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1. Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes

Author: Federal Ministry of Education and Research (Germany), German Research Foundation, Jesús Maestre, Silvia [0000-0002-1874-4628], Mir, Pablo [0000-0003-1656-302X], Thomsen, Mirja, Marth, Katrin, Loens, Sebastian, Everding, Judith, Junker, Johanna, Borngräber, Friederike, Ott, Fabian, Jesús Maestre, Silvia, Gelderblom, Mathias, Odorfer, Thorsten, Kuhlenbäumer, Gregor, Kim, Han-Joon, Schaeffer, Eva, Becktepe, Jos, Kasten, Meike, Brüggemann, Norbert, Pfister, Robert, Kollewe, Katja, Krauss, Joachim K., Lohmann, Ebba, Hinrichs, Frauke, Berg, Daniela, Jeon, Beomseok, Busch, Hauke, Altenmüller, Eckart, Mir, Pablo, Kamm, Christoph, Volkmann, Jens, Zittel, Simone, Ferbert, Andreas, Zeuner, Kirsten E., Rolfs, Arndt, Bauer, Peter, Kühn, Andrea A., Bäumer, Tobias, Klein, Christine, Lohmann, Katja, Federal Ministry of Education and Research (Germany), German Research Foundation, Jesús Maestre, Silvia [0000-0002-1874-4628], Mir, Pablo [0000-0003-1656-302X], Thomsen, Mirja, Marth, Katrin, Loens, Sebastian, Everding, Judith, Junker, Johanna, Borngräber, Friederike, Ott, Fabian, Jesús Maestre, Silvia, Gelderblom, Mathias, Odorfer, Thorsten, Kuhlenbäumer, Gregor, Kim, Han-Joon, Schaeffer, Eva, Becktepe, Jos, Kasten, Meike, Brüggemann, Norbert, Pfister, Robert, Kollewe, Katja, Krauss, Joachim K., Lohmann, Ebba, Hinrichs, Frauke, Berg, Daniela, Jeon, Beomseok, Busch, Hauke, Altenmüller, Eckart, Mir, Pablo, Kamm, Christoph, Volkmann, Jens, Zittel, Simone, Ferbert, Andreas, Zeuner, Kirsten E., Rolfs, Arndt, Bauer, Peter, Kühn, Andrea A., Bäumer, Tobias, Klein, Christine, and Lohmann, Katja
Abstract: [Background] Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD)., [Objectives] To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes., [Methods] We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature., [Results] We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic., [Conclusion] This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants.
Published: 2024

2. Dopamine agonist therapy in Parkinson’s disease: Spanish expert consensus on its use in different clinical situations

Author: Santos García, Diego, primary, Pagonabarraga Mora, Javier, additional, Escamilla Sevilla, Francisco, additional, García Ruiz, Pedro J., additional, Infante Ceberio, Jon, additional, Kulisevsky Bojarski, Jaime, additional, Linazasoro Cristóbal, Gurutz, additional, Luquín Piudo, María Rosario, additional, Martínez Castrillo, Juan Carlos, additional, Jesús Maestre, Silvia, additional, Vela Desojo, Lydia, additional, Campos Lucas, Francisco J., additional, Caballero Martínez, Fernando, additional, and Mir, Pablo, additional
Published: 2023
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3. Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], MJFF [sponsor], H2020 (Orchestra) [sponsor], Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Karen, Marder, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramirez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Gregor, Kuhlenbäumer, Kühn, Andrea A., Borngräber, Friederike, de Michele, Giuseppe, De Rosa, Anna, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Jolanta, Dorszewska, Carr, Jonathan, Ferese, Rosangela, Stefano, Gambardella, Chase, Bruce, Markopoulou, Katerina, Wataru, Satake, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Gen c, Gen Cer, de Carvalho Aguiar, Patricia, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, van de Warrenburg, Bart, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Joong, Kim Yun, Winkelmann, Juliane, Sue, Carolyn M., Eng-King, Tan, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Parimal, Das, Mollenhauer, Brit, Gatto, Emilia M., Skaalum, Petersen Maria, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, N, Alcalay Roy, Thaler, Avner, Farrer, Matthew J., Kathrin, Brockmann, Corvol, Jean-Christophe, Klein, Christine, Albanese, Alberto, Alcalay, Roy N., Aldakheel, Amaal, Alkhairallah, Thamer, Bashayer, Al-Mubarak, Al-Tassan, Nada, Paolo, Amami, Araujo, Leite Marco Antonio, Ferraz, Henrique Ballalai, Bardien, Soraya, Melinda, Barkhuizen, Barrett, Matthew J., Ba sak, A. Nazl I, Bilgic, Basar, Bloem, Bastiaan R., Bonifati, Vincenzo, Brockmann, Kathrin, Cesarini, Martin Emiliano, Ju, Chung Sun, Guedes, Leonor Correia, Lorraine, Clark, Dieguez, Elena, Dorszewska, Jolanta, Fung, Victor S. C., Pilar, Gómez-Garre, Hattori, Nobutaka, Faycel, Hentati, Januario, Cristina, Maestre, Silvia Jesús, Kaasinen, Valtteri, Hiroshi, Kataoka, Kievit, Anneke A., Kim, Yun Joong, Christine, Klein, Kuhlenbäumer, Gregor, Lim, Jia Lun, Timothy, Lynch, Marder, Karen, May, Patrick, McCarthy, Allan, Briceno, Hugo Morales, Morris, Huw, Mosejova, Alexandra, Cakmak, Özgür Öztop, Orr-Urtreger, Avi, Pachchek, Sinthuja, Periñ\'an, Maria Teresa, Procopio, Radha, Ruiz-Martinez, Javier, Pereira, João Santos, Satake, Wataru, Soto-Beasley, Alexandra I., Sousa, Mário, Tan, Eng-King, Tepge c, Fatih, Uyguner, Oya, Walton, Ronald L., H, Williams-Gray Caroline, Isabel, Wurster, Bao-Rong, Zhang, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], MJFF [sponsor], H2020 (Orchestra) [sponsor], Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Karen, Marder, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramirez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Gregor, Kuhlenbäumer, Kühn, Andrea A., Borngräber, Friederike, de Michele, Giuseppe, De Rosa, Anna, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Jolanta, Dorszewska, Carr, Jonathan, Ferese, Rosangela, Stefano, Gambardella, Chase, Bruce, Markopoulou, Katerina, Wataru, Satake, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Gen c, Gen Cer, de Carvalho Aguiar, Patricia, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, van de Warrenburg, Bart, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Joong, Kim Yun, Winkelmann, Juliane, Sue, Carolyn M., Eng-King, Tan, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Parimal, Das, Mollenhauer, Brit, Gatto, Emilia M., Skaalum, Petersen Maria, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, N, Alcalay Roy, Thaler, Avner, Farrer, Matthew J., Kathrin, Brockmann, Corvol, Jean-Christophe, Klein, Christine, Albanese, Alberto, Alcalay, Roy N., Aldakheel, Amaal, Alkhairallah, Thamer, Bashayer, Al-Mubarak, Al-Tassan, Nada, Paolo, Amami, Araujo, Leite Marco Antonio, Ferraz, Henrique Ballalai, Bardien, Soraya, Melinda, Barkhuizen, Barrett, Matthew J., Ba sak, A. Nazl I, Bilgic, Basar, Bloem, Bastiaan R., Bonifati, Vincenzo, Brockmann, Kathrin, Cesarini, Martin Emiliano, Ju, Chung Sun, Guedes, Leonor Correia, Lorraine, Clark, Dieguez, Elena, Dorszewska, Jolanta, Fung, Victor S. C., Pilar, Gómez-Garre, Hattori, Nobutaka, Faycel, Hentati, Januario, Cristina, Maestre, Silvia Jesús, Kaasinen, Valtteri, Hiroshi, Kataoka, Kievit, Anneke A., Kim, Yun Joong, Christine, Klein, Kuhlenbäumer, Gregor, Lim, Jia Lun, Timothy, Lynch, Marder, Karen, May, Patrick, McCarthy, Allan, Briceno, Hugo Morales, Morris, Huw, Mosejova, Alexandra, Cakmak, Özgür Öztop, Orr-Urtreger, Avi, Pachchek, Sinthuja, Periñ\'an, Maria Teresa, Procopio, Radha, Ruiz-Martinez, Javier, Pereira, João Santos, Satake, Wataru, Soto-Beasley, Alexandra I., Sousa, Mário, Tan, Eng-King, Tepge c, Fatih, Uyguner, Oya, Walton, Ronald L., H, Williams-Gray Caroline, Isabel, Wurster, and Bao-Rong, Zhang
Abstract: BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2 VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34\%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward cl
Published: 2023

4. Suicidal ideation among people with Parkinson's disease and comparison with a control group

Author: Fundación Centro de Investigación de Enfermedades Neurológicas, Alpha Bioresearch, Instituto de Salud Carlos III, Santos-García, Diego [0000-0002-3126-5111], Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., García Díaz, Iago, Íñiguez-Alvarado, María Cristina, Jesús Maestre, Silvia, Buongiorno, Maria Teresa, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, Fundación Centro de Investigación de Enfermedades Neurológicas, Alpha Bioresearch, Instituto de Salud Carlos III, Santos-García, Diego [0000-0002-3126-5111], Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., García Díaz, Iago, Íñiguez-Alvarado, María Cristina, Jesús Maestre, Silvia, Buongiorno, Maria Teresa, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, and Mir, Pablo
Abstract: [Background] Detection of suicidal ideation (SI) is key for trying to prevent suicide. The aim of this study was to analyze the frequency of SI and related factors in Spanish people with Parkinson's Disease (PwPD) and to compare them with a control group., [Methods] PD patients and controls recruited from the Spanish cohort COPPADIS from January 2016 to November 2017 were included. Two visits were conducted: V0 (baseline); V2 (2-year ± 1 month follow-up). SI was defined as a score ≥1 on item nine of the Beck Depression Inventory-II (BDI-II). Regression analyses were conducted to identify factors related to SI., [Results] At baseline, 693 PwPD (60.2% males; 62.59 ± 8.91 years old) and 207 controls (49.8% males; 60.99 ± 8.32 years old) were included. No differences between PwPD and controls were detected in SI frequency at either V0 (5.1% [35/693] vs. 4.3% [9/207]; p = 0.421) or at V2 (5.1% [26/508] vs. 4.8% [6/125]; p = 0.549). Major depression (MD) and a worse quality of life were associated with SI at both visits in PwPD: V0 (MD, OR = 5.63; p = 0.003; PDQ-39, OR = 1.06; p = 0.021); V2 (MD, OR = 4.75; p = 0.027; EUROHIS-QOL8, OR = 0.22; p = 0.006). A greater increase in the BDI-II total score from V0 to V2 was the only factor predicting SI at V2 (OR = 1.21; p = 0.002) along with an increase in the total number of non-antiparkinsonian drugs (OR = 1.39; p = 0.041)., [Conclusion] The frequency of SI (5%) in PwPD was similar to in controls. Depression, a worse quality of life, and a greater comorbidity were related to SI.
Published: 2023

5. Sex Differences in Motor and Non-Motor Symptoms among Spanish Patients with Parkinson's Disease

Author: Fundación Centro de Investigación de Enfermedades Neurológicas, Alpha Bioresearch, Instituto de Salud Carlos III, Santos-García, Diego [0000-0002-3126-5111], Laguna, Ariadna [0000-0002-9732-6677], Hernández-Vara, Jorge [0000-0002-9129-5224], Cores Bartolomé, Carlos [0000-0002-8352-2263], García Díaz, Iago [0000-0003-3304-0714], Cabo, Iria [0000-0003-2436-6499], González-Aramburu, Isabel [0000-0002-3696-4093], Gómez Mayordomo, Víctor [0000-0001-9343-8439], Martínez-Castrillo, J. C. [0000-0001-7744-6850], Sánchez Alonso, Pilar [0000-0003-0496-4707], López-Ariztegui, Nuria [0000-0001-7172-3191], Menéndez-González, Manuel [0000-0002-5218-0774], Martínez-Martín, Pablo [0000-0003-0837-5280], Mir, Pablo [0000-0003-1656-302X], Santos-García, Diego, Laguna, Ariadna, Hernández-Vara, Jorge, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., Íñiguez-Alvarado, María Cristina, García Díaz, Iago, Jesús Maestre, Silvia, Buongiorno, Maria Teresa, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Menéndez-González, Manuel, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, COPPADIS Study Group, Fundación Centro de Investigación de Enfermedades Neurológicas, Alpha Bioresearch, Instituto de Salud Carlos III, Santos-García, Diego [0000-0002-3126-5111], Laguna, Ariadna [0000-0002-9732-6677], Hernández-Vara, Jorge [0000-0002-9129-5224], Cores Bartolomé, Carlos [0000-0002-8352-2263], García Díaz, Iago [0000-0003-3304-0714], Cabo, Iria [0000-0003-2436-6499], González-Aramburu, Isabel [0000-0002-3696-4093], Gómez Mayordomo, Víctor [0000-0001-9343-8439], Martínez-Castrillo, J. C. [0000-0001-7744-6850], Sánchez Alonso, Pilar [0000-0003-0496-4707], López-Ariztegui, Nuria [0000-0001-7172-3191], Menéndez-González, Manuel [0000-0002-5218-0774], Martínez-Martín, Pablo [0000-0003-0837-5280], Mir, Pablo [0000-0003-1656-302X], Santos-García, Diego, Laguna, Ariadna, Hernández-Vara, Jorge, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., Íñiguez-Alvarado, María Cristina, García Díaz, Iago, Jesús Maestre, Silvia, Buongiorno, Maria Teresa, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Menéndez-González, Manuel, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, and COPPADIS Study Group
Abstract: [Background and objective] Sex plays a role in Parkinson's disease (PD) mechanisms. We analyzed sex difference manifestations among Spanish patients with PD., [Patients and Methods] PD patients who were recruited from the Spanish cohort COPPADIS from January 2016 to November 2017 were included. A cross-sectional and a two-year follow-up analysis were conducted. Univariate analyses and general linear model repeated measure were used., [Results] Results: At baseline, data from 681 PD patients (mean age 62.54 ± 8.93) fit the criteria for analysis. Of them, 410 (60.2%) were males and 271 (39.8%) females. There were no differences between the groups in mean age (62.36 ± 8.73 vs. 62.8 ± 9.24; p = 0.297) or in the time from symptoms onset (5.66 ± 4.65 vs. 5.21 ± 4.11; p = 0.259). Symptoms such as depression (p < 0.0001), fatigue (p < 0.0001), and pain (p < 0.00001) were more frequent and/or severe in females, whereas other symptoms such as hypomimia (p < 0.0001), speech problems (p < 0.0001), rigidity (p < 0.0001), and hypersexuality (p < 0.0001) were more noted in males. Women received a lower levodopa equivalent daily dose (p = 0.002). Perception of quality of life was generally worse in females (PDQ-39, p = 0.002; EUROHIS-QOL8, p = 0.009). After the two-year follow-up, the NMS burden (Non-Motor Symptoms Scale total score) increased more significantly in males (p = 0.012) but the functional capacity (Schwab and England Activities of Daily Living Scale) was more impaired in females (p = 0.001)., [Conclusion] The present study demonstrates that there are important sex differences in PD. Long-term prospective comparative studies are needed.
Published: 2023

6. Falls Predict Acute Hospitalization in Parkinson's Disease

Author: Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Suárez Castro, Ester, Hernández-Vara, Jorge, Jesús Maestre, Silvia, Mir, Pablo, Cosgaya, Marina, Martí, María-José, Pastor, Pau, Cabo, Iria, Seijo, Manuel, Legarda, Inés, Vives, Bárbara, Caballol, Nuria, Ruiz Martínez, Javier, Croitoru, Ioana, Cubo, Esther, Miranda, Javier, Alonso Losada, María G., Labandeira, Carmen, López-Ariztegui, Nuria, Morales Casado, M. I., González-Aramburu, Isabel, Infante, Jon, Escalante, Sonia, Bernardo, Noemí, Blázquez-Estrada, Marta, Menéndez-González, Manuel, García Caldentey, Juan, Borrué, Carmen, Vela, Lydia, Catalán, Maria José, Gómez Mayordomo, Víctor, Kurtis, Mónica, Prieto López, Cristina, Ordás, Carlos, Nogueira, Víctor, López-Manzanares, Lydia, Ávila-Rivera, María A., Puente, Víctor, García Moreno, J. M., Solano Vila, Berta, Álvarez-Sauco, María, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Gastón, Itziar, Kulisevsky, Jaime, Valero, Caridad, Fábregues-Boixar, Oriol de, González Ardura, Jessica, López-Díaz, Luis M., Martínez-Martín, Pablo, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Suárez Castro, Ester, Hernández-Vara, Jorge, Jesús Maestre, Silvia, Mir, Pablo, Cosgaya, Marina, Martí, María-José, Pastor, Pau, Cabo, Iria, Seijo, Manuel, Legarda, Inés, Vives, Bárbara, Caballol, Nuria, Ruiz Martínez, Javier, Croitoru, Ioana, Cubo, Esther, Miranda, Javier, Alonso Losada, María G., Labandeira, Carmen, López-Ariztegui, Nuria, Morales Casado, M. I., González-Aramburu, Isabel, Infante, Jon, Escalante, Sonia, Bernardo, Noemí, Blázquez-Estrada, Marta, Menéndez-González, Manuel, García Caldentey, Juan, Borrué, Carmen, Vela, Lydia, Catalán, Maria José, Gómez Mayordomo, Víctor, Kurtis, Mónica, Prieto López, Cristina, Ordás, Carlos, Nogueira, Víctor, López-Manzanares, Lydia, Ávila-Rivera, María A., Puente, Víctor, García Moreno, J. M., Solano Vila, Berta, Álvarez-Sauco, María, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Gastón, Itziar, Kulisevsky, Jaime, Valero, Caridad, Fábregues-Boixar, Oriol de, González Ardura, Jessica, López-Díaz, Luis M., and Martínez-Martín, Pablo
Abstract: [Background] There is a need for identifying risk factors for hospitalization in Parkinson’s disease (PD) and also interventions to reduce acute hospital admission., [Objective] To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort., [Methods] PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit., [Results] Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065–5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319–6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757–8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124–4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080–8.322; p = 0.035) was an independent predictor of AH., [Conclusion] Falls is an independent predictor of AH in PD patients.
Published: 2023

7. Embracing Monogenic Parkinson's Disease:The MJFF Global Genetic PD Cohort

Author: Vollstedt, Eva Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Marder, Karen, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin Hsien, Kuo, Ming Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Boon, Agnita J.W., Riess, Olaf, Bonifati, Vincenzo, Kievit, Anneke A., Vollstedt, Eva Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Marder, Karen, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin Hsien, Kuo, Ming Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Boon, Agnita J.W., Riess, Olaf, Bonifati, Vincenzo, and Kievit, Anneke A.
Abstract: Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view towa
Published: 2023

8. Risk of Cognitive Impairment in Patients With Parkinson’s Disease With Visual Hallucinations and Subjective Cognitive Complaints

Author: Fundación Degen, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., Paz González, J. M., Martínez Miró, Cristina, Jesús Maestre, Silvia, Aguilar, Miquel, Pastor, Pau, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Maria A. Ávila Rivera,o, Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, COPPADIS Study Group, Fundación Degen, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., Paz González, J. M., Martínez Miró, Cristina, Jesús Maestre, Silvia, Aguilar, Miquel, Pastor, Pau, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Maria A. Ávila Rivera,o, Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, and COPPADIS Study Group
Abstract: [Background and Purpose] Visual hallucinations (VH) and subjective cognitive complaints (SCC) are associated with cognitive impairment (CI) in Parkinson’s disease. Our aims were to determine the association between VH and SCC and the risk of CI development in a cohort of patients with Parkinson’s disease and normal cognition (PD-NC)., [Methods] Patients with PD-NC (total score of >80 on the Parkinson’s Disease Cognitive Rating Scale [PD-CRS]) recruited from the Spanish COPPADIS cohort from January 2016 to November 2017 were followed up after 2 years. Subjects with a score of ≥1 on domain 5 and item 13 of the Non-Motor Symptoms Scale at baseline (V0) were considered as “with SCC” and “with VH,” respectively. CI at the 2-year follow-up (plus or minus 1 month) (V2) was defined as a PD-CRS total score of <81., [Results] At V0 (n=376, 58.2% males, age 61.14±8.73 years [mean±SD]), the frequencies of VH and SCC were 13.6% and 62.2%, respectively. VH were more frequent in patients with SCC than in those without: 18.8% (44/234) vs 4.9% (7/142), p<0.0001. At V2, 15.2% (57/376) of the patients had developed CI. VH presenting at V0 was associated with a higher risk of CI at V2 (odds ratio [OR]=2.68, 95% confidence interval=1.05–6.83, p=0.0.039) after controlling for the effects of age, disease duration, education, medication, motor and nonmotor status, mood, and PD-CRS total score at V0. Although SCC were not associated with CI at V2, presenting both VH and SCC at V0 increased the probability of having CI at V2 (OR=3.71, 95% confidence interval=1.36–10.17, p=0.011)., [Conclusions] VH were associated with the development of SCC and CI at the 2-year follow-up in patients with PD-NC.
Published: 2023

9. Staging Parkinson’s Disease According to the MNCD (Motor/Non-motor/Cognition/Dependency) Classification Correlates with Disease Severity and Quality of Life

Author: Fundación Degen, Alpha Bioresearch, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., Íñiguez-Alvarado, María Cristina, García Díaz, Iago, Jesús Maestre, Silvia, Buongiorno, Maria Teresa, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Menéndez-González, Manuel, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Calopa, Matildeoo, Carrillo, Fátima, Escamilla-Sevilla, Francisco, Freire, Eric, Gómez Esteban, Juan Carlos, García-Ramos, Rocío, Luquín, María Rosario Isabel, Martínez Torres, Irene, Sesar Ignacio, Ángel, Martínez-Martín, Pablo, Mir, Pablo, COPPADIS Study Group, Fundación Degen, Alpha Bioresearch, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., Íñiguez-Alvarado, María Cristina, García Díaz, Iago, Jesús Maestre, Silvia, Buongiorno, Maria Teresa, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Menéndez-González, Manuel, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Calopa, Matildeoo, Carrillo, Fátima, Escamilla-Sevilla, Francisco, Freire, Eric, Gómez Esteban, Juan Carlos, García-Ramos, Rocío, Luquín, María Rosario Isabel, Martínez Torres, Irene, Sesar Ignacio, Ángel, Martínez-Martín, Pablo, Mir, Pablo, and COPPADIS Study Group
Abstract: Background: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD)., Objective: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity., Methods: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort fromJanuary 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL:1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8)., Results: Four hundred and thirty-nine PD patients (62.05±7.84 years old; 59% males) were included. MNCD stage was:stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advancedMNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p< 0.0001) and EUROHIS-QOL8 (p< 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages., Conclusion: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD.
Published: 2023

10. Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease

Author: Instituto de Salud Carlos III, Hospital Universitario Virgen del Rocío, CSIC-JA-USE - Instituto de Biomedicina de Sevilla (IBIS), European Commission, Junta de Andalucía, Ministerio de Educación (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Muñoz-Delgado, Laura, Macías García, Daniel, Periñán, María Teresa, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Jiménez-Jaraba, María Valle, Benítez Zamora, Belén, Díaz-Belloso, Rafael, García-Díaz, Sergio, Martín-Bórnez, Miguel, Pineda-Sánchez, Rocío, Carrillo, Fátima, Gómez-Garre, Pilar, Mir, Pablo, Instituto de Salud Carlos III, Hospital Universitario Virgen del Rocío, CSIC-JA-USE - Instituto de Biomedicina de Sevilla (IBIS), European Commission, Junta de Andalucía, Ministerio de Educación (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Muñoz-Delgado, Laura, Macías García, Daniel, Periñán, María Teresa, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Jiménez-Jaraba, María Valle, Benítez Zamora, Belén, Díaz-Belloso, Rafael, García-Díaz, Sergio, Martín-Bórnez, Miguel, Pineda-Sánchez, Rocío, Carrillo, Fátima, Gómez-Garre, Pilar, and Mir, Pablo
Abstract: Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis of Parkinson’s disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation, has been reported to be higher in patients with PD than in healthy controls (HCs). The present study was aimed at determining if the peripheral inflammatory immune response could be influenced by the genetic background of patients with PD. We included a discovery cohort with 222 patients with PD (132 sporadic PD, 44 LRRK2-associated PD (with p.G2019S and p.R1441G variants), and 46 GBA-associated PD), as well as 299 HCs. Demographic and clinical data were recorded. Leukocytes and their subpopulations, and the NLR were measured in peripheral blood. Multivariate lineal regression and post-hoc tests were applied to determine the differences among the groups. Subsequently, a replication study using the Parkinson’s Progression Markers Initiative cohort was performed which included 401 patients with PD (281 sPD patients, 66 LRRK2-PD patients, 54 GBA-PD patients) and a group of 174 HCs. Patients with sporadic PD and GBA-associated PD showed a significantly lower lymphocyte count, a non-significantly higher neutrophil count and a significantly higher NLR than HCs. The peripheral inflammatory immune response of patients with LRRK2-associated PD did not differ from HCs. Our study supports the involvement of a peripheral inflammatory immune response in the pathophysiology of sPD and GBA-associated PD. However, this inflammatory response was not found in LRRK2-associated PD, probably reflecting different pathogenic inflammatory mechanisms.
Published: 2023

11. Staging Parkinson's disease according to the MNCD classification correlates with caregiver burden

Author: Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Junta de Andalucía, European Commission, Fundación Alimerka, Sociedad Andaluza de Neurología, Jacques and Gloria Gossweiler Foundation, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., García Díaz, Iago, Íñiguez-Alvarado, María Cristina, Paz, José Manuel, Jesús Maestre, Silvia, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Mendoza, Zebenzui, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Seijo, Manuel, Valero, Caridad, Alonso Redondo, Rubén, Buongiorno, Maria Teresa, Ordás, Carlos, Menéndez-González, Manuel, McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, COPPADIS Study Group, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Junta de Andalucía, European Commission, Fundación Alimerka, Sociedad Andaluza de Neurología, Jacques and Gloria Gossweiler Foundation, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., García Díaz, Iago, Íñiguez-Alvarado, María Cristina, Paz, José Manuel, Jesús Maestre, Silvia, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Mendoza, Zebenzui, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Seijo, Manuel, Valero, Caridad, Alonso Redondo, Rubén, Buongiorno, Maria Teresa, Ordás, Carlos, Menéndez-González, Manuel, McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, and COPPADIS Study Group
Abstract: [Background and objective] Recently, we demonstrated that staging Parkinson's disease (PD) with a novel simple classification called MNCD, based on four axes (motor, non-motor, cognition, and dependency) and five stages, correlated with disease severity and patients’ quality of life. Here, we analyzed the correlation of MNCD staging with PD caregiver's status., [Patients and methods] Data from the baseline visit of PD patients and their principal caregiver recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD total score (from 0 to 12) and MNCD stages (from 1 to 5) in this cross-sectional analysis. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), PQ-10, and EUROHIS-QOL 8-item index (EUROHIS-QOL8)., [Results] Two hundred and twenty-four PD patients (63 ± 9.6 years old; 61.2% males) and their caregivers (58.5 ± 12.1 years old; 67.9% females) were included. The frequency of MNCD stages was 1, 7.6%; 2, 58.9%; 3, 31.3%; and 4–5, 2.2%. A more advanced MNCD stage was associated with a higher score on the ZCBI (p < .0001) and CSI (p < .0001), and a lower score on the PQ-10 (p = .001), but no significant differences were observed in the BDI-II (p = .310) and EUROHIS-QOL8 (p = .133). Moderate correlations were observed between the MNCD total score and the ZCBI (r = .496; p < .0001), CSI (r = .433; p < .0001), and BDI-II (r = .306; p < .0001) in caregivers., [Conclusion] Staging PD according to the MNCD classification is correlated with caregivers’ strain and burden.
Published: 2023

12. Homocysteine levels, genetic background, and cognitive impairment in Parkinson’s disease

Author: Conferencia de Rectores de las Universidades Españolas, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Universidad de Sevilla, Periñán, María Teresa, Macías García, Daniel, Jesús Maestre, Silvia, Martín-Rodríguez, Juan Francisco, Muñoz-Delgado, Laura, Jiménez-Jaraba, María Valle, Buiza-Rueda, Dolores, Bonilla-Toribio, Marta, Adarmes Gómez, A. D., Gómez-Garre, Pilar, Mir, Pablo, Conferencia de Rectores de las Universidades Españolas, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Universidad de Sevilla, Periñán, María Teresa, Macías García, Daniel, Jesús Maestre, Silvia, Martín-Rodríguez, Juan Francisco, Muñoz-Delgado, Laura, Jiménez-Jaraba, María Valle, Buiza-Rueda, Dolores, Bonilla-Toribio, Marta, Adarmes Gómez, A. D., Gómez-Garre, Pilar, and Mir, Pablo
Abstract: [Background] Hyperhomocysteinemia is considered an independent risk factor for cognitive impairment., [Objective] To study the correlation between homocysteine levels and cognitive impairment in patients with PD., [Methods] We conducted a case–control study that included 246 patients with PD, of whom 32 were cognitively impaired. The levels of homocysteine, folate, and vitamin B12 were measured in peripheral blood. Multivariate logistic regression analysis was applied to determine differences in homocysteine levels between PD patients with and without cognitive impairment. A meta-analysis was performed to clarify the role of Hcy levels in PD with cognitive decline. Five polymorphisms in genes involved in Hcy metabolism, including MTHFR rs1801133 and rs1801131, COMT rs4680, MTRR rs1801394, and TCN2 rs1801198, were genotyped., [Results] Our case–control study showed that homocysteine levels were associated with cognitive impairment in PD after adjusting for possible confounding factors such as levodopa equivalent daily dose. The results of our meta-analysis further supported the positive association between homocysteine levels and cognition in PD. We found that the MTHFR rs1801133 TT genotype led to higher homocysteine levels in PD patients, whereas the MTHFR rs1801131 CC genotype resulted in higher folate levels. However, the polymorphisms studied were not associated with cognitive impairment in PD., [Conclusions] Increased homocysteine levels were a risk factor for cognitive decline in PD. However, no association was found between polymorphisms in genes involved in homocysteine metabolism and cognitive impairment in PD. Large-scale studies of ethnically diverse populations are required to definitively assess the relationship between MTHFR and cognitive impairment in PD.
Published: 2023

13. Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Author: Michael J. Fox Foundation for Parkinson's Research, Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Marder, Karen, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim, Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramírez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Kuhlenbäumer, Gregor, Kühn, Andrea A., Borngräber, Friederike, Michele, Giuseppe de, Rosa, Anna De, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Dorszewska, Jolanta, Carr, Jonathan, Ferese, Rosangela, Gambardella, Stefano, Chase, Bruce, Markopoulou, Katerina, Satake, Wataru, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Genç, Gençer, Aguiar, Patricia de Carvalho, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, Warrenburg, Bart van de, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Kim, Yun Joong, Winkelmann, Juliane, Sue, Carolyn M., Tan, Eng-King, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Das, Parimal, Mollenhauer, Brit, Gatto, Emilia M., Petersen, Maria Skaalum, Hattori, Nobutaka, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, Alcalay, Roy N., Thaler, Avner, Farrer, Matthew J., Brockmann, Kathrin, Corvol, Jean-Christophe, Klein, Christine, on behalf of the MJFF Global Genetic Parkinson's Disease Study Group, Michael J. Fox Foundation for Parkinson's Research, Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Marder, Karen, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim, Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramírez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Kuhlenbäumer, Gregor, Kühn, Andrea A., Borngräber, Friederike, Michele, Giuseppe de, Rosa, Anna De, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Dorszewska, Jolanta, Carr, Jonathan, Ferese, Rosangela, Gambardella, Stefano, Chase, Bruce, Markopoulou, Katerina, Satake, Wataru, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Genç, Gençer, Aguiar, Patricia de Carvalho, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, Warrenburg, Bart van de, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Kim, Yun Joong, Winkelmann, Juliane, Sue, Carolyn M., Tan, Eng-King, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Das, Parimal, Mollenhauer, Brit, Gatto, Emilia M., Petersen, Maria Skaalum, Hattori, Nobutaka, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, Alcalay, Roy N., Thaler, Avner, Farrer, Matthew J., Brockmann, Kathrin, Corvol, Jean-Christophe, Klein, Christine, and on behalf of the MJFF Global Genetic Parkinson's Disease Study Group
Abstract: [Background] As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited., [Objective] The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD., [Methods] We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed., [Results] We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published., [Conclusions] Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Published: 2023

14. Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project

Author: Michael J. Fox Foundation for Parkinson's Research, Cambridge Biomedical Research Centre, National Institute for Health and Care Research (US), Vollstedt, Eva-Juliane, Madoev, Harutyun, Aasly, Anna, Ahmad-Annuar, Azlina, Al-Mubarak, Bashayer, Alcalay, Roy N., Álvarez, Victoria, Amorín, Ignacio, Annesi, Grazia, Arkadir, David, Bardien, Soraya, Barker, Roger A., Barkhuizen, Melinda, Basak, A. Nazli, Bonifati, Vincenzo, Boon, Agnita, Brighina, Laura, Brockmann, Kathrin, Carmine Belin, Andrea, Carr, Jonathan, Clarimon, Jordi, Cornejo-Olivas, Mario, Correia Guedes, Leonor, Corvol, Jean-Christophe, Crosiers, David, Damásio, Joana, Das, Parimal, Aguiar, Patricia de Carvalho, Rosa, Anna De, Dorszewska, Jolanta, Ertan, Sibel, Ferese, Rosangela, Ferreira, Joaquim, Gatto, Emilia, Genç, Gençer, Giladi, Nir, Gómez-Garre, Pilar, Hanagasi, Hasmet, Hattori, Nobutaka, Hentati, Faycal, Hoffman-Zacharska, Dorota, Illarioshkin, Sergey N., Jankovic, Joseph, Jesús Maestre, Silvia, Kaasinen, Valtteri, Kievit, Anneke, Klivenyi, Peter, Kostic, Vladimir, Koziorowski, Dariusz, Kühn, Andrea A., Lang, Anthony E., Lim, Shen-Yang, Lin, Chin-Hsien, Lohmann, Katja, Markovic, Vladana, Martikainen, Mika Henrik, Mellick, George, Merello, Marcelo, Milanowski, Lukasz, Mir, Pablo, Öztop-Çakmak, Özgür, Pimentel, Márcia Mattos Gonçalves, Pulkes, Teeratorn, Puschmann, Andreas, Rogaeva, Ekaterina, Sammler, Esther M., Skaalum Petersen, Maria, Skorvanek, Matej, Spitz, Mariana, Suchowersky, Oksana, Tan, Ai Huey, Termsarasab, Pichet, Thaler, Avner, Tumas, Vitor, Valente, Enza Maria, Warrenburg, Bart van de, Williams-Gray, Caroline H., Wu, Ruey-Mei, Zhang, Baorong, Zimprich, Alexander, Solle, Justin, Padmanabhan, Shalini, Klein, Christine, Michael J. Fox Foundation for Parkinson's Research, Cambridge Biomedical Research Centre, National Institute for Health and Care Research (US), Vollstedt, Eva-Juliane, Madoev, Harutyun, Aasly, Anna, Ahmad-Annuar, Azlina, Al-Mubarak, Bashayer, Alcalay, Roy N., Álvarez, Victoria, Amorín, Ignacio, Annesi, Grazia, Arkadir, David, Bardien, Soraya, Barker, Roger A., Barkhuizen, Melinda, Basak, A. Nazli, Bonifati, Vincenzo, Boon, Agnita, Brighina, Laura, Brockmann, Kathrin, Carmine Belin, Andrea, Carr, Jonathan, Clarimon, Jordi, Cornejo-Olivas, Mario, Correia Guedes, Leonor, Corvol, Jean-Christophe, Crosiers, David, Damásio, Joana, Das, Parimal, Aguiar, Patricia de Carvalho, Rosa, Anna De, Dorszewska, Jolanta, Ertan, Sibel, Ferese, Rosangela, Ferreira, Joaquim, Gatto, Emilia, Genç, Gençer, Giladi, Nir, Gómez-Garre, Pilar, Hanagasi, Hasmet, Hattori, Nobutaka, Hentati, Faycal, Hoffman-Zacharska, Dorota, Illarioshkin, Sergey N., Jankovic, Joseph, Jesús Maestre, Silvia, Kaasinen, Valtteri, Kievit, Anneke, Klivenyi, Peter, Kostic, Vladimir, Koziorowski, Dariusz, Kühn, Andrea A., Lang, Anthony E., Lim, Shen-Yang, Lin, Chin-Hsien, Lohmann, Katja, Markovic, Vladana, Martikainen, Mika Henrik, Mellick, George, Merello, Marcelo, Milanowski, Lukasz, Mir, Pablo, Öztop-Çakmak, Özgür, Pimentel, Márcia Mattos Gonçalves, Pulkes, Teeratorn, Puschmann, Andreas, Rogaeva, Ekaterina, Sammler, Esther M., Skaalum Petersen, Maria, Skorvanek, Matej, Spitz, Mariana, Suchowersky, Oksana, Tan, Ai Huey, Termsarasab, Pichet, Thaler, Avner, Tumas, Vitor, Valente, Enza Maria, Warrenburg, Bart van de, Williams-Gray, Caroline H., Wu, Ruey-Mei, Zhang, Baorong, Zimprich, Alexander, Solle, Justin, Padmanabhan, Shalini, and Klein, Christine
Abstract: Parkinson’s disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson’s Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.
Published: 2023

15. Cognitive impairment and dementia in young onset Parkinson’s disease

Author: Fundación Degén, Alpha Bioresearch, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., García Díaz, Iago, Íñiguez-Alvarado, María Cristina, Paz, José Manuel, Jesús Maestre, Silvia, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Mendoza, Zebenzui, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Seijo, Manuel, Valero, Caridad, Alonso Redondo, Rubén, Buongiorno, Maria Teresa, Ordás, Carlos, Menéndez-González, Manuel, McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, COPPADIS Study Group, Fundación Degén, Alpha Bioresearch, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., García Díaz, Iago, Íñiguez-Alvarado, María Cristina, Paz, José Manuel, Jesús Maestre, Silvia, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Mendoza, Zebenzui, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Seijo, Manuel, Valero, Caridad, Alonso Redondo, Rubén, Buongiorno, Maria Teresa, Ordás, Carlos, Menéndez-González, Manuel, McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, and COPPADIS Study Group
Abstract: [Background and objective] Patients with young-onset Parkinson’s disease (YOPD) have a slower progression. Our aim was to analyze the change in cognitive function in YOPD compared to patients with a later onset and controls., [Patients and methods] Patients with Parkinson’s disease (PD) and controls from the COPPADIS cohort were included. Cognitive function was assessed with the Parkinson’s Disease Cognitive Rating Scale (PD-CRS) at baseline (V0), 2-year ± 1 month (V2y), and 4-year ± 3 months follow-up (V4y). Regarding age from symptoms onset, patients were classified as YOPD (< 50 years) or non-YOPD (≥ 50). A score in the PD-CRS < 81 was defined as cognitive impairment (CI): ≤ 64 dementia; 65–80 mild cognitive impairment (MCI)., [Results] One-hundred and twenty-four YOPD (50.7 ± 7.9 years; 66.1% males), 234 non-YOPD (67.8 ± 7.8 years; 59.3% males) patients, and 205 controls (61 ± 8.3 years; 49.5% males) were included. The score on the PD-CRS and its subscore domains was higher at all visits in YOPD compared to non-YOPD patients and to controls (p < 0.0001 in all analysis), but no differences were detected between YOPD patients and controls. Only non-YOPD patients had significant impairment in their cognitive function from V0 to V4y (p < 0.0001). At V4y, the frequency of dementia and MCI was 5% and 10% in YOPD compared to 25.2% and 22.3% in non-YOPD patients (p < 0.0001). A lower score on the Parkinson’s Disease Sleep Scale at baseline was a predictor of CI at V4y in YOPD patients (Adjusted R2 = 0.61; OR = 0.965; p = 0.029)., [Conclusion] Cognitive dysfunction progressed more slowly in YOPD than in non-YOPD patients.
Published: 2023

16. Changes in Principal Caregiver Mood Affects the Mood of the Parkinson’s Disease Patient: The Vicious Cycle of Illness

Author: Fundación Degen, Alpha Bioresearch, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., Íñiguez-Alvarado, María Cristina, García Díaz, Iago, Jesús Maestre, Silvia, Buongiorno, Maria Teresa, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Menéndez-González, Manuel, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, COPPADIS Study Group, Fundación Degen, Alpha Bioresearch, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., Íñiguez-Alvarado, María Cristina, García Díaz, Iago, Jesús Maestre, Silvia, Buongiorno, Maria Teresa, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Menéndez-González, Manuel, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, and COPPADIS Study Group
Abstract: Background: Although many studies have analyzed what factors contribute to caregiver burden in Parkinson’s disease (PD), there is currently no knowledge about how the status of the caregiver could impact the patient., Objective: The aim of this study was to analyze how the change in the caregiver’s status influences PD patients., Methods: PD patients and their caregivers who were recruited from January/2016 to November/2017 from 35 centers in Spain from the COPPADIS cohort were included in the study (V0). They were evaluated again at 2-year follow-up (V2). Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), and EUROHIS-QOL 8-item index (EUROHIS-QOL8) at V0 and V2. Multivariate models were used to analyze the impact of the change from V0 to V2 () on the caregiver’s status over the change in the patient’s status., Results: BDI-II and EUROHIS-QOL8 in the caregiver predicted BDI-II ( = 0.32; p < 0.0001; R2 = 0.71) and EUROHIS-QOL8 ( = 0.39; p < 0.0001; R2 = 0.68) in the patient, respectively. Variables related to the caregiver were not associated with changes in the patient´s health-related QoL (PDQ-39 [39-item Parkinson’s disease Questionnaire]) or autonomy for activities of daily-living (ADLS [Schwab & England Activities of Daily Living Scale])., Conclusion: The change in the caregiver’s mood and global QoL was associated with the change in the patient’s mood and global QoL, respectively, independently of other variables of the disease influencing both patient´s aspects. Based on this finding, it could be of great importance to detect depression in the principal caregiver of a patient and act on it as earlier as possible.
Published: 2023

17. Prevalence and Factors Associated with Drooling in Parkinson’s Disease: Results from a Longitudinal Prospective Cohort and Comparison with a Control Group

Author: Fundación Degen, Alpha Bioresearch, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., Íñiguez-Alvarado, María Cristina, Jesús Maestre, Silvia, Buongiorno, Maria Teresa, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, Study Group COPPADIS, Fundación Degen, Alpha Bioresearch, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Feal Painceiras, María J., Íñiguez-Alvarado, María Cristina, Jesús Maestre, Silvia, Buongiorno, Maria Teresa, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, and Study Group COPPADIS
Abstract: Introduction. Drooling in Parkinson’s disease (PD) is frequent but often goes underrecognized. Our aim was to examine the prevalence of drooling in a PD cohort and compare it with a control group. Specifcally, we identifed factors associated with drooling and conducted subanalyses in a subgroup of very early PD patients. Patients and Methods. PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30-day follow-up (V2) from 35 centers in Spain from the COPPADIS cohort were included in this longitudinal prospective study. Subjects were classifed as with or without drooling according to item 19 of the NMSS (Nonmotor Symptoms Scale) at V0, V1 (1-year ± 15 days), and V2 for patients and at V0 and V2 for controls. Results. Te frequency of drooling in PD patients was 40.1% (277/691) at V0 (2.4% (5/201) in controls; p < 0.0001), 43.7% (264/604) at V1, and 48.2% (242/502) at V2 (3.2% (4/124) in controls; p < 0.0001), with a period prevalence of 63.6% (306/481). Being older (OR = 1.032; p = 0.012), being male (OR = 2.333; p < 0.0001), having greater nonmotor symptom (NMS) burden at the baseline (NMSS total score at V0; OR = 1.020; p < 0.0001), and having a greater increase in the NMS burden from V0 to V2 (change in the NMSS total score from V0 to V2; OR = 1.012; p < 0.0001) were identifed as independent predictors of drooling after the 2-year follow-up. Similar results were observed in the group of patients with ≤2 years since symptom onset, with a cumulative prevalence of 64.6% and a higher score on the UPDRS-III at V0 (OR = 1.121; p = 0.007) as a predictor of drooling at V2. Conclusion. Drooling is frequent in PD patients even at the initial onset of the disease and is associated with a greater motor severity and NMS burden.
Published: 2023

18. Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Author: Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Karen, Marder, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramirez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Gregor, Kuhlenbäumer, Kühn, Andrea A., Borngräber, Friederike, de Michele, Giuseppe, De Rosa, Anna, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Jolanta, Dorszewska, Carr, Jonathan, Ferese, Rosangela, Stefano, Gambardella, Chase, Bruce, Markopoulou, Katerina, Wataru, Satake, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Gen c, Gen Cer, de Carvalho Aguiar, Patricia, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, van de Warrenburg, Bart, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Joong, Kim Yun, Winkelmann, Juliane, Sue, Carolyn M., Eng-King, Tan, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Parimal, Das, Mollenhauer, Brit, Gatto, Emilia M., Skaalum, Petersen Maria, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, N, Alcalay Roy, Thaler, Avner, Farrer, Matthew J., Kathrin, Brockmann, Corvol, Jean-Christophe, Klein, Christine, Albanese, Alberto, Alcalay, Roy N., Aldakheel, Amaal, Alkhairallah, Thamer, Bashayer, Al-Mubarak, Al-Tassan, Nada, Paolo, Amami, Araujo, Leite Marco Antonio, Ferraz, Henrique Ballalai, Bardien, Soraya, Melinda, Barkhuizen, Barrett, Matthew J., Ba sak, A. Nazl I, Bilgic, Basar, Bloem, Bastiaan R., Bonifati, Vincenzo, Brockmann, Kathrin, Cesarini, Martin Emiliano, Ju, Chung Sun, Guedes, Leonor Correia, Lorraine, Clark, Dieguez, Elena, Dorszewska, Jolanta, Fung, Victor S. C., Pilar, Gómez-Garre, Hattori, Nobutaka, Faycel, Hentati, Januario, Cristina, Maestre, Silvia Jesús, Kaasinen, Valtteri, Hiroshi, Kataoka, Kievit, Anneke A., Kim, Yun Joong, Christine, Klein, Kuhlenbäumer, Gregor, Lim, Jia Lun, Timothy, Lynch, Marder, Karen, May, Patrick, McCarthy, Allan, Briceno, Hugo Morales, Morris, Huw, Mosejova, Alexandra, Cakmak, Özgür Öztop, Orr-Urtreger, Avi, Pachchek, Sinthuja, Periñ\'an, Maria Teresa, Procopio, Radha, Ruiz-Martinez, Javier, Pereira, João Santos, Satake, Wataru, Soto-Beasley, Alexandra I., Sousa, Mário, Tan, Eng-King, Tepge c, Fatih, Uyguner, Oya, Walton, Ronald L., H, Williams-Gray Caroline, Isabel, Wurster, Bao-Rong, Zhang, Fonds National de la Recherche - FnR [sponsor], MJFF [sponsor], H2020 (Orchestra) [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
Subjects: Neurologie [D14] [Sciences de la santé humaine], Neurology [D14] [Human health sciences], Genetics & genetic processes [F10] [Life sciences], Parkinson's disease, monogenic PD, Génétique & processus génétiques [F10] [Sciences du vivant]
Abstract: BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2 VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34\%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Published: 2023

19. Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias

Author: Martínez-Rubio, Dolores, primary, Hinarejos, Isabel, additional, Sancho, Paula, additional, Gorría-Redondo, Nerea, additional, Bernadó-Fonz, Raquel, additional, Tello, Cristina, additional, Marco-Marín, Clara, additional, Martí-Carrera, Itxaso, additional, Martínez-González, María Jesús, additional, García-Ribes, Ainhoa, additional, Baviera-Muñoz, Raquel, additional, Sastre-Bataller, Isabel, additional, Martínez-Torres, Irene, additional, Duat-Rodríguez, Anna, additional, Janeiro, Patrícia, additional, Moreno, Esther, additional, Pías-Peleteiro, Leticia, additional, Gordo, Mar O’Callaghan, additional, Ruiz-Gómez, Ángeles, additional, Muñoz, Esteban, additional, Martí, Maria Josep, additional, Sánchez-Monteagudo, Ana, additional, Fuster, Candela, additional, Andrés-Bordería, Amparo, additional, Pons, Roser Maria, additional, Jesús-Maestre, Silvia, additional, Mir, Pablo, additional, Lupo, Vincenzo, additional, Pérez-Dueñas, Belén, additional, Darling, Alejandra, additional, Aguilera-Albesa, Sergio, additional, and Espinós, Carmen, additional
Published: 2022
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20. Transcriptomic analysis reveals an association of FCGBP with Parkinson's disease

Author: European Commission, Instituto de Salud Carlos III, Junta de Andalucía, Gómez-Garre, Pilar [0000-0002-0437-6182], Provini, Federica [0000-0001-9063-2658], Claudio Franceschi [0000-0001-9841-6386], Pablo Mir [0000-0003-1656-302X], Gómez-Garre, Pilar, Periñán, María Teresa, Jesús Maestre, Silvia, Bacalini, Maria Giulia, Garagnani, Paolo, Mollenhauer, Brit, Pirazzini, Chiara, Provini, Federica, Trenkwalder, Claudia, Franceschi, Claudio, Mir, Pablo, European Commission, Instituto de Salud Carlos III, Junta de Andalucía, Gómez-Garre, Pilar [0000-0002-0437-6182], Provini, Federica [0000-0001-9063-2658], Claudio Franceschi [0000-0001-9841-6386], Pablo Mir [0000-0003-1656-302X], Gómez-Garre, Pilar, Periñán, María Teresa, Jesús Maestre, Silvia, Bacalini, Maria Giulia, Garagnani, Paolo, Mollenhauer, Brit, Pirazzini, Chiara, Provini, Federica, Trenkwalder, Claudia, Franceschi, Claudio, and Mir, Pablo
Abstract: Transcriptomics in Parkinson’s disease (PD) offers new insights into the molecular mechanism of PD pathogenesis. Several pathways, such as inflammation and protein degradation, have been identified by differential gene expression analysis. Our aim was to identify gene expression differences underlying the disease etiology and the discovery of pre-symptomatic risk biomarkers for PD from a multicenter study in the context of the PROPAG-AGEING project. We performed RNA sequencing from 47 patients with de novo PD, 10 centenarians, and 65 healthy controls. Using identified differentially expressed genes, functional annotations were assigned using gene ontology to unveil significant enriched biological processes. The expression of 16 selected genes was validated using OpenArray® assays and samples from independent cohorts of 201 patients with advanced PD, 340 healthy siblings of PD patients, and 177 healthy controls. Differential gene expression analysis identified higher FCGBP expression in patients with de novo PD compared with healthy controls and compared with centenarians. Furthermore, FCGBP showed no differences in terms of population origin or aging process. The increased FCGBP expression was validated in patients with advanced PD and their siblings. Thus, we provided evidence for an upregulation of FCGBP mRNA levels not only in patients with PD but also in individuals at putative higher risk of PD, suggesting that it could be important in gut–brain PD interaction, mediating the connection between microbiota and intestinal inflammatory processes, as well as neuroinflammation and neurodegeneration.
Published: 2022

21. Parkinson's Disease Motor Subtypes Change with the Progression of the Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up

Author: Santos-García, Diego, Canfield, Hector, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Naya Ríos, Lucía, García Roca, Lucía, Martínez Miró, Cristina, Jesús Maestre, Silvia, Aguilar, Miquel, Pastor, Pau, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, COPPADIS Study Group, Santos-García, Diego, Canfield, Hector, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Naya Ríos, Lucía, García Roca, Lucía, Martínez Miró, Cristina, Jesús Maestre, Silvia, Aguilar, Miquel, Pastor, Pau, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, and COPPADIS Study Group
Abstract: [Background] Motor phenotype (MP) can be associated with a different prognosis in Parkinson's disease (PD), but it is not fixed and can change over time., [Objective] Our aim was to analyze how the MP changed over time and to identify factors associated with the changes in PD patients from a multicenter Spanish PD cohort., [Methods] PD patients who were recruited from January-2016 to November-2017 (baseline visit; V0) and evaluated again at a 2-year±30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort, were included in this study.MP was calculated at both visits based on Jankovic classification in TD (tremor dominant), IND (indeterminate), or PIGD (postural instability and gait difficulty). Sociodemographic and clinical data were collected, including serum biomarkers., [Results] Five hundred eleven patients (62.57±8.59 years old; 59.2%males) were included in the study. At V0, MP was: 47.4%(242/511) TD; 36.6%(187/511) PIGD; 16%(82/511) IND. Up to 38%(194/511) of the patients changed their phenotype from V0 to V2, being the most frequent from TD to IND (8.4%) and from TD to PIGD (6.7%). A worse cognitive status (OR = 0.966) and less autonomy for activities of daily living (OR = 0.937) at V0 and a greater increase in the globalNMS burden (OR = 1.011) from V0 to V2 were associated with changing from TD to another phenotype after 2-year follow-up., [Conclusion] The MP in PD can change over time. With disease progression, the percentage of cases with non-tremoric MP increases. PD patients who changed from TD to postural instability and gait difficulty increased NMS burden significantly.
Published: 2022

22. Increased homocysteine levels correlate with cortical structural damage in Parkinson's disease

Author: Centres de Recerca de Catalunya, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundació La Marató de TV3, Instituto de Salud Carlos III, European Commission, Universidad de Sevilla, Sampedro, Frederic, Martínez-Horta, Saúl, Horta-Barba, Andrea, Grothe, Michel J., Labrador, Miguel Ángel, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Carrillo, Fátima, Puig-Davi, Arnau, Roldán, Florinda, Aguilar Barberá, Miquel, Pastor, Pau, Escalante, Sonia, Solano Vila, Berta, Cots Foraster, Ana, Ruiz Martínez, Javier, Carrillo Padilla, Francisco, Pueyo Morlans, Mercedes, González-Aramburu, Isabel, Infante, Jon, Hernández-Vara, Jorge, Fábregues-Boixar, Oriol de, Deus Fonticoba, T. de, Ávila, Asunción, Martínez-Castrillo, J. C., Bejr-Kasem, Helena, Campolongo, Antonia, Pascual-Sedano, Berta, COPPADIS Study Group, Martínez-Martín, Pablo, Santos-García, Diego, Mir, Pablo, Kulisevsky, Jaime, Centres de Recerca de Catalunya, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundació La Marató de TV3, Instituto de Salud Carlos III, European Commission, Universidad de Sevilla, Sampedro, Frederic, Martínez-Horta, Saúl, Horta-Barba, Andrea, Grothe, Michel J., Labrador, Miguel Ángel, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Carrillo, Fátima, Puig-Davi, Arnau, Roldán, Florinda, Aguilar Barberá, Miquel, Pastor, Pau, Escalante, Sonia, Solano Vila, Berta, Cots Foraster, Ana, Ruiz Martínez, Javier, Carrillo Padilla, Francisco, Pueyo Morlans, Mercedes, González-Aramburu, Isabel, Infante, Jon, Hernández-Vara, Jorge, Fábregues-Boixar, Oriol de, Deus Fonticoba, T. de, Ávila, Asunción, Martínez-Castrillo, J. C., Bejr-Kasem, Helena, Campolongo, Antonia, Pascual-Sedano, Berta, COPPADIS Study Group, Martínez-Martín, Pablo, Santos-García, Diego, Mir, Pablo, and Kulisevsky, Jaime
Abstract: [Background] Blood homocysteine appears to be increased in Parkinson's disease (PD) and may play a role in the development and progression of this disorder. However, the specific contribution of abnormal homocysteine levels to cortical degeneration in PD remains elusive., [Objective] To characterize the cortical structural correlates of homocysteine levels in PD., [Methods] From the COPPADIS cohort, we identified a subset of PD patients and healthy controls (HC) with available homocysteine and imaging data. Surface-based vertex-wise multiple regression analyses were performed to investigate the cortical macrostructural (cortical thinning) and microstructural (increased intracortical diffusivity) correlates of homocysteine levels in this sample., [Results] A total of 137 PD patients and 43 HC were included. Homocysteine levels were increased in the PD group (t = −2.2, p = 0.03), correlating in turn with cognitive performance (r = −0.2, p = 0.03). Homocysteine in PD was also associated with frontal cortical thinning and, in a subset of patients with available DTI data, with microstructural damage in frontal and posterior-cortical regions (p < 0.05 Monte-Carlo corrected)., [Conclusions] Homocysteine in PD appears to be associated with cognitive performance and structural damage in the cerebral cortex. These findings not only reinforce the presence and importance of cortical degeneration in PD, but also suggest that homocysteine plays a role among the multiple pathological processes thought to be involved in its development.
Published: 2022

23. Early downregulation of hsa-miR-144-3p in serum from drug-naïve Parkinson's disease patients

Author: Zago, Elisa, Dal Molin, Alessandra, Dimitri, Giovanna Maria, Xumerle, Luciano, Pirazzini, Chiara, Bacalini, Maria Giulia, Maturo, Maria Giovanna, Azevedo, Tiago, Spasov, Simeon, Gómez-Garre, Pilar, Periñán, María Teresa, Jesús Maestre, Silvia, Baldelli, Luca, Sambati, Luisa, Calandra-Buonaura, Giovanna, Garagnani, Paolo, Provini, Federica, Cortelli, Pietro, Mir, Pablo, Trenkwalder, Claudia, Mollenhauer, Brit, Franceschi, Claudio, Liò, Pietro, Nardini, Christine, PROPAG-AGEING Consortium, Zago, Elisa, Dal Molin, Alessandra, Dimitri, Giovanna Maria, Xumerle, Luciano, Pirazzini, Chiara, Bacalini, Maria Giulia, Maturo, Maria Giovanna, Azevedo, Tiago, Spasov, Simeon, Gómez-Garre, Pilar, Periñán, María Teresa, Jesús Maestre, Silvia, Baldelli, Luca, Sambati, Luisa, Calandra-Buonaura, Giovanna, Garagnani, Paolo, Provini, Federica, Cortelli, Pietro, Mir, Pablo, Trenkwalder, Claudia, Mollenhauer, Brit, Franceschi, Claudio, Liò, Pietro, Nardini, Christine, and PROPAG-AGEING Consortium
Abstract: Advanced age represents one of the major risk factors for Parkinson's Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson's Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson's Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson's Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson's Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson's Disease patients, and healthy siblings of Parkinson's Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson's Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson's Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson's Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson's Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson's Disease.
Published: 2022

24. Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias

Author: Pediatría, Pediatria, Martínez Rubio, Dolores, Hinarejos, Isabel, Sancho, Paula, Gorría Redondo, Nerea, Bernadó Fonz, Raquel, Tello, Cristina, Marco Marín, Clara, Martí Carrera, María Itxaso, Martínez González, María Jesús, García Ribes, Ainhoa, Baviera Muñoz, Raquel, Sastre Bataller, Isabel, Martínez Torres, Irene, Duat Rodríguez, Anna, Janeiro, Patrícia, Moreno, Esther, Pías Peleteiro, Leticia, O’Callaghan Gordo, Mar, Ruiz Gómez, Ángeles, Muñoz, Esteban, Martí, Maria Josep, Sánchez Monteagudo, Ana, Fuster, Candela, Andrés Bordería, Amparo, Pons, Roser Maria, Jesús Maestre, Silvia, Mir, Pablo, Lupo, Vincenzo, Pérez Dueñas, Belén, Darling, Alejandra, Aguilera Albesa, Sergio, Espinós, Carmen, Pediatría, Pediatria, Martínez Rubio, Dolores, Hinarejos, Isabel, Sancho, Paula, Gorría Redondo, Nerea, Bernadó Fonz, Raquel, Tello, Cristina, Marco Marín, Clara, Martí Carrera, María Itxaso, Martínez González, María Jesús, García Ribes, Ainhoa, Baviera Muñoz, Raquel, Sastre Bataller, Isabel, Martínez Torres, Irene, Duat Rodríguez, Anna, Janeiro, Patrícia, Moreno, Esther, Pías Peleteiro, Leticia, O’Callaghan Gordo, Mar, Ruiz Gómez, Ángeles, Muñoz, Esteban, Martí, Maria Josep, Sánchez Monteagudo, Ana, Fuster, Candela, Andrés Bordería, Amparo, Pons, Roser Maria, Jesús Maestre, Silvia, Mir, Pablo, Lupo, Vincenzo, Pérez Dueñas, Belén, Darling, Alejandra, Aguilera Albesa, Sergio, and Espinós, Carmen
Abstract: Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.
Published: 2022

25. Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias

Author: Instituto de Salud Carlos III, European Commission, Fundació La Marató de TV3, Generalitat Valenciana, Ministerio de Educación, Cultura y Deporte (España), Fundació per Amor a L'Art, Marco-Marín, Clara [0000-0002-8813-3515], Martínez-Rubio, Dolores, Hinarejos, Isabel, Sancho, Paula, Gorría-Redondo, Nerea, Bernado-Fonz, Raquel, Tello, Cristina, Marco-Marín, Clara, Martí-Carrera, Itxaso, Martínez-González, María Jesús, García-Ribes, Ainhoa, Baviera-Muñoz, Raquel, Sastre-Bataller, Isabel, Martínez-Torres, Irene, Duat-Rodriguez, Anna, Janeiro, Patricia, Moreno, Esther, Pías-Peleteiro, Leticia, Gordo, Mar, O'Callaghan Ruiz-Gómez, Ángeles, Muñoz, Esteban, Martí, Maria Josep, Sánchez-Monteagudo, Ana, Fuster, Candela, Andrés-Bordería, Amparo, Pons, Roser Maria, Jesús-Maestre, Silvia, Mir, Pablo, Lupo, Vincenzo, Pérez-Dueñas, Belén, Darling, Alejandra, Aguilera-Albesa, Sergio, Espinós, Carmen, Instituto de Salud Carlos III, European Commission, Fundació La Marató de TV3, Generalitat Valenciana, Ministerio de Educación, Cultura y Deporte (España), Fundació per Amor a L'Art, Marco-Marín, Clara [0000-0002-8813-3515], Martínez-Rubio, Dolores, Hinarejos, Isabel, Sancho, Paula, Gorría-Redondo, Nerea, Bernado-Fonz, Raquel, Tello, Cristina, Marco-Marín, Clara, Martí-Carrera, Itxaso, Martínez-González, María Jesús, García-Ribes, Ainhoa, Baviera-Muñoz, Raquel, Sastre-Bataller, Isabel, Martínez-Torres, Irene, Duat-Rodriguez, Anna, Janeiro, Patricia, Moreno, Esther, Pías-Peleteiro, Leticia, Gordo, Mar, O'Callaghan Ruiz-Gómez, Ángeles, Muñoz, Esteban, Martí, Maria Josep, Sánchez-Monteagudo, Ana, Fuster, Candela, Andrés-Bordería, Amparo, Pons, Roser Maria, Jesús-Maestre, Silvia, Mir, Pablo, Lupo, Vincenzo, Pérez-Dueñas, Belén, Darling, Alejandra, Aguilera-Albesa, Sergio, and Espinós, Carmen
Abstract: Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.
Published: 2022

26. Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients

Author: Baldelli, Luca, Schade, Sebastian, Jesús Maestre, Silvia, Schreglmann, Sebastian R., Gómez Garre, María del Pilar, Mir Rivera, Pablo, Labrador-Espinosa, Miguel Á., Periñán Tocino, María Teresa, and Universidad de Sevilla. Departamento de Medicina
Abstract: A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had
Published: 2021

27. Lack of validation of variants associated with cervical dystonia risk: A GWAS replication study

Author: Gómez-Garre, Pilar, Huertas-Fernández, Ismael, Cáceres-Redondo, María Teresa, Alonso-Canovas, Araceli, Bernal-Bernal, Inmaculada, Blanco-Ollero, Alberto, Bonilla-Toribio, Marta, Burguera, Juan Andrés, Carballo, Manuel, Carrillo, Fatima, Catalán-Alonso, José M., Escamilla-Sevilla, Francisco, Espinosa-Rosso, Raul, Fernández-Moreno, María Carmen, García-Caldentey, Juan, García-Moreno, José Manuel, Giacometti-Silveira, Sandra, Gutiérrez-García, Javier, Jesús-Maestre, Silvia, López-Valdés, Eva, Martínez-Castrillo, Juan Carlos, Medialdea-Natera, María Pilar, Méndez-Lucena, Carolina, Mínguez-Castellanos, Adolfo, Moya, Miguel Angel, Ochoa-Sepulveda, Juan José, Ojea, Tomas, Rodríguez, Nuria, Rubio-Agusti, Ignacio, Sillero-Sánchez, Miriam, del Val, Javier, Vargas-González, Laura, and Mir, Pablo
Published: 2014
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28. Teaching Video NeuroImage: Clues in Myoclonus Evaluation

Author: Vélez Gómez, Beatriz, Jesús Maestre, Silvia, Macías García, Daniel, Lechón, Beatriz, Mir, Pablo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, and Fundación Alicia Koplowitz
Abstract: A 53-year-old woman was presented for the evaluation of visual disturbances, generalized and multifocal myoclonus, and progressive ataxia that began at age 30 years (cf. Video 1). Bilateral cherry-red spots in the macula (figure) and a cortical origin in the EEG-EMG coregistration with back-averaging were observed. Reduced neuraminidase activity in fibroblasts and the homozygous mutation c.403G>A in the NEU1 gene confirmed the diagnosis of sialidosis type I., This research was supported by grants from the Spanish Ministry of Science and Innovation [RTC2019-007150-1], the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) [PI14/01823, PI16/01575, PI18/01898, and PI19/01576], the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526 and CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0471-2013, PE-0210-2018, PI-0459-2018, and PE-0186-2019], and the Fundación Alicia Koplowitz. Silvia Jesús has a “Acción B Clínicos-Investigadores” (Action B Clinicians-Researchers) contract [B-0007-2019] funded by the “Consejería de Salud y Familiar,” and Daniel Macías-García has a Río Hortega contract [CM18/00142] funded by the Health Institute Carlos III.
Published: 2021

29. Integrating genetic and clinical data to predict impulse control disorders in Parkinson's disease

Author: Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Junta de Andalucía, Sociedad Andaluza de Neurología, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Jacques and Gloria Gossweiler Foundation, Jesús Maestre, Silvia, Perinán, María Teresa, Cortés, C., Buiza-Rueda, Dolores, Macías García, Daniel, Adarmes Gómez, A. D., Muñoz‐Delgado, Laura, Labrador, Miguel Ángel, Tejera-Parrado, Cristina, Gómez-Garre, Pilar, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Junta de Andalucía, Sociedad Andaluza de Neurología, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Jacques and Gloria Gossweiler Foundation, Jesús Maestre, Silvia, Perinán, María Teresa, Cortés, C., Buiza-Rueda, Dolores, Macías García, Daniel, Adarmes Gómez, A. D., Muñoz‐Delgado, Laura, Labrador, Miguel Ángel, Tejera-Parrado, Cristina, and Gómez-Garre, Pilar
Abstract: [Background and purpose] Impulse control disorders (ICDs) are frequent in Parkinson’s disease (PD), with associated clinical and genetic risk factors. This study was aimed at analyzing the clinical features and the genetic background that underlie ICDs in PD., [Methods] We included 353 patients with PD in this study (58.9% men, mean age 62.4 ± 10.58 years, mean age at disease onset 52.71 ± 11.94 years). We used the validated Questionnaire for Impulsive–Compulsive Disorders in Parkinson’s Disease for ICDs screening. Motor, nonmotor, and treatment‐related features were evaluated according to the presence of ICDs. Twenty‐one variants related to dopaminergic, serotonergic, glutamatergic, and opioid neurotransmitter systems were assessed. Association studies between polymorphisms and ICDs were performed. The combination of clinical and genetic variables was analyzed with receiver operating characteristic curves to assess the predictability of experiencing ICDs., [Results] Impulse control disorders appeared in 25.1% of the cases. Patients with ICDs were younger and presented a higher rate of anxiety. Treatment with dopamine agonists increased the risk of ICDs and it was dose dependent (P < 0.05). Genetic association studies showed that the DOPA decarboxylase gene (DDC), rs1451375, might modulate the risk of ICDs. Plotting the clinical–genetic model, the predictability of ICDs increased 11% (area under curve = 0.80; z = 3.22, P = 0.001) when adding the genotype data for single nucleotide polymorphisms., [Conclusions] Polymorphisms in DDC might act as risk markers for ICDs in PD. The predictability of experiencing ICDs increased by adding genetic factors to clinical features. It is therefore important to assess the patient’s genetic background to identify individuals at risk for ICDs.
Published: 2021

30. Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients

Author: Universidad de Sevilla. Departamento de Medicina, Baldelli, Luca, Schade, Sebastian, Jesús Maestre, Silvia, Schreglmann, Sebastian R., Gómez Garre, María del Pilar, Mir Rivera, Pablo, Labrador-Espinosa, Miguel Á., Periñán Tocino, María Teresa, Universidad de Sevilla. Departamento de Medicina, Baldelli, Luca, Schade, Sebastian, Jesús Maestre, Silvia, Schreglmann, Sebastian R., Gómez Garre, María del Pilar, Mir Rivera, Pablo, Labrador-Espinosa, Miguel Á., and Periñán Tocino, María Teresa
Abstract: A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had <1% probability of having prodromal PD; 100 between 1 and 10%, 26 siblings between 10 and 80%, one fulfilled the criteria for prodromal PD. According to the current analysis, we cannot confirm the increased risk of PD siblings for prodromal PD. Siblings showed a heterogeneous distribution of prodromal PD markers and probability. Additional parameters, including strong disease markers, should be investigated to verify if these results depend on validity and sensitivity of prodromal PD criteria, or if siblings’ risk is not elevated.
Published: 2021

31. Predictors of Loss of Functional Independence in Parkinson’s Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up and Comparison with a Control Group

Author: Curemos el Párkinson, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Naya Ríos, Lucía, García Roca, Lucía, Martínez Miró, Cristina, Canfield, Hector, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Pastor, Pau, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo-Martínez, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, Curemos el Párkinson, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Naya Ríos, Lucía, García Roca, Lucía, Martínez Miró, Cristina, Canfield, Hector, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Pastor, Pau, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Gómez Mayordomo, Víctor, Nogueira, Víctor, Puente, Víctor, Dotor, Julio, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo-Martínez, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Alonso Redondo, Rubén, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, and Mir, Pablo
Abstract: [Background and objective] The aim of this study was to compare the progression of independence in activities of daily living (ADL) in Parkinson’s disease (PD) patients versus a control group, as well as to identify predictors of disability progression and functional dependency (FD)., [Patients and Methods] PD patients and control subjects, who were recruited from 35 centers of Spain from the COPPADIS cohort between January 2016 and November 2017 (V0), were included. Patients and subjects were then evaluated again at the 2-year follow-up (V2). Disability was assessed with the Schwab & England Activities of Daily Living Scale (S&E-ADLS) at V0 and V2. FD was defined as an S&E-ADLS score less than 80%., [Results] In the PD group, a significant decrease in the S&E-ADLS score from V0 to V2 (N = 507; from 88.58 ± 10.19 to 84.26 ± 13.38; p < 0.0001; Cohen’s effect size = −0.519) was observed but not in controls (N = 124; from 98.87 ± 6.52 to 99.52 ± 2.15; p = 0.238). When only patients considered functional independent at baseline were included, 55 out of 463 (11.9%) converted to functional dependent at V2. To be a female (OR = 2.908; p = 0.009), have longer disease duration (OR = 1.152; p = 0.002), have a non-tremoric motor phenotype at baseline (OR = 3.574; p = 0.004), have a higher score at baseline in FOGQ (OR = 1.244; p < 0.0001) and BDI-II (OR = 1.080; p = 0.008), have a lower score at baseline in PD-CRS (OR = 0.963; p = 0.008), and have a greater increase in the score from V0 to V2 in UPDRS-IV (OR = 1.168; p = 0.0.29), FOGQ (OR = 1.348; p < 0.0001) and VAFS-Mental (OR = 1.177; p = 0.013) (adjusted R-squared 0.52; Hosmer and Lemeshow test = 0.94) were all found to be independent predictors of FD at V2., [Conclusions] In conclusion, autonomy for ADL worsens in PD patients compared to controls. Cognitive impairment, gait problems, fatigue, depressive symptoms, more advanced disease, and a non-tremor phenotype are independent predictors of FD in the short-term.
Published: 2021

32. Predictors of clinically significant quality of life impairment in Parkinson’s disease

Author: AbbVie Pharmaceuticals, Abbott Laboratories, Allergan Foundation, BIAL Foundation, Merz Pharma, UCB Pharma, Zambon, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Sociedad Andaluza de Neurología, Jacques and Gloria Gossweiler Foundation, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Muñoz, Guillermo, Paz González, J. M., Martínez Miró, Cristina, Suárez, Ester, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Pastor, Pau, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López Manzanares, Luis, González-Aramburu, Isabel, Ávila-Rivera, María A., Catalán, M. J., Nogueira, Víctor, Puente, Víctor, Ruíz de Arcos, María, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Clavero, Pedro, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo-Martínez, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, Mir, Pablo, AbbVie Pharmaceuticals, Abbott Laboratories, Allergan Foundation, BIAL Foundation, Merz Pharma, UCB Pharma, Zambon, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Sociedad Andaluza de Neurología, Jacques and Gloria Gossweiler Foundation, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Santos-García, Diego, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, Muñoz, Guillermo, Paz González, J. M., Martínez Miró, Cristina, Suárez, Ester, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Pastor, Pau, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López Manzanares, Luis, González-Aramburu, Isabel, Ávila-Rivera, María A., Catalán, M. J., Nogueira, Víctor, Puente, Víctor, Ruíz de Arcos, María, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Clavero, Pedro, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo-Martínez, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Ordás, Carlos, López-Díaz, Luis M., McAfee, Darrian, Martínez-Martín, Pablo, and Mir, Pablo
Abstract: Quality of life (QOL) plays an important role in independent living in Parkinson’s disease (PD) patients, being crucial to know what factors impact QoL throughout the course of the disease. Here we identified predictors of QoL impairment in PD patients from a Spanish cohort. PD patients recruited from 35 centers of Spain from the COPPADIS cohort from January 2016, to November 2017, were followed up during 2 years. Health-related QoL (HRQoL) and global QoL (GQoL) were assessed with the 39-item Parkinson’s disease Questionnaire (PDQ-39) and the EUROHIS-QOL 8-item index (EUROHIS-QOL8), respectively, at baseline (V0) and at 24 months ± 1 month (V2). Clinically significant QoL impairment was defined as presenting an increase (PDQ-39SI) or decrement (EUROHIS-QOL8) at V2 ≥ 10% of the score at baseline (V0). A comparison with a control group was conducted for GQoL. GQoL did not change significantly in PD patients (N = 507; p = 0.686) or in the control group (N = 119; p = 0.192). The mean PDQ-39SI was significantly increased in PD patients (62.7 ± 8.5 years old; 58.8% males; N = 500) by 21.6% (from 16.7 ± 13 to 20.3 ± 16.4; p < 0.0001) at V2. Ninety-three patients (18.6%) presented a clinically significant HRQoL impairment at V2. To be younger (OR = 0.896; 95% CI 0.829–0.968; p = 0.006), to be a female (OR = 4.181; 95% CI 1.422–12.290; p = 0.009), and to have a greater increase in BDI-II (Beck Depression Inventory-II) (OR = 1.139; 95% CI 1.053–1.231; p = 0.001) and NMSS (Non-Motor Symptoms Scale) (OR = 1.052; 95% CI 1.027–1.113; p < 0.0001) total scores from V0 to V2 were associated with clinically significant HRQoL impairment at the 2-year follow-up (Hosmer–Lemeshow test, p = 0.665; R 2 = 0.655). An increase in ≥5 and ≥10 points of BDI-II and NMSS total score at V2 multiplied the probability of presenting clinically significant HRQoL impairment by 5 (OR = 5.453; 95% CI 1.663–17.876; p = 0.005) and 8 (OR = 8.217; 95% CI, 2.975–22.696; p = 0.002), respectively. In conclusion
Published: 2021

33. Teaching Video NeuroImage: Clues in Myoclonus Evaluation

Author: Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Vélez Gómez, Beatriz, Jesús Maestre, Silvia, Macías García, Daniel, Lechón, Beatriz, Mir, Pablo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Vélez Gómez, Beatriz, Jesús Maestre, Silvia, Macías García, Daniel, Lechón, Beatriz, and Mir, Pablo
Abstract: A 53-year-old woman was presented for the evaluation of visual disturbances, generalized and multifocal myoclonus, and progressive ataxia that began at age 30 years (cf. Video 1). Bilateral cherry-red spots in the macula (figure) and a cortical origin in the EEG-EMG coregistration with back-averaging were observed. Reduced neuraminidase activity in fibroblasts and the homozygous mutation c.403G>A in the NEU1 gene confirmed the diagnosis of sialidosis type I.
Published: 2021

34. Diplopia Is Frequent and Associated with Motor and Non-Motor Severity in Parkinson’s Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up

Author: Instituto de Salud Carlos III, Takeda Pharmaceutical Company, International Parkinson and Movement Disorder Society, AbbVie Pharmaceuticals, Abbott Laboratories, Allergan Foundation, BIAL Foundation, Merz Pharma, UCB Pharma, Zambon, Ministerio de Economía y Competitividad (España), European Commission, Junta de Andalucía, Sociedad Andaluza de Neurología, Jacques and Gloria Gossweiler Foundation, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Santos-García, Diego, Naya Ríos, Lucía, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, García Roca, Lucía, Feal Painceiras, María J., Martínez Miró, Cristina, Canfield, Hector, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Pastor, Pau, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Mir, Pablo, Instituto de Salud Carlos III, Takeda Pharmaceutical Company, International Parkinson and Movement Disorder Society, AbbVie Pharmaceuticals, Abbott Laboratories, Allergan Foundation, BIAL Foundation, Merz Pharma, UCB Pharma, Zambon, Ministerio de Economía y Competitividad (España), European Commission, Junta de Andalucía, Sociedad Andaluza de Neurología, Jacques and Gloria Gossweiler Foundation, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Santos-García, Diego, Naya Ríos, Lucía, Deus Fonticoba, T. de, Cores Bartolomé, Carlos, García Roca, Lucía, Feal Painceiras, María J., Martínez Miró, Cristina, Canfield, Hector, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Pastor, Pau, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., and Mir, Pablo
Abstract: [Background and objective] Diplopia is relatively common in Parkinson’s disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it., [Patients and Methods] PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as “with diplopia” or “without diplopia” according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls., [Results] The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269–4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012–1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson’s Disease Rating Scale–III (OR = 1.039; 95%CI, 1.023–1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001–1.057; p = 0.049) scores were independent factors associated with diplopia (R2 = 0.25; Hosmer and Lemeshow test, p = 0.716)., [Conclusions] Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity.
Published: 2021

35. Peripheral Immune Profile and Neutrophil-to-Lymphocyte Ratio in Parkinson's Disease

Author: Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Universidad de Sevilla, Muñoz-Delgado, Laura, Macías García, Daniel, Jesús Maestre, Silvia, Martín-Rodríguez, Juan Francisco, Labrador, Miguel Ángel, Jiménez-Jaraba, María Valle, Adarmes Gómez, A. D., Carrillo, Fátima, Mir, Pablo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Universidad de Sevilla, Muñoz-Delgado, Laura, Macías García, Daniel, Jesús Maestre, Silvia, Martín-Rodríguez, Juan Francisco, Labrador, Miguel Ángel, Jiménez-Jaraba, María Valle, Adarmes Gómez, A. D., Carrillo, Fátima, and Mir, Pablo
Abstract: [Background] The neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is a well-established inflammatory marker, but its role in Parkinson's disease (PD) remains unclear., [Objectives] To determine whether a different peripheral immune profile and NLR were present in PD patients., [Methods] We conducted a case–control study that included 377 PD patients and 355 healthy controls (HCs). Leukocytes, subpopulations, and the NLR were measured. Multivariate linear regression analyses were applied to determine the differences between groups and the association between NLR and clinical characteristics in PD. A meta-analysis was performed to clarify the association between NLR and PD., [Results] In our case–control study, the NLR was significantly higher in PD patients compared with HCs (2.47 ± 1.1 vs. 1.98 ± 0.91, P < 0.001). No association between NLR and age at onset, disease severity, or disease duration was found. The meta-analysis showed that the NLR was likely to be higher in PD patients., [Conclusions] PD patients had an altered peripheral immune profile and a higher NLR compared with HCs. © 2021 International Parkinson and Movement Disorder Society
Published: 2021

36. Identifying comorbidities and lifestyle factors contributing to the cognitive profile of early Parkinson’s disease

Author: Curemos el Párkinson, Martínez-Horta, Saúl, Bejr-Kasem, Helena, Horta-Barba, Andrea, Pascual-Sedano, Berta, Santos-García, Diego, Deus Fonticoba, T. de, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Planellas, Lluís, García Caldentey, Juan, Caballol, Nuria, Vives-Pastor, Bárbara, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Catalán, M. J., López-Díaz, Luis M., Puente, Víctor, García-Moreno, José Manuel, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Blázquez-Estrada, Marta, Seijo-Martínez, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Prieto-Jurczynska, Cristina, Martínez-Martín, Pablo, Mir, Pablo, Kulisevsky, Jaime, Curemos el Párkinson, Martínez-Horta, Saúl, Bejr-Kasem, Helena, Horta-Barba, Andrea, Pascual-Sedano, Berta, Santos-García, Diego, Deus Fonticoba, T. de, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Planellas, Lluís, García Caldentey, Juan, Caballol, Nuria, Vives-Pastor, Bárbara, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Catalán, M. J., López-Díaz, Luis M., Puente, Víctor, García-Moreno, José Manuel, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Gastón, Itziar, Blázquez-Estrada, Marta, Seijo-Martínez, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, González Ardura, Jessica, Prieto-Jurczynska, Cristina, Martínez-Martín, Pablo, Mir, Pablo, and Kulisevsky, Jaime
Abstract: [Background] Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson’s disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials., [Methods] Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study., [Results] Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005)., [Conclusions] We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD.
Published: 2021

37. In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study

Author: Alzheimer Forschung Initiative, Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Curemos el Párkinson, Universidad de Sevilla, Grothe, Michel J., Labrador, Miguel Ángel, Jesús Maestre, Silvia, Macías García, Daniel, Adarmes Gómez, A. D., Carrillo, Fátima, Iglesias Camacho, Elena, Franco-Rosado, Pablo, Roldán, Florinda, Martín-Rodríguez, Juan Francisco, Aguilar Barberá, Miquel, Pastor, Pau, Escalante, Sonia, Solano Vila, Berta, Cots Foraster, Ana, Ruiz Martínez, Javier, Carrillo Padilla, Francisco, Pueyo Morlans, Mercedes, González-Aramburu, Isabel, Infante, Jon, Hernández-Vara, Jorge, Fábregues-Boixar, Oriol de, Deus Fonticoba, T. de, Pascual-Sedano, Berta, Kulisevsky, Jaime, Martínez-Martín, Pablo, Santos-García, Diego, Mir, Pablo, Alzheimer Forschung Initiative, Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Curemos el Párkinson, Universidad de Sevilla, Grothe, Michel J., Labrador, Miguel Ángel, Jesús Maestre, Silvia, Macías García, Daniel, Adarmes Gómez, A. D., Carrillo, Fátima, Iglesias Camacho, Elena, Franco-Rosado, Pablo, Roldán, Florinda, Martín-Rodríguez, Juan Francisco, Aguilar Barberá, Miquel, Pastor, Pau, Escalante, Sonia, Solano Vila, Berta, Cots Foraster, Ana, Ruiz Martínez, Javier, Carrillo Padilla, Francisco, Pueyo Morlans, Mercedes, González-Aramburu, Isabel, Infante, Jon, Hernández-Vara, Jorge, Fábregues-Boixar, Oriol de, Deus Fonticoba, T. de, Pascual-Sedano, Berta, Kulisevsky, Jaime, Martínez-Martín, Pablo, Santos-García, Diego, and Mir, Pablo
Abstract: [Introduction] We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia., [Methods] The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models., [Results] Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02)., [Conclusions] Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.
Published: 2021

38. Staging Parkinson’s Disease Combining Motor and Nonmotor Symptoms Correlates with Disability and Quality of Life

Author: Santos-García, Diego, Deus Fonticoba, T. de, Paz González, J. M., Cores Bartolomé, Carlos, Valdés Aymerich, Lorena, Muñoz Enríquez, J. G., Suárez, Ester, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Pastor, Pau, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Catalán, M. J., Nogueira, Víctor, Puente, Víctor, García-Moreno, José Manuel, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso, Gemma, López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo-Martínez, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, Ardura, Jessica, Ordás, Carlos, López-Díaz, Luis M., Mir, Pablo, Martínez-Martín, Pablo, Santos-García, Diego, Deus Fonticoba, T. de, Paz González, J. M., Cores Bartolomé, Carlos, Valdés Aymerich, Lorena, Muñoz Enríquez, J. G., Suárez, Ester, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Pastor, Pau, Planellas, Lluís, Cosgaya, Marina, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Catalán, M. J., Nogueira, Víctor, Puente, Víctor, García-Moreno, José Manuel, Borrué, Carmen, Solano Vila, Berta, Álvarez-Sauco, María, Vela, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso, Gemma, López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Blázquez-Estrada, Marta, Seijo-Martínez, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Mónica, Fábregues-Boixar, Oriol de, Ardura, Jessica, Ordás, Carlos, López-Díaz, Luis M., Mir, Pablo, and Martínez-Martín, Pablo
Abstract: [Introduction] In a degenerative disorder such as Parkinson’s disease (PD), it is important to establish clinical stages that allow to know the course of the disease. Our aim was to analyze whether a scale combining Hoehn and Yahr’s motor stage (H&Y) and the nonmotor symptoms burden (NMSB) (assessed by the nonmotor symptoms scale (NMSS)) provides information about the disability and the patient’s quality of life (QoL) with regard to a defined clinical stage., [Materials and Methods] Cross-sectional study in which 603 PD patients from the COPPADIS cohort were classified according to H&Y (1, stage I; 2, stage II; 3, stage III; 4, stage IV/V) and NMSB (A: NMSS = 0–20; B: NMSS = 21–40; C: NMSS = 41–70; D: NMSS ≥ 71) in 16 stages (HY.NMSB, from 1A to 4D). QoL was assessed with the PDQ-39SI, PQ-10, and EUROHIS-QOL8 and disability with the Schwab&England ADL (Activities of Daily Living) scale., [Results] A worse QoL and greater disability were observed at a higher stage of H&Y and NMSB (). Combining both (HY.NMSB), patients in stages 1C and 1D and 2C and 2D had significantly worse QoL and/or less autonomy for ADL than those in stages 2A and 2B and 3A and 3B, respectively (; e.g., PDQ-39SI in 1D [n = 15] vs 2A [n = 101]: 28.6 ± 17.1 vs 7.9 ± 5.8; )., [Conclusion] The HY.NMSB scale is simple and reflects the degree of patient involvement more accurately than the H&Y. Patients with a lower H&Y stage may be more affected if they have a greater NMS burden.
Published: 2021

39. Levodopa-Induced Dyskinesia in Parkinson Disease Specifically Associates with Dopaminergic Depletion in Sensorimotor-Related Functional Subregions of the Striatum

Author: Labrador, Miguel Ángel, Grothe, Michel J., Macías García, Daniel, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Muñoz-Delgado, Laura, Fernández-Rodríguez, Paula, Martín-Rodríguez, Juan Francisco, Huertas, Ismael, García-Solís, David, Mir, Pablo, Labrador, Miguel Ángel, Grothe, Michel J., Macías García, Daniel, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Muñoz-Delgado, Laura, Fernández-Rodríguez, Paula, Martín-Rodríguez, Juan Francisco, Huertas, Ismael, García-Solís, David, and Mir, Pablo
Abstract: [Purpose] To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum., [Methods] Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker’s Initiative using mixed linear model analysis., [Results] Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker’s Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = −2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time., [Conclusion] Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.
Published: 2021

40. Serum lipid profile among sporadic and familial forms of Parkinson’s disease

Author: Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Ministerio de Educación, Cultura y Deporte (España), Macías García, Daniel, Periñán, María Teresa, Muñoz-Delgado, Laura, Jiménez-Jaraba, María Valle, Labrador, Miguel Ángel, Jesús Maestre, Silvia, Buiza-Rueda, Dolores, Méndez-Del Barrio, Carlota, Adarmes Gómez, A. D., Gómez-Garre, Pilar, Mir, Pablo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Ministerio de Educación, Cultura y Deporte (España), Macías García, Daniel, Periñán, María Teresa, Muñoz-Delgado, Laura, Jiménez-Jaraba, María Valle, Labrador, Miguel Ángel, Jesús Maestre, Silvia, Buiza-Rueda, Dolores, Méndez-Del Barrio, Carlota, Adarmes Gómez, A. D., Gómez-Garre, Pilar, and Mir, Pablo
Abstract: Brain cholesterol metabolism has been described as altered in Parkinson’s disease (PD) patients. Serum lipid levels have been widely studied in PD with controversial results among different populations and age groups. The present study is aimed at determining if the serum lipid profile could be influenced by the genetic background of PD patients. We included 403 PD patients (342 sporadic PD patients, 30 GBA-associated PD patients, and 31 LRRK2-associated PD patients) and 654 healthy controls (HCs). Total cholesterol, HDL, LDL, and triglycerides were measured in peripheral blood. Analysis of covariance adjusting for sex and age (ANCOVA) and post hoc tests were applied to determine the differences within lipid profiles among the groups. Multivariate ANCOVA revealed significant differences among the groups within cholesterol and LDL levels. GBA-associated PD patients had significantly lower levels of total cholesterol and LDL compared to LRRK2-associated PD patients and HCs. The different serum cholesterol levels in GBA-associated PD might be related to diverse pathogenic mechanisms. Our results support the hypothesis of lipid metabolism disruption as one of the main PD pathogenic mechanisms in patients with GBA-associated PD. Further studies would be necessary to explore their clinical implications.
Published: 2021

41. Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients

Author: European Commission, Baldelli, Luca, Schade, Sebastian, Jesús Maestre, Silvia, Schreglmann, Sebastian R., Sambati, Luisa, Gómez-Garre, Pilar, Halsband, Claire, Calandra-Buonaura, Giovanna, Adarmes Gómez, A. D., Sixel-Döring, Friederike, Zenesini, Corrado, Pirazzini, Chiara, Garagnani, Paolo, Bacalini, Maria Giulia, Bhatia, Kailash P., Cortelli, Pietro, Mollenhauer, Brit, Franceschi, Claudio, Mir, Pablo, Trenkwalder, Claudia, Provini, Federica, European Commission, Baldelli, Luca, Schade, Sebastian, Jesús Maestre, Silvia, Schreglmann, Sebastian R., Sambati, Luisa, Gómez-Garre, Pilar, Halsband, Claire, Calandra-Buonaura, Giovanna, Adarmes Gómez, A. D., Sixel-Döring, Friederike, Zenesini, Corrado, Pirazzini, Chiara, Garagnani, Paolo, Bacalini, Maria Giulia, Bhatia, Kailash P., Cortelli, Pietro, Mollenhauer, Brit, Franceschi, Claudio, Mir, Pablo, Trenkwalder, Claudia, and Provini, Federica
Abstract: A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had <1% probability of having prodromal PD; 100 between 1 and 10%, 26 siblings between 10 and 80%, one fulfilled the criteria for prodromal PD. According to the current analysis, we cannot confirm the increased risk of PD siblings for prodromal PD. Siblings showed a heterogeneous distribution of prodromal PD markers and probability. Additional parameters, including strong disease markers, should be investigated to verify if these results depend on validity and sensitivity of prodromal PD criteria, or if siblings’ risk is not elevated.
Published: 2021

42. Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review

Author: Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Universidad de Sevilla, Ministerio de Educación, Cultura y Deporte (España), Gómez-Garre, Pilar, Jesús Maestre, Silvia, Periñán, María Teresa, Adarmes Gómez, A. D., Alonso Cánovas, Araceli, Blanco-Ollero, Alberto, Buiza-Rueda, Dolores, Carrillo, Fátima, Catalán, M. J., Val, Javier del, Escamilla-Sevilla, Francisco, Espinosa-Rosso, Raúl, Fernández-Moreno, María Carmen, García Moreno, J. M., García-Ruiz, Pedro José, Giacometti-Silveira, Sandra, Gutiérrez-García, Javier, López-Valdés, Eva, Macías García, Daniel, Martínez-Castrillo, J. C., Martínez Torres, Irene, Medialdea-Natera, María Pilar, Mínguez-Castellanos, Adolfo, Moya, Miguel Ángel, Ochoa-Sepúlveda, Juan José, Ojea, Tomás, Rodríguez, Nuria, Sillero-Sánchez, Miriam, Tejera-Parrado, Cristina, Mir, Pablo, Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Universidad de Sevilla, Ministerio de Educación, Cultura y Deporte (España), Gómez-Garre, Pilar, Jesús Maestre, Silvia, Periñán, María Teresa, Adarmes Gómez, A. D., Alonso Cánovas, Araceli, Blanco-Ollero, Alberto, Buiza-Rueda, Dolores, Carrillo, Fátima, Catalán, M. J., Val, Javier del, Escamilla-Sevilla, Francisco, Espinosa-Rosso, Raúl, Fernández-Moreno, María Carmen, García Moreno, J. M., García-Ruiz, Pedro José, Giacometti-Silveira, Sandra, Gutiérrez-García, Javier, López-Valdés, Eva, Macías García, Daniel, Martínez-Castrillo, J. C., Martínez Torres, Irene, Medialdea-Natera, María Pilar, Mínguez-Castellanos, Adolfo, Moya, Miguel Ángel, Ochoa-Sepúlveda, Juan José, Ojea, Tomás, Rodríguez, Nuria, Sillero-Sánchez, Miriam, Tejera-Parrado, Cristina, and Mir, Pablo
Abstract: [Objective] We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature., [Methods] A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high-resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed., [Results] Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively., [Conclusions] There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult-onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT-TOR1A and DYT-GNAL, with DYT-THAP1 likely to be an intermediate phenotype.
Published: 2021

43. Increased homocysteine levels correlate with cortical structural damage in Parkinson's disease

Author: Sampedro, Frederic, Martínez-Horta, Saúl, Horta-Barba, Andrea, Grothe, Michel J., Labrador, Miguel Ángel, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Carrillo, Fátima, Puig-Davi, Arnau, Roldán, Florinda, Aguilar Barberá, Miquel, Pastor, Pau, Escalante, Sonia, Solano Vila, Berta, Cots Foraster, A., Ruiz Martínez, Javier, Carrillo Padilla, Francisco, Pueyo Morlans, M., González-Aramburu, Isabel, Infante, Jon, Hernández-Vara, Jorge, Fábregues-Boixar, Oriol de, Deus Fonticoba, T. de, Ávila, Asunción, Martínez-Castrillo, J. C., Bejr-Kasem, Helena, Campolongo, Antonia, Pascual-Sedano, Berta, COPPADIS Study Group, Martínez-Martín, Pablo, Santos-García, Diego, Mir, Pablo, Kulisevsky, Jaime, Centres de Recerca de Catalunya, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundació La Marató de TV3, Instituto de Salud Carlos III, European Commission, and Universidad de Sevilla
Subjects: Cerebral Cortex, Neurology, Parkinson's disease, Humans, Parkinson Disease, Neuroimaging, Neurology (clinical), Cerebral Cortical Thinning, Magnetic Resonance Imaging, Homocysteine
Abstract: [Background] Blood homocysteine appears to be increased in Parkinson's disease (PD) and may play a role in the development and progression of this disorder. However, the specific contribution of abnormal homocysteine levels to cortical degeneration in PD remains elusive., [Objective] To characterize the cortical structural correlates of homocysteine levels in PD., [Methods] From the COPPADIS cohort, we identified a subset of PD patients and healthy controls (HC) with available homocysteine and imaging data. Surface-based vertex-wise multiple regression analyses were performed to investigate the cortical macrostructural (cortical thinning) and microstructural (increased intracortical diffusivity) correlates of homocysteine levels in this sample., [Results] A total of 137 PD patients and 43 HC were included. Homocysteine levels were increased in the PD group (t = −2.2, p = 0.03), correlating in turn with cognitive performance (r = −0.2, p = 0.03). Homocysteine in PD was also associated with frontal cortical thinning and, in a subset of patients with available DTI data, with microstructural damage in frontal and posterior-cortical regions (p < 0.05 Monte-Carlo corrected)., [Conclusions] Homocysteine in PD appears to be associated with cognitive performance and structural damage in the cerebral cortex. These findings not only reinforce the presence and importance of cortical degeneration in PD, but also suggest that homocysteine plays a role among the multiple pathological processes thought to be involved in its development., This work was partially supported by funds from CERCA, CIBERNED, la Marató de TV3 (grants #2014/U/477 and #20142910), Fondo de Investigaciones Sanitarias (grants #PI15/00962 and #PI18/01717FIS), Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional (FEDER). MJG receives support from the “Miguel Servet” program [CP19/00031] and a research grant [PI20/00613] from the ISCIII-FEDER. MALE receives support from the VI-PPIT-US project at the University of Seville [USE-20046-J].
Published: 2022
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44. COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015): an ongoing global Parkinson's disease project about disease progression with more than 1000 subjects included. Results from the baseline evaluation

Author: Santos-García, Diego, Jesús Maestre, Silvia, Aguilar Barberá, Miquel, Planellas, Lluís, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, Cabo-Lopez, Iria, López-Manzanares, Lydia, González-Aramburu, Isabel, Ávila-Rivera, María A., Catalán, M. J., López-Díaz, Luis M., Puente, Víctor, García Moreno, J. M., Borrué, Carmen, Solano Vila, B., Álvarez Sauco, María, Vela-Desojo, Lydia, Escalante, Sonia, Cubo, Esther, Carrillo Padilla, Francisco, Martínez-Castrillo, J. C., Sánchez Alonso, Pilar, Alonso Losada, G., López-Ariztegui, Nuria, Gastón, Itziar, Kulisevsky, Jaime, Menéndez-González, Manuel, Seijo-Martínez, Manuel, Ruiz Martínez, Javier, Valero, Caridad, Kurtis, Monica, Fábregues-Boixar, Oriol de, González Ardura, J., Prieto Jurczynska, C., Martínez-Martín, Pablo, and Mir, Pablo
Subjects: Quality of life, Non‐motor symptoms, Parkinson's disease, Mood, Gait, Motor fluctuations
Abstract: [Background and purpose]: In Parkinson's disease (PD ), the course of the disorder is highly variable between patients. Well‐designed, prospective studies for identifying PD progression biomarkers are necessary. Our aim was to show the results of baseline evaluations of an ongoing global PD project, COPPADIS ‐2015 (Co hort of Patients with PA rkinson's DI sease in Spain, 2015)., [Methods]: This was an observational, descriptive, nationwide study (Spain). The recruitment period ended in October 2017. Baseline evaluation included more than 15 validated scales and complementary studies in a subgroup of participants., [Results]: In total, 1174 subjects from 35 centres were considered valid for baseline analysis: 694 patients (62.6 ± 8.9 years old, 60.3% males), 273 caregivers (58.5 ± 11.9 years old, 31.8% males) and 207 controls (61 ± 8.3 years old, 49.5% males). The mean disease duration was 5.5 ± 4.4 years. Hoehn and Yahr stage was 1 or 2 in 90.7% of the patients whilst 33.9% and 18.1% of them presented motor fluctuations and dyskinesias, respectively. The mean Non‐Motor Symptoms Scale total score was 45.4 ± 38.1, and 30.4% of the patients presented cognitive impairment, 16.1% major depression, 12.7% impulse control disorder, 7.2% compulsive behaviour, 57.2% pain and 13.2% falls. Compared to the control group, PD patients presented a significantly higher burden of non‐motor symptoms and a worse quality of life. More than 300 subjects conducted complementary studies (serum biomarkers, genetic and neuroimaging)., [Conclusions]: Parkinson's disease is a complex disorder and different non‐motor symptoms are frequently present and are more prevalent than in controls. In real clinical practice it is important to ask for them.
Published: 2019

45. The impact of freezing of gait on functional dependency in Parkinson’s disease with regard to motor phenotype

Author: AbbVie Pharmaceuticals, UCB Pharma, Lundbeck Foundation, Krka Farmacéutica, Zambon, BIAL Foundation, Teva Pharmaceutical Industries, Merz Pharma, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Abbott Laboratories, Allergan Foundation, European Commission, Sociedad Andaluza de Neurología, Jacques and Gloria Gossweiler Foundation, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Nutricia Foundation, Italfarmaco, Qualigen, Sanofi, Genzyme, Boston Foundation, International Parkinson and Movement Disorder Society, Santos-García, Diego, Deus Fonticoba, T. de, Suárez-Castro. Ester, Aneiros Díaz, A., Feal Painceiras, María J., Paz González, J. M., García-Sancho, Carlos, Jesús Maestre, Silvia, Mir, Pablo, Planellas, Lluís, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, González-Aramburu, Isabel, Ávila-Rivera, María A., Catalán, M. J., Nogueira, Víctor, Álvarez-Sauco, María, Vela-Desojo, Lydia, Escalante, Sonia, Cubo, Esther, Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, Martínez-Martín, Pablo, AbbVie Pharmaceuticals, UCB Pharma, Lundbeck Foundation, Krka Farmacéutica, Zambon, BIAL Foundation, Teva Pharmaceutical Industries, Merz Pharma, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Abbott Laboratories, Allergan Foundation, European Commission, Sociedad Andaluza de Neurología, Jacques and Gloria Gossweiler Foundation, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Nutricia Foundation, Italfarmaco, Qualigen, Sanofi, Genzyme, Boston Foundation, International Parkinson and Movement Disorder Society, Santos-García, Diego, Deus Fonticoba, T. de, Suárez-Castro. Ester, Aneiros Díaz, A., Feal Painceiras, María J., Paz González, J. M., García-Sancho, Carlos, Jesús Maestre, Silvia, Mir, Pablo, Planellas, Lluís, García Caldentey, Juan, Caballol, Nuria, Legarda, Inés, Hernández-Vara, Jorge, González-Aramburu, Isabel, Ávila-Rivera, María A., Catalán, M. J., Nogueira, Víctor, Álvarez-Sauco, María, Vela-Desojo, Lydia, Escalante, Sonia, Cubo, Esther, Sánchez Alonso, Pilar, Alonso Losada, María G., López-Ariztegui, Nuria, and Martínez-Martín, Pablo
Abstract: Background and objective: Freezing of gait (FOG) is a disabling symptom more frequent in Parkinson’s disease (PD) patients with postural instability gait difficulty (PIGD) phenotype. The aim of this study was to determine the prevalence of self-reported FOG in a large group of PD patients as well as assess its relationship with functional dependency with regard to motor phenotype. Methods: The data correspond to the baseline evaluation of the COPPADIS-2015 study. Patients with FOG were identified as those with a score of 1 or greater on item-3 of the freezing of gait questionnaire (FOG-Q). Functional dependency was defined as a Schwab and England (S&E) ADL scale score less than 80%. PIGD and non-PIGD (tremor dominant + indeterminate) groups were considered regarding to motor phenotype. Results: Among the 689 PD patients (62.6 ± 8.9 years old, 59.8% males), 240 reported FOG (34.8%), whereas 63 presented functional dependency (9.1%). A total of 22.1% of patients with FOG presented functional dependency vs. only 2.2% of those without FOG (p < 0.0001). FOG was related to functional dependency (OR = 3.470; 95%CI 1.411–8.530; p = 0.007) after adjustment to age, gender, disease duration, daily equivalent levodopa dose, comorbidity (number of non-antiparkinsonian drugs/day), motor status (UPDRS-III), PIGD phenotype, motor complications (UPDRS-IV), NMS burden (NMSS total score), cognition (PD-CRS), and mood (BDI-II). However, according to motor phenotype, FOG was related to functional dependency only in PIGD patients (OR = 7.163; 95%CI 1.206–42.564; p = 0.030). Conclusions: Self-reported FOG is associated with functional dependency in PIGD but not in non-PIGD motor phenotype patients.
Published: 2020

46. Analysis of p.Tyr307Asn variant in the LRP10 gene in Parkinson’s disease in southern Spain

Author: Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Ministerio de Educación, Cultura y Deporte (España), Periñán, María Teresa, Macías García, Daniel, Buiza-Rueda, Dolores, Guijarro-Albaladejo, Beatriz, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Escuela, Rocío, Vigo-Ortega, Rosario, Gómez-Garre, Pilar, Mir, Pablo, Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación Alicia Koplowitz, Ministerio de Educación, Cultura y Deporte (España), Periñán, María Teresa, Macías García, Daniel, Buiza-Rueda, Dolores, Guijarro-Albaladejo, Beatriz, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Escuela, Rocío, Vigo-Ortega, Rosario, Gómez-Garre, Pilar, and Mir, Pablo
Abstract: Lipoprotein receptor-related protein 10 (LRP10) has been proposed as a novel causative gene for autosomal dominant Parkinson’s disease (PD), and the c.919T>A (p.Tyr307Asn) variant has been identified as possibly involved in the development of familial PD and PD with dementia. We screened for the p.Tyr307Asn variant in a southern Spain population of 679 PD patients, of who 129 were familial cases, and 1217 unrelated healthy controls. A total of 3 carriers of the LRP10 p.Tyr307Asn variant were identified: 1 PD patient and 2 healthy controls. Together with the absence of a family history of PD, this finding might suggest a low penetrance variant as well as a limited role for p.Tyr307Asn in PD in our cohort. Nevertheless, a family history of Alzheimer’s disease in the LRP10 p.Tyr307Asn carriers provides evidence for a possible association with dementia.
Published: 2020

47. Non-motor symptom burden in patients with Parkinson’s disease with impulse control disorders and compulsive behaviours: results from the COPPADIS cohort

Author: Curemos el Párkinson, Jesús Maestre, Silvia, Labrador, Miguel Ángel, Adarmes Gómez, A. D., Méndel-Del Barrio, C., Martínez-Castrillo, J. C., Alonso Cánovas, Araceli, Sánchez Alonso, Pilar, Novo Ponte, S., Alonso Losada, María G., López-Ariztegui, Nuria, Segundo Rodríguez, J. C., Morales Casado, M. I., Gastón, Itziar, Lacruz, F., Clavero, Pedro, Kulisevsky, Jaime, Pagonabarraga-Mora, Javier, Pascual-Sedano, Berta, Martínez-Martín, Pablo, Santos-García, Diego, Mir, Pablo, Curemos el Párkinson, Jesús Maestre, Silvia, Labrador, Miguel Ángel, Adarmes Gómez, A. D., Méndel-Del Barrio, C., Martínez-Castrillo, J. C., Alonso Cánovas, Araceli, Sánchez Alonso, Pilar, Novo Ponte, S., Alonso Losada, María G., López-Ariztegui, Nuria, Segundo Rodríguez, J. C., Morales Casado, M. I., Gastón, Itziar, Lacruz, F., Clavero, Pedro, Kulisevsky, Jaime, Pagonabarraga-Mora, Javier, Pascual-Sedano, Berta, Martínez-Martín, Pablo, Santos-García, Diego, and Mir, Pablo
Abstract: The study was aimed at analysing the frequency of impulse control disorders (ICDs) and compulsive behaviours (CBs) in patients with Parkinson’s disease (PD) and in control subjects (CS) as well as the relationship between ICDs/CBs and motor, nonmotor features and dopaminergic treatment in PD patients. Data came from COPPADIS-2015, an observational, descriptive, nationwide (Spain) study. We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) for ICD/CB screening. The association between demographic data and ICDs/CBs was analyzed in both groups. In PD, this relationship was evaluated using clinical features and treatment-related data. As result, 613 PD patients (mean age 62.47 ± 9.09 years, 59.87% men) and 179 CS (mean age 60.84 ± 8.33 years, 47.48% men) were included. ICDs and CBs were more frequent in PD (ICDs 12.7% vs. 1.6%, p < 0.001; CBs 7.18% vs. 1.67%, p = 0.01). PD patients had more frequent previous ICDs history, premorbid impulsive personality and antidepressant treatment (p < 0.05) compared with CS. In PD, patients with ICDs/CBs presented younger age at disease onset, more frequent history of previous ICDs and premorbid personality (p < 0.05), as well as higher comorbidity with nonmotor symptoms, including depression and poor quality of life. Treatment with dopamine agonists increased the risk of ICDs/CBs, being dose dependent (p < 0.05). As conclusions, ICDs and CBs were more frequent in patients with PD than in CS. More nonmotor symptoms were present in patients with PD who had ICDs/CBs compared with those without. Dopamine agonists have a prominent effect on ICDs/CBs, which could be influenced by dose.
Published: 2020

48. Orthostatic Myoclonus Secondary to Central Pontine Myelinolysis

Author: Instituto de Salud Carlos III, Muñoz‐Delgado, Laura, Macías García, Daniel, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Palomar, F. J., Carrillo, Fátima, Mir, Pablo, Instituto de Salud Carlos III, Muñoz‐Delgado, Laura, Macías García, Daniel, Jesús Maestre, Silvia, Adarmes Gómez, A. D., Palomar, F. J., Carrillo, Fátima, and Mir, Pablo
Abstract: Orthostatic myoclonus (OM) is a recently reported cause of “unsteadiness” or “shaky legs” during orthostatism and gait.1 We report on a middle‐aged woman with OM secondary to a central pontine myelinolysis (CPM). To the best of our knowledge, there have been no previous cases reported of OM attributed to a structural lesion involving the pons, which might reveal some clues to its pathophysiology.
Published: 2020

49. Movement disorders. Etiology. Classification. Chorea syndromes and dystonia

Author: Jesús Maestre, Silvia
Subjects: Circuito de los ganglios de la base, Myoclonus, congenital, hereditary, and neonatal diseases and abnormalities, Distonía, Mioclonías, Huntington's disease, Corea, Parkinsonism, nervous system diseases, Movements disorders, Enfermedad de Huntington, Chorea, Parkinsonismo, Dystonía, mental disorders, Trastornos del movimiento, Basal ganglia circuit
Abstract: [ES] La semiología de los trastornos del movimiento es variada. Se pueden clasificar según el tipo de movimiento y síndrome. Entre los síndromes hipocinéticos destaca el parkinsonismo y entre los hipercinéticos la distonía, las mioclonías, los tic y la corea. La etiología es diversa y, a nivel fisiopatológico, predomina la disfunción de los ganglios de la base con sus conexiones corticales. La distonía se caracteriza por una contracción anormal de músculos agonistas y antagonistas, dando lugar a posturas anormales. Según la clasificación de las distonías, esas se clasifican siguiendo dos grandes axis, las características clínicas y la etiología. Dentro de la etiología con causa genética, se han identificado más de veinte loci, denominados previamente DYT. La corea hace referencia a movimientos aleatorios, sin propósito e involuntarios que pueden ser secundarios a múltiples causas, entre ellas las enfermedades genéticamente determinadas. La enfermedad de Huntington es una entidad autosómico dominante por expansión patológica de tripletes en el gen HTT. Se trata de una enfermedad neurodegenerativa, en la que pueden coexistir múltiples trastornos del movimiento como corea, distonía y parkinsonismo. El tratamiento tanto de la distonía primaria o genéticamente determinada como el de la enfermedad de Huntington y otras causas primarias de corea son sintomáticas. [EN] Semiology of movement disorders is varied. They are classified by movement type and syndrome. Parkinsonism is the most prominent hypokinetic syndrome; while among hypokinetic highlight dystonia, myoclonus, tic and chorea. The etiology is diverse, predominating pathophysiologically the dysfunction of basal ganglia and its cortical connections. Abnormal contraction of agonist and antagonist muscles takes place in dystonia, causing abnormal postures. Dystonias are classified according to the area of the body that is affected, clinical characteristics and etiology. More than twenty loci, previously named DYT loci, haven been identified in genetic dystonia. Chorea describes involuntary, purposeless and irregular movements. Several causes can lead to choreic movements, for example genetically determined diseases. Huntington's disease is an autosomal-dominant disease caused by a pathological triplet repeat expansion in HTT gene. It is a neurodegenerative disorder co-existing with multiple movement disorders (chorea, dystonia and parkinsonism). Primary and genetically determined dystonia as well as Huntington's disease and other primary chorea, are treated symptomatically.
Published: 2019

50. Role of ANO3 mutations in dystonia: A large-scale mutational screening study

Author: Federal Ministry of Education and Research (Germany), Olschewski, Luisa, Jesús Maestre, Silvia, Kim, Han-Joon, Tunc, Sinem, Löns, Sebastian, Junker, Johanna, Zeuner, Kirsten E., Kühn, Andrea A., Kuhlenbäumer, Gregor, Schäffer, Eva, Berg, Daniela, Kasten, Meike, Ferbert, Andreas, Altenmüller, Eckart, Brüggemann, Norbert, Bauer, Peter, Rolfs, Arndt, Jeon, Beomseok, Bäumer, Tobias, Mir, Pablo, Klein, Christine, Lohmann, Katja, Federal Ministry of Education and Research (Germany), Olschewski, Luisa, Jesús Maestre, Silvia, Kim, Han-Joon, Tunc, Sinem, Löns, Sebastian, Junker, Johanna, Zeuner, Kirsten E., Kühn, Andrea A., Kuhlenbäumer, Gregor, Schäffer, Eva, Berg, Daniela, Kasten, Meike, Ferbert, Andreas, Altenmüller, Eckart, Brüggemann, Norbert, Bauer, Peter, Rolfs, Arndt, Jeon, Beomseok, Bäumer, Tobias, Mir, Pablo, Klein, Christine, and Lohmann, Katja
Abstract: [Background] The role of ANO3 variants as a monogenic cause of dystonia is still under debate because of its relatively high frequency also in controls., [Objective] To screen >1000 patients with movement disorders for rare ANO3 variants., [Methods] We searched for rare ANO3 variants in 729 dystonia and 294 Parkinson's disease (PD) patients using a gene panel. Variants were validated by Sanger sequencing. For one variant carrier, family members were available for segregation analysis., [Results] Nine carriers (seven with dystonia [1.0%], two with PD [0.7%]) of seven different rare, protein-changing variants were identified. None of these variants has been previously reported in dystonia patients. Two of the variants in dystonia patients were found recurrently: p.Arg328Cys was detected in two Korean and p.Arg969Gln in two German patients. The frequency of these two variants in our sample seemed to be higher as in ethnically matched samples from the Genome Aggregation Database (GnomAD). Further, we identified a patient with early-onset, generalized dystonia with a de-novo variant in ANO3 (p.Val561Glu). Of note, she benefitted from deep brain stimulation., [Conclusion] This study confirms the relatively high frequency of rare, protein-changing ANO3 variants in both dystonia and non-dystonia patients indicating that not all variants contribute to the disease. Thus, disease relevance of novel variants remains difficult to interpret and functional studies are warranted for a better understanding of the role of ANO3 variants in dystonia. In contrast, de-novo variants in childhood-onset, generalized dystonia seem to represent an as yet underestimated phenotypic expression of changes in ANO3.
Published: 2019

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