The lack of knowledge about the onset and progression of Parkinson's disease (PD) hampers its early diagnosis and treatment. Metabolomics might shed light on the PD imprint seeking a broader view of ...the biochemical remodeling induced by this disease in an early and pre-symptomatic stage and unveiling potential biomarkers. To achieve this goal, we took advantage of the great potential of the European Prospective Study on Nutrition and Cancer (EPIC) cohort to apply metabolomics searching for early diagnostic PD markers. This cohort consisted of healthy volunteers that were followed for around 15 years until June 2011 to ascertain incident PD. For this untargeted metabolomics-based study, baseline preclinical plasma samples of 39 randomly selected individuals that developed PD (Pre-PD group) and the corresponding control group were analyzed using a multiplatform approach. Data were statistically analyzed and exposed alterations in 33 metabolites levels, including significantly lower levels of free fatty acids (FFAs) in the preclinical samples from PD subjects. These results were then validated by adopting a targeted HPLC-QqQ-MS approach. After integrating all the metabolites affected, our finding revealed alterations in FFAs metabolism, mitochondrial dysfunction, oxidative stress, and gut-brain axis dysregulation long before the development of PD hallmarks. Although the biological purpose of these events is still unknown, the remodeled metabolic pathways highlighted in this work might be considered worthy prognostic biomarkers of early prodromal PD. The findings revealed by this work are of inestimable value since this is the first study conducted with samples collected many years before the disease development.
Abstract
The increasing capacity of today’s technology represents great advances in diagnosing diseases using standard procedures supported by computer science. Deep learning techniques are able to ...extract the characteristics of temporal signals to study their patterns and diagnose diseases such as essential tremor. However, these techniques require a large amount of data to train the neural network and achieve good results, and the more data the network has, the more accurate the final model implemented. In this work we propose the use of a data augmentation technique to improve the accuracy of a Long short-term memory system in the diagnosis of essential tremor. For this purpose, the multivariate Empirical Mode Decomposition method will be used to decompose the original temporal signals collected from control subjects and patients with essential tremor. The time series obtained from the decomposition, covering different frequency ranges, will be randomly shuffled and combined to generate new artificial samples for each group. Then, both the generated artificial samples and part of the real samples will be used to train the LSTM network, and the remaining original samples will be used to test the model. The experimental results demonstrate the capability of the proposed method, which is compared to a set of 10 different data augmentation methods, and in all cases outperforms all other methods. In the best case, the proposed method increases the accuracy of the classifier from 83.20% to almost 93% when artificial samples are generated, which is a promising result when only small databases are available.
Parkinson's disease (PD) is a progressive neurodegenerative disorder, diagnosed according to the clinical criteria that occur in already advanced stages of PD. The definition of biomarkers for the ...early diagnosis of PD represents a challenge that might improve treatment and avoid complications in this disease. Therefore, we propose a set of reliable samples for the identification of altered metabolites to find potential prognostic biomarkers for early PD.
This case-control study included plasma samples of 12 patients with PD and 21 control subjects, from the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC)-Navarra cohort, part of the EPIC-Spain study. All the case samples were provided by healthy volunteers who were followed-up for 15.9 (±4.1) years and developed PD disease later on, after the sample collection. Liquid chromatography coupled to tandem mass spectrometry was used for the analysis of samples.
Out of 40 that were selected and studied due to their involvement in established cases of PD, seven significantly different metabolites between PD cases and healthy control subjects were obtained in this study (benzoic acid, palmitic acid, oleic acid, stearic acid, myo-inositol, sorbitol, and quinolinic acid). These metabolites are related to mitochondrial dysfunction, the oxidative stress, and the mechanisms of energy production.
We propose the samples from the EPIC study as reliable and invaluable samples for the search of early biomarkers of PD. Likewise, this study might also be a starting point in the establishment of a well-founded panel of metabolites that can be used for the early detection of this disease.
Essential tremor (ET) is a highly prevalent neurological disorder characterized by action-induced tremors involving the hand, voice, head, and/or face. Importantly, hand tremor is present in nearly ...all forms of ET, resulting in impaired fine motor skills and diminished quality of life. To advance early diagnostic approaches for ET, automated handwriting tasks and magnetic resonance imaging (MRI) offer an opportunity to develop early essential clinical biomarkers. In this study, we present a novel approach for the early clinical diagnosis and monitoring of ET based on integrating handwriting and neuroimaging analysis. We demonstrate how the analysis of fine motor skills, as measured by an automated Archimedes’ spiral task, is correlated with neuroimaging biomarkers for ET. Together, we present a novel modeling approach that can serve as a complementary and promising support tool for the clinical diagnosis of ET and a large range of tremors.
Parkinson's disease (PD) is characterized by a great clinical heterogeneity. Nevertheless, the biological drivers of this heterogeneity have not been completely elucidated and are likely to be ...complex, arising from interactions between genetic, epigenetic, and environmental factors. Despite this heterogeneity, the clinical patterns of monogenic forms of PD have usually maintained a good clinical correlation with each mutation once a sufficient number of patients have been studied. Mutations in LRRK2 are the most commonly known genetic cause of autosomal dominant PD known to date. Furthermore, recent genome-wide association studies have revealed variations in LRRK2 as significant risk factors also for the development of sporadic PD. The LRRK2-R1441G mutation is especially frequent in the population of Basque ascent based on a possible founder effect, being responsible for almost 50% of cases of familial PD in our region, with a high penetrance. Curiously, Lewy bodies, considered the neuropathological hallmark of PD, are absent in a significant subset of LRRK2-PD cases. Indeed, these cases appear to be associated with a less aggressive primarily pure motor phenotype. The aim of our research is to examine the clinical phenotype of R1441G-PD patients, more homogeneous when we compare it with sporadic PD patients or with patients carrying other LRRK2 mutations, and reflect on the value of the observed correlation in the genetic forms of PD. The clinical heterogeneity of PD leads us to think that there may be as many different diseases as the number of people affected. Undoubtedly, genetics constitutes a relevant key player, as it may significantly influence the phenotype, with differences according to the mutation within the same gene, and not only in familial PD but also in sporadic forms. Thus, extending our knowledge regarding genetic forms of PD implies an expansion of knowledge regarding sporadic forms, and this may be relevant due to the future therapeutic implications of all forms of PD.
•tSMS is a portable, inhibitory, non-invasive brain stimulation technique.•Repeated sessions of home-based tSMS of the motor cortex are feasible and safe.•tSMS may provide subjective benefit for the ...treatment of levodopa-induced dyskinesias.
Essential tremor (ET) is the most common movement disorder. In fact, its prevalence is about 20 times higher than that of Parkinson's disease. In addition, studies have shown that a high percentage ...of cases, between 50 and 70%, are estimated to be of genetic origin. The gold standard test for diagnosis, monitoring and to differentiate between both pathologies is based on the drawing of the Archimedes' spiral. Our major challenge is to develop the simplest system able to correctly classify Archimedes' spirals, therefore we will exclusively use the information of the
and
coordinates. This is the minimum information provided by any digitizing device. We explore the use of features from drawings related to the Discrete Cosine Transform as part of a wider cross-study for the diagnosis of essential tremor held at Biodonostia. We compare the performance of these features against other classic and already analyzed ones. We outperform previous results using a very simple system and a reduced set of features. Because the system is simple, it will be possible to implement it in a portable device (microcontroller), which will receive the
and
coordinates and will issue the classification result. This can be done in real time, and therefore without needing any extra job from the medical team. In future works these new drawing-biomarkers will be integrated with the ones obtained in the previous Biodonostia study. Undoubtedly, the use of this technology and user-friendly tools based on indirect measures could provide remarkable social and economic benefits.
Among neural disorders related to movement, essential tremor has the highest prevalence; in fact, it is twenty times more common than Parkinson’s disease. The drawing of the Archimedes’ spiral is the ...gold standard test to distinguish between both pathologies. The aim of this paper is to select non-linear biomarkers based on the analysis of digital drawings. It belongs to a larger cross study for early diagnosis of essential tremor that also includes genetic information. The proposed automatic analysis system consists in a hybrid solution: Machine Learning paradigms and automatic selection of features based on statistical tests using medical criteria. Moreover, the selected biomarkers comprise not only commonly used linear features (static and dynamic), but also other non-linear ones: Shannon entropy and Fractal Dimension. The results are hopeful, and the developed tool can easily be adapted to users; and taking into account social and economic points of view, it could be very helpful in real complex environments.
Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to ...stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they accumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate idiopathic PD patients who will benefit from LRRK2-related therapeutics.
Biomedical systems produce biosignals that arise from interaction mechanisms. In a general form, those mechanisms occur across multiple scales, both spatial and temporal, and contain linear and ...non-linear information. In this framework, entropy measures are good candidates in order provide useful evidence about disorder in the system, lack of information in time-series and/or irregularity of the signals. The most common movement disorder is essential tremor (ET), which occurs 20 times more than Parkinson’s disease. Interestingly, about 50%–70% of the cases of ET have a genetic origin. One of the most used standard tests for clinical diagnosis of ET is Archimedes’ spiral drawing. This work focuses on the selection of non-linear biomarkers from such drawings and handwriting, and it is part of a wider cross study on the diagnosis of essential tremor, where our piece of research presents the selection of entropy features for early ET diagnosis. Classic entropy features are compared with features based on permutation entropy. Automatic analysis system settled on several Machine Learning paradigms is performed, while automatic features selection is implemented by means of ANOVA (analysis of variance) test. The obtained results for early detection are promising and appear applicable to real environments.
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