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1. Study in Parkinson’s disease of exercise phase 3 (SPARX3): study protocol for a randomized controlled trial

Author

Charity G. Patterson, Elizabeth Joslin, Alexandra B. Gil, Wendy Spigle, Todd Nemet, Lana Chahine, Cory L. Christiansen, Ed Melanson, Wendy M. Kohrt, Martina Mancini, Deborah Josbeno, Katherine Balfany, Garett Griffith, Mac Kenzie Dunlap, Guillaume Lamotte, Erin Suttman, Danielle Larson, Chantale Branson, Kathleen E. McKee, Li Goelz, Cynthia Poon, Barbara Tilley, Un Jung Kang, Malú Gámez Tansey, Nijee Luthra, Caroline M. Tanner, Jacob M. Haus, Giamila Fantuzzi, Nikolaus R. McFarland, Paulina Gonzalez-Latapi, Tatiana Foroud, Robert Motl, Michael A. Schwarzschild, Tanya Simuni, Kenneth Marek, Anna Naito, Codrin Lungu, Daniel M. Corcos, and The SPARX3-PSG Investigators

Subjects
Parkinson disease, Endurance exercise, Treadmill exercise, Exercise dose response, DaTscan™ SPECT, Gait assessment, Medicine (General), R5-920
Abstract

Abstract Background To date, no medication has slowed the progression of Parkinson’s disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline. Methods This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60–65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80–85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity. Discussion SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health. Trial registration ClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.

Published
2022
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2. The TOPAZ study: a home-based trial of zoledronic acid to prevent fractures in neurodegenerative parkinsonism

Author

Caroline M. Tanner, Steven R. Cummings, Michael A. Schwarzschild, Ethan G. Brown, E. Ray Dorsey, Alberto J. Espay, Nicholas B. Galifianakis, Samuel M. Goldman, Irene Litvan, Nijee Luthra, Nikolaus R. McFarland, Kyle T. Mitchell, David G. Standaert, Douglas C. Bauer, Susan L. Greenspan, James C. Beck, and Kenneth W. Lyles

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

Abstract The Trial of Parkinson’s And Zoledronic acid (TOPAZ, https://clinicaltrials.gov/ct2/show/NCT03924414 ) is a unique collaboration between experts in movement disorders and osteoporosis to test the efficacy of zoledronic acid, an FDA-approved parenteral treatment for osteoporosis, for fracture prevention in people with neurodegenerative parkinsonism. Aiming to enroll 3,500 participants age 65 years or older, TOPAZ is one of the largest randomized, placebo-controlled clinical trials ever attempted in parkinsonism. The feasibility of TOPAZ is enhanced by its design as a U.S.- wide home-based trial without geographical limits. Participants receive information from multiple sources, including specialty practices, support groups and websites. Conducting TOPAZ in participants’ homes takes advantage of online consent technology, the capacity to confirm diagnosis using telemedicine and the availability of research nursing to provide screening and parenteral therapy in homes. Home-based clinical research may provide an efficient, convenient, less expensive method that opens participation in clinical trials to almost anyone with parkinsonism.

Published
2021
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3. Hoehn and Yahr Stage and Striatal Dat-SPECT Uptake Are Predictors of Parkinson’s Disease Motor Progression

Author

Holly Jackson, Judith Anzures-Cabrera, Kirsten I. Taylor, Gennaro Pagano, PASADENA Investigators, Prasinezumab Study Group, Claudia Altendorf, Chareyna Anandan, Giulia Andrews, Solène Ansquer, Raphaele Arrouasse, Sana Aslam, Jean-Philippe Azulay, Jeanette Baker, Ernest Balaguer Martinez, Shadi Barbu, Kara Bardram, Danny Bega, Helena Bejr-Kasem Marco, Isabelle Benatru, Eve Benchetrit, Felix Bernhard, Amir Besharat, Sagari Bette, Amelie Bichon, Andrew Billnitzer, Sophie Blondeau, Thomas Boraud, Freiderike Borngräber, James Boyd, Kathrin Brockmann, Matthew Brodsky, Ethan Brown, Christof Bruecke, Fabienne Calvas, Monica Canelo, Federico Carbone, Claire Carroll, Laura Casado Fernandez, Catherine Cassé-Perrot, Anna Castrioto, Helene Catala, Justine Chan, Samia Cheriet, Anthony Ciabarra, Joseph Classen, Juliana Coleman, Robert Coleman, Yaroslau Compta, Anne-Gaëlle Corbillé, Jean-Christophe Corvol, Mariana Cosgaya, Nabila Dahodwala, Philippe Damier, Elodie David, Thomas Davis, Marissa Dean, Berengere Debilly, Janell DeGiorgio, Andres Deik, Laure Delaby, Marie-Helene Delfini, Pascal Derkinderen, Philipp Derost, Maria de Toledo, Lisa Deuel, Ann Marie Diaz-Hernandez, Cameron Dietiker, Karina Dimenshteyn, Julio Dotor, Franck Durif, Jens Ebentheuer, Karla Maria Eggert, Sara Eichau Madueño, Claudia Eickhoff, Aaron Ellenbogen, Philipp Ellmerer, Ines Esparragosa Vazquez, Alexandre Eusebio, Siobhan Ewert, John Fang, Danielle Feigenbaum, Frederique Fluchere, Alexandra Foubert-Samier, Marie Fournier, Anne Fradet, Valerie Fraix, Samuel Frank, Franca Fries, Monique Galitzky, Marisol Gallardó Pérez, Jose Manuel García Moreno, Carmen Gasca, Thomas Gasser, Joyce Gibbons, Caroline Giordana, Alicia Gonzalez Martinez, Ira Goodman, Arantza Gorospe, Marie Goubeaud, David Grabli, Mangone Graziella, Stephan Grimaldi, Jeffrey Gross, Raquel Guimaraes-Costa, Andreas Hartmann, Christian Hartmann, Travis Hassell, Robert Hauser, Antonio Hernandez, Jorge Hernandez-Vara, Guenter Hoeglinger, Christian Homedes, Andrea Horta-Barba, Jean-Luc Houeto, Julius Huebl, Jennifer Hui, Stuart Isaacson, Joseph Jankovic, Annette Janzen, Junior Jauregui, Jocelyne Jiao, Maria Jose Marti Domenech, Xavier Joseph, Srinath Kadimi, Pat Kaminski, Silja Kannenberg, Jan Kassubek, Maya Katz, Kevin Klos, Shannon Klos, Christopher Kobet, Jennifer Koebert, Patricia Krause, Andrea Kuehn, Jaime Kulisevsky Bojarsky, Rajeev Kumar, Martin Kunz, Lille Kurvits, Kimberly Kwei, Simon Laganiere, Brice Laurens, Johannes Levin, Oren Levy, Peter LeWitt, Gurutz Linazasoro Cristóbal, Irene Litvan, Karlo Lizarraga, Katherine Longardner, Rocio Lopez, Lydia Lopez Manzanares, Sara Lucas del Pozo, Maria Rosario Luquin Puido, Nijee Luthra, Kelly Lyons, Sylvia Maass, Gerrit Machetanz, Yolanda Macias, David Maltete, Jorge Uriel Manez Miro, Louise-Laure Mariani, Juan Marin, Kathrin Marini, Ana Marques, Gloria Marti, Saul Martinez, Wassilios Meissner, Sara Meoni, Brit Mollenhauer, Dunia Mon Martinez, Johnson Moon, Elena Moro, Peter Morrison, Christoph Muehlberg, Manpreet Multani, Christine Murphy, Anthony Nicholas, Rajesh Pahwa, Antonio Palasi, Heidi Pape, Neepa Patel, Prity Patel, Marina Peball, Elizabeth Peckham, Terry Peery, Rafael Perez, Jesus Perez, Alisa Petit, Elmar Pinkhardt, Werner Poewe, Elsa Pomies, Cecile Preterre, Joseph Quinn, Olivier Rascol, Philippe Remy, Irene Richard, Benjamin Roeben, Emily Ruether, Jost-Julian Rumpf, David Russell, Hayet Salhi, Daniela Samaniego-Toro, Alexandra Samier-Foubert, Antonio Sanchez, Emmanuelle Schmitt, Alfons Schnitzler, Oliver Schorr, Julie Schwartzbard, Kerstin Schweyer, Klaus Seppi, Victoria Sergo, Holly Shill, Andrew Siderowf, Tanya Simuni, Umberto Spampinato, Ashok Sriram, Natividad Stover, Caroline Tanner, Arjun Tarakad, Carolyn Taylor, Claire Thalamus, Thomas Toothaker, Nadege Van Blercom, Nora Vanegas-Arrogave, Lydia Vela, Sylvian Vergnet, Tiphaine Vidal, Jonathan Vöglein, Ryan Walsh, Cheryl Waters, Mirko Wegscheider, Endy Weidinger, Caroline Weill, Gregor Wenzel, Tatiana Witjas, Isabel Wurster, Brenton Wright, Milan Zimmermann, Rafael Zuzuarregui, Markus Abt, Atieh Bamdadian, Teresa Barata, Nicholas Barbet, Sara Belli, Frank Boess, Azad Bonni, Edilio Borroni, Anne Boulay, Markus Britschgi, Jerome Chague, Valerie Cosson, Christian Czech, Dennis Deptula, Cheikh Diack, Rachelle Doody, Juergen Dukart, Giulia D’Urso, Sebastian Dziadek, Hannah Eddleston, Chris Edgar, Laurent Essioux, Morgan Farell, Rebecca Finch, Paulo Fontoura, Waltraud Gruenbauer, Andrea Hahn, Stefan Holiga, Michael Honer, Shirin Jadidi, Kelly Johnson-Wood, Markus Keller, Timothy Kilchenmann, Martin Koller, Thomas Kremer, Thomas Kustermann, Claire Landsdall, Michael Lindemann, Florian Lipsmeier, Cecile Luzy, Marianne Manchester, Maddalena Marchesi, Ferenc Martenyi, Meret Martin-Facklam, Katerina Mironova, Annabelle Monnet, Emma Moore, Daniel K Ness, Markus Niggli, Tania Nikolcheva, Susanne Ostrowitzki GP, Benedicte Passmard, Agnes Poirier, Anke Post, Megana Prasad, Nathalie Pross, Tiffany Quock, Benedicte Ricci, Ellen Rose, Christoph Sarry, Christine Schubert, Dennis Selkoe, Jeff Sevigny, Kaycee Sink, Hannah Staunton, Tim Steven, Alexander Strasak, Hanno Svoboda KT, Radhika Tripuraneni, Dylan Trundell, Daniel Umbricht, Lynne Verselis, Annamarie Vogt, Ekaterina Volkova-Volkmar, Cornelia Weber, Silke Weber, and Wagner Zago

Subjects
PASADENA, PPMI (Parkinson’s Progression Markers Initiative), Parkinson’s disease, progression predictors, ridge regression, disease stage, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Currently, no treatments available for Parkinson’s disease (PD) can slow PD progression. At the early stage of the disease, only a subset of individuals with PD progress quickly, while the majority have a slowly progressive form of the disease. In developing treatments that aim to slow PD progression, clinical trials aim to include individuals who are likely to progress faster, such that a treatment effect, if one exists, can be identified easier and earlier. The aim of the present study was to identify baseline predictors of clinical progression in early PD. We analyzed 12-month data acquired from the PASADENA trial Part 1 (NCT03100149, n = 76 participants who were allocated to the placebo arm and did not start symptomatic therapy) and the Parkinson’s Progression Markers Initiative (PPMI) study (n = 139 demographically and clinically matched participants). By using ridge regression models including clinical characteristics, imaging, and non-imaging biomarkers, we found that Hoehn and Yahr stage and dopamine transporter single-photon emission computed tomography specific binding ratios (Dat-SPECT SBR) in putamen ipsilateral to the side of motor symptom onset predicted PD progression at the early stage of the disease. Further studies are needed to confirm the validity of these predictors to identify with high accuracy individuals with early PD with a faster progression phenotype.

Published
2021
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4. A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data

Author

Gennaro Pagano, Frank G. Boess, Kirsten I. Taylor, Benedicte Ricci, Brit Mollenhauer, Werner Poewe, Anne Boulay, Judith Anzures-Cabrera, Annamarie Vogt, Maddalena Marchesi, Anke Post, Tania Nikolcheva, Gene G. Kinney, Wagner M. Zago, Daniel K. Ness, Hanno Svoboda, Markus Britschgi, Susanne Ostrowitzki, Tanya Simuni, Kenneth Marek, Martin Koller, Jeff Sevigny, Rachelle Doody, Paulo Fontoura, Daniel Umbricht, Azad Bonni, PASADENA Investigators, Prasinezumab Study Group, Claudia Altendorf, Chareyna Anandan, Giulia Andrews, Solène Ansquer, Raphaele Arrouasse, Sana Aslam, Jean-Philippe Azulay, Jeanette Baker, Ernest Balaguer Martinez, Shadi Barbu, Kara Bardram, Danny Bega, Helena Bejr-Kasem Marco, Isabelle Benatru, Eve Benchetrit, Felix Bernhard, Amir Besharat, Sagari Bette, Amelie Bichon, Andrew Billnitzer, Sophie Blondeau, Thomas Boraud, Freiderike Borngräber, James Boyd, Kathrin Brockmann, Matthew Brodsky, Ethan Brown, Christof Bruecke, Fabienne Calvas, Monica Canelo, Federico Carbone, Claire Carroll, Laura Casado Fernandez, Catherine Cassé-Perrot, Anna Castrioto, Helene Catala, Justine Chan, Samia Cheriet, Anthony Ciabarra, Joseph Classen, Juliana Coleman, Robert Coleman, Yaroslau Compta, Anne-Gaëlle Corbillé, Jean-Christophe Corvol, Mariana Cosgaya, Nabila Dahodwala, Philippe Damier, Elodie David, Thomas Davis, Marissa Dean, Berengere Debilly, Janell DeGiorgio, Andres Deik, Laure Delaby, Marie-Helene Delfini, Pascal Derkinderen, Philipp Derost, Maria de Toledo, Lisa Deuel, Ann Marie Diaz-Hernandez, Cameron Dietiker, Karina Dimenshteyn, Julio Dotor, Franck Durif, Jens Ebentheuer, Karla Maria Eggert, Sara Eichau Madueño, Claudia Eickhoff, Aaron Ellenbogen, Philipp Ellmerer, Ines Esparragosa Vazquez, Alexandre Eusebio, Siobhan Ewert, John Fang, Danielle Feigenbaum, Frederique Fluchere, Alexandra Foubert-Samier, Marie Fournier, Anne Fradet, Valerie Fraix, Samuel Frank, Franca Fries, Monique Galitzky, Marisol Gallardó Pérez, Jose Manuel García Moreno, Carmen Gasca, Thomas Gasser, Joyce Gibbons, Caroline Giordana, Alicia Gonzalez Martinez, Ira Goodman, Arantza Gorospe, Marie Goubeaud, David Grabli, Mangone Graziella, Stephan Grimaldi, Jeffrey Gross, Raquel Guimaraes-Costa, Andreas Hartmann, Christian Hartmann, Travis Hassell, Robert Hauser, Antonio Hernandez, Jorge Hernandez-Vara, Günter Höglinger, Christian Homedes, Andrea Horta-Barba, Jean-Luc Houeto, Julius Huebl, Jennifer Hui, Stuart Isaacson, Joseph Jankovic, Annette Janzen, Junior Jauregui, Jocelyne Jiao, Maria Jose Marti Domenech, Xavier Joseph, Srinath Kadimi, Pat Kaminski, Silja Kannenberg, Jan Kassubek, Maya Katz, Kevin Klos, Shannon Klos, Christopher Kobet, Jennifer Koebert, Patricia Krause, Andrea Kuehn, Jaime Kulisevsky Bojarsky, Rajeev Kumar, Martin Kunz, Lille Kurvits, Kimberly Kwei, Simon Laganiere, Brice Laurens, Johannes Levin, Oren Levy, Peter LeWitt, Gurutz Linazasoro Cristóbal, Irene Litvan, Karlo Lizarraga, Katherine Longardner, Rocio Lopez, Lydia Lopez Manzanares, Sara Lucas del Pozo, Maria Rosario Luquin Puido, Nijee Luthra, Kelly Lyons, Sylvia Maass, Gerrit Machetanz, Yolanda Macias, David Maltete, Jorge Uriel Manez Miro, Louise-Laure Mariani, Juan Marin, Kathrin Marini, Ana Marques, Gloria Marti, Saul Martinez, Wassilios Meissner, Sara Meoni, Dunia Mon Martinez, Johnson Moon, Elena Moro, Peter Morrison, Christoph Muehlberg, Manpreet Multani, Christine Murphy, Anthony Nicholas, Rajesh Pahwa, Antonio Palasi, Heidi Pape, Neepa Patel, Prity Patel, Marina Peball, Elizabeth Peckham, Terry Peery, Rafael Perez, Jesus Perez, Alisa Petit, Elmar Pinkhardt, Elsa Pomies, Cecile Preterre, Joseph Quinn, Olivier Rascol, Philippe Remy, Irene Richard, Benjamin Roeben, Emily Ruether, Jost-Julian Rumpf, David Russell, Hayet Salhi, Daniela Samaniego-Toro, Alexandra Samier-Foubert, Antonio Sanchez, Emmanuelle Schmitt, Alfons Schnitzler, Oliver Schorr, Julie Schwartzbard, Kerstin Schweyer, Klaus Seppi, Victoria Sergo, Holly Shill, Andrew Siderowf, Umberto Spampinato, Ashok Sriram, Natividad Stover, Caroline Tanner, Arjun Tarakad, Carolyn Taylor, Claire Thalamus, Thomas Toothaker, Nadege Van Blercom, Nora Vanegas-Arrogave, Lydia Vela, Sylvian Vergnet, Tiphaine Vidal, Jonathan Vöglein, Ryan Walsh, Cheryl Waters, Mirko Wegscheider, Endy Weidinger, Caroline Weill, Gregor Wenzel, Tatiana Witjas, Isabel Wurster, Brenton Wright, Milan Zimmermann, Rafael Zuzuarregui, Markus Abt, Atieh Bamdadian, Teresa Barata, Nicholas Barbet, Sara Belli, Frank Boess, Edilio Borroni, Jerome Chague, Valerie Cosson, Christian Czech, Dennis Deptula, Cheikh Diack, Juergen Dukart, Giulia D'Urso, Sebastian Dziadek, Hannah Eddleston, Chris Edgar, Laurent Essioux, Morgan Farell, Rebecca Finch, Waltraud Gruenbauer, Andrea Hahn, Stefan Holiga, Michael Honer, Shirin Jadidi, Kelly Johnson-Wood, Markus Keller, Timothy Kilchenmann, Thomas Kremer, Thomas Kustermann, Claire Landsdall, Michael Lindemann, Florian Lipsmeier, Cecile Luzy, Marianne Manchester, Ferenc Martenyi, Meret Martin-Facklam, Katerina Mironova, Annabelle Monnet, Emma Moore, Daniel K Ness, Markus Niggli, Benedicte Passmard, Agnes Poirier, Megana Prasad, Nathalie Pross, Tiffany Quock, Ellen Rose, Christoph Sarry, Christine Schubert, Dennis Selkoe, Kaycee Sink, Hannah Staunton, Tim Steven, Alexander Strasak, Kirsten Taylor, Radhika Tripuraneni, Dylan Trundell, Lynne Verselis, Ekaterina Volkova-Volkmar, Cornelia Weber, Silke Weber, and Wagner Zago

Subjects
Parkinson's disease, alpha-synuclein (α-syn), prasinezumab, monoclonal antibodies, disease progression, MDS-UPDRS = Movement Disorder Society—Unified Parkinson's Disease Rating Scale, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease.Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD.Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society—Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.Trial Registration: NCT03100149.

Published
2021
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5. The TOPAZ study: a home-based trial of zoledronic acid to prevent fractures in neurodegenerative parkinsonism

Author

Ethan G. Brown, Michael A. Schwarzschild, James C. Beck, Kenneth W. Lyles, Caroline M. Tanner, Nikolaus R. McFarland, E. Ray Dorsey, David G. Standaert, Douglas C. Bauer, Irene Litvan, Steven R. Cummings, Nijee Luthra, Nicholas B. Galifianakis, Alberto J. Espay, Samuel M. Goldman, Susan L. Greenspan, and Kyle T. Mitchell

Subjects
Aging, medicine.medical_specialty, Telemedicine, Parkinson's disease, Clinical Trials and Supportive Activities, Osteoporosis, MEDLINE, Specialty, Neurodegenerative, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Phase IV trials, Clinical Research, medicine, 030212 general & internal medicine, RC346-429, Parkinson's Disease, business.industry, Prevention, Parkinsonism, Neurosciences, Health Services, medicine.disease, Brain Disorders, Clinical trial, Clinical research, Zoledronic acid, Neurology, Neurological, Physical therapy, Neurology (clinical), Neurology. Diseases of the nervous system, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

The Trial of Parkinson’s And Zoledronic acid (TOPAZ, https://clinicaltrials.gov/ct2/show/NCT03924414) is a unique collaboration between experts in movement disorders and osteoporosis to test the efficacy of zoledronic acid, an FDA-approved parenteral treatment for osteoporosis, for fracture prevention in people with neurodegenerative parkinsonism. Aiming to enroll 3,500 participants age 65 years or older, TOPAZ is one of the largest randomized, placebo-controlled clinical trials ever attempted in parkinsonism. The feasibility of TOPAZ is enhanced by its design as a U.S.- wide home-based trial without geographical limits. Participants receive information from multiple sources, including specialty practices, support groups and websites. Conducting TOPAZ in participants’ homes takes advantage of online consent technology, the capacity to confirm diagnosis using telemedicine and the availability of research nursing to provide screening and parenteral therapy in homes. Home-based clinical research may provide an efficient, convenient, less expensive method that opens participation in clinical trials to almost anyone with parkinsonism.

Published
2021

6. Vitamin B12 measurements across neurodegenerative disorders

Author

Nijee Luthra, Ariane H. Marcus, Chadwick W. Christine, and Nancy K. Hills

Subjects
0301 basic medicine, medicine.medical_specialty, Pediatrics, Aging, Neurology, Disease, Neurodegenerative, Alzheimer's Disease, Progressive supranuclear palsy, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Rare Diseases, mental disorders, Acquired Cognitive Impairment, Subacute combined degeneration, Medicine, 2.1 Biological and endogenous factors, Vitamin B12, Alzheimer's Disease Related Dementias (ADRD), lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Nutrition, Parkinson's Disease, business.industry, Dementia with Lewy bodies, Prevention, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), nutritional and metabolic diseases, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Cyanocobalamin, Neurological, Subacute Combined Degeneration, Dementia, business, 030217 neurology & neurosurgery, Research Article, Frontotemporal dementia
Abstract

Background Vitamin B12 deficiency causes a number of neurological features including cognitive and psychiatric disturbances, gait instability, neuropathy, and autonomic dysfunction. Clinical recognition of B12 deficiency in neurodegenerative disorders is more challenging because it causes defects that overlap with expected disease progression. We sought to determine whether B12 levels at the time of diagnosis in patients with Parkinson’s disease (PD) differed from those in patients with other neurodegenerative disorders. Methods We performed a cross-sectional analysis of B12 levels obtained around the time of diagnosis in patients with PD, Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB), Alzheimer’s disease (AD), Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD), or Mild Cognitive Impairment (MCI). We also evaluated the rate of B12 decline in PD, AD, and MCI. Results In multivariable analysis adjusted for age, sex, and B12 supplementation, we found that B12 levels were significantly lower at time of diagnosis in patients with PD than in patients with PSP, FTD, and DLB. In PD, AD, and MCI, the rate of B12 decline ranged from − 17 to − 47 pg/ml/year, much greater than that reported for the elderly population. Conclusions Further studies are needed to determine whether comorbid B12 deficiency affects progression of these disorders.

Published
2020
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7. Cerebellar Deep Brain Stimulation for Acquired Hemidystonia

Author

Philip A. Starr, Ian O. Bledsoe, Nijee Luthra, Ethan G. Brown, Jill L. Ostrem, and Svjetlana Miocinovic

Subjects
0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Cerebellum, medicine.medical_specialty, Deep brain stimulation, cerebellum, medicine.medical_treatment, Bioengineering, Neurodegenerative, 030105 genetics & heredity, Deep cerebellar nuclei, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Physical medicine and rehabilitation, Clinical Research, Basal ganglia, otorhinolaryngologic diseases, medicine, Stroke, Research Articles, Dystonia, Assistive Technology, business.industry, Rehabilitation, Neurosciences, medicine.disease, Gait, Brain Disorders, nervous system diseases, medicine.anatomical_structure, Neurology, Neurological, Neurology (clinical), business, Complication, 030217 neurology & neurosurgery
Abstract

Background The cerebellum's role in dystonia is increasingly recognized. Dystonia can be a disabling and refractory condition; deep brain stimulation can help many patients, but it is traditionally less effective in acquired dystonia. New surgical targets would be instrumental in providing treatment options and understanding dystonia further. Objective To evaluate the efficacy of deep brain stimulation of the cerebellum in acquired dystonia. Methods We report our management of a 37-year-old woman with severe left arm and leg dystonia, a complication of an ischemic stroke in childhood. She had already had 2 thalamotomies with only transient benefit. These procedures, in addition to her initial stroke that had damaged the basal ganglia, left traditional deep brain stimulation targets unavailable. Results After implantation of bilateral deep cerebellar nuclei, dystonia improved with a 40% reduction in severity on scales and subjective reports of improved posturing, gait, and pain. This improvement has been maintained for almost 2 years after implantation. Conclusion Cerebellar stimulation has potential for therapeutic benefit in acquired dystonia and should be further explored.

Published
2020
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8. Longevity factor klotho and resistance to cognitive deficits in a transgenic mouse model and in individuals with Parkinson’s disease

Author

Sylvain Lesne, Luke W. Bonham, Dena B. Dubal, Lauren Broestl, Rohan Sehgal, Alexandre Betourne, Dan Wang, Jill L. Ostrem, Jennifer S. Yokoyama, Arturo J. Moreno, Jonathan Lin, and Nijee Luthra

Subjects
Genetically modified mouse, medicine.medical_specialty, Parkinson's disease, business.industry, media_common.quotation_subject, Longevity, Cognition, urologic and male genital diseases, medicine.disease, female genital diseases and pregnancy complications, Endocrinology, Internal medicine, medicine, business, Klotho, media_common
Abstract

Aging is the primary risk factor for Parkinson’s disease (PD) and cognitive impairment from PD is a major and unmet biomedical challenge. Klotho, a pleiotropic protein, extends lifespan and enhances cognition. Whether longevity factors such as klotho can counteract PD-related mortality and deficits in mice or associate with resistance to PD in humans is unknown. Here we show that transgenic elevation of klotho increased lifespan, improved synaptic and cognitive, but not motor, functions in mice, and decreased steady state α-synuclein levels in the brains of mice that express wildtype human α-synuclein. In humans, a genetic variant of KLOTHO that increases circulating klotho levels associated with better executive cognition and less CSF abnormalities of α-synuclein in individuals with PD. Thus, klotho can counteract cognitive deficits related to PD, possibly modulating α-synuclein levels – and these findings may be relevant to new therapeutic pathways for human PD.

Published
2020
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9. Prospective Home-use Study on Non-invasive Neuromodulation Therapy for Essential Tremor

Author

Nicole Calakos, Lan Luo, Rohit Dhall, Holly A. Shill, Olga Waln, Paula Chidester, Mark Hallett, Michael J. Soileau, Adam Simmons, Brian N. Maddux, Peter A LeWitt, Rajesh Pahwa, Nijee Luthra, Melita T. Petrossian, Rajeev Kumar, John C. Morgan, Pravin Khemani, Cameron Dietiker, Christopher Way, Kathryn H. Rosenbluth, Ejaz A. Shamim, Scott L. Delp, Stuart Isaacson, Fernando Pagan, Apoorva Rajagopal, Mark F. Lew, Nabila Dahodwala, Theresa A. Zesiewicz, William G. Ondo, Jessica Tate, Elizabeth Peckham, Winona Tse, and Pinky Agarwal

Subjects
Adult, Male, medicine.medical_specialty, Activities of daily living, Essential Tremor, non-invasive, Electric Stimulation Therapy, Wrist, stimulation, Article, Young Adult, Quality of life, Outcome Assessment, Health Care, medicine, Humans, Prospective Studies, Adverse effect, Prospective cohort study, Aged, Aged, 80 and over, clinical trials, Essential tremor, business.industry, Middle Aged, medicine.disease, Hand, tremor, Neuromodulation (medicine), Median Nerve, Clinical trial, medicine.anatomical_structure, neuromodulation, Physical therapy, Female, Radial Nerve, business
Abstract

Highlights This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction and improves quality of life for many essential tremor patients. Background: Two previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. This current study evaluated efficacy and safety of the therapy over three months of repeated home use. Methods: This was a prospective, open-label, post-clearance, single-arm study with 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice daily for three months. Pre-specified co-primary endpoints were improvements on clinician-rated Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and patient-rated Bain & Findley Activities of Daily Living (BF-ADL) dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, Clinical and Patient Global Impression scores (CGI-I, PGI-I), and Quality of Life in Essential Tremor (QUEST) survey. Results: 205 patients completed the study. The co-primary endpoints were met (p≪0.0001), with 62% (TETRAS) and 68% (BF-ADL) of ‘severe’ or ‘moderate’ patients improving to ‘mild’ or ‘slight’. Clinicians (CGI-I) reported improvement in 68% of patients, 60% (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92% of patients improved, and 54% of patients experienced ≥50% improvement in tremor power. Device-related adverse events (e.g., wrist discomfort, skin irritation, pain) occurred in 18% of patients. No device-related serious adverse events were reported. Discussion: This study suggests that non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction in many essential tremor patients.

Published
2020

10. An Acute Randomized Controlled Trial of Noninvasive Peripheral Nerve Stimulation in Essential Tremor

Author

Rohit Dhall, Rajesh Pahwa, Nijee Luthra, Paula Chidester, Samuel Richard Hamner, Scott L. Delp, Kelly E. Lyons, Ryder P. Gwinn, Jill L. Ostrem, Susie Ro, Cameron Dietiker, and Erika K. Ross

Subjects
Male, Movement disorders, medicine.medical_treatment, Essential Tremor, Stimulation, law.invention, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Randomized controlled trial, law, Activities of Daily Living, medicine, Clinical endpoint, Humans, Clinical Trials, Peripheral Nerves, Neurostimulation, Aged, Aged, 80 and over, Essential tremor, business.industry, Archimedean spiral, General Medicine, Middle Aged, Wrist, medicine.disease, tremor, 3. Good health, Editor's Choice, Anesthesiology and Pain Medicine, medicine.anatomical_structure, Neurology, PERIPHERAL NERVE STIMULATION, Anesthesia, symbols, Transcutaneous Electric Nerve Stimulation, Upper limb, movement disorders, noninvasive stimulation, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, neurostimulation
Abstract

OBJECTIVE To evaluate the safety and effectiveness of a wrist-worn peripheral nerve stimulation device in patients with essential tremor (ET) in a single in-office session. METHODS This was a randomized controlled study of 77 ET patients who received either treatment stimulation (N = 40) or sham stimulation (N = 37) on the wrist of the hand with more severe tremor. Tremor was evaluated before and immediately after the end of a single 40-minute stimulation session. The primary endpoint compared spiral drawing in the stimulated hand using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) Archimedes spiral scores in treatment and sham groups. Additional endpoints included TETRAS upper limb tremor scores, subject-rated tasks from the Bain and Findley activities of daily living (ADL) scale before and after stimulation as well as clinical global impression-improvement (CGI-I) rating after stimulation. RESULTS Subjects who received peripheral nerve stimulation did not show significantly larger improvement in the Archimedes spiral task compared to sham but did show significantly greater improvement in upper limb TETRAS tremor scores (p = 0.017) compared to sham. Subject-rated improvements in ADLs were significantly greater with treatment (49% reduction) than with sham (27% reduction; p = 0.001). A greater percentage of ET patients (88%) reported improvement in the stimulation group as compared to the sham group (62%) according to CGI-I ratings (p = 0.019). No significant adverse events were reported; 3% of subjects experienced mild adverse events. CONCLUSIONS Peripheral nerve stimulation in ET may provide a safe, well-tolerated, and effective treatment for transient relief of hand tremor symptoms.

Published
2018

11. Factors Influencing the Management of Unruptured Intracranial Aneurysms

Author

Thomas C. Origitano, Katherine M Podraza, Nijee Luthra, Michael J. Schneck, and Rebecca L. Gillani

Subjects
medicine.medical_specialty, Subarachnoid hemorrhage, subarachnoid hemorrhage, Psychological intervention, Neurosurgery, decision making, 03 medical and health sciences, 0302 clinical medicine, Aneurysm, Chart review, Intervention (counseling), medicine, 030212 general & internal medicine, cardiovascular diseases, Multiple aneurysms, Intensive care medicine, business.industry, General Engineering, medicine.disease, Natural history, cerebral aneurysm, Neurology, unruptured intracranial aneurysm, cardiovascular system, Medical emergency, Decision process, business, 030217 neurology & neurosurgery
Abstract

Background Deciding how to manage an unruptured intracranial aneurysm can be difficult for patients and physicians due to controversies about management. The decision as to when and how to intervene may be variable depending on physicians' interpretation of available data regarding natural history and morbidity and mortality of interventions. Another significant factor in the decision process is the patients' conception of the risks of rupture and interventions and the psychological burden of harboring an unruptured intracranial aneurysm. Objective To describe which factors are being considered when patients and their physicians decide how to manage unruptured intracranial aneurysms. Materials & methods In a retrospective chart review study, we identified patients seen for evaluation of an unruptured intracranial aneurysm. Data was collected regarding patient and aneurysm characteristics. The physician note pertaining to the management decision was reviewed for documented reasons for intervention. Results Of 88 patients included, 36 (41%) decided to undergo open or endovascular surgery for at least one unruptured intracranial aneurysm. Multiple aneurysms were present in 14 (16%) patients. Younger patients and current smokers were more likely to undergo surgery, but gender and race did not affect management. Aneurysm size and location strongly influenced management. The most common documented reasons underlying the decision of whether to intervene were the risk of rupture, aneurysm size, and risks of the procedure. For 23 aneurysms (21%), there were no factors documented for the management decision. Conclusion The risk of rupture of unruptured intracranial aneurysms may be underestimated by currently available natural history data. Major factors weighed by physicians in management decisions include aneurysm size and location, the patient's age, and medical comorbidities along with the risk of procedural complications. Additional data is needed to define specific aneurysm characteristics and patient factors that influence rupture, in particular in small aneurysms. Physicians should carefully document their rationale along with the patient's perspective given the controversial nature of these management decisions.

Published
2016

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