RESUMEN
Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.
Asunto(s)
Discinesia Inducida por Medicamentos , Levodopa , Oxidopamina , Animales , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/metabolismo , Levodopa/farmacología , Oxidopamina/toxicidad , Ratones , Masculino , Ratones Endogámicos C57BL , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Antiparkinsonianos/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Receptores de Serotonina 5-HT4/metabolismo , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/inducido químicamente , Piridinas/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Piperidinas , PirimidinasRESUMEN
We report the third case of FADS due to biallelic DOK7 variants, which further strengthens the association of DOK7 with this lethal phenotype and lack of genotype phenotype correlation.
Asunto(s)
Artrogriposis , Humanos , Artrogriposis/genética , Fenotipo , Proteínas Musculares/genéticaRESUMEN
Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.
Asunto(s)
Artrogriposis , Feto , Fenotipo , Humanos , Femenino , Masculino , Artrogriposis/genética , Artrogriposis/diagnóstico , Artrogriposis/patología , Feto/patología , Secuenciación del Exoma , Contractura/genética , Contractura/diagnóstico , Contractura/patología , Embarazo , Ultrasonografía Prenatal , Mutación , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/patologíaRESUMEN
ATP1A2 encodes a subunit of sodium/potassium-transporting adenosine triphosphatase (Na+ /K+ -ATPase). Heterozygous pathogenic variants of ATP1A2 cause familial hemiplegic migraine, alternating hemiplegia of childhood, and developmental and epileptic encephalopathy. Biallelic loss-of-function variants in ATP1A2 lead to fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, resulting in fetal death. Here, we describe a patient with compound heterozygous ATP1A2 variants consisting of missense and nonsense variants. He survived after birth with brain malformations and the fetal akinesia/hypokinesia sequence. We report a novel type of compound heterozygous variant that might extend the disease spectrum of ATP1A2.
Asunto(s)
Microcefalia , Migraña con Aura , Masculino , Humanos , Hipocinesia , ATPasa Intercambiadora de Sodio-Potasio/genética , Microcefalia/diagnóstico , Microcefalia/genética , Hemiplejía , SíndromeRESUMEN
OBJECTIVE: Assess the utility of a Sub-Tenon's anesthesia (STA) protocol to provide suitable operating conditions for canine cataract surgery and compare it to an alternative low-dose neuromuscular blockade (LD-NMB) protocol used for canine cataract surgery. PROCEDURES: Clinical study of dog eyes undergoing cataract surgery with either an STA or LD-NMB protocol. While intraoperative vitreal expansion scores and intraoperative complications were collected prospectively, globe position, intraocular pressure, return of vision, and postoperative complications were collected retrospectively. Statistical testing was used to compare results between the STA and the LD-NMB groups for the data available. RESULTS: A total of 224 eyes from 126 dogs were assessed, with 133/224 (59.4%) eyes from 99/126 (78.6%) dogs receiving STA and 91/124 (40.6%) eyes from 72/126 (57.1%) dogs receiving LD-NMB. Forty-five of these dogs (45/126; 37.7%) received STA for one eye and LD-NMB for the other eye. There was no significant change in intraocular pressure measurements following STA administration. This was not measured for the LD-NMB group. The globe achieved a central position in 110/133 (82.7%) of eyes that received STA. This was not measured for the LD-NMB group. Intraoperative vitreal expansion scores were slightly higher in STA-treated eyes compared to LD-NMB-treated eyes. The intraoperative complication rate for STA-treated eyes was higher (73/133; 54.8%) compared to NMB-treated eyes (12/91; 13.2%). The most common intraoperative complication for STA was chemosis (64/133; 48.1%), the risk of which increased with an increase in the volume of local anesthetic injected. The post-operative complication rate was higher in STA-treated eyes (28/133; 21.1%) compared to NMB-treated eyes (16/91; 17.6%). Post-operative corneal ulceration was the most common postoperative complication in STA-treated eyes (6/133; 4.5%). CONCLUSION: The STA protocol described resulted in suitable operating conditions, but more intraoperative and postoperative complications compared to the LD-NMB protocol. Despite these complications, the STA protocol did not cause a significant deleterious impact on post-operative outcomes as defined in the present study.
Asunto(s)
Catarata , Enfermedades de los Perros , Bloqueo Neuromuscular , Facoemulsificación , Perros , Animales , Bloqueo Neuromuscular/veterinaria , Estudios Retrospectivos , Facoemulsificación/veterinaria , Anestésicos Locales , Anestesia Local/veterinaria , Complicaciones Posoperatorias/veterinaria , Catarata/veterinaria , Complicaciones Intraoperatorias/veterinaria , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/cirugíaRESUMEN
Early-morning off periods, causing early-morning akinesia, can lead to significant motor and nonmotor morbidity in levodopa-treated fluctuating Parkinson's disease (PD) cases. Despite validated bedside scales in clinical practice, such early-morning off periods may remain undetected unless specific wearable technologies, such as the Parkinson's KinetiGraph™ (PKG) watch, are used. We report five PD cases for whom the PKG detected early-morning off periods that were initially clinically undetected and as such, untreated. These five cases serve as exemplars of this clinical gap in care. Post-PKG assessment, clinicians were alerted and targeted therapies helped abolish the early-morning off periods.
Asunto(s)
Enfermedad de Parkinson , Dispositivos Electrónicos Vestibles , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/fisiopatología , Masculino , Anciano , Femenino , Persona de Mediana Edad , Levodopa/uso terapéuticoRESUMEN
Cardiotoxicity caused by adrenergic receptor agonists overdosing or stress-induced catecholamine release promotes cardiomyopathy, resembling Takotsubo cardiomyopathy (TC). TC is characterized by transient regional systolic dysfunction of the left ventricle. The animal models of TC and modalities for assessing regional wall motion abnormalities in animal models are lacking. We previously reported the protective role of a small noncoding microRNA-204-5p (miR-204) in cardiomyopathies, but its role in TC remains unknown. Here we compared the impact of miR-204 absence on phenylephrine (PE)-induced and transaortic constriction (TAC)-induced changes in cardiac muscle motion in the posterior and anterior apical, mid, and basal segments of the left ventricle using 2-dimensional speckle-tracking echocardiography (2-STE). Wildtype and miR-204-/- mice were subjected to cardiac stress in the form of PE for four weeks or TAC-induced pressure overload for five weeks. PE treatment increased longitudinal and radial motion in the apex of the left ventricle and shortened the peak motion time of all left ventricle segments. The TAC led to decreased longitudinal and radial motion in the left ventricle segments, and there was no difference in the peak motion time. Compared to wildtype mice, PE-induced peak cardiac muscle motion time in the anterior base of the left ventricle was significantly earlier in the miR-204-/- mice. There was no difference in TAC-induced peak cardiac muscle motion time between wildtype and miR-204-/- mice. Our findings demonstrate that PE and TAC induce regional wall motion abnormalities that 2-STE can detect. It also highlights the role of miR-204 in regulating cardiac muscle motion during catecholamine-induced cardiotoxicity.
Asunto(s)
Cardiomiopatías , MicroARNs , Cardiomiopatía de Takotsubo , Animales , Ratones , Fenilefrina/farmacología , Cardiotoxicidad , Ecocardiografía/métodos , MicroARNs/genéticaRESUMEN
Arthrogryposis multiplex congenita (AMC) [also known as multiple joints contracture or Fetal Akinesia Deformation Sequence (FADS)] is etiologically a heterogeneous condition with an estimated incidence of approximately 1 in 3000 live births and much higher incidence when prenatally diagnosed cases are included. The condition can be acquired or secondary to fetal exposures and can also be caused by a variety of single-gene disorders affecting the brain, spinal cord, peripheral nerves, neuromuscular junction, muscle, and a variety of disorders affecting the connective tissues (Niles et al., Prenatal Diagnosis, 2019; 39:720-731). The introduction of next-generation gene sequencing uncovered many genes and causative variants of AMC but also identified genes that cause both dominant and recessive inherited conditions with the variability of clinical manifestations depending on the genes and variants. Molecular diagnosis in these cases is not only important for prognostication but also for the determination of recurrence risk and for providing reproductive options including preimplantation and prenatal diagnosis. TTN, the largest known gene in the human genome, has been known to be associated with autosomal dominant dilated cardiomyopathy. However, homozygote and compound heterozygote pathogenic variants with recessive inheritance have rarely been reported. We report the effect of recessive variants located within the fetal IC and/or N2BA isoforms in association with severe FADS in three families. All parents were healthy obligate carriers and none of them had cardiac or skeletal muscle abnormalities. This report solidifies FADS as an alternative phenotypic presentation associated with homozygote/compound heterozygous pathogenic variants in the TTN.
Asunto(s)
Artrogriposis , Embarazo , Femenino , Humanos , Artrogriposis/diagnóstico , Artrogriposis/genética , Diagnóstico Prenatal , Homocigoto , Atención Prenatal , Síndrome , Conectina/genéticaRESUMEN
Foetal akinesia deformation sequence (FADS) represents a group of disorders resulting from absent or diminished in utero foetal mobility. The aetiology is multifactorial, including genetic, environmental, maternal, and foetal causes. The absence of foetal movements leading to multiple joint contractures, pulmonary hypoplasia, and intrauterine growth restriction are the key features of foetal akinesia deformation sequence. Herein we describe the case of a 30-year-old gravida 4 (para 2+1) who came for foetal ultrasound at 28 weeks of gestation due to decreased foetal movements. Ultrasound showed features of FADS with fixed flexed position of foetal limbs, pulmonary hypoplasia, polyhydramnios, and intrauterine growth restriction. The timely use of ultrasound enables early detection of these cases and aids in appropriate counselling and management.
Asunto(s)
Artrogriposis , Contractura , Embarazo , Femenino , Humanos , Adulto , Retardo del Crecimiento Fetal/diagnóstico por imagen , Retardo del Crecimiento Fetal/genética , Artrogriposis/diagnóstico por imagen , Artrogriposis/genética , Ultrasonografía PrenatalRESUMEN
Fetal akinesia and contractures can be caused by mutations in various genes that lead to overlapping phenotypes with contractures, rocker bottom feet, cerebellar hypoplasia, ventriculomegaly, growth retardation, pulmonary hypoplasia, cystic hygroma and cleft palate in various combinations. Cerebro-oculo-facio-skeletal (COFS) syndrome is a condition resulting from defects in DNA repair pathway, and genes involved include ERCC1 (COFS), ERCC2 (XPD), ERCC5(XPG), and ERCC6 (CSB). It is a severe disorder presenting in fetal or neonatal period with microcephaly, arthrogryposis, prominent nose, and kyphoscoliosis, and leads to early death in childhood. We report a baby with antenatally identified arthrogryposis in which the homozygous pathogenic variant in exon 8 was identified in ERCC5 gene, by targeted next generation sequencing. This was predicted to cause premature chain termination in the protein. ERCC5 gene is mainly implicated in xeroderma pigmentosum, sometimes in COFS syndrome.
Asunto(s)
Artrogriposis/genética , Síndrome de Cockayne/genética , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Predisposición Genética a la Enfermedad , Proteínas Nucleares/genética , Factores de Transcripción/genética , Artrogriposis/complicaciones , Artrogriposis/diagnóstico , Artrogriposis/patología , Niño , Síndrome de Cockayne/complicaciones , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/patología , Reparación del ADN/genética , Femenino , Humanos , Microcefalia/diagnóstico , Microcefalia/genética , Microcefalia/patología , Diagnóstico Prenatal , Xerodermia Pigmentosa/diagnóstico , Xerodermia Pigmentosa/genética , Xerodermia Pigmentosa/patologíaRESUMEN
Fetal movement is essential to normal human development. If the fetus does not move for whatever reason, then multiple organs and organ systems develop secondary and tertiary effects not normally present. Most of these are deformations with secondary structural damage.
Asunto(s)
Anomalías Múltiples/patología , Artrogriposis/patología , Movimiento Fetal , Feto/patología , Humanos , SíndromeRESUMEN
The mechanism for dynamic left ventricular outflow tract obstruction (LVOTO) after acute coronary syndromes (ACS) is thought to be apical infarction with compensatory hyperkinesia of the residual normally perfused basal segments of the myocardium. However, herein, we report a patient with ACS and dynamic LVOTO (peak gradient of 250 mm Hg at rest) that could not be secondary to apical akinesia. We propose a potential alternative mechanism leading to dynamic LVOTO in ACS, namely, the interplay between sigmoid septum, basal hyperkinesis, and outflow tract narrowing induced by afterload reduction due to acute myocardial ischemia itself.
Asunto(s)
Síndrome Coronario Agudo , Cardiopatías Congénitas , Obstrucción del Flujo Ventricular Externo , Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/diagnóstico por imagen , Humanos , Hipercinesia , Obstrucción del Flujo Ventricular Externo/complicaciones , Obstrucción del Flujo Ventricular Externo/diagnóstico por imagenRESUMEN
INTRODUCTION: The majority of arthrogryposis multiplex congenita (AMC) and lethal forms of AMC such as foetal akinesia deformation sequence (FADS) cases are missed prenatally. We have demonstrated the additional value of foetal motor assessment and evaluation in a multidisciplinary team for the period 2007-2016. An applied care pathway was developed for foetuses presenting with joint contracture(s) in one anatomic region (e.g., talipes equinovarus [TEV]), more than one body part with non-progressive contractures and motility (AMC) and with deterioration over time (FADS). METHODS: The multidisciplinary team of Amsterdam University Medical Centre Expertise Centre FADS and AMC developed the care pathway. Additional tools are provided including a motor assessment by ultrasound examination and a post-mortem assessment form. RESULTS: An eight-step care pathway is presented with a proposed timing for prenatal sonographic examination, genetic examinations, multidisciplinary meetings, prenatal and postnatal counselling of the parents by a specialist also treating after birth, and the follow-up of prenatal and postnatal findings with counselling for future pregnancies. DISCUSSION/CONCLUSION: The scheduled serial structural and motor sonograpahic assessment together with follow-up examinations and genetic analysis should be tailored per prenatal centre per available resources. The multidisciplinary care pathway may pave the way to increase the detection rate and diagnosis of isolated contracture(s), TEV with underlying genetic causes, and the rare phenotypes AMC/FADS and prompt treatment after birth within expertise teams.
Asunto(s)
Artrogriposis , Contractura , Artrogriposis/diagnóstico por imagen , Artrogriposis/genética , Contractura/diagnóstico por imagen , Contractura/genética , Vías Clínicas , Femenino , Feto , Humanos , EmbarazoRESUMEN
PURPOSE: Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood. METHODS: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA). RESULTS: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant in TNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis. CONCLUSION: Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.
Asunto(s)
Enfermedades Fetales/genética , Factores de Intercambio de Guanina Nucleótido/genética , Proteínas de Unión al ARN/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Transactivadores/genética , Adolescente , Adulto , Artrogriposis/genética , Artrogriposis/patología , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Femenino , Enfermedades Fetales/patología , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Adulto JovenRESUMEN
We present a case of lethal fetal akinesia deformation sequence (FADS) caused by a frameshift variant in trans with a 148 kbp deletion encompassing 3-36 exons of AGRN. Pathogenic variants in AGRN have been described in families with a form of congenital myasthenic syndrome (CMS), manifesting in the early childhood with variable fatigable muscle weakness. To the best of our knowledge, this is the first case of FADS caused by defects in AGRN gene. FADS has been reported to be caused by pathogenic variants in genes previously associated with CMS including these involved in endplate development and maintenance: MuSK, DOK7, and RAPSN. FADS seems to be the most severe form of CMS. None of the reported in the literature CMS cases associated with AGRN had two null variants, like the case presented herein. This indicates a strong genotype-phenotype correlation.
Asunto(s)
Agrina/genética , Artrogriposis/genética , Genes Letales/genética , Síndromes Miasténicos Congénitos/genética , Adulto , Artrogriposis/diagnóstico por imagen , Artrogriposis/patología , Niño , Femenino , Feto/diagnóstico por imagen , Feto/patología , Humanos , Masculino , Mutación/genética , Síndromes Miasténicos Congénitos/patología , Linaje , EmbarazoRESUMEN
Fetal akinesia deformation sequence (FADS) is a clinically and genetically heterogeneous condition. Pathogenic variants in DOK7 are known to cause myasthenic syndrome, congenital, 10 (MIM#254300) and, rarely (reported in a single family) lethal FADS. Herein, we describe a biallelic variant c.1263dupC in DOK7, known to cause congenital myasthenic syndrome 10, causing lethal FADS in a consanguineous family. The present report illustrates wide phenotypic variability caused by biallelic pathogenic variants in DOK7. We also describe the second family with FADS due to pathogenic variants in DOK7.
Asunto(s)
Anomalías Múltiples/patología , Artrogriposis/patología , Discapacidades del Desarrollo/patología , Feto/patología , Proteínas Musculares/genética , Mutación , Anomalías Múltiples/genética , Artrogriposis/genética , Discapacidades del Desarrollo/genética , Femenino , Feto/metabolismo , Frecuencia de los Genes , Edad Gestacional , Humanos , LinajeRESUMEN
Recessive variants in the GLDN gene, which encodes the gliomedin protein and is involved in nervous system development, have recently been associated with Arthrogryposis Multiplex Congenita (AMC), a heterogenous condition characterized by congenital contractures of more than one joint. Two cohorts of patients with GLDN-associated AMC have previously been described, evolving the understanding of the condition from lethal to survivable with the provision of significant neonatal support. Here, we describe one additional patient currently living with the syndrome, having one novel variant, p.Leu365Phe, for which we provide functional data supporting its pathogenicity. We additionally provide experimental data for four other previously reported variants lacking functional evidence, including p.Arg393Lys, the second variant present in our patient. We discuss unique and defining clinical features, adding calcium-related findings which appear to be recurrent in the GLDN cohort. Finally, we compare all previously reported patients and draw new conclusions about scope of illness, with emphasis on the finding of pulmonary hypoplasia, suggesting that AMC secondary to GLDN variants may be best fitted under the umbrella of fetal akinesia deformation sequence (FADS).
Asunto(s)
Artrogriposis/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Artrogriposis/patología , Preescolar , Femenino , Humanos , Mutación , LinajeRESUMEN
This study in Parkinson's disease examined how spatiotemporal parameters in gait bradykinesia link to difficulty in terminating posture and initiating gait locomotion. 41 idiopathic Parkinson's disease patients and 15 age-matched healthy subjects participated in this study. After the patients fixated on a visual-fixation-target, gait was triggered by visual or vocal cue-stimulus. The LED instructed subjects to quickly achieve their own comfortable walking speed on a level floor. The posterior-anterior force of the y-axis vectors of sole relating to soleus and tibialis-anterior EMGs were examined. Step-gain was defined as the duration of the swing-phase relative that of the contralateral stance-phase. Dynamic-ratio was defined as the duration the fore-foot phase relative to that of the ipsilateral stance-phase as forward-oriented movement in each step. The pause in tonic soleus EMG was defined as the off-latency of posture (termination) and the onset of a tibialis-anterior EMG-burst as the on-latency of gait. In Parkinson's disease, soleus off-latencies were prolonged, whereas tibialis-anterior on-latencies were less prolonged. Unsynchronized off/on-latency differences correlated with spatiotemporal parameters of dynamic-ratios, step-gains, gait-initiation, and gait speed in gait bradykinesia. Delayed EMG off-latencies correlated with prolonged motor-latencies in gait bradykinesia as delayed initial backward body-shift. A delayed and deficient initial backward body-shift of y-axis vector was linked to each difficulty in terminating posture and initiating gait, changing to random gait akinesia. Gait bradykinesia in Parkinson's disease stemmed from unsynchronized off/on-latency EMG activities, linking to each difficulty in terminating posture and initiating gait synergic movement through an initial backward body-shift.
Asunto(s)
Fenómenos Biomecánicos/fisiología , Pie/fisiopatología , Trastornos Neurológicos de la Marcha/fisiopatología , Hipocinesia/fisiopatología , Músculo Esquelético/fisiopatología , Enfermedad de Parkinson/fisiopatología , Postura/fisiología , Anciano , Anciano de 80 o más Años , Electromiografía , Femenino , Trastornos Neurológicos de la Marcha/etiología , Humanos , Hipocinesia/etiología , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicacionesRESUMEN
In Parkinson's disease (PD), abnormal movements consisting of hypokinetic and hyperkinetic manifestations commonly lead to nocturnal distress and sleep impairment, which significantly impact quality of life. In PD patients, these nocturnal disturbances can reflect disease-related complications (e.g., nocturnal akinesia), primary sleep disorders (e.g., rapid eye movement behaviour disorder), or both, thus requiring different therapeutic approaches. Wearable technologies based on actigraphy and innovative sensors have been proposed as feasible solutions to identify and monitor the various types of abnormal nocturnal movements in PD. This narrative review addresses the topic of abnormal nocturnal movements in PD and discusses how wearable technologies could help identify and assess these disturbances. We first examine the pathophysiology of abnormal nocturnal movements and the main clinical and instrumental tools for the evaluation of these disturbances in PD. We then report and discuss findings from previous studies assessing nocturnal movements in PD using actigraphy and innovative wearable sensors. Finally, we discuss clinical and technical prospects supporting the use of wearable technologies for the evaluation of nocturnal movements.
Asunto(s)
Movimiento , Enfermedad de Parkinson , Dispositivos Electrónicos Vestibles , Actigrafía , Humanos , Hipercinesia/diagnóstico , Hipocinesia/diagnóstico , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Calidad de Vida , Sueño , Trastornos del Sueño-Vigilia/etiologíaRESUMEN
BACKGROUND: Deep brain stimulation (DBS) is a well-accepted treatment of Parkinson's disease (PD). Motor phenotypes include tremor-dominant (TD), akinesia-rigidity (AR), and postural instability gait disorder (PIGD). The mechanism of action in how DBS modulates motor symptom relief remains unknown. OBJECTIVE: Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to determine whether the functional activity varies in response to DBS depending on PD phenotypes. MATERIALS AND METHODS: Subjects underwent an fMRI scan with DBS cycling ON and OFF. The effects of DBS cycling on BOLD activation in each phenotype were documented through voxel-wise analysis. For each region of interest, ANOVAs were performed using T-values and covariate analyses were conducted. Further, a correlation analysis was performed comparing stimulation settings to T-values. Lastly, T-values of subjects with motor improvement were compared to those who worsened. RESULTS: As a group, BOLD activation with DBS-ON resulted in activation in the motor thalamus (p < 0.01) and globus pallidus externa (p < 0.01). AR patients had more activation in the supplementary motor area (SMA) compared to PIGD (p < 0.01) and TD cohorts (p < 0.01). Further, the AR cohort had more activation in primary motor cortex (MI) compared to the TD cohort (p = 0.02). Implanted nuclei (p = 0.01) and phenotype (p = <0.01) affected activity in MI and phenotype alone affected SMA activity (p = <0.01). A positive correlation was seen between thalamic activation and pulse-width (p = 0.03) and between caudate and total electrical energy delivered (p = 0.04). CONCLUSIONS: These data suggest that DBS modulates network activity differently based on patient motor phenotype. Improved understanding of these differences may further our knowledge about the mechanisms of DBS action on PD motor symptoms and to optimize treatment.