Publications by authors named "Iñigo Gabilondo"

39 Publications

Foveal Remodeling of Retinal Microvasculature in Parkinson's Disease.

Front Neurosci 2021 12;15:708700. Epub 2021 Jul 12.

Neurodegenerative Diseases Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.

Background: Retinal microvascular alterations have been previously described in Parkinson's disease (PD) patients using optical coherence tomography angiography (OCT-A). However, an extensive description of retinal vascular morphological features, their association with PD-related clinical variables and their potential use as diagnostic biomarkers has not been explored.

Methods: We performed a cross-sectional study including 49 PD patients (87 eyes) and 40 controls (73 eyes). Retinal microvasculature was evaluated with Spectralis OCT-A and cognitive status with Montreal Cognitive Assessment. Unified PD Rating Scale and disease duration were recorded in patients. We extracted microvascular parameters from superficial and deep vascular plexuses of the macula, including the area and circularity of foveal avascular zone (FAZ), skeleton density, perfusion density, vessel perimeter index, vessel mean diameter, fractal dimension (FD) and lacunarity using Python and MATLAB. We compared the microvascular parameters between groups and explored their association with thickness of macular layers and clinical outcomes. Data were analyzed with General Estimating Equations (GEE) and adjusted for age, sex, and hypertension. Logistic regression GEE models were fitted to predict diagnosis of PD versus controls from microvascular, demographic, and clinical data. The discrimination ability of models was tested with receiver operating characteristic curves.

Results: FAZ area was significantly smaller in patients compared to controls in superficial and deep plexuses, whereas perfusion density, skeleton density, FD and lacunarity of capillaries were increased in the foveal zone of PD. In the parafovea, microvascular parameters of superficial plexus were associated with ganglion cell-inner plexiform layer thickness, but this was mainly driven by PD with mild cognitive impairment. No such associations were observed in controls. FAZ area was negatively associated with cognition in PD (non-adjusted models). Foveal lacunarity, combined with demographic and clinical confounding factors, yielded an outstanding diagnostic accuracy for discriminating PD patients from controls.

Conclusion: Parkinson's disease patients displayed foveal microvascular alterations causing an enlargement of the vascular bed surrounding FAZ. Parafoveal microvascular alterations were less pronounced but were related to inner retinal layer thinning. Retinal microvascular abnormalities helped discriminating PD from controls. All this supports OCT-A as a potential non-invasive biomarker to reveal vascular pathophysiology and improve diagnostic accuracy in PD.
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http://dx.doi.org/10.3389/fnins.2021.708700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311167PMC
July 2021

Foveal Pit Morphology Characterization: A Quantitative Analysis of the Key Methodological Steps.

Entropy (Basel) 2021 Jun 1;23(6). Epub 2021 Jun 1.

Biomedical Engineering Department, Faculty of Engineering (MU-ENG), Mondragon Unibertsitatea, 20500 Mondragón, Spain.

Disentangling the cellular anatomy that gives rise to human visual perception is one of the main challenges of ophthalmology. Of particular interest is the foveal pit, a concave depression located at the center of the retina that captures light from the gaze center. In recent years, there has been a growing interest in studying the morphology of the foveal pit by extracting geometrical features from optical coherence tomography (OCT) images. Despite this, research has devoted little attention to comparing existing approaches for two key methodological steps: the location of the foveal center and the mathematical modelling of the foveal pit. Building upon a dataset of 185 healthy subjects imaged twice, in the present paper the image alignment accuracy of four different foveal center location methods is studied in the first place. Secondly, state-of-the-art foveal pit mathematical models are compared in terms of fitting error, repeatability, and bias. The results indicate the importance of using a robust foveal center location method to align images. Moreover, we show that foveal pit models can improve the agreement between different acquisition protocols. Nevertheless, they can also introduce important biases in the parameter estimates that should be considered.
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http://dx.doi.org/10.3390/e23060699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227188PMC
June 2021

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

Neurology 2021 07 28;97(2):68-79. Epub 2021 Apr 28.

From the Department of Neurology, Medical Faculty (A.A., O.A., H.-P.H., O.M., S.M., M.R., P.A.), Heinrich-Heine University Düsseldorf, Germany; Department of Neurology (A.C.-H., A.J.G.), University of California San Francisco; Departments of Neurology, Population Health, and Ophthalmology (L.J.B., R.K.), NYU Grossman School of Medicine, New York, NY; Mulier Institute (L.B.), Centre for Research on Sports in Society, Utrecht, the Netherlands; Scientific Institute San Raffaele (P.B.), Milan, Italy; Centre for Public Health (A.A.B.), Queen's University Belfast, Northern Ireland, UK; Division of Neuroimmunology (P.A.C., S. Saidha), Johns Hopkins University, Baltimore, MD; Departments of Clinical Neurosciences and Surgery (F.C.), University of Calgary, Alberta, Canada; Institut d'Investigacións Biomediques August Pi iSunyer (IDIBAPS) and Hospital Clinic (B.S.-D., E.H.M.-L., P.V.), University of Barcelona, Spain; Bascom Palmer Eye Institute (D.C.D.), University of Miami Miller School of Medicine, FL; Department of Ophthalmology (N.F.), University Medical Center, Göttingen; Department of Ophthalmology (R.P.F., F.G.H.), University of Bonn, Germany; Department of Neurology (J.L.F., G.P.-J.), Rigshospitalet Glostrup and University of Copenhagen, Denmark; Laboratory of Neuroimmunology (E.F., T.F.), Stanford University School of Medicine, CA; Institute of Ophthalmology (D.G.-H.), National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology (D.G.-H.), London, UK; Biocruces Bizkaia Health Research Institute (I.G.), Barakaldo, Spain; Department of Neurosciences (J.S.G.), University of California, San Diego; Brain and Mind Centre (H.-P.H.), University of Sydney, Australia; Department of Neurology (H.-P.H.), Medical University of Vienna, Austria; Institute of Clinical Neuroimmunology (J.H.), LMU Hospital, Ludwig-Maximilians Universität München, Germany; UConn Health Comprehensive MS Center, Division of Multiple Sclerosis and Neuroimmunology, Department of Neurology (J.I.), University of Connecticut School of Medicine, Farmington; Faculty of Medicine and Health Sciences (A.K.), Macquarie University, Sydney, Australia; Department of Neurology (B.K., T.K.), Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Germany; Department of Medicine and Radiology (S.K.), University of Melbourne, Australia; Department of Neurology with Institute of Translational Neurology (J.K.), University of Münster; Eye Center, Medical Center, Faculty of Medicine (W.A.L.), University of Freiburg, Germany; Experimental Neurophysiology Unit (L.L.), Institute of Experimental Neurology (INSPE), IRCCS San Raffaele, University Vita-Salute San Raffaele, Milan, Italy; Lille Neurosciences & Cognition (O.O.), Univ Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC), France; Experimental and Clinical Research Center (F.P., H.G.Z., A.U.B.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Moorfields Eye Hospital (A.P.), The National Hospital for Neurology and Neurosurgery, Queen Square, UCL Institute of Neurology, London, UK; Neuro-ophthalmology Expert Center (A.P.), Amsterdam UMC, the Netherlands; Department of Neurology, First Faculty of Medicine (J.L.P.), Charles University and General University Hospital in Prague, Czech Republic; Department of Ophthalmology (G.R.), Ramon y Cajal Hospital, Medicine University of Alcalá, Madrid, Spain; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf, Germany; Department of Neurology (S. Schippling), University Hospital Zurich, Switzerland; Departments of Ophthalmology, Neuroscience, and Physiology (J.S.S.), NYU Langone Health, NYU Grossman School of Medicine, New York; Departments of Biomedical Engineering, Electrical and Computer Engineering (J.S.S.), NYU Tandon School of Engineering, Brooklyn, NY; Thomas Jefferson University Medical College (R.C.S.), Philadelphia, PA; Queen Square MS Centre, Department of Neuroinflammation (A.T.), UCL Institute of Neurology, University College London, UK; Departments of Ophthalmology and Clinical Research (S.W.), Bern University Hospital, University of Bern, Switzerland; Division of Neurology, Department of Pediatrics (E.A.Y.), Hospital for Sick Children, Division of Neurosciences and Mental Health SickKids Research Institute, University of Toronto, Canada; Department of Clinical Neurosciences (P.Y.-W.-M.), University of Cambridge; Moorfields Eye Hospital (P.Y.-W.-M.), London, UK; University of California (A.U.B.), Irvine; and IMSVISUAL (A.A., A.C.-H., O.A., L.J.B., L.B., P.A.C., F.C., J.L.F., E.F., T.F., I.G., J.S.G., A.J.G., H.-P.H., J.H., J.I., R.K., A.K., B.K., T.K., J.K., L.L., E.H.M.-L., S.M., O.O., F.P., A.P., G.P.-J., J.L.P., M.R., S. Saidha, S. Schippling, R.C.S., P.V., E.A.Y., H.G.Z., A.U.B., P.A.), International Multiple Sclerosis Visual System Consortium, Middleton, WI.

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.

Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.

Results: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.

Conclusions: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.
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http://dx.doi.org/10.1212/WNL.0000000000012125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279566PMC
July 2021

Quantitative analysis of dysautonomia in patients with autonomic dysreflexia.

J Neurol 2021 Aug 25;268(8):2985-2994. Epub 2021 Feb 25.

Autonomic Center (NeuroTek), San Juan de Dios Hospital, Santurtzi, Spain.

Autonomic dysreflexia (AD) is a life-threatening condition for individuals with cervical or high-thoracic spinal cord injury (SCI). The profile of autonomic dysfunction in AD using validated clinical autonomic tests has not been described so far, although it could be useful to identify SCI patients at greater risk of developing AD non-invasively. With this objective, 37 SCI patients (27% female) were recruited, and hemodynamic and cardiac parameters were continuously monitored to determine the presence of AD, defined as an increase of systolic blood pressure of 20 mmHg or higher after bladder filling with saline. Then, standard autonomic function testing was performed, including Deep Breathing, Valsalva Manoeuvre and Tilt Table Test. Finally, baroreflex sensitivity (BRS), and spectral analysis of heart rate and blood pressure variability were measured at rest. Catecholamines and vasopressin levels were also measured at supine and upright positions. The severity of SCI was assessed through clinical and radiological examinations. AD was observed in 73.3% of SCI patients, being 63.6% of them asymptomatic during the dysreflexive episode. AD patients displayed a drop in sympathetic outflow, as determined by decreased noradrenalin plasma levels, reduced sympathovagal balance and increased BRS. In line with decreased sympathetic activity, the incidence of neurogenic orthostatic hypotension was higher in AD patients. Our results provide novel evidence regarding the autonomic dysfunction in SCI patients with AD compared to non-AD patients, posing non-invasively measured autonomic parameters as a powerful clinical tool to predict AD in SCI patients.
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http://dx.doi.org/10.1007/s00415-021-10478-wDOI Listing
August 2021

Retinal Thickness Predicts the Risk of Cognitive Decline in Parkinson Disease.

Ann Neurol 2021 01 9;89(1):165-176. Epub 2020 Nov 9.

Neurodegenerative Diseases Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.

Objective: This study was undertaken to analyze longitudinal changes of retinal thickness and their predictive value as biomarkers of disease progression in idiopathic Parkinson's disease (iPD).

Methods: Patients with Lewy body diseases were enrolled and prospectively evaluated at 3 years, including patients with iPD (n = 42), dementia with Lewy bodies (n = 4), E46K-SNCA mutation carriers (n = 4), and controls (n = 17). All participants underwent Spectralis retinal optical coherence tomography and Montreal Cognitive Assessment, and Unified Parkinson's Disease Rating Scale score was obtained in patients. Macular ganglion cell-inner plexiform layer complex (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness reduction rates were estimated with linear mixed models. Risk ratios were calculated to evaluate the association between baseline GCIPL and pRNFL thicknesses and the risk of subsequent cognitive and motor worsening, using clinically meaningful cutoffs.

Results: GCIPL thickness in the parafoveal region (1- to 3-mm ring) presented the largest reduction rate. The annualized atrophy rate was 0.63μm in iPD patients and 0.23μm in controls (p < 0.0001). iPD patients with lower parafoveal GCIPL and pRNFL thickness at baseline presented an increased risk of cognitive decline at 3 years (relative risk [RR] = 3.49, 95% confidence interval [CI] = 1.10-11.1, p = 0.03 and RR = 3.28, 95% CI = 1.03-10.45, p = 0.045, respectively). We did not identify significant associations between retinal thickness and motor deterioration.

Interpretation: Our results provide evidence of the potential use of optical coherence tomography-measured parafoveal GCIPL thickness to monitor neurodegeneration and to predict the risk of cognitive worsening over time in iPD. ANN NEUROL 2021;89:165-176.
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http://dx.doi.org/10.1002/ana.25944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756646PMC
January 2021

Autonomic dysfunction is associated with neuropsychological impairment in Lewy body disease.

J Neurol 2020 Jul 13;267(7):1941-1951. Epub 2020 Mar 13.

Neurodegenerative Diseases Group, Biocruces Bizkaia Health Research Institute, Plaza de Cruces 12, CP, 48903, Barakaldo, Bizkaia, Spain.

Objective: This study aimed to analyze the association of autonomic dysfunction with cognition, depression, apathy, and fatigue in Lewy body disease (LBD).

Methods: We included 61 patients [49 with idiopathic Parkinson's disease, 7 with dementia with Lewy bodies, and 5 E46K-SNCA mutation carriers] and 22 healthy controls. All participants underwent a comprehensive battery of neuropsychological and clinical measures, autonomic symptom assessment with the SCOPA-AUT, analysis of non-invasive hemodynamic parameters during deep breathing, the Valsalva maneuver, and a 20-min tilt test, and electrochemical skin conductance measurement at rest (Sudoscan). Student's t tests were used to assess group differences, and bivariate correlations and stepwise linear regressions to explore associations between autonomic function, cognition, depression, apathy, and fatigue.

Results: Compared to controls, patients who had significant impairment (p < 0.05) in cognition, higher depression, apathy, and fatigue, more autonomic symptoms and objective autonomic dysfunction, reduced deep breathing heart rate variability [expiratory-to-inspiratory (E/I) ratio], prolonged pressure recovery time, and lower blood pressure in Valsalva late phase II and phase IV, while 24.1% had orthostatic hypotension in the tilt test. Autonomic parameters significantly correlated with cognitive and neuropsychiatric outcomes, systolic blood pressure during the Valsalva maneuver predicting apathy and depression. The E/I ratio was the main predictor of cognitive performance (17.6% for verbal fluency to 32.8% for visual memory).

Conclusion: Cardiovascular autonomic dysfunction is associated with cognitive and neuropsychiatric impairment in LBD, heart rate variability during deep breathing and systolic blood pressure changes during the Valsalva procedure are the main predictors of neuropsychological performance and depression/apathy symptoms, respectively.
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http://dx.doi.org/10.1007/s00415-020-09783-7DOI Listing
July 2020

Brain connectivity and cognitive functioning in individuals six months after multiorgan failure.

Neuroimage Clin 2020 23;25:102137. Epub 2019 Dec 23.

Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain; IKERBASQUE, The Basque Foundation for Science, Bilbao, Spain; Department of Cell Biology and Histology, University of the Basque Country (UPV/EHU), Leioa, Spain. Electronic address:

Multiorgan failure (MOF) is a life-threating condition that affects two or more systems of organs not involved in the disorder that motivates admission to an Intensive Care Unit (ICU). Patients who survive MOF frequently present long-term functional, neurological, cognitive, and psychiatric sequelae. However, the changes to the brain that explain such symptoms remain unclear.

Objective: To determine brain connectivity and cognitive functioning differences between a group of MOF patients six months after ICU discharge and healthy controls (HC).

Methods: 22 MOF patients and 22 HC matched by age, sex, and years of education were recruited. Both groups were administered a 3T magnetic resonance imaging (MRI), including structural T1 and functional BOLD, as well as a comprehensive neuropsychological evaluation that included tests of learning and memory, speed of information processing and attention, executive function, visual constructional abilities, and language. Voxel-based morphometry was used to analyses T1 images. For the functional data at rest, functional connectivity (FC) analyses were performed.

Results: There were no significant differences in structural imaging and neuropsychological performance between groups, even though patients with MOF performed worse in all the cognitive tests. Functional neuroimaging in the default mode network (DMN) showed hyper-connectivity towards sensory-motor, cerebellum, and visual networks. DMN connectivity had a significant association with the severity of MOF during ICU stay and with the neuropsychological scores in tests of attention and visual constructional abilities.

Conclusions: In MOF patients without structural brain injury, DMN connectivity six months after ICU discharge is associated with MOF severity and neuropsychological impairment, which supports the use of resting-state functional MRI as a potential tool to predict the onset of long-term cognitive deficits in these patients. Similar to what occurs at the onset of other pathologies, the observed hyper-connectivity might suggest network re-adaptation following MOF.
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http://dx.doi.org/10.1016/j.nicl.2019.102137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957787PMC
December 2020

Reply to: Clinical and cognitive correlates of selective regional retina thinning in dementia with lewy bodies.

Mov Disord 2019 10;34(10):1584

Neurodegenerative Diseases Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.

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http://dx.doi.org/10.1002/mds.27850DOI Listing
October 2019

Contribution of the GABAergic System to Non-Motor Manifestations in Premotor and Early Stages of Parkinson's Disease.

Front Pharmacol 2019 30;10:1294. Epub 2019 Oct 30.

Neurodegenerative Diseases Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.

Non-motor symptoms are common in Parkinson's disease (PD) and they represent a major source of disease burden. Several non-motor manifestations, such as rapid eye movement sleep behavior disorder, olfactory loss, gastrointestinal abnormalities, visual alterations, cognitive and mood disorders, are known to precede the onset of motor signs. Nonetheless, the mechanisms mediating these alterations are poorly understood and probably involve several neurotransmitter systems. The dysregulation of GABAergic system has received little attention in PD, although the spectrum of non-motor symptoms might be linked to this pathway. This Mini Review aims to provide up-to-date information about the involvement of the GABAergic system for explaining non-motor manifestations in early stages of PD. Therefore, special attention is paid to the clinical data derived from patients with isolated REM sleep behavior disorder or drug-naïve patients with PD, as they represent prodromal and early stages of the disease, respectively. This, in combination with animal studies, might help us to understand how the disturbance of the GABAergic system is related to non-motor manifestations of PD.
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http://dx.doi.org/10.3389/fphar.2019.01294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831739PMC
October 2019

Rehabilitation, the Great Absentee of Virtual Coaching in Medical Care: Scoping Review.

J Med Internet Res 2019 10 1;21(10):e12805. Epub 2019 Oct 1.

Department of Neurorehabilitation Sciences, Casa Cura Policlinico, Milano, Italy.

Background: In the last few years, several studies have focused on describing and understanding how virtual coaches (ie, coaching program or smart device aiming to provide coaching support through a variety of application contexts) could be key drivers for health promotion in home care settings. As there has been enormous technological progress in the field of artificial intelligence and data processing in the past decade, the use of virtual coaches gains an augmented attention in the considerations of medical innovations.

Objective: This scoping review aimed at providing an overview of the applications of a virtual coach in the clinical field. In particular, the review focused on the papers that provide tangible information for coaching activities with an active implication for engaging and guiding patients who have an ongoing plan of care.

Methods: We aimed to investigate the use of the term virtual coach in the clinical field performing a methodical review of the relevant literature indexed on PubMed, Scopus, and Embase databases to find virtual coach papers focused on specific activities dealing with clinical or medical contexts, excluding those aimed at surgical settings or electronic learning purposes.

Results: After a careful revision of the inclusion and exclusion criteria, 46 records were selected for the full-text review. Most of the identified articles directly or indirectly addressed the topic of physical activity. Some papers were focused on the use of virtual coaching (VC) to manage overweight or nutritional issues. Other papers dealt with technological interfaces to facilitate interactions with patients suffering from different chronic clinical conditions such as heart failure, chronic obstructive pulmonary disease, depression, and chronic pain.

Conclusions: Although physical activity is a healthy practice that is most encouraged by a virtual coach system, in the current scenario, rehabilitation is the great absentee. This paper gives an overview of the tangible applications of this tool in the medical field and may inspire new ideas for future research on VC.
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http://dx.doi.org/10.2196/12805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774233PMC
October 2019

Using Acute Optic Neuritis Trials to Assess Neuroprotective and Remyelinating Therapies in Multiple Sclerosis.

JAMA Neurol 2020 02;77(2):234-244

Center of Neuroimmunology, Service of Neurology, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, University of Barcelona, Barcelona, Spain.

Importance: Neuroprotective and remyelinating therapies are required for multiple sclerosis (MS), and acute optic neuritis (AON) is a potential condition to evaluate such treatments.

Objective: To comprehensively assess key biological and methodological aspects of AON trials for testing neuroprotection and remyelination in MS.

Design, Setting, And Participants: The AON-VisualPath prospective cohort study was conducted from February 2011 to November 2018 at the Hospital Clinic of University of Barcelona, Barcelona, Spain. Consecutive patients with AON were prospectively enrolled in the cohort and followed up for 18 months. Data analyses occurred from November 2018 to February 2019.

Exposures: Participants were followed up for 18 months using optical coherence tomography, visual acuity tests, and in a subset of 25 participants, multifocal visual evoked potentials.

Main Outcomes And Measures: Dynamic models of retinal changes and nerve conduction and their associations with visual end points; and eligibility criteria, stratification, and sample-size estimation for future trials.

Results: A total of 60 patients (50 women [83%]; median age, 34 years) with AON were included. The patients studied displayed early and intense inner retinal thinning, with a thinning rate of approximately 2.38 μm per week in the ganglion cell plus inner plexiform layer (GCIPL) during the first 4 weeks. Eyes with AON displayed a 6-month change in latency of about 20 milliseconds, while the expected change in the eyes of healthy participants by random variability was 0.13 (95% CI, -0.80 to 1.06) milliseconds. The strongest associations with visual end points were for the 6-month intereye difference in 2.5% low-contrast letter acuity, which was correlated with the peripapillary retinal nerve fiber layer thinning (adjusted R2, 0.57), GCIPL thinning (adjusted R2, 0.50), and changes in mfVEP latency (adjusted R2, 0.26). A 5-letter increment in high-contrast visual acuity at presentation (but not sex or age) was associated with 6-month retinal thinning (1.41 [95% CI, 0.60-2.23] μm less peripapillary retinal nerve fiber layer thinning thinning; P = .001; adjusted R2, 0.20; 0.86 [95% CI, 0.35-1.37] μm less GCIPL thinning; P = .001; adjusted R2, 0.19) but not any change in multifocal visual evoked potential latency. To demonstrate 50% efficacy in GCIPL thinning or change in multifocal visual evoked potential latency, a 6-month, 2-arm, parallel-group trial would need 37 or 50 participants per group to test a neuroprotective or remyelinating drug, respectively (power, 80%; α, .05).

Conclusions And Relevance: Acute optic neuritis is a suitable condition to test neuroprotective and remyelinating therapies after acute inflammation, providing sensitive markers to assess the effects on both processes and prospective visual recovery within a manageable timeframe and with a relatively small sample size.
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http://dx.doi.org/10.1001/jamaneurol.2019.3283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777247PMC
February 2020

Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K-SNCA mutation carriers.

Parkinsonism Relat Disord 2019 08 5;65:139-145. Epub 2019 Jun 5.

Neurodegenerative Diseases Group, Biocruces Bizkaia Health Research Institute, Cruces-Barakaldo, Bizkaia, Spain; Neurology Department, Cruces University Hospital, Cruces-Barakaldo, Bizkaia, Spain. Electronic address:

Background And Objective: In 2004 we described the E46K mutation in alpha-synuclein gene (E46K-SNCA), a rare point mutation causing an aggressive Lewy body disease with early prominent non-motor features and small fiber denervation of myocardium. Considering the potential interest of the skin as a target for the development of biomarkers in Parkinson's Disease (PD), in this work we aimed to evaluate structural and functional integrity of small autonomic nerve fibers and phosphorylated alpha-synuclein (p-synuclein) deposition in the skin of E46K-SNCA carriers as compared to those observed in parkin gene mutation (PARK2) carriers and healthy controls.

Patients And Methods: We studied 7 E46K-SNCA carriers (3 dementia with Lewy bodies, 2 pure autonomic failure, 1 PD and 1 asymptomatic), 2 PARK2 carriers and 2 healthy controls to quantify intraepidermal nerve fiber density and p-synuclein deposition with cervical skin punch biopsies (immunohistochemistry against anti PGP9.5/UCHL-1, TH and p-synuclein) and sudomotor function with electrochemical skin conductance (ESC) (SudoScan).

Results: All E46K-SNCA carriers had moderate to severe p-synuclein deposits and small fiber neurodegeneration in different epidermal and dermal structures including nerve fascicles and glands, especially in carriers with Pure Autonomic Failure, while p-synuclein aggregates where absent in healthy controls and in one of two PARK2 carriers. The severity of the latter skin abnormalities in E46K-SNCA were correlated with sudomotor dysfunction (lower ESC) in hands (p = 0.035).

Interpretation: These results together with our previous findings support the relevance of E46K-SNCA mutation as a suitable model to study small fiber neuropathy in Lewy body diseases.
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http://dx.doi.org/10.1016/j.parkreldis.2019.05.038DOI Listing
August 2019

Parafoveal thinning of inner retina is associated with visual dysfunction in Lewy body diseases.

Mov Disord 2019 09 28;34(9):1315-1324. Epub 2019 May 28.

Neurodegenerative Diseases Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.

Background: Retinal optical coherence tomography findings in Lewy body diseases and their implications for visual outcomes remain controversial. We investigated whether region-specific thickness analysis of retinal layers could improve the detection of macular atrophy and unravel its association with visual disability in Parkinson's disease.

Methods: Patients with idiopathic Parkinson's disease (n = 63), dementia with Lewy bodies (n = 8), and E46K mutation carriers in the α-synuclein gene (E46K-SNCA) (n = 4) and 34 controls underwent Spectralis optical coherence tomography macular scans and a comprehensive battery of visual function and cognition tests. We computed mean retinal layer thicknesses of both eyes within 1-, 2-, 3-, and 6-mm diameter macular discs and in concentric parafoveal (1- to 2-mm, 2- to 3-mm, 1- to 3-mm) and perifoveal (3- to 6-mm) rings. Group differences in imaging parameters and their relationship with visual outcomes were analyzed. A multivariate logistic model was developed to predict visual impairment from optical coherence tomography measurements in Parkinson's disease, and cutoff values were determined with receiver operating characteristic analysis.

Results: When compared with controls, patients with dementia with Lewy bodies had significant thinning of the ganglion cell-inner plexiform layer complex within the central 3-mm disc mainly because of differences in 1- to 3-mm parafoveal thickness. This parameter was strongly correlated in patients, but not in controls, with low contrast visual acuity and visual cognition outcomes (P < .05, False Discovery Rate), achieving 88% of accuracy in predicting visual impairment in Parkinson's disease.

Conclusion: Our findings support that parafoveal thinning of ganglion cell-inner plexiform complex is a sensitive and clinically relevant imaging biomarker for Lewy body diseases, specifically for Parkinson's disease. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790692PMC
September 2019

Myocardial MIBG scintigraphy in genetic Parkinson's disease as a model for Lewy body disorders.

Eur J Nucl Med Mol Imaging 2019 02 15;46(2):376-384. Epub 2018 Oct 15.

Neurodegenerative Diseases Group, Biocruces-Bizkaia Health Research Institute, Plaza de Cruces 12, CP 48903, Barakaldo, Bizkaia, Spain.

Purpose: To identify myocardial sympathetic denervation patterns suggestive of Lewy body (LB) pathology in patients with genetic and idiopathic parkinsonisms by I-metaiodobenzylguanidine (MIBG) scintigraphy.

Methods: We retrospectively analysed myocardial MIBG images acquired with a dual-head gamma camera and low-energy high-resolution collimator (LEHR) in 194 patients with suspected synucleinopathy or atypical parkinsonism, including 34 with genetic Parkinson's disease (PD; 4 PARK1, 8 PARK2 and 22 PARK8), 85 with idiopathic PD (iPD), 6 with idiopathic REM sleep behaviour disorder (iRBD), 17 with dementia with LB (DLB), 40 with multiple system atrophy (MSA) and 12 with progressive supranuclear palsy (PSP), and in 45 healthy controls. We calculated heart-to-mediastinum MIBG uptake ratios (HMR) at 15 min and 4 h (HMR4H) for the LEHR and standardized medium-energy collimators, to obtain classification accuracies and optimal cut-off values for HMR using supervised classification and ROC analyses.

Results: While patients with LB disorders had markedly lower HMR4H than controls (controls 1.86 ± 0.26, iPD 1.38 ± 0.29, iRBD 1.23 ± 0.09, PARK1 1.20 ± 0.09, DLB 1.17 ± 0.11; p < 0.05), for the remaining patient categories differences were smaller (PARK8 1.51 ± 0.32; p < 0.05) or not significant (MSA 1.82 ± 0.37, PSP 1.59 ± 0.23, PARK2 1.51 ± 0.30; p > 0.05). The diagnostic accuracy of HMR4H was highest in patients with LB disorders (PARK1, iPD, DLB, iRBD; 89% to 97%) and lowest in those with PARK2, PARK8, PSP and MSA (65% to 76%), with an optimal HMR4H cut-off value of 1.72 for discriminating most patients with LB disorders including iPD and 1.40 for discriminating those with aggressive LB spectrum phenotypes (DLB, PARK1 and iRBD).

Conclusion: Our study including patients with a wide spectrum of genetic and idiopathic parkinsonisms with different degrees of LB pathology further supports myocardial MIBG scintigraphy as an accurate tool for discriminating patients with LB spectrum disorders.
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http://dx.doi.org/10.1007/s00259-018-4183-0DOI Listing
February 2019

Structure-function multi-scale connectomics reveals a major role of the fronto-striato-thalamic circuit in brain aging.

Hum Brain Mapp 2018 12 13;39(12):4663-4677. Epub 2018 Jul 13.

Biocruces Health Research Institute, Barakaldo, Spain.

Physiological aging affects brain structure and function impacting morphology, connectivity, and performance. However, whether some brain connectivity metrics might reflect the age of an individual is still unclear. Here, we collected brain images from healthy participants (N = 155) ranging from 10 to 80 years to build functional (resting state) and structural (tractography) connectivity matrices, both data sets combined to obtain different connectivity features. We then calculated the brain connectome age-an age estimator resulting from a multi-scale methodology applied to the structure-function connectome, and compared it to the chronological age (ChA). Our results were twofold. First, we found that aging widely affects the connectivity of multiple structures, such as anterior cingulate and medial prefrontal cortices, basal ganglia, thalamus, insula, cingulum, hippocampus, parahippocampus, occipital cortex, fusiform, precuneus, and temporal pole. Second, we found that the connectivity between basal ganglia and thalamus to frontal areas, also known as the fronto-striato-thalamic (FST) circuit, makes the major contribution to age estimation. In conclusion, our results highlight the key role played by the FST circuit in the process of healthy aging. Notably, the same methodology can be generally applied to identify the structural-functional connectivity patterns correlating to other biomarkers than ChA.
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http://dx.doi.org/10.1002/hbm.24312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866396PMC
December 2018

Seronegative and seropositive autoimmune autonomic ganglionopathy (AAG): Same clinical picture, same response to immunotherapy.

J Neuroimmunol 2018 06 4;319:68-70. Epub 2018 Apr 4.

Autonomic and Movement Disorders Unit, Neurodegenerative diseases, Biocruces Health Research Institute, Barakado, Bizkaia, Spain; Department of Neurosciences, University of Basque Country, Leioa, Spain. Electronic address:

Two patients with a syndrome of pandisautonomia with clinical criteria of AAG are provided. Both patients present a similar clinical picture and response to immunosuppressive treatment. One of them has positive antibodies against the ganglionic nicotinic acetylcholine (gAChr) and the other does not. This brief article serves to reflect the spectrum of AAG, at a clinical level, in laboratory tests and in the response to immunotherapy, independently of the presence of positive gAChr antibodies.
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http://dx.doi.org/10.1016/j.jneuroim.2018.03.018DOI Listing
June 2018

Multicenter reliability of semiautomatic retinal layer segmentation using OCT.

Neurol Neuroimmunol Neuroinflamm 2018 May 13;5(3):e449. Epub 2018 Mar 13.

NeuroCure Clinical Research Center (T.O., F.P., A.U.B.), Charité-Universitätsmedizin Berlin, Germany; Department of Ophthalmology (G.L.T.), University Hospital Zurich, University of Zurich; Neuroimmunology and Multiple Sclerosis Research Section (S.L., S.S.), Department of Neurology, University Hospital Zurich, University of Zurich, Switzerland; Center of Neuroimmunology (I.G., P.V.), Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS)-Hospital Clinic, Barcelona, Spain; Division of Neuroinflammation and Glial Biology (R.N., C.S., A.J.G.), Department of Neurology, University of California San Francisco; Neuro-ophthalmology Division (A.J.G.), Department of Ophthalmology, University of California, San Francisco; Multiple Sclerosis Center (L.B., A.P.), Departments of Neurology and Ophthalmology, Neuro-ophthalmology Expertise Centre, VUmc, Amsterdam and Moorfields Eye Hospital (A.P.), The National Hospital for Neurology and Neurosurgery and UCL, United Kingdom; Clinical and Experimental Multiple Sclerosis Research Center (F.P.), Department of Neurology, Charité-Universitätsmedizin Berlin; Experimental and Clinical Research Center (F.P., A.U.B.), Charité-Universitätsmedizin Berlin and Max-Delbrück Center for Molecular Medicine, Germany; Department of Methods and Experimental Psychology (I.G.), Faculty of Psychology and Education, Universidad de Deusto, Bilbao, Spain.

Objective: To evaluate the inter-rater reliability of semiautomated segmentation of spectral domain optical coherence tomography (OCT) macular volume scans.

Methods: Macular OCT volume scans of left eyes from 17 subjects (8 patients with MS and 9 healthy controls) were automatically segmented by Heidelberg Eye Explorer (v1.9.3.0) beta-software (Spectralis Viewing Module v6.0.0.7), followed by manual correction by 5 experienced operators from 5 different academic centers. The mean thicknesses within a 6-mm area around the fovea were computed for the retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer (OPL), and outer nuclear layer (ONL). Intraclass correlation coefficients (ICCs) were calculated for mean layer thickness values. Spatial distribution of ICC values for the segmented volume scans was investigated using heat maps.

Results: Agreement between raters was good (ICC > 0.84) for all retinal layers, particularly inner retinal layers showed excellent agreement across raters (ICC > 0.96). Spatial distribution of ICC showed highest values in the perimacular area, whereas the ICCs were poorer for the foveola and the more peripheral macular area. The automated segmentation of the OPL and ONL required the most correction and showed the least agreement, whereas differences were less prominent for the remaining layers.

Conclusions: Automated segmentation with manual correction of macular OCT scans is highly reliable when performed by experienced raters and can thus be applied in multicenter settings. Reliability can be improved by restricting analysis to the perimacular area and compound segmentation of GCL and IPL.
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http://dx.doi.org/10.1212/NXI.0000000000000449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852947PMC
May 2018

Building Bridges through Science.

Neuron 2017 Nov;96(4):730-735

The Scripps Research Institute, La Jolla, CA 92037, USA.

Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge" initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.
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http://dx.doi.org/10.1016/j.neuron.2017.09.028DOI Listing
November 2017

Progressive multifocal leukoencephalopathy 11 years after liver transplantation: a case report.

J Neurovirol 2017 12 12;23(6):929-931. Epub 2017 Sep 12.

Department of Neurology, Cruces University Hospital, Plaza Cruces S/N, 48903, Barakaldo, Basque Country, Spain.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system caused by JC virus. Only ten cases of PML have been reported so far in liver transplant recipients. We present a case of liver posttransplantation PML with characteristic clinical and brain MRI findings, but with an atypical late onset, developed 11 years after transplantation and after single-drug, long-term (8 years), and low-dose (750 mg twice a day) immunosuppression with mycophenolate mofetil (MMF). This is the latest onset of PML associated to liver transplant reported. The present case should help physicians to be aware of PML after transplantation, even in the long term and even under low doses of immunosuppressants, especially MMF.
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http://dx.doi.org/10.1007/s13365-017-0578-0DOI Listing
December 2017

The Retina in Multiple System Atrophy: Systematic Review and Meta-Analysis.

Front Neurol 2017 24;8:206. Epub 2017 May 24.

Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, NY, United States.

Background: Multiple system atrophy (MSA) is a rare, adult-onset, rapidly progressive fatal synucleinopathy that primarily affects oligodendroglial cells in the brain. Patients with MSA only rarely have visual complaints, but recent studies of the retina using optical coherence tomography (OCT) showed atrophy of the peripapillary retinal nerve fiber layer (RNFL) and to a lesser extent the macular ganglion cell layer (GCL) complex.

Methods: We performed a literature review and meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses guidelines for studies published before January 2017, identified through PubMed and databases, which reported OCT-related outcomes in patients with MSA and controls. A random-effects model was constructed.

Results: The meta-analysis search strategy yielded 15 articles of which 7 met the inclusion criteria. The pooled difference in the average thickness of the RNFL was -5.48 μm (95% CI, -6.23 to -4.73;  < 0.0001), indicating significant thinning in patients with MSA. The pooled results showed significant thinning in all the specific RNFL quadrants, except in the temporal RNFL quadrant, where the thickness in MSA and controls was similar [pooled difference of 1.11 µm (95% CI, -4.03 to 6.26;  = 0.67)]. This pattern of retinal damage suggests that MSA patients have preferential loss of retinal ganglion cells projecting to the magnocellular pathway (M-cells), which are mainly located in the peripheral retina and are not essential for visual acuity. Visual acuity, on the other hand, relies mostly on macular ganglion cells projecting to the parvocellular pathway (P-cells) through the temporal portion of the RNFL, which are relatively spared in MSA patients.

Conclusion: The retinal damage in patients with MSA differs from that observed in patients with Parkinson disease (PD). Patients with MSA have more relative preservation of temporal sector of the RNFL and less severe atrophy of the macular GCL complex. We hypothesize that in patients with MSA there is predominant damage of large myelinated optic nerve axons like those originating from the M-cells. These large axons may require higher support from oligodendrocytes. Conversely, in patients with PD, P-cells might be more affected.
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http://dx.doi.org/10.3389/fneur.2017.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443142PMC
May 2017

The influence of posterior visual pathway damage on visual information processing speed in multiple sclerosis.

Mult Scler 2017 Aug 14;23(9):1276-1288. Epub 2016 Nov 14.

Department of Methods and Experimental Psychology, Faculty of Psychology and Education, Universidad de Deusto, Bilbao, Spain.

Background: The injury of visual pathway and abnormalities of visual processing speed (VPS) are frequent in MS, but their association remains unexplored.

Objective: To evaluate the impact of posterior visual pathway structural and functional integrity on VPS of MS patients.

Methods: Cross-sectional study of 30 MS patients and 28 controls, evaluating the association of a VPS tests composite (Salthouse Perceptual Comparison test, Trail Making Test A and Symbol Digit Modalities Test) with 3T MRI visual cortex thickness, optic radiations (OR) diffusion tensor imaging indexes, and medial visual component (MVC) functional connectivity (FC) (MVC-MVC FC (iFC) and MVC-brain FC (eFC)) by linear regression, removing the effect of premorbid IQ, fatigue, and depression.

Results: V2 atrophy, lower OR fractional anisotropy (FA) and MVC FC significantly influenced VPS in MS (at none or lesser extent in controls), even after removing the effect of Expanded Disability Status Scale and previous optic neuritis (V2 ( r = 0.210): β = +0.366, p = 0.046; OR FA ( r = 0.243): β = +0.378, p = 0.034; MVC iFC, for example, left cuneus ( r = 0.450): β = -0.613, p < 0.001; MVC eFC, for example, right precuneus-postcentral gyrus ( r = 0.368): β = -0.466, p = 0.002).

Conclusion: Posterior visual pathway integrity, structural (V2 thickness and OR FA) and functional (MVC FC), may explain respectively up to 24% and 45% of VPS variability in MS.
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http://dx.doi.org/10.1177/1352458516676642DOI Listing
August 2017

Long-term impact on quality of life of subthalamic nucleus stimulation in Parkinson's disease.

J Neurol 2016 May 10;263(5):895-905. Epub 2016 Mar 10.

Neurology Department, Cruces University Hospital, Plaza de Cruces s/n, 48903, Barakaldo, Spain.

Long-term impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on health-related quality of life (HRQOL) and associated factors in patients with Parkinson's disease (PD) are not clear. In this prospective study, we included 69 PD patients (64 % men, mean age 61.3 ± 7.4 and disease duration 13.2 ± 5.7 years) undergoing STN-DBS. They were evaluated preoperatively (baseline), 1 and 5 years postoperatively assessing 39-item Parkinson's Disease Questionnaire (PDQ-39), Schwab and England Activities of Daily Living Scale (SEADL), Unified Parkinson's Disease Rating Scale (UPDRS) off- and on-medication, patient diaries, dopaminergic treatment, mortality and surgical complications. Five years postoperatively, off-medication, there were improvements from baseline in UPDRS-II and III total (27.2 and 26.7 %, respectively) and SEADL (18.6 % more completely independent patients) (p < 0.05) scores, while on-medication, there was a deterioration in UPDRS-III (37.8 %, mainly axial signs) (p < 0.05) and minor improvements in SEADL (3.7 %). While at 1 year PDQ-39, the summary index improved substantially (36.5 %) (p < 0.05), at 5 years patients regressed (only 8.8 %) (p < 0.05), though changes in PDQ-39 subscores remained significant, with improvements in ADL (18.8 %), emotional well-being (19.0 %), stigma (36.4 %) and discomfort (20.6 %), despite worsening in communication (47.8 %) (p < 0.05). Lower preoperative PDQ-39 summary index and greater 1-year UPDRS-III-off total score gain predicted better long-term HRQOL. STN-DBS produces long-term improvements in HRQOL in PD. Preoperative HRQOL and short-term postoperative changes in off-medication motor status may predict long-term HRQOL in PD following STN-DBS.
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http://dx.doi.org/10.1007/s00415-016-8077-4DOI Listing
May 2016

Autonomic involvement in Parkinsonian carriers of PARK2 gene mutations.

Parkinsonism Relat Disord 2015 Jul 23;21(7):717-22. Epub 2015 Apr 23.

Neurodegenerative Unit, Biocruces Research Institute, Bilbao, Spain; Neurology Service, Cruces University Hospital, Baracaldo, Biscay, Spain; Department of Neurosciences, School of Medicine and Dentistry University of the Basque Country, Leioa, Biscay, Spain. Electronic address:

Background And Objectives: The objective of this study was to assess the presence of autonomic nervous system dysfunction in PARK2 mutation carriers.

Patients And Methods: We performed a cross-sectional analysis of 8 PARK2 carriers (age: 60.1 ± 12.8 years) and 13 individuals with idiopathic PD (iPD) (age: 59.2 ± 8.9 years). Autonomic dysfunction was measured using the SCOPA-AUT questionnaire, non-invasive autonomic tests and responses of noradrenaline and vasopressin levels to postural changes. Myocardial sympathetic denervation was assessed with metaiodobenzylguanidine (MIBG) scintigraphy. This damage was further investigated in postmortem epicardial tissue of one PARK2 carrier and three control cases (two PD patients and one subject without PD).

Results: The prevalence of autonomic symptoms and orthostatic hypotension (OH) was lower in PARK2 mutation carriers than in iPD patients (SCOPA OUT: 3.4 ± 4.8 vs. 14.7 ± 7.2, p < 0.001; OH: present in three iPD patients but none of the PARK2 mutation carriers). Second, sympathetic myocardial denervation was less severe in PARK2 mutation carriers compared to controls, both in MIBG scintigraphy (late H/M uptake ratio: 1.52 ± 0.35 vs. 1.32 ± 0.25 p < 0.05) and in postmortem tissue study. Interestingly, axonal alpha-synuclein deposits were absent in epicardial tissue of the PARK2 mutation carrier while they were present in the two PD patients.

Interpretation: Our study supports the view that autonomic nervous system dysfunction and myocardial sympathetic denervation are less pronounced in PARK2 mutation carriers than in individuals with iPD, suggesting that the involvement of small peripheral sympathetic nerve fibers is a minor pathological hallmark in PARK2 carriers.
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http://dx.doi.org/10.1016/j.parkreldis.2015.04.012DOI Listing
July 2015

Dynamics of retinal injury after acute optic neuritis.

Ann Neurol 2015 Mar 14;77(3):517-28. Epub 2015 Feb 14.

Center of Neuroimmunology and Department of Neurology, August Pi Sunyer Institute of Biomedical Research, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.

Objective: We set out to assess the dynamics of retinal injury after acute optic neuritis (ON) and their association with clinical visual outcomes.

Methods: Thirty-one consecutive patients with acute ON were prospectively analyzed over a 6-month follow-up period. Each month, we used optical coherence tomography (OCT) to assess the thickness of peripapillary retinal nerve fiber layer (pRNFL) and segmented macular layers, as well as high-contrast visual acuity, low-contrast visual acuity (LCVA), color visual acuity (CVA), and visual fields (VF).

Results: In this prospective study, we found that 6 months after clinical onset, ON eyes suffered a reduction in pRNFL (-45.3 μm) and macular thickness (-17.3 μm). Macular atrophy was due to the decrease of macular RNFL thickness (-7.8 μm) and that of the ganglion cell layer and inner plexiform layer (GCIP, -11.3 μm), whereas the thickness of the outer retinal layers increased slightly. The macular RNFL and GCIP thickness decreased in parallel, yet it always occurred more rapidly and more severely for the GCIP. The change in the GCIP thickness in the first month predicted the visual impairment by month 6; a decrease ≥ of 4.5 μm predicted poor LCVA (sensitivity of 93% and specificity of 88%), and a decrease of ≥ 7 μm predicted poor VF and CVA (sensitivity of 78% and 100% and specificity of 63% and 66%, respectively).

Interpretation: Retinal axonal and neuronal damage develops quickly after ON onset. Assessment of ganglion cell layer thickness by OCT after ON onset can be used as an imaging marker of persistent visual disability.
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http://dx.doi.org/10.1002/ana.24351DOI Listing
March 2015

The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS.

BMC Res Notes 2014 Dec 15;7:910. Epub 2014 Dec 15.

Center of Neuroimmunology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) - Hospital Clinic of Barcelona, Casanova 145, Planta 3A, 08036 Barcelona, Spain.

Background: Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations.

Findings: The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-aged MS population in Barcelona, Spain. We started the recruitment of patients in the early phase of MS in 2010 and it remains permanently open. All patients undergo a complete neurological and ophthalmological examination including measurements of physical and disability (Expanded Disability Status Scale; Multiple Sclerosis Functional Composite and neuropsychological tests), disease activity (relapses) and visual function testing (visual acuity, color vision and visual field). The MS-VisualPath protocol also assesses the presence of anxiety and depressive symptoms (Hospital Anxiety and Depression Scale), general quality of life (SF-36) and visual quality of life (25-Item National Eye Institute Visual Function Questionnaire with the 10-Item Neuro-Ophthalmic Supplement). In addition, the imaging protocol includes both retinal (Optical Coherence Tomography and Wide-Field Fundus Imaging) and brain imaging (Magnetic Resonance Imaging). Finally, multifocal Visual Evoked Potentials are used to perform neurophysiological assessment of the visual pathway.

Discussion: The analysis of the visual pathway with advance imaging and electrophysilogical tools in parallel with clinical information will provide significant and new knowledge regarding neurodegeneration in MS and provide new clinical and imaging biomarkers to help monitor disease progression in these patients.
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http://dx.doi.org/10.1186/1756-0500-7-910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300678PMC
December 2014

Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis.

PLoS One 2014 1;9(12):e113936. Epub 2014 Dec 1.

Center of Neuroimmunology, Service of Neurology, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

Objective: Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study.

Methods: Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5 were randomized to receive IV 1-2×10(6) bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects.

Results: At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1-8.8 vs 12.3, 95% CI = 4.4-34.5, p = 0.064), and at the end of study to reduced mean GEL (-2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients.

Conclusion: Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113936PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250058PMC
December 2015

Colour vision impairment is associated with disease severity in multiple sclerosis.

Mult Scler 2014 08 7;20(9):1207-16. Epub 2014 Jan 7.

Center of Neuroimmunology and Department of Neurology, Hospital Clinic of Barcelona, Spain

Background: Colour vision assessment correlates with damage of the visual pathway and might be informative of overall brain damage in multiple sclerosis (MS).

Objective: The objective of this paper is to investigate the association between impaired colour vision and disease severity.

Methods: We performed neurological and ophthalmic examinations, as well as magnetic resonance imaging (MRI) and optical coherence tomography (OCT) analyses, on 108 MS patients, both at baseline and after a follow-up of one year. Colour vision was evaluated by Hardy, Rand and Rittler plates. Dyschromatopsia was defined if colour vision was impaired in either eye, except for participants with optic neuritis (ON), for whom only the unaffected eye was considered. We used general linear models adjusted for sex, age, disease duration and MS treatment for comparing presence of dyschromatopsia and disease severity.

Results: Impaired colour vision in non-ON eyes was detected in 21 out of 108 patients at baseline. At baseline, patients with dyschromatopsia had lower Multiple Sclerosis Functional Composite (MSFC) scores and Brief Repeatable Battery-Neuropsychology executive function scores than those participants with normal colour vision. In addition, these patients had thinner retinal nerve fiber layer (RNFL), and smaller macular volume, normalized brain volume and normalized gray matter volume (NGMV) at baseline. Moreover, participants with incident dyschromatopsia after one-year follow-up had a greater disability measured by the Expanded Disability Status Scale and MSFC-20 and a greater decrease in NGMV than participants with normal colour vision.

Conclusions: Colour vision impairment is associated with greater MS severity.
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http://dx.doi.org/10.1177/1352458513517591DOI Listing
August 2014

Trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis.

Ann Neurol 2014 Jan 2;75(1):98-107. Epub 2014 Jan 2.

Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain.

Objective: To evaluate the association between the damage to the anterior and posterior visual pathway as evidence of the presence of retrograde and anterograde trans-synaptic degeneration in multiple sclerosis (MS).

Methods: We performed a longitudinal evaluation on a cohort of 100 patients with MS, acquiring retinal optical coherence tomography to measure anterior visual pathway damage (peripapillary retinal nerve fiber layer [RNFL] thickness and macular volume) and 3T brain magnetic resonance imaging (MRI) for posterior visual pathway damage (volumetry and spectroscopy of visual cortex, lesion volume within optic radiations) at inclusion and after 1 year. Freesurfer and SPM8 software was used for MRI analysis. We evaluated the relationships between the damage in the anterior and posterior visual pathway by voxel-based morphometry (VBM), multiple linear regressions, and general linear models.

Results: VBM analysis showed that RNFL thinning was specifically associated with atrophy of the visual cortex and with lesions in optic radiations at study inclusion (p < 0.05). Visual cortex volume (β = +0.601, 95% confidence interval [CI] = +0.04 to +1.16), N-acetyl aspartate in visual cortex (β = +1.075, 95% CI = +0.190 to +1.961), and lesion volume within optic radiations (β = -2.551, 95% CI = -3.910 to -1.192) significantly influenced average RNFL thinning at study inclusion independently of other confounders, especially optic neuritis (ON). The model indicates that a decrease of 1cm(3) in visual cortex volume predicts a reduction of 0.6μm in RNFL thickness. This association was also observed after 1 year of follow-up. Patients with severe prior ON (adjusted difference = -3.01, 95% CI = -5.08 to -0.95) and mild prior ON (adjusted difference = -1.03, 95% CI = -3.02 to +0.95) had a lower adjusted mean visual cortex volume than patients without ON.

Interpretation: Our results suggest the presence of trans-synaptic degeneration as a contributor to chronic axon damage in MS.
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http://dx.doi.org/10.1002/ana.24030DOI Listing
January 2014

Cognitive functions in multiple sclerosis: impact of gray matter integrity.

Mult Scler 2014 Apr 4;20(4):424-32. Epub 2013 Sep 4.

Center for Neuroimmunology, Service of Neurology, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.

Objectives: Our aim was to investigate the impact of gray matter (GM) integrity on cognitive performance in multiple sclerosis (MS), and its relationship with white matter (WM) integrity and presence of lesions.

Methods: Sixty-seven patients with MS and 26 healthy controls underwent voxel-based analysis of diffusion tensor images (DTI) in GM and tract-based spatial statistics (TBSS) from WM to identify the regional correlations between cognitive functions and integrity. Lesion probability mapping (LPM) was generated for correlation analysis with cognition. Multiple linear regression analyses were used to identify the imaging measures associated with cognitive scores.

Results: Compared with controls, patients showed abnormal DTI indices in several GM regions and in most WM tracts. Impairment in DTI indices in specific GM regions was associated with worse performance of distinct cognitive functions. Those regions showed anatomical correspondence with cognitively relevant tracts in TBSS and LPM. The combination of regional GM and WM DTI and lesion volume accounted for 36-51% of the variance of memory and attention scores. Regional GM DTI explained less than 5% of that variance.

Conclusion: GM and WM integrity of specific networks influences cognitive performance in MS. However, GM damage assessed by DTI only adds a small increment to the explained variance by WM in predicting cognitive functioning.
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http://dx.doi.org/10.1177/1352458513503722DOI Listing
April 2014

Late-onset anti-NMDA receptor encephalitis.

Neurology 2013 Sep 14;81(12):1058-63. Epub 2013 Aug 14.

From the Department of Neurology (M.J.T., I.G., M.R.R., F.G., J.D.), Hospital Clinic, Universitat de Barcelona/Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Department of Neurology and Neurosciences (M.J.T., L.M., M.R.R., R.B.-G., J.D.), Perelman School of Medicine, Hospital of the University of Pennsylvania, Philadelphia; Department of Neurology (T.I.), Kitasato University School of Medicine, Sagamihara; Department of Neurology (I.K.), Brain Research Institute, Niigata University, Japan; Department of Neurology (L.B.), Hospital Universitario La Fe, Valencia; Biostatistics and Data Management Platform (A.T.), IDIBAPS, Hospital Clinic; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain.

Objective: To describe the clinical features and outcome of anti-NMDA receptor (NMDAR) encephalitis in patients ≥45 years old.

Method: Observational cohort study.

Results: In a cohort of 661 patients with anti-NMDAR encephalitis, we identified 31 patients ≥45 years old. Compared with younger adults (18-44 years), older patients were more often male (45% vs. 12%, p < 0.0001), had lower frequency of tumors (23% vs. 51%, p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p = 0.009) and treatment (7 vs. 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0-2 at 2 years, 60% vs. 80%, p < 0.026). In multivariable analysis, younger age (odds ratio [OR] 0.15, confidence interval [CI] 0.05-0.39, p = 0.0001), early treatment (OR 0.60, CI 0.47-0.78, p < 0.0001), no need for intensive care (OR 0.09, CI 0.04-0.22, p < 0.0001), and longer follow-up (p < 0.0001) were associated with good outcome. Rituximab and cyclophosphamide were effective when first-line immunotherapies failed (OR 2.93, CI 1.10-7.76, p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow-up.

Conclusions: Anti-NMDAR encephalitis is less severe in patients ≥45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome.
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http://dx.doi.org/10.1212/WNL.0b013e3182a4a49cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795591PMC
September 2013
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