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Title: | Cerebellar morphometric and spectroscopic biomarkers for Machado-Joseph Disease | Authors: | 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 |
Keywords: | Machado-Joseph disease (MJD); Spinocerebellar ataxia type 3 (SCA3); Magnetic resonance imaging (MRI); Proton magnetic resonance spectroscopy (1H-MRS) biomarkers; Motor performance | Issue Date: | 2022 | Project: | SpreadSilencing (POCI-01–0145-FEDER-029716) BIGDATIMAGE (CENTRO-01–0145-FEDER-000016) Imagene (POCI-01–0145-FEDER-016807) CancelStem (POCI-01–0145-FEDER-016390), SFR/BPD/87732/2012 SFRH/ BD/65341/2009 SFRH/BPD/85024/2012 SFRH/BPD/66705/2009 SFRH/BPD/112863/2015 SAICTPAC/0010/2015 PTDC/NEU-NMC/0084/2014 CENTRO-01-0145-FEDER-000008/BrainHealth2020 UID/NEU/04539/2019 PINFRA/22095/2016 |
Serial title, monograph or event: | Acta Neuropathologica Communications | Volume: | 10 | Issue: | 1 | Abstract: | 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. | URI: | https://hdl.handle.net/10316/102828 | ISSN: | 2051-5960 | DOI: | 10.1186/s40478-022-01329-4 | Rights: | openAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais FFUC- Artigos em Revistas Internacionais FMUC Medicina - Artigos em Revistas Internacionais I&D CIBB - Artigos em Revistas Internacionais IIIUC - Artigos em Revistas Internacionais I&D MARE - Artigos em Revistas Internacionais I&D CIBIT - Artigos em Revistas Internacionais I&D ICNAS - Artigos em Revistas Internacionais FCTUC Eng.Electrotécnica - Artigos em Revistas Internacionais I&D IBILI - Artigos em Revistas Internacionais |
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