Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/102828
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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