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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.

Abstract Background The identification of circulating biomarkers that closely correlate with Parkinson’s Disease (PD) has failed several times in the past. Nevertheless, in this pilot study, a translational approach was conducted, allowing the evaluation of the plasma levels of two mitochondrial-related proteins, whose combination leads to a robust model with potential diagnostic value to discriminate the PD patients from matched controls. Methods The proposed translational approach was initiated by the analysis of secretomes from cells cultured under control or well-defined oxidative stress conditions, followed by the identification of proteins related to PD pathologic mechanisms that were altered between the two states. This pipeline was further translated into the analysis of undepleted plasma samples from 28 control and 31 PD patients. Results From the secretome analysis, several mitochondria-related proteins were found to be differentially released between control and stress conditions and to be able to distinguish the two secretomes. Similarly, two mitochondrial-related proteins were found to be significantly changed in a PD cohort compared to matched controls. Moreover, a linear discriminant model with potential diagnostic value to discriminate PD patients was obtained using the combination of these two proteins. Both proteins are associated with apoptotic mitochondrial changes, which may correspond to potential indicators of cell death. Moreover, one of these proteins, the VPS35 protein, was reported in plasma for the first time, and its quantification was only possible due to its previous identification in the secretome analysis. Conclusions In this work, an adaptation of a translational pipeline for biomarker selection was presented and transposed to neurological diseases, in the present case Parkinson’s Disease. The novelty and success of this pilot study may arise from the combination of: i) a translational research pipeline, where plasma samples are interrogated using knowledge previously obtained from the evaluation of cells’ secretome under oxidative stress; ii) the combined used of statistical analysis and an informed selection of candidates based on their link with relevant disease mechanisms, and iii) the use of SWATH-MS, an untargeted MS method that allows a complete record of the analyzed samples and a targeted data extraction of the quantitative values of proteins previously identified.

Abstract Background This study aims to test response inhibition in premanifest Huntington’s disease individuals (Pre-HD), in the context of a saccadic paradigm with working memory demands and fronto-executive load as a way to measure inhibitory control deficits and impulsive behavior in Huntington’s disease (HD). Methods The oculomotor function of 15 Pre-HD and 22 Control individuals was assessed using an experimental paradigm comprising four horizontal saccadic tasks: prosaccade (PS), antisaccade (AS), 1- or 2-back memory prosaccade (MPS), and 1- or 2-back memory antisaccade (MAS). Success rate, latency, directional and timing errors were calculated for each task. A comprehensive battery of neuropsychological tests was also used to assess the overall cognitive functioning of study participants. Statistical correlations between oculomotor, clinical and cognitive measures were computed for the Pre-HD group. Results Pre-HD participants showed reduced success rate in the AS task, increased direction errors in the AS and MAS tasks and decreased latency in the MAS task when compared to Controls, despite presenting similar executive and memory scores in the conventional neuropsychological tests applied. Significant associations were identified between specific AS and MAS parameters and disease-related measures, cognitive skills and other oculomotor results of Pre-HD participants. Conclusions Our results show that oculomotor performance in premanifest Huntington’s disease deteriorates once inhibitory control, working memory and/or fronto-executive load are added to the task. A more automatic pattern of performance, including a faster response time and directionally erroneous eye movements were detected in the oculomotor behavior of the Pre-HD group—these alterations were significantly correlated with disease stage and cognitive status. Our saccadic paradigm was able to capture impulsivity and inhibitory control deficits in a group of Pre-HD individuals on average far from symptom onset, thus holding the potential to identify the earliest disease-related changes.