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| Author(s): |
Anelyssa Cysne Frota D'Abreu
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2009-01-27 |
| Examining board members: |
Fernando Cendes;
Egberto Reis Barbosa;
Antonio Carlos dos Santos;
Carlos Alberto Mantovani Guerreiro;
Li Min Li
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| Advisor: | Fernando Cendes |
| Abstract | |
Machado-Joseph disease or spinocerebellar ataxia type 3 (SCA3/MJD) is an autosomal dominant ataxia resulting from an expansion of a CAG triplet at the MDJ1 gene located on chromosome 14q. Clinically, it is characterized by cerebellar ataxia, peripheral neuropathy, pyramidal and extrapyramidal syndrome and ophthalmoplegia. The age of onset is variable and inversely correlated with the size of the CAG expansion. Patients with early symptoms tend to have a more severe clinical picture, and the anticipation phenomenon was described in these patients. MJD/SCA3 is progressive and there is no specific treatment. The objectives of this study were: 1) to prospectively evaluate a significant number of patients with MJD/SCA3, through standardized questionnaires and validated scales; 2) To assess the current clinical tools for the evaluation of patients with MJD/SCA3; 3) To perform a longitudinal neuroimaging study in MJD/SCA3, correlating those findings with genetical and clinical markers. Patients were evaluated in a systematic manner through a standardized clinical form, neurological examination, ICARS (International cooperative ataxia rating scale) and UMSARS (Unified Multiple System Atrophy Rating Scale), and Magnetic Resonance Imaging of the brain (MRI). In thirty patients we were able to repeat the MRI after an interval of approximately 12 months. Initially, we investigated whether the ICARS and UMSARS would be suitable for the clinical evaluation of these patients. Both scales (ICARS and UMSARS) had adequate internal consistency with scores a> 0.90. However, the oculomotor subscore (ICARS) obtained a = 0.08. Intraclass correlation coefficient was 0.94 for ICARS, 0.96 for UMSARS-I-II UMSARS to 0.97 and 0.94 for UMSARS-IV ("global disability score" (GDS)). There was an almost perfect correlation between the scores of ICARS and UMARS-II. There was clearly an interference of symptoms other than ataxia in total scores of both scales. Especially patients with dystonia, regardless of clinical subtype, showed the highest scores. Moreover, the total ICARS score showed to be sensitive to change after a period of one year, demonstrating the validity of the scale in the longitudinal evaluation of patients. As this project was inserted into a larger project, involving the evaluation of non-motor symptoms, we evaluated 52 patients for the presence of sleep related complains. We interviewed all patients through a standardized sleep questionnaire and performed the Epworth Sleepiness Scale (ESS). Of these, 23 had ESS scores above 10, suggesting excessive daytime sleepiness. An interesting finding was the high frequency of patients with insomnia (19 patients). We also observed eleven patients with symptoms suggestive of restless legs syndrome, and eight with symptoms suggestive of REM behavior disorder (RBD). Sixteen patients used some kind of sleep inducing medication. The neuroimaging evaluation involved different analysis techniques. The initial step was the visual evaluation of the MRI sequences. We observed cerebellar atrophy in 28 patients; atrophy of the pons in 20 and atrophy of the medulla in 19; enlargement of the 4th ventricle in 17 and atrophy of the cerebellar peduncles on 12. Mild diffuse cortical atrophy was observed in 12 patients, while in six it was restricted to the frontal lobes. Twelve patients had areas of non-specific hyperintense lesions in the deep white matter. The second step was the analysis of the spectroscopy (MRS) data. We performed manual measurements of the peak area for NAA, Cr and Cho and compared NAA/Cr and Cho/Cr ratios between patients and control groups. We observed lower values of NAA / Cr in MJD when compared to controls (1.63 +/-0.41 (1.15-2.76) vs. 1.97+/-0.51 (1.50-2.92); U test = 219,000, p <0.001). The values of NAA/Cr did not correlate with any clinical variable or CAG repeat size. Due to the difference in age between controls and patients, we performed in a blinded fashion, a pairing between both groups, which resulted in a group of 15 patients and 15 controls. In this subgroup, the differences between NAA/Cr remained (U test = 44,000, p = 0.004). However, a difference between the levels of Cho/Cr was also found (0.86 + / -0.14 (0.71-1.15) and 0.98 + / -0.14 (0.78-1.23); U test = 53,000, p = 0014). Voxel-based morphometry (VBM) analysis occurred in two stages. At first, we compared patients to a control group. In the second analysis, we compare paired images of each patient with an approximate average interval of 12 months. We observed significant grey matter atrophy (p<0.01) at: frontal lobes (precentral, inferior, superior, middle frontal gyrus); parietal lobes (postcentral, inferior, superior, angular, supramarginal gyrus); middle temporal gyrus; cingulate gyrus; putamen. White matter atrophy was restricted to the cerebellum. Multiple areas showed an inverse correlation with CAG, age, age of onset and duration of illness. The longitudinal analysis, however, did not show a significant progression of brain pathology; possibly due to floor effect or the short follow-up interval. In order to confirm the VBM findings, we use a software for semi-automatic MRS analysis to compare MRS results from the first and second MRS failed to demonstrate a significant change in this interval. At last, we performed a comparative study between thalamic grey matter density and thalamic volume between patients and controls. There was a significant difference between grey matter density in patients (130.359 +/-16.758) and controls (153.193 +/- 23.599; p<0.001); as well as thalamic volumes (7862.5+/- 712.5 mm3 versus 8592.3+/-712.5 mm3; p<0.001). Thalamic volumes were significantly smaller in patients with dystonia when compared to patients without dystonia (7456.2+/-814.2 versus 7984.4+/- 644.8 mm3; p=0.0049). There was no significant correlation between thalamic volume and CAG repeat length, disease duration, age of onset and age (AU) | |