Author(s):
Miranda, Catarina Oliveira ; Nobre, Rui Jorge ; Paiva, Vítor Hugo ; Duarte, João Valente ; Castelhano, João ; Petrella, Lorena Itati ; Sereno, José ; Santana, Magda ; Afonso, Sónia ; Januário, Cristina ; Castelo Branco, Miguel ; Almeida, Luís Pereira de
Date: 2022
Persistent ID: https://hdl.handle.net/10316/102828
Origin: Estudo Geral - Universidade de Coimbra
Subject(s): Machado-Joseph disease (MJD); Spinocerebellar ataxia type 3 (SCA3); Magnetic resonance imaging (MRI); Proton magnetic resonance spectroscopy (1H-MRS) biomarkers; Motor performance; Animals; Biomarkers; Cerebellum; Glutamic Acid; Humans; Mice; Mice, Transgenic; Taurine; Machado-Joseph Disease
Description
Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is the most common form of dominant SCA worldwide. Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (1H-MRS) provide promising non-invasive diagnostic and follow-up tools, also serving to evaluate therapies efficacy. However, pre-clinical studies showing relationship between MRI-MRS based biomarkers and functional performance are missing, which hampers an efficient clinical translation of therapeutics. This study assessed motor behaviour, neurochemical profiles, and morphometry of the cerebellum of MJD transgenic mice and patients aiming at establishing magnetic-resonance-based biomarkers. 1H-MRS and structural MRI measurements of MJD transgenic mice were performed with a 9.4 Tesla scanner, correlated with motor performance on rotarod and compared with data collected from human patients. We found decreased cerebellar white and grey matter and enlargement of the fourth ventricle in both MJD mice and human patients as compared to controls. N-acetylaspartate (NAA), NAA + N-acetylaspartylglutamate (NAA + NAAG), Glutamate, and Taurine, were significantly decreased in MJD mouse cerebellum regardless of age, whereas myo-Inositol (Ins) was increased at early time-points. Lower neurochemical ratios levels (NAA/Ins and NAA/total Choline), previously correlated with worse clinical status in SCAs, were also observed in MJD mice cerebella. NAA, NAA + NAAG, Glutamate, and Taurine were also positively correlated with MJD mice motor performance. Importantly, these 1H-MRS results were largely analogous to those found for MJD in human studies and in our pilot data in human patients. We have established a magnetic resonance-based biomarker approach to monitor novel therapies in preclinical studies and human clinical trials.
UID/4950/2020, UID/NEU/04539/2019, as well as SynSpread, ESMI and ModelPolyQ under the EU Joint Program—Neurodegenerative Disease Research (JPND), the last two co-funded by the European Union H2020 program, GA No.643417; by the Association Française contre les Myopathies-Téléthon no. 21163, by National Ataxia Foundation (USA), the American Portuguese Biomedical Research Fund (APBRF—no grant number) and the Richard Chin and Lily Lock Machado-Joseph Disease Research Fund (no grant number). Our Laboratory received funding from these Institutions herein referred.
