathies with rimmed vacuoles have pathogenic mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) and Z-band alternatively spliced PDZ motif-containing protein (ZASP) genes. METHODS: We investigated a patient with distal myopathy with rimmed vacuoles by muscle biopsy and sequenced 6 candidate genes. RESULTS: The patient carried GNE compound heterozygous missense mutations (p.V421A and p.N635K) and a ZASP variant (p.D673N). This patient also presented with distal weakness sparing the quadriceps muscles and had atypical results for Z-band-associated protein immunostaining. This finding indicates that the GNE mutations are pathogenic, and the diagnosis is compatible with GNE myopathy. CONCLUSIONS: By combining pathological studies and candidate gene screening, we identified a patient with GNE myopathy due to novel GNE compound heterozygous mutations.
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Proteínas Adaptadoras Transductoras de Señales/genética , Tamización de Portadores Genéticos , Proteínas con Dominio LIM/genética , Complejos Multienzimáticos/genética , Músculo Esquelético/patología , Enfermedades Musculares/genética , Femenino , Humanos , Persona de Mediana Edad , Músculo Esquelético/química , Enfermedades Musculares/patología , Mutación Missense/genética , Vacuolas/genética , Vacuolas/patologíaRESUMEN
Accumulating efforts have been made to investigate cognitive impairment in stroke patients, but little has been focused on mild stroke. Research on the impact of mild stroke and different lesion locations on cognitive impairment is still limited. To investigate the underlying mechanisms of cognitive dysfunction in mild stroke at different lesion locations, electroencephalograms (EEGs) were recorded in three groups (40 patients with cortical stroke (CS), 40 patients with subcortical stroke (SS), and 40 healthy controls (HC)) during a visual oddball task. Power envelope connectivity (PEC) was constructed based on EEG source signals, followed by graph theory analysis to quantitatively assess functional brain network properties. A classification framework was further applied to explore the feasibility of PEC in the identification of mild stroke. The results showed worse behavioral performance in the patient groups, and PECs with significant differences among three groups showed complex distribution patterns in frequency bands and the cortex. In the delta band, the global efficiency was significantly higher in HC than in CS (p = 0.011), while local efficiency was significantly increased in SS than in CS (p = 0.038). In the beta band, the small-worldness was significantly increased in HC compared to CS (p = 0.004). Moreover, the satisfactory classification results (76.25% in HC vs. CS, and 80.00% in HC vs. SS) validate the potential of PECs as a biomarker in the detection of mild stroke. Our findings offer some new quantitative insights into the complex mechanisms of cognitive impairment in mild stroke at different lesion locations, which may facilitate post-stroke cognitive rehabilitation.
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Although consistent evidence has revealed that cognitive impairment is a common sequela in patients with mild stroke, few studies have focused on it, nor the impact of lesion location on cognitive function. Evidence on the neural mechanisms underlying the effects of mild stroke and lesion location on cognitive function is limited. This prompted us to conduct a comprehensive and quantitative study of functional brain network properties in mild stroke patients with different lesion locations. Specifically, an empirical approach was introduced in the present work to explore the impact of mild stroke-induced cognitive alterations on functional brain network reorganization during cognitive tasks (i.e., visual and auditory oddball). Electroencephalogram functional connectivity was estimated from three groups (i.e., 40 patients with cortical infarctions, 48 patients with subcortical infarctions, and 50 healthy controls). Using graph theoretical analysis, we quantitatively investigated the topological reorganization of functional brain networks at both global and nodal levels. Results showed that both patient groups had significantly worse behavioral performance on both tasks, with significantly longer reaction times and reduced response accuracy. Furthermore, decreased global and local efficiency were found in both patient groups, indicating a mild stroke-related disruption in information processing efficiency that is independent of lesion location. Regarding the nodal level, both divergent and convergent node strength distribution patterns were revealed between both patient groups, implying that mild stroke with different lesion locations would lead to complex regional alterations during visual and auditory information processing, while certain robust cognitive processes were independent of lesion location. These findings provide some of the first quantitative insights into the complex neural mechanisms of mild stroke-induced cognitive impairment and extend our understanding of underlying alterations in cognition-related brain networks induced by different lesion locations, which may help to promote post-stroke management and rehabilitation.
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BACKGROUNDS: Botulinum toxin type A (BoNT/A) is extensively applied in spasticity and dystonia as it cleaves synaptosome-associated protein 25 (SNAP25) in the presynaptic terminals, thereby inhibiting neurotransmission. An increasing number of randomized clinical trials have suggested that glabellar BoNT/A injection improves depressive symptoms in patients with major depressive disorder (MDD). However, the underlying neuronal circuitry of BoNT/A-regulated depression remains largely uncharacterized. RESULTS: Here, we modeled MDD using mice subjected to chronic restraint stress (CRS). By pre-injecting BoNT/A into the unilateral whisker intrinsic musculature (WIM), and performing behavioral testing, we showed that pre-injection of BoNT/A attenuated despair- and anhedonia-like phenotypes in CRS mice. By applying immunostaining of BoNT/A-cleaved SNAP25 (cl.SNAP25197), subcellular spatial localization of SNAP25 with markers of cholinergic neurons (ChAT) and post-synaptic membrane (PSD95), and injection of monosynaptic retrograde tracer CTB-488-mixed BoNT/A to label the primary nucleus of the WIM, we demonstrated that BoNT/A axonal retrograde transported to the soma of whisker-innervating facial motoneurons (wFMNs) and subsequent transcytosis to synaptic terminals of second-order neurons induced central effects. Furthermore, using transsynaptic retrograde and monosynaptic antegrade viral neural circuit tracing with c-Fos brain mapping and co-staining of neural markers, we observed that the CRS-induced expression of c-Fos and CaMKII double-positive neurons in the ventrolateral periaqueductal grey (vlPAG), which sent afferents to wFMNs, was down-regulated 3 weeks after BoNT/A facial pre-administration. Strikingly, the repeated and targeted silencing of the wFMNs-projecting CaMKII-positive neurons in vlPAG with a chemogenetic approach via stereotactic injection of recombinant adeno-associated virus into specific brain regions of CRS mice mimicked the antidepressant-like action of BoNT/A pre-treatment. Conversely, repeated chemogenetic activation of this potential subpopulation counteracted the BoNT/A-improved significant antidepressant behavior. CONCLUSION: We reported for the first time that BoNT/A inhibited the wFMNs-projecting vlPAG excitatory neurons through axonal retrograde transport and cell-to-cell transcytosis from the injected location of the WIM to regulate depressive-like phenotypes of CRS mice. For the limited and the reversibility of side effects, BoNT/A has substantial advantages and potential application in MDD.
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Gradual loss of neuronal structure and function due to impaired blood-brain barrier (BBB) and neuroinflammation are important factors in multiple sclerosis (MS) progression. Our previous studies demonstrated that the C16 peptide and angiopoietin 1 (Ang-1) compound (C + A) could modulate inflammation and vascular protection in many models of MS. In this study, nanotechnology and a novel nanovector of the leukocyte chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) were used to examine the effects of C + A on MS. The acute experimental autoimmune encephalomyelitis (EAE) model of MS was established in Lewis rats. The C + A compounds were conjugated to control nano-carriers and fMLP-nano-carriers and administered to animals by intravenous injection. The neuropathological changes in the brain cortex and spinal cord were examined using multiple approaches. The stimulation of vascular injection sites was examined using rabbits. The results showed that all C + A compounds (C + A alone, nano-carrier C + A, and fMLP-nano-carrier C + A) reduced neuronal inflammation, axonal demyelination, gliosis, neuronal apoptosis, vascular leakage, and BBB impairment induced by EAE. In addition, the C + A compounds had minimal side effects on liver and kidney functions. Furthermore, the fMLP-nano-carrier C + A compound had better effects compared to C + A alone and the nano-carrier C + A. This study indicated that the fMLP-nano-carrier C + A could attenuate inflammation-related pathological changes in EAE and may be a potential therapeutic strategy for the treatment of MS and EAE.
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Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Ratas , Animales , Conejos , N-Formilmetionina Leucil-Fenilalanina/química , N-Formilmetionina Leucil-Fenilalanina/farmacología , Esclerosis Múltiple/tratamiento farmacológico , Liposomas , Angiopoyetina 1/uso terapéutico , Ratas Endogámicas Lew , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Inflamación/tratamiento farmacológicoRESUMEN
Alzheimer's disease (AD) is a neurological disorder characterized by neuronal cell death, tau pathology, and excessive inflammatory responses. Several vascular risk factors contribute to damage of the blood-brain barrier (BBB), secondary leak-out of blood vessels, and infiltration of inflammatory cells, which aggravate the functional disability and pathological changes in AD. Growth factor angiopoietin-1 (Ang-1) can stabilize the endothelium and reduce endothelial permeability by binding to receptor tyrosine kinase 2 (Tie2). C16 peptide (KAFDITYVRLKF) selectively binds to integrin ανß3 and competitively inhibits leukocyte transmigration into the central nervous system by interfering with leukocyte ligands. In the present study, 45 male Sprague-Dawley (SD) rats were randomly divided into three groups: vehicle group, C16 peptide + Ang1 (C + A) group, and sham control group. The vehicle and C + A groups were subjected to two-vessel occlusion (2-VO) with artery ligation followed by Aß1-42 injection into the hippocampus. The sham control group underwent sham surgery and injection with an equal amount of phosphate-buffered saline (PBS) instead of Aß1-42. The C + A group was administered 1 mL of drug containing 2 mg of C16 and 400 µg of Ang-1 daily for 2 weeks. The sham control and vehicle groups were administered 1 mL of PBS for 2 weeks. Our results showed that treatment with Ang-1 plus C16 improved functional disability and reduced neuronal death by inhibiting inflammatory cell infiltration, protecting vascular endothelial cells, and maintaining BBB permeability. The results suggest that these compounds may be potential therapeutic agents for AD and warrant further investigation.
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Background: Levodopa is regarded as a standard medication in Parkinson disease (PD) treatment. However, long-term administration of levodopa leads to levodopa-induced dyskinesia (LID), which can markedly affect patient quality of life. Previous studies have shown that neuroinflammation in the brain plays a role in LID and increases potential neuroinflammatory mediators associated with the side effects of levodopa. Objective: The treatment effect of C16 (a peptide that competitively binds integrin αvß3 and inhibits inflammatory cell infiltration) and angiopoietin-1 (Ang-1; a vascular endothelial growth factor vital for blood vessel protection), along with levodopa, was evaluated in a rodent model of PD. Methods: We administered a combination of C16 and Ang-1 in a rodent model of PD induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Seventy-five mice were randomly divided into five treatment groups: control, vehicle, levodopa, C16+Ang-1, and levodopa+C16+Ang-1. Behavioral, histological, and electrophysiological experiments were used to determine neuron function and recovery. Results: The results showed that C16+Ang-1 treatment alleviated neuroinflammation in the CNS and promoted the recovery effects of levodopa on neural function. Conclusion: Our study suggests that C16+Ang-1 can compensate for the shortcomings of levodopa, improve the CNS microenvironment, and ameliorate the effects of levodopa. This treatment strategy could be developed as a combinatorial therapeutic in the future.
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BACKGROUND AND OBJECTIVE: Striatal plasticity alterations caused by endoplasmic reticulum (ER) stress is supposed to be critically involved in the mechanism of DYT1 dystonia. In the current study, we expanded this research field by investigating the critical role of ER stress underlying synaptic plasticity impairment imposed by mutant heterozygous Tor1a+/- in a DYT1 dystonia mouse model. METHODS: Heterozygous Tor1a+/- mouse model for DYT1 dystonia was established. Wild-type (Tor1a+/+, N=10) and mutant (Tor1a+/-, N=10) mice from post-natal day P25 to P35 were randomly distributed to experimental and control groups. Patch-clamp and current-clamp recordings of SPNs were conducted with intracellular electrodes for electrophysiological analyses. Striatal changes of the direct and indirect pathways were investigated via immunofluorescence. Golgi-Cox staining was conducted to observe spine morphology of SPNs. To quantify postsynaptic signaling proteins in striatum, RNA-Seq, qRT-PCR and WB were performed in striatal tissues. RESULTS: Long-term depression (LTD) was failed to be induced, while long-term potentiation (LTP) was further strengthened in striatal spiny projection neurons (SPNs) from the Tor1a+/- DYT1 dystonia mice. Spine morphology analyses revealed a significant increase of both number of mushroom type spines and spine width in Tor1a+/- SPNs. In addition, increased AMPA receptor function and the reduction of NMDA/AMPA ratio in the postsynaptic of Tor1a+/- SPNs was observed, along with increased ER stress protein levels in striatum of Tor1a+/- DYT1 dystonia mice. Notably, ER stress inhibitors, tauroursodeoxycholic acid (TUDCA), could rescue LTD as well as AMPA currents. CONCLUSION: The current study illustrated the role of ER stress in mediating structural and functional plasticity alterations in Tor1a+/- SPNs. Inhibition of the ER stress by TUDCA is beneficial in reversing the deficits at the cellular and molecular levels. Remedy of dystonia associated neurological and motor functional impairment by ER stress inhibitors could be a recommendable therapeutic agent in clinical practice.
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Cuerpo Estriado/metabolismo , Distonía/metabolismo , Estrés del Retículo Endoplásmico , Chaperonas Moleculares/metabolismo , Plasticidad Neuronal , Animales , Modelos Animales de Enfermedad , Distonía/genética , Distonía/fisiopatología , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Femenino , Humanos , Potenciación a Largo Plazo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Chaperonas Moleculares/genéticaRESUMEN
Animal studies have indicated that increased blood-brain barrier (BBB) permeability and inflammatory cell infiltration are involved during the progression of Parkinson's disease (PD). This study used C16, a peptide that competitively binds to integrin αvß3 and inhibits inflammatory cell infiltration, as well as angiopoietin-1 (Ang-1), an endothelial growth factor crucial for blood vessel protection, to reduce inflammation and improve the central nervous system (CNS) microenvironment in murine models of PD. The combination of C16 and Ang-1 yielded better results compared to the individual drugs alone in terms of reducing dopaminergic neuronal apoptosis, ameliorating cognitive impairment, and electrophysiological dysfunction, attenuating inflammation in the CNS microenvironment, and improving the functional disability in PD mice or rats. These results suggest neuroprotective and anti-inflammatory properties of the C16 peptide plus Ang-1 in PD.
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Dystonia is a disorder associated with abnormalities in many brain regions including the basal ganglia and cerebellum. The toxin 3-Nitropropionic acid (3-NP) can induce neuropathologies in the mice striatum and nigra substance, including excitotoxicity, neuroinflammation, and extensive neuronal atrophy, characterized by progressive motor dysfunction, dystonia, and memory loss, mimicking those observed in humans. We established a mouse model of dystonia by administering 3-NP. Given the reported neuroprotective effects of the endothelial growth factor angiopoietin-1 (Ang-1) and the anti-inflammatory integrin αvß3 binding peptide C16, we performed this study to evaluate their combined effects on 3-NP striatal toxicity and their therapeutic potential with multiple methods using an in vivo mouse model. Sixty mice were equally and randomly divided into three groups: control, 3-NP treatment, and 3-NP+C16+Ang-1 treatment. Behavioral and electrophysiological tests were conducted and the effect of the combined C16+Ang-1 treatment on neural function recovery was determined. We found that C16+Ang-1 treatment alleviated 3-NP-induced behavioral, biochemical, and cellular alterations in the central nervous system and promoted function recovery by restoring vascular permeability and reducing inflammation in the micro-environment. In conclusion, our results confirmed the neuroprotective effect of combined C16+Ang-1 treatment and suggest their potential as a complementary therapeutic against 3-NP-induced dystonia.
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Angiopoyetina 1/uso terapéutico , Encéfalo/efectos de los fármacos , Distonía/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Neuroprotección , Péptidos/uso terapéutico , Angiopoyetina 1/farmacología , Animales , Antiinflamatorios , Encéfalo/patología , Encéfalo/fisiopatología , Permeabilidad Capilar , Sistema Nervioso Central , Cuerpo Estriado , Modelos Animales de Enfermedad , Quimioterapia Combinada , Distonía/inducido químicamente , Distonía/patología , Distonía/fisiopatología , Factores de Crecimiento Endotelial , Masculino , Ratones Endogámicos C57BL , Neuronas , Nitrocompuestos , Péptidos/farmacología , Propionatos , Distribución AleatoriaRESUMEN
Given the limited power of neuropsychological tests, there is a need for a simple, reliable means, such as gait, to identify mild dementia and its subtypes. However, gait characteristics of patients with post-stroke dementia (PSD) and Alzheimer's disease (AD) are unclear. We sought to describe their gait signatures and to explore gait parameters distinguishing PSD from post-stroke non-dementia (PSND) and patients with AD. We divided 3-month post-stroke patients into PSND and PSD groups based on the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the activity of daily living (ADL). Thirty-one patients with AD and thirty-two healthy controls (HCs) were also recruited. Ten gait parameters in one single and two dual-task gait tests (counting-backward or naming-animals while walking) were compared among the groups, with adjustment for baseline demographic covariates and the MMSE score. The area under the receiver operating characteristic curve (AUC) was used to identify parameters discriminating PSD from individuals with PSND and AD. Patients with PSD and patients with AD showed impaired stride length, velocity, stride time, and cadence while patients with PSD had altered stance and swing phase proportions (all p ≤ 0.01, post hoc). Patients with AD had smaller toe-off (ToA) and heel-to-ground angles (HtA) (p ≤ 0.01) than HCs in dual-task gait tests. Individuals with PSD had a shorter stride length, slower velocity, and altered stance and swing phase percentages in all tests (p ≤ 0.01), but a higher coefficient of variation of stride length (CoVSL) and time (CoVST) only in the naming animals-task gait test (p ≤ 0.001) than individuals with PSND. ToA and HtA in the naming animals-task gait test were smaller in individuals with AD than those with PSD (p ≤ 0.01). Statistical significance persisted after adjusting for demographic covariates, but not for MMSE. The pace and the percentage of stance or swing phase in all tests, CoVST in the dual-task paradigm, and CoVSL only in the naming animals-task gait test (moderate accuracy, AUC > 0.700, p ≤ 0.01) could distinguish PSD from PSND. Furthermore, the ToA and HtA in the naming animals-task gait paradigm discriminated AD from PSD (moderate accuracy, AUC > 0.700, p ≤ 0.01). Thus, specific gait characteristics could allow early identification of PSD and may allow non-invasive discrimination between PSD and AD, or even other subtypes of dementia.
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BACKGROUND: Previous studies have demonstrated that hippocampal atrophy is a hallmark of dementia and can be used to predict the outcome of post-stroke demented (PSD) patients. The hippocampus consists of several subfields but their involvement in the pathophysiology of the PSD remains unclear. OBJECTIVE: The present study aimed to investigate volumetric alterations of hippocampal subfields in patients with PSD. METHODS: High-resolution T1-weighted images were collected from 27 PSD and 28 post-stroke nondemented (PSND) patients who recovered from ischemic stroke, and 17 age-matched normal control (NC). We estimated the volumes of the hippocampal subfields using FreeSurfer 6.0 which segmented the hippocampus into 12 subfields in each hemisphere. The volumetric differences between the groups were evaluated by the two-sample tests after regressing out the age, sex, education, and total intracranial volume. RESULTS: Compared with NC group, PSD group showed smaller volumes in the entire hippocampus and its subfields, and such differences were not found in PSND group. Moreover, we found the dementia-specific atrophy in the left granule cell layer of dentate gyrus (GC-DG) and CA4 in the PSD patients compared with NC and PSND. Regression analysis showed positive correlations between the changes of cognitive performance and the asymmetry index in the CA3/4 and GC-DG of the PSD group. Furthermore, we found that the volumes of hippocampal subfields provided a better classification performance than the entire hippocampus. CONCLUSION: Our findings suggest that the hippocampus is reduced in the PSD patients and it presents a selective subfield involvement.
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Demencia/etiología , Demencia/patología , Hipocampo/patología , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/patología , Adulto , Anciano , Atrofia/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Deep learning has always been at the forefront of scientific research. It has also been applied to medical research. Hereditary spinocerebellar ataxia (SCA) is characterized by gait abnormalities and is usually evaluated semi-quantitatively by scales. However, more detailed gait characteristics of SCA and related objective methods have not yet been established. Therefore, the purpose of this study was to evaluate the gait characteristics of SCA patients, as well as to analyze the correlation between gait parameters, clinical scales, and imaging on deep learning. METHODS: Twenty SCA patients diagnosed by genetic detection were included in the study. Ten patients who were tested via functional magnetic resonance imaging (fMRI) were included in the SCA imaging subgroup. All SCA patients were evaluated with the International Cooperative Ataxia Rating Scale (ICARS) and Scale for the Assessment and Rating of Ataxia (SARA) clinical scales. The gait control group included 16 healthy subjects, and the imaging control group included seven healthy subjects. Gait data consisting of 10â¯m of free walking of each individual in the SCA group and the gait control group were detected by wearable gait-detection equipment. Stride length, stride time, velocity, supporting-phase percentage, and swinging-phase percentage were extracted as gait parameters. Cerebellar volume and the midsagittal cerebellar proportion in the posterior fossa (MRVD) were calculated according to MR. RESULTS: There were significant differences in stride length, velocity, supporting-phase percentage, and swinging-phase percentage between the SCA group and the gait control group. The stride length and stride velocity of SCA groups were lower while supporting phase was longer than those of the gait control group. SCA group's velocity was negatively correlated with both the ICARS and SARA scores. The cerebellar volume and MRVD of the SCA imaging subgroup were significantly smaller than those of the imaging control group. MRVD was significantly correlated with ICARS and SARA scores, as well as stride velocity variability. CONCLUSION: SCA gait parameters were characterized by a reduced stride length, slower walking velocity, and longer supporting phase. Additionally, a smaller cerebellar volume correlated with an increased irregularity in gait. Gait characteristics exhibited considerable clinical relevance to hereditary SCA. We conclude that a combination of gait parameters, ataxia scales, and MRVD may represent more objective markers for clinical evaluations of SCA.
Asunto(s)
Aprendizaje Profundo , Marcha/fisiología , Ataxias Espinocerebelosas/fisiopatología , Adulto , Factores de Edad , Anciano , Fenómenos Biomecánicos , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Factores Sexuales , Método Simple Ciego , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/genética , Adulto JovenRESUMEN
Amyotrophic lateral sclerosis (ALS) is an adult disorder of neurodegeneration that manifests as the destruction of upper and lower motor neurons. Beta-N-methylamino-L-alanine (L-BMAA), an amino acid not present in proteins, was found to cause intraneuronal protein misfolding and to induce ALS/Parkinsonism dementia complex (PDC), which presents symptoms analogous to those of Alzheimer's-like dementia and Parkinsonism. L-serine suppresses the erroneous incorporation of L-BMAA into proteins in the human nervous system. In this study, angiopoietin-1, an endothelial growth factor crucial for vascular development and angiogenesis, and the integrin αvß3 binding peptide C16, which inhibits inflammatory cell infiltration, were utilized to improve the local microenvironment within the central nervous system of an ALS/PDC rodent model by minimizing inflammation. Our results revealed that L-serine application yielded better effects than C16+ angiopoietin-1 treatment alone for alleviating apoptotic and autophagic changes and improving cognition and electrophysiological dysfunction, but not for improving the inflammatory micro-environment in the central nerve system, while further advances in attenuating the functional disability and pathological impairment induced by L-BMAA could be achieved by co-treatment with C16 and angiopoietin-1 in addition to L-serine. Therefore, C16+ angiopoietin-1 could be beneficial as a supplement to promote the effects of L-serine treatment.