Novos biomarcadores morfométricos do cerebelo por ressonância magnética: validação na doença de Machado-Joseph

Abstract

The Machado-Joseph Disease (MJD), or type 3 spinocerebelar ataxia (SCA3), is an hereditary autossomic dominant and degenerative disease that was described for the first time among Portuguese individuals. This disease mainly affects the cerebellum and usually becomes manifest between the fifth and the seventh decade of life, and includes dysarthria and march ataxia. The objective of this thesis was to develop a morphometric, in vivo, non-invasive biomarker with high space resolution, sensibility and replicability for the identification of SCA3 cases. The necessary focus on the cerebellum for the effect has the additional benefit of helping to better understand this structure, that is so relevant but less studied than the rest of the brain. This thesis included a functional magnetic resonance (fMRI) which revealed a decrease of cerebellar activations on an initial stage of the DMJ, which suggested that functional differences may occur even prior to of early morphological alterations. We also identified compensatory phenomena, that were dependent of task difficulty. Particularly, it was observed the volume activation decrease at the cerebellum level on SCA3 carriers’ patients group after having performed a functional paradigm that required participants to perform synchornous and asyncronous motor tasks. A quantitative analysis of the morphometric transformations using MR is useful on the identification of early lesions and, above all, on the cerebellum diseases’ progression monitoring. However, the majority of previous studies were carried out in advanced stages of the disease and with low statistical power and/or signal/noise relation, which was overcome by the strong collaboration with the University Hopstial and ICNAS’ technological facilities in Coimbra. Additionally, alterations identified in other studies were often analyzed as general group differences, regarding its pathological profile instead of the development of a biomarker, which was the primary objective of this thesis. This study required the acquisition of high resolution MR images at 3T and the extraction of morphometric information using Voxel-Based Morphometry (VBM), a whole brain analysis method to determine, without bias, an atrophy pattern facing a control group or correlated with genetic and clinical metrics. This analytical process was complemented by the use of a model based on statistical classifiers, to define XVIII predictive values, sensibility and specificity, in order to validate a method with clinical application, especially at the disease’s progression monitoring level. The study carried out using VBM enabled to identify important areas of neurodegeneration in the SCA3 carriers’ patients, namely at the thalamus, cerebellum, parietal lobe (post-central gyrus) and insula level. In order to define a biomarker, ataxias were the chosen model, since their relation with cerebellar pathology is known. The development of this morphometric biomarker is an important tool for the realization and monitoring of clinical essays, whose observations enable the validation of their result’s objective measures, in order to for example, identify pre-clinical alterations that may justify the treatment of mutations’ carriers without stablished disease. Neuroimaging and neuropathology have consistently demonstrated cerebellar alterations. Here we further aimed to discover whole-brain functional biomarkers, based on parametric performance-level-dependent signals. The study was performed in 13 patients with early SCA3 and 14 healthy participants. We used a combined parametric behavioral/functional neuroimaging design to investigate disease fingerprints, as a function of performance levels, coupled with structural MRI and voxel-based morphometry. Functional magnetic resonance imaging (fMRI) was designed to parametrically analyze behavior and neural responses to audio-paced bilateral thumb movements at temporal frequencies of 1, 3, and 5 Hz. Our performance-level-based design probing neuronal correlates of motor coordination enabled the discovery that neural activation and behavior show critical loss of parametric modulation specifically in SCA3, associated with frequency-dependent cortico/subcortical activation/deactivation patterns. Cerebellar/cortical rate-dependent dissociation patterns could clearly differentiate between groups irrespective of grey matter loss. Our findings suggest functional reorganization of the motor network and indicate a possible role of fMRI as a tool to monitor disease progression in SCA3. Accordingly, fMRI patterns proved to be potential biomarkers in early SCA3, as tested by receiver operating characteristic analysis of both behavior and neural activation at different frequencies. Discrimination analysis based on BOLD signal in response to the applied parametric finger-tapping task significantly often reached >80% sensitivity and specificity in single regions-of-interest. Functional fingerprints based on cerebellar and cortical BOLD performance dependent signal modulation can thus be combined as diagnostic and/or therapeutic targets in hereditary ataxia.