Publications by authors named "Gabriel Robert"

102 Publications

Functional Role of the Cerebellum in Parkinson Disease: A PET Study.

Neurology 2021 Jun 28;96(23):e2874-e2884. Epub 2021 Apr 28.

From the Department of Neurology (A.R., J.-F.H., S.D., P.S., M.V.) and Reference Center for Rare Intellectual Disability (A.R.), Medical Genetics Department, Rennes University Hospital; Behaviour and Basal Ganglia Research Unit (A.R., J.-F.H., S.D., P.S., D.D., J.D., M.G., F.L.J., M.V., G.R.), University of Rennes, Rennes; Department of Pharmacology (T.D.), INSERM U1171, University of Lille; Department of Psychiatry (D.D., M.G., G.R.), Guillaume Regnier Hospital; and Department of Nuclear Medicine (F.L.J.), Eugene Marquis Centre, Rennes, France.

Objectives: To test for cerebellar involvement in motor and nonmotor impairments in Parkinson disease (PD) and to determine patterns of metabolic correlations with supratentorial brain structures, we correlated clinical motor, cognitive, and psychiatric scales with cerebellar metabolism.

Methods: We included 90 patients with PD. Motor, cognitive, and psychiatric domains were assessed, and resting-state FDG-PET metabolic imaging was performed. The motor, cognitive, and psychiatric scores were entered separately into a principal component analysis. We looked for correlations between these 3 principal components and cerebellar metabolism. Furthermore, we extracted the mean glucose metabolism value for each significant cerebellar cluster and looked for patterns of cerebrum-cerebellum metabolic correlations.

Results: Severity of impairment was correlated with increased metabolism in the anterior lobes and vermis (motor domain); the right crus I, crus II, and declive (cognitive domain); and the right crus I and crus II (psychiatric domain). No results survived multiple testing corrections regarding the psychiatric domain. Moreover, we found distributed and overlapping, but not identical, patterns of metabolic correlations for motor and cognitive domains. Specific supratentorial structures (cortical structures, basal ganglia, and thalamus) were strongly correlated with each of the cerebellar clusters.

Conclusions: These results confirm the role of the cerebellum in nonmotor domains of PD, with differential but overlapping patterns of metabolic correlations suggesting the involvement of cerebello-thalamo-striatal-cortical loops.
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http://dx.doi.org/10.1212/WNL.0000000000012036DOI Listing
June 2021

Multimodal brain imaging connectivity analyses of emotional and motivational deficits in depression among women.

J Psychiatry Neurosci 2021 Apr 12;46(2):E303-E312. Epub 2021 Apr 12.

From the EA 4712 Comportement et noyaux gris centraux, Université de Rennes 1, France (Robert, Batail, Drapier); the Psychiatry Department, Centre Hospitalier Guillaume Régnier, 108 Boulevard Général Leclerc, 35000, Rennes, France (Robert, Domain, Batail, Drapier); the Radiology Department, CHU Rennes, 2 Rue Henri le Guilloux, 35000 Rennes, France (Bannier, Ferre); the University of Rennes, CNRS, Inria, Inserm, IRISA UMR 6074, Empenn-ERL U 1228, 35000 Rennes, France (Bannier, Corouge, Ferre, Barillot); the Institut de Neurosciences de la Timone, Campus Santé Timone, 27, Bd Jean Moulin 13005 Marseille, France (Comte); the University of Lille & CHU Lille, Inserm, U1171, Degenerative and Vascular Cognitive Disorders, 59000, Lille, France (Dondaine); and the Psychiatry Department, CHU Saint-Etienne, Team PsyR2-Centre de Recherche en Neuroscience de Lyon, (CRNL) CNRS UMR 5292-Inserm U1028, University of Lyon and Saint Etienne, France (Fakra).

Background: Major depressive disorder (MDD) is characterized by impaired cortical-subcortical functional connectivity. Apathy adds to functional impairment, but its cerebral basis in MDD remains unknown. Our objective was to describe impairments in functional connectivity during emotional processing in MDD (with varying levels of congruency and attention), and to determine their correlation with apathy.

Methods: We used the Variable Attention Affective Task during functional MRI, followed by diffusion-weighted MRI, to assess 55 right-handed women (30 with MDD and 25 healthy controls) between September 2012 and February 2015. We estimated functional connectivity using generalized psychophysiologic interaction and anatomic connectivity with tract-based spatial statistics. We measured apathy using the Apathy Evaluation Scale.

Results: We found decreased functional connectivity between the left amygdala and the left anterior cingulate cortex (ACC) during negative stimuli in participants with MDD (t54 = 4.2; p = 0.035, family-wise error [FWE]-corrected). During high-attention stimuli, participants with MDD showed reduced functional connectivity between the right dorsolateral prefrontal cortex (dlPFC) and the right ACC (t54 = 4.06, pFWE = 0.02), but greater functional connectivity between the right dlPFC and the right amygdala (t54 = 3.35, p = 0.048). Apathy was associated with increased functional connectivity between the right dlPFC and the right ACC during high-attention stimuli (t28 = 5.2, p = 0.01) and increased fractional anisotropy in the right posterior cerebellum, the anterior and posterior cingulum and the bilateral internal capsule (all pFWE < 0.05).

Limitations: Limitations included a moderate sample size, concomitant antidepressant therapy and no directed connectivity.

Conclusion: We found that MDD was associated with impairments in cortical-subcortical functional connectivity during negative stimuli that might alter the recruitment of networks engaged in attention. Apathy-related features suggested networks similar to those observed in degenerative disorders, but possible different mechanisms.
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http://dx.doi.org/10.1503/jpn.200074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061737PMC
April 2021

Analysis of mir-9 Expression Pattern in Rat Retina during Postnatal Development.

Int J Mol Sci 2021 Mar 4;22(5). Epub 2021 Mar 4.

Department of Experimental Zoology and Neurobiology, University of Pécs, 7624 Pécs, Hungary.

It is well established that miR-9 contributes to retinal neurogenesis. However, little is known about its presence and effects in the postnatal period. To expand our knowledge, miRNA-small RNA sequencing and in situ hybridization supported by RT-qPCR measurement were carried out. Mir-9 expression showed two peaks in the first three postnatal weeks in Wistar rats. The first peak was detected at postnatal Day 3 (P3) and the second at P10, then the expression gradually decreased until P21. Furthermore, we performed in silico prediction and established that miR-9 targets OneCut2 or synaptotagmin-17. Another two microRNAs (mir-135, mir-218) were found from databases which also target these proteins. They showed a similar tendency to mir-9; their lowest expression was at P7 and afterwards, they showed increase. We revealed that miR-9 is localized mainly in the inner retina. Labeling was observed in ganglion and amacrine cells. Additionally, horizontal cells were also marked. By dual miRNA-in situ hybridization/immunocytochemistry and qPCR, we revealed alterations in their temporal and spatial expression. Our results shed light on the significance of mir-9 regulation during the first three postnatal weeks in rat retina and suggest that miRNA could act on their targets in a stage-specific manner.
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http://dx.doi.org/10.3390/ijms22052577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961372PMC
March 2021

Transcatheter aortic valve replacement performed with selective telemetry monitoring: A prospective study.

Int J Cardiol 2021 05 20;330:158-163. Epub 2021 Feb 20.

Department of Cardiology, CHU Montpellier, Montpellier University, Montpellier, France. Electronic address:

Background: Telemetry monitoring (TM) with or without intensive care unit (ICU) admission is the standard of care after Transcatheter aortic valve replacement (TAVR). Regarding to improvements of the technique and procedural results, TM may be considered only in selected patients. We aimed to confirm feasibility and safety of selective TM in patients undergoing TAVR.

Methods: We prospectively evaluated 449 consecutive patients undergoing TAVR. Patients were transferred to general cardiology ward (GCW) without TM after the procedure when stable clinical state, transfemoral access, no baseline right bundle branch block (RBBB), left ventricular ejection fraction (LVEF) > 40%, and no complication including any electrocardiogram (ECG) change within 1 h after the procedure ("low-risk" group). Others patients were considered for TM in ICU ("high-risk" group). The primary endpoint evaluated in-hospital major adverse events after unit admission according to VARC-2 criteria.

Results: The mean age was 81.8 ± 7.5 years and mean EuroSCORE II was 7.5 ± 4.8%. In total, 116 patients (25.8%) were considered as "low-risk" patients and 163 patients (36.3%) were referred to GCW, including those with immediate pacemaker implantation. A total of 96 patients (21.3%) reached the primary endpoint including mainly conductive disorders (12.8%). No major adverse events, particularly no late severe conductive disorder, occurred in the "low-risk" group (negative predictive value of 100%). Baseline RBBB (p < 0.01), LVEF < 40% (p = 0.02) and "high-risk" group (p < 0.01) were predictive of outcomes.

Conclusions: Using rigorous periprocedural selection criteria, patients' admission in GCW without TM can be routinely and safely performed in 1/3 of patients after TAVR.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.028DOI Listing
May 2021

PACAP for Retinal Health: Model for Cellular Aging and Rescue.

Int J Mol Sci 2021 Jan 5;22(1). Epub 2021 Jan 5.

Experimental Zoology and Neurobiology, University of Pécs, 7624 Pécs, Hungary.

Retinal aging is the result of accumulating molecular and cellular damage with a manifest decline in visual functions. Somatostatin (SST) and pituitary adenylate cyclase-activating polypeptide (PACAP) have been implicated in neuroprotection through regulating disparate aspects of neuronal activity (survival, proliferation and renewal). The aim of the present study was to validate a transgenic model for SST-expressing amacrine cells and to investigate the chronic effect of PACAP on the aging of SSTergic and dopaminergic cells of the retina. SST-tdTomato transgenic mice that were 6, 12 and 18 months old were treated intravitreally with 100 pmol of PACAP every 3 months. The density of SST and dopaminergic amacrine cells was assessed in whole-mounted retinas. Cells displaying the transgenic red fluorescence were identified as SST-immunopositive amacrine cells. By comparing the three age groups. PACAP treatment was shown to induce a moderate elevation of cell densities in both the SST and dopaminergic cell populations in the 12- and 18-month-old animals. By contrast, the control untreated and saline-treated retinas showed a minor cell loss. In conclusion, we report a reliable transgenic model for examining SSTergic amacrine cells. The fundamental novelty of this study is that PACAP could increase the cell density in matured retinal tissue, anticipating new therapeutic potential in age-related pathological processes.
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http://dx.doi.org/10.3390/ijms22010444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796228PMC
January 2021

Protective effects of the novel amine-oxidase inhibitor multi-target drug SZV 1287 on streptozotocin-induced beta cell damage and diabetic complications in rats.

Biomed Pharmacother 2021 Feb 15;134:111105. Epub 2020 Dec 15.

Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12, H-7624, Pécs, Hungary; Molecular Pharmacology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624, Pécs, Hungary; PharmInVivo Ltd., Szondi György u. 10, H-7629, Pécs, Hungary. Electronic address:

Diabetes mellitus is a common metabolic disease leading to hyperglycemia due to insufficient pancreatic insulin production or effect. Amine oxidase copper containing 3 (AOC3) is an enzyme that belongs to the semicarbazide-sensitive amine oxidase family, which may be a novel therapeutic target to treat diabetic complications. We aimed to explore the effects of AOC3 inhibition and to test the actions of our novel AOC3 inhibitor multi-target drug candidate, SZV 1287, compared to a selective reference compound, LJP 1207, in an 8-week long insulin-controlled streptozotocin (STZ)-induced (60 mg/kg i.p.) rat diabetes model. Both AOC3 inhibitors (20 mg/kg, daily s.c. injections) were protective against STZ-induced pancreatic beta cell damage determined by insulin immunohistochemistry and radioimmunoassay, neuropathic cold hypersensitivity measured by paw withdrawal latency decrease from 0 °C water, and retinal dysfunction detected by electroretinography. SZV 1287 showed greater inhibitory effects on beta cell damage, and reduced retinal apoptosis shown by histochemistry. Mechanical hypersensitivity measured by aesthesiometry, cardiac dysfunction and nitrosative stress determined by echocardiography and immunohistochemistry/Western blot, respectively, serum Na, K, fructosamine, and urine microalbumin, creatinine, total protein/creatinine ratio alterations did not develop in response to diabetes. None of these parameters were influenced by the treatments except for SZV 1287 reducing serum fructosamine and LJP 1207 increasing urine creatinine. We provide the first evidence for protective effects of AOC3 inhibition on STZ-induced pancreatic beta cell damage, neuropathic cold hypersensitivity and diabetic retinal dysfunction. Long-term treatment with our novel multi-target analgesic candidate, SZV 1287, is safe and effective also under diabetic conditions.
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http://dx.doi.org/10.1016/j.biopha.2020.111105DOI Listing
February 2021

Myocardial Injury After Balloon Predilatation Versus Direct Transcatheter Aortic Valve Replacement: Insights From the DIRECTAVI Trial.

J Am Heart Assoc 2020 12 10;9(24):e018405. Epub 2020 Dec 10.

Department of Cardiology Montpellier University Hospital Montpellier France.

Background Myocardial injury is associated with higher mortality after transcatheter aortic valve replacement (TAVR) and might be increased by prior balloon aortic valvuloplasty (BAV). We aimed to evaluate the impact of prior BAV versus direct prosthesis implantation on myocardial injury occurring after (TAVR) with balloon-expandable prostheses. Methods and Results The DIRECTAVI (Direct Transcatheter Aortic Valve Implantation) trial, an open-label randomized study, demonstrated noninferiority of TAVR without BAV (direct TAVR group) compared with systematic BAV (BAV group) with the Edwards SAPIEN 3 valve. High-sensitivity troponin was assessed before and the day after the procedure. Incidence of myocardial injury after the procedure (high-sensitivity troponin elevation >15× the upper reference limit [14 ng/L]) was the main end point. Impact of myocardial injury on 1-month adverse events (all-cause mortality, stroke, major bleeding, major vascular complications, transfusion, acute kidney injury, heart failure, pacemaker implantation, and aortic regurgitation) was evaluated. Preprocedure and postprocedure high-sensitivity troponin levels were available in 211 patients. The mean age of patients was 83 years (78-87 years), with 129 men (61.1%). Mean postprocedure high-sensitivity troponin was 124.9±81.4 ng/L in the direct TAVR group versus 170.4±127.7 ng/L in the BAV group (=0.007). Myocardial injury occurred in 42 patients (19.9%), including 13 patients (12.2%) in the direct TAVR group and 29 (27.9%) in the BAV group (=0.004). BAV increased by 2.8-fold (95% CI, 1.4-5.8) myocardial injury probability. Myocardial injury was associated with 1-month adverse events (=0.03). Conclusions BAV increased the incidence and magnitude of myocardial injury after TAVR with new-generation balloon-expandable valves. Myocardial injury was associated with 1-month adverse events. These results argue in favor of direct SAPIEN 3 valve implantation. Registration URL: https://www.Clinicaltrials.gov; Unique identifier: NCT02729519.
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http://dx.doi.org/10.1161/JAHA.120.018405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955361PMC
December 2020

Deep brain stimulation of the internal globus pallidus does not affect the limbic circuit in patients with Parkinson's disease: a PET study.

J Neurol 2021 Feb 10;268(2):701-706. Epub 2020 Sep 10.

Department of Nuclear Medicine, Eugene Marquis Center, University of Rennes 1, Avenue de la bataille Flandres-Dunkerque, 35000, Rennes, France.

Introduction: Internal globus pallidus (GPi) deep brain stimulation (DBS) is a safe and effective alternative treatment in Parkinson's disease (PD) for patients with cognitive impairment. However, no study has yet investigated metabolic changes within a large series of patients undergoing GPi stimulation.

Objective: We assessed motor, cognitive and psychiatric changes, as well as modifications in brain glucose metabolism measured with FDG-PET, before and after bilateral GPi-DBS.

Methods: In the same week, 32 patients with PD underwent a motor, cognitive and psychiatric assessment and a resting-state FDG-PET scan, 4 months before and 4 months after GPi-DBS surgery. For the voxelwise metabolic change assessment, the p value was controlled for multiple comparisons using the family wise error rate.

Results: After GPi-DBS surgery, patients showed a significant overall improvement in motor status. No cognitive or psychiatric changes were observed after surgery. Nor were any clusters with significantly relative metabolic changes found in the limbic circuit after surgery. Clusters with significantly relative metabolic changes were observed in the left and right Brodmann area (BA) 6, the right BA 9, the right and left BA 39 and the left BA 17.

Conclusion: The present study confirmed that GPi-DBS is an effective treatment in patients with advanced PD, owing to metabolic changes in the areas involved in motor execution. The absence of relative metabolic decrease in the limbic circuit and the few changes affecting the associative circuit could explain why GPi-DBS is cognitively safe.
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http://dx.doi.org/10.1007/s00415-020-10212-yDOI Listing
February 2021

Surgical stress and cytoskeletal changes in lens epithelial cells following manual and femtosecond laser-assisted capsulotomy.

Int J Ophthalmol 2020 18;13(6):927-934. Epub 2020 Jun 18.

Department of Medical Biology and Central Electron Microscopic Laboratory, University of Pécs Medical School, Pécs 7624, Hungary.

Aim: To study the effect of mechanical stress on the cytoskeleton in lens epithelial cells following conventional phacoemulsification surgery (CPS) and femtosecond laser-assisted cataract surgery (FLACS).

Methods: The cytoskeleton of the epithelial cells of the anterior lens capsules (ALC) removed by CPS and FLACS was examined by immunohistochemistry. Expression of the intermediate filament, glial fibrillary acidic protein (GFAP), and glutamine synthetase (GS) immunoreactivity were detected. In order to map the actin network of cells, fluorescently labeled phalloidin was used. The samples were examined using confocal laser scanning microscopy.

Results: GFAP expression was visible in a larger number of the epithelial cells after CPS compared to FLACS. In CPS sample's epithelial cells, GFAP immunoreactivity indicated robust morphological change. Regarding the actin filaments, the presence of tubular elements connecting epithelial cells, regular actin pattern and marked cortical network after CPS were found. Following FLACS, the actin cytoskeleton of the epithelial cells remained densely structured, and the tubular elements were undetectable, however, the above-mentioned regular actin pattern and the marked cortical network were visible.

Conclusion: The conventional removal of the ALC induces more robust changes of the cytoskeleton of the lens epithelial cells.
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http://dx.doi.org/10.18240/ijo.2020.06.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270246PMC
June 2020

Prior Balloon Valvuloplasty Versus Direct Transcatheter Aortic Valve Replacement: Results From the DIRECTAVI Trial.

JACC Cardiovasc Interv 2020 03;13(5):594-602

Department of Cardiology, CHU Nimes, Montpellier University, Nimes, France.

Objectives: The aim of this study was to evaluate device success of transcatheter aortic valve replacement (TAVR) using new-generation balloon-expandable prostheses with or without balloon aortic valvuloplasty (BAV).

Background: Randomized studies are lacking comparing TAVR without BAV against the conventional technique of TAVR with BAV.

Methods: DIRECTAVI (Direct Transcatheter Aortic Valve Implantation) was an open-label noninferiority study that randomized patients undergoing TAVR using the Edwards SAPIEN 3 valve with or without prior balloon valvuloplasty. The primary endpoint was the device success rate according to Valve Academic Research Consortium-2 criteria, which was evaluated using a 7% noninferiority margin. The secondary endpoint included procedural and 30-day adverse events.

Results: Device success was recorded for 184 of 236 included patients (78.0%). The rate of device success in the direct implantation group (n = 97 [80.2%]) was noninferior to that in the BAV group (n = 87 [75.7%]) (mean difference 4.5%; 95% confidence interval: -4.4% to 13.4%; p = 0.02 for noninferiority). No severe prosthesis-patient mismatch or severe aortic regurgitation occurred in any group. In the direct implantation group, 7 patients (5.8%) required BAV to cross the valve. Adverse events were related mainly to pacemaker implantation (20.9% in the BAV group vs. 19.0% in the direct implantation group; p = 0.70). No significant difference was found between the 2 strategies in duration of procedure, contrast volume, radiation exposure, or rate of post-dilatation.

Conclusions: Direct TAVR without prior BAV was noninferior to the conventional strategy using BAV with new-generation balloon-expandable valves, but without procedural simplification. BAV was needed to cross the valve in a few patients, suggesting a need for upstream selection on the basis of patient anatomy. (TAVI Without Balloon Predilatation [of the Aortic Valve] SAPIEN 3 [DIRECTAVI]; NCT02729519).
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http://dx.doi.org/10.1016/j.jcin.2019.12.006DOI Listing
March 2020

Association of Gray Matter and Personality Development With Increased Drunkenness Frequency During Adolescence.

JAMA Psychiatry 2020 04;77(4):409-419

Department of Psychiatry and Addictology, Medical Faculty, University of Montreal, Montréal, Québec, Canada.

Importance: Alcohol abuse correlates with gray matter development in adolescents, but the directionality of this association remains unknown.

Objective: To investigate the directionality of the association between gray matter development and increase in frequency of drunkenness among adolescents.

Design, Setting, And Participants: This cohort study analyzed participants of IMAGEN, a multicenter brain imaging study of healthy adolescents in 8 European sites in Germany (Mannheim, Dresden, Berlin, and Hamburg), the United Kingdom (London and Nottingham), Ireland (Dublin), and France (Paris). Data from the second follow-up used in the present study were acquired from January 1, 2013, to December 31, 2016, and these data were analyzed from January 1, 2016, to March 31, 2018. Analyses were controlled for sex, site, socioeconomic status, family history of alcohol dependency, puberty score, negative life events, personality, cognition, and polygenic risk scores. Personality and frequency of drunkenness were assessed at age 14 years (baseline), 16 years (first follow-up), and 19 years (second follow-up). Structural brain imaging scans were acquired at baseline and second follow-up time points.

Main Outcomes And Measures: Increases in drunkenness frequency were measured by latent growth modeling, a voxelwise hierarchical linear model was used to observe gray matter volume, and tensor-based morphometry was used for gray matter development. The hypotheses were formulated before the data analyses.

Results: A total of 726 adolescents (mean [SD] age at baseline, 14.4 [0.38] years; 418 [58%] female) were included. The increase in drunkenness frequency was associated with accelerated gray matter atrophy in the left posterior temporal cortex (peak: t1,710 = -5.8; familywise error (FWE)-corrected P = 7.2 × 10-5; cluster: 6297 voxels; P = 2.7 × 10-5), right posterior temporal cortex (cluster: 2070 voxels; FWE-corrected P = .01), and left prefrontal cortex (peak: t1,710 = -5.2; FWE-corrected P = 2 × 10-3; cluster: 10 624 voxels; P = 1.9 × 10-7). According to causal bayesian network analyses, 73% of the networks showed directionality from gray matter development to drunkenness increase as confirmed by accelerated gray matter atrophy in late bingers compared with sober controls (n = 20 vs 60; β = 1.25; 95% CI, -2.15 to -0.46; t1,70 = 0.3; P = .004), the association of drunkenness increase with gray matter volume at age 14 years (β = 0.23; 95% CI, 0.01-0.46; t1,584 = 2; P = .04), the association between gray matter atrophy and alcohol drinking units (β = -0.0033; 95% CI, -6 × 10-3 to -5 × 10-4; t1,509 = -2.4; P = .02) and drunkenness frequency at age 23 years (β = -0.16; 95% CI, -0.28 to -0.03; t1,533 = -2.5; P = .01), and the linear exposure-response curve stratified by gray matter atrophy and not by increase in frequency of drunkenness.

Conclusions And Relevance: This study found that gray matter development and impulsivity were associated with increased frequency of drunkenness by sex. These results suggest that neurotoxicity-related gray matter atrophy should be interpreted with caution.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.4063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990803PMC
April 2020

Tandem Lesions Arising from 5-(Uracilyl)methyl Peroxyl Radical Addition to Guanine: Product Analysis and Mechanistic Studies.

Chem Res Toxicol 2020 02 27;33(2):565-575. Epub 2019 Dec 27.

Département de Biochimie, Faculté de Médecine et des Sciences de la Santé , Université de Sherbrooke , Sherbrooke , Québec J1H 5N4 , Canada.

The reaction of hydroxyl radical (HO) with thymine in DNA generates 5-(uracilyl)-methyl radicals (T) and the corresponding methylperoxyl radical (TOO) in the presence of O, which in turn propagates damage by reacting with a vicinal nucleobase. This leads to so-called double or tandem lesions. Because methyl oxidation products of thymine are major products, we investigated the reactivity of TOO using a photolabile precursor: 5-(phenylthiomethyl)uracil (T). The precursor was prepared and incorporated into a DNA trinucleotide: 5'-d(GpTpA)-3' (G-T-A). Upon photolysis, the resulting products were characterized by LC-MS/MS. Thereby, we identified four tandem lesions involving GpT, which include either 2,6-diamino-4-hydroxy-5-formamidopyrimidine (fapyG) or 8-oxo-7,8-dihydroguanine (oxoG) in tandem with either 5-formyluracil (fU) or 5-hydroxymethyluracil (hmU). The formation of these tandem lesions is explained by initial addition of TOO to the C8 of guanine moiety, giving an N7-guanine cross-linked radical. The latter radical undergoes either reduction to an 7,8-saturated endoperoxide or oxidation to an 7,8-unsaturated endoperoxide, which transform into fapyG-fU-A and oxoG-fU-A, respectively. This is supported by the effect of a reducing (dithiothreitol) and oxidizing agent (Fe) on product formation. This study expands the repertoire of tandem lesions that can occur at GpT sequences and underlines the importance of redox environment.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00407DOI Listing
February 2020

Neuroprotective Potential of Pituitary Adenylate Cyclase Activating Polypeptide in Retinal Degenerations of Metabolic Origin.

Front Neurosci 2019 9;13:1031. Epub 2019 Oct 9.

Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary.

Pituitary adenylate cyclase-activating polypeptide (PACAP1-38) is a highly conserved member of the secretin/glucagon/VIP family. The repressive effect of PACAP1-38 on the apoptotic machinery has been an area of active research conferring a significant neuroprotective potential onto this peptide. A remarkable number of studies suggest its importance in the etiology of neurodegenerative disorders, particularly in relation to retinal metabolic disorders. In our review, we provide short descriptions of various pathological conditions (diabetic retinopathy, excitotoxic retinal injury and ischemic retinal lesion) in which the remedial effect of PACAP has been well demonstrated in various animal models. Of all the pathological conditions, diabetic retinopathy seems to be the most intriguing as it develops in 75% of patients with type 1 and 50% of patients with type 2 diabetes, with concomitant progression to legal blindness in about 5%. Several animal models have been developed in recent years to study retinal degenerations and out of these glaucoma and age-related retina degeneration models bear human recapitulations. PACAP neuroprotection is thought to operate through enhanced cAMP production upon binding to PAC1-R. However, the underlying signaling network that leads to neuroprotection is not fully understood. We observed that (i) PACAP is not equally efficient in the above conditions; (ii) in some cases more than one signaling pathways are activated; (iii) the coupling of PAC1-R and signaling is stage dependent; and (iv) PAC1-R is not the only receptor that must be considered to interpret the effects in our experiments. These observations point to a complex signaling mechanism, that involves alternative routes besides the classical cAMP/protein kinase A pathway to evoke the outstanding neuroprotective action. Consequently, the possible contribution of the other two main receptors (VPAC1-R and VPAC2-R) will also be discussed. Finally, the potential medical use of PACAP in some retinal and ocular disorders will also be reviewed. By taking advantage of, low-cost synthesis technologies today, PACAP may serve as an alternative to the expensive treatment modelities currently available in ocular or retinal conditions.
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http://dx.doi.org/10.3389/fnins.2019.01031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794456PMC
October 2019

Identification of neurobehavioural symptom groups based on shared brain mechanisms.

Nat Hum Behav 2019 12 7;3(12):1306-1318. Epub 2019 Oct 7.

NeuroSpin, CEA, Université Paris-Saclay, Gif-sur-Yvette, France.

Most psychopathological disorders develop in adolescence. The biological basis for this development is poorly understood. To enhance diagnostic characterization and develop improved targeted interventions, it is critical to identify behavioural symptom groups that share neural substrates. We ran analyses to find relationships between behavioural symptoms and neuroimaging measures of brain structure and function in adolescence. We found two symptom groups, consisting of anxiety/depression and executive dysfunction symptoms, respectively, that correlated with distinct sets of brain regions and inter-regional connections, measured by structural and functional neuroimaging modalities. We found that the neural correlates of these symptom groups were present before behavioural symptoms had developed. These neural correlates showed case-control differences in corresponding psychiatric disorders, depression and attention deficit hyperactivity disorder in independent clinical samples. By characterizing behavioural symptom groups based on shared neural mechanisms, our results provide a framework for developing a classification system for psychiatric illness that is based on quantitative neurobehavioural measures.
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http://dx.doi.org/10.1038/s41562-019-0738-8DOI Listing
December 2019

Pituitary Adenylate Cyclase-Activating Polypeptide: 30 Years in Research Spotlight and 600 Million Years in Service.

J Clin Med 2019 Sep 18;8(9). Epub 2019 Sep 18.

Department of Experimental Zoology and Neurobiology, University of Pécs, 7624 Pécs, Hungary.

Emerging from the depths of evolution, pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors (i.e., PAC1, VPAC1, VPAC2) are present in multicellular organisms from Tunicates to humans and govern a remarkable number of physiological processes. Consequently, the clinical relevance of PACAP systems spans a multifaceted palette that includes more than 40 disorders. We aimed to present the versatility of PACAP1-38 actions with a focus on three aspects: (1) when PACAP1-38 could be a cause of a malfunction, (2) when PACAP1-38 could be the cure for a malfunction, and (3) when PACAP1-38 could either improve or impair biology. PACAP1-38 is implicated in the pathophysiology of migraine and post-traumatic stress disorder whereas an outstanding protective potential has been established in ischemia and in Alzheimer's disease. Lastly, PACAP receptors could mediate opposing effects both in cancers and in inflammation. In the light of the above, the duration and concentrations of PACAP agents must be carefully set at any application to avoid unwanted consequences. An enormous amount of data accumulated since its discovery (1989) and the first clinical trials are dated in 2017. Thus in the field of PACAP research: "this is not the end, not even the beginning of the end, but maybe the end of the beginning."
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http://dx.doi.org/10.3390/jcm8091488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780647PMC
September 2019

Benzodiazepine use and brain amyloid load in nondemented older individuals: a florbetapir PET study in the Multidomain Alzheimer Preventive Trial cohort.

Neurobiol Aging 2019 12 14;84:61-69. Epub 2019 Aug 14.

UMR 1253, iBrain, Université de Tours, Inserm, Tours, France; CHU de Tours, Tours, France.

It remains unclear whether benzodiazepines (BZDs) constitute a risk factor for Alzheimer's disease (AD). In this study, we investigated associations between chronic use of BZDs and brain amyloid load, a hallmark of AD, in 268 nondemented older individuals. F-florbetapir positron emission tomography scans were performed to assess amyloid load as measured by standardized uptake value ratios, which were compared between chronic BZD users and nonusers using adjusted multiple linear regressions. Short- versus long-acting BZDs were also considered in the analyses. Standardized uptake value ratios were significantly lower in BZD users (n = 47) than in nonusers (n = 221), independent of multiple adjustments. The effect was stronger for short-acting BZDs than for long-acting BZDs. This is the first large clinical study showing a reduced brain amyloid load in chronic BZD users, especially with short-acting BZDs. Our results do not support the view of BZD use as a risk factor for AD and instead support the involvement of pharmacological mechanisms related to neuronal hyperactivity, neuroinflammation, and sleep quality as potential targets for blocking amyloid accumulation.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.08.008DOI Listing
December 2019

Recommendations for the Nonpharmacological Treatment of Apathy in Brain Disorders.

Am J Geriatr Psychiatry 2020 04 9;28(4):410-420. Epub 2019 Aug 9.

Université Côte d'Azur, CoBTeK lab (VM, FB, RD, AG, AK,AT, RZ, PR), Nice, France; Association Innovation Alzheimer (VM, PR), Nice, France; Centre Hospitalier Universitaire (CHU) de Nice (RD, PR), CMRR, Nice, France.

Apathy is a common neuropsychiatric syndrome observed across many neurocognitive and psychiatric disorders. Although there are currently no definitive standard therapies for the treatment of apathy, nonpharmacological treatment (NPT) is often considered to be at the forefront of clinical management. However, guidelines on how to select, prescribe, and administer NPT in clinical practice are lacking. Furthermore, although new Information and Communication Technologies (ICT) are beginning to be employed in NPT, their role is still unclear. The objective of the present work is to provide recommendations for the use of NPT for apathy, and to discuss the role of ICT in this domain, based on opinions gathered from experts in the field. The expert panel included 20 researchers and healthcare professionals working on brain disorders and apathy. Following a standard Delphi methodology, experts answered questions via several rounds of web-surveys, and then discussed the results in a plenary meeting. The experts suggested that NPT are useful to consider as therapy for people presenting with different neurocognitive and psychiatric diseases at all stages, with evidence of apathy across domains. The presence of a therapist and/or a caregiver is important in delivering NPT effectively, but parts of the treatment may be performed by the patient alone. NPT can be delivered both in clinical settings and at home. However, while remote treatment delivery may be cost and time-effective, it should be considered with caution, and tailored based on the patient's cognitive and physical profile and living conditions.
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http://dx.doi.org/10.1016/j.jagp.2019.07.014DOI Listing
April 2020

Cannabis-Associated Psychotic-like Experiences Are Mediated by Developmental Changes in the Parahippocampal Gyrus.

J Am Acad Child Adolesc Psychiatry 2020 05 18;59(5):642-649. Epub 2019 Jul 18.

Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Objective: Cannabis consumption during adolescence has been reported as a risk factor for psychotic-like experiences (PLEs) and schizophrenia. However, brain developmental processes associated with cannabis-related PLEs are still poorly described.

Method: A total of 706 adolescents from the general population who were recruited by the IMAGEN consortium had structural magnetic resonance imaging scans at both 14 and 19 years of age. We used deformation-based morphometry to map voxelwise brain changes between the two time points, using the pairwise algorithm in SPM12b. We used an a priori region-of-interest approach focusing on the hippocampus/parahippocampus to perform voxelwise linear regressions. Lifetime cannabis consumption was assessed using the European School Survey Project on Alcohol and other Drugs (ESPAD), and PLEs were assessed with the Comprehensive Assessment Psychotic-like experiences (CAPE) tool. We first tested whether hippocampus/parahippocampus development was associated with PLEs. Then we formulated and tested an a priori simple mediation model in which uncus development mediates the association between lifetime cannabis consumption and PLEs.

Results: We found that PLEs were associated with reduced expansion within a specific region of the right hippocampus/parahippocampus formation, the uncus (p = .002 at the cluster level, p = .018 at the peak level). The partial simple mediation model revealed a significant total effect from lifetime cannabis consumption to PLEs (b = 0.069, 95% CI = 0.04-0.1, p =2 × 10), as well as a small yet significant, indirect effect of right uncus development (0.004; 95% CI = 0.0004-0.01, p = .026).

Conclusion: We show here that the uncus development is involved in the cerebral basis of PLEs in a population-based sample of healthy adolescents.
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http://dx.doi.org/10.1016/j.jaac.2019.05.034DOI Listing
May 2020

Hemodynamic Performances and Clinical Outcomes in Patients Undergoing Valve-in-Valve Versus Native Transcatheter Aortic Valve Implantation.

Am J Cardiol 2019 07 18;124(1):90-97. Epub 2019 Apr 18.

Department of Cardiology, Montpellier University hospital, Montpellier University, France; PhyMedExp, University of Montpellier, Montpellier, France. Electronic address:

Valve-in-valve (ViV) transcatheter aortic valve implantation (TAVI) emerged has a less invasive treatment than surgery for patients with degenerated bioprosthesis. However, few data are currently available regarding results of ViV versus TAVI in native aortic valve. We aimed to compare hemodynamic performances and 1-year outcomes between patients who underwent ViV procedure and patients who underwent non-ViV TAVI. This bicentric study included all patients who underwent aortic ViV procedure for surgical bioprosthetic aortic failure between 2013 and 2017. All patients who underwent TAVI were included in the analysis during the same period. ViV and non-ViV patients were matched with 1:2 ratio according to size, type of TAVI device, age (±5 years), sex, and STS score. Primary end point was hemodynamic performance including mean aortic gradient and aortic regurgitation at 1-year follow-up. A total of 132 patients were included, 49 in the ViV group and 83 in the non-ViV group. Mean age was 82.8 ± 5.9 years, 55.3% were female. Mean STS score was 5.2% ± 3.1%. Self-expandable valves were implanted in 78.8% of patients. At 1-year follow-up, aortic mean gradient was significantly higher in ViV group (18.1 ± 9.4 mm Hg vs 11.4 ± 5.4 mm Hg; p < 0.0001) and 17 (38.6%) patients had a mean aortic gradient ≥20 mm Hg vs 6 (7.8%) in the non-ViV group (p = 0.0001). Aortic regurgitation > grade 2 were similar in both groups (p = 0.71). In the ViV group, new pacemaker implantation was less frequent (p = 0.01) and coronary occlusions occurred only in ViV group (n = 2 [4.1%]). At 1-year follow-up, 3 patients (2.3%) died from cardiac cause, 1 (2.1%) in the ViV group vs 2 (2.4%) in the non-ViV group (p = 0.9). There was no stroke. In conclusion, compared with TAVI in native aortic stenosis, ViV appears as a safe and feasible strategy in patients with impaired bioprosthesis. As 1-year hemodynamic performances seem better in native TAVI procedure, long-term follow-up should be assessed to determinate the impact of residual stenosis on outcomes and durability.
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http://dx.doi.org/10.1016/j.amjcard.2019.04.009DOI Listing
July 2019

Adolescent binge drinking disrupts normal trajectories of brain functional organization and personality maturation.

Neuroimage Clin 2019 31;22:101804. Epub 2019 Mar 31.

School of Mathematical Sciences, Fudan University, Shanghai 200433, PR China; Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, PR China; Department of Computer Science, University of Warwick, Coventry, UK; Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, PR China; Shanghai Center for Mathematical Sciences, Shanghai, PR China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), Ministry of Education, PR China.

Adolescent binge drinking has been associated with higher risks for the development of many health problems throughout the lifespan. Adolescents undergo multiple changes that involve the co-development processes of brain, personality and behavior; therefore, certain behavior, such as alcohol consumption, can have disruptive effects on both brain development and personality maturation. However, these effects remain unclear due to the scarcity of longitudinal studies. In the current study, we used multivariate approaches to explore discriminative features in brain functional architecture, personality traits, and genetic variants in 19-year-old individuals (n = 212). Taking advantage of a longitudinal design, we selected features that were more drastically altered in drinkers with an earlier onset of binge drinking. With the selected features, we trained a hierarchical model of support vector machines using a training sample (n = 139). Using an independent sample (n = 73), we tested the model and achieved a classification accuracy of 71.2%. We demonstrated longitudinally that after the onset of binge drinking the developmental trajectory of improvement in impulsivity slowed down. This study identified the disrupting effects of adolescent binge drinking on the developmental trajectories of both brain and personality.
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http://dx.doi.org/10.1016/j.nicl.2019.101804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451196PMC
January 2020

PARP Inhibitor Protects Against Chronic Hypoxia/Reoxygenation-Induced Retinal Injury by Regulation of MAPKs, HIF1α, Nrf2, and NFκB.

Invest Ophthalmol Vis Sci 2019 04;60(5):1478-1490

Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, Pécs, Hungary.

Purpose: In the eye, chronic hypoxia/reoxygenation (H/R) contributes to the development of a number of ocular disorders. H/R induces the production of reactive oxygen species (ROS), leading to poly(ADP-ribose) polymerase-1 (PARP1) activation that promotes inflammation, cell death, and disease progression. Here, we analyzed the protective effects of the PARP1 inhibitor olaparib in H/R-induced retina injury and investigated the signaling mechanisms involved.

Methods: A rat retinal H/R model was used to detect histologic and biochemical changes in the retina.

Results: H/R induced reductions in the thickness of most retinal layers, which were prevented by olaparib. Furthermore, H/R caused increased levels of Akt and glycogen synthase kinase-3β phosphorylation, which were further increased by olaparib, contributing to retina protection. By contrast, H/R-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinases (MAPK) phosphorylation and activation were reduced by olaparib, via mitogen-activated protein kinase phosphatase 1 (MKP-1) expression. In addition, H/R-induced hypoxia-inducible factor 1α (HIF1α) levels were decreased by olaparib, which possibly contributed to reduced VEGF expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was slightly increased by H/R and was further activated by olaparib. Nuclear factor-κB (NFκB) was also activated by H/R through phosphorylation (Ser536) and acetylation (Lys310) of the p65 subunit, although this was significantly reduced by olaparib.

Conclusions: Olaparib reduced H/R-induced degenerative changes in retinal morphology. The protective mechanisms of olaparib most probably involved Nrf2 activation and ROS reduction, as well as normalization of HIF1α and related VEGF expression. In addition, olaparib reduced inflammation by NFκB dephosphorylation/inactivation, possibly via the PARP1 inhibition-MKP-1 activation-p38 MAPK inhibition pathway. PARP inhibitors represent potential therapeutics in H/R-induced retinal disease.
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http://dx.doi.org/10.1167/iovs.18-25936DOI Listing
April 2019

White matter abnormalities in depression: A categorical and phenotypic diffusion MRI study.

Neuroimage Clin 2019 4;22:101710. Epub 2019 Feb 4.

Centre Hospitalier Guillaume Régnier, Academic Psychiatry Department, 35703 Rennes, France; Univ of Rennes, "Behavior and Basal Ganglia" research unit (EA 4712), Rennes, France.

Mood depressive disorder is one of the most disabling chronic diseases with a high rate of everyday life disability that affects 350 million people around the world. Recent advances in neuroimaging have reported widespread structural abnormalities, suggesting a dysfunctional frontal-limbic circuit involved in the pathophysiological mechanisms of depression. However, a variety of different white matter regions has been implicated and is sought to suffer from lack of reproducibility of such categorical-based biomarkers. These inconsistent results might be attributed to various factors: actual categorical definition of depression as well as clinical phenotype variability. In this study, we 1/ examined WM changes in a large cohort (114 patients) compared to a healthy control group and 2/ sought to identify specific WM alterations in relation to specific depressive phenotypes such as anhedonia (i.e. lack of pleasure), anxiety and psychomotor retardation -three core symptoms involved in depression. Consistent with previous studies, reduced white matter was observed in the genu of the corpus callosum extending to the inferior fasciculus and posterior thalamic radiation, confirming a frontal-limbic circuit abnormality. Our analysis also reported other patterns of increased fractional anisotropy and axial diffusivity as well as decreased apparent diffusion coefficient and radial diffusivity in the splenium of the corpus callosum and posterior limb of the internal capsule. Moreover, a positive correlation between FA and anhedonia was found in the superior longitudinal fasciculus as well as a negative correlation in the cingulum. Then, the analysis of the anxiety and diffusion metric revealed that increased anxiety was associated with greater FA values in genu and splenium of corpus callosum, anterior corona radiata and posterior thalamic radiation. Finally, the motor retardation analysis showed a correlation between increased Widlöcher depressive retardation scale scores and reduced FA in the body and genu of the corpus callosum, fornix, and superior striatum. Through this twofold approach (categorical and phenotypic), this study has underlined the need to move forward to a symptom-based research area of biomarkers, which help to understand the pathophysiology of mood depressive disorders and to stratify precise phenotypes of depression with targeted therapeutic strategies.
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http://dx.doi.org/10.1016/j.nicl.2019.101710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406626PMC
December 2019

The Neuroprotective Peptide PACAP1-38 Contributes to Horizontal Cell Development in Postnatal Rat Retina.

Invest Ophthalmol Vis Sci 2019 02;60(2):770-778

Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary.

Purpose: PACAP1-38, a member of the secretin/glucagon superfamily, is expressed in the developing retina with documented neuroprotective effects. However, its function in retinal cell differentiation has yet to be elucidated. Our goals, therefore, were to identify PAC1 expressing cells morphologically, investigate the PACAP1-38 action functionally, and establish PACAP1-38 regulated events developmentally during the first postnatal week in rat retina.

Methods: P1 retinal sections or whole mounts of Wistar rats were used to reveal PAC1 and calbindin immunoreactive structures. P1, P3, or P7 pups were injected intravitreally with 100 pmol PACAP1-38. Tissues were harvested 24 hours post-treatment, then processed for calbindin immunohistochemistry to determine horizontal cell number, or 6, 12, 24 hours post-treatment for real-time PCR and immunoblots to detect PCNA expression. To localize proliferating cells, anti-PCNA antibody was applied.

Results: We showed various PAC1 expressing cells in RPE, NBL, and GCL in P1 retina including calbindin positive horizontal cells. We found that PACAP1-38 induced a marked cell number increase at P3 and P7 and showed upregulated cell proliferation as its mechanism; however, it was ineffective at P1. PACAP1-38 induced proliferative cells localized in the NBL, and double-marker studies demonstrated that the induced proliferative cells were horizontal cells.

Conclusions: PACAP1-38 appears to act in retinal differentiation by inducing mitosis selectively in a time and cell specific manner through PAC1. The control of horizontal cell proliferation raises the novel possibilities that (1) PACAP1-38 may be a major player in retinal patterning and (2) PACAP signaling may be critical in retinoblastoma.
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http://dx.doi.org/10.1167/iovs.18-25719DOI Listing
February 2019

Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents: A Voxelwise and Genome-Wide Association Study.

JAMA Psychiatry 2019 04;76(4):435-445

Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité, Universitätsmedizin Berlin, Germany.

Importance: Deviation from normal adolescent brain development precedes manifestations of many major psychiatric symptoms. Such altered developmental trajectories in adolescents may be linked to genetic risk for psychopathology.

Objective: To identify genetic variants associated with adolescent brain structure and explore psychopathologic relevance of such associations.

Design, Setting, And Participants: Voxelwise genome-wide association study in a cohort of healthy adolescents aged 14 years and validation of the findings using 4 independent samples across the life span with allele-specific expression analysis of top hits. Group comparison of the identified gene-brain association among patients with schizophrenia, unaffected siblings, and healthy control individuals. This was a population-based, multicenter study combined with a clinical sample that included participants from the IMAGEN cohort, Saguenay Youth Study, Three-City Study, and Lieber Institute for Brain Development sample cohorts and UK biobank who were assessed for both brain imaging and genetic sequencing. Clinical samples included patients with schizophrenia and unaffected siblings of patients from the Lieber Institute for Brain Development study. Data were analyzed between October 2015 and April 2018.

Main Outcomes And Measures: Gray matter volume was assessed by neuroimaging and genetic variants were genotyped by Illumina BeadChip.

Results: The discovery sample included 1721 adolescents (873 girls [50.7%]), with a mean (SD) age of 14.44 (0.41) years. The replication samples consisted of 8690 healthy adults (4497 women [51.8%]) from 4 independent studies across the life span. A nonsynonymous genetic variant (minor T allele of rs13107325 in SLC39A8, a gene implicated in schizophrenia) was associated with greater gray matter volume of the putamen (variance explained of 4.21% in the left hemisphere; 8.66; 95% CI, 6.59-10.81; P = 5.35 × 10-18; and 4.44% in the right hemisphere; t = 8.90; 95% CI, 6.75-11.19; P = 6.80 × 10-19) and also with a lower gene expression of SLC39A8 specifically in the putamen (t127 = -3.87; P = 1.70 × 10-4). The identified association was validated in samples across the life span but was significantly weakened in both patients with schizophrenia (z = -3.05; P = .002; n = 157) and unaffected siblings (z = -2.08; P = .04; n = 149).

Conclusions And Relevance: Our results show that a missense mutation in gene SLC39A8 is associated with larger gray matter volume in the putamen and that this association is significantly weakened in schizophrenia. These results may suggest a role for aberrant ion transport in the etiology of psychosis and provide a target for preemptive developmental interventions aimed at restoring the functional effect of this mutation.
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http://dx.doi.org/10.1001/jamapsychiatry.2018.4126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450291PMC
April 2019

Apathy alters emotional arousal in chronic schizophrenia

J Psychiatry Neurosci 2019 01;44(1):54-61

From the University Department of Psychiatry, Guillaume Régnier Hospital, Rennes, France (Batail, D. Drapier, Robert); University of Lille, Inserm, CHU Lille, U1171, Degenerative and Vascular Cognitive Disorders, F-59000, Lille, France (Dondaine); Behaviour and Basal Ganglia Laboratory (EA 4712), University of Rennes, Rennes, France (Batail, Le Jeune, Sauleau, S. Drapier, Vérin, D. Drapier, Robert); Eugène Marquis Centre, Rennes, France (Le Jeune); Neurophysiology Department, Rennes University Hospital, Rennes, France (Sauleau); Movement Disorders Unit, Rennes University Hospital, Rennes, France (S. Drapier, Vérin); Psychiatry Department, Pitié-Salpêtrière Hospital, Paris, France (Millet); University of Louvain-la-Neuve, Louvain-la-Neuve, Belgium (Philippot).

Background: Within the heterogeneity of schizophrenia, apathy constitutes an independent cluster of negative symptoms associated with poor outcomes. Attempts to identify an emotional deficit in patients who have schizophrenia with negative symptoms have yielded mixed results, and studies that focus on the relationship between apathy and emotional disorders are lacking.

Methods: We set out to remedy this shortcoming using a validated battery of film excerpts to induce positive and negative emotions in patients with chronic schizophrenia with (n = 20) or without (n = 20) apathy, and in controls (n = 20) comparable for age, sex and socioeconomic status. We assessed emotions using an innovative but validated technique to evaluate tonic and phasic electrodermal activity and subjective feelings using a standardized visual analogue scale.

Results: Using a qualitative measure of apathy, we did not find a specific decrease in tonic activity during the induction of positive emotions. However, we did observe that patients with apathy showed reduced tonic activity independent of valence (i.e., for both positive and negative emotions) compared with controls and patients without apathy. Moreover, the quantitative measure of apathy (Apathy Evaluation Scale) was the only significant factor, explaining 24% of the variance in tonic activity during induction of positive emotions after controlling for confounding factors.

Limitations: Electrodermal activity was the only physiologic measure we acquired. We induced several emotions sequentially that might have overlapped with each other, but we added an emotional “washout” period and randomized the order of each film excerpt to limit this possibility.

Conclusion: Taken together, these results suggest that apathy in schizophrenia could impair tonic activity during positive emotions. Treatments aimed at enhancing positive emotions may help alleviate apathy in schizophrenia.
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http://dx.doi.org/10.1503/jpn.170172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306283PMC
January 2019

Effects of continuous subcutaneous apomorphine infusion in Parkinson's disease without cognitive impairment on motor, cognitive, psychiatric symptoms and quality of life.

J Neurol Sci 2018 12 7;395:113-118. Epub 2018 Oct 7.

"Behavior and Basal Ganglia" Research Unit (EA 4712), University of Rennes 1, Rennes, France; Department of Neurology, Rennes University Hospital, Rennes, France.

Introduction: Treatment optimization using continuous subcutaneous apomorphine infusion (CSAI) improves the control of motor fluctuations of patients with Parkinson's disease (PD). Although CSAI seems to be cognitively and behaviorally safe and to improve the quality of life, very few studies have investigated its influence in these domains, especially in patients without cognitive impairment.

Methods: We estimated the impact of CSAI on motor symptoms, cognition, psychiatric domains and quality of life in parkinsonian patients without cognitive impairment by comparing the scores of 22 patients assessed before and 6 months after the start of add-on CSAI.

Results: Optimized treatment with CSAI was associated with i) reduced motor fluctuations, ii) unchanged cognition, iii) unchanged psychiatric domains, and iv) improved quality of life in physical and psychological aspects.

Conclusion: In PD patients without cognitive impairment, CSAI improves motor symptoms and quality of life and, as suggested by previous studies, alters neither cognition nor mental health.
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http://dx.doi.org/10.1016/j.jns.2018.10.010DOI Listing
December 2018

Sensitive fluorescent hybridisation protocol development for simultaneous detection of microRNA and cellular marker proteins (in the retina).

Histochem Cell Biol 2018 Nov 7;150(5):557-566. Epub 2018 Aug 7.

Department of Experimental Zoology and Neurobiology, University of Pécs, Ifjúság útja 6, Pécs, 7624, Hungary.

Nowadays, increasing number of microRNAs are found to have crucial roles in various physiological processes through gene expression regulation via RNA silencing as a result of base pairing with complementary mRNA sequences. To reveal the spatial distribution of microRNA expression in tissues, in situ hybridisation is the only method developed to date. This work aims to provide a novel approach to obtain information on the possible involvement of microRNA-s in regulatory processes under experimental conditions by enhancing fluorescent detection of microRNA labelling. Developing Wistar rats were used as a model system to analyse retinal microRNA expression in the first 3 postnatal weeks. Using cryosections, the crucial elements of optimal labels were (1) the concentration and duration of proteinase K treatment, (2) hybridisation temperature of microRNA probes and (3) temperature of stringency washes. Further improvements made possible to combine our in situ hybridisation protocol with double-label immunofluorescence allowing for the simultaneous detection of microRNA-s with high sensitivity and a neuronal cell marker and/or a synaptic marker protein. Thus, the regulatory microRNA-s can be localised in an identified cell type along with its potential target protein. We believe that our protocol can be easily adapted for a variety of tissues of different origins, developmental stages and experimental conditions.
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http://dx.doi.org/10.1007/s00418-018-1705-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182695PMC
November 2018

Hemispheric specialization of the basal ganglia during vocal emotion decoding: Evidence from asymmetric Parkinson's disease and FDG PET.

Neuropsychologia 2018 10 21;119:1-11. Epub 2018 Jul 21.

Neuroscience of Emotion and Affective Dynamics' laboratory, Department of Psychology and Educational Sciences, and Swiss Center for Affective Sciences, University of Geneva, Switzerland; Behavior and Basal Ganglia' research unit, University of Rennes 1, Rennes University Hospital, France; Neuropsychology Unit, Department of Neurology, University Hospitals of Geneva, Switzerland. Electronic address:

The possible hemispheric specialization of the basal ganglia during emotional prosody (i.e., vocal emotion) processing has still to be elucidated. Coupled with affective measures and neuroimaging, Parkinson's disease offers a unique opportunity to study this question, on account of its characteristically asymmetric striatal dysfunction, which translates into predominantly contralateral motor symptoms. We investigated the cerebral metabolic bases of emotional prosody recognition in patients with Parkinson's disease with left- versus right-lateralized motor symptoms, postulating that patients with greater right hemispheric brain dysfunction have a specific impairment that correlates with the metabolic modification of a brain network known to be involved in emotional prosody. A total of 38 patients performed a validated emotional prosody recognition task and underwent a resting-state F-18 fluorodeoxyglucose PET scan, as well as clinical, motor, neuropsychological, and psychiatric assessments. Patients' performances were compared with those of 45 healthy controls. As expected, vocal emotion recognition was significantly poorer among patients with left-sided motor symptoms than among both right-sided patients and controls. There was no significant difference between right-sided patients and controls. This effect was observed for both the total score and the happiness subscore. Interestingly, regressions showed that the greater the emotional misattribution, the greater the patients' age and asymmetric motor symptom severity. Finally, at the metabolic level, positive correlations were found between the happiness recognition subscore and the metabolism of the right orbitofrontal cortex in patients with left-sided motor symptoms. A right orbitofrontal-basal ganglia coupling seems to be specifically involved in the vocal emotion recognition deficit observed in Parkinson's disease. The asymmetry of motor symptoms is thus an important clinical factor, in that it may influence the presence or severity of affective disorders in Parkinson's disease.
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http://dx.doi.org/10.1016/j.neuropsychologia.2018.07.023DOI Listing
October 2018

Pituitary Adenylate Cyclase Activating Polypeptide (PACAP1-38) Exerts Both Pro and Anti-Apoptotic Effects on Postnatal Retinal Development in Rat.

Neuroscience 2018 08 12;385:59-66. Epub 2018 Jun 12.

Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary.

PACAP1-38, a ubiquitous and multifunctional regulator has been in the focus of neurotoxicity research due to its impressive neuroprotective potential. Although the literature extensively demonstrated its repressive effect on the apoptotic machinery in neurodegenerative models, there is a striking absence of analysis on its role in normal development. We performed quantitative analyses on caspase activity in developing retina upon 100, 50, 25 or 1 pmol intravitreal PACAP1-38 injection from postnatal day 1 (P1) through P7 in Wistar rats. Retinas were harvested at 6, 12, 18, 24 or 48 h post-injection. Apoptotic activity was revealed using fluorescent caspase 3/7 enzyme assay, western blots and TUNEL assay. Unexpectedly, we found that 100 pmol PACAP1-38 increased the activity of caspase 3/7 at P1 and P5 whereas it had no effect at P7. At P3, as a biphasic effect, PACAP1-38 repressed active caspase 3/7 at 18 h post-injection while increased their activity in 24 h post-injection. Amounts, smaller than 100 pmol, could not inhibit apoptosis whereas 50, 25 or 1 pmol PACAP1-38 could evoke significant elevation in caspase 3/7 activity. TUNEL-positive cells appeared in the proximal part of inner nuclear as well as ganglion cell layers in response to PACAP1-38 treatment. The fundamental novelty of these results is that PACAP1-38 induces apoptosis during early postnatal retinogenesis. The dose as well as stage-dependent response suggests that PACAP1-38 has a Janus face in apoptosis regulation. It not only inhibits development-related apoptosis, but as a long-term effect, facilitates it.
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http://dx.doi.org/10.1016/j.neuroscience.2018.06.008DOI Listing
August 2018

Genetic variability in selected date palm ( L.) cultivars of United Arab Emirates using ISSR and DAMD markers.

3 Biotech 2018 Feb 2;8(2):109. Epub 2018 Feb 2.

1Department of Aridland Agriculture, College of Food and Agriculture, United Arab Emirates University, P.O. Box 15551, Al-Ain, United Arab Emirates.

Nine (9) different date palm ( L.) cultivars from UAE, which differ in their flower timings were selected to determine the polymorphism and genetic relationship between these cultivars. Hereditary differences and interrelationships were assessed utilizing inter-simple sequence repeat (ISSR) and directed amplification of minisatellite DNA region (DAMD) primers. Analysis on eight DAMD and five ISSR markers produced total of 113 amplicon including 99 polymorphic and 14 monomorphic alleles with a polymorphic percentage of 85.45. The average polymorphic information content for the two-marker system was almost similar (DAMD, 0.445 and ISSR, 0.459). UPGMA based clustering of DAMD and ISSR revealed that mid-season cultivars, Mkh (Khlas) and MB (Barhee) grouped together to form a subcluster in both the marker systems. The genetic similarity analysis followed by clustering of the cumulative data from the DAMD and ISSR resulted in two major clusters with two early-season cultivars (ENg and Ekn), two mid-season cultivars (MKh and MB) and one late-season cultivar (Lkhs) in cluster 1, cluster 2 includes two late-season cultivars, one early-season cultivar and one mid-season cultivar. The cluster analysis of both DAMD and ISSR marker revealed that, the patterns of variation between some of the tested cultivars were similar in both DNA marker systems. Hence, the present study signifies the applicability of DAMD and ISSR marker system in detecting genetic diversity of date palm cultivars flowering at different seasons. This may facilitate the conservation and improvement of date palm cultivars in the future.
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http://dx.doi.org/10.1007/s13205-018-1108-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796938PMC
February 2018