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1. Cognitive engagement may slow clinical progression and brain atrophy in Huntington’s disease

Author

Audrey E. De Paepe, Yemila Plana-Alcaide, Clara Garcia-Gorro, Nadia Rodriguez-Dechicha, Irene Vaquer, Matilde Calopa, Ruth de Diego-Balaguer, and Estela Camara

Subjects
Brain maintenance, Cognitive engagement, Gray matter volume, Huntington’s disease, Longitudinal, Neurodegeneration, Medicine, Science
Abstract

Key points An early cognitively active lifestyle can confer benefits to preserved motor and psychiatric function in addition to cognitive performance in Huntington’s disease. 2) More cognitively active individuals show decreased gray matter volume atrophy (e.g., brain maintenance) in the medial frontal gyrus, supplementary area, and middle cingulate cortex at longitudinal follow-up. 3) Such brain regions may act as neural hubs in circuits that integrate functionally diverse processes spanning cognitive, motor, and psychiatric domains.

Published
2024
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2. Disentangling the neurobiological bases of temporal impulsivity in Huntington's disease

Author

Helena Pardina‐Torner, Audrey E. De Paepe, Clara Garcia‐Gorro, Nadia Rodriguez‐Dechicha, Irene Vaquer, Matilde Calopa, Jesus Ruiz‐Idiago, Celia Mareca, Ruth deDiego‐Balaguer, and Estela Camara

Subjects
delay discounting, diffusion MRI, Huntington's disease, impulsivity, white matter, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Background Despite its impact on daily life, impulsivity in Huntington's disease (HD) is understudied as a neuropsychiatric symptom. Our aim is to characterize temporal impulsivity in HD and to disentangle the white matter correlate associated with impulsivity. Methods Forty‐seven HD individuals and 36 healthy controls were scanned and evaluated for temporal impulsivity using a delay‐discounting (DD) task and complementary Sensitivity to Punishment and Sensitivity to Reward Questionnaire. Diffusion tensor imaging was employed to characterize the structural connectivity of three limbic tracts: the uncinate fasciculus (UF), the accumbofrontal tract (NAcc‐OFC), and the dorsolateral prefrontal cortex connectig the caudate nucleus (DLPFC‐cn). Multiple linear regression analyses were applied to analyze the relationship between impulsive behavior and white matter microstructural integrity. Results Our results revealed altered structural connectivity in the DLPC‐cn, the NAcc‐OFC and the UF in HD individuals. At the same time, the variability in structural connectivity of these tracts was associated with the individual differences in temporal impulsivity. Specifically, increased structural connectivity in the right NAcc‐OFC and reduced connectivity in the left UF were associated with higher temporal impulsivity scores. Conclusions The present findings highlight the importance of investigating the spectrum of temporal impulsivity in HD. As, while less prevalent than other psychiatric features, this symptom is still reported to significantly impact the quality of life of patients and caregivers. This study provides evidence that individual differences observed in temporal impulsivity may be explained by variability in limbic frontostriatal tracts, while shedding light on the role of sensitivity to reward in modulating impulsive behavior through the selection of immediate rewards.

Published
2024
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3. Patient and caregiver outcomes with levodopa-carbidopa intestinal gel in advanced Parkinson’s disease

Author

Francesc Valldeoriola, María José Catalán, Francisco Escamilla-Sevilla, Eric Freire, Jesús Olivares, Esther Cubo, Diego Santos García, Matilde Calopa, Pablo Martínez-Martín, Juan Carlos Parra, Gloria Arroyo, and José Matías Arbelo

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Levodopa-carbidopa intestinal gel (LCIG) has shown to be efficacious in motor and non-motor symptoms (NMS). Nevertheless, studies with patient Quality of Life (QoL) as a primary endpoint are scarce. To assess the effect of LCIG on Advanced Parkinson’s Disease (APD) patients QoL. Secondarily, the impact on motor symptoms and NMS, emotional well-being, treatment satisfaction, and caregiver QoL, stress, disease burden, anxiety, depression, and work impairment were also investigated. In this prospective, 6-month multicenter postmarketing observational study, LCIG was administered to 59 patients with APD. Endpoints were assessed using validated scales and questionnaires. LCIG significantly improved patient QoL (PDQ-39 mean change ± standard deviation from baseline, −12.8 ± 14.6; P

Published
2021
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4. Effects of Levodopa-Carbidopa Intestinal Gel Compared with Optimized Medical Treatment on Nonmotor Symptoms in Advanced Parkinson’s Disease: INSIGHTS Study

Author

Sun Ju Chung, Matilde Calopa, Maria G. Ceravolo, Nicola Tambasco, Angelo Antonini, K. Ray Chaudhuri, Weining Z. Robieson, Olga Sánchez-Soliño, Cindy Zadikoff, Man Jin, and Luigi M. Barbato

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Background. Nonmotor symptoms (NMS) are common in advanced Parkinson’s disease (APD) and reduce health-related quality of life. Objective. The aim of the study was to evaluate levodopa-carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) on NMS in APD. Methods. INSIGHTS was a phase 3b, open-label, randomized, multicenter study in patients with APD (LCIG or OMT, 26 weeks) (NCT02549092). Primary outcomes assessed were total NMS (NMS scale (NMSS) and PD sleep scale (PDSS-2)). Key secondary outcomes included the Unified PD Rating Scale (UPDRS) Part II, Clinical Global Impression of Change (CGI-C), and PD Questionnaire-8 (PDQ-8). Additional secondary measures of Patient Global Impression of Change (PGIC), King’s PD Pain Scale (KPPS), and Parkinson Anxiety Scale (PAS) also were evaluated. Finally, safety was assessed. Results. Out of 89 patients randomized, 87 were included in the analysis (LCIG, n = 43; OMT, n = 44). There were no significant differences in NMSS or PDSS-2 total score changes (baseline to Week 26) between LCIG and OMT; within-group changes were significant for NMSS (LCIG, p

Published
2022
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5. Huntington Disease Health Related Quality of Life, Function and Well Being: The Patient’s Perspective

Author

Pérez-Pérez, Jesús, García-López, Sofía, Valle, Tamara Fernández, Painous, Cèlia, Querol-Pascual, Maria Rosa, Ruiz, Pedro J. García, Diago, Elena Bellosta, Cubo Delgado, Esther, Pastor, Barbara Vives, Villaplana, María Carmen Peiró, Santana, Idaira Martín, Blázquez Estrada, Marta, Garride, Matilde Calopa, Mir, Pablo, Álvarez, Carmen, Maurino, Jorge, de Prado, Anna, and López-Sendón, José Luis

Published
2024
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6. Intestinal Levodopa/Carbidopa Infusion as a Therapeutic Option for Unresponsive Freezing of Gait after Deep Brain Stimulation in Parkinson’s Disease

Author

Belén González-Herrero, Serge Jauma-Classen, Roser Gómez-Llopico, Gerard Plans, and Matilde Calopa

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Background. Treatment of freezing of gait (FOG) is always challenging because of its unpredictable nature and multifactorial physiopathology. Intestinal levodopa infusion has been proposed in recent years as a valuable option for its improvement. FOG in Parkinson’s disease (PD) can appear after deep brain stimulation in patients who never had gait symptoms. Objective. To study the effects of intestinal levodopa/carbidopa infusion in unresponsive-FOG that appears in PD patients treated with subthalamic nucleus deep brain stimulation. Methods. We retrospectively collected and analyzed demographic, clinical, and therapeutic data from five PD patients treated with subthalamic nucleus stimulation who developed unresponsive-FOG and received intestinal levodopa/carbidopa infusion as an alternative therapy. FOG was measured based on scores in item 14 of the Unified Parkinson’s Disease Rating Scale before and after intestinal levodopa infusion. Results. Administration of intestinal levodopa caused improvement of FOG in the “ON” state in four patients (80%) by 2 or more points in item 14 of the Unified Parkinson’s Disease Rating Scale. The improvement was maintained for at least 12 months. Conclusions. Intestinal levodopa infusion may be a valuable therapeutic option for unresponsive-FOG developed after subthalamic nucleus deep brain stimulation.

Published
2020
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7. MNCD: A New Tool for Classifying Parkinson’s Disease in Daily Clinical Practice

Author

Diego Santos García, María Álvarez Sauco, Matilde Calopa, Fátima Carrillo, Francisco Escamilla Sevilla, Eric Freire, Rocío García Ramos, Jaime Kulisevsky, Juan Carlos Gómez Esteban, Inés Legarda, María Rosario Isabel Luquín, Juan Carlos Martínez Castrillo, Pablo Martínez-Martin, Irene Martínez-Torres, Pablo Mir, and Ángel Sesar Ignacio

Subjects
cognition, dependency, non-motor symptoms, motor symptoms, Parkinson’s disease, Medicine (General), R5-920
Abstract

Background and objective: Parkinson’s disease (PD) is a clinically heterogeneous disorder in which the symptoms and prognosis can be very different among patients. We propose a new simple classification to identify key symptoms and staging in PD. Patients and Methods: Sixteen movement disorders specialists from Spain participated in this project. The classification was consensually approved after a discussion and review process from June to October 2021. The TNM classification and the National Institutes of Health Stroke Scale (NIHSS) were considered as models in the design. Results: The classification was named MNCD and included 4 major axes: (1) motor symptoms; (2) non-motor symptoms; (3) cognition; (4) dependency for activities of daily living (ADL). Motor axis included 4 sub-axes: (1) motor fluctuations; (2) dyskinesia; (3) axial symptoms; (4) tremor. Four other sub-axes were included in the non-motor axis: (1) neuropsychiatric symptoms; (2) autonomic dysfunction; (3) sleep disturbances and fatigue; (4) pain and sensory disorders. According to the MNCD, 5 stages were considered, from stage 1 (no disabling motor or non-motor symptoms with normal cognition and independency for ADL) to 5 (dementia and dependency for basic ADL). Conclusions: A new simple classification of PD is proposed. The MNCD classification includes 4 major axes and 5 stages to identify key symptoms and monitor the evolution of the disease in patients with PD. It is necessary to apply this proof of concept in a properly designed study.

Published
2021
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8. Present and Future of Parkinson’s Disease in Spain: PARKINSON-2030 Delphi Project

Author

Diego Santos García, Marta Blázquez-Estrada, Matilde Calopa, Francisco Escamilla-Sevilla, Eric Freire, Pedro J. García Ruiz, Francisco Grandas, Jaime Kulisevsky, Lydia López-Manzanares, Juan Carlos Martínez Castrillo, Pablo Mir, Javier Pagonabarraga, Francisco Pérez-Errazquin, José María Salom, Beatriz Tijero, Francesc Valldeoriola, Rosa Yáñez, Arantxa Avilés, and María-Rosario Luquín

Subjects
diagnosis, economic impact, epidemiology, management, mortality, Parkinson’s disease, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Parkinson’s disease (PD) is a chronic progressive and irreversible disease and the second most common neurodegenerative disease worldwide. In Spain, it affects around 120.000–150.000 individuals, and its prevalence is estimated to increase in the future. PD has a great impact on patients’ and caregivers’ lives and also entails a substantial socioeconomic burden. The aim of the present study was to examine the current situation and the 10-year PD forecast for Spain in order to optimize and design future management strategies. This study was performed using the modified Delphi method to try to obtain a consensus among a panel of movement disorders experts. According to the panel, future PD management will improve diagnostic capacity and follow-up, it will include multidisciplinary teams, and innovative treatments will be developed. The expansion of new technologies and studies on biomarkers will have an impact on future PD management, leading to more accurate diagnoses, prognoses, and individualized therapies. However, the socio-economic impact of the disease will continue to be significant by 2030, especially for patients in advanced stages. This study highlighted the unmet needs in diagnosis and treatment and how crucial it is to establish recommendations for future diagnostic and therapeutic management of PD.

Published
2021
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9. Can suitable candidates for levodopa/carbidopa intestinal gel therapy be identified using current evidence?

Author

Maria José Catalán, Angelo Antonini, Matilde Calopa, Ovidiu Băjenaru, Oriol de Fábregues, Adolfo Mínguez-Castellanos, Per Odin, José Manuel García-Moreno, Stephen W. Pedersen, Zvezdan Pirtošek, and Jaime Kulisevsky

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Advanced Parkinson's disease (APD) is characterized by increased functional disability, caused by motor complications, the presence of axial symptoms, and emergent disease- and drug-related non-motor symptoms. One of the advanced therapies available is intrajejunal infusion of levodopa/carbidopa intestinal gel (LCIG); however, patient selection for this treatment is sometimes difficult, particularly because of overlapping indications with other alternatives.In recent years, strong evidence has supported the use of LCIG in treating motor fluctuations associated with APD, and several clinical studies provide emerging evidence for additional benefits of LCIG treatment in certain patients. This article provides an overview of the published literature on the benefits, limitations, and drawbacks of LCIG in relation to PD symptoms, the psychosocial impact of the disease, and the quality of life of patients, with the aim of determining candidates for whom treatment with LCIG would be beneficial. According to current evidence, patients with APD (defined as inability to achieve optimal control of the disease with conventional oral treatment), a relatively well-preserved cognitive-behavioral status, and good family/caregiver would count as suitable candidates for LCIG treatment. Contraindications in the opinion of the authors are severe dementia and active psychosis. Keywords: Parkinson's disease, Intrajejunal infusion of levodopa/carbidopa intestinal gel, Duodopa, Motor symptoms, Non-motor symptoms, Quality of life

Published
2017
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10. Specific patterns of brain alterations underlie distinct clinical profiles in Huntington's disease

Author

Clara Garcia-Gorro, Alberto Llera, Saul Martinez-Horta, Jesus Perez-Perez, Jaime Kulisevsky, Nadia Rodriguez-Dechicha, Irene Vaquer, Susana Subira, Matilde Calopa, Esteban Muñoz, Pilar Santacruz, Jesus Ruiz-Idiago, Celia Mareca, Christian F. Beckmann, Ruth de Diego-Balaguer, and Estela Camara

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Huntington's disease (HD) is a genetic neurodegenerative disease which involves a triad of motor, cognitive and psychiatric disturbances. However, there is great variability in the prominence of each type of symptom across individuals. The neurobiological basis of such variability remains poorly understood but would be crucial for better tailored treatments. Multivariate multimodal neuroimaging approaches have been successful in disentangling these profiles in other disorders. Thus we applied for the first time such approach to HD. We studied the relationship between HD symptom domains and multimodal measures sensitive to grey and white matter structural alterations. Forty-three HD gene carriers (23 manifest and 20 premanifest individuals) were scanned and underwent behavioural assessments evaluating motor, cognitive and psychiatric domains. We conducted a multimodal analysis integrating different structural neuroimaging modalities measuring grey matter volume, cortical thickness and white matter diffusion indices – fractional anisotropy and radial diffusivity. All neuroimaging measures were entered into a linked independent component analysis in order to obtain multimodal components reflecting common inter-subject variation across imaging modalities. The relationship between multimodal neuroimaging independent components and behavioural measures was analysed using multiple linear regression. We found that cognitive and motor symptoms shared a common neurobiological basis, whereas the psychiatric domain presented a differentiated neural signature. Behavioural measures of different symptom domains correlated with different neuroimaging components, both the brain regions involved and the neuroimaging modalities most prominently associated with each type of symptom showing differences. More severe cognitive and motor signs together were associated with a multimodal component consisting in a pattern of reduced grey matter, cortical thickness and white matter integrity in cognitive and motor related networks. In contrast, depressive symptoms were associated with a component mainly characterised by reduced cortical thickness pattern in limbic and paralimbic regions. In conclusion, using a multivariate multimodal approach we were able to disentangle the neurobiological substrates of two distinct symptom profiles in HD: one characterised by cognitive and motor features dissociated from a psychiatric profile. These results open a new view on a disease classically considered as a uniform entity and initiates a new avenue for further research considering these qualitative individual differences. Keywords: Linked ICA, Data fusion, Huntington's disease, Neurodegeneration, Clinical profiles, Structural MRI

Published
2019
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11. White matter cortico-striatal tracts predict apathy subtypes in Huntington's disease

Author

Audrey E. De Paepe, Joanna Sierpowska, Clara Garcia-Gorro, Saül Martinez-Horta, Jesus Perez-Perez, Jaime Kulisevsky, Nadia Rodriguez-Dechicha, Irene Vaquer, Susana Subira, Matilde Calopa, Esteban Muñoz, Pilar Santacruz, Jesus Ruiz-Idiago, Celia Mareca, Ruth de Diego-Balaguer, and Estela Camara

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Apathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited. Objectives: To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. Methods: Forty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains. Results: We elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract. Conclusions: The current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders. Keywords: Apathy, Diffusion MRI, Huntington's disease, Individual differences, Neurodegeneration, White matter microstructure

Published
2019
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12. Correction: Huntington Disease Health Related Quality of Life, Function and Well Being: The Patient’s Perspective

Author

Pérez-Pérez, Jesús, García-López, Sofía, Valle, Tamara Fernández, Painous, Cèlia, Querol-Pascual, Maria Rosa, Ruiz, Pedro J. García, Diago, Elena Bellosta, Cubo Delgado, Esther, Pastor, Barbara Vives, Villaplana, María Carmen Peiró, Santana, Idaira Martín, Blázquez Estrada, Marta, Garride, Matilde Calopa, Mir, Pablo, Álvarez, Carmen, Maurino, Jorge, de Prado, Anna, and López-Sendón, José Luis

Published
2024
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13. Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers.

Author

Claustre Pont-Sunyer, Alex Iranzo, Carles Gaig, Ana Fernández-Arcos, Dolores Vilas, Francesc Valldeoriola, Yaroslau Compta, Ruben Fernández-Santiago, Manel Fernández, Angels Bayés, Matilde Calopa, Pilar Casquero, Oriol de Fàbregues, Serge Jaumà, Victor Puente, Manel Salamero, Maria José Martí, Joan Santamaría, and Eduard Tolosa

Subjects
Medicine, Science
Abstract

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).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.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.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.

Published
2015
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14. Nonmotor symptoms in LRRK2 G2019S associated Parkinson's disease.

Author

Carles Gaig, Dolores Vilas, Jon Infante, María Sierra, Inés García-Gorostiaga, Mariateresa Buongiorno, Mario Ezquerra, Maria José Martí, Francesc Valldeoriola, Miquel Aguilar, Matilde Calopa, Jorge Hernandez-Vara, and Eduardo Tolosa

Subjects
Medicine, Science
Abstract

Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined.To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients.The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated.University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p

Published
2014
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15. Immediate-release/extended-release amantadine (OS320) to treat Parkinson's disease with levodopa-induced dyskinesia: Analysis of the randomized, controlled ALLAY-LID studies

Author

Azulay, Jean-Philippe, Balaguer, Ernest, Bhatia, Perminder, Bodis-Wollner, Ivan, Brownstone, Paul, Boulloche, Nicolas, Calegan, Gerald J., II, Castelnovo, Giovanni, Chou, Kelvin L., Corvol, Jean-Christophe, Danisi, Fabio, Defebvre, Luc, Desojo, Lydia Vela, Durif, Franck, Ehret, Reinhard, Evans, Bradley K., Forchetti, Concetta, Friedman, Joseph H., Fogel, Wolfgang, Garniga, Matilde Calopa, Gil, Ramon A., Ginsberg, Paul L., Glasberg, Mark R., Griffith, Alida, Groves, Jeffrey W., Gudesblatt, Mark, Hermanowicz, Neal, Herrera, Maria A., Houeto, Jean-Luc, Hutchman, Robert M., Isaacson, Stuart H., Jagadeesan, Singar, Jog, Mandar, Keegan, Andrew, Klostermann, Fabian, Krystkowiak, Pierre, Kulisevsky Bojarsky, Jaime, Kumar, Rajeev, Lacey, Dennis, Lasker, Bruce, LaVaccare, John, Lavallee, Michelle M., Piudo, Maria Rosario Luquin, Mahler, Andreas, Domenech, Maria José Martí, Martinez Castrillo, Juan Carlos, Mate, Laszlo J., Mendis, Tilak, Metman, Leonard Verhagen, Muhlack, Siegfried Martin, Müller, Thomas, Park, Ariane, Patton, James, Peckham, Elizabeth, Grandas Pérez, Francisco, Rabin, Marcie, Rascol, Olivier, Reifschneider, Gerd, Remy, Philippe, Rivera, Pablo Mir, Schwarz, Johannes, Roullet-Solignac, Isabelle, Salazar, Gabriel, Sergay, Stephen M., Sherman, Scott, Shubin, Richard, Spikol, Lorraine, Steigerwald, Frank, Tönges, Lars, Truong, Daniel D., Ugarte, Antonio, Vivancos Matellano, Francisco, Witte, Arnold, Zesiewicz, Theresa, Zauber, Sarah Elizabeth, deVries, Tina, Jaros, Mark, Quartel, Adrian, and Jacobs, David

Published
2022
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16. Delineating apathy profiles in Huntington's disease with the short-Lille Apathy Rating Scale

Author

Audrey E. De Paepe, Clara Garcia-Gorro, Saül Martinez-Horta, Jesus Perez Perez, Jaime Kulisevsky, Nadia Rodriguez-Dechicha, Irene Vaquer, Susana Subira, Matilde Calopa, Pilar Santacruz, Esteban Muñoz, Celia Mareca, Jesus Ruiz-Idiago, Ruth de Diego-Balaguer, and Estela Camara

Subjects
Huntington Disease, Neurology, Apathy, Emotions, Humans, Reproducibility of Results, Brain, Neurology (clinical), Geriatrics and Gerontology
Abstract

Apathy, a prevalent feature in neurological disorders including Huntington's disease (HD), is characterized by a reduction in goal-directed behavior across cognitive, auto-activation (i.e., self-activating thoughts/behavior), and emotional domains. Nonetheless, current diagnostic criteria are incapable of distinguishing multidimensional apathy profiles. Meanwhile, the short-Lille Apathy Rating Scale (LARS-s) bears potential as an operative diagnostic tool to disentangle apathy dimensions in clinical practice. The present study thereby examines the psychometric properties and factor structure of the LARS-s to tap into apathy profiles and their underlying neural correlates in HD.Forty HD individuals were scanned and evaluated for apathy using the LARS-s, assessed for reliability and validity in HD, and the short-Problem Behavior Assessment (PBA-s). To study the dimensional structure of apathy, principal component analysis (PCA) of the LARS-s was implemented. Resulting factors were associated with gray matter volume through whole-brain voxel-based morphometry.The LARS-s demonstrated satisfactory psychometric properties, sharing convergent validity with PBA-s apathy and discriminant validity against depression. PCA resulted in three factors representative of apathy profiles across cognitive, auto-activation, and emotional domains. Anatomically, global apathy was significantly related with large-scale motor, cognitive, and limbic networks. Exploratory analyses of apathy profiles revealed correspondence between each factor and distinct cortical and subcortical nodes.The LARS-s is capable of capturing the multidimensional spectrum of apathy. At the same time, apathy profiles in HD are underpinned by functionally diverse neural networks. Such findings promote the continued study of apathy domains to pinpoint personalized therapeutic targets in neurologic disorders in addition to HD.

Published
2022
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17. Disentangling the neurobiological bases of temporal impulsivity in Huntington’s disease

Author

Helena Pardina-Torner, Audrey E. De Paepe, Clara Garcia-Gorro, Nadia Rodriguez-Dechicha, Matilde Calopa, Jesus Ruiz-Idiago, Celia Mareca, Ruth de Diego-Balaguer, and Estela Camara

Abstract

BackgroundDespite its impact on daily life, impulsivity in Huntington’s disease (HD) is understudied as a neuropsychiatric symptom. Our aim is to characterize temporal impulsivity in HD, evaluated through a Delay Discounting (DD) task, and to disentangle the underlying white matter correlates in HD.MethodsForty-seven HD individuals and thirty-six healthy controls conducted a DD task and complementary Sensitivity to Punishment and Sensitivity to Reward (SR) Questionnaire. Diffusion-tensor imaging was employed to characterize the structural connectivity of two limbic tracts: the uncinate fasciculus (UF) and the accumbofrontal tract (NAcc-OFC). Multiple linear regression analyses were applied to analyze the relationship between impulsive behavior and white-matter microstructural integrity.ResultsAltered structural connectivity in both the NAcc-OFC and UF in HD individuals was observed. Moreover, the variability in structural connectivity of these tracts was associated with the individual differences in temporal impulsivity. Specifically, increased structural connectivity in the right NAcc-OFC predicted increased temporal impulsivity, while reduced connectivity in the left UF was associated with higher temporal impulsivity scores.LimitationsOther cognitive mechanisms and white matter tracts may play a role in temporal impulsivity.ConclusionsThis study provides evidence that individual differences observed in impulsivity may be explained by variability in limbic fronto-striatal tracts. We emphasize the importance of investigating the spectrum of impulsivity in HD, less prevalent than other psychiatric features, but impacting the quality of life of patients and their caregivers.

Published
2023
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18. A proof-of-concept study with SOM3355 (bevantolol hydrochloride) for reducing chorea in Huntington's disease

Author

Josep Gamez, Matilde Calopa, Esteban Muñoz, Aileen Ferré, Oscar Huertas, Kevin McAllister, Núria Reig, Catherine Scart‐Grès, Raúl Insa, and Jaime Kulisevsky

Subjects
Pharmacology, Pharmacology (medical)
Abstract

The study's aim is to investigate the efficacy and safety of SOM3355 (bevantolol hydrochloride), a βA randomized, placebo-controlled proof-of-concept study was performed in 32 HD patients allocated to 2 arms of 4 sequential 6-week periods each. Patients received placebo and SOM3355 at 100 and 200 mg twice daily in a crossover design. The primary endpoint was improvement by at least 2 points in the total maximal chorea score in any active drug period compared with the placebo period.The primary endpoint was met in 57.1% of the patients. Improvements ≥3, ≥4, ≥5 and ≥6 points vs. placebo treatment were observed in 28.6, 25.0, 17.9 and 10.7% of the patients, respectively. A mixed-model analysis found a significant improvement in the total maximal chorea score of -1.14 (95% confidence interval, -2.11 to -0.16; P = .0224) with 200 mg twice daily SOM3355 treatment compared with placebo treatment. These results were paralleled by Clinical and Patient Global Impression of Change ratings (secondary endpoints). An elevation in plasma prolactin levels by 1.7-1.9-fold was recorded (P .005), probably reflecting the effect on the dopamine pathway, consistent with vesicular monoamine transporter type 2 inhibition. The most frequent adverse events during SOM3355 administration were mild to moderate.Within the limits of this study, the results suggest that SOM3355 reduces chorea in patients with HD and is well-tolerated. Larger studies are necessary to confirm its therapeutic utility as an antichoreic drug. EudraCT number: 2018-000203-16 and ClinicalTrials.gov Identifier: NCT03575676.

Published
2022

20. Immediate-release/extended-release amantadine (OS320) to treat Parkinson's disease with levodopa-induced dyskinesia: Analysis of the randomized, controlled ALLAY-LID studies

Author

Rascol, Olivier, primary, Tönges, Lars, additional, deVries, Tina, additional, Jaros, Mark, additional, Quartel, Adrian, additional, Jacobs, David, additional, Azulay, Jean-Philippe, additional, Balaguer, Ernest, additional, Bhatia, Perminder, additional, Bodis-Wollner, Ivan, additional, Brownstone, Paul, additional, Boulloche, Nicolas, additional, Calegan, Gerald J., additional, Castelnovo, Giovanni, additional, Chou, Kelvin L., additional, Corvol, Jean-Christophe, additional, Danisi, Fabio, additional, Defebvre, Luc, additional, Desojo, Lydia Vela, additional, Durif, Franck, additional, Ehret, Reinhard, additional, Evans, Bradley K., additional, Forchetti, Concetta, additional, Friedman, Joseph H., additional, Fogel, Wolfgang, additional, Garniga, Matilde Calopa, additional, Gil, Ramon A., additional, Ginsberg, Paul L., additional, Glasberg, Mark R., additional, Griffith, Alida, additional, Groves, Jeffrey W., additional, Gudesblatt, Mark, additional, Hermanowicz, Neal, additional, Herrera, Maria A., additional, Houeto, Jean-Luc, additional, Hutchman, Robert M., additional, Isaacson, Stuart H., additional, Jagadeesan, Singar, additional, Jog, Mandar, additional, Keegan, Andrew, additional, Klostermann, Fabian, additional, Krystkowiak, Pierre, additional, Kulisevsky Bojarsky, Jaime, additional, Kumar, Rajeev, additional, Lacey, Dennis, additional, Lasker, Bruce, additional, LaVaccare, John, additional, Lavallee, Michelle M., additional, Piudo, Maria Rosario Luquin, additional, Mahler, Andreas, additional, Domenech, Maria José Martí, additional, Martinez Castrillo, Juan Carlos, additional, Mate, Laszlo J., additional, Mendis, Tilak, additional, Metman, Leonard Verhagen, additional, Muhlack, Siegfried Martin, additional, Müller, Thomas, additional, Park, Ariane, additional, Patton, James, additional, Peckham, Elizabeth, additional, Grandas Pérez, Francisco, additional, Rabin, Marcie, additional, Rascol, Olivier, additional, Reifschneider, Gerd, additional, Remy, Philippe, additional, Rivera, Pablo Mir, additional, Schwarz, Johannes, additional, Roullet-Solignac, Isabelle, additional, Salazar, Gabriel, additional, Sergay, Stephen M., additional, Sherman, Scott, additional, Shubin, Richard, additional, Spikol, Lorraine, additional, Steigerwald, Frank, additional, Truong, Daniel D., additional, Ugarte, Antonio, additional, Vivancos Matellano, Francisco, additional, Witte, Arnold, additional, Zesiewicz, Theresa, additional, and Zauber, Sarah Elizabeth, additional

Published
2022
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21. Immediate-release/extended-release amantadine (OS320) to treat Parkinson's disease with levodopa-induced dyskinesia: Analysis of the randomized, controlled ALLAY-LID studies

Author

Olivier Rascol, Lars Tönges, Tina deVries, Mark Jaros, Adrian Quartel, David Jacobs, Jean-Philippe Azulay, Ernest Balaguer, Perminder Bhatia, Ivan Bodis-Wollner, Paul Brownstone, Nicolas Boulloche, Gerald J. Calegan, Giovanni Castelnovo, Kelvin L. Chou, Jean-Christophe Corvol, Fabio Danisi, Luc Defebvre, Lydia Vela Desojo, Franck Durif, Reinhard Ehret, Bradley K. Evans, Concetta Forchetti, Joseph H. Friedman, Wolfgang Fogel, Matilde Calopa Garniga, Ramon A. Gil, Paul L. Ginsberg, Mark R. Glasberg, Alida Griffith, Jeffrey W. Groves, Mark Gudesblatt, Neal Hermanowicz, Maria A. Herrera, Jean-Luc Houeto, Robert M. Hutchman, Stuart H. Isaacson, Singar Jagadeesan, Mandar Jog, Andrew Keegan, Fabian Klostermann, Pierre Krystkowiak, Jaime Kulisevsky Bojarsky, Rajeev Kumar, Dennis Lacey, Bruce Lasker, John LaVaccare, Michelle M. Lavallee, Maria Rosario Luquin Piudo, Andreas Mahler, Maria José Martí Domenech, Juan Carlos Martinez Castrillo, Laszlo J. Mate, Tilak Mendis, Leonard Verhagen Metman, Siegfried Martin Muhlack, Thomas Müller, Ariane Park, James Patton, Elizabeth Peckham, Francisco Grandas Pérez, Marcie Rabin, Gerd Reifschneider, Philippe Remy, Pablo Mir Rivera, Johannes Schwarz, Isabelle Roullet-Solignac, Gabriel Salazar, Stephen M. Sergay, Scott Sherman, Richard Shubin, Lorraine Spikol, Frank Steigerwald, Daniel D. Truong, Antonio Ugarte, Francisco Vivancos Matellano, Arnold Witte, Theresa Zesiewicz, and Sarah Elizabeth Zauber

Subjects
Antiparkinson Agents, Levodopa, Dyskinesia, Drug-Induced, Treatment Outcome, Neurology, Double-Blind Method, Amantadine, Humans, Parkinson Disease, Neurology (clinical), Geriatrics and Gerontology
Abstract

Immediate-release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER®) contains an IR outer layer and ER core for once-daily dosing.Report individual and pooled results for the similarly designed double-blind, placebo-controlled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID.PD patients with LID were randomized to IR/ER-amantadine 193 mg, 258 mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II + III and Fatigue Severity Scale.Overall, 222 individuals enrolled (N = 87 ALLAY-LID I, N = 135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were -5.5 [-9.8, -1.2], p = 0.012 and -5.2 [-9.5, -0.9], p = 0.017, respectively. IR/ER-amantadine 258 mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193 mg), 18.7% (258 mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively).IR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.

Published
2021

22. F40 Proof-of-concept study testing SOM3355, a VMAT2 inhibitor for the treatment of chorea in huntington’s disease

Author

Oscar Huertas, Aileen Ferré, Kevin McAllister, Jaime Kulisevsky, Josep Gamez, Núria Reig, Raul Insa, Catherine Scart-Grès, Esteban Muñoz, and Matilde Calopa

Subjects
medicine.medical_specialty, Movement disorders, business.industry, Chorea, Placebo, medicine.disease, Crossover study, Huntington's disease, Rating scale, Internal medicine, VMAT2 inhibitor, Clinical endpoint, Medicine, medicine.symptom, business
Abstract

Background SOM3355 (bevantolol hydrochloride), a β1-adrenoceptor blocker used in hypertension, was identified as a vesicular monoamine transporter type 2 (VMAT2) inhibitor by artificial intelligence screening, and then selected by in vitro functional studies as the best candidate to be repositioned for treatment of dyskinetic movement disorders, such as chorea in Huntington’s disease (HD). Aim A proof-of-concept phase IIa study was performed to assess SOM3355 efficacy and safety in patients with HD presenting chorea. Methods In this double-blind, randomized, crossover, placebo-controlled study, 32 patients were randomly assigned to one of the two arms of 4 sequential 6-week periods to receive placebo and SOM3355 at 100 and 200 mg BID in a crossover design. The primary endpoint was the improvement of at least 2 points in the total maximal chorea (TMC) score of the Unified Huntington’s Disease Rating Scale (UHDRS) in any SOM3355 period compared with the placebo period. Results Almost 60% of the patients had improvements in the TMC score of at least 2 points in any period with SOM3355 compared with placebo, thus reaching the primary endpoint. Even greater TMC score improvements of 3, 4, 5, and 6 points compared with placebo were seen with SOM3355 in 28.6%, 25.0%, 17.9%, and 10.7% of the patients, respectively. The mixed-model analysis comparing the different periods revealed significant improvement in the TMC score with SOM3355 at 200 mg BID compared with placebo (P = 0.0224), as confirmed in Clinical and Patient Global Impression of Change ratings. Mild elevations in plasma prolactin levels were recorded with SOM3355 (P Conclusion This study confirms that SOM3355 reduces chorea in patients with HD and has a good safety profile.

Published
2021
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23. E08 Tracking the neurodegeneration pattern of the anterior thalamic radiations in HD: a focus on brain iron, white matter integrity and metabolites

Author

Clara Garcia-Gorro, Jesús Pérez-Pérez, Celia Mareca, Nadia Rodriguez-Dechicha, Esteban Muñoz, Susana Subirà, Estela Camara, Irene Vaquer, Jaime Kulisevsky, Jesus Ruiz-Idiago, Saul Martinez-Horta, Pilar Santacruz, Ruth de Diego-Balaguer, Montserrat Domingo Ayllón, and Matilde Calopa

Subjects
Relaxometry, biology, business.industry, Neurodegeneration, Neuropsychology, Striatum, Creatine, medicine.disease, Pathophysiology, White matter, Ferritin, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, medicine, biology.protein, business, Neuroscience
Abstract

Background HD is a suitable model to monitor the whole neurodegeneration process. Huntington’s disease (HD) affects primarily the striatum, but loss of white matter (WM) integrity and iron homeostasis disruption have been also described. These anomalies together with metabolite profiles could unveil the pathophysiologic mechanisms involved. Aims To assess the temporal and spatial progression of neurodegeneration on both anterior thalamic radiations (ATR). Methods Thirty-one HD gene carriers and twenty-four controls underwent neuropsychological evaluation and were scanned at 3T-MRI unit. A multimodal study was conducted to measure relaxometry, diffusivity and spectroscopy as proxies of iron, WM microstructure and metabolite composition, respectively. Three statistical approaches (average, segmental, along-the-tract) were performed, with MANOVA and post-hoc Tukey test to evaluate differences among groups and Pearson test to assess correlations. Results ATR disintegration began in premanifest individuals and progressed in extent and severity in manifest patients. WM damage was more extensive in the right ATR that could translate a higher vulnerability and showed a spatial gradient from subcortical to deep WM in favour of the dying-back hypothesis. Iron was increased in the left ATR in premanifest individuals that might uncover a dysregulated myelination or an abnormal ferritin accumulation. NAA and creatine decreased exclusively in manifest patients suggesting neuronal loss and mitochondrial dysfunction. Furthermore, imaging parameters could be used as biomarkers given their links with clinical scores. Conclusions The complex neurodegeneration pattern of ATR in HD can help to understand the pathophysiological mechanisms underlying HD progression. The multimodal approach and along-the-tract analysis allow for a more comprehensive evaluation of neurodegeneration.

Published
2021
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24. F24 Unsupervised clustering reveals longitudinal psychiatric signatures in HD

Author

Ruth de Diego-Balaguer, Alexia Giannoula, Estela Camara, Pilar Santacruz, Nadia Rodriguez-Dechicha, Esteban Muñoz, Matilde Calopa, Celia Mareca, Laura I. Furlong, Clara Garcia-Gorro, Jesus Ruiz-Idiago, Jaime Kulisevsky, Saul Martinez-Horta, Susana Subirà, Ferran Sanz, Irene Vaquer, Audrey E De Paepe, and Jesús Pérez-Pérez

Subjects
Computer science, business.industry, Pattern recognition, Artificial intelligence, business, Unsupervised clustering
Published
2021
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25. Gray Matter Vulnerabilities Predict Longitudinal Development of Apathy in Huntington's Disease

Author

Irene Vaquer, Pilar Santacruz, Clara Garcia-Gorro, Susana Subirà, Ruth de Diego-Balaguer, Nadia Rodriguez-Dechicha, Esteban Muñoz, Estela Camara, Jaime Kulisevsky, Matilde Calopa, Jesús Pérez-Pérez, Audrey E De Paepe, Saul Martinez-Horta, Alberto Ara, Celia Mareca, and Jesus Ruiz-Idiago

Subjects
0301 basic medicine, Cingulate cortex, medicine.medical_specialty, longitudinal, Apathy, apathy, Disease, Huntington's chorea, computer.software_genre, Gray (unit), s disease, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Physical medicine and rehabilitation, Magnetic resonance imaging, Huntington's disease, Corea de Huntington, Voxel, Imatges per ressonància magnètica, medicine, Humans, Gray Matter, Cervell, individual differences, structural MRI, medicine.diagnostic_test, business.industry, Huntington&apos, Malalties neurodegeneratives, neurodegeneration, Brain, Neurodegenerative Diseases, medicine.disease, Magnetic Resonance Imaging, Huntington Disease, 030104 developmental biology, Neurology, Female, Neurology (clinical), medicine.symptom, business, computer, 030217 neurology & neurosurgery
Abstract

Background Apathy, a common neuropsychiatric disturbance in Huntington's disease (HD), is subserved by a complex neurobiological network. However, no study has yet employed a whole-brain approach to examine underlying regional vulnerabilities that may precipitate apathy changes over time. Objectives To identify whole-brain gray matter volume (GMV) vulnerabilities that may predict longitudinal apathy development in HD. Methods Forty-five HD individuals (31 female) were scanned and evaluated for apathy and other neuropsychiatric features using the short-Problem Behavior Assessment for a maximum total of six longitudinal visits (including baseline). In order to identify regions where changes in GMV may describe changes in apathy, we performed longitudinal voxel-based morphometry (VBM) on those 33 participants with a magnetic resonance imaging (MRI) scan on their second visit at 18 +/- 6 months follow-up (78 MRI datasets). We next employed a generalized linear mixed-effects model (N = 45) to elucidate whether initial and specific GMV may predict apathy development over time. Results Utilizing longitudinal VBM, we revealed a relationship between increases in apathy and specific GMV atrophy in the right middle cingulate cortex (MCC). Furthermore, vulnerability in the right MCC volume at baseline successfully predicted the severity and progression of apathy over time. Conclusions This study highlights that individual differences in apathy in HD may be explained by variability in atrophy and initial vulnerabilities in the right MCC, a region implicated in action-initiation. These findings thus serve to facilitate the prediction of an apathetic profile, permitting targeted, time-sensitive interventions in neurodegenerative disease with potential implications in otherwise healthy populations. (c) 2021 International Parkinson and Movement Disorder Society

Published
2021

26. Subclinical affective and cognitive fluctuations in Parkinson's disease: a randomized double-blind double-dummy study of Oral vs. Intrajejunal Levodopa

Author

Ane Crespo-Cuevas, Antonia Campolongo, Cristina Izquierdo-Barrionuevo, Javier Pagonabarraga, Helena Bejr-Kasem, Berta Pascual-Sedano, Saul Martinez-Horta, Juan Marín-Lahoz, Jaime Kulisevsky, Matilde Calopa, Andrea Horta-Barba, Víctor Puente, Oriol De Fabregues, Ignacio Aracil-Bolaños, and Jesús Pérez-Pérez

Subjects
Levodopa, Parkinson's disease, Placebo, Antiparkinson Agents, 03 medical and health sciences, 0302 clinical medicine, Cognition, Oral administration, medicine, Humans, 030212 general & internal medicine, Cross-Over Studies, business.industry, Carbidopa, Parkinson Disease, medicine.disease, Crossover study, Drug Combinations, Mood, Neurology, Anesthesia, Anxiety, Neurology (clinical), medicine.symptom, business, Gels, 030217 neurology & neurosurgery, medicine.drug
Abstract

Chronic levodopa treatment in Parkinson’s disease (PD) may promote undesirable motor and non-motor fluctuations. Compared to chronic oral levodopa treatment, continuous infusion of levodopa/carbidopa intestinal gel (LCIG) in advanced PD reduces motor fluctuations. However, differences in their effect on acute non-motor changes were not formally demonstrated. We performed a randomized, double-blind, double-dummy, crossover study to compare acute non-motor changes between intermittent oral immediate-release carbidopa/levodopa (LC-IR) and LCIG. After > 12-h OFF, thirteen PD patients chronically treated with LCIG and without history of non-motor swings, were allocated to receive first, LCIG infusion plus three oral doses of placebo, or placebo infusion plus three oral doses of LC-IR. Over-encapsulated oral medication (LC-IR or placebo) was administered every 2 h. We monitored plasmatic levels of levodopa, motor status (UPDRS-III), mood, anxiety, and frontal functions at baseline (0-h) and hourly after each oral challenge. Repeated-measures ANOVAs showed significant group by treatment interaction indicating more fluctuations of levodopa plasma levels with LC-IR. No significant interactions were seen in the temporal profile of motor status, anxiety, mood and cognition. However, point-to-point parametric and nonparametric tests showed a significant more marked and more sustained improvement in anxiety scores under LCIG. A significant improvement of mood and verbal fluency was seen a + 3-h only under LCIG. Our sample of advanced PD patients exhibited moderate but significant non-motor fluctuations. LCIG was associated with a more favorable profile of acute affective and cognitive fluctuations that was particularly expressed at the first part of the infusion curve.

Published
2020

27. Intestinal Levodopa/Carbidopa Infusion as a Therapeutic Option for Unresponsive Freezing of Gait after Deep Brain Stimulation in Parkinson’s Disease

Author

Roser Gómez-Llopico, Serge Jauma-Classen, Belén González-Herrero, Gerard Plans, and Matilde Calopa

Subjects
010407 polymers, Levodopa, Parkinson's disease, Deep brain stimulation, Article Subject, genetic structures, Fisiologia patològica, medicine.medical_treatment, Neuroscience (miscellaneous), 01 natural sciences, 03 medical and health sciences, 0302 clinical medicine, Malaltia de Parkinson, medicine, RC346-429, Pathological physiology, business.industry, medicine.disease, Gait, Pathophysiology, 0104 chemical sciences, nervous system diseases, Psychiatry and Mental health, Carbidopa, Anesthesia, Levodopa carbidopa, Neurology (clinical), Neurology. Diseases of the nervous system, business, 030217 neurology & neurosurgery, Subthalamic nucleus stimulation, medicine.drug, Research Article
Abstract

Background. Treatment of freezing of gait (FOG) is always challenging because of its unpredictable nature and multifactorial physiopathology. Intestinal levodopa infusion has been proposed in recent years as a valuable option for its improvement. FOG in Parkinson’s disease (PD) can appear after deep brain stimulation in patients who never had gait symptoms. Objective. To study the effects of intestinal levodopa/carbidopa infusion in unresponsive-FOG that appears in PD patients treated with subthalamic nucleus deep brain stimulation. Methods. We retrospectively collected and analyzed demographic, clinical, and therapeutic data from five PD patients treated with subthalamic nucleus stimulation who developed unresponsive-FOG and received intestinal levodopa/carbidopa infusion as an alternative therapy. FOG was measured based on scores in item 14 of the Unified Parkinson’s Disease Rating Scale before and after intestinal levodopa infusion. Results. Administration of intestinal levodopa caused improvement of FOG in the “ON” state in four patients (80%) by 2 or more points in item 14 of the Unified Parkinson’s Disease Rating Scale. The improvement was maintained for at least 12 months. Conclusions. Intestinal levodopa infusion may be a valuable therapeutic option for unresponsive-FOG developed after subthalamic nucleus deep brain stimulation.

Published
2020

28. Identification of genetic variants associated with Huntington's disease progression

Author

Davina J Hensman Moss, Antonio F Pardiñas, Douglas Langbehn, Kitty Lo, Blair R Leavitt, Raymund Roos, Alexandra Durr, Simon Mead, Peter Holmans, Lesley Jones, Sarah J Tabrizi, A Coleman, R Dar Santos, J Decolongon, A Sturrock, E Bardinet, C Jauff Ret, D Justo, S Lehericy, C Marelli, K Nigaud, R Valabrègue, SJA van den Bogaard, E M Dumas, J van der Grond, EP t'Hart, C Jurgens, M-N Witjes-Ane, N Arran, J Callaghan, C Stopford, C Frost, R Jones, N Hobbs, N Lahiri, R Ordidge, G Owen, T Pepple, J Read, M Say, E Wild, A Patel, N C Fox, C Gibbard, I Malone, H Crawford, D Whitehead, S Keenan, D M Cash, C Berna, N Bechtel, S Bohlen, A Hoff Man, P Kraus, E Axelson, C Wang, T Acharya, S Lee, W Monaco, C Campbell, S Queller, K Whitlock, M Campbell, E Frajman, C Milchman, A O'Regan, I Labuschagne, J Stout, B Landwehrmeyer, D Craufurd, R Scahill, S Hicks, C Kennard, H Johnson, A Tobin, HD Rosas, R Reilmann, B Borowsky, C Pourchot, S C Andrews, Anne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael Bonelli, Jean-Marc Burgunder, Stephen Dunnett, Joaquim Ferreira, Olivia Handley, Arvid Heiberg, Torsten Illmann, G. Bernhard Landwehrmeyer, Jamie Levey, Maria A. Ramos-Arroyo, Jørgen Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A.C. Roos, A Rojo Sebastián, Sarah Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Monica Bascuñana Garde, Sabrina Betz, Reineke Bos, Jenny Callaghan, Adrien Come, Leonor Correia Guedes, Daniel Ecker, Ana Maria Finisterra, Ruth Fullam, Mette Gilling, Lena Gustafsson, Olivia J Handley, Carina Hvalstedt, Christine Held, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saül Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Michael Orth, Hélène Padieu, Laurent Paterski, Nadia Peppa, Martina Di Renzo, Amandine Rialland, Niini Røren, Pavla Šašinková, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Wildson Vieira da Silva, Marleen R van Walsem, Carina Whalstedt, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Raphael M. Bonelli, Sabine Lilek, Karen Hecht, Brigitte Herranhof, Anna Holl, Hans-Peter Kapfhammer, Michael Koppitz, Markus Magnet, Nicole Müller, Daniela Otti, Annamaria Painold, Karin Reisinger, Monika Scheibl, Helmut Schöggl, Jasmin Ullah, Eva-Maria Braunwarth, Florian Brugger, Lisa Buratti, Eva-Maria Hametner, Caroline Hepperger, Christiane Holas, Anna Hotter, Anna Hussl, Christoph Müller, Werner Poewe, Klaus Seppi, Fabienne Sprenger, Gregor Wenning, Andrea Boogaerts, Godelinde Calmeyn, Isabelle Delvaux, Dirk Liessens, Nele Somers, Michel Dupuit, Cécile Minet, Dominique van Paemel, Pascale Ribaï, Dimphna van Reijen, Jirí Klempír, Veronika Majerová, Jan Roth, Irena Stárková, Lena E. Hjermind, Oda Jacobsen, Jørgen E. Nielsen, Ida Unmack Larsen, Tua Vinther-Jensen, Heli Hiivola, Hannele Hyppönen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau, Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Rekha Barthélémy, Christelle De Bruycker, Maryline Cabaret Anne-Sophie Carette, Eric Decorte Luc Defebvre, Marie Delliaux, Arnaud Delval, Alain Destee, Kathy Dujardin, Marie-Hélène Lemaire, Sylvie Manouvrier, Mireille Peter, Lucie Plomhouse, Bernard Sablonnière, Clémence Simonin, Stéphanie Thibault-Tanchou, Isabelle Vuillaume, Marcellin Bellonet, Hassan Berrissoul, Stéphanie Blin, Françoise Courtin, Cécile Duru, Véronique Fasquel, Olivier Godefroy, Pierre Krystkowiak, Béatrice Mantaux, Martine Roussel, Sandrine Wannepain, Jean-Philippe Azulay, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Laura Mundler, Mathieu Anheim, Celine Julié, Ouhaid Lagha Boukbiza, Nadine Longato, Gabrielle Rudolf, Christine Tranchant, Marie-Agathe Zimmermann, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J. Werner, Harald Gelderblom, Josef Priller, Harald Prüß, Eike Jakob Spruth, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Peter Kotz, Christian Prehn, Carsten Saft, Herwig Lange, Robert Maiwald, Matthias Löhle, Antonia Maass, Simone Schmidt, Cecile Bosredon, Alexander Storch, Annett Wolz, Martin Wolz, Philipp Capetian, Johann Lambeck, Birgit Zucker, Kai Boelmans, Christos Ganos, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Heike Gorzolla, Christoph Schrader, Pawel Tacik, Michael Ribbat, Bernhard Longinus, Katrin Bürk, Jens Carsten Möller, Ida Rissling, Mark Mühlau, Alexander Peinemann, Michael Städtler, Adolf Weindl, Juliane Winkelmann, Cornelia Ziegler, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Eva Hölzner, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Natalia Weber, Matthias Dose, Gabriele Leythäuser, Ralf Marquard, Tina Raab, Alexandra Wiedemann, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Christina Lang, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süßmuth, Sonja Trautmann, Patrick Weydt, Claudia Cormio, Vittorio Sciruicchio, Claudia Serpino, Marina de Tommaso, Sabina Capellari, Pietro Cortelli, Roberto Galassi, Giovanni Rizzo, Roberto Poda, Cesa Scaglione, Elisabetta Bertini, Elena Ghelli, Andrea Ginestroni, Francesca Massaro, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giovanni Abbruzzese, Monica Bandettini di Poggio, Giovanna Ferrandes, Paola Mandich, Roberta Marchese, Alberto Albanese, Daniela Di Bella, Anna Castaldo, Stefano Di Donato, Cinzia Gellera, Silvia Genitrini, Caterina Mariotti, Lorenzo Nanetti, Dominga Paridi, Paola Soliveri, Chiara Tomasello, Giuseppe De Michele, Luigi Di Maio, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Elena Salvatore, Pierpaolo Sorrentino, Enrico Amico, Mariagrazia Favellato, Annamaria Griguoli, Irene Mazzante, Martina Petrollini, Ferdinando Squitieri, Barbara D'Alessio, Chiara Esposito, Rita Bentivoglio, Marina Frontali, Arianna Guidubaldi, Tamara Ialongo, Gioia Jacopini, Carla Piano, Silvia Romano, Francesco Soleti, Maria Spadaro, Monique S.E. van Hout, Marloes E. Verhoeven, Jeroen P.P. van Vugt, A. Marit de Weert, J.J.W. Bolwijn, M. Dekker, B. Kremer, K.L. Leenders, J.C.H. van Oostrom, Simon J.A. van den Bogaard, Eve M. Dumas, Ellen P. 't Hart, Berry Kremer, C.C.P. Verstappen, Olaf Aaserud, Jan Frich C, Ragnhild Wehus, Kathrine Bjørgo, Madeleine Fannemel, Per F. 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P., Aaserud, Olaf, Jan Frich, C., Wehus, Ragnhild, Bjã¸rgo, Kathrine, Fannemel, Madeleine, Gã¸rvell, Per F., Lorentzen, Eirin, Retterstã¸l, Lar, Stokke, Bodil, Bjã¸rnevoll, Inga, Sando, Sigrid Botne, Dziadkiewicz, Artur, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Blaszcyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasinska-Myga, Barbara, Klodowska-Duda, Gabriela, Opala, Gregorz, Stompel, Daniel, Banaszkiewicz, Krzysztof, Bocwinska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Malgorzata, Krawczyk, Malgorzata, Rudzinska, Monika, Szczygiel, Elzbieta, Szczudlik, Andrzej, Wasielewska, Anna, Wã³jcik, Magdalena, Bryl, Anna, Ciesielska, Anna, Klimberg, Aneta, Marcinkowski, Jerzy, Samara, Husam, Sempolowicz, Justyna, Gogol, Anna, Janik, Piotr, Kwiecinski, Hubert, Jamrozik, Zygmunt, Antczak, Jakub, Jachinska, Katarzyna, Krysa, Wioletta, Rakowicz, Maryla, Richter, Przemyslaw, Rola, Rafal, Ryglewicz, Danuta, Sienkiewicz-Jarosz, Halina, Stepniak, Iwona, Sulek, Anna, Zdzienicka, Elzbieta, Zieora-Jakutowicz, Karolina, Ferreira, Joaquim J, Coelho, Miguel, Mendes, Tiago, Valadas, Anabela, Andrade, Carlo, Gago, Miguel, Garrett, Carolina, Guerra, Maria Rosália, Herrera, Carmen Durán, Garcia, Patrocinio Moreno, Barbera, Miquel Aguilar, Guia, Dolors Badene, Hernanz, Laura Casa, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastiã¡n, Ana Rojo, Carruesco, Gemma Tome, Bas, Jordi, Busquets, Nãºria, Calopa, Matilde, Robert, Misericordia Floriach, Viladrich, Celia Mareca, Idiago, Jesús Miguel Ruiz, Riballo, Antonio Villa, Cubo, Esther, Polo, Cecilia Gil, Mariscal, Natividad, Rivadeneyra, Perez Jessica, Barrero, Francisco, Morales, Bla, Fenollar, Marã­a, Garcã­a, Rocío García-Ramo, Ortega, Paloma, Villanueva, Clara, Alegre, Javier, Bascuã±ana, Mã³nica, Caldentey, Juan Garcia, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Frech, Fernando Alonso, Ruã­z, Pedro J. García, Martínez-Descals, Asunciã³n, Guerrero, Rosa, Artiga, María José Saiz, Sã¡nchez, Vicenta, Perea, María Fuensanta Noguera, Fortuna, Lorenza, Manzanares, Salvadora, Reinante, Gema, Torres, María Martirio Antequera, Moreau, Laura Vivanco, González González, Sonia, Guisasola, Luis Menéndez, Salvador, Carlo, Martã­n, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazãº, Lopera, Mónica Rodriguez, Arques, Penelope Nava, Rodrã­guez, María José Torre, Pastor, Barbara Vive, Gaston, Itziar, Martinez-Jaurrieta, Maria Dolore, Moreno, Jose Manuel Garcia, Lucena, Carolina Mendez, Damas, Fatima, Cortegana, Hermoso Eva Pacheco, Peã±a, José Chacón, Redondo, Lui, Carrillo, Fã¡tima, Teresa Cáceres, Marã­a, Mir, Pablo, Suarez, María José Lama, Vargas-González, Laura, Bosca, Maria E., Brugada, Francisco Castera, Burguera, Juan Andre, Campos, Anabel, Vilaplana, Garcia Carmen Peiró, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, Høsterey-Ugander, Ulrika, Linnsand, Petra, Neleborn-Lingefjärd, Liselotte, Wentzel, Magnu, Loutfi, Ghada, Olofsson, Carina, Stattin, Eva-Lena, Westman, Laila, Wikstrã¶m, Birgitta, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schã¼pbach, Michael, Weber Zaugg, Sabine, Hauer, Maria, Gonzenbach, Roman, Jung, Hans H., Mihaylova, Violeta, Petersen, Jen, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, Simpson, Sheila A, Summers, Fiona, Ure, Alexandra, Vaughan, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Armstrong, Matthew, Barker, Roger A., O'Keefe, Deidre, Di Pietro, Anna, Fisher, Kate, Goodman, Anna, Hill, Susan, Kershaw, Ann, Mason, Sarah, Paterson, Nicole, Raymond, Lucy, Swain, Rachel, Guzman, Natalie Valle, Busse, Monica, Butcher, Cynthia, Clenaghan, Catherine, Hunt, Sarah, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Edwards, Maureen, Carrie, Ho, Hughes, Teresa, Mcgill, Marie, Pearson, Pauline, Porteous, Mary, Smith, Paul, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Burrows, Liz, Chu, Carol, Fletcher, Amy, Gallantrae, Deena, Hamer, Stephanie, Harding, Alison, Klã¶ppel, Stefan, Kraus, Alison, Laver, Fiona, Lewis, Monica, Longthorpe, Mandy, Markova, Ivana, Raman, Ashok, Robertson, Nicola, Silva, Mark, Thomson, Aileen, Wild, Sue, Yardumian, Pam, Evans, Carole, Gallentrae, Deena, Hobson, Emma, Jamieson, Stuart, Musgrave, Hannah, Rowett, Liz, Toscano, Jean, Bourne, Colin, Clapton, Jackie, Clayton, Carole, Dipple, Heather, Freire-Patino, Dawn, Grant, Janet, Gross, Diana, Hallam, Caroline, Middleton, Julia, Murch, Ann, Thompson, Catherine, Alusi, Sundu, Davies, Rhy, Foy, Kevin, Gerrans, Emily, Pate, Louise, Andrews, Thomasin, Dougherty, Andrew, Golding, Charlotte, Kavalier, Fred, Laing, Hana, Lashwood, Alison, Robertson, Dene, Ruddy, Deborah, Santhouse, Alastair, Whaite, Anna, Bruno, Stefania, Doherty, Karen, Haider, Salman, Hensman, Davina, Lahiri, Nayana, Novak, Marianne, Patel, Aakta, Rosser, Elisabeth, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Rogers, Dawn, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Armstrong, Richard, Dixon, Kathryn, Nemeth, Andrea H, Siuda, Gill, Valentine, Ruth, David, Harrison, Hughes, Max, Parkinson, Andrew, Soltysiak, Beverley, Bandmann, Oliver, Bradbury, Alyson, Gill, Paul, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Kazoka, Mbombe, O'Donovan, Kirsty, Taylor, Cat, Tidswell, Katherine, Quarrell, Oliver, Lau, Puay Ngoh, Pica, Emmanul, Tan, Louis, Amsterdam Neuroscience - Neurodegeneration, Neurology, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Moss, Davina J Hensman, Lo, Kitty, Pardiñas, Antonio F, Santos, R Dar, Ret, C Jauff, Valabrègue, R., Witjes-Ane, M. -N., Man, A Hoff, Bachoud-Lévi, Anne-Catherine, Nielsen, Jørgen, Päivärinta, Markku, Sebastián, A Rojo, Wahlström, Jan, Garde, Monica Bascuñana, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mütze, Lisanne, Padieu, Hélène, Røren, Niini, Šašinková, Pavla, Witjes-Ané, Marie-Noelle, Müller, Nicole, Schöggl, Helmut, Müller, Christoph, Minet, Cécile, Ribaï, Pascale, Klempír, Jirí, Majerová, Veronika, Stárková, Irena, Nielsen, Jørgen E., Hyppönen, Hannele, Gohier, Bénédicte, Guérid, Marie-Anne, Duché, Charlotte, Lafoucrière, Danielle, Barthélémy, Rekha, Lemaire, Marie-Hélène, Sablonnière, Bernard, Simonin, Clémence, Thibault-Tanchou, Stéphanie, Blin, Stéphanie, Courtin, Françoise, Duru, Cécile, Fasquel, Véronique, Mantaux, Béatrice, Fluchere, Frédérique, Julié, Celine, Prüß, Harald, Löhle, Matthia, Münchau, Alexander, Bürk, Katrin, Möller, Jens Carsten, Mühlau, Mark, Städtler, Michael, Hölzner, Eva, Leythäuser, Gabriele, Süßmuth, Sigurd, Marchese, Roberta, DI MAIO, Luigi, ’t Hart, Ellen P., Bjørgo, Kathrine, Gørvell, Per F., Retterstøl, Lar, Bjørnevoll, Inga, Wójcik, Magdalena, Guerra, Maria Rosália, Herrera, Carmen Durán, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastián, Ana Rojo, Busquets, Núria, Idiago, Jesús Miguel Ruiz, Fenollar, María, García, Rocío García-Ramo, Bascuñana, Mónica, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Ruíz, Pedro J García, Martínez-Descals, Asunción, Artiga, María José Saiz, Sánchez, Vicenta, Perea, María Fuensanta Noguera, Torres, María Martirio Antequera, González González, Sonia, Guisasola, Luis Menéndez, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Rodríguez, María José Torre, Peña, José Chacón, Carrillo, Fátima, Teresa Cáceres, María, Suarez, María José Lama, Vargas-González, Laura, Vilaplana, Garcia Carmen Peiró, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Wikström, Birgitta, Schüpbach, Michael, Ho, Carrie, Klöppel, Stefan, Harrison, David, Cardiff University, University of Iowa [Iowa City], University of British Columbia (UBC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UCL, Institute of Neurology [London], National Oceanography Centre [Southampton] (NOC), University of Southampton, Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), TRACK-HD investigators, Pardinas, Antonio F, Langbehn, Douglas, Lee, S Hong, TRACK-HD Investigators, and REGISTRY Investigators

Subjects
0301 basic medicine, Oncology, Registrie, Genome-wide association study, Longitudinal Studie, Disease, Bioinformatics, Severity of Illness Index, Principal Component Analysi, Longitudinal Studies, Registries, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Huntington disease, DNA-Binding Proteins, Settore MED/26 - NEUROLOGIA, Adult, Genome-Wide Association Study, Humans, Huntington Disease, MutS Homolog 3 Protein, Principal Component Analysis, Disease Progression, Neurology (clinical), huntingtin gene, age of onest, Huntington’s disease, Human, medicine.medical_specialty, cag repeat, instability, DNA-Binding Protein, Clinical Neurology, Principal component analysis, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, Huntington's disease, Internal medicine, medicine, SNP, genome-wide association study, medicine.disease, R1, meta-analysis, Minor allele frequency, 030104 developmental biology, Age of onset, Trinucleotide repeat expansion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Published
2017
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29. Efficacy of long-term continuous subcutaneous apomorphine infusion in advanced Parkinsonʼs disease with motor fluctuations: A multicenter study

Author

García Ruiz, Pedro J., Ignacio, Ángel Sesar, Pensado, Begoña Ares, García, Alfonso Castro, Frech, Fernando Alonso, López, Mercedes Álvarez, González, José Arbelo, Octavio, Joan Baiges, Burguera Hernández, Juan Andrés, Garriga, Matilde Calopa, Blanco, Dulce Campos, García, Belén Castaño, Cordero, Manuel Carballo, Peña, José Chacón, Ibáñez, Anna Espino, Onisalde, Aránzazu Gorospe, Giménez-Roldán, Santiago, Ibáñez, Pilar Granés, Vara, Jorge Hernández, Alonso, Ramón Ibáñez, Jiménez Jiménez, Félix Javier, Krupinski, Jerzy, Bojarsky, Jaime Kulisevsky, Ramírez, Inés Legarda, García, Elena Lezcano, Martínez-Castrillo, Juan Carlos, González, Dolores Mateo, Rodríguez, Francesc Miquel, Mir, Pablo, Fargas, Elena Muñoz, Inchausti, José Obeso, Romero, Jesús Olivares, Plana, José Olivé, Vallejo, Pilar Otermin, Sedano, Berta Pascual, de Colosía Rama, Víctor Pérez, López-Fraile, Isabel Pérez, Comes, Albert Planas, Periz, Víctor Puente, Rodríguez Oroz, María Cruz, García, Dolores Sevillano, Pérez, Pilar Solís, Muñoz, José Suárez, Gamo, Julia Vaamonde, Merino, Caridad Valero, Serra, Francesc Valldeoriola, Velázquez Pérez, José Miguel, Baña, Rosa Yáñez, and Capdepon, Ivana Zamarbide

Published
2008
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30. Cerebrospinal fluid cytokines in multiple system atrophy: A cross-sectional Catalan MSA registry study

Author

Matilde Calopa, Lluís Planellas, Ana Cámara, Esteban Muñoz, Darly M. Giraldo, Serge Jauma Classen, Asunción Ávila, Jorge Hernández-Vara, Rubén Fernández-Santiago, Francesc Valldeoriola, Paloma Bravo, Montserrat Pujol, Carles Gaig, J. Pagonabarraga, Mario Ezquerra, Teresa Botta, Neus Fabregat, Sara P. Dias, Miquel Aguilar, José Ríos, Manel Fernández, Marta Pulido-Salgado, Eduardo Tolosa, Àngels Bayés, Oriol De Fabregues, Gian Gaetano Tartaglia, Pau Pastor, Claustre Pont, Víctor Puente, Yaroslau Compta, Almudena Sánchez, Josep Saura, Jaume Campdelacreu, Celia Painous, Nuria Caballol, María José Martí, Alexandra Pérez-Soriano, and Graduate School

Subjects
0301 basic medicine, Eotaxin, Male, medicine.medical_specialty, Parkinson's disease, medicine.medical_treatment, Pilot Projects, Logistic regression, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Atrophy, CHLC NEU, Internal medicine, medicine, Humans, Registries, Aged, Inflammation, medicine.diagnostic_test, Receiver operating characteristic, Lumbar puncture, business.industry, Multiple system atrophy, Multiple System Atrophy, Middle Aged, medicine.disease, Biomarkers, Cytokines, Cross-Sectional Studies, Female, Spain, 030104 developmental biology, Cytokine, Neurology, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

Introduction: Neuroinflammation is a potential player in neurodegenerative conditions, particularly the aggressive ones, such as multiple system atrophy (MSA). Previous reports on cytokine levels in MSA using serum or cerebrospinal fluid (CSF) have been inconsistent, including small samples and a limited number of cytokines, often without comparison to Parkinson's disease (PD), a main MSA differential diagnosis. Methods: Cross-sectional study of CSF levels of 38 cytokines using a multiplex assay in 73 participants: 39 MSA patients (19 with parkinsonian type [MSAp], 20 with cerebellar type [MSAc]; 31 probable, 8 possible), 19 PD patients and 15 neurologically unimpaired controls. None of the participants was under non-steroidal anti-inflammatory drugs at the time of the lumbar puncture. Results: There were not significant differences in sex and age among participants. In global non-parametric comparisons FDR-corrected for multiple comparisons, CSF levels of 5 cytokines (FGF-2, IL-10, MCP-3, IL-12p40, MDC) differed among the three groups. In pair-wise FDR-corrected non-parametric comparisons 12 cytokines (FGF-2, eotaxin, fractalkine, IFN-α2, IL-10, MCP-3, IL-12p40, MDC, IL-17, IL-7, MIP-1β, TNF-α) were significantly higher in MSA vs. non-MSA cases (PD + controls pooled together). Of these, MCP-3 and MDC were the most significant ones, also differed in MSA vs. PD, and were significant MSA-predictors in binary logistic regression models and ROC curves adjusted for age. CSF levels of fractalkine and MIP-1α showed a strong and significant positive correlation with UMSARS-2 scores. Conclusion: Increased CSF levels of cytokines such as MCP-3, MDC, fractalkine and MIP-1α deserve consideration as potential diagnostic or severity biomarkers of MSA. info:eu-repo/semantics/publishedVersion

Published
2019

31. White matter cortico-striatal tracts predict apathy subtypes in Huntington's disease

Author

Jesús Pérez-Pérez, Celia Mareca, Nadia Rodriguez-Dechicha, Matilde Calopa, Jesus Ruiz-Idiago, Susana Subirà, Clara Garcia-Gorro, Audrey E De Paepe, Saul Martinez-Horta, Estela Camara, Jaime Kulisevsky, Joanna Sierpowska, Irene Vaquer, Ruth de Diego-Balaguer, Pilar Santacruz, and Esteban Muñoz

Subjects
Male, Caudate nucleus, Disease, lcsh:RC346-429, 0302 clinical medicine, Neural Pathways, Apathy, Cervell, 05 social sciences, Neurodegeneration, Brain, Cognition, Huntington's disease, Middle Aged, White Matter, Diffusion Tensor Imaging, Huntington Disease, medicine.anatomical_structure, Neurology, lcsh:R858-859.7, Female, medicine.symptom, Adult, Cognitive Neuroscience, Huntington's chorea, lcsh:Computer applications to medicine. Medical informatics, 050105 experimental psychology, Diffusion MRI, White matter, 03 medical and health sciences, Magnetic resonance imaging, Corea de Huntington, Imatges per ressonància magnètica, medicine, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, lcsh:Neurology. Diseases of the nervous system, Neuro- en revalidatiepsychologie, business.industry, Neuropsychology and rehabilitation psychology, medicine.disease, nervous system, Individual differences, White matter microstructure, Neurology (clinical), business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Background: Apathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited. Objectives: To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. Methods: Forty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains. Results: We elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract. Conclusions: The current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders. Keywords: Apathy, Diffusion MRI, Huntington's disease, Individual differences, Neurodegeneration, White matter microstructure

Published
2019

32. Nigral and striatal connectivity alterations in asymptomaticLRRK2mutation carriers: A magnetic resonance imaging study

Author

M. Quintana, Eduardo Tolosa, Hugo C. Baggio, Yaroslau Compta, María José Martí, Carme Junqué, Miquel Aguilar, Barbara Segura, Francesc Valldeoriola, Jorge Hernández-Vara, Àngels Bayés, Matilde Calopa, Claustre Pont-Sunyer, and Dolores Vilas

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, medicine.diagnostic_test, Resting state fMRI, Precuneus, Parietal lobe, Magnetic resonance imaging, Biology, Asymptomatic, nervous system diseases, Cuneus, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Neurology, Mutation (genetic algorithm), medicine, Neurology (clinical), medicine.symptom, Asymptomatic carrier, Neuroscience, 030217 neurology & neurosurgery
Abstract

Background The study of functional connectivity by means of magnetic resonance imaging (MRI) in asymptomatic LRRK2 mutation carriers could contribute to the characterization of the prediagnostic phase of LRRK2-associated Parkinson's disease (PD). The objective of this study was to characterize MRI functional patterns during the resting state in asymptomatic LRRK2 mutation carriers. Methods We acquired structural and functional MRI data of 18 asymptomatic LRRK2 mutation carriers and 18 asymptomatic LRRK2 mutation noncarriers, all first-degree relatives of LRRK2-PD patients. Starting from resting-state data, we analyzed the functional connectivity of the striatocortical and the nigrocortical circuitry. Structural brain data were analyzed by voxel-based morphometry, cortical thickness, and volumetric measures. Results Asymptomatic LRRK2 mutation carriers had functional connectivity reductions between the caudal motor part of the left striatum and the ipsilateral precuneus and superior parietal lobe. Connectivity in these regions correlated with subcortical gray-matter volumes in mutation carriers. Asymptomatic carriers also showed increased connectivity between the right substantia nigra and bilateral occipital cortical regions (occipital pole and cuneus bilaterally and right lateral occipital cortex). No intergroup differences in structural MRI measures were found. In LRRK2 mutation carriers, age and functional connectivity correlated negatively with striatal volumes. Additional analyses including only subjects with the G2019S mutation revealed similar findings. Conclusions Asymptomatic LRRK2 mutation carriers showed functional connectivity changes in striatocortical and nigrocortical circuits compared with noncarriers. These findings support the concept that altered brain connectivity precedes the onset of classical motor features in a genetic form of PD. © 2016 International Parkinson and Movement Disorder Society

Published
2016
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33. An active cognitive lifestyle as a potential neuroprotective factor in Huntington's disease

Author

Jaime Kulisevsky, Maria Garau-Rolandi, Nadia Rodriguez-Dechicha, Clara Garcia-Gorro, Esteban Muñoz, Irene Vaquer, Ruth de Diego-Balaguer, Saul Martinez-Horta, Matilde Calopa, Pilar Santacruz, Susana Subirà, Celia Mareca, Jesus Ruiz-Idiago, Jesús Pérez-Pérez, Anira Escrichs, and Estela Camara

Subjects
Male, Heterozygote, Cognitive Neuroscience, Rest, Experimental and Cognitive Psychology, Disease, 050105 experimental psychology, Executive functions, 03 medical and health sciences, Behavioral Neuroscience, Executive Function, 0302 clinical medicine, Cognition, Huntington's disease, Cognitive Reserve, Neural Pathways, medicine, Humans, 0501 psychology and cognitive sciences, Effects of sleep deprivation on cognitive performance, Resting-state fMRI, Neurodegeneration, Gray Matter, Life Style, Anterior cingulate cortex, Brain Mapping, Cognitive engagement, Resting state fMRI, 05 social sciences, Brain, Organ Size, Middle Aged, Protective Factors, medicine.disease, Magnetic Resonance Imaging, Neuroprotection, medicine.anatomical_structure, Huntington Disease, Disease Progression, Female, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

A cognitive stimulating lifestyle has been observed to confer cognitive benefits in multiple neurodegenerative diseases. However, the underlying neurobiological basis of this phenomenon remains unclear. Huntington's disease can provide a suitable model to study the effects and neural mechanisms of cognitive engagement in neurodegeneration. In this study, we investigate the effect of lifestyle factors such as education, occupation and engagement in cognitive activities in Huntington's disease gene carriers on cognitive performance and age of onset as well as the underlying neural changes sustaining these effects, measured by magnetic resonance imaging. Specifically, we analyzed both gray matter volume and the strength of connectivity of the executive control resting-state network. High levels of cognitive engagement were significantly associated with more preserved executive functions, a delay in the appearance of symptoms, reduced volume loss of the left precuneus and the bilateral caudate and a modulation of connectivity strength of anterior cingulate cortex and left angular gyrus with the executive control network. These findings suggest that a cognitively stimulating lifestyle may promote brain maintenance by modulating the executive control resting-state network and conferring protection against neurodegeneration, which results in a delayed onset of symptoms and improved performance in executive functions.

Published
2018

34. Cerebrospinal fluid levels of coenzyme Q10 are reduced in multiple system atrophy

Author

Francesc Valldeoriola, Lluís Planellas, Francesca Antonelli, Darly M. Giraldo, Serge Jaumà, Manel Fernández, Paloma Bravo, Claustre Pont-Sunyer, Mario Ezquerra, Josep Saura, Rubén Fernández-Santiago, Eduard Tolosa, Jaume Campdelacreu, Domenica Marchese, Nuria Caballol, Esteban Muñoz, María José Martí, Oriol De Fabregues, Pau Pastor, Montserrat Pujol, Matilde Calopa, Yaroslau Compta, Marta Soto, Ana Cámara, Víctor Puente, Gian Gaetano Tartaglia, Jorge Hernández-Vara, Teresa Botta-Orfila, Javier Pagonabarraga, Àngels Bayés, Ferran Torres, and Asunción Ávila

Subjects
0301 basic medicine, Male, Movement disorders, Parkinson's disease, Ubiquinone, Atypical parkinsonisms, chemistry.chemical_compound, 0302 clinical medicine, Cerebrospinal fluid, Supranuclear Palsy, Registries, Parkinson Disease, Middle Aged, Pathophysiology, Biomarker, Coenzyme Q10, Multiple system atrophy, Progressive supranuclear palsy, Aged, Biomarkers, Cross-Sectional Studies, Female, Humans, Multiple System Atrophy, Supranuclear Palsy, Progressive, Neurology, Biomarker (medicine), medicine.symptom, medicine.medical_specialty, 03 medical and health sciences, Atrophy, stomatognathic system, Progressive, Internal medicine, mental disorders, medicine, business.industry, medicine.disease, nervous system diseases, 030104 developmental biology, Endocrinology, nervous system, chemistry, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

Introduction The finding of mutations of the COQ2 gene and reduced coenzyme Q10 levels in the cerebellum in multiple system atrophy (MSA) suggest that coenzyme Q10 is relevant to MSA pathophysiology. Two recent studies have reported reduced coenzyme Q10 levels in plasma and serum (respectively) of MSA patients compared to Parkinson's disease and/or control subjects, but with largely overlapping values, limited comparison with other parkinsonisms, or dependence on cholesterol levels. We hypothesized that cerebrospinal fluid (CSF) is reliable to assess reductions in coenzyme Q10 as a candidate biomarker of MSA. Methods In this preliminary cross-sectional study we assessed CSF coenzyme Q10 levels in 20 patients with MSA from the multicenter Catalan MSA Registry and of 15 PD patients, 10 patients with progressive supranuclear palsy (PSP), and 15 control subjects from the Movement Disorders Unit Biosample Collection of Hospital Clinic de Barcelona. A specific ELISA kit was used to determine CSF coenzyme Q10 levels. CSF coenzyme Q10 levels were compared in MSA vs. the other groups globally, pair-wise, and by binary logistic regression models adjusted for age, sex, disease severity, disease duration, and dopaminergic treatment. Results CSF coenzyme Q10 levels were significantly lower in MSA than in other groups in global and pair-wise comparisons, as well as in multivariate regression models. Receiver operating characteristic curve analyses yielded significant areas under the curve for MSA vs. PD, PSP and controls. Conclusions These findings support coenzyme Q10 relevance in MSA. Low CSF coenzyme Q10 levels deserve further consideration as a biomarker of MSA.

Published
2018

35. Clinical and imaging markers in premotor LRRK2 G2019S mutation carriers

Author

Miquel Aguilar, Francisco Lomeña, Pilar Casquero, María José Martí, Dolores Vilas, Eduardo Tolosa, Ramiro Álvarez, Francesc Valldeoriola, Jorge Hernández-Vara, José Ríos, Víctor Puente, Claustre Pont-Sunyer, Oriol De Fabregues, Lourdes Ispierto, Yaroslau Compta, Serge Jaumà, Pilar Quílez, Jaume Campdelacreu, and Matilde Calopa

Subjects
Adult, Genetic Markers, Male, Heterozygote, medicine.medical_specialty, Pathology, Ultrasonography, Doppler, Transcranial, Population, Substantia nigra, Protein Serine-Threonine Kinases, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Asymptomatic, Gastroenterology, Young Adult, G2019s mutation, Internal medicine, medicine, Humans, education, Aged, Dopamine transporter, Aged, 80 and over, Tomography, Emission-Computed, Single-Photon, Dopamine Plasma Membrane Transport Proteins, education.field_of_study, biology, business.industry, Echogenicity, Parkinson Disease, Middle Aged, LRRK2, Transcranial Doppler, Substantia Nigra, Neurology, Mutation, biology.protein, Female, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, business
Abstract

Substantia nigra hyperechogenicity (SN+) has been proposed as a risk marker of Parkinson's disease (PD). Asymptomatic LRRK2 mutation carriers (aLRRK2+), at high risk for developing PD, provide an opportunity for the study of preclinical biomarkers.To assess SN echogenicity and other echographic features in LRRK2 G2019S carriers and their clinical and imaging correlates.Transcranial sonography was performed in 26 LRRK2 G2019S PD patients, 50 first-degree relatives, 31 idiopathic PD (IPD) patients and 26 controls. SN echogenicity and other echographic features were assessed in all study subjects. Dopamine transporter imaging (DAT-SPECT) was performed in 29 first-degree relatives.75% of the LRRK2-PD and 87.5% of the IPD showed SN+ (p = 0.087). aLRRK2+ had a higher frequency of SN+ than non carriers (58.3% vs. 25%, p = 0.039) and controls (58.3% vs. 12.5%; p = 0.002) and had a larger area of SN echogenicity than non carriers (p = 0.030) and controls (p0.001). The width of the third ventricle was significantly lower in LRRK2-PD than in IPD (1.9 mm [1.38; 2.75] vs. 3.0 mm [2.3; 5.3]; p = 0.003). Four out of 5 (80%) of the aLRRK2+ with an abnormal DAT-SPECT and four of the 5 (80%) of those with REM sleep behaviour disorder (RBD) had SN+.SN+ is very frequent in LRRK2-PD and aLRRK2+. Most aLRRK2 with possible surrogate markers of PD such as abnormal DAT-SPECT or RBD, also had SN+, which supports that this echofeature might be a marker of PD in these asymptomatic population.

Published
2015
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36. Long-term response to continuous duodenal infusion of levodopa/carbidopa gel in patients with advanced Parkinson disease: The Barcelona registry

Author

Berta Pascual-Sedano, Antonia Campolongo, Oriol de Fabregues-Nebot, Francesca Antonelli, Matilde Calopa, Mariateresa Buongiorno, Eduardo Tolosa, Ana Cámara, Jaime Kulisevsky, Francesc Valldeoriola, Jorge Hernández-Vara, María José Martí, and Víctor Puente

Subjects
Male, Dyskinesia, Drug-Induced, Levodopa, Pediatrics, medicine.medical_specialty, Duodenum, Perforation (oil well), Disease, Pharmacology, Antiparkinson Agents, medicine, Humans, Infusions, Parenteral, Registries, Adverse effect, Aged, Aged, 80 and over, Cellulite, Dyskinesias, business.industry, Carbidopa, Parkinson Disease, Middle Aged, medicine.disease, Treatment Outcome, Neurology, Dyskinesia, Spain, Female, Observational study, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, business, Gels, Follow-Up Studies, medicine.drug
Abstract

Introduction Continuous infusion of levodopa/carbidopa intestinal gel (LCIG) is an effective treatment for patients with advanced Parkinson Disease (PD) that cannot be further improved by oral therapy. Methods We conducted an observational, prospective, and multicenter study to collect, in a large sample of PD treated with LCIG, long-term information about the outcome and safety of the treatment. The assessments were performed before LCIG, 1, 3, 6 months after, and ever since, every 6 months. Results We studied 72 patients with a mean observation time of 22 months and a maximum of 48 months. During follow-up 28 patients discontinued the treatment, especially for lack of efficacy or adverse events related to the drug. We obtained a significant improvement of motor and non-motor fluctuations, mean off time and some non-motor symptoms. A significant increase in the percentage of time with dyskinesias was found in patients having less than 50% of the day with dyskinesias before LCIG. However, patients having already many dyskinesias before LCIG experienced a significant decrease of the troublesome dyskinesias, meaning that outcomes might be different depending on specific clinical characteristics. Adverse effects were in general minor but one case of intestinal perforation and one of abdominal cellulite were observed. Conclusions We confirmed that LCIG is a very effective treatment option for advanced PD; however considering the findings that dyskinesia can increase and the potential for serious side effects, we suggest the necessity for development of guidelines that better define the profile of responders.

Published
2015
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37. Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry

Author

Lacramioara Perju-Dumbrava, Lars Bergmann, Anjum Misbahuddin, Francesc Valldeoriola, Stephen Wørlich Pedersen, Chris van der Linden, Stephan Bohlhalter, Erik H. Danielsen, David, Maurizio Zibetti, Björn Hauptmann, Oriol De Fabregues, Ashley Yegin, Martin Nevrly, K. Ray Chaudhuri, Jeff Blackie, M.M. Ponsen, Christoph Redecker, Anne Jeanjean, Kenn Freddy Pedersen, Jan Kassubek, Mihaela Simu, Philippe Busson, Barbara A. Pickut, Pierre R. Burkhard, József Attila Szász, Per Odin, Bogdan Ovidiu Popescu, Ene Amalia, Angelo Antonini, Robert Jech, Thomas E. Kimber, Matthias Bode, Kari Anne Bjørnarå, Ivan Milanov, Bruno Bergmans, Espen Dietrichs, Luc Defebvre, Christofer Lundqvist, Jesper Clausen, Michaela Kaiserová, Valérie Delvaux, Werner Poewe, Martin Wolz, Sophie Dethy, Jaime Kulisevsky, Cleanthe Spanaki, Anette Storstein, Michel Rijntjes, F. Ory Magne, Pietro Marano, T. van Laar, Tove Henriksen, Christian Winkler, Ovidiu Bajenaru, Spyridon Konitsiotis, Michel Van Zandijcke, Ransmayr Gerhard, F. Viallet, Koray Onuk, Guy Arnold, Kirsten Hahn, Jo Leenders, Mariachiara Sensi, Jorge Hernández-Vara, Zikos Panayiotis, Nicola Modugno, Volker Tomantschger, Matilde Calopa, Zvezdan Pirtošek, Paul Bourgeois, Graziano Gusmaroli, Christoph Schrader, Ioan Buraga, Víctor Puente, Rejko Krüger, Alexander Storch, Tatiana Witjas, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, GLORIA study co-investigators, and Movement Disorder (MD)

Subjects
0301 basic medicine, Male, Parkinson's disease, Neurology, Routine patient care, Levodopa-carbidopa intestinal gel, Motor symptoms, Non-motor symptoms, Antiparkinson Agents, Levodopa, 0302 clinical medicine, Quality of life, Gériatrie - gérontologie, Medicine, Registries, Parkinson Disease/drug therapy, Intubation, Gastrointestinal, Carbidopa/administration & dosage, Carbidopa, Parkinson Disease, Middle Aged, Safety profile, Drug Combinations, Female, medicine.symptom, Gastrointestinal, medicine.medical_specialty, Levodopa/administration & dosage, 03 medical and health sciences, Rating scale, Internal medicine, Neurologie, Antiparkinson Agents/administration & dosage, Humans, Aged, business.industry, medicine.disease, nervous system diseases, ddc:616.8, 030104 developmental biology, Mood, Dyskinesia, Levodopa carbidopa, Physical therapy, Geriatrics and Gerontology, Neurology (clinical), Human medicine, Intubation, business, Gels, 030217 neurology & neurosurgery
Abstract

Introduction This registry evaluated the 24-month safety and efficacy of levodopa-carbidopa intestinal gel (LCIG) treatment in advanced Parkinson's disease (PD) patients under routine clinical care. Methods Motor fluctuations, dyskinesia, non-motor symptoms, quality of life, and safety were evaluated. Observations were fully prospective for treatment-naïve patients (60% of patients) and partially retrospective for patients with ≤12 months of pre-treatment with LCIG (40% of patients). Hours of “On” and “Off” time were assessed with a modified version of the Unified Parkinson's Disease Rating Scale part IV items 32 and 39. Results Overall, 375 patients were enrolled by 75 movement disorder centers in 18 countries and 258 patients completed the registry. At 24 months LCIG treatment led to significant reductions from baseline in “Off” time (hours/day) (mean ± SD = −4.1 ± 3.5, P < 0.001), “On” time with dyskinesia (hours/day) (−1.1 ± 4.8, P = 0.006), Non-Motor Symptom Scale total (−16.7 ± 43.2, P < 0.001) and individual domains scores, and Parkinson's Disease Questionnaire-8 item total score (−7.1 ± 21.0, P < 0.001). Adverse events deemed to have a possible/probable causal relationship to treatment drug/device were reported in 194 (54%) patients; the most frequently reported were decreased weight (6.7%), device related infections (5.9%), device dislocations (4.8%), device issues (4.8%), and polyneuropathy (4.5%). Conclusions LCIG treatment led to sustained improvements in motor fluctuations, non-motor symptoms particularly sleep/fatigue, mood/cognition and gastrointestinal domains, as well as quality of life in advanced PD patients over 24 months. Safety events were consistent with the established safety profile of LCIG., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2017
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38. Clinical manifestations of intermediate allele carriers in Huntington disease

Author

Cubo E., Ramos-Arroyo M. A., Martinez-Horta S., Martinez-Descalls A., Calvo S., Gil-Polo CAnne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael M Bonelli, Jean-Marc Burgunder, Stephen B Dunnett, Joaquim J Ferreira, Olivia J Handley, Arvid Heiberg, Torsten Illmann, G Bernhard Landwehrmeyer, Jamie Levey, Maria Ramos-Arroyo, Jørgen E Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A C Roos, Ana Rojo Sebastián, Sarah J Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Adrien Come, Leonor Correia Guedes, Ana Maria Finisterra, Monica Bascuñana Garde, Reineke Bos, Sabrina Betz, Jenny Callaghan, Selene Capodarca, Sébastien Charpentier, Wildson Vieira da Silva, Martina Di Renzo, Daniel Ecker, Ruth Fullam, Camille Genoves, Mette Gilling, Carina Hvalstedt, Christine Held, Andrea Horta-Barba, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saul Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Helene Padieu, Laurent Paterski, Nadia Peppa, Beate Rindal, Dawn Rogers, Niini Røren, Pavla Šašinková, Yuri Seliverstov, Catherine Taylor, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Marleen R van Walsem, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Elizaveta Yudina, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Cécile Minet, Pascale Ribaï, Dominique Van Paemel, Lena Hjermind, Oda Jacobsen, Suzanne Lindquist, Jørgen Nielsen, Lisbeth Regeur, Jette Stockholm, Ida Unmack Larsen, Christina Vangsted-Hansen, Tua Vinther-Jensen, Pia Eklund, Heli Hiivola, Hannele Hypponen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Julie Prouzet, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Anne-Catherine Bachoud-Lévi, Farideh Badei, Lotfi Boudali, Catherine Bourdet, Laurent Cléret, Maryline Couette, Cécile Focseneanu, Laurie Lemoine, Graça Morgado, Mehdi Sebaiti, Claire Thiriez, Laetitia Vervoitte, Katia Youssov, Jean-Philippe Azulay, Christelle Chabot, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Christine Garreau, Aicha Ghenam, Hélène Grosjean, Laura Mundler, Marielle Nowak, Roland Raseta, Maïté Bertrand, Fabienne Calvas, Samia Cheriet, Laurent Marquine, Michèle Pierre, Jérémie Pariente, Sandrine Rolland, Alice Seris, Valérie Vaquie, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J Werner, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Carsten Saft, Kai Boelmans, Christos Ganos, Ines Goerendt, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Michael Orth, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Flverly Francis, Sabine Gayde-Stephan, Heike Gorzolla, Bianca Kramer, Rebecca Minschke, Christoph Schrader, Pawel Tacik, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Nicole Göpfert, Eva Hölzner, Herwig Lange, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Nathalia Weber, Michael Bachmeier, Matthias Dose, Nina Hofstetter, Ralf Marquard, Alzbeta Mühlbäck, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süssmuth, Sonja Trautmann, Patrick Weydt, Stephan Klebe, Thomas Musacchio, Christine Leypold, Kerstin Nöth, Claudia Cormio, Marina de Tommaso, Anna Rita Dellomonaco, Olimpia Difruscolo, Giovanni Franco, Vittorio Sciruicchio, Claudia Serpino, Michela Figorilli, Francesco Marrosu, Antonella Muroni, Valeria Piras, Melisa Vacca, Caterina Bartoli, Elisabetta Bertini, Fernanda Fortunato, Elena Ghelli, Andrea Ginestroni, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giuseppe De Michele, Luigi Di Maio, Carlo Rinaldi, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Pierpaolo Sorrentino, Elena Salvatore, Tecla Tucci, Milena Cannella, Valentina Codella, Francesca De Gregorio, Annunziata De Nicola, Francesca Elifani, Tiziana Martino, Francesca Lovo, Irene Mazzante, Martina Petrollini, Maria Simonelli, Ferdinando Squitieri, Maurizio Vezza, Barbara D'Alessio, Chiara Esposito, Giulia Coarelli, Michela Ferraldeschi, Marina Frontali, Gioia Jacopini, Giovanni Ristori, Silvia Romano, Monique S E van Hout, Jeroen P P van Vugt, A Marit de Weert, Marloes Verhoeven, Simon J A van den Bogaard, Eve M Dumas, Ellen P 't Hart, Milou Jacobs, Anne Kampstra, Anne Schoonderbeek, Nils Olav Aanonsen, Olaf Aaserud, Liv Barnett, Kathrine Bjørgo, Nancy Borgerød, Elisabeth Dramstad, Madeleine Fannemel, Jan Frich, Helen Gundersen, Per Gørvell, Kathrine Haggag, Cecilie Haggag Johannessen, Lars Retterstøl, Oddveig Rosby, Jutta Rummel, Alma Sikiric, Olga Solberg, Marleen van Walsem, Ragnhild Wehus, Artur Dziadkiewicz, Agnieszka Konkel, Ewa Narożańska, Malgorzata Nowak, Piotr Robowski, Emilia Sitek, Jaroslaw Slawek, Witold Soltan, Michal Szinwelski, Michał Arkuszewski, Magdalena Błaszczyk, Magdalena Boczarska-Jedynak, Ewelina Ciach-Wysocka, Agnieszka Gorzkowska, Barbara Jasińska-Myga, Aleksandra Kaczmarczyk, Gabriela Kłodowska-Duda, Grzegorz Opala, Monika Rudzińska, Daniel Stompel, Krzysztof Banaszkiewicz, Dorota Boćwińska, Kamila Bojakowska-Jaremek, Małgorzata Dec, Natalia Grabska, Malgorzata Krawczyk, Ewelina Kubowicz, Michalina Malec-Litwinowicz, Agata Stenwak, Andrzej Szczudlik, Elżbieta Szczygieł, Magdalena Wójcik, Anna Wasielewska, Jacek Anioła Anna Bryl, Anna Ciesielska, Aneta Klimberg, Jerzy Marcinkowski, Husam Samara, Justyna Sempołowicz, Bartłomiej Wiśniewski, Anna Gogol, Piotr Janik, Zygmunt Jamrozik, Anna Kaminska, Hubert Kwiecinski, Jakub Antczak, Katarzyna Jachinska, Wioletta Krysa, Maryla Rakowicz, Przemyslaw Richter, Rafal Rola, Danuta Ryglewicz, Halina Sienkiewicz-Jarosz, Iwona Stępniak, Anna Sułek, Elzbieta Zdzienicka, Karolina Ziora-Jakutowicz, Cristina Januário, Filipa Júlio, Ana Salgueiro, Miguel Coelho, Tiago Mendes, Mário Miguel Rosa, Anabela Valadas, Cristina Semedo, Ana Calado, Joana Morgado, Margarida Dias, Manuel Almeida, Carmen Durán Herrera, Patrocinio Garcia Moreno, Jordi Bas, Núria Busquets, Matilde Calopa, Serge Jaumà Classen, Nadia Rodríguez Dedichá, Miquel Aguilar Barbera, Sonia Arribas Pardo, Dolors Badenes Guia, Noemi Calzado, Laura Casas Hernanz, Juan Pablo Tartari Díaz-Zorita, Judit López Catena, Pilar Quiléz Ferrer, Gemma Tome Carruesco, Misericordia Floriach Robert, Cèlia Mareca Viladrich, Elvira Roca, Jesús Miguel Ruiz Idiago, Antonio Villa Riballo, Antonia Campolongo, Ramon Fernandez de Bobadilla, Jaime Kulisevsky Bojarsky, Javier Pagonabarraga, Jesus Perez Perez, Carolina Villa, Maria Angeles Acera Gil, Koldo Berganzo Corrales, Juan Carlos Gomez Esteban, Amaia González, Beatriz Tijero Merino, Esther Cubo, Natividad Mariscal, Sandra Gutierrez Romero, José Matías Arbelo, Rocío Malo de Molina, Idaira Martín, Juan Manuel Periañez, Beatriz Udaeta, Fernando Alonso-Frech, Belén Frades, Marina Ávila Villanueva, Maria Ascension Zea Sevilla, Fernando Alonso Frech, María Del Mar Fenollar, Rocío García-Ramos García, Clara Villanueva, Mónica Bascuñana, Marta Fatás Ventura, Juan García Caldentey, Guillermo García Ribas, Justo García de Yébenes, José Luis López-Sendón Moreno, Verónica Mañanes Barral, Cici Feliz Feliz, Pedro José García Ruíz, Ana García, Rosa Guerrero López, Antonio Herranz Bárcenas, Asunción Martínez-Descals, Angel Martínez Pueyo, Veronica Puertas Martin, Noelia Rodríguez Martínez, María José Sainz Artiga, Vicenta Sánchez, Javier Del Val Fernandez, Carmen Antúnez Almagro, Salvadora Manzanares, Juan Marín Muñoz, María Martirio Antequera Torres, Fuensanta Noguera Perea, Laura Vivancos Moreau, Sonia González, Luis Menéndez Guisasola, Carlos Salvador, René Ribacoba, Pablo Sánchez Lozano, Marta Para Prieto, Aránzazu Gorospe, Inés Legarda Ramirez, Penelope Navas Arques, Monica Rodriguez Lopera, Barbara Vives Pastor, Itziar Gaston, Maria Antonia Ramos-Arroyo, Maria Dolores Martinez-Jaurrieta, José Manuel García Moreno, Carolina Mendez Lucena, José Chacón Peña, Fátima Damas Hermoso, Eva Pacheco Cortegana, Luis Redondo, Cristina Melgar Fernandez, Maite Paredes Mata, Maria Dolores Romero Lemos, Maria Bosca, Juan Andres Burguera, Francisco Castera Brugada Carmen Peiró Vilaplana, Elena Bellosta Diago, Javier López Del Val, Laura Martinez Martinez, Elena López, Peter Berglund, Radu Constantinescu, Gunnel Fredlund, Ulrika Høsterey-Ugander, Liselotte Neleborn-Lingefjärd, Yanik Stebler, Alain Kaelin, Irene Romero, Michael Schüpbach, Sabine Weber Zaugg, Lorna Downie, Roisin Jack, Kirsty Matheson, Zosia Miedzybrodzka, Daniela Rae, Sheila A Simpson, Fiona Summers, Alexandra Ure, Vivien Vaughn, Shahbana Akhtar, Jenny Crooks, Adrienne Curtis, Jenny de Souza, John Piedad, Hugh Rickards, Jan Wright, Elizabeth Coulthard, Louise Gethin, Beverley Hayward, Kasia Sieradzan, Monica Busse, Cynthia Butcher, Stephen Dunnett, Catherine Clenaghan, Sarah Hunt, Lesley Jones, Una Jones, Hanan Khalil, Michael Owen, Kathleen Price, Anne Rosser, Peter Brockie, Jillian Foster, Nicola Johns, Sue McKenzie, Jean Rothery, Gareth Thomas, Shona Yates, Alyson Andrew, Julie Frost, Rupert Noad, Jeremy Cosgrove, Deena Gallantree, Stephanie Hamer, Emma Hobson, Stuart Jamieson, Alison Kraus, Mandy Longthorpe, Ivana Markova, Hannah Musgrave, Caroline Peacy, Ashok Raman, Liz Rowett, Jean Toscano, Sue Wild, Carole Clayton, Pam Yardumian, Heather Dipple, Dawn Freire- Patino, Caroline Hallam, Julia Middleton, Uruj Anjum, Jan Coebergh, Charlotte Eddy, Nayana Lahiri, Meriel McEntagart, Michael Patton, Maria Peterson, Sarah Rose, Thomasin Andrews, Stefanie Brown, Stefania Bruno, Elvina Chu, Karen Doherty, Charlotte Golding, Salman Haider, Davina Hensman, Monica Lewis, Marianne Novak, Aakta Patel, Joy Read, Nicola Robertson, Elisabeth Rosser, Sarah Tabrizi, Rachel Taylor, Thomas Warner, Edward Wild, Natalie Arran, Judith Bek, David Craufurd, Marianne Hare, Liz Howard, Susan Huson, Liz Johnson, Mary Jones, Ashok Krishnamoorthy, Helen Murphy, Emma Oughton, Lucy Partington-Jones, Andrea Sollom, Julie Snowden, Cheryl Stopford, Jennifer Thompson, Iris Trender-Gerhard, Nichola Verstraelen, Leann Westmoreland, Ginette Cass, Lynn Davidson, Jill Davison, Neil Fullerton, Katrina Holmes, Suresh Komati, Sharon McDonnell, Zeid Mohammed, Karen Morgan, Lois Savage, Baldev Singh, Josh Wood, Andrea H Nemeth, Gill Siuda, Ruth Valentine, Kathryn Dixon, Richard Armstrong, David Harrison, Max Hughes, Sandra Large, John O Donovan, Amy Palmer, Andrew Parkinson, Beverley Soltysiak, Leanne Timings, Josh Williams, Oliver Bandmann, Alyson Bradbury, Helen Fairtlough, Kay Fillingham, Isabella Foustanos, Paul Gill, Mbombe Kazoka, Kirsty O'Donovan, Louise Nevitt, Oliver Quarrell, Cat Taylor, Katherine Tidswell, Lesley Gowers, Kingsley Powell, Pamela Bethwaite, Rachel Edwards, Kathleen Fuller, Michelle Phillips, Univ Angers, Okina, E., Cubo, M. A., Ramos-Arroyo, S., Martinez-Horta, A., Martinez-Descall, S., Calvo, CAnne-Catherine Bachoud-Lévi, Gil-Polo, Rita Bentivoglio, Anna, Biunno, Ida, M Bonelli, Raphael, Burgunder, Jean-Marc, B Dunnett, Stephen, J Ferreira, Joaquim, J Handley, Olivia, Heiberg, Arvid, Illmann, Torsten, Bernhard Landwehrmeyer, G, Levey, Jamie, Ramos-Arroyo, Maria, E Nielsen, Jørgen, Pro Koivisto, Susana, Päivärinta, Markku, C Roos, Raymund A, Rojo Sebastián, Ana, J Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlström, Jan, Zaremba, Jacek, Baake, Verena, Barth, Katrin, Come, Adrien, Correia Guedes, Leonor, Maria Finisterra, Ana, Bascuñana Garde, Monica, Bos, Reineke, Betz, Sabrina, Callaghan, Jenny, Capodarca, Selene, Charpentier, Sébastien, Vieira da Silva, Wildson, Di Renzo, Martina, Ecker, Daniel, Fullam, Ruth, Genoves, Camille, Gilling, Mette, Hvalstedt, Carina, Held, Christine, Horta-Barba, Andrea, Koppers, Kerstin, Lamanna, Claudia, Laurà, Matilde, Martínez Descals, Asunción, Martinez-Horta, Saul, Mestre, Tiago, Minster, Sara, Monza, Daniela, Mütze, Lisanne, Oehmen, Martin, Padieu, Helene, Paterski, Laurent, Peppa, Nadia, Rindal, Beate, Rogers, Dawn, Røren, Niini, Šašinková, Pavla, Seliverstov, Yuri, Taylor, Catherine, Timewell, Erika, Townhill, Jenny, Trigo Cubillo, Patricia, R van Walsem, Marleen, Witjes-Ané, Marie-Noelle, Witkowski, Grzegorz, Wright, Abigail, Yudina, Elizaveta, Zielonka, Daniel, Zielonka, Eugeniusz, Zinzi, Paola, Minet, Cécile, Ribaï, Pascale, Van Paemel, Dominique, Hjermind, Lena, Jacobsen, Oda, Lindquist, Suzanne, Nielsen, Jørgen, Regeur, Lisbeth, Stockholm, Jette, Unmack Larsen, Ida, Vangsted-Hansen, Christina, Vinther-Jensen, Tua, Eklund, Pia, Hiivola, Heli, Hypponen, Hannele, Martikainen, Kirsti, Tuuha, Katri, Allain, Philippe, Bonneau Marie Bost, Dominique, Gohier, Bénédicte, Guérid, Marie-Anne, Olivier, Audrey, Prouzet, Julie, Prundean, Adriana, Scherer-Gagou, Clarisse, Verny, Christophe, Babiloni, Blandine, Debruxelles, Sabrina, Duché, Charlotte, Goizet, Cyril, Jameau, Laetitia, Lafoucrière, Danielle, Spampinato, Umberto, Bachoud-Lévi, Anne-Catherine, Badei, Farideh, Boudali, Lotfi, Bourdet, Catherine, Cléret, Laurent, Couette, Maryline, Focseneanu, Cécile, Lemoine, Laurie, Morgado, Graça, Sebaiti, Mehdi, Thiriez, Claire, Vervoitte, Laetitia, Youssov, Katia, Azulay, Jean-Philippe, Chabot, Christelle, Delfini, Marie, Eusebio, Alexandre, Fluchere, Frédérique, Garreau, Christine, Ghenam, Aicha, Grosjean, Hélène, Mundler, Laura, Nowak, Marielle, Raseta, Roland, Bertrand, Maïté, Calvas, Fabienne, Cheriet, Samia, Marquine, Laurent, Pierre, Michèle, Pariente, Jérémie, Rolland, Sandrine, Seris, Alice, Vaquie, Valérie, Michael Kosinski, Christoph, Milkereit, Eva, Probst, Daniela, Reetz, Kathrin, Sass, Christian, Schiefer, Johanne, Schlangen, Christiane, J Werner, Corneliu, Ellrichmann, Gisa, Herrmann, Lennard, Hoffmann, Rainer, Kaminski, Barbara, Saft, Carsten, Boelmans, Kai, Ganos, Christo, Goerendt, Ine, Heinicke, Walburgi, Hidding, Ute, Lewerenz, Jan, Münchau, Alexander, Orth, Michael, Schmalfeld, Jenny, Stubbe, Lar, Zittel, Simone, Diercks, Gabriele, Dressler, Dirk, Francis, Flverly, Gayde-Stephan, Sabine, Gorzolla, Heike, Kramer, Bianca, Minschke, Rebecca, Schrader, Christoph, Tacik, Pawel, Bechtel, Natalie, Beckmann, Heike, Bohlen, Stefan, Göpfert, Nicole, Hölzner, Eva, Lange, Herwig, Reilmann, Ralf, Rohm, Stefanie, Rumpf, Silke, Schepers, Sigrun, Weber, Nathalia, Bachmeier, Michael, Dose, Matthia, Hofstetter, Nina, Marquard, Ralf, Mühlbäck, Alzbeta, Buck, Andrea, Connemann, Julia, Geitner, Carolin, Kesse, Andrea, Landwehrmeyer, Bernhard, Lezius, Franziska, Nepper, Solveig, Niess, Anke, Schneider, Ariane, Schwenk, Daniela, Süssmuth, Sigurd, Trautmann, Sonja, Weydt, Patrick, Klebe, Stephan, Musacchio, Thoma, Leypold, Christine, Nöth, Kerstin, Cormio, Claudia, de Tommaso, Marina, Rita Dellomonaco, Anna, Difruscolo, Olimpia, Franco, Giovanni, Sciruicchio, Vittorio, Serpino, Claudia, Figorilli, Michela, Marrosu, Francesco, Muroni, Antonella, Piras, Valeria, Vacca, Melisa, Bartoli, Caterina, Bertini, Elisabetta, Fortunato, Fernanda, Ghelli, Elena, Ginestroni, Andrea, Mechi, Claudia, Paganini, Marco, Piacentini, Silvia, Pradella, Silvia, Maria Romoli, Anna, Sorbi, Sandro, DE MICHELE, Giuseppe, Di Maio, Luigi, Rinaldi, Carlo, Massarelli, Marco, Peluso, Silvio, Roca, Alessandro, Russo, CINZIA VALERIA, Sorrentino, Pierpaolo, Salvatore, Elena, Tucci, Tecla, Cannella, Milena, Codella, Valentina, De Gregorio, Francesca, De Nicola, Annunziata, Elifani, Francesca, Martino, Tiziana, Lovo, Francesca, Mazzante, Irene, Petrollini, Martina, Simonelli, Maria, Squitieri, Ferdinando, Vezza, Maurizio, D'Alessio, Barbara, Esposito, Chiara, Coarelli, Giulia, Ferraldeschi, Michela, Frontali, Marina, Jacopini, Gioia, Ristori, Giovanni, Romano, Silvia, E van Hout, Monique S, P van Vugt, Jeroen P, Marit de Weert, A, Verhoeven, Marloe, A van den Bogaard, Simon J, M Dumas, Eve, P 't Hart, Ellen, Jacobs, Milou, Kampstra, Anne, Schoonderbeek, Anne, Olav Aanonsen, Nil, Aaserud, Olaf, Barnett, Liv, Bjørgo, Kathrine, Borgerød, Nancy, Dramstad, Elisabeth, Fannemel, Madeleine, Frich, Jan, Gundersen, Helen, Gørvell, Per, Haggag, Kathrine, Haggag Johannessen, Cecilie, Retterstøl, Lar, Rosby, Oddveig, Rummel, Jutta, Sikiric, Alma, Solberg, Olga, van Walsem, Marleen, Wehus, Ragnhild, Dziadkiewicz, Artur, Konkel, Agnieszka, Narożańska, Ewa, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Arkuszewski, Michał, Błaszczyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasińska-Myga, Barbara, Kaczmarczyk, Aleksandra, Kłodowska-Duda, Gabriela, Opala, Grzegorz, Rudzińska, Monika, Stompel, Daniel, Banaszkiewicz, Krzysztof, Boćwińska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Małgorzata, Grabska, Natalia, Krawczyk, Malgorzata, Kubowicz, Ewelina, Malec-Litwinowicz, Michalina, Stenwak, Agata, Szczudlik, Andrzej, Szczygieł, Elżbieta, Wójcik, Magdalena, Wasielewska, Anna, Anioła Anna Bryl, Jacek, Ciesielska, Anna, Klimberg, Aneta, Marcinkowski, Jerzy, Samara, Husam, Sempołowicz, Justyna, Wiśniewski, Bartłomiej, Gogol, Anna, Janik, Piotr, Jamrozik, Zygmunt, Kaminska, Anna, Kwiecinski, Hubert, Antczak, Jakub, Jachinska, Katarzyna, Krysa, Wioletta, Rakowicz, Maryla, Richter, Przemyslaw, Rola, Rafal, Ryglewicz, Danuta, Sienkiewicz-Jarosz, Halina, Stępniak, Iwona, Sułek, Anna, Zdzienicka, Elzbieta, Ziora-Jakutowicz, Karolina, Januário, Cristina, Júlio, Filipa, Salgueiro, Ana, Coelho, Miguel, Mendes, Tiago, Miguel Rosa, Mário, Valadas, Anabela, Semedo, Cristina, Calado, Ana, Morgado, Joana, Dias, Margarida, Almeida, Manuel, Durán Herrera, Carmen, Garcia Moreno, Patrocinio, Bas, Jordi, Busquets, Núria, Calopa, Matilde, Jaumà Classen, Serge, Rodríguez Dedichá, Nadia, Aguilar Barbera, Miquel, Arribas Pardo, Sonia, Badenes Guia, Dolor, Calzado, Noemi, Casas Hernanz, Laura, Pablo Tartari Díaz-Zorita, Juan, López Catena, Judit, Quiléz Ferrer, Pilar, Tome Carruesco, Gemma, Floriach Robert, Misericordia, Mareca Viladrich, Cèlia, Roca, Elvira, Miguel Ruiz Idiago, Jesú, Villa Riballo, Antonio, Campolongo, Antonia, Fernandez de Bobadilla, Ramon, Kulisevsky Bojarsky, Jaime, Pagonabarraga, Javier, Perez Perez, Jesu, Villa, Carolina, Angeles Acera Gil, Maria, Berganzo Corrales, Koldo, Carlos Gomez Esteban, Juan, González, Amaia, Tijero Merino, Beatriz, Cubo, Esther, Mariscal, Natividad, Gutierrez Romero, Sandra, Matías Arbelo, José, Malo de Molina, Rocío, Martín, Idaira, Manuel Periañez, Juan, Udaeta, Beatriz, Alonso-Frech, Fernando, Frades, Belén, Ávila Villanueva, Marina, Ascension Zea Sevilla, Maria, Alonso Frech, Fernando, Del Mar Fenollar, María, García-Ramos García, Rocío, Villanueva, Clara, Bascuñana, Mónica, Fatás Ventura, Marta, García Caldentey, Juan, García Ribas, Guillermo, García de Yébenes, Justo, Luis López-Sendón Moreno, José, Mañanes Barral, Verónica, Feliz Feliz, Cici, José García Ruíz, Pedro, García, Ana, Guerrero López, Rosa, Herranz Bárcenas, Antonio, Martínez-Descals, Asunción, Martínez Pueyo, Angel, Puertas Martin, Veronica, Rodríguez Martínez, Noelia, José Sainz Artiga, María, Sánchez, Vicenta, Del Val Fernandez, Javier, Antúnez Almagro, Carmen, Manzanares, Salvadora, Marín Muñoz, Juan, Martirio Antequera Torres, María, Noguera Perea, Fuensanta, Vivancos Moreau, Laura, González, Sonia, Menéndez Guisasola, Lui, Salvador, Carlo, Ribacoba, René, Sánchez Lozano, Pablo, Para Prieto, Marta, Gorospe, Aránzazu, Legarda Ramirez, Iné, Navas Arques, Penelope, Rodriguez Lopera, Monica, Vives Pastor, Barbara, Gaston, Itziar, Antonia Ramos-Arroyo, Maria, Dolores Martinez-Jaurrieta, Maria, Manuel García Moreno, José, Mendez Lucena, Carolina, Chacón Peña, José, Damas Hermoso, Fátima, Pacheco Cortegana, Eva, Redondo, Lui, Melgar Fernandez, Cristina, Paredes Mata, Maite, Dolores Romero Lemos, Maria, Bosca, Maria, Andres Burguera, Juan, Castera Brugada Carmen Peiró Vilaplana, Francisco, Bellosta Diago, Elena, López Del Val, Javier, Martinez Martinez, Laura, López, Elena, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schüpbach, Michael, Weber Zaugg, Sabine, Downie, Lorna, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, A Simpson, Sheila, Summers, Fiona, Ure, Alexandra, Vaughn, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Busse, Monica, Butcher, Cynthia, Dunnett, Stephen, Clenaghan, Catherine, Hunt, Sarah, Jones, Lesley, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Andrew, Alyson, Frost, Julie, Noad, Rupert, Cosgrove, Jeremy, Gallantree, Deena, Hamer, Stephanie, Hobson, Emma, Jamieson, Stuart, Kraus, Alison, Longthorpe, Mandy, Markova, Ivana, Musgrave, Hannah, Peacy, Caroline, Raman, Ashok, Rowett, Liz, Toscano, Jean, Wild, Sue, Clayton, Carole, Yardumian, Pam, Dipple, Heather, Freire- Patino, Dawn, Hallam, Caroline, Middleton, Julia, Anjum, Uruj, Coebergh, Jan, Eddy, Charlotte, Lahiri, Nayana, Mcentagart, Meriel, Patton, Michael, Peterson, Maria, Rose, Sarah, Andrews, Thomasin, Brown, Stefanie, Bruno, Stefania, Chu, Elvina, Doherty, Karen, Golding, Charlotte, Haider, Salman, Hensman, Davina, Lewis, Monica, Novak, Marianne, Patel, Aakta, Read, Joy, Robertson, Nicola, Rosser, Elisabeth, Tabrizi, Sarah, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Krishnamoorthy, Ashok, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Cass, Ginette, Davidson, Lynn, Davison, Jill, Fullerton, Neil, Holmes, Katrina, Komati, Suresh, Mcdonnell, Sharon, Mohammed, Zeid, Morgan, Karen, Savage, Loi, Singh, Baldev, Wood, Josh, H Nemeth, Andrea, Siuda, Gill, Valentine, Ruth, Dixon, Kathryn, Armstrong, Richard, Harrison, David, Hughes, Max, Large, Sandra, O Donovan, John, Palmer, Amy, Parkinson, Andrew, Soltysiak, Beverley, Timings, Leanne, Williams, Josh, Bandmann, Oliver, Bradbury, Alyson, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Gill, Paul, Kazoka, Mbombe, O'Donovan, Kirsty, Nevitt, Louise, Quarrell, Oliver, Taylor, Cat, Tidswell, Katherine, Gowers, Lesley, Powell, Kingsley, Bethwaite, Pamela, Edwards, Rachel, Fuller, Kathleen, Phillips, Michelle, Cubo, E., Ramos-Arroyo, M. A., Martinez-Horta, S., Martinez-Descalls, A., Russo, C. V., Calvo, S., Gil-Polo, C., Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Ramos-Arroyo, María A., Martínez-Descalls, Asunción, Calvo, Sara, and Gil-Polo, Cecilia

Subjects
0301 basic medicine, Registrie, Adult, Male, medicine.medical_specialty, Aging, Heterozygote, Genetic counseling, Motor Disorders, Disease, Severity of Illness Index, 03 medical and health sciences, Cognition Disorder, 0302 clinical medicine, Trinucleotide Repeats, Internal medicine, medicine, Humans, Registries, Allele, Motor Disorder, Alleles, Huntingtin Protein, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Medicine (all), Trinucleotide Repeat, Cognition, Genetic Status, Middle Aged, Phenotype, Europe, Settore MED/26 - NEUROLOGIA, 030104 developmental biology, Huntington Disease, Case-Control Studies, Cohort, medicine (all), neurology (clinical), controlled clinical trial (topic), Quality of Life, Female, Neurology (clinical), business, Case-Control Studie, Cognition Disorders, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Human
Abstract

International audience; OBJECTIVE: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry.METHODS: We assessed a cohort of participants at risk with RESULTS: Of 12,190 participants, 657 (5.38%) with CONCLUSIONS: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling.CLINICALTRIALSGOV IDENTIFIER: NCT01590589.

Published
2016

39. Placebo effect characteristics observed in a single, international, longitudinal study in Huntington's disease

Author

Anne-Catherine Bachoud-Lévi, Gregor Wenning, Josef Priller, Klaus Seppi, Matilde Calopa, Cyril Goizet, Carsten Saft, Josep Gamez, Piotr Janik, Jean-Francois Demonet, Georg Bernhard Landwehrmeyer, Miguel González, and Ines M. Del Puerto

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, education.field_of_study, Longitudinal study, Population, Retrospective cohort study, medicine.disease, Placebo, Clinical trial, Neurology, Huntington's disease, Rating scale, Internal medicine, mental disorders, Severity of illness, medicine, Physical therapy, Neurology (clinical), education, Psychology
Abstract

BACKGROUND Classically, clinical trials are based on the placebo-control design. Our aim was to analyze the placebo effect in Huntington's disease. METHODS Placebo data were obtained from an international, longitudinal, placebo-controlled trial for Huntington's disease (European Huntington's Disease Initiative Study Group). One-hundred and eighty patients were evaluated using the Unified Huntington Disease Rating Scale over 36 months. A placebo effect was defined as an improvement of at least 50% over baseline scores in the Unified Huntington Disease Rating Scale, and clinically relevant when at least 10% of the population met it. RESULTS Only behavior showed a significant placebo effect, and the proportion of the patients with placebo effect ranged from 16% (first visit) to 41% (last visit). Nondepressed patients with better functional status were most likely to be placebo-responders over time. CONCLUSIONS In Huntington's disease, behavior seems to be more vulnerable to placebo than overall motor function, cognition, and function

Published
2011
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40. Impact of apathy on health-related quality of life in recently diagnosed Parkinson's disease: The ANIMO study

Author

Gemma Mas Sese, Fernando Sanchez-Lopez, Antonio Callén, Raul Martinez-Fernandez, José Luis Sánchez Menoyo, Berta María Pascual Sedano, Pilar Sanchez, Matilde Calopa, JORGE HERNANDEZ-VARA, Lydia Lopez Manzanares, Teresa Bernal, Juan Carlos Gomez-Esteban, José Marey-Lopez, José María Ramirez-Moreno, Alberto Bergareche, Antonio Candeliere Merlicco, Francisco Escamilla Sevilla, and Oriol De Fabregues

Subjects
education.field_of_study, medicine.medical_specialty, business.industry, Population, Disease, Odds ratio, humanities, Confidence interval, Neurology, Quality of life, Rating scale, Internal medicine, medicine, Physical therapy, Outpatient clinic, Apathy, Neurology (clinical), medicine.symptom, education, business
Abstract

The impact of apathy on health-related quality of life (HRQOL) in recently diagnosed Parkinson's disease (PD) has not been systematically investigated. The objective of this cross-sectional survey (ANIMO study) was to examine the contribution of apathy to HRQOL in a Spanish sample of recently diagnosed PD patients. PD patients, diagnosed within 2 years of inclusion, were recruited at 102 outpatient clinics in 82 communities throughout Spain. Apathy was quantified using the Lille Apathy Rating Scale and HRQOL with the EuroQol-5D questionnaire. A mean EuroQol-5D index score of 0.89 obtained from population references in Spain was used as the cutoff for this study. The relationship between apathy and the dichotomized EuroQol-5D index score (

Published
2011
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41. Correlations between gray matter reductions and cognitive deficits in dementia with Lewy Bodies and Parkinson's disease with dementia

Author

Carme Junqué, Montserrat Juncadella, Cristina Sánchez-Castañeda, Ramón Reñé, Carles Falcon, Matilde Calopa, Serge Jaumà, Jaume Campdelacreu, Blanca Ramirez-Ruiz, and Jordi Gascon

Subjects
medicine.medical_specialty, Parkinson's disease, medicine.diagnostic_test, Dementia with Lewy bodies, Cognitive disorder, Audiology, medicine.disease, behavioral disciplines and activities, nervous system diseases, Central nervous system disease, Atrophy, nervous system, Neurology, Frontal lobe, mental disorders, medicine, Dementia, Neurology (clinical), Neuropsychological assessment, Psychology, Psychiatry
Abstract

There is controversy regarding whether Dementia with Lewy Bodies (DLB) and Parkinson's disease with dementia (PDD) may or not be different manifestations of the same disorder. The purpose of the present study was to investigate possible correlations between brain structure and neuropsychological functions in clinically diagnosed patients with DLB and PDD. The study sample consisted of 12 consecutively referred DLB patients, 16 PDD patients, and 16 healthy control subjects recruited from an outpatient setting, who underwent MRI and neuropsychological assessment. Voxel-based morphometry results showed that DLB patients had greater gray matter atrophy in the right superior frontal gyrus, the right premotor area and the right inferior frontal lobe compared to PDD. Furthermore, the anterior cingulate and prefrontal volume correlated with performance on the Continuous Performance Test while the right hippocampus and amygdala volume correlated with Visual Memory Test in the DLB group. In conclusion, DLB patients had more fronto-temporal gray matter atrophy than PDD patients and these reductions correlated with neuropsychological impairment.

Published
2009
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42. Nigral and striatal connectivity alterations in asymptomatic LRRK2 mutation carriers: A magnetic resonance imaging study

Author

Dolores, Vilas, Bàrbara, Segura, Hugo C, Baggio, Claustre, Pont-Sunyer, Yaroslau, Compta, Francesc, Valldeoriola, María, José Martí, María, Quintana, Angels, Bayés, Jorge, Hernández-Vara, Matilde, Calopa, Miquel, Aguilar, Carme, Junqué, and Eduardo, Tolosa

Subjects
Adult, Cerebral Cortex, Male, Prodromal Symptoms, Parkinson Disease, Middle Aged, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Magnetic Resonance Imaging, Nuclear Family, Neostriatum, Substantia Nigra, Mutation, Connectome, Humans, Female
Abstract

The study of functional connectivity by means of magnetic resonance imaging (MRI) in asymptomatic LRRK2 mutation carriers could contribute to the characterization of the prediagnostic phase of LRRK2-associated Parkinson's disease (PD). The objective of this study was to characterize MRI functional patterns during the resting state in asymptomatic LRRK2 mutation carriers.We acquired structural and functional MRI data of 18 asymptomatic LRRK2 mutation carriers and 18 asymptomatic LRRK2 mutation noncarriers, all first-degree relatives of LRRK2-PD patients. Starting from resting-state data, we analyzed the functional connectivity of the striatocortical and the nigrocortical circuitry. Structural brain data were analyzed by voxel-based morphometry, cortical thickness, and volumetric measures.Asymptomatic LRRK2 mutation carriers had functional connectivity reductions between the caudal motor part of the left striatum and the ipsilateral precuneus and superior parietal lobe. Connectivity in these regions correlated with subcortical gray-matter volumes in mutation carriers. Asymptomatic carriers also showed increased connectivity between the right substantia nigra and bilateral occipital cortical regions (occipital pole and cuneus bilaterally and right lateral occipital cortex). No intergroup differences in structural MRI measures were found. In LRRK2 mutation carriers, age and functional connectivity correlated negatively with striatal volumes. Additional analyses including only subjects with the G2019S mutation revealed similar findings.Asymptomatic LRRK2 mutation carriers showed functional connectivity changes in striatocortical and nigrocortical circuits compared with noncarriers. These findings support the concept that altered brain connectivity precedes the onset of classical motor features in a genetic form of PD. © 2016 International Parkinson and Movement Disorder Society.

Published
2015

43. Age at Onset in LRRK2-Associated PD is Modified by SNCA Variants

Author

María José Martí, Francesc Valldeoriola, Teresa Botta-Orfila, Oswaldo Lorenzo-Betancor, Manel Fernández, Eduard Tolosa, Yaroslau Compta, Miquel Aguilar, Claustre Pont-Sunyer, Mario Ezquerra, Rubén Fernández-Santiago, Jorge Hernández-Vara, Matilde Calopa, Pau Pastor, Lluis Samaranch, and Oriol de Fabregas

Subjects
Adult, Male, medicine.medical_specialty, Neurology, Genotype, Genes, Recessive, Disease, Protein Serine-Threonine Kinases, Biology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Proteomics, Polymorphism, Single Nucleotide, Cellular and Molecular Neuroscience, medicine, Humans, Neurochemistry, Age of Onset, Gene, Aged, Genes, Dominant, Genetics, Kinase, Genetic variants, Genetic Variation, Parkinson Disease, General Medicine, Middle Aged, LRRK2, nervous system diseases, alpha-Synuclein, Female
Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) and α-synuclein (SNCA) genes are known genetic causes of Parkinson's disease (PD). Recently, a genetic variant in SNCA has been associated with a lower age at onset in idiopathic PD (IPD). We genotyped the SNCA polymorphism rs356219 in 84 LRRK2-associated PD patients carrying the G2019S mutation. We found that a SNCA genetic variant is associated with an earlier age at onset in LRRK2-associated PD. Our results support the notion that SNCA variants can modify the pathogenic effect of LRRK2 mutations as described previously for IPD.

Published
2012
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44. Further extension of the H1 haplotype associated with progressive supranuclear palsy

Author

José Luis Molinuevo, María José Martí, Mario Ezquerra, Matilde Calopa, Pau Pastor, Esteban Muñoz, Eduardo Tolosa, Rafael Oliva, and Francesc Valldeoriola

Subjects
Genetics, Mutation, biology, Haplotype, Tau protein, Single-nucleotide polymorphism, medicine.disease, medicine.disease_cause, eye diseases, Progressive supranuclear palsy, Exon, Neurology, Genotype, medicine, biology.protein, Neurology (clinical), Allele
Abstract

The recent finding of disequilibrium among several polymorphisms along the tau gene and the strong association of one of the two haplotypes formed by these polymorphisms (H1) with progressive supranuclear palsy (PSP) suggests that a single allele in or near the tau gene at 17q21 is responsible for increased risk in most of the PSP cases. We sought to determine whether mutations in the tau gene are responsible for the disease in 45 sporadic PSP patients. Furthermore, we analyzed some markers located in the common region of linkage (D17S800-D17S791), associated with some cases of familial frontotemporal dementia (FTDP-17), and the SNPs rs1816 and rs937 close to the tau gene, to determine their possible association with sporadic PSP. We did not find pathogenic mutations in exons 9, 10, 12, or 13 of the tau gene, indicating that tau mutations in both the splice-site region of the exon 10 and in the microtubule-binding region of tau gene are not a cause of PSP in this study group. We found significant overrepresentation of the haplotypes H1, extended up to the promoter of the tau gene (H1P), in PSP patients as compared with controls. In addition, a significant overrepresentation of the D17S810 2/2 and 3/2 genotypes, of the SNP rs1816 A/A, and of the SNP rs937 delG/delG genotypes was detected in PSP, further extending the haplotype described previously. These results are consistent with the hypothesis that a change either in the 5' or in the 3' flanking regions of the tau gene, or even other genes contained in the H1E haplotype, could increase the genetic susceptibility to PSP.

Published
2002
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45. Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson's Disease

Author

Mario Ezquerra, Dolores Vilas, Matilde Calopa, Carles Gaig, Jon Infante, María Sierra, Inés García-Gorostiaga, Mariateresa Buongiorno, Miquel Aguilar, Francesc Valldeoriola, María José Martí, Eduardo Tolosa, Jorge Hernández-Vara, and Universidad de Cantabria

Subjects
Male, Sleep Wake Disorders, Pediatrics, medicine.medical_specialty, Constipation, Parkinson's disease, Mutation, Missense, Excessive daytime sleepiness, lcsh:Medicine, Disease, Protein Serine-Threonine Kinases, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Olfaction Disorders, Sex Factors, Hyposmia, Malaltia de Parkinson, medicine, Medicine and Health Sciences, Humans, Psychiatry, lcsh:Science, Depression (differential diagnoses), Trastorns del son, Aged, Multidisciplinary, Movement Disorders, business.industry, Depression, Parkinsonism, lcsh:R, Case-control study, Neurodegenerative Diseases, Parkinson Disease, Sleep disorders, Middle Aged, medicine.disease, nervous system diseases, Neurology, Case-Control Studies, Female, lcsh:Q, medicine.symptom, business, Research Article
Abstract

BACKGROUND: Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. OBJECTIVE: To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. METHODS: The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. RESULTS: University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p

Published
2014

46. D24 Intact emotional impulsivity in huntington’s disease despite altered structural connectivity in the uncinate fasciculus

Author

Clara Garcia-Gorro, Nuria Caballol, Pilar Santacruz, Celia Mareca, Estela Camara, Matilde Calopa, Irene Vaquer, Jesus M Ruiz, Susana Subirà, Nadia Rodriguez-Dechicha, Esteban Muñoz, Jaime Kulisevsky, Silvia Marco-Garcia, Saul Martinez-Horta, J. M. Pérez, Joan Orpella-Garcia, and Ruth de Diego-Balaguer

Subjects
Cued speech, Emotional impulsivity, medicine.medical_specialty, business.industry, media_common.quotation_subject, Uncinate fasciculus, Audiology, Impulsivity, medicine.disease, Developmental psychology, Psychiatry and Mental health, Huntington's disease, medicine, Impulse (psychology), Trait, Surgery, Neurology (clinical), medicine.symptom, business, media_common, Diffusion MRI
Abstract

Background Impulsivity in Huntington’s disease (HD) patients has been understudied despite its clear impact in daily life. Although it is known that there are different types of impulsivity, this trait has been mainly studied through impulsive actions in cued go/no-go tasks that contain an important motor component, while the more purely emotional/choice component of impulsivity in HD remains unknown. Objective To study the neurobiological basis that characterise individual differences in emotional impulsivity in HD. Methods Thirty-one controls and 32 HD patients (11 of which were pre-symptomatic) were scanned using diffusion tensor imaging (DTI) to study the relationship between the structural connectivity of the uncinate fasciculus (UF), the main tract involved in the motivational circuit, and the impulsivity trait (k), evaluated with a delay discounting task. Results No significant difference was observed in k between the two groups. In controls, k correlated with both right and left UF, whereas in HD patients, k correlated only with the left UF. On the other hand, only the right UF was found to be affected in HD patients compared with controls. Conclusion This study reveals that HD patients do not differ from controls in the impulse behaviour associated with delay discounting choices. Moreover, the connectivity pattern observed in HD patients and controls is consistent with previous studies that show that individual differences in microstructure integrity of the left UF are related to impulsivity levels in delay discounting tasks.

Published
2016
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47. D23 The effect of cognitive reserve on age of onset and executive functions in huntington’s disease and its neurobiological bases

Author

Estela Camara, Nuria Caballol, Nadia Rodriguez-Dechicha, Clara Garcia-Gorro, Celia Mareca, Jesus M Ruiz, Saul Martinez-Horta, Jaime Kulisevsky, J. M. Pérez, Susana Subirà, Matilde Calopa, Maria Garau-Rolandi, Irene Vaquer, Ruth de Diego-Balaguer, Pilar Santacruz, Esteban Muñoz, and Anira Escrichs

Subjects
Resting state fMRI, Working memory, Cognitive flexibility, Precuneus, medicine.disease, Executive functions, Psychiatry and Mental health, medicine.anatomical_structure, Huntington's disease, medicine, Surgery, Neurology (clinical), Age of onset, Psychology, Neuroscience, Cognitive reserve
Abstract

Background Although age of onset of Huntington’s disease (HD) is mainly determined by the size of the CAG repeat expansion, other factors may play a role. One potential factor is Cognitive Reserve (CR), as it has been shown in other neurodegenerative disorders and ageing. Objective The objective of this study is to investigate the effect of CR on age of onset in HD and to examine the neural bases underlying the individual differences in executive function that could be due to the effects of CR in HD. Methods Thirty-one HD patients completed a CR questionnaire and were scanned using functional magnetic resonance imaging. We analysed the Resting State Executive Control Network (RS-ECN), a novel approach to study the brain areas underlying executive function. The strength of connectivity with this network was calculated voxel-wise. The difference between the theoeretical and estimated age of onset (26 symptomatic-HD) was calculated for each patient. Results Our results revealed that high levels of CR significantly delayed the appearance of clinical symptoms. Functional connectivity and morphometry analysis showed a brain reorganisation modulated by CR, which changed the connectivity strength in the anterior cingulate cortex, in the left superior parietal cortex (SPC) and slowed the volume loss in the bilateral precuneus and the bilateral caudate. Furthermore, higher strength of connectivity in the left SPC was related to better performance in cognitive flexibility (TMT B-A) and working memory (Backward Digits Span) tasks. Conclusions These findings provide converging evidence that CR might act as a protective mechanism for the progression of the disease, delaying the onset of symptoms and improving the performance in executive functions by modulating the RS-ECN and slowing brain atrophy.

Published
2016
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48. Clinical Correlates of Apathy in Patients Recently Diagnosed with Parkinson's Disease: The ANIMO Study

Author

Gemma Mas Sese, Antonio Callén, Raul Martinez-Fernandez, José Luis Sánchez Menoyo, Laura Gonzalez-Mera, Pilar Sanchez, Matilde Calopa, JORGE HERNANDEZ-VARA, José Marey-Lopez, José María Ramirez-Moreno, Alberto Bergareche, and Oriol De Fabregues

Subjects
Male, medicine.medical_specialty, Parkinson's disease, Epidemiology, Cross-sectional study, Apathy, Comorbidity, Lower risk, Sex Factors, Rating scale, Risk Factors, Internal medicine, Activities of Daily Living, medicine, Prevalence, Outpatient clinic, Humans, Sex Distribution, Psychiatry, Depression (differential diagnoses), Aged, Original Paper, business.industry, Depression, Parkinson Disease, medicine.disease, Cross-Sectional Studies, Spain, Educational Status, Regression Analysis, Female, Neurology (clinical), medicine.symptom, business
Abstract

Objective: Little is known about apathy in the early stages of Parkinson’s disease (PD). We determined the clinical correlates of apathy in a large representative sample of patients recently diagnosed with PD (ANIMO study). Methods: PD patients, diagnosed within 2 years of inclusion, were recruited in 102 outpatient clinics situated in 82 populations throughout Spain. Apathy was quantified using the Lille Apathy Rating Scale (LARS). Clinical comparisons and correlations were performed using nonparametric tests. Regression analyses were used to test the association of clinical variables with apathy. Results: We recruited 557 PD patients (60.3% men) with a mean age of 68.8 ± 9.7 years, and UPDRS motor score of 21.1 ± 10.8. Apathy only was diagnosed in 186 (33.4%), and apathy and depression in 215 patients (38.6%). Patients with higher comorbidity (OR = 1.10, 95% CI 1.01–1.20, p = 0.001), motor impairment (OR = 1.07, 95% CI 1.03–1.10, p < 0.0001), and lower education (OR = 2.16, 95% CI 1.21–3.85, p = 0.009) had higher odds of having apathy, in contrast to patients living in a rural environment (OR = 0.35, 95% CI 0.32–0.85, p = 0.01), and left predominant PD motor laterality (OR = 0.34, 95% CI 0.13–0.88, p = 0.01). LARS scores were significantly correlated with UPDRS motor scores (rs = 0.44, p < 0.001), predominantly with axial score (rs = 0.43, p < 0.001). Conclusions: In PD, apathy is a very common and disabling nonmotor symptom separable from depression. Patients living in a rural environment, with lower comorbidity and motor impairment, higher education background, and left predominant PD motor laterality are at lower risk of suffering from apathy.

Published
2012

49. Bilateral striatal lesions in childhood

Author

Alfons Macaya, Matilde Calopa, Alex Rovira, Milagros Losada, Manuel Roig, and Encarnacion Riudor

Subjects
Male, medicine.medical_specialty, Lesion, Central nervous system disease, Necrosis, Basal Ganglia Diseases, Developmental Neuroscience, Seizures, Basal ganglia, medicine, Humans, Child, Retrospective Studies, Ultrasonography, Dystonia, Athetosis, medicine.diagnostic_test, business.industry, Infant, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Corpus Striatum, Hypotonia, Surgery, Treatment Outcome, Neurology, El Niño, Child, Preschool, Pediatrics, Perinatology and Child Health, Consciousness Disorders, Female, Neurology (clinical), Radiology, medicine.symptom, Tomography, X-Ray Computed, business
Abstract

From 1983 to 1991, 13 patients were identified with a clinical radiologic association characterized by acute or persistent neurologic dysfunction and bilateral lesions in the basal ganglia region demonstrated by ultrasound, computed tomography, or magnetic resonance imaging. Initial clinical manifestations of this group of patients were characterized by extrapyramidal signs (i.e., dystonia 9, hypotonia 2, athetosis 1, rigidity 1), altered state of consciousness in 5, and seizures in 3. The outcomes of most of these patients were poor: 10 had motor sequelae, 9 cognitive impairment, and 4 died. The outcomes of 2 patients, however, were much better than what was expected from the initial presentation. Based on current and previous reports, the diagnostic approach and classification of patients with neurologic dysfunction and bilateral striatal lesions are presented.

Published
1993
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50. E26 Abnormal Functional Connectivity in Huntington's Disease During a Sequential Motor Task

Author

Matilde Calopa, Nuria Caballol, Celia Mareca, R. de Diego-Balaguer, Nadia Rodriguez-Dechicha, Pilar Santacruz, Jaume Kulisevsky, Jesús Pérez-Pérez, Adrià Vila, Irene Vaquer, Jesus M Ruiz, Susana Subirà, Saul Martinez-Horta, C García-Gorro, Estela Camara, and Esteban Muñoz

Subjects
medicine.medical_specialty, Cerebellum, Brain activity and meditation, Putamen, Functional connectivity, Thalamus, Dopaminergic, medicine.disease, SMA, Psychiatry and Mental health, medicine.anatomical_structure, nervous system, Huntington's disease, Internal medicine, medicine, Cardiology, Surgery, Neurology (clinical), Psychology, Neuroscience
Abstract

Introduction Huntington’s disease (HD) is a neurodegenerative disorder that induces striatal and cortical neuronal dysfunction and loss which main symptom is motor impairment. Goals to study whether this motor impairment is accompanied by changes in brain activity and functional connectivity. Methods Fifteen early stage HD patients with a UHDRS motor score > 5 (9 men, mean age = 48 ± 8.9, mean TFC = 11.7 ± 1.17) and 15 controls (9 men, mean age = 46.6 ± 8.1) matched in age, gender and educational background underwent 3T structural and functional MRI scanning while they performed a sequential tapping task with their right or left hand in alternated blocks. Results Compared to rest blocks, active tapping activated the contralateral primary motor, premotor and supplementary motor areas, thalamus and cerebellum in both patients and controls. However, in the right hand condition, patients deactivated the right putamen to a greater extent than controls, which suggests that patients need a greater inhibition of the ipsilateral putamen in order to suppress the movement of the opposite hand. Furthermore, HD patients showed less activation in the right putamen during the left hand condition compared to controls. These effects could be ascribed to the general imbalance in the Go and No-Go cortico-striatal pathways that is believed to occur in HD. The left precentral gyrus, was selected as a seed region for a whole brain functional connectivity analysis. Compared with controls, right precentral gyrus, right SMA and right putamen were more connected (negatively) to the left precentral gyrus in patients. This indicates that not only the right putamen, but all the right motor circuit undergoes a greater deactivation in HD patients when they move their left hand. In addition, the negative functional connectivity between the left precentral gyrus and the right putamen showed a positive correlation with the motor-UHDRS score and the TFC score. Conclusions These results indicate that HD patients need to inhibit the contralateral motor circuit of the moving hand to compensate for the hyperactivation of the dopaminergic system that underlies their motor symptoms. This effect is specific to the right hemisphere, showing an asymmetry of the motor circuit dysfunction.

Published
2014
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