Publications by authors named "Elodie Martin"

66 Publications

Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway.

Int J Mol Sci 2021 Apr 9;22(8). Epub 2021 Apr 9.

Unité de Biologie Fonctionnelle et Adaptative (BFA), Université de Paris-CNRS, UMR8251 4 rue Marie Andrée Lagroua Weill Halle, CEDEX 13, 75205 Paris, France.

Huntington's disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the huntingtin gene (). In spite of considerable efforts, there is currently no treatment to stop or delay the disease. Although is expressed ubiquitously, most of our knowledge has been obtained on neurons. More recently, the impact of mutant huntingtin (mHTT) on other cell types, including glial cells, has received growing interest. It is currently unclear whether new pathological pathways could be identified in these cells compared to neurons. To address this question, we performed an in vivo screen for modifiers of mutant huntingtin (HTT-548-128Q) induced pathology in Drosophila adult glial cells and identified several putative therapeutic targets. Among them, we discovered that partial nej/dCBP depletion in these cells was protective, as revealed by strongly increased lifespan and restored locomotor activity. Thus, dCBP promotes the HD pathology in glial cells, in contrast to previous opposite findings in neurons. Further investigations implicated the transcriptional activator Foxo as a critical downstream player in this glial protective pathway. Our data suggest that combinatorial approaches combined to specific tissue targeting may be required to uncover efficient therapies in HD.
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http://dx.doi.org/10.3390/ijms22083884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069648PMC
April 2021

Current-Induced Spin Torques on Single GdFeCo Magnetic Layers.

Adv Mater 2021 Mar 19;33(12):e2007047. Epub 2021 Feb 19.

Institute Jean Lamour, Université de Lorraine, CNRS, Nancy, F-54000, France.

Spintronics exploit spin-orbit coupling (SOC) to generate spin currents, spin torques, and, in the absence of inversion symmetry, Rashba and Dzyaloshinskii-Moriya interactions. The widely used magnetic materials, based on 3d metals such as Fe and Co, possess a small SOC. To circumvent this shortcoming, the common practice has been to utilize the large SOC of nonmagnetic layers of 5d heavy metals (HMs), such as Pt, to generate spin currents and, in turn, exert spin torques on the magnetic layers. Here, a new class of material architectures is introduced, excluding nonmagnetic 5d HMs, for high-performance spintronics operations. Very strong current-induced torques exerted on single ferrimagnetic GdFeCo layers, due to the combination of large SOC of the Gd 5d states and inversion symmetry breaking mainly engineered by interfaces, are demonstrated. These "self-torques" are enhanced around the magnetization compensation temperature and can be tuned by adjusting the spin absorption outside the GdFeCo layer. In other measurements, the very large emission of spin current from GdFeCo, 80% (20%) of spin anomalous Hall effect (spin Hall effect) symmetry is determined. This material platform opens new perspectives to exert "self-torques" on single magnetic layers as well as to generate spin currents from a magnetic layer.
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http://dx.doi.org/10.1002/adma.202007047DOI Listing
March 2021

Radiotherapy Plus Procarbazine, Lomustine, and Vincristine Versus Radiotherapy Plus Temozolomide for IDH-Mutant Anaplastic Astrocytoma: A Retrospective Multicenter Analysis of the French POLA Cohort.

Oncologist 2021 05 15;26(5):e838-e846. Epub 2021 Feb 15.

Department of Radiotherapy, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Oncopole 1, Toulouse, France.

Background: IDH-mutant anaplastic astrocytomas (AAs) are chemosensitive tumors for which the best choice of adjuvant chemotherapy between procarbazine, lomustine, and vincristine (PCV) or temozolomide (TMZ) after radiotherapy (RT) remains unclear.

Methods: In a large cohort of patients with histologically proven 2016 World Health Organization classification AA with IDH1/2 mutations included in the French national POLA cohort (n = 355), the primary objective was to compare progression-free survival (PFS) between the two treatment regimens (n = 311). Secondary endpoints were overall survival (OS), progression type, pseudoprogression rate, and toxicity.

Results: The 4-year PFS in the RT + PCV arm was 70.8% versus 53.5% in the RT + TMZ arm, with a hazard ratio (HR) of 0.58 (95% confidence interval [CI], 0.38-0.87; p = .0074) in univariable analysis and 0.63 (95% CI, 0.41-0.97; p = .0348) in multivariable analysis. The 4-year OS in the RT + PCV arm was 84.3% versus 76.6% in the RT + TMZ arm, with an HR of 0.57 (95% CI, 0.30-1.05; p = .0675) in univariable analysis. Toxicity was significantly higher in the RT + PCV arm with more grade ≥3 toxicity (46.7% vs. 8.6%, p < .0001).

Conclusion: RT + PCV significantly improved PFS compared with RT + TMZ for IDH-mutant AA. However, RT + TMZ was better tolerated.

Implications For Practice: In the absence of fully conducted randomized trials comparing procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) in adjuvant treatment after radiotherapy (RT) for the management of IDH-mutant anaplastic astrocytoma (AA) and a similar level of evidence, these two chemotherapies are both equally recommended in international guidelines. This study in a national cohort of IDH-mutant AA defined according the 2016 World Health Organization (WHO) classification shows for the first time that the RT + PCV regimen significantly improves progression-free survival in comparison with the RT + TMZ regimen. Even if at the time of analysis the difference in overall survival was not significant, this result provides new evidence for the debate about the chemotherapy regimen to prescribe in adjuvant treatment to RT for WHO 2016 IDH-mutant AA.
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http://dx.doi.org/10.1002/onco.13701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100568PMC
May 2021

Laparoscopic closure of the pouch of Douglas by a peritoneal running suture. A minimally invasive and prosthetic-free technique to prevent excessive dose delivery to the small bowel during pelvic irradiation for prostate cancer.

Clin Transl Radiat Oncol 2021 Jan 1;26:71-78. Epub 2020 Dec 1.

Department of Radiation Oncology, Institut Universitaire du Cancer de Toulouse, 1, avenue Irène Joliot-Curie, 31100 Toulouse, France.

Background And Purpose: Prostate radiotherapy relies on the delivery of high doses that can be obstructed when a small bowel loop descends in the pelvis. We present a laparoscopic minimally invasive prosthetic-free technique closing the Douglas' pouch with a peritoneal running suture to cordon off the bowel from the pelvis and hence allow optimal irradiation.

Materials And Methods: Prostate cancer patients referred for radiotherapy and whose planning-CT revealed a bowel loop trapped in the pelvis were proposed the procedure, followed by a new planning-CT. This proof-of-concept study reports postoperative follow-up and dosimetric benefits.

Results: The procedure was performed in ten patients (2016-2020) as a same-day surgery for nine. Median operative time was 34 min (range 22-50) and no relevant intraoperative complication occurred. The third patient of the series presented a small bowel hernia through the peritoneal suture at the 15th postoperative day requiring a laparotomic desincarceration without major consequences. Regarding the small bowel, median D1cc (dose to 1 cc) was 65.5 Gy and 55.5 Gy (p = 0.005) before and after procedure. Median V60 (volume receiving ≥60 Gy) was 10.2 cc and 0.0 cc (p = 0.005). In the immediate vicinity of the small bowel (5 mm), median D1cc was 68.3 Gy and 57.7 Gy (p = 0.005). Radiotherapy was safely delivered to all patients.

Conclusion: Laparoscopic closure of the Douglas' pouch by a peritoneal suture is an efficient technique to cordon off inconvenient ectopic small bowel loops. It prevents excessive bowel irradiation and hence facilitates curative prostate radiotherapy. The technique could be applied to other pelvic malignancies.
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http://dx.doi.org/10.1016/j.ctro.2020.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721662PMC
January 2021

Bruton's Tyrosine Kinase Inhibition Promotes Myelin Repair.

Brain Plast 2020 Oct 1;5(2):123-133. Epub 2020 Oct 1.

Sorbonne Université, Inserm, CNRS, Institut du Cerveau et de la Moelle Épinière, GH Pitié-Salpêtrière, F-75013 Paris, France.

Background: Microglia are the resident macrophages of the central nervous system (CNS). In multiple sclerosis (MS) and related experimental models, microglia have either a pro-inflammatory or a pro-regenerative/pro-remyelinating function. Inhibition of Bruton's tyrosine kinase (BTK), a member of the Tec family of kinases, has been shown to block differentiation of pro-inflammatory macrophages in response to granulocyte-macrophage colony-stimulating factor . However, the role of BTK in the CNS is unknown.

Methods: Our aim was to investigate the effect of BTK inhibition on myelin repair in and experimental models of demyelination and remyelination. The remyelination effect of a BTK inhibitor (BTKi; BTKi-1) was then investigated in LPC-induced demyelinated cerebellar organotypic slice cultures and metronidazole-induced demyelinated transgenic tadpoles.

Results: Cellular detection of BTK and its activated form BTK-phospho-Y223 (p-BTK) was determined by immunohistochemistry in organotypic cerebellar slice cultures, before and after lysophosphatidylcholine (LPC)-induced demyelination. A low BTK signal detected by immunolabeling under normal conditions in cerebellar slices was in sharp contrast to an 8.5-fold increase in the number of BTK-positive cells observed in LPC-demyelinated slice cultures. Under both conditions, approximately 75% of cells expressing BTK and p-BTK were microglia and 25% were astrocytes. Compared with spontaneous recovery, treatment of demyelinated slice cultures and MTZ-demyelinated transgenic tadpoles with BTKi resulted in at least a 1.7-fold improvement of remyelination.

Conclusion: Our data demonstrate that BTK inhibition is a promising therapeutic strategy for myelin repair.
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http://dx.doi.org/10.3233/BPL-200100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685672PMC
October 2020

Improving patient selection for immuno-oncology phase 1 trials: External validation of six prognostic scores in a French Cancer Center.

Int J Cancer 2020 Nov 24. Epub 2020 Nov 24.

Department of Biostatistics, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole (IUCT-O), Toulouse, France.

We compared the performance of six prognostic scores (Royal Marsden Hospital, MDACC: MD Anderson Clinical Center and MDACC + NLR: neutrophil-to-lymphocyte ratio, MD Anderson - immune checkpoint inhibitors (MDA-ICI), GRIm: Gustave Roussy Immune Score and LIPI: Lung Immune Prognostic Index) in predicting overall survival (OS) in phase I trial patients treated with immune checkpoint inhibitors (ICI). Medical records of patients with advanced solid tumors enrolled in ICI phase I trials between 2015 and 2018 at Institut Universitaire du Cancer de Toulouse-Oncopole were reviewed. The performance of prognostic scores on OS was compared using different criteria. A total of 259 patients were included. Median age was 63 years (range: 18-83). Main primary cancers were melanoma (19%), head and neck (16%), lung (13%) and bladder (10%). With a median follow-up of 15 months (95% confidence interval [CI] = [11.6;17.5]), median OS was 12.5 months (95% CI = [10.3;16.0]). All scores were associated with OS. The MDACC, LIPI and GRIm scores performed better than the others. Concordance of risk group assignment between the scoring systems was poor. According to our results, the MDACC, GRIm and LIPI scores better suited to ICI phase I settings. Adequate scoring would allow better patient selection in early ICI trials, especially during the critical period of dose escalation, and in proof-of-concept expansion cohorts.
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http://dx.doi.org/10.1002/ijc.33409DOI Listing
November 2020

Positioning accuracy of a single-isocenter multiple targets SRS treatment: A comparison between Varian TrueBeam CBCT and Brainlab ExacTrac.

Phys Med 2020 Dec 19;80:267-273. Epub 2020 Nov 19.

Department of Medical Physics, Cancer University Institute - Oncopole, Toulouse, France.

Purpose: This study compared the positioning accuracy between cone-beam CT (CBCT) and ExacTrac (ETX) for a single-isocenter multiple target stereotactic radiosurgery (SRS) on two TrueBeam STx systems.

Methods: A single-isocenter treatment plan was simulated on an anthropomorphic head phantom with six spherical steel ball bearings (BBs). One of the BBs was chosen to be the isocenter. The five off-isocenter targets were located at various distances from the isocenter. MV portal images were generated to evaluate the deviations between the expected and the real center of the targets after CBCT and ETX positioning, respectively.

Results: The evaluation of the positioning accuracy for the isocenter target showed that CBCT and ETX positioning provided comparable, sub-millimetric results. Deviations in positioning accuracy were also calculated for all other targets, also showing comparable results for CBCT and ETX. Moreover, our study showed that the deviation between CBCT and ETX positioning were in better agreement for TBSTx1 and deviated slightly higher on TBSTx2 (maximum: 1.23 mm at S/I direction), due to a less perfect alignment between the CBCT coordinate system and the ETX coordinate system on TBSTx2 compared to TBSTx1. This study also showed a correlation between the target positioning accuracy and the distance to the isocenter.

Conclusion: The positioning accuracy of ETX and CBCT for targets located at isocenter and off-isocenter locations was compared on two treatment machines and found comparable. Our study highlights the importance of a proper calibration procedure, to ensure correct alignment between the CBCT, ETX and machine coordinate systems.
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http://dx.doi.org/10.1016/j.ejmp.2020.10.022DOI Listing
December 2020

Indoleamine 2,3-Dioxygenase Is Involved in Interferon Gamma's Anti-BKPyV Activity in Renal Cells.

Viruses 2020 08 7;12(8). Epub 2020 Aug 7.

UR4294, Infectious Agents, Resistance and Chemotherapy, University Health Research Center, University of Picardie Jules Verne, F-80054 Amiens, France.

Reactivation of BK polyomavirus (BKPyV) infection is frequently increasing in transplant recipients treated with potent immunosuppressants and highlights the importance of immune system components in controlling viral reactivation. However, the immune response to BKPyV in general and the role of antiviral cytokines in infection control in particular are poorly understood. Here, we investigated the efficacy of interferons (IFN) alpha, lambda and gamma with regard to the BKPyV multiplication in Vero cells. Treatment with IFN-gamma inhibited the expression of the viral protein VP1 in a dose-dependent manner and decreased the expression of early and late viral transcripts. Viral inhibition by IFN-gamma was confirmed in human cells (Caki-1 cells and renal proximal tubular epithelial cells). One of the IFN-stimulated genes most strongly induced by IFN-gamma was the coding for the enzyme indoleamine 2,3 dioxygenase (IDO), which is known to limit viral replication and regulates the host immune system. The antiviral activity induced by IFN-gamma could be reversed by the addition of an IDO inhibitor, indicating that IDO has a specific role in anti-BKPyV activity. A better understanding of the action mechanism of these IFN-gamma-induced antiviral proteins might facilitate the development of novel therapeutic strategies.
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http://dx.doi.org/10.3390/v12080865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472348PMC
August 2020

A Drosophila model of Friedreich ataxia with CRISPR/Cas9 insertion of GAA repeats in the frataxin gene reveals in vivo protection by N-acetyl cysteine.

Hum Mol Genet 2020 10;29(17):2831-2844

Université de Paris, BFA Unit of Functional and Adaptative Biology, UMR 8251, CNRS, Paris F-75013, France.

Friedreich ataxia (FA) is caused by GAA repeat expansions in the first intron of FXN, the gene encoding frataxin, which results in decreased gene expression. Thanks to the high degree of frataxin conservation, the Drosophila melanogaster fruitfly appears as an adequate animal model to study this disease and to evaluate therapeutic interventions. Here, we generated a Drosophila model of FA with CRISPR/Cas9 insertion of approximately 200 GAA in the intron of the fly frataxin gene fh. These flies exhibit a developmental delay and lethality associated with decreased frataxin expression. We were able to bypass preadult lethality using genetic tools to overexpress frataxin only during the developmental period. These frataxin-deficient adults are short-lived and present strong locomotor defects. RNA-Seq analysis identified deregulation of genes involved in amino-acid metabolism and transcriptomic signatures of oxidative stress. In particular, we observed a progressive increase of Tspo expression, fully rescued by adult frataxin expression. Thus, Tspo expression constitutes a molecular marker of the disease progression in our fly model and might be of interest in other animal models or in patients. Finally, in a candidate drug screening, we observed that N-acetyl cysteine improved the survival, locomotor function, resistance to oxidative stress and aconitase activity of frataxin-deficient flies. Therefore, our model provides the opportunity to elucidate in vivo, the protective mechanisms of this molecule of therapeutic potential. This study also highlights the strength of the CRISPR/Cas9 technology to introduce human mutations in endogenous orthologous genes, leading to Drosophila models of human diseases with improved physiological relevance.
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http://dx.doi.org/10.1093/hmg/ddaa170DOI Listing
October 2020

Effects of Chronic Masitinib Treatment in APPswe/PSEN1dE9 Transgenic Mice Modeling Alzheimer's Disease.

J Alzheimers Dis 2020 ;76(4):1339-1345

ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France.

Background: Masitinib is a selective tyrosine kinase inhibitor that modulates mast cells activity. A previous phase II study reported a cognitive effect of masitinib in patients with Alzheimer's disease.

Objective: We aimed to shed light on the mode of action of masitinib in Alzheimer's disease.

Methods/results: We demonstrated here that chronic oral treatment of APPswe/PSEN1dE9 transgenic mice modeling Alzheimer's disease restored normal spatial learning performance while having no impacts on amyloid-β loads nor on neuroinflammation. However, masitinib promoted a recovery of synaptic markers. Complete genetic depletion of mast cells in APPswe/PSEN1dE9 mice similarly rescued synaptic impairments.

Conclusion: These results underline that masitinib therapeutic efficacy might primarily be associated with a synapto-protective action in relation with mast cells inhibition.
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http://dx.doi.org/10.3233/JAD-200466DOI Listing
June 2021

Predicting Pain Trajectories in the One Year Following Breast Cancer Diagnosis-An Observational Study.

J Clin Med 2020 Jun 18;9(6). Epub 2020 Jun 18.

CHU Clermont-Ferrand, Inserm, Centre d'Investigation Clinique, CIC Inserm 1405, F-63000 Clermont-Ferrand, France.

The impact of psychosocial vulnerability on pain in the year following breast cancer diagnosis has been little studied. To identify a score of psychosocial vulnerability (cognitive, emotional, quality of life and precariousness parameters) as a predictor of a pain trajectory, we conducted an observational prospective study and included women with newly diagnosed breast cancer. One year follow-up with 3 visits (day of breast cancer diagnosis; 6 and 12 months) aimed to identify distinct pain-time trajectories. Baseline psychosocial vulnerability was characterized by z-score transformation, a higher score representing a more vulnerable patient. A total of 89 patients were included (59.3 ± 10.7 years). Two trajectories of pain were identified-"Transient Pain trajectory" (TP) (39/89 patients) and "Persistent Pain trajectory" (PP) (50/89). A significant difference of pain over time between trajectories (PP vs. TP at 6 months: 2.23 ± 0.23 vs. 0.27 ± 0.09, < 0.001) was observed. Psychosocial vulnerability showed a large effect size (d, -0.82; 95% CI, -1.25 to -0.38; < 0.001) and a higher score in "Persistent pain trajectory" (PP vs. TP: 0.12 ± 0.36 vs. -0.14 ± 0.26, < 0.001). A predictive vulnerability marker of pain development is proposed and could be used at cancer diagnosis to orientate the care pathway of patients experiencing breast cancer.
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http://dx.doi.org/10.3390/jcm9061907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356308PMC
June 2020

Implication of 5-HT in the Dysregulation of Chloride Homeostasis in Prenatal Spinal Motoneurons from the G93A Mouse Model of Amyotrophic Lateral Sclerosis.

Int J Mol Sci 2020 Feb 7;21(3). Epub 2020 Feb 7.

University of Bordeaux, CNRS, INCIA, UMR 5287, F-33000 Bordeaux, France.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. The early presymptomatic onset of abnormal processes is indicative of cumulative defects that ultimately lead to a late manifestation of clinical symptoms. It remains of paramount importance to identify the primary defects that underlie this condition and to determine how these deficits lead to a cycle of deterioration. We recently demonstrated that prenatal E17.5 lumbar spinal motoneurons (MNs) from SOD1 mice exhibit a KCC2-related alteration in chloride homeostasis, i.e., the E is more depolarized than in WT littermates. Here, using immunohistochemistry, we found that the SOD1 lumbar spinal cord is less enriched with 5-HT descending fibres than the WT lumbar spinal cord. High-performance liquid chromatography confirmed the lower level of the monoamine 5-HT in the SOD1 spinal cord compared to the WT spinal cord. Using ex vivo perforated patch-clamp recordings of lumbar MNs coupled with pharmacology, we demonstrated that 5-HT strongly hyperpolarizes the E by interacting with KCC2. Therefore, the deregulation of the interplay between 5-HT and KCC2 may explain the alteration in chloride homeostasis detected in prenatal SOD1 MNs. In conclusion, 5-HT and KCC2 are two likely key factors in the presymptomatic phase of ALS, particular in familial ALS involving the SOD1 mutation.
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http://dx.doi.org/10.3390/ijms21031107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039234PMC
February 2020

Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1.

Nat Commun 2020 01 23;11(1):437. Epub 2020 Jan 23.

Inserm UMR1037, Cancer Research Center of Toulouse, 31037, Toulouse, France.

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.
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http://dx.doi.org/10.1038/s41467-019-14218-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978345PMC
January 2020

Relaxation of synaptic inhibitory events as a compensatory mechanism in fetal SOD spinal motor networks.

Elife 2019 12 23;8. Epub 2019 Dec 23.

University of Bordeaux, CNRS, INCIA, UMR 5287, Bordeaux, France.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons (MNs) during late adulthood. Here, with the aim of identifying early changes underpinning ALS neurodegeneration, we analyzed the GABAergic/glycinergic inputs to E17.5 fetal MNs from SOD1 (SOD) mice in parallel with chloride homeostasis. Our results show that IPSCs are less frequent in SOD animals in accordance with a reduction of synaptic VIAAT-positive terminals. SOD MNs exhibited an E10 mV more depolarized than in WT MNs associated with a KCC2 reduction. Interestingly, SOD GABAergic/glycinergic IPSCs and evoked GABAR-currents exhibited a slower decay correlated to elevated [Cl]. Computer simulations revealed that a slower relaxation of synaptic inhibitory events acts as compensatory mechanism to strengthen GABA/glycine inhibition when E is more depolarized. How such mechanisms evolve during pathophysiological processes remain to be determined, but our data indicate that at least SOD1 familial ALS may be considered as a neurodevelopmental disease.
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http://dx.doi.org/10.7554/eLife.51402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974356PMC
December 2019

Dextromethorphan and memantine after ketamine analgesia: a randomized control trial.

Drug Des Devel Ther 2019 2;13:2677-2688. Epub 2019 Aug 2.

Université Clermont Auvergne, Pharmacologie Fondamentale Et Clinique de la Douleur, Neuro-Dol, Inserm 1107, F-63000 Clermont-Ferrand, France.

Purpose: Intravenous ketamine is often prescribed in severe neuropathic pain. Oral -methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the frequency of ketamine infusions and hospital admissions. This clinical trial aimed at assessing whether oral dextromethorphan or memantine might prolong pain relief after intravenous ketamine.

Patients And Methods: A multicenter randomized controlled clinical trial included 60 patients after ketamine infusion for refractory neuropathic pain. Dextromethorphan (90 mg/day), memantine (20 mg/day) or placebo was given for 12 weeks (n=20 each) after ketamine infusion. The primary endpoint was pain intensity at one month. Secondary endpoints included pain, sleep, anxiety, depression, cognitive function and quality of life evaluations up to 12 weeks.

Results: At 1 month, dextromethorphan maintained ketamine pain relief (Numeric Pain Scale: 4.01±1.87 to 4.05±2.61, =0.53) and diminished pain paroxysms (=0.03) while pain intensity increased significantly with memantine and placebo (=0.04). At 3 months, pain remained lower than at inclusion (=0.001) and was not significantly different in the three groups. Significant benefits were observed on cognitive-affective domains and quality of life for dextromethorphan and memantine (<0.05).

Conclusions: Oral dextromethorphan given after ketamine infusion extends pain relief during one month and could help patients to better cope with pain. Future studies should include larger populations stratified on pharmacogenetics screening. Optimization of an oral drug that could extend ketamine antihyperalgesia, with fewer hospital admissions, remains a prime challenge in refractory neuropathic pain.
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http://dx.doi.org/10.2147/DDDT.S207350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683947PMC
April 2020

Prognostic role of CD4 T-cell depletion after frontline fludarabine, cyclophosphamide and rituximab in chronic lymphocytic leukaemia.

BMC Cancer 2019 Aug 14;19(1):809. Epub 2019 Aug 14.

Department of Haematology, Toulouse-Oncopole University Cancer Institute (IUCT-O), 1 Avenue Irene Joliot-Curie, 31059, Toulouse, France.

Background: Eradication of minimal residual disease (MRD), at the end of Fludarabine-Cyclophosphamide-Rituximab (FCR) treatment, is a validated surrogate marker for progression-free and overall survival in chronic lymphocytic leukaemia. But such deep responses are also associated with severe immuno-depletion, leading to infections and the development of secondary cancers.

Methods: We assessed, blood MRD and normal immune cell levels at the end of treatment, in 162 first-line FCR patients, and analysed survival and adverse event.

Results: Multivariate Landmark analysis 3 months after FCR completion identified unmutated IGHV status (HR, 2.03, p = 0.043), the level of MRD reached (intermediate versus low, HR, 2.43, p = 0.002; high versus low, HR, 4.56, p = 0.002) and CD4 > 200/mm (HR, 3.30, p <  0.001) as factors independently associated with progression-free survival (PFS); neither CD8 nor NK counts were associated with PFS. The CD4 count was associated with PFS irrespective of IGHV mutational status, but only in patients with detectable MRD (HR, 3.51, p = 0.0004, whereas it had no prognostic impact in MRD < 10 patients: p = 0.6998). We next used a competitive risk model to investigate whether immune cell subsets could be associated with the risk of infection and found no association between CD4, CD8 and NK cells and infection.

Conclusions: Consolidation/maintenance trials based on detectable MRD after FCR should investigate CD4 T-cell numbers both as a selection and a response criterion, and consolidation treatments should target B-cell/T-cell interactions.
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http://dx.doi.org/10.1186/s12885-019-5971-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694602PMC
August 2019

Alpha6-Integrin Regulates FGFR1 Expression through the ZEB1/YAP1 Transcription Complex in Glioblastoma Stem Cells Resulting in Enhanced Proliferation and Stemness.

Cancers (Basel) 2019 Mar 22;11(3). Epub 2019 Mar 22.

INSERM UMR.1037-Cancer Research Center of Toulouse (CRCT)/University Paul Sabatier Toulouse III, 31037 Toulouse, France.

Glioblastoma (GBM) is the most lethal primary brain tumor in adults and is known to be particularly aggressive and resistant to anti-cancer therapies, mainly due to the presence of GBM stem cells (GBMSC). By in vitro approaches supported by analysis from patients' databases, we determined how α6-integrin and Fibroblast Growth Factor Receptor 1 (FGFR1) work in concert to regulate proliferation and stemness of GBMSC. We showed that α6-integrin regulates the expression of FGFR1 and its target gene Fokhead Box M1 (FOXM1) via the ZEB1/YAP1 transcription complex. These results were in accordance with the positive correlation observed in GBM between α6-integrin expression and its target genes ZEB1/YAP1, FGFR1, and FOXM1 in the databases, TCGA and Rembrandt. In addition, the clinical data demonstrate that GBM patients with high levels of the five genes signature, including α6-integrin, ZEB1/YAP1, FGFR1 and FOXM1, have a significantly shorter overall survival. In vitro, we observed a similar decrease in the expression of stemness-related factors, neurospheres forming capacity, as well as spheroids growth when α6-integrin or FGFR1 was blocked individually with specific siRNA, whereas the combination of both siRNA led to a significantly higher inhibition of spheres formation. These data suggest that co-administration of anti-FGFR1 and anti-α6-integrin could provide an improved therapeutic response in GBMSC.
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http://dx.doi.org/10.3390/cancers11030406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468800PMC
March 2019

[The purinergic receptor P2X7, a new therapeutic target in Alzheimer' disease].

Med Sci (Paris) 2019 Feb 18;35(2):97-99. Epub 2019 Feb 18.

Sorbonne Université, Inserm, CNRS, Institut de la Vision, 17, rue Moreau, 75012 Paris, France.

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http://dx.doi.org/10.1051/medsci/2019017DOI Listing
February 2019

Early Circulating Tumour DNA Variations Predict Tumour Response in Melanoma Patients Treated with Immunotherapy.

Acta Derm Venereol 2019 Feb;99(2):206-210

Département de Biologie Médicale Oncologique, Institut Claudius Regaud, IUCT-O, FR-31059 Toulouse, France.

Antibodies targeting immune checkpoints were recently approved for metastatic melanoma. However, not all patients will respond to the treatment and some will experience grade III-IV immune-related adverse events. Therefore, early identification of non-responder patients would greatly aid clinical practice. Detection of circulating tumour DNA (ctDNA) is a non-invasive approach to monitor tumour response. Digital droplet PCR was used to quantify BRAF and NRAS mutations in the plasma of patients with metastatic melanoma treated with immunotherapy. In 16 patients, ctDNA variations mirrored tumour response (p = 0.034) and ctDNA augmentation during follow-up detected tumour progression with 100% specificity. In 13 patients, early ctDNA variation was associated with clinician decision at first evaluation (p = 0.0046), and early ctDNA increase with shorter progression-free survival (median 21 vs. 145 days; p = 0.001). Monitoring ctDNA variations early during immunotherapy may help clinicians rapidly to discriminate non-responder patients, allow early adaptation of therapeutic strategies, and reduce exposure to ineffective, expensive treatment.
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http://dx.doi.org/10.2340/00015555-3080DOI Listing
February 2019

Profiling Immune Escape in Hodgkin's and Diffuse large B-Cell Lymphomas Using the Transcriptome and Immunostaining.

Cancers (Basel) 2018 Oct 31;10(11). Epub 2018 Oct 31.

Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, 31100 Toulouse, France.

Therapeutic blockade of PD-1/PD-L1 shows promising results in Hodgkin's lymphoma (HL) and in some diffuse large B-cell lymphoma (DLBCL) patients, but biomarkers predicting such responses are still lacking. To this end, we recently developed a transcriptional scoring of immune escape (IE) in cancer biopsies. Using this method in DLBCL, we identified four stages of IE correlated with overall survival, but whether Hodgkin's lymphomas (HL) also display this partition was unknown. Thus, we explored the transcriptomic profiles of ~1000 HL and DLBCL using a comparative meta-analysis of their bulk microarrays. Relative to DLBCL, the HL co-clustered at the advanced stage of immune escape, displaying significant enrichment of both IE and T-cell activation genes. Analyses via transcriptome deconvolution and immunohistochemistry showed more CD3⁺ and CD4⁺ tumor-infiltrating lymphocytes (TILs) in HL than DLBCL. Both HL and non-GCB DLBCL shared a high abundance of infiltrating CD8⁺ T-cells, but HL had less CD68⁺CD163⁺ macrophages. The same cellular distribution of PD-1 and TIM-3 was observed in HL and DLBCL, though HL had more PD-L1 tumor cells and LAG-3 ME cells. This study illuminates the advanced stage of immune activation and escape in HL, consistent with the response to checkpoint blockade therapies for this type of lymphoma.
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http://dx.doi.org/10.3390/cancers10110415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266061PMC
October 2018

New role of P2X7 receptor in an Alzheimer's disease mouse model.

Mol Psychiatry 2019 01 22;24(1):108-125. Epub 2018 Jun 22.

Inserm, CNRS, Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.

Extracellular aggregates of amyloid β (Aβ) peptides, which are characteristic of Alzheimer's disease (AD), act as an essential trigger for glial cell activation and the release of ATP, leading to the stimulation of purinergic receptors, especially the P2X7 receptor (P2X7R). However, the involvement of P2X7R in the development of AD is still ill-defined regarding the dual properties of this receptor. Particularly, P2X7R activates the NLRP3 inflammasome leading to the release of the pro-inflammatory cytokine, IL-1β; however, P2X7R also induces cleavage of the amyloid precursor protein generating Aβ peptides or the neuroprotective fragment sAPPα. We thus explored in detail the functions of P2X7R in AD transgenic mice. Here, we show that P2X7R deficiency reduced Aβ lesions, rescued cognitive deficits and improved synaptic plasticity in AD mice. However, the lack of P2X7R did not significantly affect the release of IL-1β or the levels of non-amyloidogenic fragment, sAPPα, in AD mice. Instead, our results show that P2X7R plays a critical role in Aβ peptide-mediated release of chemokines, particularly CCL3, which is associated with pathogenic CD8 T cell recruitment. In conclusion, our study highlights a novel detrimental function of P2X7R in chemokine release and supports the notion that P2X7R may be a promising therapeutic target for AD.
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http://dx.doi.org/10.1038/s41380-018-0108-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756107PMC
January 2019

Identification of cardioprotective drugs by medium-scale pharmacological screening on a cardiac model of Friedreich's ataxia.

Dis Model Mech 2018 07 20;11(7). Epub 2018 Jul 20.

Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France

Friedreich's ataxia (FA) is caused by reduced levels of frataxin, a highly conserved mitochondrial protein. There is currently no effective treatment for this disease, which is characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Methylene Blue (MB) was highly efficient to prevent these cardiac dysfunctions. Here, we used this model to screen the Prestwick Chemical Library, comprising 1280 compounds. Eleven drugs significantly reduced the cardiac dilatation, some of which may possibly lead to therapeutic applications in the future. The one with the strongest protective effects was paclitaxel, a microtubule-stabilizing drug. In parallel, we characterized the histological defects induced by frataxin deficiency in cardiomyocytes and observed strong sarcomere alterations with loss of striation of actin fibers, along with full disruption of the microtubule network. Paclitaxel and MB both improved these structural defects. Therefore, we propose that frataxin inactivation induces cardiac dysfunction through impaired sarcomere assembly or renewal due to microtubule destabilization, without excluding additional mechanisms. This study is the first drug screening of this extent performed on a model of cardiac disease. Thus, it also brings the proof of concept that cardiac functional imaging in adult flies is usable for medium-scale pharmacological screening, with potent identification of cardioprotective drugs in various contexts of cardiac diseases.
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http://dx.doi.org/10.1242/dmm.033811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078405PMC
July 2018

Complex role of chemokine mediators in animal models of Alzheimer's Disease.

Biomed J 2018 02 27;41(1):34-40. Epub 2018 Mar 27.

Inserm UMRS_1127, Paris, France; Sorbonne University, Paris, France; CNRS UMR7225, Paris France; Brain and Spine Institute (ICM), Paris, France. Electronic address:

Chemokines are a family of cytokines, first described to play a role in the immune system. However, neurons and glial cells also express chemokines and their receptors. In the central nervous system, chemokines are involved in several neural functions, in particular in the control of cell communications and neuronal activity. In pathological conditions, chemokines participate in neuroinflammatory and neurodegenerative processes. In Alzheimer's disease (AD), chemokines play a role in the development of the two main lesions, amyloid β plaques and neurofibrillary tangles. In addition, they contribute to the inflammatory response by recruiting T cells and controlling microglia/macrophages activation. Actually, targeting inflammatory pathways seems a promising therapeutic approach for the treatment of AD patients. This review summarizes our current knowledge on the roles of chemokines in AD animal models and the underlying mechanisms in which they take part. Better knowledge of the role of chemokines and their cellular receptors in AD could open new therapeutic perspectives.
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http://dx.doi.org/10.1016/j.bj.2018.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138613PMC
February 2018

An Advanced Formulation of a Magnesium Dietary Supplement Adapted for a Long-Term Use Supplementation Improves Magnesium Bioavailability: In Vitro and Clinical Comparative Studies.

Biol Trace Elem Res 2018 Nov 9;186(1):1-8. Epub 2018 Mar 9.

Pharmacologie Fondamentale et Clinique de la Douleur, Neuro-Dol, Université Clermont Auvergne, Inserm 1107, F-63000, Clermont-Ferrand, France.

While general recommendations are for 300-mg magnesium intake a day, an advanced low-dose formulation of magnesium chloride, ChronoMag®, was designed to provide 100 mg of magnesium element, thus decreasing the risk of gastrointestinal side effects and allowing long-term supplementation in health conditions related to low magnesium levels. The present study aimed to compare magnesium release profile and bioavailability between this patented low-dose continuous-release magnesium chloride tablet (100 mg magnesium element) and a reference tablet at the usually prescribed dose (300 mg magnesium element). Magnesium release profile was determined by dissolving the tablets in solutions simulating the gastrointestinal tract environment. A randomized double-blind crossover controlled trial of ChronoMag® versus reference tablet (3 × 100 mg magnesium element tablets) in 12 normo-magnesemic healthy volunteers was conducted to evaluate the bioavailability of the patented magnesium chloride tablets (two 50 mg magnesium tablets, once-a-day intake). While the reference tablet released 100% of its magnesium within 1 h of dissolution, release from the magnesium chloride formulation was continuous for 6 h. Cumulative urinary magnesium levels compared to those with the reference tablet were 76% (0-5 h), 89% (0-10 h), and 87% (0-24 h). Elimination after 24 h was fairly similar with both supplements. Our results suggest that the new magnesium chloride formulation, providing continuous low-dose magnesium release throughout the gastrointestinal tract, improves absorption and bioavailability. This formulation conforms to the physiological mechanism of magnesium absorption throughout the digestive tract, allowing high absorption, and may improve gastrointestinal tolerance in long-term use.
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http://dx.doi.org/10.1007/s12011-018-1277-2DOI Listing
November 2018

Karyopherin α-3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3.

Proc Natl Acad Sci U S A 2018 03 23;115(11):E2624-E2633. Epub 2018 Feb 23.

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany;

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell, , and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective orthologs Emb, Cdm, and Kap-α3. While overexpression of CRM1/Emb demonstrated positive effects in , KPNA3/Kap-α3 emerged as the most promising target, as knockdown via multiple RNAi lines demonstrated its ability to shuttle both truncated and full-length expanded ataxin-3, rescue neurodegeneration, restore photoreceptor formation, and reduce aggregation. Furthermore, knockout in SCA3 mice resulted in an amelioration of molecular and behavioral disturbances such as total activity, anxiety, and gait. Since KPNA3 is known to function as an import protein and recognize nuclear localization signals (NLSs), this work unites ataxin-3 structure to the nuclear pore machinery and provides a link between karyopherins, NLS signals, and polyglutamine disease, as well as demonstrates that KPNA3 is a key player in the pathogenesis of SCA3.
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http://dx.doi.org/10.1073/pnas.1716071115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856529PMC
March 2018

Biology of the BKPyV: An Update.

Viruses 2017 11 3;9(11). Epub 2017 Nov 3.

EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.

The BK virus (BKPyV) is a member of the family first isolated in 1971. BKPyV causes frequent infections during childhood and establishes persistent infections with minimal clinical implications within renal tubular cells and the urothelium. However, reactivation of BKPyV in immunocompromised individuals may cause serious complications. In particular, with the implementation of more potent immunosuppressive drugs in the last decade, BKPyV has become an emerging pathogen in kidney and bone marrow transplant recipients where it often causes associated nephropathy and haemorrhagic cystitis, respectively. Unfortunately, no specific antiviral against BKPyV has been approved yet and the only therapeutic option is a modulation of the immunosuppressive drug regimen to improve immune control though it may increase the risk of rejection. A better understanding of the BKPyV life cycle is thus needed to develop efficient treatment against this virus. In this review, we provide an update on recent advances in understanding the biology of BKPyV.
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http://dx.doi.org/10.3390/v9110327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707534PMC
November 2017

Localized neuropathic pain: an expert consensus on local treatments.

Drug Des Devel Ther 2017 13;11:2709-2718. Epub 2017 Sep 13.

Unité d'Evaluation et Traitement de la Douleur, Voiron.

Background: Pain localization is one of the hallmarks for the choice of first-line treatment in neuropathic pain. This literature review has been conducted to provide an overview of the current knowledge regarding the etiology and pathophysiology of localized neuropathic pain (LNP), its assessment and the existing topical pharmacological treatments.

Materials And Methods: Literature review was performed using Medline from 2010 to December 2016, and all studies involving LNP and treatments were examined. A multidisciplinary expert panel of five pain specialists in this article reports a consensus on topical approaches that may be recommended to alleviate LNP and on their advantages in clinical practice.

Results: Successive international recommendations have included topical 5% lidocaine and 8% capsaicin for LNP treatment. The expert panel considers that these compounds can be a first-line treatment for LNP, especially in elderly patients and patients with comorbidities and polypharmacy. Regulatory LNP indications should cover the whole range of LNP and not be restricted to specific etiologies or sites. Precautions for the use of plasters must be followed cautiously.

Conclusion: Although there is a real need for more randomized controlled trials for both drugs, publications clearly demonstrate excellent risk/benefit ratios, safety, tolerance and continued efficacy throughout long-term treatment. A major advantage of both plasters is that they have proven efficacy and may reduce the risk of adverse events such as cognitive impairment, confusion, somnolence, dizziness and constipation that are often associated with systemic neuropathic pain treatment and reduce the quality of life. Topical modalities also may be used in combination with other drugs and analgesics with limited drug-drug interactions.
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http://dx.doi.org/10.2147/DDDT.S142630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604568PMC
July 2018

[Tau and cognitive disorders: a role for T lymphocytes].

Med Sci (Paris) 2017 Oct 10;33(10):817-819. Epub 2017 Oct 10.

Université de Lille, Inserm, CHU-Lille, UMR S 1172, Alzheimer et Tauopathies, LabEx DISTALZ, 1, place de Verdun, 59045 Lille, France.

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http://dx.doi.org/10.1051/medsci/20173310002DOI Listing
October 2017

Alteration of rhythmic unimanual tapping and anti-phase bimanual coordination in Alzheimer's disease: A sign of inter-hemispheric disconnection?

Hum Mov Sci 2017 Oct 25;55:43-53. Epub 2017 Jul 25.

Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, France. Electronic address:

Little attention is paid to motor control in Alzheimer's disease (AD) although it is a relevant sign of central nervous system integrity and functioning. In particular, unimanual and bimanual tapping is a relevant paradigm because it requires intra- and inter-hemispheric transfer (IHT). Previous results indicate that both unimanual and anti-phase tapping requires more IHT than in-phase tapping, especially produced without external stimulation. The aim of the present study was to test the production of unimanual, bimanual in-phase and anti-phase tapping with a synchronization-continuation paradigm with and without visual stimulation in AD patients (N=9) and control participants (N=12). In accordance with our hypothesis, these results suggest that unimanual and anti-phase tapping is more altered in AD than in control participants. Moreover, performance is globally more variable in the AD group. These alterations are discussed in terms of possible IHT modulation, in line with functional and structural findings in AD, revealing changes in the connectivity of brain regions across hemispheres and white matter damage.
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http://dx.doi.org/10.1016/j.humov.2017.07.007DOI Listing
October 2017
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