Publications by authors named "David Devos"

128 Publications

The role of the surface ligand on the performance of electrochemical SARS-CoV-2 antigen biosensors.

Anal Bioanal Chem 2021 Feb 22. Epub 2021 Feb 22.

Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520 - IEMN, F-59000, Lille, France.

Point-of-care (POC) technologies and testing programs hold great potential to significantly improve diagnosis and disease surveillance. POC tests have the intrinsic advantage of being able to be performed near the patient or treatment facility, owing to their portable character. With rapid results often in minutes, these diagnostic platforms have a high positive impact on disease management. POC tests are, in addition, advantageous in situations of a shortage of skilled personnel and restricted availability of laboratory-based analytics. While POC testing programs are widely considered in addressing health care challenges in low-income health systems, the ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections could largely benefit from fast, efficient, accurate, and cost-effective point-of-care testing (POCT) devices for limiting COVID-19 spreading. The unrestrained availability of SARS-CoV-2 POC tests is indeed one of the adequate means of better managing the COVID-19 outbreak. A large number of novel and innovative solutions to address this medical need have emerged over the last months. Here, we critically elaborate the role of the surface ligands in the design of biosensors to cope with the current viral outbreak situation. Their notable effect on electrical and electrochemical sensors' design will be discussed in some given examples. Graphical abstract.
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http://dx.doi.org/10.1007/s00216-020-03137-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897554PMC
February 2021

Parkinson's disease: Content analysis of patient online discussion forums. A prospective observational study using Netnography.

Patient Educ Couns 2021 Jan 28. Epub 2021 Jan 28.

Department of General Practice, University of Lille, Lille, France; CN2R-Centre National de Ressources et de Résilience, Lille, France.

Objectives: To assess the users' characteristics, discussion contents, and the atmosphere of virtual peer communities.

Methods: A qualitative, prospective study was conducted using the Netnography method. The most popular, publicly accessible French discussion forums were investigated. The web users' quotes were collected from May to October 2018. Data analysis triangulation was performed by two researchers using the NVivo 12® software.

Results: The users discussed their experience with Parkinson's disease (PD) in a warm atmosphere. 23 discussion threads were analysed: 302 messages posted by 70 users (70% were females; the average illness duration was 6 years); 115 encoded nodes were created. Five user profiles appeared: leader, follower, expert, mixed, and undetermined. Common preoccupations were a lack of time and listening from the physicians' side. Three themes emerged: managing symptoms, living with PD, and sharing illness experiences. Users sought actively for a cure to limit or stop disease evolution, using alternative and complementary therapies to optimize their daily condition.

Conclusions: Online forums foster person's informal learnings about coping with PD. Healthcare professionals can use these learnings to optimize person-centred support.

Practice Implications: During consultations, healthcare professionals should invite persons to discuss their online activity, informal learnings, beliefs and expectations towards therapeutic strategies.
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http://dx.doi.org/10.1016/j.pec.2021.01.028DOI Listing
January 2021

Texture-based markers from structural imaging correlate with motor handicap in Parkinson's disease.

Sci Rep 2021 Feb 1;11(1):2724. Epub 2021 Feb 1.

Université de Lille, INSERM, U1172, CHU-Lille, Lille Neuroscience Cognition Research Centre, 1 place de Verdun, 59000, Lille, France.

There is a growing need for surrogate biomarkers for Parkinson's disease (PD). Structural analysis using magnetic resonance imaging with T1-weighted sequences has the potential to quantify histopathological changes. Degeneration is typically measured by the volume and shape of morphological changes. However, these changes appear late in the disease, preventing their use as surrogate markers. We investigated texture changes in 108 individuals, divided into three groups, matched in terms of sex and age: (1) healthy controls (n = 32); (2) patients with early-stage PD (n = 39); and (3) patients with late-stage PD and severe L-dopa-related complications (n = 37). All patients were assessed in off-treatment conditions. Statistical analysis of first- and second-order texture features was conducted in the substantia nigra, striatum, thalamus and sub-thalamic nucleus. Regions of interest volumetry and voxel-based morphometry were performed for comparison. Significantly different texture features were observed between the three populations, with some showing a gradual linear progression between the groups. The volumetric changes in the two PD patient groups were not significantly different. Texture features were significantly associated with clinical scores for motor handicap. These results suggest that texture features, measured in the nigrostriatal pathway at PD diagnosis, may be useful in predicting clinical progression of motor handicap.
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http://dx.doi.org/10.1038/s41598-021-81209-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851138PMC
February 2021

Do kinematic gait parameters help to discriminate between fallers and non-fallers with Parkinson's disease?

Clin Neurophysiol 2021 Feb 19;132(2):536-541. Epub 2020 Dec 19.

Univ. Lille, Inserm, U1172 - Lille Neuroscience and Cognition, F-59000 Lille, France; Neurology and Movement Disorders Department, Lille University Medical Center, F-59000 Lille, France; Lille Center of Excellence for Neurodegenerative Diseases, LiCEND, France.

Objective: Although a number of clinical factors have been linked to falls in Parkinson's disease (PD), the diagnostic value of gait parameters remains subject to debate. The objective of this retrospective study was to determine to what extent the combination of gait parameters with clinical characteristics can distinguish between fallers and non-fallers.

Methods: Using a video motion system, we recorded gait in 174 patients with PD. The patients' clinical characteristics (including motor status, cognitive status, disease duration, dopaminergic treatment and any history of falls or freezing of gait) were noted. The considered kinematic gait parameters included indices of gait bradykinesia and hypokinesia, asymmetry, variability, and foot clearance. After a parameters selection using an ANCOVA analysis, support vector machine algorithm was used to build classification models for distinguishing between fallers and non-fallers. Two models were built, the first included clinical data only while the second incorporated the selected gait parameters.

Results: The "clinical-only" model had an accuracy of 94% for distinguishing between fallers and non-fallers. The model incorporating additional gait parameters including stride time and foot clearance performed even better, with an accuracy of up to 97%.

Conclusion: Although fallers differed significantly from non-fallers with regard to disease duration, motor impairment or dopaminergic treatment, the addition of gait parameters such as foot clearance or stride time to clinical variables increased the model's discriminant power.

Significance: This predictive model now needs to be validated in prospective cohorts.
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http://dx.doi.org/10.1016/j.clinph.2020.11.027DOI Listing
February 2021

Personality dimensions of patients can change during the course of parkinson's disease.

PLoS One 2021 7;16(1):e0245142. Epub 2021 Jan 7.

Toulouse NeuroImaging Center, University of Toulouse, Inserm, UPS, Toulouse, France.

Background: Studies assessing personality dimensions by the "Temperament and Character Inventory" (TCI) have previously found an association between Parkinson's disease (PD) and lower Novelty Seeking and higher Harm Avoidance scores. Here, we aimed to describe personality dimensions of PD patients with motor fluctuations and compare them to a normative population and other PD populations.

Methods: All PD patients awaiting Deep Brain Stimulation (DBS) answered the TCI before neurosurgery. Their results were compared to those of historical cohorts (a French normative population, a de novo PD population, and a PD population with motor fluctuations).

Results: Most personality dimensions of our 333 included PD patients with motor fluctuations who are candidates for DBS were different from those of the normative population and some were also different from those of the De Novo PD population, whereas they were similar to those of another population of PD patients with motor fluctuations.

Conclusions: During the course of PD, personality dimensions can change in parallel with the development of motor fluctuations, either due to the evolution of the disease and/or dopaminergic treatments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245142PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790271PMC
January 2021

Extensive characterization of the composition and functional activities of five preparations of human platelet lysates for dedicated clinical uses.

Platelets 2020 Nov 27:1-14. Epub 2020 Nov 27.

Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University , Taipei, Taiwan.

Human platelet lysates (HPLs), rich in various growth factors and cell growth-promoting molecules, encompass a new range of blood products that are being used for regenerative medicine, cell therapies, and tissue engineering. Well-characterized dedicated preparations, tailor-made to best fit specific therapeutic applications, are needed for optimal clinical efficacy and safety. Here, five types of HPL were prepared from the same platelet concentrates and extensively characterized to determine and compare their proteins, growth factors, cytokines, biochemical profiles, thrombin-generating capacities, thrombin-associated proteolytic activities, phospholipid-associated procoagulant potential, contents of extracellular vesicles expressing phosphatidylserine and tissue factor, and antioxidative properties. Our results revealed that all five HPL preparations contained detectable supraphysiological levels, in the ca. 0.1 ~ 350-ng/ml range, of all growth factors assessed, except insulin-like growth factor-1 detected only in HPL containing plasma. There were significant differences observed among these HPLs in total protein content, fibrinogen, complement components C3 and C4, albumin, and immunoglobulin G, and, most importantly, in their functional coagulant and procoagulant activities and antioxidative capacities. Our data revealed that the biochemical and functional properties of HPL preparations greatly vary depending upon their mode of production, with potential impacts on the safety and efficacy for certain clinical indications. Modes of preparation of HPLs should be carefully designed, and the product properties carefully evaluated based on the intended therapeutic use to ensure optimal clinical outcomes.
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http://dx.doi.org/10.1080/09537104.2020.1849603DOI Listing
November 2020

Trends in Glucocerebrosides Research: A Systematic Review.

Front Physiol 2020 29;11:558090. Epub 2020 Oct 29.

Univ. Lille, Inserm, CHU-Lille, Lille Neuroscience and Cognition, Lille, France.

Glucocerebrosides are sphingolipid components of cell membranes that intervene in numerous cell biological processes and signaling pathways and that deregulation is implicated in human diseases such as Gaucher disease and Parkinson's disease. In the present study, we conducted a systematic review using document co-citation analysis, clustering and visualization tools to explore the trends and knowledge structure of glucocerebrosides research as indexed in the Science Citation Index Expanded database (1956-present). A co-citation network of 5,324 publications related to glucocerebrosides was constructed. The analysis of emerging categories and keywords suggested a growth of research related to neurosciences over the last decade. We identified ten major areas of research (e.g., clusters) that developed over time, from the oldest (i.e., on or ) to the most recent ones (i.e., on , or ). We provided for each cluster the most cited publications and a description of their intellectual content. We moreover identified emerging trends in glucocerebrosides research by detecting the surges in the rate of publication citations in the most recent years. In conclusion, this study helps to apprehend the most significant lines of research on glucocerebrosides. This should strengthen the connections between scientific communities studying glycosphingolipids to facilitate advances, especially for the most recent researches on cancer drug resistance and Parkinson's disease.
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http://dx.doi.org/10.3389/fphys.2020.558090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658098PMC
October 2020

Seven Solutions for Neuroprotection in Parkinson's Disease.

Mov Disord 2021 Feb 13;36(2):306-316. Epub 2020 Nov 13.

The Cure Parkinson's Trust, London, United Kingdom.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra and accumulation of iron and alpha-synuclein; it follows a characteristic pattern throughout the nervous system. Despite decades of successful preclinical neuroprotective studies, no drug has then shown efficacy in clinical trials. Considering this dilemma, we have reviewed and organized solutions of varying importance that can be exclusive or additive, and we outline approaches to help generate successful development of neuroprotective drugs for PD: (1) select patients in which the targeted mechanism is involved in the pathological process associated with the monitoring of target engagement, (2) combine treatments that target multiple pathways, (3) establish earliest interventions and develop better prodromal biomarkers, (4) adopt rigorous methodology and specific disease-relevant designs for disease-modifying clinical trials, (5) customize drug with better brain biodistribution, (6) prioritize repurposed drugs as a first line approach, and (7) adapt preclinical models to the targeted mechanisms with translational biomarkers to increase their predictive value. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28379DOI Listing
February 2021

Glycosphingolipids and neuroinflammation in Parkinson's disease.

Mol Neurodegener 2020 10 17;15(1):59. Epub 2020 Oct 17.

Univ. Lille, Inserm, CHU-Lille, Lille Neuroscience & Cognition, 1 Place de Verdun, 59006, Lille, France.

Parkinson's disease is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons of the nigrostriatal pathway and the formation of neuronal inclusions known as Lewy bodies. Chronic neuroinflammation, another hallmark of the disease, is thought to play an important role in the neurodegenerative process. Glycosphingolipids are a well-defined subclass of lipids that regulate crucial aspects of the brain function and recently emerged as potent regulators of the inflammatory process. Deregulation in glycosphingolipid metabolism has been reported in Parkinson's disease. However, the interrelationship between glycosphingolipids and neuroinflammation in Parkinson's disease is not well known. This review provides a thorough overview of the links between glycosphingolipid metabolism and immune-mediated mechanisms involved in neuroinflammation in Parkinson's disease. After a brief presentation of the metabolism and function of glycosphingolipids in the brain, it summarizes the evidences supporting that glycosphingolipids (i.e. glucosylceramides or specific gangliosides) are deregulated in Parkinson's disease. Then, the implications of these deregulations for neuroinflammation, based on data from human inherited lysosomal glycosphingolipid storage disorders and gene-engineered animal studies are outlined. Finally, the key molecular mechanisms by which glycosphingolipids could control neuroinflammation in Parkinson's disease are highlighted. These include inflammasome activation and secretion of pro-inflammatory cytokines, altered calcium homeostasis, changes in the blood-brain barrier permeability, recruitment of peripheral immune cells or production of autoantibodies.
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http://dx.doi.org/10.1186/s13024-020-00408-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568394PMC
October 2020

Impact of Subthalamic Deep Brain Stimulation on Impulse Control Disorders in Parkinson's Disease: A Prospective Study.

Mov Disord 2020 Oct 6. Epub 2020 Oct 6.

Department of Neurology, NS-PARK/F-CRIN, Strasbourg University Hospital, Fédération de Médecine Translationnelle de Médecine de Strasbourg, Strasbourg, France.

Background: Impact of subthalamic deep brain stimulation (DBS) on impulse control disorders (ICD) in Parkinson's disease (PD) remains controversial.

Objectives: The objectives of this study were to analyze the natural history of ICD between baseline and 1 year after subthalamic DBS in patients with PD and to identify predictive factors, taking into account the positions of the active contact and stimulation parameters.

Methods: We analyzed postoperative modifications of ICD based on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. ICD status and Ardouin Scale of Behaviour in PD were assessed at baseline and 1 year following subthalamic DBS. Location of active contacts within the 3 subthalamic nucleus functional territories was investigated.

Results: A total of 217 were patients included. Of the patients, 10.6% had ICD at baseline of which 95.6% improved at 1 year following subthalamic DBS; 3.6% of the patients experienced de novo ICD at 1 year following subthalamic DBS. Dopamine agonist dose reduction (from 309.8 to 109.3 mg) was the main driver of ICD regression (P = 0.05). Higher preoperative dyskinesias were associated with poorer ICD evolution (P = 0.04). Whereas baseline apathy was a risk factor of de novo ICD (P = 0.02), ICD improvement correlated with postoperative apathy (P = 0.004). Stimulation power and position of active contacts-mainly located within the sensorimotor part of the subthalamic nucleus-did not influence ICD.

Conclusions: This 1-year, postoperative follow-up study showed ICD regression and dopaminergic drug reduction with optimal position of the active contacts within the subthalamic nucleus. Whereas patients with PD with preoperative ICD were prone to postoperative apathy, we also showed that those with preoperative apathy had a higher risk to experience postoperative de novo ICD, further highlighting the meaningful influence of postoperative management of dopaminergic medication on outcome and the continuum between apathy and ICD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28320DOI Listing
October 2020

Segregation of ATP10B variants in families with autosomal recessive parkinsonism.

Acta Neuropathol 2020 11 5;140(5):783-785. Epub 2020 Sep 5.

Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Hôpital de la Salpêtrière, Inserm U 1127, CNRS UMR 7225, 75013, Paris, France.

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http://dx.doi.org/10.1007/s00401-020-02219-6DOI Listing
November 2020

Early cognitive decline after bilateral subthalamic deep brain stimulation in Parkinson's disease patients with GBA mutations.

Parkinsonism Relat Disord 2020 07 9;76:56-62. Epub 2020 Jun 9.

Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France. Electronic address:

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on motor complications in advanced Parkinson's disease (PD) but does not modify disease progression. Genetic forms of PD have been associated with different cognitive progression profiles.

Objective: To assess the effect of PD-related genetic mutations on cognitive outcome after STN-DBS.

Methods: Patients with STN-DBS were screened for LRRK2, GBA, and PRKN mutations at the Pitié-Salpêtrière Hospital between 1997 and 2009. Patients with known monogenetic forms of PD from six other centers were also included. The Mattis Dementia Rating Scale (MDRS) was used to evaluate cognition at baseline and one-year post-surgery. The standardized Unified PD Rating Scale (UPDRS) evaluation On and Off medication/DBS was also administered. A generalized linear model adjusted for sex, ethnicity, age at onset, and disease duration was used to evaluate the effect of genetic factors on MDRS changes.

Results: We analyzed 208 patients (131 males, 77 females, 54.3 ± 8.8 years) including 25 GBA, 18 LRRK2, 22 PRKN, and 143 PD patients without mutations. PRKN patients were younger and had a longer disease duration at baseline. A GBA mutation was the only significant genetic factor associated with MDRS change (β = -2.51, p = 0.009). GBA mutation carriers had a more pronounced post-operative MDRS decline (3.2 ± 5.1) than patients with LRRK2 (0.9 ± 4.8), PRKN (0.5 ± 2.7) or controls (1.4 ± 4.4). The motor response to DBS was similar between groups.

Conclusion: GBA mutations are associated with early cognitive decline following STN-DBS. Neuropsychological assessment and discussions on the benefit/risk ratio of DBS are particularly important for this population.
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http://dx.doi.org/10.1016/j.parkreldis.2020.04.002DOI Listing
July 2020

Ferroptosis and its potential role in the physiopathology of Parkinson's Disease.

Prog Neurobiol 2021 Jan 26;196:101890. Epub 2020 Jul 26.

Department of Medical Pharmacology, Lille University, INSERM UMRS_1172, University Hospital Centre, LICEND COEN Centre, LilNCog - Lille Neuroscience & Cognition, 59000, France; Université du Littoral Côte d'Opale-1, place de l'Yser, BP 72033, 59375, Dunkerque Cedex, France.

Parkinson's Disease (PD) is a common and progressive neurodegenerative disorder characterised by motor impairments as well as non-motor symptoms. While dopamine-based therapies are effective in fighting the symptoms in the early stages of the disease, a lack of neuroprotective drugs means that the disease continues to progress. Along with the traditionally recognised pathological hallmarks of dopaminergic neuronal death and intracellular α-synuclein (α-syn) depositions, iron accumulation, elevated oxidative stress and lipid peroxidation damage are further conspicuous features of PD pathophysiology. However, the underlying mechanisms linking these pathological hallmarks with neurodegeneration still remain unclear. Ferroptosis, a regulated iron dependent cell death pathway involving a lethal accumulation of lipid peroxides, shares several features with PD pathophysiology. Interestingly, α-syn has been functionally linked with the metabolism of both iron and lipid, suggesting a possible interplay between dysregulated α-syn and other PD pathological hallmarks related to ferroptosis. This review will address the importance for understanding these disease mechanisms that could be targeted therapeutically. Anti-ferroptosis molecules are neuroprotective in PD animal models and the anti-ferroptotic iron chelator, deferiprone, slowed disease progression and improved motor function in two independent clinical trials for PD. An ongoing larger multi-centre phase 2 clinical trial will confirm the therapeutic potential of deferiprone and the relevance of ferroptosis in PD. This review addresses the known pathological features of PD in relation to the ferroptosis pathway with therapeutic implications of targeting this cell death pathway.
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http://dx.doi.org/10.1016/j.pneurobio.2020.101890DOI Listing
January 2021

Functional correlates of cognitive slowing in Parkinson's disease.

Parkinsonism Relat Disord 2020 07 19;76:3-9. Epub 2020 May 19.

Lille Neuroscience and Cognition, UMR 1172, Team1 Degenerative and vascular cognitive disorders, Lille, France; Lille University Medical Center, Department of Neurology, Lille, France. Electronic address:

Although attentional impairments (particularly cognitive slowing) are frequent in Parkinson's disease (PD), the mechanisms underlying these phenomena have not been fully characterized. The MRI-compatible version of the Symbol Digit Modalities Test (SDMT) has been applied to healthy individuals but not previously to patients with PD. We sought to assess functional changes in brain activation patterns associated with cognitive slowing in PD. Eighteen patients with PD and 11 matched healthy controls (HCs) were enrolled. High-resolution three-dimensional T1-weighted images and blood-oxygen-level-dependent images were acquired during the SDMT. SDMT-related brain networks for the HC and PD groups were extracted from one-sample T-test maps. In each hemisphere, correlated regions were identified by selecting 120 voxels around the peak of each significant cluster (p<0.001). Regions of interest were then analyzed. When performing the SDMT, both groups displayed activation in the frontal, parietal and occipital regions known to be involved in attention. In the PD group, activation was lower in several parts of the cerebellum, left and right occipital cortices, and right supramarginal gyrus. In eight of these regions, fMRI activation was positively correlated with performance in the SDMT task. Our results suggest that the right supramarginal gyrus (an important interface for information integration), the cerebellum, and the left and right occipital cortices are involved in cognitive slowing in PD. A lower level of brain activation was associated with greater cognitive impairment.
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http://dx.doi.org/10.1016/j.parkreldis.2020.05.006DOI Listing
July 2020

Amyloidogenic processing of Alzheimer's disease β-amyloid precursor protein induces cellular iron retention.

Mol Psychiatry 2020 09 22;25(9):1958-1966. Epub 2020 May 22.

The ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, UK.

The proteolytic cleavage of β-amyloid precursor protein (APP) to form the amyloid beta (Aβ) peptide is related to the pathogenesis of Alzheimer's disease (AD) because APP mutations that influence this processing either induce familial AD or mitigate the risk of AD. Yet Aβ formation itself may not be pathogenic. APP promotes neuronal iron efflux by stabilizing the cell-surface presentation of ferroportin, the only iron export channel of cells. Mislocalization of APP can promote iron retention, thus we hypothesized that changes in endocytotic trafficking associated with altered APP processing could contribute to the neuronal iron elevation and oxidative burden that feature in AD pathology. Here, we demonstrate, using genetic and pharmacological approaches, that endocytotic amyloidogenic processing of APP impairs iron export by destabilizing ferroportin on the cell surface. Conversely, preferential non-amyloidogenic processing of APP at the cell surface promotes ferroportin stabilization to decrease intraneuronal iron. A new Aβ-independent hypothesis emerges where the amyloidogenic processing of APP, combined with age-dependent iron elevation in the tissue, increases pro-oxidant iron burden in AD.
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http://dx.doi.org/10.1038/s41380-020-0762-0DOI Listing
September 2020

Personality Dimensions Are Associated with Quality of Life in Fluctuating Parkinson's Disease Patients (PSYCHO-STIM).

J Parkinsons Dis 2020 ;10(3):1057-1066

ToNIC, Toulouse NeuroImaging Center, University of Toulouse, Inserm, UPS, Toulouse, France.

Background: Parkinson's disease (PD) negatively affects patients' Quality of Life (QoL) which depends on both objective criteria such as physical health and subjective ones such as worries and norms according to personal believes. Therefore, QoL could be also associated to personality dimensions in chronic neurological diseases such as PD.

Objective: Our objective was thus to study the potential association between personality dimensions and QoL in PD patients with motor fluctuations before Deep Brain Stimulation of the Sub-Thalamic Nucleus (DBS-STN).

Methods: Data were obtained from the French multicentric cohort study Predi-Stim. All PD patients awaiting DBS-STN and responding to the inclusion criteria at the time of the study were included. All participants answered the "Temperament and Character Inventory" (TCI) and the PDQ-39 before surgery. Analyses were made using adjusted univariate generalized linear regression models to evaluate a potential association between TCI dimensions and PDQ-39 scores.

Results: Three hundred thirty-three consecutive patients were included. The temperament Harm Avoidance was negatively associated with QoL (p = 1e-4, R2= 0.33), whereas the character Self-Directedness was positively associated with mental component of QoL (p = 2e-4, R2= 0.33) in PD patients with motor fluctuations awaiting DBS-STN.

Conclusions: PD patients with motor fluctuations, with lower Harm Avoidance and higher Self-Directedness scores have the best QoL mainly at an emotional and social level. Therapeutic education of these PD patients focusing on their personal resources may thus be important to improve their well-being.
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http://dx.doi.org/10.3233/JPD-191903DOI Listing
January 2020

Efficacy of tDCS for bipolar depression in a patient with spinocerebellar ataxia: A case report.

Bipolar Disord 2020 06 18;22(4):422-424. Epub 2020 May 18.

Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, France.

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http://dx.doi.org/10.1111/bdi.12924DOI Listing
June 2020

Intraventricular dopamine infusion alleviates motor symptoms in a primate model of Parkinson's disease.

Neurobiol Dis 2020 06 20;139:104846. Epub 2020 Mar 20.

Medical Pharmacology Department, Univ Lille, Inserm, CHU Lille, UMR_S1171, Lille F-59000, France. Electronic address:

Background: Continuous compensation of dopamine represents an ideal symptomatic treatment for Parkinson's disease (PD). The feasibility in intracerebroventricular administration (i.c.v.) of dopamine previously failed because of unresolved dopamine oxidation.

Objectives: We aim to test the feasibility, safety margins and efficacy of continuous i.c.v. of anaerobic-dopamine (A-dopamine) with a pilot translational study in a non-human primate model of PD.

Methods: Continuous and circadian i.c.v. of A-dopamine was administered through a micro-pump connected to a subcutaneous catheter implanted into the right frontal horn of 8 non-human primates treated with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). A-dopamine was assessed at acute doses previously reported for dopamine as well as evaluating the long term therapeutic index of A-dopamine in comparison to anaerobically prepared L-dopa or methyl ester L-dopa.

Results: Over 60 days of a continuous circadian i.c.v. of A-dopamine improved motor symptoms (therapeutic index from 30 to 70 mg/day) without tachyphylaxia. No dyskinesia was observed even with very high doses. Death after 1 to 10 days (without neuronal alteration) was only observed with doses in excess of 160 mg whereas L-dopa i.c.v. was not effective at any dose. The technical feasibility of the administration regimen was confirmed for an anaerobic preparation of dopamine and for administration of a minimal infusion volume by micro-pump at a constant flow that prevented obstruction.

Conclusion: Continuous circadian i.c.v. of A-dopamine appears to be feasible and shows efficacy without dyskinesia with a safe therapeutic index.
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http://dx.doi.org/10.1016/j.nbd.2020.104846DOI Listing
June 2020

Neurological Phenotypes Associated with AAAS-Related Disorders: Spastic Ataxia and Complex Spastic Paraplegia.

Cerebellum 2020 Jun;19(3):465-468

Medical Genetics Division, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos 2350, Porto Alegre, RS, Zip Code 90.035-903, Brazil.

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http://dx.doi.org/10.1007/s12311-020-01123-9DOI Listing
June 2020

Heat-treated human platelet pellet lysate modulates microglia activation, favors wound healing and promotes neuronal differentiation .

Platelets 2020 Feb 27:1-12. Epub 2020 Feb 27.

Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.

The neurorestorative efficacy of human platelet lysates in neurodegenerative disorders is still under investigation. Platelets prepared from standard and pathogen reduced platelet concentrates were pelletized, washed, concentrated, and subjected to freeze-thawing. The lysate was heated to 56°C for 30 min and characterized. Toxicity was evaluated using SH-SY5Y neuroblastoma, BV-2 microglial, and EA-hy926 endothelial cells. Inflammatory activity was tested by examining tumor necrosis factor (TNF) and cyclooxygenase (COX)-2 expressions by BV-2 microglia with or without stimulation by lipopolysaccharides (LPS). The capacity to stimulate wound healing was evaluated by a scratch assay, and the capacity to differentiate SH-SY5Y into neurons was also examined. Platelet lysates contained a range of neurotrophins. They were not toxic to SH-SY5Y, EA-hy926, or BV-2 cells, did not induce the expression of TNF or COX-2 inflammatory markers by BV-2 microglia, and decreased inflammation after LPS stimulation. They stimulated the wound closure in the scratch assay and induced SH-SY5Y differentiation as revealed by the increased length of neurites as well as β3-tubulin and neurofilament staining. These data confirm the therapeutic potential of platelet lysates in the treatment of disorders of the central nervous system and support further evaluation as novel neurorestorative biotherapy in preclinical models.
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http://dx.doi.org/10.1080/09537104.2020.1732324DOI Listing
February 2020

Author Correction: A ferroptosis-based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis.

Sci Rep 2020 Feb 19;10(1):3312. Epub 2020 Feb 19.

Biomedical Imaging Laboratory, CNRS, INSERM, Sorbonne University, Paris, France.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-58956-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031233PMC
February 2020

Conservative iron chelation for neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis.

J Neural Transm (Vienna) 2020 02 7;127(2):189-203. Epub 2020 Jan 7.

Service de Pharmacologie Clinique et Service de Neurologie NS-Park/FCRIN Network LICEND COEN Center Lille, Université de Lille, CHU de Lille, INSERM, UMRS_1171, Lille, France.

Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer's disease, AD), automaticity (Parkinson's disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.
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http://dx.doi.org/10.1007/s00702-019-02138-1DOI Listing
February 2020

The neuroprotective activity of heat-treated human platelet lysate biomaterials manufactured from outdated pathogen-reduced (amotosalen/UVA) platelet concentrates.

J Biomed Sci 2019 Oct 31;26(1):89. Epub 2019 Oct 31.

Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, 250 Wu-Xing Street, Taipei, 11031, Taiwan.

Background: Effective neurorestorative therapies of neurodegenerative diseases must be developed. There is increasing interest in using human platelet lysates, rich in neurotrophic factors, as novel disease-modifying strategy of neurodegeneration. To ensure virus safety, pathogen reduction treatments should be incorporated in the preparation process of the platelet concentrates used as source material. We therefore investigated whether platelet concentrates (PC) pathogen-inactivated using a licensed photo-inactivation treatment combining photosensitive psoralen (amotosalen) and UVA irradiation (Intercept) can serve as source material to prepare platelet lysates with preserved neuroprotective activity in Parkinson's disease models.

Methods: Intercept treated-PCs were centrifuged, when reaching expiry day (7 days after collection), to remove plasma and platelet additive solution. The platelet pellet was re-suspended and concentrated in phosphate buffer saline, subjected to 3 freeze-thaw cycles (- 80 °C/37 °C) then centrifuged to remove cell debris. The supernatant was recovered and further purified, or not, by heat-treatment as in our previous investigations. The content in proteins and neurotrophic factors was determined and the toxicity and neuroprotective activity of the platelet lysates towards LUHMES cells or primary cortical/hippocampal neurons were assessed using ELISA, flow cytometry, cell viability and cytotoxicity assays and proteins analysis by Western blot.

Results: Platelet lysates contained the expected level of total proteins (ca. 7-14 mg/mL) and neurotrophic factors. Virally inactivated and heat-treated platelet lysates did not exert detectable toxic effects on neither Lund human mesencephalic dopaminergic LUHMES cell line nor primary neurons. When used at doses of 5 and 0.5%, they enhanced the expression of tyrosine hydroxylase and neuron-specific enolase in LUHMES cells and did not significantly impact synaptic protein expression in primary neurons, respectively. Furthermore, virally-inactivated platelet lysates tested were found to exert very strong neuroprotection effects on both LUHMES and primary neurons exposed to erastin, an inducer of ferroptosis cell death.

Conclusion: Outdated Intercept pathogen-reduced platelet concentrates can be used to prepare safe and highly neuroprotective human heat-treated platelet pellet lysates. These data open reassuring perspectives in the possibility to develop an effective biotherapy using virally-inactivated platelet lysates rich in functional neurotrophins for neuroregenerative medicine, and for further bio-industrial development. However, the data should be confirmed in animal models.
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http://dx.doi.org/10.1186/s12929-019-0579-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822406PMC
October 2019

Dyspnea Is a Specific Symptom in Parkinson's Disease.

J Parkinsons Dis 2019 ;9(4):785-791

Department of Neurology, Expert Center for Parkinson's Disease, INSERM UMRS_1171, Lille University Medical Center, LICEND COEN center, Lille, France.

Background: Dyspnea is a multidimensional sensation that is reported in Parkinson's disease (PD). The multidimensional dyspnea profile (MDP) questionnaire can help to distinguish the perceptive dimension and the emotion response.

Objective: The aim was to assess the clinical features associated with dyspnea using the MDP questionnaire in order to determine which aspects of the symptom was linked with anxiety, depression or motor severity of the disease.

Methods: Non-demented patients were asked whether they experienced shortness of breath in the last month. In case of positive answer, dyspnea was assessed by the MDP. MDS-UPDRS, global cognitive performance, non-motor symptoms and quality of life were assessed.

Results: 60/163 patients were dyspneic since 4.6±2.4 years. The most frequent best sensory quality (SQ) described were: hyperpnoea (35%), physical breathing effort (25%) and air hunger (20%). Hyperpnoea and air hunger had the highest SQ intensity. Anxiety had the highest intensity in the emotional domain.

Conclusion: Dyspnea is a frequent symptom in PD, with specific presentations and two main aspects: one related with anxiety and another with ventilation control impairment.
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http://dx.doi.org/10.3233/JPD-191713DOI Listing
July 2020

Mobility Deficits Assessed With Mobile Technology: What Can We Learn From Brain Iron-Altered Animal Models?

Front Neurol 2019 8;10:833. Epub 2019 Aug 8.

Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.

Recent developments in mobile technology have enabled the investigation of human movements and mobility under natural conditions, i.e., in the home environment. Iron accumulation in the basal ganglia is deleterious in Parkinson's disease (i.e., iron accumulation with lower striatal level of dopamine). The effect of iron chelation (i.e., re-deployment of iron) in Parkinson's disease patients is currently tested in a large investigator-initiated multicenter study. Conversely, restless legs syndrome (RLS) is associated with iron depletion and higher striatal level of dopamine. To determine from animal models which movement and mobility parameters might be associated with iron content modulation and the potential effect of therapeutic chelation inhuman. We recapitulated pathophysiological aspects of the association between iron, dopamine, and neuronal dysfunction and deterioration in the basal ganglia, and systematically searched PubMed to identify original articles reporting about quantitatively assessed mobility deficits in animal models of brain iron dyshomeostasis. We found six original studies using murine and fly models fulfilling the inclusion criteria. Especially postural and trunk stability were altered in animal models with iron overload. Animal models with lowered basal ganglia iron suffered from alterations in physical activity, mobility, and sleep fragmentation. From preclinical investigations in the animal model, we can deduce that possibly also in humans with iron accumulation in the basal ganglia undergoing therapeutic chelation may primarily show changes in physical activity (such as daily "motor activity"), postural and trunk stability and sleep fragmentation. These changes can readily be monitored with currently available mobile technology.
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http://dx.doi.org/10.3389/fneur.2019.00833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694697PMC
August 2019

Past and Future of Neurotrophic Growth Factors Therapies in ALS: From Single Neurotrophic Growth Factor to Stem Cells and Human Platelet Lysates.

Front Neurol 2019 2;10:835. Epub 2019 Aug 2.

Department of Medical Pharmacology, Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that typically results in death within 3-5 years after diagnosis. To date, there is no curative treatment and therefore an urgent unmet need of neuroprotective and/or neurorestorative treatments. Due to their spectrum of capacities in the central nervous system-e.g., development, plasticity, maintenance, neurogenesis-neurotrophic growth factors (NTF) have been exploited for therapeutic strategies in ALS for decades. In this review we present the initial strategy of using single NTF by different routes of administration to the use of stem cells transplantation to express a multiple NTFs-rich secretome to finally focus on a new biotherapy based on the human platelet lysates, the natural healing system containing a mix of pleitropic NTF and having immunomodulatory function. This review highlights that this latter treatment may be crucial to power the neuroprotection and/or neurorestoration therapy requested in this devastating disease.
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http://dx.doi.org/10.3389/fneur.2019.00835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688198PMC
August 2019

Matrix-Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging of Lipids in Experimental Model of Traumatic Brain Injury Detecting Acylcarnitines as Injury Related Markers.

Anal Chem 2019 09 28;91(18):11879-11887. Epub 2019 Aug 28.

Université de Lille , INSERM, U1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000 Lille , France.

Identifying new lipid markers linked to traumatic brain injury (TBI) is of major importance in characterizing their central role in the regeneration process and inflammatory response in such an injury model. In the present study, an advanced lipidomics analysis using high spectral resolution matrix-assisted laser desorption/ionization-mass spectrometry imaging was performed on different brain regions in an experimental rat model of moderate controlled cortical impact (CCI) while considering different time points (1 day, 3 days, 7 days, and 10 days) assessing the acute and subacute phase after injury. Our results revealed a new family of lipids, the acylcarnitines, as TBI-lipid related markers, with maximum expression at 3 days after impact and main colocalization within resident microglia of the brain. Furthermore, our experiments highlighted the upregulation of these acylcarnitine lipids, secreted by microglia, in the ipsilateral , the main region in the brain affected in Parkinson's disease (PD).
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http://dx.doi.org/10.1021/acs.analchem.9b02633DOI Listing
September 2019

Mapping Spatiotemporal Microproteomics Landscape in Experimental Model of Traumatic Brain Injury Unveils a link to Parkinson's Disease.

Mol Cell Proteomics 2019 08 16;18(8):1669-1682. Epub 2019 Jun 16.

‡Université de Lille, INSERM, U1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000 Lille, France

Traumatic brain injury (TBI) represents a major health concerns with no clinically-approved FDA drug available for therapeutic intervention. Several genomics and neuroproteomics studies have been employed to decipher the underlying pathological mechanisms involved that can serve as potential neurotherapeutic targets and unveil a possible underlying relation of TBI to other secondary neurological disorders. In this work, we present a novel high throughput systems biology approach using a spatially resolved microproteomics platform conducted on different brain regions in an experimental rat model of moderate of controlled cortical injury (CCI) at a temporal pattern postinjury (1 day, 3 days, 7 days, and 10 days). Mapping the spatiotemporal landscape of signature markers in TBI revealed an overexpression of major protein families known to be implicated in Parkinson's disease (PD) such as GPR158, HGMB1, synaptotagmin and glutamate decarboxylase in the ipsilateral bioinformatics docking experiments indicated the potential correlation between TBI and PD through alpha-synuclein. In an model, stimulation with palmitoylcarnitine triggered an inflammatory response in macrophages and a regeneration processes in astrocytes which also further confirmed the TBI proteomics data. Taken together, this is the first study to assess the microproteomics landscape in TBI, mainly in the thus revealing a potential predisposition for PD or Parkinsonism post-TBI.
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http://dx.doi.org/10.1074/mcp.RA119.001604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683007PMC
August 2019

Is TNF inhibitor exposure a risk factor for amyotrophic lateral sclerosis?

Fundam Clin Pharmacol 2019 Dec 29;33(6):689-694. Epub 2019 May 29.

Regional Pharmacovigilance Centre of Caen, University Hospital Centre of Caen, UMR, UMR University of Caen Normandie/Inserm U1075, Caen, France.

TNFα modulation has been reported to be either beneficial or detrimental in amyotrophic lateral sclerosis (ALS) and therefore appears as a key issue. We analysed the relationship between TNFα inhibitor (TNFi) exposure and ALS. We performed descriptive analysis of ALS reports in patients treated with TNFi, registered in the French Pharmacovigilance Database (FPvD) and disproportionality analyses by the 'case'/'non-case' method in FPvD and worldwide database (Vigibase ). The 8 retrieved ALS cases from the FPvD were 5 with limb-onset and 3 with bulbar-onset forms, in patients aged 43-75 years old, mainly treated for inflammatory rheumatism. The time to onset of the first symptoms ranged from 12 to 108 months, and the cumulative TNFi exposure before the diagnosis ranged from 12 to 120 months. TNFi was discontinued and thereafter survival ranged between 12 and 20 months. Disproportionality analyses showed significant associations between TNFi exposure and ALS in the FPvD and Vigibase (160 ALS cases), regardless comparators. A putative association between TNFi and ALS must be interpreted cautiously, but TNFi could act as a predisposing or risk factor. TNFi should therefore be avoided in patients with a known risk of ALS and discontinued in the case of neurological signs of ALS.
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http://dx.doi.org/10.1111/fcp.12480DOI Listing
December 2019

A ferroptosis-based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis.

Sci Rep 2019 02 27;9(1):2918. Epub 2019 Feb 27.

Biomedical Imaging Laboratory, CNRS, INSERM, Sorbonne University, Paris, France.

Accurate patient stratification into prognostic categories and targeting Amyotrophic Lateral Sclerosis (ALS)-associated pathways may pave the way for promising trials. We evaluated blood-based prognostic indicators using an array of pathological markers. Plasma samples were collected as part of a large, phase III clinical trial (Mitotarget/TRO19622) at months 1, 6, 12 and 18. The ALSFRS-r score was used as a proxy of disease progression to assess the predictive value of candidate biological indicators. First, established clinical predictors were evaluated in all 512 patients. Subsequently, pathologic markers, such as proxies of neuronal integrity (Neurofilament light chain and phosphorylated heavy chain), DNA oxidation (8-oxo-2'-desoxyguanosine), lipid peroxidation (4-hydroxy-2-nonenal, isoprostane), inflammation (interleukin-6) and iron status (ferritin, hepcidin, transferrin) were assessed in a subset of 109 patients that represented the whole cohort. Markers of neuronal integrity, DNA and lipid oxidation, as well as iron status at baseline are accurate predictors of disability at 18-month follow-up. The composite scores of these markers in association with established clinical predictors enable the accurate forecasting of functional decline. The identified four biomarkers are all closely associated with 'ferroptosis', a recently discovered form of programmed cell death with promising therapeutic targets. The predictive potential of these pathophysiology-based indicators may offer superior patient stratification for future trials, individualised patient care and resource allocation.
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http://dx.doi.org/10.1038/s41598-019-39739-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393674PMC
February 2019