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1. Parkinson's disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration.

Author

Carola, G, Malagarriga, D, Calatayud, C, Pons-Espinal, M, Blasco-Agell, L, Richaud-Patin, Y, Fernandez-Carasa, I, Baruffi, V, Beltramone, S, Molina, E, Dell'Era, P, Toledo-Aral, JJ, Tolosa, E, Muotri, AR, Garcia Ojalvo, J, Soriano, J, Raya, A, and Consiglio, A

Abstract

A deeper understanding of early disease mechanisms occurring in Parkinson's disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time. Compared to control neuronal networks, LRRK2 PD patients' networks displayed an elevated bursting behavior, in the absence of neurodegeneration. By combining functional calcium imaging, biophysical modeling, and DAn-lineage tracing, we found a decrease in DAn neurite density that triggered overall functional alterations in PD neuronal networks. Our data implicate early dysfunction as a prime focus that may contribute to the initiation of downstream degenerative pathways preceding DAn loss in PD, highlighting a potential window of opportunity for pre-symptomatic assessment of chronic degenerative diseases.

Published
2021

4. Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy

Author

Obeso, JA, Stamelou, M, Goetz, CG, Poewe, W, Lang, AE, Weintraub, D, Burn, D, Halliday, GM, Bezard, E, Przedborski, S, Lehericy, S, Brooks, DJ, Rothwell, JC, Hallett, M, DeLong, MR, Marras, C, Tanner, CM, Ross, GW, Langston, JW, Klein, C, Bonifati, V, Jankovic, J, Lozano, AM, Deuschl, G, Bergman, H, Tolosa, E, Rodriguez‐Violante, M, Fahn, S, Postuma, RB, Berg, D, Marek, K, Standaert, DG, Surmeier, DJ, Olanow, CW, Kordower, JH, Calabresi, P, Schapira, AHV, and Stoessl, AJ

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Brain Disorders, Parkinson's Disease, Neurological, Anniversaries and Special Events, History, 19th Century, History, 20th Century, History, 21st Century, Humans, Parkinson Disease, Shaking Palsy, Parkinson's disease, years anniversary, Human Movement and Sports Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Published
2017

5. Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations

Author

Williams, David, Lafontaine, Anne Louise, Marras, Connie, Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Stewart, Alistair J., Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Lorenzl, Stefan, Ludolph, Albert, Benecke, Reiner, Hoglinger, Gunter, Lipp, Axel, Reichmann, Heinz, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Miller, Bruce L., Lobach, Iryna V., Roberson, Erik, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Litvan, Irene, Knopman, David S., Schneider, Lon S., Doody, Rachelle S., Golbe, Lawrence I., Roberson, Erik D., Koestler, Mary, Jack, Clifford R., Jr., Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, Morimoto, Bruce H., Nuebling G, Georg, Hensler, Mira, Paul, Sabine, Zwergal, Andreas, Heuer, Hilary W., Tartaglia, Maria C., McGinnis, Scott M., Dickerson, Bradford C., Kornak, John, Schuff, Norbert, Rabinovici, Gil D., Rosen, Howard J., Boxer, Adam L., Gómez, J.C., Tijero, B., Berganzo, K., Garc'ıa de Yebenes, J., Lopez Sendón, J.L., Garcia, G., Tolosa, E., Buongiorno, M.T., Bargalló, N., Burguera, J.A., Martinez, I., Ruiz-Mart'ınez, J., Narrativel, I., Vivancos, F., Ybot, I., Aguilar, M., Quilez, P., Boada, M., Lafuente, A., Hernandez, I., López-Lozano, J.J., Mata, M., Kupsch, A., Lipp, A., Ebersbach, G., Schmidt, T., Hahn, K., Höglinger, G., Höllerhage, M., Oertel, W.H., Respondek, G., Stamelou, M., Reichmann, H., Wolz, M., Schneider, C., Klingelhöfer, L., Berg, D., Maetzler, W., Srulijes, K.K., Ludolph, A., Kassubek, J., Steiger, M., Tyler, K., Burn, D.J., Morris, L., Lees, A., Ling, H., Hauser, R., McClain, T., Truong, D., Jenkins, S., Litvan, I., Houghton, D., Ferrara, J., Bordelon, Y., Gratiano, A., Golbe, L., Mark, M., Uitti, R., Ven Gerpen, J., Brittain, Claire, McCarthy, Andrew, Irizarry, Michael C., McDermott, Dana, Biglan, Kevin, Höglinger, Günter U., and del Ser, Teodoro

Published
2019
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6. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

Author

Sugier, P, Lucotte, E, Domenighetti, C, Law, M, Iles, M, Brown, K, Amos, C, Mckay, J, Hung, R, Karimi, M, Bacq-Daian, D, Boland-Auge, A, Olaso, R, Deleuze, J, Lesueur, F, Ostroumova, E, Kesminiene, A, de Vathaire, F, Guenel, P, Sreelatha, A, Schulte, C, Grover, S, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Nakayama, A, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, van de Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Rodstrom, E, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Truong, T, Elbaz, A, Sugier P. -E., Lucotte E. A., Domenighetti C., Law M. H., Iles M. M., Brown K., Amos C., McKay J. D., Hung R. J., Karimi M., Bacq-Daian D., Boland-Auge A., Olaso R., Deleuze J. -F., Lesueur F., Ostroumova E., Kesminiene A., de Vathaire F., Guenel P., Sreelatha A. A. K., Schulte C., Grover S., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Nakayama A., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., van de Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Guedes L. C., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N., Ran C., Belin A. C., Puschmann A., Rodstrom E. Y., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., Truong T., Elbaz A., Sugier, P, Lucotte, E, Domenighetti, C, Law, M, Iles, M, Brown, K, Amos, C, Mckay, J, Hung, R, Karimi, M, Bacq-Daian, D, Boland-Auge, A, Olaso, R, Deleuze, J, Lesueur, F, Ostroumova, E, Kesminiene, A, de Vathaire, F, Guenel, P, Sreelatha, A, Schulte, C, Grover, S, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Nakayama, A, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, van de Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Rodstrom, E, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Truong, T, Elbaz, A, Sugier P. -E., Lucotte E. A., Domenighetti C., Law M. H., Iles M. M., Brown K., Amos C., McKay J. D., Hung R. J., Karimi M., Bacq-Daian D., Boland-Auge A., Olaso R., Deleuze J. -F., Lesueur F., Ostroumova E., Kesminiene A., de Vathaire F., Guenel P., Sreelatha A. A. K., Schulte C., Grover S., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Nakayama A., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., van de Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Guedes L. C., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N., Ran C., Belin A. C., Puschmann A., Rodstrom E. Y., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., Truong T., and Elbaz A.

Abstract

Background: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective: We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods: We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. Results: We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven b

Published
2023

7. Thymic Atrophy and Immune Dysregulation in Infants with Complex Congenital Heart Disease

Author

Bremer, S.J., additional, Boxnick, A., additional, Glau, L., additional, Biermann, D., additional, Thiele, F., additional, Billeb, E., additional, May, J., additional, Kolster, M., additional, Hackbusch, R., additional, Fortmann, M.I., additional, Hübler, M., additional, Kozlik-Feldmann, R., additional, Tolosa, E., additional, Sachweh, J.S., additional, and Gieras, A., additional

Published
2024
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9. Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease

Author

Domenighetti, C, Sugier, P, Sreelatha, A, Schulte, C, Grover, S, Mohamed, O, Portugal, B, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Duga, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, Van De Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Elbaz, A, Domenighetti C., Sugier P. -E., Sreelatha A. A. K., Schulte C., Grover S., Mohamed O., Portugal B., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Duga S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Kawamura Y., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., Van De Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Guedes L. C., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N. L., Ran C., Belin A. C., Puschmann A., Hellberg C., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., Elbaz A., Domenighetti, C, Sugier, P, Sreelatha, A, Schulte, C, Grover, S, Mohamed, O, Portugal, B, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Duga, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, Van De Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Elbaz, A, Domenighetti C., Sugier P. -E., Sreelatha A. A. K., Schulte C., Grover S., Mohamed O., Portugal B., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Duga S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Kawamura Y., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., Van De Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Guedes L. C., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N. L., Ran C., Belin A. C., Puschmann A., Hellberg C., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., and Elbaz A.

Abstract

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants =67 years old and cases with disease duration =7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Published
2022

10. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study

Author

Domenighetti, C, Sugier, P, Ashok Kumar Sreelatha, A, Schulte, C, Grover, S, Mohamed, O, Portugal, B, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Duga, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, van de Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Correia Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Elbaz, A, Domenighetti C., Sugier P. -E., Ashok Kumar Sreelatha A., Schulte C., Grover S., Mohamed O., Portugal B., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Duga S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Kawamura Y., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., van de Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Correia Guedes L., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N. L., Ran C., Belin A. C., Puschmann A., Hellberg C., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., Elbaz A., Domenighetti, C, Sugier, P, Ashok Kumar Sreelatha, A, Schulte, C, Grover, S, Mohamed, O, Portugal, B, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Duga, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, van de Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Correia Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Elbaz, A, Domenighetti C., Sugier P. -E., Ashok Kumar Sreelatha A., Schulte C., Grover S., Mohamed O., Portugal B., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Duga S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Kawamura Y., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., van de Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Correia Guedes L., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N. L., Ran C., Belin A. C., Puschmann A., Hellberg C., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., and Elbaz A.

Abstract

Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society.

Published
2022

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

Author

Vollstedt, E.J., Schaake, S., Lohmann, K., Padmanabhan, S., Brice, A., Lesage, S., Tesson, C., Vidailhet, M., Wurster, I., Hentati, F., Mirelman, A., Giladi, N., Marder, K., Waters, C., Fahn, S., Kasten, M., Brüggemann, N., Borsche, M., Foroud, T., Tolosa, E., Garrido, A., Annesi, G., Gagliardi, M., Bozi, M., Stefanis, L., Ferreira, J.J., Guedes, L. Correia, Avenali, M., Petrucci, S., Clark, L., Fedotova, E.Y., Abramycheva, N.Y., Alvarez, V., Menéndez-González, M., Maestre, S. Jesús, Gómez-Garre, P., Mir, P., Belin, A.C., Ran, C., Lin, Chih-Yu, Kuo, M.C., Crosiers, D., Wszolek, Z.K., Ross, O.A., Jankovic, J., Nishioka, K., Funayama, M., Clarimon, J., Williams-Gray, C.H., Camacho, M., Cornejo-Olivas, M., Torres-Ramirez, L., Wu, Y.R., Lee-Chen, G.J., Morgadinho, A., Pulkes, T., Termsarasab, P., Berg, D., Kuhlenbäumer, G., Kühn, A.A., Borngräber, F., Michele, G. de, Rosa, A. De, Zimprich, A., Puschmann, A., Mellick, G.D., Dorszewska, J., Carr, J., Ferese, R., Gambardella, S., Chase, B., Markopoulou, K., Satake, W., Toda, T., Rossi, M., Merello, M., Lynch, T., Olszewska, D.A., Lim, S.Y., Ahmad-Annuar, A., Tan, A.H., Al-Mubarak, B., Hanagasi, H., Koziorowski, D., Ertan, S., Genç, G., Aguiar, P. de Carvalho, Barkhuizen, M., Pimentel, M.M.G., Saunders-Pullman, R., Warrenburg, B.P.C. van de, Bressman, S., Toft, M., Appel-Cresswell, S., Lang, A.E., Skorvanek, M., Boon, A.J., Krüger, R., Sammler, E.M., Tumas, V., et al., Vollstedt, E.J., Schaake, S., Lohmann, K., Padmanabhan, S., Brice, A., Lesage, S., Tesson, C., Vidailhet, M., Wurster, I., Hentati, F., Mirelman, A., Giladi, N., Marder, K., Waters, C., Fahn, S., Kasten, M., Brüggemann, N., Borsche, M., Foroud, T., Tolosa, E., Garrido, A., Annesi, G., Gagliardi, M., Bozi, M., Stefanis, L., Ferreira, J.J., Guedes, L. Correia, Avenali, M., Petrucci, S., Clark, L., Fedotova, E.Y., Abramycheva, N.Y., Alvarez, V., Menéndez-González, M., Maestre, S. Jesús, Gómez-Garre, P., Mir, P., Belin, A.C., Ran, C., Lin, Chih-Yu, Kuo, M.C., Crosiers, D., Wszolek, Z.K., Ross, O.A., Jankovic, J., Nishioka, K., Funayama, M., Clarimon, J., Williams-Gray, C.H., Camacho, M., Cornejo-Olivas, M., Torres-Ramirez, L., Wu, Y.R., Lee-Chen, G.J., Morgadinho, A., Pulkes, T., Termsarasab, P., Berg, D., Kuhlenbäumer, G., Kühn, A.A., Borngräber, F., Michele, G. de, Rosa, A. De, Zimprich, A., Puschmann, A., Mellick, G.D., Dorszewska, J., Carr, J., Ferese, R., Gambardella, S., Chase, B., Markopoulou, K., Satake, W., Toda, T., Rossi, M., Merello, M., Lynch, T., Olszewska, D.A., Lim, S.Y., Ahmad-Annuar, A., Tan, A.H., Al-Mubarak, B., Hanagasi, H., Koziorowski, D., Ertan, S., Genç, G., Aguiar, P. de Carvalho, Barkhuizen, M., Pimentel, M.M.G., Saunders-Pullman, R., Warrenburg, B.P.C. van de, Bressman, S., Toft, M., Appel-Cresswell, S., Lang, A.E., Skorvanek, M., Boon, A.J., Krüger, R., Sammler, E.M., and Tumas, V., et al.

Abstract

Item does not contain fulltext, 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

Published
2023

12. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

Author

Sugier, P.E., Lucotte, E.A., Domenighetti, C., Law, M.H., Iles, M.M., Brown, K., Amos, C., McKay, J.D., Hung, R.J., Karimi, M., Bacq-Daian, D., Boland-Augé, A., Olaso, R., Deleuze, J.F., Lesueur, F., Ostroumova, E., Kesminiene, A., Vathaire, F. de, Guénel, P., Sreelatha, A.A.K., Schulte, C., Grover, S., May, P., Bobbili, D.R., Radivojkov-Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Koks, S., Taba, P., Lesage, S., Brice, A., Corvol, J.C., Chartier-Harlin, M.C., Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Nakayama, A., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y. J., Kolber, P., Warrenburg, B.P.C. van de, Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Guedes, L.C., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez-Fairen, M., Wirdefeldt, K., Pedersen, N., Ran, C., Belin, A.C., Puschmann, A., Rödström, E.Y., Clarke, C.E., Morrison, K.E., Tan, M., Krainc, D., Burbulla, L.F., Farrer, M.J., Kruger, R., Gasser, T., Sharma, M., Truong, T., Elbaz, A., Sugier, P.E., Lucotte, E.A., Domenighetti, C., Law, M.H., Iles, M.M., Brown, K., Amos, C., McKay, J.D., Hung, R.J., Karimi, M., Bacq-Daian, D., Boland-Augé, A., Olaso, R., Deleuze, J.F., Lesueur, F., Ostroumova, E., Kesminiene, A., Vathaire, F. de, Guénel, P., Sreelatha, A.A.K., Schulte, C., Grover, S., May, P., Bobbili, D.R., Radivojkov-Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Koks, S., Taba, P., Lesage, S., Brice, A., Corvol, J.C., Chartier-Harlin, M.C., Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Nakayama, A., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y. J., Kolber, P., Warrenburg, B.P.C. van de, Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Guedes, L.C., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez-Fairen, M., Wirdefeldt, K., Pedersen, N., Ran, C., Belin, A.C., Puschmann, A., Rödström, E.Y., Clarke, C.E., Morrison, K.E., Tan, M., Krainc, D., Burbulla, L.F., Farrer, M.J., Kruger, R., Gasser, T., Sharma, M., Truong, T., and Elbaz, A.

Abstract

Item does not contain fulltext, BACKGROUND: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. OBJECTIVE: We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. METHODS: We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. RESULTS: We confirmed a previously reported positive genetic correlation of PD with melanoma (G(corr) = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (G(corr) = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driv

Published
2023

13. Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD cohort

Author

Ertan, Fatoş Sibel (ORCID 0000-0003-1339-243X & YÖK ID 112829), Vollstedt, E.J.; Schaake, S.; Lohmann, K.; Padmanabhan, S.; Brice, A.; Lesage, S.; Tesson, C.; Vidailhet, M.; Wurster, I.; Hentati, F.; Mirelman, A.; Giladi, N.; Marder, K.; Waters, C.; Fahn, S.; Kasten, M.; Brüggemann, N.; Borsche, M.; Foroud, T.; Tolosa, E.; Garrido, A.; Annesi, G.; Gagliardi, M.; Bozi, M.; Stefanis, L.; Ferreira, J.J.; Guedes, L.C.; Avenali, M.; Petrucci, S.; Clark, L.; Fedotova, E.Y.; Abramycheva, N.Y.; Alvarez, V.; Menéndez-González, M.; Maestre, SJ.; Gómez-Garre, P.; Mir, P.; Belin, A.C.; Ran, C.; Lin, C.H.; Kuo, M.C.; Crosiers, D.; Wszolek, Z.K.; Ross, O.A.; Jankovic, J.; Nishioka, K.; Funayama, M.; Clarimon, J.; Williams-Gray, C.H.; Camacho, M.; Cornejo-Olivas, M.; Torres-Ramirez, L.; Wu, YR.; Lee-Chen, G.J.; Morgadinho, A.; Pulkes, T.; Termsarasab, P.; Berg, D.; Kuhlenbäumer, G.; Kühn, A.A.; Borngräber, F.; de Michele, G.; De Rosa, A.; Zimprich, A.; Puschmann, A.; Mellick, GD.; Dorszewska, J.; Carr, J.; Ferese, R.; Gambardella, S.; Chase, B.; Markopoulou, K.; Satake, W.; Toda, T.; Rossi, M.; Merello, M.; Lynch, T.; Olszewska, D.A.; Lim, S.Y.; Ahmad-Annuar, A.; Tan, A.H.; Al-Mubarak, B.; Hanagasi, H.; Koziorowski, D.; Genç, G.; Aguiar, P.D.; Barkhuizen, M.; Pimentel, M.M.G.; Saunders-Pullman, R.; van de Warrenburg, B.; Bressman, S.; Toft, M.; Appel-Cresswell, S.; Lang, A.E.; Skorvanek, M.; Boon, A.J.W.; Krüger, R.; Sammler, E.M.; Tumas, V.; Zhang, B.R.; Garraux, G.; Chung, SJ.; Kim, Y.J.; Winkelmann, J.; Sue, C.M.; Tan, E.K.; Damásio, J.; Klivényi, P.; Kostic, V.S.; Arkadir, D.; Martikainen, M.; Borges, V.; Hertz, J.M.; Brighina, L.; Spitz, M.; Suchowersky, O.; Riess, O.; Das, P.; Mollenhauer, B.; Gatto, E.M.; Petersen, M.S.; Hattori, N.; Wu, R.M.; Illarioshkin, S.N.; Valente, E.M.; Aasly, J.O.; Aasly, A.; Alcalay, R.N.; Thaler, A.; Farrer, M.J.; Brockmann, K.; Corvol, J.C.; Klein, C., School of Medicine, Ertan, Fatoş Sibel (ORCID 0000-0003-1339-243X & YÖK ID 112829), Vollstedt, E.J.; Schaake, S.; Lohmann, K.; Padmanabhan, S.; Brice, A.; Lesage, S.; Tesson, C.; Vidailhet, M.; Wurster, I.; Hentati, F.; Mirelman, A.; Giladi, N.; Marder, K.; Waters, C.; Fahn, S.; Kasten, M.; Brüggemann, N.; Borsche, M.; Foroud, T.; Tolosa, E.; Garrido, A.; Annesi, G.; Gagliardi, M.; Bozi, M.; Stefanis, L.; Ferreira, J.J.; Guedes, L.C.; Avenali, M.; Petrucci, S.; Clark, L.; Fedotova, E.Y.; Abramycheva, N.Y.; Alvarez, V.; Menéndez-González, M.; Maestre, SJ.; Gómez-Garre, P.; Mir, P.; Belin, A.C.; Ran, C.; Lin, C.H.; Kuo, M.C.; Crosiers, D.; Wszolek, Z.K.; Ross, O.A.; Jankovic, J.; Nishioka, K.; Funayama, M.; Clarimon, J.; Williams-Gray, C.H.; Camacho, M.; Cornejo-Olivas, M.; Torres-Ramirez, L.; Wu, YR.; Lee-Chen, G.J.; Morgadinho, A.; Pulkes, T.; Termsarasab, P.; Berg, D.; Kuhlenbäumer, G.; Kühn, A.A.; Borngräber, F.; de Michele, G.; De Rosa, A.; Zimprich, A.; Puschmann, A.; Mellick, GD.; Dorszewska, J.; Carr, J.; Ferese, R.; Gambardella, S.; Chase, B.; Markopoulou, K.; Satake, W.; Toda, T.; Rossi, M.; Merello, M.; Lynch, T.; Olszewska, D.A.; Lim, S.Y.; Ahmad-Annuar, A.; Tan, A.H.; Al-Mubarak, B.; Hanagasi, H.; Koziorowski, D.; Genç, G.; Aguiar, P.D.; Barkhuizen, M.; Pimentel, M.M.G.; Saunders-Pullman, R.; van de Warrenburg, B.; Bressman, S.; Toft, M.; Appel-Cresswell, S.; Lang, A.E.; Skorvanek, M.; Boon, A.J.W.; Krüger, R.; Sammler, E.M.; Tumas, V.; Zhang, B.R.; Garraux, G.; Chung, SJ.; Kim, Y.J.; Winkelmann, J.; Sue, C.M.; Tan, E.K.; Damásio, J.; Klivényi, P.; Kostic, V.S.; Arkadir, D.; Martikainen, M.; Borges, V.; Hertz, J.M.; Brighina, L.; Spitz, M.; Suchowersky, O.; Riess, O.; Das, P.; Mollenhauer, B.; Gatto, E.M.; Petersen, M.S.; Hattori, N.; Wu, R.M.; Illarioshkin, S.N.; Valente, E.M.; Aasly, J.O.; Aasly, A.; Alcalay, R.N.; Thaler, A.; Farrer, M.J.; Brockmann, K.; Corvol, J.C.; Klein, C., and School of Medicine

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, Open Access funding enabled and organized by Projekt DEAL. Funding text 1: Carolyn M. Sue: Intellectual Property Rights: WO 2015/157794 A1. Advisory Boards: AbbVie. Employment: Northern Sydney Local Health District, Sydney, Australia. Honoraria: The International Movement Disorder Society for course directorships and invited lectures. Patents: WO 2015/157794 A1. Grants: 2018–22 NHMRC Partnership grant (APP1151906); 2018–22 MRFF NHMRC Practitioner Fellowship (App1136800); 2020–2025 NHMRC Partnership grant (APP11179029); 2020–2023 NHMRC Ideas Grant (APP1184403); 2021–5 MRFF 2020 Genomics Health Futures Mission Grant (APP2007959); 2021–23 ASAP Project grant ; Funding text 2: Natalya Y. Abramycheva: Employment: Research Center of Neurology, Ministry of Science and Higher Education of the Russian Federation, Moscow, Russia. Grants: Russian Science Foundation ; Funding text 3: Rachel Saunders?Pullman: Employment: Icahn School of Medicine at Mount Sinai, New York City, New York, USA. Grants: NIH 1U01NS107016?01A1; Bigglesworth Family Foundation. Others: Bachmann?Strauss Chair ; Funding text 4: Zbigniew K. Wszolek: Advisory Boards: Vigil Neuroscience, Inc. Employment: Mayo Clinic, Jacksonville, Florida, USA. Grants: NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, PI or co?PI on Biohaven Pharmaceuticals, Inc. (BHV4157?206 and BHV3241?301), Neuraly, Inc. (NLY01?PD?1), and Vigil Neuroscience, Inc. (VGL101?01.001 and VGL101?01.002). He also serves as the co?PI of the Mayo Clinic APDA Center for Advanced Research. Others: Donations from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation ; Funding text 5: Vladimir S. Kostic: Employment: School of Medicine, University of Belgrade, Serbia. Grants: Project No 175090 Ministry of Education, Science and Technological Development of Serbia. Project ??28 Serbian Academy of S

Published
2023

14. Clinical and Immunological Consequences of Early-life Thymectomy in Children with Congenital Heart Disease.

Author

Thiele, F., Stute, F., Boxnick, A., Bremer, S. J., Biermann, D., Pagel, J., Glau, L., Murko, S., Gehbauer, C., Krause, A., Olfe, J., Lütgehetmann, M., Gramer, G., Haag, F., Kozlik-Feldmann, R., Hübler, M., Sachweh, J. S., Tolosa, E., and Gieras, A.

Subjects
THYMECTOMY, CONGENITAL heart disease, T-cell exhaustion, LYMPHOPENIA, IMMUNOLOGIC memory
Abstract

This article discusses the clinical and immunological consequences of early-life thymectomy in children with congenital heart disease (CHD). Thymectomy, the removal of the thymus, is often performed during cardiovascular surgery in these children. The study found that thymectomized children commonly exhibit lymphopenia and an altered T cell profile, including a decrease in naïve CD4 and CD8 cells and an increase in memory T cells. They also observed signs of premature immune aging, reduced thymic output, and potential risks of autoimmune development later in life. The findings highlight the importance of monitoring the long-term consequences of early-life thymectomy. [Extracted from the article]

Published
2024
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20. Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort

Author

Simuni, T, Merchant, K, Brumm, MC, Cho, H, Caspell-Garcia, C, Coffey, CS, Chahine, LM, Alcalay, RN, Nudelman, K, Foroud, T, Mollenhauer, B, Siderowf, A, Tanner, C, Iwaki, H, Sherer, T, Marek, K, Seibyl, J, Coffey, C, Tosun-Turgut, D, Shaw, LM, Trojanowski, JQ, Singleton, A, Kieburtz, K, Toga, A, Galasko, D, Poewe, W, Poston, K, Bressman, S, Reimer, A, Arnedo, V, Clark, A, Frasier, M, Kopil, C, Chowdhury, S, Casaceli, C, Dorsey, R, Wilson, R, Mahes, S, Salerno, C, Ahrens, M, Brumm, M, Cho, HR, Fedler, J, LaFontant, D-E, Kurth, R, Crawford, K, Casalin, P, Malferrari, G, Weisz, MG, Orr-Urtreger, A, Trojanowski, J, Shaw, L, Montine, T, Baglieri, C, Christini, A, Russell, D, Dahodwala, N, Giladi, N, Factor, S, Hogarth, P, Standaert, D, Hauser, R, Jankovic, J, Saint-Hilaire, M, Richard, I, Shprecher, D, Fernandez, H, Brockmann, K, Rosenthal, L, Barone, P, Espayc, A, Rowe, D, Marder, K, Santiago, A, Hu, S-C, Isaacson, S, Corvol, J-C, Martinez, JR, Tolosa, E, Tai, Y, Politis, M, Smejdir, D, Rees, L, Williams, K, Kausar, F, Richardson, W, Willeke, D, Peacock, S, Sommerfeld, B, Freed, A, Wakeman, K, Blair, C, Guthrie, S, Harrell, L, Hunter, C, Thomas, C-A, James, R, Zimmerman, G, Brown, V, Mule, J, Hilt, E, Ribb, K, Ainscough, S, Wethington, M, Ranola, M, Santana, HM, Moreno, J, Raymond, D, Speketer, K, Carvajal, L, Carvalo, S, Croitoru, I, Garrido, A, Payne, LM, Viswanth, V, Severt, L, Facheris, M, Soares, H, Mintun, MA, Cedarbaum, J, Taylor, P, Biglan, K, Vandenbroucke, E, Sheikh, ZH, Bingol, B, Fischer, T, Sardi, P, Forrat, R, Reith, A, Egebjerg, J, Hillert, GA, Saba, B, Min, C, Umek, R, Mather, J, De Santi, S, Post, A, Boess, F, Taylor, K, Grachev, I, Avbersek, A, Muglia, P, Tauscher, J, and Michael J Fox Foundation

Abstract

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as

Published
2022

22. Consensus on the treatment of dysphagia in Parkinson's disease

Author

Schindler, A., Pizzorni, N., Cereda, E., Cosentino, G., Avenali, M., Montomoli, C., Abbruzzese, G., Antonini, A., Barbiera, F., Benazzo, M., Benarroch, E., Bertino, G., Clave, P., Cortelli, P., Eleopra, R., Ferrari, C., Hamdy, S., Huckabee, M. -L., Lopiano, L., Marchese-Ragona, R., Masiero, S., Michou, E., Occhini, A., Pacchetti, C., Pfeiffer, R. F., Restivo, D. A., Rondanelli, M., Ruoppolo, G., Sandrini, G., Schapira, A., Stocchi, F., Tolosa, E., Valentino, F., Zamboni, M., Zangaglia, R., Zappia, M., Tassorelli, C., Alfonsi, E., Schindler A., Pizzorni N., Cereda E., Cosentino G., Avenali M., Montomoli C., Abbruzzese G., Antonini A., Barbiera F., Benazzo M., Benarroch E., Bertino G., Clave P., Cortelli P., Eleopra R., Ferrari C., Hamdy S., Huckabee M.-L., Lopiano L., Marchese-Ragona R., Masiero S., Michou E., Occhini A., Pacchetti C., Pfeiffer R.F., Restivo D.A., Rondanelli M., Ruoppolo G., Sandrini G., Schapira A., Stocchi F., Tolosa E., Valentino F., Zamboni M., Zangaglia R., Zappia M., Tassorelli C., and Alfonsi E.

Subjects
Consensus, Parkinson's disease, Clinical Neurology, Consensu, Consensus development conference, Deglutition disorders, Nutrition, Rehabilitation, Humans, Italy, Deglutition Disorders, Parkinson Disease, QUALITY-OF-LIFE, INTENSIVE VOICE TREATMENT, otorhinolaryngologic diseases, Deglutition Disorder, NEUROMUSCULAR ELECTRICAL-STIMULATION, Science & Technology, SUBTHALAMIC NUCLEUS, ESPEN GUIDELINES, Neurosciences, PULMONARY-FUNCTION, TREATMENT LSVT(R), OROPHARYNGEAL DYSPHAGIA, SWALLOWING DISORDERS, Neurosciences & Neurology, DEEP-BRAIN-STIMULATION, Life Sciences & Biomedicine, Human
Abstract

BACKGROUND: Dysphagia is common in Parkinson's disease (PD). The effects of antiparkinsonian drugs on dysphagia are controversial. Several treatments for dysphagia are available but there is no consensus on their efficacy in PD. OBJECTIVE: To conduct a systematic review of the literature and to define consensus statements on the treatment of dysphagia in PD and related nutritional management. METHODS: A multinational group of experts in the field of neurogenic dysphagia and/or Parkinson's disease conducted a systematic evaluation of the literature and reported the results according to PRISMA guidelines. The evidence from the retrieved studies was analyzed and discussed in a consensus conference organized in Pavia, Italy, and the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. RESULTS: The literature review retrieved 64 papers on treatment and nutrition of patients with PD and dysphagia, mainly of Class IV quality. Based on the literature and expert opinion in cases where the evidence was limited or lacking, 26 statements were developed. CONCLUSIONS: The statements developed by the Consensus panel provide a guidance for a multi-disciplinary treatment of dysphagia in patients with PD, involving neurologists, otorhinolaryngologists, gastroenterologists, phoniatricians, speech-language pathologists, dieticians, and clinical nutritionists. ispartof: JOURNAL OF THE NEUROLOGICAL SCIENCES vol:430 ispartof: location:Netherlands status: published

Published
2021
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23. P2.14-03 Restored Ubiquitination and Degradation of Exon 14 Skipped MET with Proteolysis Targeting Chimeras

Author

Mansfield, A., primary, Reddy Mallareddy, J., additional, Yang, L., additional, Lin, W.-H., additional, Feathers, R., additional, Ayers-Ringler, J., additional, Tolosa, E., additional, Kizhake, S., additional, Kubica, S., additional, Boghean, L., additional, Alvarez, S., additional, Naldrett, M.J., additional, Singh, S., additional, Rana, S., additional, Zahid, M., additional, Smadbeck, J., additional, Johnson, S.H., additional, Harris, F., additional, Sotiriou, S., additional, Karagouga, G., additional, McCune, A., additional, Schaefer-Klein, J., additional, Quiñones-Hinojosa, A., additional, Roden, A., additional, Kosari, F., additional, Cheville, J., additional, Vasmatzis, G., additional, Anastasiadis, P., additional, Borad, M., additional, and Natarajan, A., additional

Published
2022
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24. Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder

Author

Boeve, B.F., Silber, M.H., Ferman, T.J., Lin, S.C., Benarroch, E.E., Schmeichel, A.M., Ahlskog, J.E., Caselli, R.J., Jacobson, S., Sabbagh, M., Adler, C., Woodruff, B., Beach, T.G., Iranzo, A., Gelpi, E., Santamaria, J., Tolosa, E., Singer, C., Mash, D.C., Luca, C., Arnulf, I., Duyckaerts, C., Schenck, C.H., Mahowald, M.W., Dauvilliers, Y., Graff-Radford, N.R., Wszolek, Z.K., Parisi, J.E., Dugger, B., Murray, M.E., and Dickson, D.W.

Published
2013
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30. Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease

Author

Domenighetti, C., Sugier, P.E., Sreelatha, A.A.K., Schulte, C., Grover, S., Mohamed, O., Portugal, B., May, P., Bobbili, D.R., Radivojkov-Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Koks, S., Taba, P., Lesage, S., Brice, A., Corvol, J.C., Chartier-Harlin, M.C., Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Duga, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Kawamura, Y., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y. J., Kolber, P., Warrenburg, B.P.C. van de, Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Guedes, L.C., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez-Fairen, M., Wirdefeldt, K., Pedersen, N.L., Ran, C., Belin, A.C., Puschmann, A., Hellberg, C., Clarke, C.E., Morrison, K.E., Tan, M., Krainc, D., Burbulla, L.F., Farrer, M.J., Krüger, R., Gasser, T., Sharma, M., Elbaz, A., Domenighetti, C., Sugier, P.E., Sreelatha, A.A.K., Schulte, C., Grover, S., Mohamed, O., Portugal, B., May, P., Bobbili, D.R., Radivojkov-Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Koks, S., Taba, P., Lesage, S., Brice, A., Corvol, J.C., Chartier-Harlin, M.C., Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Duga, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Kawamura, Y., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y. J., Kolber, P., Warrenburg, B.P.C. van de, Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Guedes, L.C., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez-Fairen, M., Wirdefeldt, K., Pedersen, N.L., Ran, C., Belin, A.C., Puschmann, A., Hellberg, C., Clarke, C.E., Morrison, K.E., Tan, M., Krainc, D., Burbulla, L.F., Farrer, M.J., Krüger, R., Gasser, T., Sharma, M., and Elbaz, A.

Abstract

Item does not contain fulltext, BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Published
2022

31. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study

Author

Domenighetti, C., Sugier, P‐E, Ashok Kumar Sreelatha, A., Schulte, C., Grover, S., Mohamed, O., Portugal, B., May, P., Bobbili, D.R., Radivojkov‐Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Kõks, S., Taba, P., Lesage, S., Brice, A., Corvol, J‐C, Chartier‐Harlin, M‐C, Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Duga, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Kawamura, Y., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y.J., Kolber, P., Warrenburg, B.P.C., Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Correia Guedes, L., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez‐Fairen, M., Wirdefeldt, K., Pedersen, N.L., Ran, C., Belin, A.C., Puschmann, A., Hellberg, C., Clarke, C.E., Morrison, K.E., Tan, M., Krainc, D., Burbulla, L.F., Farrer, M.J., Krüger, R., Gasser, T., Sharma, M., Elbaz, A., Domenighetti, C., Sugier, P‐E, Ashok Kumar Sreelatha, A., Schulte, C., Grover, S., Mohamed, O., Portugal, B., May, P., Bobbili, D.R., Radivojkov‐Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Kõks, S., Taba, P., Lesage, S., Brice, A., Corvol, J‐C, Chartier‐Harlin, M‐C, Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Duga, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Kawamura, Y., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y.J., Kolber, P., Warrenburg, B.P.C., Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Correia Guedes, L., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez‐Fairen, M., Wirdefeldt, K., Pedersen, N.L., Ran, C., Belin, A.C., Puschmann, A., Hellberg, C., Clarke, C.E., Morrison, K.E., Tan, M., Krainc, D., Burbulla, L.F., Farrer, M.J., Krüger, R., Gasser, T., Sharma, M., and Elbaz, A.

Abstract

Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society

Published
2022

34. Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease

Author

Domenighetti, C. Sugier, P.-E. Sreelatha, A.A.K. Schulte, C. Grover, S. Mohamed, O. Portugal, B. May, P. Bobbili, D.R. Radivojkov-Blagojevic, M. Lichtner, P. Singleton, A.B. Hernandez, D.G. Edsall, C. Mellick, G.D. Zimprich, A. Pirker, W. Rogaeva, E. Lang, A.E. Koks, S. Taba, P. Lesage, S. Brice, A. Corvol, J.-C. Chartier-Harlin, M.-C. Mutez, E. Brockmann, K. Deutschländer, A.B. Hadjigeorgiou, G.M. Dardiotis, E. Stefanis, L. Simitsi, A.M. Valente, E.M. Petrucci, S. Duga, S. Straniero, L. Zecchinelli, A. Pezzoli, G. Brighina, L. Ferrarese, C. Annesi, G. Quattrone, A. Gagliardi, M. Matsuo, H. Kawamura, Y. Hattori, N. Nishioka, K. Chung, S.J. Kim, Y.J. Kolber, P. Van De Warrenburg, B.P.C. Bloem, B.R. Aasly, J. Toft, M. Pihlstrøm, L. Guedes, L.C. Ferreira, J.J. Bardien, S. Carr, J. Tolosa, E. Ezquerra, M. Pastor, P. Diez-Fairen, M. Wirdefeldt, K. Pedersen, N.L. Ran, C. Belin, A.C. Puschmann, A. Hellberg, C. Clarke, C.E. Morrison, K.E. Tan, M. Krainc, D. Burbulla, L.F. Farrer, M.J. Krüger, R. Gasser, T. Sharma, M. Elbaz, A.

Abstract

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants =67 years old and cases with disease duration =7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power. © 2022 - IOS Press. All rights reserved.

Published
2022

35. Trial of Cinpanemab in Early Parkinson’s Disease

Author

Lang AE, Siderowf AD, Macklin EA, Poewe W, Brooks DJ, Fernandez HH, Rascol O, Giladi N, Stocchi F, Tanner CM, Postuma RB, Simon DK, Tolosa E, Mollenhauer B, Cedarbaum JM, Fraser K, Xiao J, Evans KC, Graham DL, Sapir I, Inra J, Hutchison RM, Yang M, Fox T, Haeberlein SB, Dam T

Published
2022
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36. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy

Author

Wenning, G.K. Stankovic, I. Vignatelli, L. Fanciulli, A. Calandra-Buonaura, G. Seppi, K. Palma, J.-A. Meissner, W.G. Krismer, F. Berg, D. Cortelli, P. Freeman, R. Halliday, G. Höglinger, G. Lang, A. Ling, H. Litvan, I. Low, P. Miki, Y. Panicker, J. Pellecchia, M.T. Quinn, N. Sakakibara, R. Stamelou, M. Tolosa, E. Tsuji, S. Warner, T. Poewe, W. Kaufmann, H.

Subjects
nervous system, stomatognathic system, parasitic diseases, mental disorders, nervous system diseases
Abstract

Background: The second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages. Objective: To develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence-based and consensus-based methodology. Methods: We identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference. Results: The criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow. Conclusions: This set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2022

37. Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Author

Storm, Catherine S., Kia, Demis A., Almramhi, Mona M., Bandres-Ciga, Sara, Finan, Chris, Noyce, A. J., Kaiyrzhanov, R., Middlehurst, B., Tan, M., Houlden, H., Morris, H. R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Quinn, J., Bubb, V., Mok, K. Y., Kinghorn, K. J., Lewis, P., Schreglmann, S. R., Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K. E., Clarke, C., Harvey, K., Jacobs, B. M., Brice, Alexis, Danjou, F., Lesage, S., Corvol, J. C., Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Schneider, S. A., Cookson, M. R., Blauwendraat, C., Craig, D. W., Billingsley, K., Makarious, M. B., Narendra, D. P., Faghri, F., Gibbs, J. R., Hernandez, D. G., Van Keuren-Jensen, K., Shulman, J. M., Iwaki, H., Leonard, H. L., Nalls, M. A., Robak, L., Bras, J., Guerreiro, R., Lubbe, S., Troycoco, T., Finkbeiner, S., Mencacci, N. E., Lungu, C., Singleton, A. B., Scholz, S. W., Reed, X., Uitti, R. J., Ross, O. A., Grenn, F. P., Moore, A., Alcalay, R. N., Wszolek, Z. K., Gan-Or, Z., Rouleau, G. A., Krohn, L., Mufti, K., van Hilten, J. J., Marinus, J., Adarmes-Gómez, A. D., Aguilar Barberà, Miquel, Álvarez Angulo, Iñaki, Alvarez, V., Barrero, F. J., Yarza, J. A. B., Bernal-Bernal, I., Blázquez Estrada, M, Bonilla-Toribio, M., Botía, J. A., Boungiorno, M. T., Buiza-Rueda, Dolores, Cámara, A., Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, Jordi, Compta, Y., Diez-Fairen, M., Dols-Icardo, Oriol, Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernández, M., Fernández-Santiago, R., Garcia, C., García-Ruiz, P., Gómez-Garre, P., Heredia, M. J. G., Gonzalez-Aramburu, I., Pagola, A. G., Hoenicka, J., Infante, J., Jesús, S., Jimenez-Escrig, A., Kulisevsky, Jaime, Labrador-Espinosa, M. A., Lopez-Sendon, J. L., de Munain Arregui, A. L., Macias, D., Torres, I. M., Marín, J., Marti, M. J., Martínez-Castrillo, J. C., Méndez-del-Barrio, C., González, M. M., Mata, M., Mínguez, A., Mir, P., Rezola, E. M., Muñoz, E., Pagonabarraga, J., Pastor, P., Errazquin, F. P., Periñán-Tocino, T., Ruiz-Martínez, J., Ruz, C., Rodriguez, A. S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J. P., Tejera-Parrado, C., Tolosa, E., Valldeoriola, F., Vargas-González, L., Vela, Lydia, Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Taba, P., Koks, S., Hassin-Baer, S., Majamaa, K., Siitonen, A., Tienari, P., Okubadejo, N. U., Ojo, O. O., Shashkin, C., Zharkinbekova, N., Akhmetzhanov, V., Kaishybayeva, G., Karimova, A., Khaibullin, T., Lynch, T. L., Hingorani, Aroon, Wood, Nicholas W.., Universitat Autònoma de Barcelona, Rosetrees Trust, John Black Charitable Foundation, University College London, King Abdulaziz University, National Institute for Health Research (UK), Universidad de Cantabria, HUS Neurocenter, Department of Neurosciences, and Clinicum

Subjects
Aging, Science, Quantitative Trait Loci, General Physics and Astronomy, Neurodegenerative, 3124 Neurology and psychiatry, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, Risk Factors, Genetics research, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Aetiology, Multidisciplinary, Genome, Parkinson's Disease, Genome, Human, Prevention, 3112 Neurosciences, Neurosciences, Brain, Genetic Variation, Parkinson Disease, General Chemistry, Mendelian Randomization Analysis, International Parkinson’s Disease Genomics Consortium, Brain Disorders, Good Health and Well Being, Gene Expression Regulation, Neurology, 5.1 Pharmaceuticals, Case-Control Studies, Neurological, Disease Progression, Development of treatments and therapeutic interventions, Human, Biotechnology
Abstract

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development., There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.

Published
2021

38. Long-Duration Progressive Supranuclear Palsy: Clinical Course and Pathological Underpinnings

Author

Jecmenica Lukic, Milica, Respondek, Gesine, Giese, Armin, Roeber, Sigrun, Herms, Jochen, Arzberger, Thomas, Höglinger, Günter, Troakes, Claire, Gelpi, Ellen, Höglinger, Günter U, Kurz, Carolin, van Swieten, John, Compta, Yaroslau, Molina-Porcel, L., Aldecoa, I., Tolosa, E., Martí, M. J., Valldeoriola, F., Pagonabarraga, J., Calopa, M., Bayès, A., Hernandez, I., Aguilar, M., Genis, D., Ferguson, Leslie W, Rajput, Alex, group, MDS-endorsed PSP study, van Swieten, John C, and Neurology

Subjects
Neurons, metabolism [Astrocytes], pathology [Supranuclear Palsy, Progressive], tau Proteins, metabolism [tau Proteins], ddc, Research Article, Research Articles, Neurology, metabolism [Neurons], Astrocytes, Disease Progression, Humans, Neurology (clinical), ddc:610, Autopsy, Supranuclear Palsy, Progressive
Abstract

Objectives: To identify the clinical characteristics of the subgroup of benign progressive supranuclear palsy with particularly long disease duration; to define neuropathological determinants underlying variability in disease duration in progressive supranuclear palsy. Methods: Clinical and pathological features were compared among 186 autopsy-confirmed cases with progressive supranuclear palsy with ≥10 years and shorter survival times. Results: The 45 cases (24.2%) had a disease duration of ≥10 years. The absence of ocular motor abnormalities within the first 3 years from disease onset was the only significant independent clinical predictor of longer survival. Histopathologically, the neurodegeneration parameters in each survival group were paralleled anatomically by the distribution of neuronal cytoplasmic inclusions, whereas the tufted astrocytes displayed anatomically an opposite severity pattern. Most interestingly, we found significantly less coiled bodies in those who survive longer, in contrast to patients with less favorable course. Interpretation: A considerable proportion of patients had a more ”benign” disease course with ≥10 years survival. They had a distinct pattern and evolution of core symptoms compared to patients with short survival. The inverted anatomical patterns of astrocytic tau distribution suggest distinct implications of these cell types in trans-cellular propagation. The tempo of disease progression appeared to be determined mostly by oligodendroglial tau, where the high degree of oligodendroglial tau pathology might affect neuronal integrity and function on top of neuronal tau pathology. The relative contribution of glial tau should be further explored in cellular and animal models. ANN NEUROL 2022.

Published
2021
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42. P.0883 Immune signature of multiple sclerosis-associated depression

Author

Brasanac, J., primary, Ramien, C., additional, Gamradt, S., additional, Tänzer, A., additional, Glau, L., additional, Ritter, K., additional, Patas, K., additional, Agorastos, A., additional, Wiedemann, K., additional, Demiralay, C., additional, Fischer, F., additional, Otte, C., additional, Bellmann-Strobl, J., additional, Friese, M.A., additional, Tolosa, E., additional, Paul, F., additional, Heesen, C., additional, Weygandt, M., additional, and Gold, S.M., additional

Published
2021
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43. Copathology in Progressive Supranuclear Palsy: Does It Matter?

Author

Jecmenica Lukic, Milica, Kurz, Carolin, Roeber, Sigrun, Arzberger, Thomas, Höglinger, Günter, Grau-Rivera, O., Compta, Y., Tolosa, E., Martí, M. J., Valldeoriola, F., Pagonabarraga, J., Calopa, M., Respondek, Gesine, Bayès, A., Hernandez, I., Aguilar, M., Genis, D., Fernandez, M., Munoz-Garcia, C., Antonell, A., Gelpi, E., Grau-Rivera, Oriol, Compta, Yaroslau, Gelpi, Ellen, Troakes, Claire, Barcelona Brain Bank collaborative group, the MDS-endorsed PSP study group, van Swieten, John C, Giese, Armin, and Neurology

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Movement disorders, epidemiology [Alzheimer Disease], Disease, Progressive supranuclear palsy, 03 medical and health sciences, 0302 clinical medicine, Time frame, medicine, Humans, ddc:610, Movement Disorders, business.industry, medicine.disease, metabolism [tau Proteins], ddc, 3. Good health, epidemiology [Supranuclear Palsy, Progressive], 030104 developmental biology, Neurology, metabolism [Brain], Concomitant, Neurology (clinical), Cerebral amyloid angiopathy, Sarcoma, medicine.symptom, business, Relevant information, 030217 neurology & neurosurgery
Abstract

BACKGROUND The influence of concomitant brain pathologies on the progression rate in PSP is unclear. OBJECTIVES To analyze the frequency and severity of copathologies and their impact on the progression in PSP. METHODS We analyzed clinic-pathological features of 101 PSP patients. Diagnoses and stages of copathologies were established according to standardized criteria, including Alzheimer's disease-related pathology, argyrophilic grains, Lewy-related pathology, transactive response DNA-binding protein 43 pathology, fused in sarcoma pathology, cerebral amyloid angiopathy, and small vessel disease. Demographic data and major clinical milestones (frequency and latency to onset) were extracted from patients' files. RESULTS Only 8% of 101 patients presented with pure PSP pathology without any copathology. Alzheimer's disease-related pathology was the most frequent (84%), followed by argyrophilic grains (58%), both occurring as single copathology or in combination with other proteinopathies or cerebrovascular disease. Lewy-related and transactive response DNA-binding protein 43 copathology occurred rarely (8% and 6%, respectively). Fused in sarcoma-positive cases were not found. While being common, copathology was mostly mild in severity, with the exception of frequently widespread argyrophilic grains. Small vessel disease was also frequent (65%). Cerebral amyloid angiopathy occurred only in the presence of Alzheimer's disease-related changes (25%). The copathologies did not have major impact on prevalence and time frame of major disease milestones. CONCLUSIONS In PSP, concomitant neurodegenerative proteinopathies or cerebrovascular diseases are frequent, but generally mild in severity. Our data confirmed that four repeat tau is still the most relevant target for PSP, whereas the impact of copathologies on progression rate appears to be of less importance. This is relevant information for the development of disease-modifying therapies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Published
2020
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