RESUMEN
BACKGROUND: Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias. OBJECTIVES: To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa. METHODS: Patients and controls underwent single-photon emission computed tomography imaging utilizing 99m Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores. RESULTS: Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial. CONCLUSION: Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Levodopa/uso terapéutico , Mutación/genética , Trastornos Parkinsonianos , Proteínas/genética , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Trastornos del Conocimiento/etiología , Estudios de Cohortes , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Humanos , Masculino , Trastornos Mentales/etiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Compuestos de Organotecnecio/farmacocinética , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/genética , Método Simple Ciego , Estadísticas no Paramétricas , Tomógrafos Computarizados por Rayos X , Tomografía Computarizada de Emisión de Fotón Único , Tropanos/farmacocinética , Adulto JovenRESUMEN
SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3â¯T MRI scan. Mean age and disease duration were 29 and 13.2â¯years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.