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Parkinson Disease: HELP
Articles by Álex Iranzo
Based on 33 articles published since 2010
(Why 33 articles?)
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Between 2010 and 2020, A. Iranzo wrote the following 33 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Precision Medicine in Rapid Eye Movement Sleep Behavior Disorder. 2019

Högl, Birgit / Santamaria, Joan / Iranzo, Alex / Stefani, Ambra. ·Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria. · Neurology Service, Multidisciplinary Sleep Unit, Hospital Clinic de Barcelona, Institut D'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, Calle Villarroel, 170, Barcelona 08036, Spain. · Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria. Electronic address: ambra.stefani@i-med.ac.at. ·Sleep Med Clin · Pubmed #31375203.

ABSTRACT: In recent years, the diagnostic approach to rapid eye movement (REM) sleep behavior disorder (RBD) has become more objective and accurate. This was achieved mainly by introduction of methods to exactly quantify electromyographic (EMG) activity in various muscles during REM sleep. The most established muscle combination for RBD diagnosis is the mentalis and upper extremity EMG. Computer-assisted systems for this analysis have been described, and an increasing number of studies looked into analysis of video events. Recently, prodromal phases of isolated RBD have been recognized.

2 Review REM sleep behaviour disorder. 2018

Dauvilliers, Yves / Schenck, Carlos H / Postuma, Ronald B / Iranzo, Alex / Luppi, Pierre-Herve / Plazzi, Giuseppe / Montplaisir, Jacques / Boeve, Bradley. ·Centre National de Référence Narcolepsie Hypersomnies, Unité des Troubles du Sommeil, Service de Neurologie, Hôpital Gui-de-Chauliac Montpellier, Montpellier, France. ydauvilliers@yahoo.fr. · INSERM, U1061, Montpellier, France, Université Montpellier, Montpellier, France. ydauvilliers@yahoo.fr. · Minnesota Regional Sleep Disorders Center, and Departments of Psychiatry, Hennepin County Medical Center and University of Minnesota Medical School, Minneapolis, MN, USA. · Department of Neurology, Montreal General Hospital, Montreal, Quebec, Canada. · Neurology Service, Multidisciplinary Sleep Unit, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · UMR 5292 CNRS/U1028 INSERM, Center of Research in Neuroscience of Lyon (CRNL), SLEEP Team, Université Claude Bernard Lyon I, Faculté de Médecine RTH Laennec, Lyon, France. · Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy. · IRCCS, Istituto delle Scienze Neurologiche, Bologna, Italy. · Department of Psychiatry, Université de Montréal, Québec, Canada and Center for Advanced Research in Sleep Medicine (CARSM), Hôpital du Sacré-Coeur de Montréal, Quebec, Canada. · Department of Neurology and Center for Sleep Medicine, Mayo Clinic, Rochester, MN, USA. ·Nat Rev Dis Primers · Pubmed #30166532.

ABSTRACT: Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia that is characterized by loss of muscle atonia during REM sleep (known as REM sleep without atonia, or RSWA) and abnormal behaviours occurring during REM sleep, often as dream enactments that can cause injury. RBD is categorized as either idiopathic RBD or symptomatic (also known as secondary) RBD; the latter is associated with antidepressant use or with neurological diseases, especially α-synucleinopathies (such as Parkinson disease, dementia with Lewy bodies and multiple system atrophy) but also narcolepsy type 1. A clinical history of dream enactment or complex motor behaviours together with the presence of muscle activity during REM sleep confirmed by video polysomnography are mandatory for a definite RBD diagnosis. Management involves clonazepam and/or melatonin and counselling and aims to suppress unpleasant dreams and behaviours and improve bedpartner quality of life. RSWA and RBD are now recognized as manifestations of an α-synucleinopathy; most older adults with idiopathic RBD will eventually develop an overt neurodegenerative syndrome. In the future, studies will likely evaluate neuroprotective therapies in patients with idiopathic RBD to prevent or delay α-synucleinopathy-related motor and cognitive decline.

3 Review The REM sleep circuit and how its impairment leads to REM sleep behavior disorder. 2018

Iranzo, Alex. ·Neurology Service, Hospital Clínic de Barcelona, C/Villarroel 170, 08036, Barcelona, Spain. airanzo@clinic.ub.es. · Institut d'Investigació Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. airanzo@clinic.ub.es. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. airanzo@clinic.ub.es. ·Cell Tissue Res · Pubmed #29846796.

ABSTRACT: REM sleep is characterized by rapid eye movements, desynchronized electroencephalographic activity, dreams and muscle paralysis that preclude the individual from acting out the action of dreams. REM sleep is generated and modulated by a complex and still poorly understood, neuronal network that involves multiple nuclei and neurotransmission systems. The key structures that generate REM sleep muscle paralysis are the subcoeruleus nucleus in the mesopontine tegmentum and the reticular formation of the ventral medial medulla. Using glutamatergic, GABAergic and glycinergic inputs, direct and indirect projections from these two areas inhibit the motoneurons of the spinal cord resulting in skeletal paralysis in REM sleep. Experimental studies in cats and rodents where the subcoeruleus nucleus and ventral medial medulla were impaired by electrolytic, pharmacological and genetic manipulations have repeatedly produced increased electromyography activity during REM sleep associated with abnormal motor behaviors (e.g., prominent twitching, attack-like behaviors). These animal models represent the pathophysiological substrate of REM sleep behavior disorder, a parasomnia in humans characterized by nightmares and abnormal vigorous behaviors (e.g., prominent jerking, shouting, kicking) linked to excessive phasic and/or tonic electromyographic activity in REM sleep. The extraordinary observation that a sleep disorder is often the first manifestation of a devastating neurodegenerative disease such as Parkinson disease carries important diagnostic implications and opens a window for neuroprotection. This review addresses the neuronal substrates of REM sleep generation and modulation and how its impairment may lead to REM sleep behavior disorder.

4 Review Parasomnias and Sleep-Related Movement Disorders in Older Adults. 2018

Iranzo, Alex. ·Neurology Service, Multidisciplinary Sleep Unit, Hospital Clinic de Barcelona, C/ Villarroel 180, Barcelona 08036, Spain. Electronic address: AIRANZO@clinic.cat. ·Sleep Med Clin · Pubmed #29412983.

ABSTRACT: Parasomnias and sleep-related movement disorders are important problems in older adults. Sleep paralysis is rare, but may occur in families. In a minority of patients with disorders of arousal, the episodes persist until the age of 70. Zolpidem and other medications may induce sleepwalking and sleep-related eating. Most patients with idiopathic rapid eye movement (REM) sleep behavior disorder eventually develop Parkinson's disease or dementia with Lewy bodies. Anti-IgLON5 disease includes abnormal behaviors in NREM and REM sleep. Restless legs syndrome prevalence increases with age. A severe form of periodic limb movements in sleep may mimic REM sleep behavior disorder.

5 Review Sleep in Neurodegenerative Diseases. 2016

Iranzo, Alex. ·Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, C/Villarroel 170, Barcelona 08036, Spain. Electronic address: airanzo@clinic.ub.es. ·Sleep Med Clin · Pubmed #26972029.

ABSTRACT: Disorders of sleep are an integral part of neurodegenerative diseases and include insomnia, sleep-wake cycle disruption, excessive daytime sleepiness that may be manifested as persistent somnolence or sudden onset of sleep episodes, obstructive and central sleep apnea, rapid eye movement sleep behavior disorder, and restless legs syndrome. The origin of these sleep disorders is multifactorial including degeneration of the brain areas that modulate sleep, the symptoms of the disease, and the effect of medications. Treatment of sleep disorders in patients with neurodegenerative diseases should be individualized and includes behavioral therapy, sleep hygiene, bright light therapy, melatonin, hypnotics, waking-promoting agents, and continuous positive airway pressure.

6 Review Parkinson disease and sleep: sleep-wake changes in the premotor stage of Parkinson disease; impaired olfaction and other prodromal features. 2013

Iranzo, Alex. ·Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, C/Villarroel 170, 08036, Barcelona, Spain. airanzo@clinic.ub.es ·Curr Neurol Neurosci Rep · Pubmed #23881622.

ABSTRACT: Parkinson disease (PD) has a premotor stage where neurodegeneration occurs before parkinsonism becomes apparent. Identification of individuals at this stage provides an opportunity to study early disease progression and test disease-modifying interventions. Hyposmia, constipation, depression and hypersomnia are part of this premotor phase and predictive of future development of PD. However, these features are common in the general population, and they are most often the result of causes other than incipient PD. In contrast, most individuals with idiopathic REM sleep behavior disorder (IRBD) eventually develop PD and other synucleinopathies. IRBD individuals with hyposmia, substantia nigra hyperechogenicity, and abnormal striatal dopamine transporter imaging findings have increased short-term risk of developing a synucleinopathy. IRBD is an optimal target to test disease-modifying agents in the PD prodromal phase. Serial dopamine transporter imaging, but not olfactory tests, may serve to monitor the disease process in future disease-modifying trials in IRBD.

7 Review Sleep-wake changes in the premotor stage of Parkinson disease. 2011

Iranzo, Alex. ·Neurology Service, Hospital Clinic, Barcelona, Spain. airanzo@clinic.ub.es ·J Neurol Sci · Pubmed #21880334.

ABSTRACT: Longitudinal studies in Parkinson disease (PD) have shown that the prevalence of sleep disorders increases with advanced disease. However, two sleep disorders, namely excessive daytime sleepiness (EDS) and REM sleep behavior disorder (RBD) have been described to antedate the development of the classical motor signs and symptoms of PD. One epidemiological study from the Honolulu-Asia Aging Study showed that aging men who reported "being sleepy most of the daily" had a threefold excess risk for developing PD after a seven-year follow-up. The origin and nature of EDS were not investigated. This study needs to be replicated. More robust data exist regarding RBD as the first manifestation of PD. RBD subjects commonly develop parkinsonism and cognitive impairment with time. Patients with the idiopathic form of RBD with decreased striatal dopamine transporters imaging, substantia nigra hyperechogenicity and hyposmia have an increased short-term risk for developing the classical motor, dysautonomic and cognitive symptoms of a synucleinopathy. Patients with idiopathic RBD, particularly those with abnormal subclinical features seen in the synucleinopathies such as decreased striatal dopamine transporters uptake, are the ideal population to be tested with disease-modifying agents in order to stop or slow down neurodegeneration in the brain.

8 Review Scales to assess sleep impairment in Parkinson's disease: critique and recommendations. 2010

Högl, Birgit / Arnulf, Isabelle / Comella, Cynthia / Ferreira, Joaquim / Iranzo, Alex / Tilley, Barbara / Trenkwalder, Claudia / Poewe, Werner / Rascol, Olivier / Sampaio, Cristina / Stebbins, Glenn T / Schrag, Anette / Goetz, Christopher G. ·Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. birgit.ho@i-med.ac.at ·Mov Disord · Pubmed #20931631.

ABSTRACT: There is a broad spectrum of sleep disturbances observed in Parkinson's disease (PD). A variety of scales have been applied to the evaluation of PD sleep and wakefulness, but only a small number have been assessed specifically for clinimetric properties in the PD population. The movement disorder society has commissioned this task force to examine these scales and to assess their use in PD. A systematic literature review was conducted to explore the use of sleep scales in PD and to determine which scales qualified for a detailed critique. The task force members, all of whom have extensive experience in assessing sleep in PD reviewed each of the scales using a structured proforma. Scales were categorized into recommended, suggested and listed according to predefined criteria. A total of 48 potential scales were identified from the search and reviewed. Twenty-nine were excluded because they did not meet review criteria or were variations of scales already included, leaving 19 scales that were critiqued and rated by the task force based on the rating criteria. Only six were found to meet criteria for recommendation or suggestion by the task force: the PD sleep scale (PDSS) and the Pittsburgh sleep quality index (PSQI) are recommended for rating overall sleep problems to screen and to measure severity, the SCOPA-sleep (SCOPA) is recommended for rating overall sleep problems both to screen and to measure severity, and for rating daytime sleepiness; the Epworth sleepiness scale (ESS) is recommended for rating daytime sleepiness to screen and to measure severity; the inappropriate sleep composite score (ISCS) is suggested for rating severe daytime sleepiness or sleep attacks to screen and to measure severity; and the Stanford sleepiness scale (SSS) is suggested for rating sleepiness and to measure severity at a specific moment. The task force does not recommend the development of new scales, but emphasizes the need for educational efforts to train physicians in sleep interview techniques and polysomnography.

9 Clinical Trial Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. 2019

Postuma, Ronald B / Iranzo, Alex / Hu, Michele / Högl, Birgit / Boeve, Bradley F / Manni, Raffaele / Oertel, Wolfgang H / Arnulf, Isabelle / Ferini-Strambi, Luigi / Puligheddu, Monica / Antelmi, Elena / Cochen De Cock, Valerie / Arnaldi, Dario / Mollenhauer, Brit / Videnovic, Aleksandar / Sonka, Karel / Jung, Ki-Young / Kunz, Dieter / Dauvilliers, Yves / Provini, Federica / Lewis, Simon J / Buskova, Jitka / Pavlova, Milena / Heidbreder, Anna / Montplaisir, Jacques Y / Santamaria, Joan / Barber, Thomas R / Stefani, Ambra / St Louis, Erik K / Terzaghi, Michele / Janzen, Annette / Leu-Semenescu, Smandra / Plazzi, Guiseppe / Nobili, Flavio / Sixel-Doering, Friederike / Dusek, Petr / Bes, Frederik / Cortelli, Pietro / Ehgoetz Martens, Kaylena / Gagnon, Jean-Francois / Gaig, Carles / Zucconi, Marco / Trenkwalder, Claudia / Gan-Or, Ziv / Lo, Christine / Rolinski, Michal / Mahlknecht, Philip / Holzknecht, Evi / Boeve, Angel R / Teigen, Luke N / Toscano, Gianpaolo / Mayer, Geert / Morbelli, Silvia / Dawson, Benjamin / Pelletier, Amelie. ·Department of Neurology, McGill University, Montreal General Hospital, Montreal, Canada. · Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, Canada. · Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Oxford Parkinson's Disease Centre (OPDC) and Oxford University, Oxford, UK. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Mayo Clinic, Rochester, MN, USA. · Unit of Sleep Medicine and Epilepsy, IRCCS, C.Mondino Foundation, Pavia, Italy. · Department of Neurology, Philipps-Universität, Marburg, Germany. · Sleep disorders unit, Pitie-Salpetriere Hospital, IHU@ICM and Sorbonne University, Paris, France. · Sleep Disorders Center, Department of Neurology, Scientific Institute Ospedale San Raffaele, Vita-Salute University, Milan, Italy. · Sleep Center, Department of Cardiovascular and Neurological Sciences, University of Cagliari, Italy. · Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. · IRCCS Institute of the Neurological Sciences, Ospedale Bellaria, ASL di Bologna, Bologna, Italy. · Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France; EuroMov, University of Montpellier, Montpellier, France. · Clinical Neurology, Dept. of Neuroscience (DINOGMI), University of Genoa, and Polyclinic San Martino Hospital, Genoa, Italy. · Department of Neurosurgery (C.T.) University Medical Center, Göttingen; Paracelsus-Elena-Klinik (B.M., C.T. F. S-D.), Kassel, Germany. · Movement Disorders Unit and Division of Sleep Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Department of Neurology and Centre of Clinical Neurosciences of the First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. · Neuroscience Research Institute, Seoul National University College of Medicine, Department of Neurology, Seoul National University Hospital, Seoul, Korea. · Institute of Physiology Charité-Universitätsmedizin Berlin. Germany. · Sleep Unit, Department of Neurology, Hôpital Gui de Chauliac, Montpellier, INSERM U1061, Montpellier, F-34093 Cedex 5 France. · Department of Biomedical and Neuromotor Sciences, Bellaria Hospital, University of Bologna, Bologna, Italy. · IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy. · Brain and Mind Centre University of Sydney, Camperdown, Australia. · National Institute of Mental Health, Klecany, Third Faculty of Medicine, Charles Unviersity, Prague, Czech Republic. · Department of Neurology, Brigham and Women's Hospital, Boston; Harvard Medical School, Boston, USA. · Institute for Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Muenster, Germany. · Department of Psychology, Université du Québec à Montréal, Montreal, Quebec, Canada. · Department of Human Genetics, McGill University, Montreal, Canada. · Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada. · Department of Neurology, Hephata Klinik, Schwalmstadt-Treysa, Germany. · Nuclear Medicine, Department of Health Sciences (DISSAL), University of Genoa and Polyclinic San Martino Hospital, Genoa, Italy. ·Brain · Pubmed #30789229.

ABSTRACT: Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

10 Article Lack of Asymmetry of Nigrostriatal Dopaminergic Function in Healthy Subjects. 2020

Garrido, Alicia / Iranzo, Alex / Stefani, Ambra / Serradell, Mònica / Muñoz-Lopetegi, Amaia / Marrero, Paula / Högl, Birgit / Gaig, Carles / Santamaria, Joan / Tolosa, Eduard / Poewe, Werner / Anonymous5011110. ·Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Center for Sleep Disorders, Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. ·Mov Disord · Pubmed #32141653.

ABSTRACT: OBJECTIVE: In right-handed patients with Parkinson's disease (PD) or isolated rapid eye movement sleep behavior disorder, dopamine transporter (DAT) [(123)I]β-carboxymethyoxy-3-β-(4-iodophenyl) tropane single photon emission computed tomography (SPECT) shows predominant nigrostriatal deficit in the left striatum. This suggests that in PD patients, the nigrostriatal system of the dominant hemisphere is more susceptible to disease-related dysfunction. To confirm this hypothesis, we investigated whether the nigrostriatal function is symmetric in healthy controls and in patients with PD. METHODS: In 113 right-handed healthy controls and 279 right-handed early-PD patients, we examined the striatal dopaminergic terminals function in each hemisphere using DAT-SPECT. RESULTS: In the controls, DAT-SPECT showed symmetric specific binding ratios in the putamen and caudate nucleus of each hemisphere. In patients with PD, the specific binding ratio was lower in the left than in the right putamen. CONCLUSIONS: Right-handed healthy controls have symmetric nigrostriatal dopaminergic function. The left hemispheric predominance of nigrostriatal deficit seen in right-handed premotor and manifest PD represents an early pathological feature of the disease. © 2020 International Parkinson and Movement Disorder Society.

11 Article Disruption of posterior brain functional connectivity and its relation to cognitive impairment in idiopathic REM sleep behavior disorder. 2020

Campabadal, A / Abos, A / Segura, B / Serradell, M / Uribe, C / Baggio, H C / Gaig, C / Santamaria, J / Compta, Y / Bargallo, N / Junque, C / Iranzo, A. ·Medical Psychology Unit, Department of Medicine. Institute of Neuroscience, University of Barcelona. Barcelona, Catalonia, Spain. · Medical Psychology Unit, Department of Medicine. Institute of Neuroscience, University of Barcelona. Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED:CB06/05/0018-ISCIII) Barcelona, Spain; Institute of Biomedical Research August Pi i Sunyer (IDIBAPS). Barcelona, Catalonia, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED:CB06/05/0018-ISCIII) Barcelona, Spain; Institute of Biomedical Research August Pi i Sunyer (IDIBAPS). Barcelona, Catalonia, Spain.; Multidisciplinary Sleep Unit, Neurology Service, Hospital Clínic, Barcelona, Catalonia, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED:CB06/05/0018-ISCIII) Barcelona, Spain; Institute of Biomedical Research August Pi i Sunyer (IDIBAPS). Barcelona, Catalonia, Spain.; Parkinson's disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona. Institute of Neuroscience, University of Barcelona, Barcelona, Catalonia, Spain. · Centre de Diagnòstic per la Imatge, Hospital Clínic, Barcelona, Catalonia, Spain. · Medical Psychology Unit, Department of Medicine. Institute of Neuroscience, University of Barcelona. Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED:CB06/05/0018-ISCIII) Barcelona, Spain; Institute of Biomedical Research August Pi i Sunyer (IDIBAPS). Barcelona, Catalonia, Spain.. Electronic address: cjunque@ub.edu. ·Neuroimage Clin · Pubmed #31911344.

ABSTRACT: BACKGROUND: Resting-state functional MRI has been proposed as a new biomarker of prodromal neurodegenerative disorders, but it has been poorly investigated in the idiopathic form of rapid-eye-movement sleep behavior disorder (IRBD), a clinical harbinger of subsequent synucleinopathy. Particularly, a complex-network approach has not been tested to study brain functional connectivity in IRBD patients. OBJECTIVES: The aim of the current work is to characterize resting-state functional connectivity in IRBD patients using a complex-network approach and to determine its possible relation to cognitive impairment. METHOD: Twenty patients with IRBD and 27 matched healthy controls (HC) underwent resting-state functional MRI with a 3T scanner and a comprehensive neuropsychological battery. The functional connectome was studied using threshold-free network-based statistics. Global and local network parameters were calculated based on graph theory and compared between groups. Head motion, age and sex were introduced as covariates in all analyses. RESULTS: IRBD patients showed reduced cortico-cortical functional connectivity strength in comparison with HC in edges located in posterior regions (p <0.05, FWE corrected). This regional pattern was also shown in an independent analysis comprising posterior areas where a decreased connectivity in 51 edges was found, whereas no significant results were detected when an anterior network was considered (p <0.05, FWE corrected). In the posterior network, the left superior parietal lobule had reduced centrality in IRBD. Functional connectivity strength between left inferior temporal lobe and right superior parietal lobule positively correlated with mental processing speed in IRBD (r = .633; p = .003). No significant correlations were found in the HC group. CONCLUSION: Our findings support the presence of disrupted posterior functional brain connectivity of IRBD patients similar to that found in synucleinopathies. Moreover, connectivity reductions in IRBD were associated with lower performance in mental processing speed domain.

12 Article Cholinergic denervation in patients with idiopathic rapid eye movement sleep behaviour disorder. 2019

Gersel Stokholm, M / Iranzo, A / Østergaard, K / Serradell, M / Otto, M / Bacher Svendsen, K / Garrido, A / Vilas, D / Fedorova, T D / Santamaria, J / Møller, A / Gaig, C / Hiraoka, K / Brooks, D J / Okamura, N / Borghammer, P / Tolosa, E / Pavese, N. ·Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark. · Department of Neurology, Hospital Clínic de Barcelona, Barcelona. · Centro de Investigación Biomédica en Red sobre Enfermedades eurodegenerativas (CIBERNED) Hospital Clínic, IDIBAPS, Universitat de Barcelona, Catalonia. · Multidisciplinary Sleep Unit, Hospital Clinic, Barcelona, Spain. · Department of Neurology, Aarhus University Hospital, Aarhus. · Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark. · Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Catalonia, Spain. · Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan. · Division of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. · Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan. ·Eur J Neurol · Pubmed #31725927.

ABSTRACT: BACKGROUND AND PURPOSE: Cholinergic dysfunction appears to play a role in the cognitive impairment observed in Parkinson's disease and dementia with Lewy bodies. The occurrence of cholinergic dysfunction in the early stages of these conditions, however, has not been investigated. The objective of this study was to investigate cholinergic function in patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD), a disorder recognized to be an early stage of both Parkinson's disease and dementia with Lewy bodies. METHODS: A total of 21 patients with polysomnography-confirmed iRBD with no evidence of parkinsonism and cognitive impairment and 10 controls underwent positron emission tomography (PET) to assess brain acetylcholinesterase levels ( RESULTS: The CONCLUSION: Reduced neocortical

13 Article Longitudinal analyses of cerebrospinal fluid α-Synuclein in prodromal and early Parkinson's disease. 2019

Mollenhauer, Brit / Caspell-Garcia, Chelsea J / Coffey, Christopher S / Taylor, Peggy / Singleton, Andy / Shaw, Leslie M / Trojanowski, John Q / Frasier, Mark / Simuni, Tanya / Iranzo, Alex / Oertel, Wolfgang / Siderowf, Andrew / Weintraub, Daniel / Seibyl, John / Toga, Arthur W / Tanner, Caroline M / Kieburtz, Karl / Chahine, Lana M / Marek, Kenneth / Galasko, Douglas / Anonymous2031132. ·Department of Neurology, University Medical Center Goettingen, Göttingen, Germany; and Paracelsus-Elena Klinik, Kassel, Germany. · Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa, USA. · BioLegend Inc., San Diego, California, USA. · Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Morris K. Udall Center of Excellence for Parkinson's Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA. · Parkinson's Disease and Movement Disorders Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. · Neurological Service, Hospital Clinic de Barcelona, Barcelona, Spain. · Department of Neurology, Philipps University Marburg, Marburg, Germany. · Department of Neurology Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA. · University of Southern California, Laboratory of Neuro Imaging, Los Angeles, California, USA. · Department of Neurology, University of California San Francisco, San Francisco, California, USA. · Clinical Trials Coordination Center, University of Rochester Medical Center, Rochester, New York, USA. · Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Neurosciences, University of California, San Diego, San Diego, California, USA. ·Mov Disord · Pubmed #31361367.

ABSTRACT: BACKGROUND: Aggregation of α-synuclein is central to the pathophysiology of PD. Biomarkers related to α-synuclein may be informative for PD diagnosis/progression. OBJECTIVES: To analyze α-synuclein in CSF in drug-naïve PD, healthy controls, and prodromal PD in the Parkinson's Progression Markers Initiative. METHODS: Over up to 36-month follow-up, CSF total α-synuclein and its association with MDS-UPDRS motor scores, cognitive assessments, and dopamine transporter imaging were assessed. RESULTS: The inception cohort included PD (n = 376; age [mean {standard deviation} years]: 61.7 [9.62]), healthy controls (n = 173; age, 60.9 [11.3]), hyposmics (n = 16; age, 68.3 [6.15]), and idiopathic rapid eye movement sleep behavior disorder (n = 32; age, 69.3 [4.83]). Baseline CSF α-synuclein was lower in manifest and prodromal PD versus healthy controls. Longitudinal α-synuclein decreased significantly in PD at 24 and 36 months, did not change in prodromal PD over 12 months, and trended toward an increase in healthy controls. The decrease in PD was not shown when CSF samples with high hemoglobin concentration were removed from the analysis. CSF α-synuclein changes did not correlate with longitudinal MDS-UPDRS motor scores or dopamine transporter scan. CONCLUSIONS: CSF α-synuclein decreases early in the disease, preceding motor PD. CSF α-synuclein does not correlate with progression and therefore does not reflect ongoing dopaminergic neurodegeneration. Decreased CSF α-synuclein may be an indirect index of changes in the balance between α-synuclein secretion, solubility, or aggregation in the brain, reflecting its overall turnover. Additional biomarkers more directly related to α-synuclein pathophysiology and disease progression and other markers to be identified by, for example, proteomics and metabolomics are needed. © 2019 International Parkinson and Movement Disorder Society.

14 Article Alpha-synuclein aggregates in the parotid gland of idiopathic REM sleep behavior disorder. 2018

Fernández-Arcos, Ana / Vilaseca, Isabel / Aldecoa, Iban / Serradell, Mónica / Tolosa, Eduard / Santamaría, Joan / Gelpi, Ellen / Iranzo, Alex. ·Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Otorhinolaryngology Service, Hospital Clínic de Barcelona, AGAUR Head Neck Clinic, CIBER Enfermedades Respiratorias, Bunyola, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain. · Neurological Tissue Bank, Biobanc-Hospital Clinic, IDIBAPS, Barcelona, Spain; Pathology Service, Biomedical Diagnostic Center-CDB, Hospital Clinic, Barcelona, Spain. · Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain. · Neurological Tissue Bank, Biobanc-Hospital Clinic, IDIBAPS, Barcelona, Spain; Institute of Neurology, Medical University of Vienna, Vienna, Austria. Electronic address: ellen.gelpimantius@medunwien.ac.at. · Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain. Electronic address: airanzo@clinic.ub.es. ·Sleep Med · Pubmed #30195197.

ABSTRACT: BACKGROUND: The neuropathological hallmark of Parkinson's disease (PD) is the presence of aggregates of phosphorylated alpha-synuclein (pAS) in the nervous system. METHOD: We report a patient with video-polysomnography-confirmed idiopathic REM sleep behavior disorder that underwent parotidectomy because of parotid gland cancer. Immunohistochemistry of the gland tissue revealed abundant pAS deposits. One year after surgery the patient was diagnosed with PD. Prompted by this observation we examined the parotid gland in 10 consecutive individuals that underwent elective parotidectomy irrespective of their clinical condition. RESULTS: One had PD and another had mild parkinsonian signs plus reduced dopamine transporter uptake in the striatum. Both had pAS deposits in the parotid gland. The remaining eight subjects had no neurological signs and pAS was found in one of them. CONCLUSION: Our study shows that the parotid gland may contain pAS pathology in the prodromal stage of PD and in manifested PD.

15 Article Dissecting premotor Parkinson's disease with multimodality neuroimaging. 2018

Iranzo, Alex. ·Neurological Service, Hospital Clinic de Barcelona, Barcelona 08036, Spain. Electronic address: airanzo@clinic.ub.es. ·Lancet Neurol · Pubmed #29866442.

ABSTRACT: -- No abstract --

16 Article α-Synuclein aggregates in labial salivary glands of idiopathic rapid eye movement sleep behavior disorder. 2018

Iranzo, Alex / Borrego, Sergi / Vilaseca, Isabel / Martí, Carles / Serradell, Mónica / Sánchez-Valle, Raquel / Kovacs, Gabor G / Valldeoriola, Francesc / Gaig, Carles / Santamaria, Joan / Tolosa, Eduard / Gelpi, Ellen. ·Neurology Service, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain. · Otorhinolaryngology Service, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red sobre Enfermedades Respiratorias, Bunyola, Spain. · Maxillofacial Surgery Service Hospital Clínic de Barcelona, Barcelona, Spain. · Institute of Neurology, Medical University of Vienna, Vienna, Austria. · Neurological Tissue Bank, Biobanc-Hospital Clinic, IDIBAPS, Barcelona, Spain. ·Sleep · Pubmed #29790977.

ABSTRACT: Study Objectives: To assess whether biopsy of the labial minor salivary glands safely detects phosphorylated α-synuclein (pAS) deposits in idiopathic rapid eye movement sleep behavior disorder (IRBD), a condition that precedes the cardinal manifestations of synuclein disorders associated with Lewy-type pathology, namely, Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Methods: In a prospective study, labial biopsy of the minor salivary glands was performed in 62 patients with IRBD, 13 patients with PD, and 10 patients with DLB who were initially diagnosed with IRBD, and in 33 controls. Aggregates of pAS were assessed by immunohistochemistry using antiserine 129-pAS antibody and the conformation-specific 5G4 antibody. Results: Sufficient biopsy material containing glandular parenchyma was obtained in all participants. Deposits of pAS were found in 31 of 62 (50%) participants with IRBD, 7 of 13 (54%) with PD, 5 of 10 (50%) with DLB, and in one of the 33 (3%) controls. Participants with IRBD, PD, and DLB with and without pAS immunoreactivity did not differ in demographic and clinical features. Adverse events were lip bruising (9.2%), swelling (6.6%), pain (2.4%), and numbness (1.7%) which were mild and transitory and did not require treatment. Conclusions: Labial minor salivary glands biopsy proved to be a safe and useful procedure to identify pAS in participants with IRBD, and in participants with PD and DLB initially diagnosed with IRBD. The biopsy provides direct histopathological evidence that IRBD represents a synucleinopathy and that could be useful for histological confirmation of synuclein pathology in PD and DLB.

17 Article Glucocerebrosidase gene variants are accumulated in idiopathic REM sleep behavior disorder. 2018

Gámez-Valero, Ana / Iranzo, Alex / Serradell, Monica / Vilas, Dolores / Santamaria, Joan / Gaig, Carles / Álvarez, Ramiro / Ariza, Aurelio / Tolosa, Eduardo / Beyer, Katrin. ·Department of Pathology, Hospital Universitari and Health Sciences Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain. · Department of Neurology and Multidisciplinary Sleep Unit, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Department of Neurology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain. · Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, CIBERNED, IDIBAPS, Universitat de Barcelona, Spain. · Department of Pathology, Hospital Universitari and Health Sciences Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: kbeyer@igtp.cat. ·Parkinsonism Relat Disord · Pubmed #29487000.

ABSTRACT: INTRODUCTION: Glucocerebrosidase (GBA) gene variants are associated with the development of the Lewy body disorders (LBD) Parkinson disease (PD) and dementia with Lewy bodies (DLB). Idiopathic REM sleep behavior disorder (IRBD) represents prodromal LBD in most instances. We investigated whether GBA variants are overrepresented in IRBD and if their presence shortens the time to conversion to clinically-defined LBD. METHODS: All GBA coding exons from 69 polysomnography-confirmed IRBD patients and 84 matched controls were sequenced by the Sanger method. RESULTS: Seven missense variants (E326K, L444P, A446T, A318G, R329C, T369M, N370S) were identified in eight (11.6%) IRBD patients and in one (1.2%) control (P = 0.026). After a mean follow-up of 8.9 ± 3.8 years from IRBD diagnosis, five subjects with GBA variants developed LBD (3 DLB and 2 PD) and three remained disease-free. The risk of developing a LBD was similar in IRBD subjects with GBA variants than in those without variants (log rank test, p = 0.935). CONCLUSIONS: In IRBD, GBA variants are 1) more frequent when compared to controls, 2) associated with impending PD and DLB but 3) not indicative of a short-term risk for LBD after IRBD diagnosis. IRBD patients carrying GBA variants could be studied with disease-modifying interventions aiming to restore the GBA metabolic pathway.

18 Article Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder. 2017

Iranzo, Alex / Santamaría, Joan / Valldeoriola, Francesc / Serradell, Monica / Salamero, Manel / Gaig, Carles / Niñerola-Baizán, Aida / Sánchez-Valle, Raquel / Lladó, Albert / De Marzi, Roberto / Stefani, Ambra / Seppi, Klaus / Pavia, Javier / Högl, Birgit / Poewe, Werner / Tolosa, Eduard / Lomeña, Francisco. ·Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Psychiatry Service, Hospital Clinic de Barcelona, Barcelona, Spain. · Biomedical Research Networking Center of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain. · Department of Neurology, Medical University Innsbruck, Austria. · Nuclear Medicine Service, Hospital Clinic Barcelona, IDIBAPS, Barcelona, Spain. ·Ann Neurol · Pubmed #28833467.

ABSTRACT: OBJECTIVE: To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic rapid eye movement sleep behavior disorder (IRBD) patients at risk for short-term development of clinically defined synucleinopathy. METHODS: Eighty-seven patients with polysomnography-confirmed IRBD underwent RESULTS: Baseline DAT deficit was found in 51 (58.6%) patients. During follow-up, 25 (28.7%) subjects developed clinically defined synucleinopathy (Parkinson's disease in 11, dementia with Lewy bodies in 13, and multiple system atrophy in 1) with mean latency of 3.2 ± 1.9 years from imaging. Kaplan-Meier survival analysis showed increased risk of incident synucleinopathy in patients with abnormal DAT-SPECT than with normal DAT-SPECT (20% vs 6% at 3 years, 33% vs 18% at 5 years; log rank test, p = 0.006). Receiver operating characteristics curve revealed that reduction of FP-CIT uptake in putamen greater than 25% discriminated patients with DAT deficit who developed synucleinopathy from patients with DAT deficit that remained disease free after 3 years of follow-up. At 5-year follow-up, DAT-SPECT had 75% sensitivity, 51% specificity, 44% positive predictive value, 80% negative predictive value, and likelihood ratio 1.54 to predict synucleinopathy. INTERPRETATION: DAT-SPECT identifies IRBD patients at short-term risk for synucleinopathy. Decreased FP-CIT putamen uptake greater than 25% predicts synucleinopathy after 3 years' follow-up. These observations may be useful to select candidates for disease modification trials in IRBD. Ann Neurol 2017;82:419-428.

19 Article Characterization of patients with longstanding idiopathic REM sleep behavior disorder. 2017

Iranzo, Alex / Stefani, Ambra / Serradell, Monica / Martí, Maria Jose / Lomeña, Francisco / Mahlknecht, Philipp / Stockner, Heike / Gaig, Carles / Fernández-Arcos, Ana / Poewe, Werner / Tolosa, Eduard / Högl, Birgit / Santamaria, Joan / Anonymous7380909. ·From the Neurology Service (A.I., M.S., M.J.M., C.G., A.F.-A., E.T., J.S.) and Nuclear Medicine Service (F.L.), Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Spain · and Department of Neurology (A.S., P.M., H.S., W.P., B.H.), Medical University Innsbruck, Austria. ·Neurology · Pubmed #28615430.

ABSTRACT: OBJECTIVE: To evaluate the presence of prodromal markers of Parkinson disease (PD) in patients with longstanding idiopathic REM sleep behavior disorder (IRBD), a small subgroup of individuals with IRBD with long-term follow-up thought not to be at risk of developing PD. METHODS: Demographic, clinical, and neuroimaging markers of PD were evaluated in 20 patients with polysomnographic-confirmed longstanding IRBD and in 32 matched controls. RESULTS: Patients were 16 men and 4 women with mean age of 72.9 ± 8.6 years and mean follow-up from IRBD diagnosis of 12.1 ± 2.6 years. Patients more often had objective smell loss (35% vs 3.4%, CONCLUSIONS: Prodromal PD markers are common in individuals with longstanding IRBD, suggesting that they are affected by an underlying neurodegenerative process. This observation may be useful for the design of disease-modifying trials to prevent PD onset in IRBD.

20 Article Longitudinal assessment of excessive daytime sleepiness in early Parkinson's disease. 2017

Amara, Amy W / Chahine, Lama M / Caspell-Garcia, Chelsea / Long, Jeffrey D / Coffey, Christopher / Högl, Birgit / Videnovic, Aleksandar / Iranzo, Alex / Mayer, Geert / Foldvary-Schaefer, Nancy / Postuma, Ron / Oertel, Wolfgang / Lasch, Shirley / Marek, Ken / Simuni, Tanya / Anonymous7160907. ·Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA. · Department of Neurology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. · Department of Biostatistics, The University of Iowa, Iowa City, Iowa, USA. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA. · Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Department of Neurology, Hephata-Klinik, Hephata Hessisches Diakoniezentrum, e.V., Schwalmstadt-Treysa, Germany. · Cleveland Clinic Neurological Institute, Cleveland, Ohio, USA. · Division of Neurology, McGill University, Montreal, Québec, Canada. · Department of Neurology, Philipps University, Marburg, Germany. · Charitable Hertie Foundation, Frankfurt, Germany. · Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA. · Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. ·J Neurol Neurosurg Psychiatry · Pubmed #28554959.

ABSTRACT: BACKGROUND: Excessive daytime sleepiness (EDS) is common and disabling in Parkinson's disease (PD). Predictors of EDS are unclear, and data on biological correlates of EDS in PD are limited. We investigated clinical, imaging and biological variables associated with longitudinal changes in sleepiness in early PD. METHODS: The Parkinson's Progression Markers Initiative is a prospective cohort study evaluating progression markers in participants with PD who are unmedicated at baseline (n=423) and healthy controls (HC; n=196). EDS was measured with the Epworth Sleepiness Scale (ESS). Clinical, biological and imaging variables were assessed for associations with EDS for up to 3 years. A machine learning approach (random survival forests) was used to investigate baseline predictors of incident EDS. RESULTS: ESS increased in PD from baseline to year 3 (mean±SD 5.8±3.5 to 7.55±4.6, p<0.0001), with no change in HC. Longitudinally, EDS in PD was associated with non-tremor dominant phenotype, autonomic dysfunction, depression, anxiety and probable behaviour disorder, but not cognitive dysfunction or motor severity. Dopaminergic therapy was associated with EDS at years 2 and 3, as dose increased. EDS was also associated with presynaptic dopaminergic dysfunction, whereas biofluid markers at year 1 showed no significant associations with EDS. A predictive index for EDS was generated, which included seven baseline characteristics, including non-motor symptoms and cerebrospinal fluid phosphorylated-tau/total-tau ratio. CONCLUSIONS: In early PD, EDS increases significantly over time and is associated with several clinical variables. The influence of dopaminergic therapy on EDS is dose dependent. Further longitudinal analyses will better characterise associations with imaging and biomarkers.

21 Article Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. 2016

Vilas, Dolores / Iranzo, Alex / Tolosa, Eduardo / Aldecoa, Iban / Berenguer, Joan / Vilaseca, Isabel / Martí, Carles / Serradell, Mónica / Lomeña, Francisco / Alós, Llucia / Gaig, Carles / Santamaria, Joan / Gelpi, Ellen. ·Neurology Service, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Neurology Service, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. Electronic address: etolosa@clinic.ub.es. · Pathology Service, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain. · Radiology Service, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain. · Otorhinolaryngology Service, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain; CIBER Enfermedades Respiratorias, Bunyola, Spain. · Maxillofacial Surgery Service, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain. · Neurology Service, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain. · Nuclear Medicine Service, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain. · Neurological Tissue Bank, Biobanc-Hospital Clinic, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Barcelona, Spain. ·Lancet Neurol · Pubmed #27039162.

ABSTRACT: BACKGROUND: The histological feature of Parkinson's disease is the presence of intraneuronal aggregates of phosphorylated α-synuclein (αSyn). In patients with Parkinson's disease, deposits of αSyn are found in the autonomic nerve fibres of the submandibular gland. Since patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) can develop Parkinson's disease and other synucleinopathies, we investigated whether αSyn deposits could also be detected in their submandibular gland nerve fibres. METHODS: We did a case-control study at the Hospital Clinic de Barcelona (Barcelona, Spain) in patients with polysomnographic-confirmed IRBD, patients with clinically diagnosed Parkinson's disease, and controls matched by age with the IRBD group. The controls were either healthy, had had elective neck surgery in the clinic, or were patients who had died in the clinic and had an autopsy. We did a transcutaneous core needle biopsy of the submandibular gland with ultrasound guidance in patients with IRBD or Parkinson's disease, and healthy controls, and without ultrasound guidance in the other controls. We assessed the presence of αSyn with immunohistochemistry using 129-phosphorylated antiserine monoclonal antibody, and analysed quantitative variables with Kruskall-Wallis tests and qualitative variables with Fisher's exact tests. FINDINGS: We did our study between July 16, 2014, and May 16, 2015, and recruited 21 patients with IRBD, 24 patients with Parkinson's disease, and 26 controls (seven healthy, 11 patients undergoing neck surgery, and eight autopsies). We obtained submandibular biopsy material containing glandular parenchyma in nine (43%) of 21 patients with IRBD, 12 (50%) of 24 patients with Parkinson's disease, and all (100%) of the 26 controls. αSyn aggregates were detected in nerve fibres of the glandular parenchyma in eight (89%) of nine patients with IRBD and eight (67%) of 12 with Parkinson's disease, but none of the controls. Of the individuals whose biopsy samples did not contain glandular parenchyma, deposits of αSyn were found in extraglandular tissues in an additional three (25%) of 12 patients with IRBD and five (42%) of 12 patients with Parkinson's disease. None of the controls showed αSyn immunoreactivity in extraglandular tissues. Of the 52 participants who had ultrasonography-guided biopsy, 11 (21%) reported mild-to-moderate local pain, and nine (17%) developed a subcutaneous haematoma; however, these adverse events were transient and did not need treatment. INTERPRETATION: Our findings suggest that, in patients with IRBD, submandibular gland biopsy is a safe procedure for the detection of αSyn aggregates. αSyn detection could be useful for histological confirmation in individuals clinically diagnosed with Parkinson's disease. FUNDING: Centre for Networked Biomedical Research in Neurodegenerative Disorders (CIBERNED), Barcelona, Spain.

22 Article Loss of dorsolateral nigral hyperintensity on 3.0 tesla susceptibility-weighted imaging in idiopathic rapid eye movement sleep behavior disorder. 2016

De Marzi, Roberto / Seppi, Klaus / Högl, Birgit / Müller, Christoph / Scherfler, Christoph / Stefani, Ambra / Iranzo, Alex / Tolosa, Eduardo / Santamarìa, Joan / Gizewski, Elke / Schocke, Michael / Skalla, Elisabeth / Kremser, Christian / Poewe, Werner. ·Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. · Neuroimaging Research Core Facility, Medical University Innsbruck, Innsbruck, Austria. · Neurology Service, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Department of Radiology, Medical University Innsbruck, Innsbruck, Austria. ·Ann Neurol · Pubmed #27016314.

ABSTRACT: We assessed loss of dorsolateral nigral hyperintensity (DNH) on high-field susceptibility-weighted imaging (SWI), a novel magnetic resonance imaging marker for Parkinson's disease (PD), in 15 subjects with idiopathic rapid eye movement sleep behavior disorder (iRBD) and compared findings to 42 healthy controls (HCs) and 104 PD patients. We found loss of DNH in at least two thirds of iRBD subjects, which approaches the rate observed in PD and is in contrast to findings in HCs. We propose that absence of DNH on high-field SWI could identify prodromal degenerative parkinsonism in iRBD. Ann Neurol 2016;79:1026-1030.

23 Article Longitudinal changes in cognition in early Parkinson's disease patients with REM sleep behavior disorder. 2016

Chahine, L M / Xie, S X / Simuni, T / Tran, B / Postuma, R / Amara, A / Oertel, W H / Iranzo, A / Scordia, C / Fullard, M / Linder, C / Purri, R / Darin, A / Rennert, L / Videnovic, A / Del Riva, P / Weintraub, D. ·The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: lamachahine@hotmail.com. · The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Northwestern University Feinberg School of Medicine, Chicago, IL, USA. · McGill University, Montréal, Québec, Canada. · University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA. · Department of Neurology, Philipps University Marburg, Germany; Charitable Hertie Foundation, Frankfurt/Main, Germany. · Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Neurology, University Hospital Donostia, San Sebastián, Spain. ·Parkinsonism Relat Disord · Pubmed #27010070.

ABSTRACT: INTRODUCTION: Cognitive decline is common in Parkinson's disease (PD), and identifying patients at highest risk for it is essential. We aimed to examine the effect of possible REM sleep behavior disorder (pRBD) on rate of cognitive decline in early PD, for both global cognition and in specific cognitive domains. METHODS: Parkinson's Progression Markers Initiative (PPMI) is a multi-site, international study of PD patients untreated at enrollment. pRBD was assessed with the REM sleep behavior disorder questionnaire (RBDSQ). Global cognition was assessed at baseline and annually using the Montreal Cognitive Assessment (MoCA) and a cognitive battery. Linear mixed effects models were used to examine the relationship between pRBD (RBDSQ≥6) and rate of change in cognitive variables. Age, sex, years of education, and baseline motor and cognitive scores were included as covariates. RESULTS: The baseline sample consisted of 423 individuals with PD, mean age 61.7 years and 65.5% male. Data was available on 389, 366, and 196 participants at 1-year, 2-year, and 3-year follow-up respectively. Possible RBD occurred in 108 (25.5%) at baseline. In multivariate analyses, baseline RBD was associated with greater annual rate of decline in MoCA score (β = -0.34, 95%CI -0.54, -0.13, p < 0.001), Symbol Digit Modalities Test (β = -0.69, 95%CI -1.3, -0.09, p = 0.024), and Hopkins Verbal Learning Test-Revised, delayed free recall (β = -0.21, 95%CI -0.41, -0.013, p = 0.037). CONCLUSIONS: Possible RBD is common in early PD and predicts future cognitive decline, particularly in attention and memory domains.

24 Article Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers. 2015

Pont-Sunyer, Claustre / Iranzo, Alex / Gaig, Carles / Fernández-Arcos, Ana / Vilas, Dolores / Valldeoriola, Francesc / Compta, Yaroslau / Fernández-Santiago, Ruben / Fernández, Manel / Bayés, Angels / Calopa, Matilde / Casquero, Pilar / de Fàbregues, Oriol / Jaumà, Serge / Puente, Victor / Salamero, Manel / José Martí, Maria / Santamaría, Joan / Tolosa, Eduard. ·Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d'Investigacions BiomediquesAugust Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · MultidisciplinarySleepDisordersUnit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d'Investigacions BiomediquesAugust Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Laboratory of Neurodegenerative Disorders, Department of Clinical and Experimental Neurology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Universitat de Barcelona, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Unidad de Parkinson Teknon, Barcelona, Spain. · NeurologyService, Hospital Universitari de Bellvitge, Barcelona, Spain. · Hospital Mateu Orfila, Maó, Menorca, Spain. · Neurology Service, Hospital Universitari Vall D'Hebron, Barcelona, Spain. · Neurology Service, Hospital Del Mar, Barcelona, Spain. · PsychologyService, Hospital Clinic,Barcelona, Spain. ·PLoS One · Pubmed #26177462.

ABSTRACT: OBJECTIVE: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). METHODS: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD. RESULTS: Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. CONCLUSIONS: Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.

25 Article Prevalence and timeline of nonmotor symptoms in idiopathic rapid eye movement sleep behavior disorder. 2015

Aguirre-Mardones, Carolina / Iranzo, Alex / Vilas, Dolores / Serradell, Mónica / Gaig, Carles / Santamaría, Joan / Tolosa, Eduardo. ·Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, C/Villarroel 170, 08036, Barcelona, Spain. ·J Neurol · Pubmed #25929658.

ABSTRACT: Parkinson disease (PD) patients may experience nonmotor symptoms (NMS) before Parkinsonism onset. Patients with idiopathic REM sleep behavior disorder (IRBD) eventually develop PD and may represent premotor PD. We aimed to evaluate the prevalence and perceived timeline of NMS in IRBD through validated scales and questionnaires used in PD research. In 44 IRBD patients and 40 matched controls, overall NMS evaluation was assessed by NMS questionnaire for Parkinson disease, olfaction by University of Pennsylvania Smell Identification Test, dysautonomia by scales for outcomes in Parkinson's disease-autonomic, constipation by Rome III criteria, depression by Hospital Anxiety and Depression Scale, cognitive impairment by Montreal cognitive assessment (MoCA) and hypersomnia by Epworth Sleepiness Scale. Patients were asked to report the perceived time of onset of hyposmia, constipation, and depression. Hyposmia (52.3 vs. 20.0 %, p = 0.002) and constipation (56.8 vs. 20.0 %, p = 0.001) were more frequent in patients than in controls. Patients reported more memory problems and showed a trend toward lower score in MoCA. Depression and hypersomnia were not more frequent in patients. The first symptom perceived was RBD in 38.6 % patients, hyposmia in 15.9 %, constipation in 11.4 %, and depression in 6.8 %. The temporal course of the NMS studied was heterogeneous. The three most common presentations were RBD followed by hyposmia; hyposmia followed by RBD; and hyposmia followed by RBD and constipation occurring at the same time span. IRBD patients frequently exhibit NMS that occur in premotor PD, particularly hyposmia and constipation. In IRBD, the perceived timeline of NMS is highly variable. This variability may suggest that pathological changes occurring in IRBD subjects are also heterogeneous and not restricted to the structures that regulate REM sleep.

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