Neuroimaging in Friedreich's ataxia : new approaches and clinical aplication

Orientadores: Marcondes Cavalcante França Junior, Andreia Vasconcellos FariaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A ataxia de Friedreich (FRDA) é a ataxia autossômica recessiva mais comum no mundo. Clinicamente, é caracterizada por início precoce, alterações sensoriais e ataxia de lenta progressão. Os estudos de imagem têm focado somente em estruturas infratentoriais, desconsiderando o envolvimento de estruturas supratentoriais, diferenças fenotípicas e duração da doença, bem como a evolução do dano neurológico. Portanto, o objetivo deste trabalho é avaliar, por meio de imagens de ressonância magnética multimodal, pacientes com ataxia de Friedreich a fim de compreender a evolução do dano encefálico, identificar o padrão de dano encefálico entre os fenótipos da doença, os sítios de depósitos de ferro extra-cerebelares e as primeiras estruturas acometidas na doença. A fim de atingir todos os objetivos, foram recrutados 25 pacientes adultos com a forma clássica da doença, 13 pacientes com início tardio e 12 pacientes pediátricos. Para quantificar a gravidade da doença foi utilizada a escala FARS. O dano estrutural de substância cinza e branca foi avaliado via imagens de ressonância magnética ponderadas em T1, T2 e DTI. Para análise de tais imagens foram utilizadas as ferramentas FreeSurfer, T1 MultiAtlas, DTI Multiatlas, SPM, SpineSeg e TBSS. As comparações de grupos revelaram comprometimento microestrutural multifocal na substância branca encefálica na FRDA, com dano extenso nos pedúnculos cerebelares, corpo caloso e tratos piramidais. Encontramos também alterações na substância cinzenta no núcleo denteado do cerebelo, tronco e córtex motor. Nós não identificamos mudanças volumétricas longitudinais, porém análises prospectivas da substância branca identificaram anormalidades microestruturais progressivas no corpo caloso, tratos piramidais e pedúnculos cerebelares superiores após um ano de seguimento. A respeito do estudo comparando o tipo clássico e o tipo tardio (cFRDA vs. LOFA), nós mostramos que ambos os fenótipos possuem um padrão de anormalidades similares, mas não idênticas. Embora sutis, as diferenças estruturais encontradas ajudam a explicar a variabilidade fenotípica entre estas duas apresentações da doença. Por exemplo, o maior dano microestrutural no trato córtico-espinhal no grupo LOFA ajuda a explicar os sinais piramidais mais exuberantes neste grupo. Não fomos capazes de identificar depósitos de ferro cerebrais nos pacientes com FRDA. Neste sentido, tais depósitos ficariam restritos somente ao núcleo denteado do cerebelo. Por fim, fomos capazes de observar que a manifestação inicial da doença, vista em pacientes pediátricos, se concentra na medula espinhal e no pedúnculo cerebelar inferiorAbstract: Friedreich¿s ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide; it is characterized by early onset, sensory abnormalities and slowly progressive ataxia. Besides that, most of neuroimaging studies have been focused only in infratentorial structures of adult patients. Furthermore, studies comparing different phenotypes of disease does not exist. Therefore, the objective of this study is to assess, using multimodal magnetic (MRI) resonance imaging, patients with Friedreich ataxia to better comprehend the progression of brain damage, to identify the pattern of damage across disease phenotypes, to identify areas with abnormal iron deposits in the brain and to characterize the structures initially damaged in early disease stages. To accomplish that, we enrolled 25 adult patients with classical FRDA, 13 patients with late-onset FRDA and 12 pediatric patients. The FARS scale was employed to quantify the disease severity. To assess the structural damage in gray and white matter, we acquired T1-weighted, T2-weighted and DTI images of the brain. To evaluate these images, we used the following tools: FreeSurfer, T1 MultiAtlas, SPM, DTI MultiAtlas, SpineSeg and TBSS. After group comparisons, there was widespread microstructural damage in the cerebral white matter, including cerebellar peduncles, corpus callosum and pyramidal tracts of patients with FRDA. We also found gray matter volumetric reduction in the dentate nuclei of the cerebellum, brainstem and motor cortex. We did not find volumetric reduction over time, but there was progressive white matter microstructural damage in the corpus callosum, pyramidal tracts and superior cerebellar peduncles after 1 year of follow-up. Regarding the disease phenotypes, we found that both classical FRDA and LOFA have similar, but not identical neuroimaging signatures. Although subtle, the structural differences might help to explain the phenotypic differences seen in both conditions. The corticospinal tracts are damaged in both conditions, but more severely in the late-onset FRDA group, which may explain why pyramidal signs are more evident in the latter subgroup. We failed to identify iron deposits in brain regions other than the dentate nuclei of patients with FRDA. Finally, we found that the spinal cord and inferior cerebellar peduncles are the structures compromised in pediatric patients with FRDADoutoradoFisiopatologia MédicaDoutor em Ciências2014/19786-7, 2015/09793-9FAPES

Neuroimaging in Hereditary Spastic Paraplegias: Current Use and Future Perspectives

Hereditary spastic paraplegias (HSP) are a large group of genetic diseases characterized by progressive degeneration of the long tracts of the spinal cord, namely the corticospinal tracts and dorsal columns. Genotypic and phenotypic heterogeneity is a hallmark of this group of diseases, which makes proper diagnosis and management often challenging. In this scenario, magnetic resonance imaging (MRI) emerges as a valuable tool to assist in the exclusion of mimicking disorders and in the detailed phenotypic characterization. Some neuroradiological signs have been reported in specific subtypes of HSP and are therefore helpful to guide genetic testing/interpretation. In addition, advanced MRI techniques enable detection of subtle structural abnormalities not visible on routine scans in the spinal cord and brain of subjects with HSP. In particular, quantitative spinal cord morphometry and diffusion tensor imaging look promising tools to uncover the pathophysiology and to track progression of these diseases. In the current review article, we discuss the current use and future perspectives of MRI in the context of HSP

Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3

Background: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity. Objective: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease. Methods: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels. Results: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume. Conclusion: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Twenty-five years since the identification of the first SCA gene: history, clinical features and perspectives for SCA1

ABSTRACT Spinocerebellar ataxias (SCA) are a clinically and genetically heterogeneous group of monogenic diseases that share ataxia and autosomal dominant inheritance as the core features. An important proportion of SCAs are caused by CAG trinucleotide repeat expansions in the coding region of different genes. In addition to genetic heterogeneity, clinical features transcend motor symptoms, including cognitive, electrophysiological and imaging aspects. Despite all the progress in the past 25 years, the mechanisms that determine how neuronal death is mediated by these unstable expansions are still unclear. The aim of this article is to review, from an historical point of view, the first CAG-related ataxia to be genetically described: SCA 1

Autonomic dysfunction is frequent and disabling in non-paraneoplastic sensory neuronopathies

Sensory neuronopathies (SN) are characterized by asymmetric non-length dependent sensory deficits and sensory ataxia. Autonomic dysfunction in SN was not yet evaluated regarding its frequency, characteristics and relationship to sensory deficits. To address these issues, we performed a comprehensive clinical and neurophysiological evaluation of a large cohort of patients with non-paraneoplastic SN (np-SN). Methods: We enrolled 50 consecutive patients with npSN and 32 age/sex-matched healthy controls. They were clinically evaluated (SCOPA-Aut scale) and underwent neurophysiological autonomic assessment (quantitative sudomotor axon reflex test, heart rate variability and sympathetic skin response). Results: Mean age of patients was 50.9 +/- 10.3 years and there were 18 men. npSN patients had higher SCOPA-Aut scores than controls (26.63 +/- 12.72 vs. 12.66 +/- 9.11, p < .001). QSART was abnormal in 92% of the patients - sweat volumes in all examined sites were smaller among patients (p < .001). Cardiovascular autonomic neuropathy was more frequent in these patients as well (p < .001). Conclusion: Altogether our results suggest that autonomic dysfunction in distinct domains is frequent in npSN patients. These findings suggest that the clinical picture of npSN is related to a double neuronopathy: sensory and autonomic.402111117FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2013/26410-0; 2013/01766-

SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage

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 3 T MRI scan. Mean age and disease duration were 29 and 13.2 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. Keywords: Complicated hereditary spastic paraplegia, SPG11, Motor neuron disorder, Thinning of the corpus callosum, White matter, Grey matter, Spinal cor

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