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Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43.
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Esclerosis Amiotrófica Lateral , Proteínas de Unión al ADN , Células Madre Pluripotentes Inducidas , Antígeno Ventral Neuro-Oncológico , Empalme Alternativo/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Antígeno Ventral Neuro-Oncológico/genética , Antígeno Ventral Neuro-Oncológico/metabolismo , Proteínas Nucleares/genética , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas Represoras/genéticaRESUMEN
The question whether life style may impair the advent or course of the disease in patients with Parkinsonism is of great importance for patients and physicians alike. We present here comprehensive information on the influence of the environment, diet (especially caffeine, nicotine, alcohol, chocolate and dairy products), physical activity and sleep on risk and course of Parkinson's disease.
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Enfermedad de Parkinson , Trastornos Parkinsonianos , Cafeína , Ejercicio Físico , Humanos , Estilo de VidaRESUMEN
The background of the freezing-of-gait (FOG) phenomenon in Parkinson's syndrome is presented in this review. The following issues are addressed: characterization of the symptom freezing and its subtypes that challenge standardized diagnostic procedures; available assessment methods generating freezing-related parameters that not only support clinical studies but can also be applied in everyday care, and current therapy options. FOG exists in different subtypes, and clinical and diagnostic definitions are limited by subjective characterization and semi-standardized tests. FOG-specific drug options are not existing, apart from the optimization of dopaminergic medication, which may also be due to the poor discriminatory power of standardized diagnostics. This is also true for deep brain stimulation. Both of these therapeutic options may be due not only to the complex neural network alterations as a motor-control correlate of FOG, but also because of challenging diagnostic assessments methodologies. Innovative, wearable, sensor-based diagnostic strategies are currently being developed, and supportive therapies using tools and technologies focusing on 'cueing' are becoming increasingly well accepted. Even though high level evidence is missing, they provide a helpful treatment option for individualized therapy. It can be assumed that these options will become particularly popular due to technological progress and likely alter the everyday treatment challenges faced by doctors and therapists.
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Trastornos Neurológicos de la Marcha/complicaciones , Trastornos Neurológicos de la Marcha/fisiopatología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/fisiopatología , Marcha , HumanosRESUMEN
BACKGROUND: The loss of the swallow-tail sign of the substantia nigra has been proposed for diagnosis of Parkinson's disease. Aim was to evaluate, if the sign occurs consistently in healthy subjects and if it can be reliably detected with high-resolution 7T susceptibility weighted imaging (SWI). METHODS: Thirteen healthy adults received SWI at 7T. 3 neuroradiologists, who were blinded to patients' diagnosis, independently classified subjects regarding the swallow-tail sign to be present or absent. Accuracy, positive and negative predictive values (PPV and NPV) as well as inter- and intra-rater reliability and internal consistency were analyzed. RESULTS: The sign could be detected in 81% of the cases in consensus reading. Accuracy to detect the sign compared to the consensus was 100, 77 and 96% for the three readers with PPV reader 1/2/3 = 1/0.45/0.83 and NPV = 1/1/1. Inter-rater reliability was excellent (inter-class correlation coefficient = 0.844, alpha = 0.871). Intra-rater reliability was good to excellent (reader 1 R/L = 0.625/0.786; reader 2 = 0.7/0.64; reader 3 = 0.9/1). CONCLUSION: The swallow-tail sign can be reliably detected. However, our data suggest its occurrence is not consistent in healthy subjects. It may be possible that one reason is an individually variable molecular organization of nigrosome 1 so that it does not return a uniform signal in SWI.
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Imagen por Resonancia Magnética/métodos , Enfermedad de Parkinson/diagnóstico por imagen , Sustancia Negra/diagnóstico por imagen , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Reproducibilidad de los ResultadosRESUMEN
Conversion of soluble α-synuclein into insoluble and fibrillar inclusions is a hallmark of Parkinson's disease and other synucleinopathies. Accumulating evidence points towards a relationship between its generation at nerve terminals and structural synaptic pathology. Little is known about the pathogenic impact of α-synuclein conversion and deposition at nigrostriatal dopaminergic synapses in transgenic mice, mainly owing to expression limitations of the α-synuclein construct. Here, we explore whether both the rat as a model and expression of the bacterial artificial chromosome construct consisting of human full-length wild-type α-synuclein could exert dopaminergic neuropathological effects. We found that the human promoter induced a pan-neuronal expression, matching the rodent α-synuclein expression pattern, however, with prominent C-terminally truncated fragments. Ageing promoted conversion of both full-length and C-terminally truncated α-synuclein species into insolube and proteinase K-resistant fibres, with strongest accumulation in the striatum, resembling biochemical changes seen in human Parkinson's disease. Transgenic rats develop early changes in novelty-seeking, avoidance and smell before the progressive motor deficit. Importantly, the observed pathological changes were associated with severe loss of the dopaminergic integrity, thus resembling more closely the human pathology.
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Cromosomas Artificiales Bacterianos/genética , Neuronas Dopaminérgicas/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Fenotipo , alfa-Sinucleína/genética , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Neuronas Dopaminérgicas/metabolismo , Humanos , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , alfa-Sinucleína/biosíntesis , alfa-Sinucleína/toxicidadRESUMEN
Parkinson disease is characterized by the loss of dopaminergic neurons mainly in the substantia nigra. Accumulation of α-synuclein and cell loss has been also reported in many other brain regions including the hippocampus, where it might impair adult neurogenesis, contributing to nonmotor symptoms. However, the molecular mechanisms of these alterations are still unknown. In this report we show that α-synuclein-accumulating adult rat hippocampus neural progenitors present aberrant neuronal differentiation, with reduction of Notch1 expression and downstream signaling targets. We characterized a Notch1 proximal promoter that contains p53 canonical response elements. In vivo binding of p53 represses the transcription of Notch1 in neurons. Moreover, we demonstrated that α-synuclein directly binds to the DNA at Notch1 promoter vicinity and also interacts with p53 protein, facilitating or increasing Notch1 signaling repression, which interferes with maturation and survival of neural progenitors cells. This study provides a molecular basis for α-synuclein-mediated disruption of adult neurogenesis in Parkinson disease.
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Regulación de la Expresión Génica , Neurogénesis , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Receptor Notch1/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , alfa-Sinucleína/metabolismo , Animales , Apoptosis , Linaje de la Célula , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Lentivirus/genética , Regiones Promotoras Genéticas , Ratas , Transducción de SeñalRESUMEN
Background: Due to the absence of robust biomarkers, and the low sensitivity and specificity of routine imaging techniques, the differential diagnosis between Parkinson's disease (PD) and multiple system atrophy (MSA) is challenging. High-field magnetic resonance imaging (MRI) opened up new possibilities regarding the analysis of pathological alterations associated with neurodegenerative processes. Recently, we have shown that quantitative susceptibility mapping (QSM) enables visualization and quantification of two major histopathologic hallmarks observed in MSA: reduced myelin density and iron accumulation in the basal ganglia of a transgenic murine model of MSA. It is therefore emerging as a promising imaging modality on the differential diagnosis of Parkinsonian syndromes. Objectives: To assess QSM on high-field MRI for the differential diagnosis of PD and MSA. Methods: We assessed 23 patients (nine PDs and 14 MSAs) and nine controls using QSM on 3T and 7T MRI scanners at two academic centers. Results: We observed increased susceptibility in MSA at 3T in prototypical subcortical and brainstem regions. Susceptibility measures of putamen, pallidum, and substantia nigra reached excellent diagnostic accuracy to separate both synucleinopathies. Increase toward 100% sensitivity and specificity was achieved using 7T MRI in a subset of patients. Magnetic susceptibility correlated with age in all groups, but not with disease duration in MSA. Sensitivity and specificity were particularly high for possible MSA, and reached 100% in the putamen. Conclusion: Putaminal susceptibility measures, in particular on ultra-high-field MRI, may distinguish MSA patients from both, PD and controls, allowing an early and sensitive diagnosis of MSA.
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Huntington's disease (HD) is a neurodegenerative disorder caused by poly-Q expansion in the Huntingtin (HTT) protein. Here, we delineate elevated mutant HTT (mHTT) levels in patient-derived cells including fibroblasts and iPSC derived cortical neurons using mesoscale discovery (MSD) HTT assays. HD patients' fibroblasts and cortical neurons recapitulate aberrant alternative splicing as a molecular fingerprint of HD. Branaplam is a splicing modulator currently tested in a phase II study in HD (NCT05111249). The drug lowers total HTT (tHTT) and mHTT levels in fibroblasts, iPSC, cortical progenitors, and neurons in a dose dependent manner at an IC50 consistently below 10 nM without inducing cellular toxicity. Branaplam promotes inclusion of non-annotated novel exons. Among these Branaplam-induced exons, there is a 115 bp frameshift-inducing exon in the HTT transcript. This exon is observed upon Branaplam treatment in Ctrl and HD patients leading to a profound reduction of HTT RNA and protein levels. Importantly, Branaplam ameliorates aberrant alternative splicing in HD patients' fibroblasts and cortical neurons. These findings highlight the applicability of splicing modulators in the treatment of CAG repeat disorders and decipher their molecular effects associated with the pharmacokinetic and -dynamic properties in patient-derived cellular models.
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Enfermedad de Huntington , Humanos , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Empalme Alternativo/genética , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Neuronas/metabolismo , Exones/genéticaRESUMEN
Several mutations that cause Parkinson's disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.
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Schizencephaly (SCH) is a clinically and etiologically heterogeneous cerebral malformation presenting as unilateral or bilateral hemispheric cleft with direct connection between the inner and outer liquor spaces. The SCH cleft is usually lined by gray matter, which appears polymicrogyric implying an associated impairment of neuronal migration. The majority of SCH patients are sporadic, but familial SCH has been described. An initial report of heterozygous mutations in the homeobox gene EMX2 could not be confirmed in 52 patients investigated in this study in agreement with two independent SCH patient cohorts published previously. SCH frequently occurs with additional cerebral malformations like hypoplasia or aplasia of the septum pellucidum or optic nerve, suggesting the involvement of genes important for the establishment of midline forebrain structures. We therefore considered holoprosencephaly (HPE)-associated genes as potential SCH candidates and report for the first time heterozygous mutations in SIX3 and SHH in a total of three unrelated patients and one fetus with SCH; one of them without obvious associated malformations of midline forebrain structures. Three of these mutations have previously been reported in independent patients with HPE. SIX3 acts directly upstream of SHH, and the SHH pathway is a key regulator of ventral forebrain patterning. Our data indicate that in a subset of patients SCH may develop as one aspect of a more complex malformation of the ventral forebrain, directly result from mutations in the SHH pathway and hence be considered as yet another feature of the broad phenotypic spectrum of holoprosencephaly.
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Proteínas del Ojo/genética , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Proteínas de Homeodominio/genética , Malformaciones del Desarrollo Cortical/genética , Mutación , Proteínas del Tejido Nervioso/genética , Secuencia de Bases , Niño , Preescolar , Femenino , Heterocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Proteína Homeobox SIX3RESUMEN
Altered expression and mutations in alpha-synuclein (alpha-syn) have been linked to Parkinson's disease (PD) and related disorders. The neurological alterations in PD patients have been associated with degeneration of dopaminergic cells and other neuronal populations. Moreover, recent studies in murine models have shown that alterations in neurogenesis might also contribute to the neurodegenerative phenotype. However, the mechanisms involved and the effects of alpha-syn expression on neurogenesis are not yet clear. To this end, murine embryonic stem (mES) cells were infected with lentiviral (LV) vectors expressing wild-type (WT) and mutant alpha-syn. Compared with mES cells infected with LV-green fluorescent protein (GFP), cells expressing WT and mutant alpha-syn showed reduced proliferation as indicated by lower 5-bromo-2'-deoxyuridine uptake, increased apoptosis, and reduced expression of neuronal markers such as neuron specific enolase and beta-III tubulin. The alterations in neurogenesis in alpha-syn-expressing mES cells were accompanied by a reduction in Notch-1 and Hairy and enhancer of split-5 (Hes-5) mRNA and protein levels. Moreover, levels of total Notch-1 and Notch intracellular domain (NICD) were lower in mES cells expressing WT and mutant alpha-syn compared with GFP controls. The reduced survival of alpha-syn-expressing mES cells was reverted by overexpressing constitutively active NICD. Similarly, in alpha-syn transgenic mice, the alterations in neurogenesis in the hippocampal subgranular zone were accompanied by decreased Notch-1, NICD, and Hes-5 expression. Together, these results suggest that accumulation of alpha-syn might impair survival of NPCs by interfering with the Notch signaling pathway. Similar mechanisms could be at play in PD and Lewy body disease.
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Diferenciación Celular/fisiología , Regulación hacia Abajo/fisiología , Células Madre Embrionarias/metabolismo , Hipocampo/metabolismo , Neuronas/metabolismo , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/biosíntesis , alfa-Sinucleína/fisiología , Animales , Proliferación Celular , Células Cultivadas , Células Madre Embrionarias/citología , Regulación del Desarrollo de la Expresión Génica/fisiología , Hipocampo/citología , Hipocampo/embriología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Transgénicos , Neuronas/citología , Receptor Notch1/genética , Células Madre/citología , Células Madre/metabolismo , alfa-Sinucleína/genéticaRESUMEN
OBJECTIVE: To identify structural white matter alterations in patients with pure hereditary spastic paraplegia (HSP) using high angular resolution diffusion tensor imaging (DTI). METHODS: We examined 37 individuals with high resolution DTI, 20 patients with pure forms of hereditary spastic paraplegia and 17 age and gender matched healthy controls. DTI was performed using a 3 T clinical scanner with whole brain tract-based spatial statistical (TBSS) analysis of the obtained fractional anisotropy (FA) data as well as a region-of-interest (ROI)-based analysis of affected tracts including the cervical spinal cord. We further conducted correlation analyses between DTI data and clinical characteristics. RESULTS: TBSS analysis in HSP patients showed significantly decreased fractional anisotropy of the corpus callosum and the corticospinal tract compared to healthy controls. ROI-based analysis confirmed significantly lower FA in HSP compared to controls in the internal capsule (0.77 vs. 0.80, p = 0.048), the corpus callosum (0.84 vs. 0.87, p = 0.048) and the cervical spinal cord (0.72 vs. 0.79, p = 0.003). FA values of the cervical spinal cord significantly correlated with disease duration. CONCLUSION: DTI metrics of the corticospinal tract from the internal capsule to the cervical spine suggest microstructural damage and axonal degeneration of motor neurons. The CST at the level of the cervical spinal cord is thereby more severely affected than the intracranial part of the CST, suggesting an ascending axonal degeneration of the CST. Since there is a significant correlation with disease duration, FA may serve as a future progression marker for assessment of the disease course in HSP.
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BACKGROUND: During developmental and adult neurogenesis, doublecortin is an early neuronal marker expressed when neural stem cells assume a neuronal cell fate. To understand mechanisms involved in early processes of neuronal fate decision, we investigated cell lines for their capacity to induce expression of doublecortin upon neuronal differentiation and develop in vitro reporter models using doublecortin promoter sequences. RESULTS: Among various cell lines investigated, the human teratocarcinoma cell line NTERA-2 was found to fulfill our criteria. Following induction of differentiation using retinoic acid treatment, we observed a 16-fold increase in doublecortin mRNA expression, as well as strong induction of doublecortin polypeptide expression. The acquisition of a neuronal precursor phenotype was also substantiated by the establishment of a multipolar neuronal morphology and expression of additional neuronal markers, such as Map2, betaIII-tubulin and neuron-specific enolase. Moreover, stable transfection in NTERA-2 cells of reporter constructs encoding fluorescent or luminescent genes under the control of the doublecortin promoter allowed us to directly detect induction of neuronal differentiation in cell culture, such as following retinoic acid treatment or mouse Ngn2 transient overexpression. CONCLUSION: Induction of doublecortin expression in differentiating NTERA-2 cells suggests that these cells accurately recapitulate some of the very early events of neuronal determination. Hence, the use of reporter genes under the control of the doublecortin promoter in NTERA-2 cells will help us to investigate factors involved early in the course of neuronal differentiation processes. Moreover the ease to detect the induction of a neuronal program in this model will permit to perform high throughput screening for compounds acting on the early neuronal differentiation mechanisms.
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Genes Reporteros/fisiología , Proteínas Asociadas a Microtúbulos/metabolismo , Neuronas/citología , Neuropéptidos/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular , Células Cultivadas , Proteínas de Dominio Doblecortina , Regulación del Desarrollo de la Expresión Génica , Humanos , Proteínas del Tejido Nervioso/metabolismo , Tretinoina/farmacologíaRESUMEN
OBJECTIVE: Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of neurodegenerative disorders resulting in progressive spasticity of the lower limbs. One form of autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) was linked to chromosomal region 15q13-21 (SPG11) and associated with mutations in the spatacsin gene. We assessed the long-term course and the mutational spectrum of spatacsin-associated ARHSP with TCC. METHODS: Neurological examination, cerebral magnetic resonance imaging (MRI), 18fluorodeoxyglucose positron emission tomography (PET), nerve biopsy, linkage and mutation analysis are presented. RESULTS: Spastic paraplegia in patients with spatacsin mutations (n = 20) developed during the second decade of life. The Spastic Paraplegia Rating Scale (SPRS) showed severely compromised walking between the second and third decades of life (mean SPRS score, >30). Impaired cognitive function was associated with severe atrophy of the frontoparietal cortex, TCC, and bilateral periventricular white matter lesions. Progressive cortical and thalamic hypometabolism in the 18fluorodeoxyglucose PET was observed. Sural nerve biopsy showed a loss of unmyelinated nerve fibers and accumulation of intraaxonal pleomorphic membranous material. Mutational analysis of spatacsin demonstrated six novel and one previously reported frameshift mutation and two novel nonsense mutations. Furthermore, we report the first two splice mutations to be associated with SPG11. INTERPRETATION: We demonstrate that not only frameshift and nonsense mutations but also splice mutations result in SPG11. Mutations are distributed throughout the spatacsin gene and emerge as major cause for ARHSP with TCC associated with severe motor and cognitive impairment. The clinical phenotype and the ultrastructural analysis suggest a disturbed axonal transport of long projecting neurons.
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Mutación , Proteínas/genética , Paraplejía Espástica Hereditaria/fisiopatología , Adulto , Encéfalo/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Codón sin Sentido , Cognición , Cuerpo Calloso/patología , Femenino , Mutación del Sistema de Lectura , Genes Recesivos , Humanos , Estudios Longitudinales , Fibras Nerviosas Amielínicas/patología , Linaje , Tomografía de Emisión de Positrones , Índice de Severidad de la Enfermedad , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/metabolismo , Paraplejía Espástica Hereditaria/psicología , Nervio Sural/patología , Tálamo/diagnóstico por imagen , Tálamo/metabolismo , CaminataRESUMEN
BACKGROUND AND OBJECTIVES: Gait impairment and reduced mobility are typical features of idiopathic Parkinson's disease (iPD) and atypical parkinsonian disorders (APD). Quantitative gait assessment may have value in the diagnostic workup of parkinsonian patients and as endpoint in clinical trials. The study aimed to identify quantitative gait parameter differences in iPD and APD patients using sensor-based gait analysis and to correlate gait parameters with clinical rating scales. SUBJECTS AND METHODS: Patients with iPD and APD including Parkinson variant multiple system atrophy and progressive supranuclear palsy matched for age, gender, and Hoehn and Yahr (≤3) were recruited at two Movement Disorder Units and assessed using standardized clinical rating scales (MDS-UPDRS-3, UMSARS, PSP-RS). Gait analysis consisted of inertial sensor units laterally attached to shoes, generating as objective targets spatiotemporal gait parameters from 4 × 10 m walk tests. RESULTS: Objective sensor-based gait analysis showed that gait speed and stride length were markedly reduced in APD compared to iPD patients. Moreover, clinical ratings significantly correlated with gait speed and stride length in APD patients. CONCLUSION: Our findings suggest that patients with APD had more severely impaired gait parameters than iPD patients despite similar disease severity. Instrumented gait analysis provides complementary rater independent, quantitative parameters that can be exploited for clinical trials and care.
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Análisis de la Marcha , Enfermedad de Parkinson , Trastornos Parkinsonianos , Velocidad al Caminar , Anciano , Estudios Transversales , Equipo para Diagnóstico , Progresión de la Enfermedad , Femenino , Análisis de la Marcha/instrumentación , Análisis de la Marcha/métodos , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/diagnóstico , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/fisiopatología , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/fisiopatología , Índice de Severidad de la Enfermedad , Parálisis Supranuclear Progresiva/diagnósticoRESUMEN
Patients suffering from Parkinson's disease (PD) present motor impairments reflected in the dynamics of the center of pressure (CoP) adjustments during quiet standing. One method to study the dynamics of CoP adjustments is the entropic half-life (EnHL), which measures the short-term correlations of a time series at different time scales. Changes in the EnHL of CoP time series suggest neuromuscular adaptations in the control of posture. In this study, we sought to investigate the immediate changes in the EnHL of CoP adjustments of patients with PD during one session of perturbed (experimental group) and unperturbed treadmill walking (control group). A total of 39 patients with PD participated in this study. The experimental group (n = 19) walked on a treadmill providing small tilting of the treadmill platform. The control group (n = 20) walked without perturbations. Each participant performed 5-min practice followed by three 5-min training blocks of walking with or without perturbation (with 3-min resting in between). Quiet standing CoP data was collected for 30 s at pre-training, after each training block, immediately post-training, and after 10 min retention. The EnHL was computed on the original and surrogates (phase-randomized) CoP signals in the medio-lateral (ML) and anterior-posterior (AP) directions. Data was analyzed using four-way mixed ANOVA. Increased EnHL values were observed for both groups (Time effect, p < 0.001) as the intervention progressed, suggesting neuromuscular adaptations in the control of posture. The EnHL of surrogate signals were significantly lower than for original signals (p < 0.001), confirming that these adaptations come from non-random control processes. There was no Group effect (p = 0.622), however by analyzing the significant Group by Direction by Time interaction (p < 0.05), a more pronounced effect in the ML direction of the perturbed group was observed. Altogether, our findings show that treadmill walking decreases the complexity of CoP adjustments, suggesting neuromuscular adaptations in balance control during a short training period. Further investigations are required to assess these adaptations during longer training intervals.
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OBJECTIVE: A prospective study is presented on the amount of targeting error that is due to rotational deviations between the atlas and the stereotactic coordinate system. MATERIALS AND METHODS: We investigated 14 volunteers with a stereotactic frame fixed to their heads by tight adhesive bands. Sagittal, coronal and axial T2-weighted MRI scans, as well as MPRage sequences, were performed. The anterior and posterior commissures and one additional point on the midline (the septum pellucidum) were determined on the axial T2-weighted images. Bilateral atlas coordinates for the subthalamic nucleus (STN), globus pallidus pars interna (GPi) and nucleus ventralis intermedius (Vim) were transformed to stereotactic frame coordinates, either without correction or by 2-point or 3-point correction. A total of 896 coordinates (x, y, z for the STN, GPi and Vim in both hemispheres) were calculated. RESULTS: Although the mean differences between the two algorithms (0.24 +/- standard deviation of 0.33 mm) were within the range of system-immanent inaccuracies in MRI-guided stereotaxy, deviations of up to 2.8 mm occurred. No significant correlation was found regarding the amount of rotational angle and the differences in x-, y-, or z-coordinates when 2-point and 3-point transformations were compared. CONCLUSIONS: The reliability of meticulous trajectory planning might be compromised significantly by using only 2-point-based correction or no calculations at all.
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Procedimientos Neuroquirúrgicos/métodos , Técnicas Estereotáxicas , Adulto , Algoritmos , Encéfalo/anatomía & histología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
Current challenges demand a profound restructuration of the global healthcare system. A more efficient system is required to cope with the growing world population and increased life expectancy, which is associated with a marked prevalence of chronic neurological disorders such as Parkinson's disease (PD). One possible approach to meet this demand is a laterally distributed platform such as the Internet of Things (IoT). Real-time motion metrics in PD could be obtained virtually in any scenario by placing lightweight wearable sensors in the patient's clothes and connecting them to a medical database through mobile devices such as cell phones or tablets. Technologies exist to collect huge amounts of patient data not only during regular medical visits but also at home during activities of daily life. These data could be fed into intelligent algorithms to first discriminate relevant threatening conditions, adjust medications based on online obtained physical deficits, and facilitate strategies to modify disease progression. A major impact of this approach lies in its efficiency, by maximizing resources and drastically improving the patient experience. The patient participates actively in disease management via combined objective device- and self-assessment and by sharing information within both medical and peer groups. Here, we review and discuss the existing wearable technologies and the Internet-of-Things concept applied to PD, with an emphasis on how this technological platform may lead to a shift in paradigm in terms of diagnostics and treatment.
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Internet , Monitoreo Ambulatorio , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/rehabilitación , Telemedicina/tendencias , Teléfono Celular , Humanos , Monitoreo Ambulatorio/instrumentación , Monitoreo Ambulatorio/métodos , Monitoreo Ambulatorio/tendenciasRESUMEN
BACKGROUND: Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established. METHODS: Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients. RESULTS: Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age. CONCLUSIONS: We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males.