Asunto(s)
Ataxia/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Síndrome del Cromosoma X Frágil/diagnóstico por imagen , Ataxia de la Marcha/diagnóstico por imagen , Temblor/diagnóstico por imagen , Adulto , Anciano , Ataxia/genética , Ataxia/fisiopatología , Fenómenos Biomecánicos , Encéfalo/patología , Estudios de Casos y Controles , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/fisiopatología , Ataxia de la Marcha/genética , Ataxia de la Marcha/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , ARN Mensajero/metabolismo , Tálamo/diagnóstico por imagen , Tálamo/patología , Temblor/genética , Temblor/fisiopatología , Expansión de Repetición de TrinucleótidoRESUMEN
Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological disorder characterized by early autonomic dysfunction, cognitive impairment, pyramidal tract and cerebellar dysfunction, and white matter loss in the central nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression. How duplication of LMNB1 leads to myelin defects is unknown. To address this question, we developed a mouse model of ADLD that overexpresses lamin B1. These mice exhibited cognitive impairment and epilepsy, followed by age-dependent motor deficits. Selective overexpression of lamin B1 in oligodendrocytes also resulted in marked motor deficits and myelin defects, suggesting these deficits are cell autonomous. Proteomic and genome-wide transcriptome studies indicated that lamin B1 overexpression is associated with downregulation of proteolipid protein, a highly abundant myelin sheath component that was previously linked to another myelin-related disorder, Pelizaeus-Merzbacher disease. Furthermore, we found that lamin B1 overexpression leads to reduced occupancy of Yin Yang 1 transcription factor at the promoter region of proteolipid protein. These studies identify a mechanism by which lamin B1 overexpression mediates oligodendrocyte cell-autonomous neuropathology in ADLD and implicate lamin B1 as an important regulator of myelin formation and maintenance during aging.
Asunto(s)
Lamina Tipo B/metabolismo , Oligodendroglía/patología , Enfermedad de Pelizaeus-Merzbacher/metabolismo , Animales , Axones/metabolismo , Axones/patología , Modelos Animales de Enfermedad , Ataxia de la Marcha/metabolismo , Ataxia de la Marcha/patología , Ataxia de la Marcha/fisiopatología , Predisposición Genética a la Enfermedad , Humanos , Lamina Tipo B/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora , Proteína Proteolipídica de la Mielina/genética , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Oligodendroglía/metabolismo , Enfermedad de Pelizaeus-Merzbacher/patología , Enfermedad de Pelizaeus-Merzbacher/fisiopatología , Regiones Promotoras Genéticas , Unión Proteica , Prueba de Desempeño de Rotación con Aceleración Constante , Convulsiones/metabolismo , Convulsiones/patología , Convulsiones/fisiopatología , Factor de Transcripción YY1/metabolismoRESUMEN
Following the hypothesis that thalamic deep brain stimulation improves ataxia in patients with essential tremor by modulating the cerebello-thalamo-cortical pathway, we examined the joint kinematics of lower limbs during uninterrupted gait in eleven patients who have been treated with bilateral thalamic stimulation for 24.7±20.3 months. Patients were assessed under routine chronic stimulation, supra-therapeutic amplitude, and off stimulation by means of an infrared movement analysis system while walking on a treadmill. Chronic thalamic DBS normalized the highly variable excursion throughout the gait cycle that characterized the subgroup of patients with longest disease duration. Supratherapeutic thalamic DBS amplitude did not reproduce such improvements while, more importantly, it induced ataxic changes of joint excursion. The normalization of kinematic abnormalities argues against the hypothesis of a cerebellar neurodegeneration in ET. Moreover, these results suggest that the beneficial effect of thalamic DBS on ataxic symptoms is limited to a narrow therapeutic window.
Asunto(s)
Articulación del Tobillo/fisiopatología , Estimulación Encefálica Profunda , Temblor Esencial/complicaciones , Ataxia de la Marcha/fisiopatología , Ataxia de la Marcha/terapia , Articulación de la Cadera/fisiopatología , Articulación de la Rodilla/fisiopatología , Tálamo , Anciano , Fenómenos Biomecánicos , Temblor Esencial/terapia , Femenino , Ataxia de la Marcha/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Rango del Movimiento ArticularRESUMEN
Patients with advanced stages of essential tremor frequently exhibit tandem gait ataxia with impaired balance control and imprecise foot placement, resembling patients with a cerebellar deficit. Thalamic deep brain stimulation, a surgical therapy for otherwise intractable cases, has been shown to improve tremor, but its impact on cerebellar-like gait difficulties remains to be elucidated. Eleven patients affected by essential tremor (five females; age 69.8 ± 3.9 years; disease duration 24.4 ± 11.2 years; follow-up after surgery 24.7 ± 20.3 months) were evaluated during the following conditions: stimulation off, stimulation on and supra-therapeutic stimulation. Ten age-matched healthy controls served as the comparison group. Locomotion by patients and controls was assessed with (i) overground gait and tandem gait; (ii) balance-assisted treadmill tandem gait and (iii) unassisted treadmill gait. The two treadmill paradigms were kinematically analysed using a 3D opto-electronic motion analysis system. Established clinical and kinesiological measures of ataxia were computed. During stimulation off, the patients exhibited ataxia in all assessment paradigms, which improved during stimulation on and worsened again during supra-therapeutic stimulation. During over ground tandem gait, patients had more missteps and slower gait velocities during stimulation off and supra-therapeutic stimulation than during stimulation on. During balance-assisted tandem gait, stimulation on reduced the temporospatial variability in foot trajectories to nearly normal values, while highly variable (ataxic) foot trajectories were observed during stimulation off and supra-therapeutic stimulation. During unassisted treadmill gait, stimulation on improved gait stability compared with stimulation off and supra-therapeutic stimulation, as demonstrated by increased gait velocity and ankle rotation. These improvements in ataxia were not a function of reduced tremor in the lower limbs or torso. In conclusion, we demonstrate the impact of thalamic stimulation on gait ataxia in patients with essential tremor with improvement by stimulation on and deterioration by supra-therapeutic stimulation, despite continued control of tremor. Thus, cerebellar dysfunction in these patients can be differentially modulated with optimal versus supra-therapeutic stimulation. The cerebellar movement disorder of essential tremor is due to a typical cerebellar deficit, not to trembling extremities. We hypothesize that deep brain stimulation affects two major regulating circuits: the cortico-thalamo-cortical loop for tremor reduction and the cerebello-thalamo-cortical pathway for ataxia reduction (stimulation on) and ataxia induction (supra-therapeutic stimulation).
Asunto(s)
Estimulación Encefálica Profunda , Temblor Esencial/complicaciones , Temblor Esencial/terapia , Ataxia de la Marcha/etiología , Ataxia de la Marcha/terapia , Tálamo/fisiología , Anciano , Ataxia/etiología , Ataxia/terapia , Fenómenos Biomecánicos , Mapeo Encefálico , Cerebelo/fisiopatología , Corteza Cerebral/fisiopatología , Electrodos , Electromiografía , Temblor Esencial/fisiopatología , Femenino , Marcha/fisiología , Ataxia de la Marcha/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Equilibrio Postural/fisiología , Técnicas EstereotáxicasRESUMEN
Pentosan polysulphate, delivered by chronic intraventricular infusion, has been proposed as a potential therapy for human prion disease. The first treated patient is still alive several years after treatment started. Here we describe in detail a case of variant Creutzfeldt-Jakob disease in which this treatment was started at a relatively early stage but had no definite clinical benefit. The patient died from disease progression 16 months after diagnosis and 5 months after pentosan polysulphate treatment was commenced.