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Michael J Fox Foundation

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https://www.readbyqxmd.com/read/29456161/the-effect-of-lrrk2-mutations-on-the-cholinergic-system-in-manifest-and-premanifest-stages-of-parkinson-s-disease-a-cross-sectional-pet-study
#1
Shu-Ying Liu, Daryl J Wile, Jessie Fanglu Fu, Jason Valerio, Elham Shahinfard, Siobhan McCormick, Rostom Mabrouk, Nasim Vafai, Jess McKenzie, Nicole Neilson, Alexandra Perez-Soriano, Julieta E Arena, Mariya Cherkasova, Piu Chan, Jing Zhang, Cyrus P Zabetian, Jan O Aasly, Zbigniew K Wszolek, Martin J McKeown, Michael J Adam, Thomas J Ruth, Michael Schulzer, Vesna Sossi, A Jon Stoessl
BACKGROUND: Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease...
February 15, 2018: Lancet Neurology
https://www.readbyqxmd.com/read/29400668/best-practices-for-generating-and-using-alpha-synuclein-pre-formed-fibrils-to-model-parkinson-s-disease-in-rodents
#2
Nicole K Polinski, Laura A Volpicelli-Daley, Caryl E Sortwell, Kelvin C Luk, Nunilo Cremades, Lindsey M Gottler, Jessica Froula, Megan F Duffy, Virginia M Lee, Terina N Martinez, Kuldip D Dave
Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting approximately one-percent of the population over the age of sixty. Although many animal models have been developed to study this disease, each model presents its own advantages and caveats. A unique new model has arisen to study the role of alpha-synuclein (aSyn) in the pathogenesis of PD. This model involves the conversion of recombinant monomeric aSyn protein to a fibrillar form-the aSyn pre-formed fibril (aSyn PFF)-which is then injected into the brain or introduced to the media in culture...
January 30, 2018: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/29305429/back-to-the-future-new-target-validated-rab-antibodies-for-evaluating-lrrk2-signalling-in-cell-biology-and-parkinson-s-disease
#3
Patrick A Eyers
The addition of phosphate groups to substrates allows protein kinases to regulate a myriad of biological processes, and contextual analysis of protein-bound phosphate is important for understanding how kinases contribute to physiology and disease. Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase linked to familial and sporadic cases of Parkinson's disease (PD). Recent work established that multiple Rab GTPases are physiological substrates of LRRK2, with Rab10 in particular emerging as a human substrate whose site-specific phosphorylation mirrors hyperactive LRRK2 lesions associated with PD...
January 5, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29159192/sex-differences-in-lrrk2-g2019s-and-idiopathic-parkinson-s-disease
#4
Marta San Luciano, Cuiling Wang, Roberto A Ortega, Nir Giladi, Karen Marder, Susan Bressman, Rachel Saunders-Pullman
Objective: To evaluate sex differences and the relative effect of G2019S LRRK2 mutations in Parkinson's disease (PD). Methods: 530 LRRK2 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and LRRK2 PD; and features were compared between IPD and LRRK2 PD separately for men and women...
November 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29103052/increasing-efficiency-of-recruitment-in-early-parkinson-s-disease-trials-a-case-study-examination-of-the-steady-pd-iii-trial
#5
Sarah Berk, Brittany L Greco, Kevin Biglan, Catherine M Kopil, Robert G Holloway, Claire Meunier, Tanya Simuni
BACKGROUND: Challenges in clinical trial recruitment threaten the successful development of improved therapies. This is particularly true in Parkinson's disease (PD) studies of disease modification where the population of interest is difficult to find and study design is more complex. OBJECTIVE: This paper seeks to understand how STEADY PD III, a National Institute of Neurological Disorders and Stroke (NINDS) funded phase 3 trial evaluating the efficacy of isradipine as a disease modifying agent for PD, was able to recruit their full target population 6 months ahead of schedule...
2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/29054815/whole-brain-radiotherapy-or-autologous-stem-cell-transplantation-as-consolidation-strategies-after-high-dose-methotrexate-based-chemoimmunotherapy-in-patients-with-primary-cns-lymphoma-results-of-the-second-randomisation-of-the-international-extranodal-lymphoma
#6
Andrés J M Ferreri, Kate Cwynarski, Elisa Pulczynski, Christopher P Fox, Elisabeth Schorb, Paul La Rosée, Mascha Binder, Alberto Fabbri, Valter Torri, Eleonora Minacapelli, Monica Falautano, Fiorella Ilariucci, Achille Ambrosetti, Alexander Roth, Claire Hemmaway, Peter Johnson, Kim M Linton, Tobias Pukrop, Jette Sønderskov Gørløv, Monica Balzarotti, Georg Hess, Ulrich Keller, Stephan Stilgenbauer, Jens Panse, Alessandra Tucci, Lorella Orsucci, Francesco Pisani, Alessandro Levis, Stefan W Krause, Hans J Schmoll, Bernd Hertenstein, Mathias Rummel, Jeffery Smith, Michael Pfreundschuh, Giuseppina Cabras, Francesco Angrilli, Maurilio Ponzoni, Martina Deckert, Letterio S Politi, Jürgen Finke, Michele Reni, Franco Cavalli, Emanuele Zucca, Gerald Illerhaus
BACKGROUND: The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested...
November 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28958801/large-scale-identification-of-clinical-and-genetic-predictors-of-motor-progression-in-patients-with-newly-diagnosed-parkinson-s-disease-a-longitudinal-cohort-study-and-validation
#7
Jeanne C Latourelle, Michael T Beste, Tiffany C Hadzi, Robert E Miller, Jacob N Oppenheim, Matthew P Valko, Diane M Wuest, Bruce W Church, Iya G Khalil, Boris Hayete, Charles S Venuto
BACKGROUND: Better understanding and prediction of progression of Parkinson's disease could improve disease management and clinical trial design. We aimed to use longitudinal clinical, molecular, and genetic data to develop predictive models, compare potential biomarkers, and identify novel predictors for motor progression in Parkinson's disease. We also sought to assess the use of these models in the design of treatment trials in Parkinson's disease. METHODS: A Bayesian multivariate predictive inference platform was applied to data from the Parkinson's Progression Markers Initiative (PPMI) study (NCT01141023)...
November 2017: Lancet Neurology
https://www.readbyqxmd.com/read/28781108/exenatide-once-weekly-versus-placebo-in-parkinson-s-disease-a-randomised-double-blind-placebo-controlled-trial
#8
Dilan Athauda, Kate Maclagan, Simon S Skene, Martha Bajwa-Joseph, Dawn Letchford, Kashfia Chowdhury, Steve Hibbert, Natalia Budnik, Luca Zampedri, John Dickson, Yazhou Li, Iciar Aviles-Olmos, Thomas T Warner, Patricia Limousin, Andrew J Lees, Nigel H Greig, Susan Tebbs, Thomas Foltynie
BACKGROUND: Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial. METHODS: In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period...
October 7, 2017: Lancet
https://www.readbyqxmd.com/read/28735833/cannabis-use-in-people-with-parkinson-s-disease-and-multiple-sclerosis-a-web-based-investigation
#9
John H Kindred, Kaigang Li, Nathaniel B Ketelhut, Felix Proessl, Brett W Fling, Justin M Honce, William R Shaffer, Thorsten Rudroff
OBJECTIVES: Cannabis has been used for medicinal purpose for thousands of years; however the positive and negative effects of cannabis use in Parkinson's disease (PD) and Multiple Sclerosis (MS) are mostly unknown. Our aim was to assess cannabis use in PD and MS and compare results of self-reported assessments of neurological disability between current cannabis users and non-users. METHODS: An anonymous web-based survey was hosted on the Michael J. Fox Foundation and the National Multiple Sclerosis Society webpages from 15 February to 15 October 2016...
August 2017: Complementary Therapies in Medicine
https://www.readbyqxmd.com/read/28734051/a-user-s-guide-for-%C3%AE-synuclein-biomarker-studies-in-biological-fluids-perianalytical-considerations
#10
REVIEW
Brit Mollenhauer, Richard Batrla, Omar El-Agnaf, Douglas R Galasko, Hilal A Lashuel, Kalpana M Merchant, Lesley M Shaw, Dennis J Selkoe, Robert Umek, Hugo Vanderstichele, Henrik Zetterberg, Jing Zhang, Chelsea Caspell-Garcia, Chris Coffey, Samantha J Hutten, Mark Frasier, Peggy Taylor
Parkinson's disease biomarkers are needed to increase diagnostic accuracy, to objectively monitor disease progression and to assess therapeutic efficacy as well as target engagement when evaluating novel drug and therapeutic strategies. This article summarizes perianalytical considerations for biomarker studies (based on immunoassays) in Parkinson's disease, with emphasis on quantifying total α-synuclein protein in biological fluids. Current knowledge and pitfalls are discussed, and selected perianalytical variables are presented systematically, including different temperature of sample collection and types of collection tubes, gradient sampling, the addition of detergent, aliquot volume, the freezing time, and the different thawing methods...
August 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28336296/serotonin-and-dopamine-transporter-pet-changes-in-the-premotor-phase-of-lrrk2-parkinsonism-cross-sectional-studies
#11
Daryl J Wile, Pankaj A Agarwal, Michael Schulzer, Edwin Mak, Katherine Dinelle, Elham Shahinfard, Nasim Vafai, Kazuko Hasegawa, Jing Zhang, Jessamyn McKenzie, Nicole Neilson, Audrey Strongosky, Ryan J Uitti, Mark Guttman, Cyrus P Zabetian, Yu-Shin Ding, Mike Adam, Jan Aasly, Zbigniew K Wszolek, Matthew Farrer, Vesna Sossi, A Jon Stoessl
BACKGROUND: People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. METHODS: We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada...
May 2017: Lancet Neurology
https://www.readbyqxmd.com/read/28069931/the-search-for-a-peripheral-biopsy-indicator-of-%C3%AE-synuclein-pathology-for-parkinson-disease
#12
REVIEW
John M Lee, Pascal Derkinderen, Jeffrey H Kordower, Roy Freeman, David G Munoz, Thomas Kremer, Wagner Zago, Samantha J Hutten, Charles H Adler, Geidy E Serrano, Thomas G Beach
The neuropathological hallmark of Parkinson disease (PD) is abnormal accumulation of α-synuclein (α-syn). Demonstrating pathological α-syn in live patients would be useful for identifying and monitoring PD patients. To date, however, imaging and biofluid approaches have not permitted premortem assessment of pathological α-syn. α-syn pathology in the peripheral nervous system of patients with PD has been demonstrated in studies dating back more than 40 years. More recent work suggests that colon, submandibular gland and skin biopsies could be useful as expedient biomarkers but histological differentiation of pathological and normal peripheral α-syn has been challenging and multiple research groups have reported variable results...
January 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/27911344/patient-perspectives-on-deep-brain-stimulation-clinical-research-in-early-stage-parkinson-s-disease
#13
RANDOMIZED CONTROLLED TRIAL
Lauren Heusinkveld, Mallory Hacker, Maxim Turchan, Madelyn Bollig, Christina Tamargo, William Fisher, Lauren McLaughlin, Adria Martig, David Charles
The FDA has approved a multicenter, double-blind, Phase III, pivotal trial testing deep brain stimulation (DBS) in 280 people with very early stage Parkinson's disease (PD; IDE#G050016). In partnership with The Michael J. Fox Foundation for Parkinson's Research, we conducted a survey to investigate motivating factors, barriers, and gender differences among potentially eligible patients for participation in a trial testing DBS in early PD compared to standard medical treatment. The majority of survey respondents (72%) indicated they would consider learning more about participating...
2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/27692902/dnm3-and-genetic-modifiers-of-age-of-onset-in-lrrk2-gly2019ser-parkinsonism-a-genome-wide-linkage-and-association-study
#14
Joanne Trinh, Emil K Gustavsson, Carles Vilariño-Güell, Stephanie Bortnick, Jeanne Latourelle, Marna B McKenzie, Chelsea Szu Tu, Ekaterina Nosova, Jaskaran Khinda, Austen Milnerwood, Suzanne Lesage, Alexis Brice, Meriem Tazir, Jan O Aasly, Laura Parkkinen, Hazal Haytural, Tatiana Foroud, Richard H Myers, Samia Ben Sassi, Emna Hentati, Fatma Nabli, Emna Farhat, Rim Amouri, Fayçal Hentati, Matthew J Farrer
BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) mutation 6055G→A (Gly2019Ser) accounts for roughly 1% of patients with Parkinson's disease in white populations, 13-30% in Ashkenazi Jewish populations, and 30-40% in North African Arab-Berber populations, although age of onset is variable. Some carriers have early-onset parkinsonism, whereas others remain asymptomatic despite advanced age. We aimed to use a genome-wide approach to identify genetic variability that directly affects LRRK2 Gly2019Ser penetrance...
November 2016: Lancet Neurology
https://www.readbyqxmd.com/read/27145382/cancer-stem-cell-secreted-macrophage-migration-inhibitory-factor-stimulates-myeloid-derived-suppressor-cell-function-and-facilitates-glioblastoma-immune-evasion
#15
Balint Otvos, Daniel J Silver, Erin E Mulkearns-Hubert, Alvaro G Alvarado, Soumya M Turaga, Mia D Sorensen, Patricia Rayman, William A Flavahan, James S Hale, Kevin Stoltz, Maksim Sinyuk, Qiulian Wu, Awad Jarrar, Sung-Hak Kim, Paul L Fox, Ichiro Nakano, Jeremy N Rich, Richard M Ransohoff, James Finke, Bjarne W Kristensen, Michael A Vogelbaum, Justin D Lathia
Shifting the balance away from tumor-mediated immune suppression toward tumor immune rejection is the conceptual foundation for a variety of immunotherapy efforts currently being tested. These efforts largely focus on activating antitumor immune responses but are confounded by multiple immune cell populations, including myeloid-derived suppressor cells (MDSCs), which serve to suppress immune system function. We have identified immune-suppressive MDSCs in the brains of GBM patients and found that they were in close proximity to self-renewing cancer stem cells (CSCs)...
August 2016: Stem Cells
https://www.readbyqxmd.com/read/27113479/the-biofind-study-characteristics-of-a-clinically-typical-parkinson-s-disease-biomarker-cohort
#16
REVIEW
Un Jung Kang, Jennifer G Goldman, Roy N Alcalay, Tao Xie, Paul Tuite, Claire Henchcliffe, Penelope Hogarth, Amy W Amara, Samuel Frank, Alice Rudolph, Cynthia Casaceli, Howard Andrews, Katrina Gwinn, Margaret Sutherland, Catherine Kopil, Lona Vincent, Mark Frasier
BACKGROUND: Identifying PD-specific biomarkers in biofluids will greatly aid in diagnosis, monitoring progression, and therapeutic interventions. PD biomarkers have been limited by poor discriminatory power, partly driven by heterogeneity of the disease, variability of collection protocols, and focus on de novo, unmedicated patients. Thus, a platform for biomarker discovery and validation in well-characterized, clinically typical, moderate to advanced PD cohorts is critically needed. METHODS: BioFIND (Fox Investigation for New Discovery of Biomarkers in Parkinson's Disease) is a cross-sectional, multicenter biomarker study that established a repository of clinical data, blood, DNA, RNA, CSF, saliva, and urine samples from 118 moderate to advanced PD and 88 healthy control subjects...
June 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27041685/cerebrospinal-fluid-biomarkers-and-clinical-features-in-leucine-rich-repeat-kinase-2-lrrk2-mutation-carriers
#17
Dolores Vilas, Leslie M Shaw, Peggy Taylor, Daniela Berg, Kathrin Brockmann, Jan Aasly, Connie Marras, Claustre Pont-Sunyer, José Ríos, Ken Marek, Eduardo Tolosa
BACKGROUND: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of inherited Parkinson's disease (PD). Nonmanifesting carriers of LRRK2 mutations are at high risk for developing PD. Information available on cerebrospinal fluid (CSF) biomarkers in LRRK2 carriers remains preliminary. OBJECTIVES: To measure CSF levels of α-synuclein, β amyloid1-42 , total-tau, and phospho-tau181 , in LRRK2-associated PD, idiopathic PD, nonmanifesting carriers, and first-degree relatives of LRRK2-associated PD patients without the mutation (nonmanifesting noncarriers)...
June 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/26976201/prognostic-value-of-medulloblastoma-extent-of-resection-after-accounting-for-molecular-subgroup-a-retrospective-integrated-clinical-and-molecular-analysis
#18
Eric M Thompson, Thomas Hielscher, Eric Bouffet, Marc Remke, Betty Luu, Sridharan Gururangan, Roger E McLendon, Darell D Bigner, Eric S Lipp, Sebastien Perreault, Yoon-Jae Cho, Gerald Grant, Seung-Ki Kim, Ji Yeoun Lee, Amulya A Nageswara Rao, Caterina Giannini, Kay Ka Wai Li, Ho-Keung Ng, Yu Yao, Toshihiro Kumabe, Teiji Tominaga, Wieslawa A Grajkowska, Marta Perek-Polnik, David C Y Low, Wan Tew Seow, Kenneth T E Chang, Jaume Mora, Ian F Pollack, Ronald L Hamilton, Sarah Leary, Andrew S Moore, Wendy J Ingram, Andrew R Hallahan, Anne Jouvet, Michelle Fèvre-Montange, Alexandre Vasiljevic, Cecile Faure-Conter, Tomoko Shofuda, Naoki Kagawa, Naoya Hashimoto, Nada Jabado, Alexander G Weil, Tenzin Gayden, Takafumi Wataya, Tarek Shalaby, Michael Grotzer, Karel Zitterbart, Jaroslav Sterba, Leos Kren, Tibor Hortobágyi, Almos Klekner, Bognár László, Tímea Pócza, Peter Hauser, Ulrich Schüller, Shin Jung, Woo-Youl Jang, Pim J French, Johan M Kros, Marie-Lise C van Veelen, Luca Massimi, Jeffrey R Leonard, Joshua B Rubin, Rajeev Vibhakar, Lola B Chambless, Michael K Cooper, Reid C Thompson, Claudia C Faria, Alice Carvalho, Sofia Nunes, José Pimentel, Xing Fan, Karin M Muraszko, Enrique López-Aguilar, David Lyden, Livia Garzia, David J H Shih, Noriyuki Kijima, Christian Schneider, Jennifer Adamski, Paul A Northcott, Marcel Kool, David T W Jones, Jennifer A Chan, Ana Nikolic, Maria Luisa Garre, Erwin G Van Meir, Satoru Osuka, Jeffrey J Olson, Arman Jahangiri, Brandyn A Castro, Nalin Gupta, William A Weiss, Iska Moxon-Emre, Donald J Mabbott, Alvaro Lassaletta, Cynthia E Hawkins, Uri Tabori, James Drake, Abhaya Kulkarni, Peter Dirks, James T Rutka, Andrey Korshunov, Stefan M Pfister, Roger J Packer, Vijay Ramaswamy, Michael D Taylor
BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium...
April 2016: Lancet Oncology
https://www.readbyqxmd.com/read/26917005/increased-peripheral-inflammation-in-asymptomatic-leucine-rich-repeat-kinase-2-mutation-carriers
#19
Nicolas Dzamko, Dominic B Rowe, Glenda M Halliday
BACKGROUND: We aimed to determine if peripheral or central inflammatory cytokines are altered in healthy subjects carrying a leucine-rich repeat kinase 2 (LRRK2) G2019S mutation, and thus genetically at risk of Parkinson's disease (PD). We also aimed to identify differences in inflammatory cytokines between LRRK2 G2019S-associated and idiopathic PD once the disease manifests. METHODS: Participants were genetically screened and phenotyped, and biological samples were collected and stored by the Michael J...
June 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/26762707/clinical-practice-guidelines-for-oral-management-of-sj%C3%A3-gren-disease-dental-caries-prevention
#20
Domenick T Zero, Michael T Brennan, Troy E Daniels, Athena Papas, Carol Stewart, Andres Pinto, Ibtisam Al-Hashimi, Mahvash Navazesh, Nelson Rhodus, James Sciubba, Mabi Singh, Ava J Wu, Julie Frantsve-Hawley, Sharon Tracy, Philip C Fox, Theresa Lawrence Ford, Stephen Cohen, Frederick B Vivino, Katherine M Hammitt
BACKGROUND: Salivary dysfunction in Sjögren disease can lead to serious and costly oral health complications. Clinical practice guidelines for caries prevention in Sjögren disease were developed to improve quality and consistency of care. METHODS: A national panel of experts devised clinical questions in a Population, Intervention, Comparison, Outcomes format and included use of fluoride, salivary stimulants, antimicrobial agents, and nonfluoride remineralizing agents...
April 2016: Journal of the American Dental Association
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