65 results on '"Wills AM"'
Search Results
2. Paraoxonase 1 (PON1) organophosphate hydrolysis is not reduced in ALS.
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Wills AM, Landers JE, Zhang H, Richter RJ, Caraganis AJ, Cudkowicz ME, Furlong CE, and Brown RH Jr
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- 2008
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3. Pacemaker-induced tachycardia caused by inappropriate response to parkinsonian tremor.
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Wills AM, Plante DT, Dukkipati SR, Corcoran CP, and Standaert DG
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- 2005
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4. Recent methods for polygenic analysis of genome-wide data implicate an important effect of common variants on cardiovascular disease risk
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Wills Amanda G, Simonson Matthew A, Keller Matthew C, and McQueen Matthew B
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Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Traditional genome-wide association studies are generally limited in their ability explain a large portion of genetic risk for most common diseases. We sought to use both traditional GWAS methods, as well as more recently developed polygenic genome-wide analysis techniques to identify subsets of single-nucleotide polymorphisms (SNPs) that may be involved in risk of cardiovascular disease, as well as estimate the heritability explained by common SNPs. Methods Using data from the Framingham SNP Health Association Resource (SHARe), three complimentary methods were applied to examine the genetic factors associated with the Framingham Risk Score, a widely accepted indicator of underlying cardiovascular disease risk. The first method adopted a traditional GWAS approach - independently testing each SNP for association with the Framingham Risk Score. The second two approaches involved polygenic methods with the intention of providing estimates of aggregate genetic risk and heritability. Results While no SNPs were independently associated with the Framingham Risk Score based on the results of the traditional GWAS analysis, we were able to identify cardiovascular disease-related SNPs as reported by previous studies. A predictive polygenic analysis was only able to explain approximately 1% of the genetic variance when predicting the 10-year risk of general cardiovascular disease. However, 20% to 30% of the variation in the Framingham Risk Score was explained using a recently developed method that considers the joint effect of all SNPs simultaneously. Conclusion The results of this study imply that common SNPs explain a large amount of the variation in the Framingham Risk Score and suggest that future, better-powered genome-wide association studies, possibly informed by knowledge of gene-pathways, will uncover more risk variants that will help to elucidate the genetic architecture of cardiovascular disease.
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- 2011
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5. Parkinson's disease variant detection and disclosure: PD GENEration, a North American study.
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Cook L, Verbrugge J, Schwantes-An TH, Schulze J, Foroud T, Hall A, Marder KS, Mata IF, Mencacci NE, Nance MA, Schwarzschild MA, Simuni T, Bressman S, Wills AM, Fernandez HH, Litvan I, Lyons KE, Shill HA, Singer C, Tropea TF, Vanegas Arroyave N, Carbonell J, Cruz Vicioso R, Katus L, Quinn JF, Hodges PD, Meng Y, Strom SP, Blauwendraat C, Lohmann K, Casaceli C, Rao SC, Ghosh Galvelis K, Naito A, Beck JC, and Alcalay RN
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- Humans, Male, Female, Aged, Middle Aged, Ubiquitin-Protein Ligases genetics, Protein Kinases genetics, Protein Deglycase DJ-1 genetics, Vesicular Transport Proteins genetics, North America, Genetic Variation genetics, Genetic Predisposition to Disease genetics, Adult, Disclosure, Genetic Counseling, Canada, United States, Parkinson Disease genetics, Parkinson Disease diagnosis, Genetic Testing methods, Glucosylceramidase genetics, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics, alpha-Synuclein genetics
- Abstract
Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson's disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more 'high risk factors' for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson's disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson's disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2024
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6. Steroid-Responsive Parkinsonism and Encephalopathy: A Case Report.
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Tofade TO, Harrold GK, Laud A, Wills AM, and Venna N
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We describe a patient who presented with rapidly progressive parkinsonism and encephalopathy and was diagnosed with seronegative autoimmune encephalitis (AE). Subacute parkinsonism as a manifestation of seronegative AE is uncommon with only a handful of similar cases published in literature. A 71-year-old man presented with severe flu like symptoms, rapidly progressive cognitive decline and was found to have parkinsonian features on examination. Initial brain magnetic resonance imaging (MRI) was unremarkable however, cerebrospinal fluid (CSF) analysis revealed a lymphocytic pleocytosis and elevated protein level. Thorough searches for neural antibodies and infectious pathogens were negative. His symptoms fluctuated initially but markedly improved within days of starting prednisone and dramatically worsened after prednisone was tapered off. His CSF pleocytosis also improved on prednisone. Relapses again resolved with resumption of prednisone. The scope of autoimmune neurology Is constantly evolving, and physicians should be aware of the diverse and heterogenous clinical presentations of autoimmune encephalitis. We aim to emphasize the importance of ruling out autoimmune encephalitis in patients presenting with acute or subacute parkinsonism. This case additionally reinforces that negative antibody tests do not exclude the diagnosis of AE., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)
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- 2024
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7. Concomitant Medications for Progressive Supranuclear Palsy: A Secondary Analysis of a Randomized Clinical Trial.
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Iyer JM, Gunzler D, Lang AE, Golbe LI, Pantelyat A, Boxer AL, and Wills AM
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- Humans, Disease Progression, Diagnosis, Differential, Supranuclear Palsy, Progressive drug therapy, Supranuclear Palsy, Progressive diagnosis
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- 2024
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8. Correction to: Clinical trial-ready patient cohorts for multiple system atrophy: coupling biospecimen and iPSC banking to longitudinal deep-phenotyping.
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Ndayisaba A, Pitaro AT, Willett AS, Jones KA, de Gusmao CM, Olsen AL, Kim J, Rissanen E, Woods JK, Srinivasan SR, Nagy A, Nagy A, Mesidor M, Cicero S, Patel V, Oakley DH, Tuncali I, Taglieri-Noble K, Clark EC, Paulson J, Krolewski RC, Ho GP, Hung AY, Wills AM, Hayes MT, Macmore JP, Warren L, Bower PG, Langer CB, Kellerman LR, Humphreys CW, Glanz BI, Dielubanza EJ, Frosch MP, Freeman RL, Gibbons CH, Stefanova N, Chitnis T, Weiner HL, Scherzer CR, Scholz SW, Vuzman D, Cox LM, Wenning G, Schmahmann JD, Gupta AS, Novak P, Young GS, Feany MB, Singhal T, and Khurana V
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- 2024
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9. Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.
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Ndayisaba A, Pitaro AT, Willett AS, Jones KA, de Gusmao CM, Olsen AL, Kim J, Rissanen E, Woods JK, Srinivasan SR, Nagy A, Nagy A, Mesidor M, Cicero S, Patel V, Oakley DH, Tuncali I, Taglieri-Noble K, Clark EC, Paulson J, Krolewski RC, Ho GP, Hung AY, Wills AM, Hayes MT, Macmore JP, Warren L, Bower PG, Langer CB, Kellerman LR, Humphreys CW, Glanz BI, Dielubanza EJ, Frosch MP, Freeman RL, Gibbons CH, Stefanova N, Chitnis T, Weiner HL, Scherzer CR, Scholz SW, Vuzman D, Cox LM, Wenning G, Schmahmann JD, Gupta AS, Novak P, Young GS, Feany MB, Singhal T, and Khurana V
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- Animals, Humans, alpha-Synuclein genetics, alpha-Synuclein metabolism, Brain, Receptors, GABA metabolism, Multiple System Atrophy diagnostic imaging, Multiple System Atrophy genetics, Multiple System Atrophy therapy, Induced Pluripotent Stem Cells, Parkinson Disease pathology
- Abstract
Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA., (© 2022. The Author(s).)
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- 2024
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10. Remote at-home wearable-based gait assessments in Progressive Supranuclear Palsy compared to Parkinson's Disease.
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Sharma M, Mishra RK, Hall AJ, Casado J, Cole R, Nunes AS, Barchard G, Vaziri A, Pantelyat A, and Wills AM
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- Aged, Female, Humans, Male, Gait, Postural Balance, Parkinson Disease diagnosis, Supranuclear Palsy, Progressive diagnosis, Wearable Electronic Devices
- Abstract
Background: Wearable sensors can differentiate Progressive Supranuclear Palsy (PSP) from Parkinson's Disease (PD) in laboratory settings but have not been tested in remote settings., Objectives: To compare gait and balance in PSP and PD remotely using wearable-based assessments., Methods: Participants with probable PSP or probable/clinically established PD with reliable caregivers, still able to ambulate 10 feet unassisted, were recruited, enrolled, and consented remotely and instructed by video conference to operate a study-specific tablet solution (BioDigit Home ™) and to wear three inertial sensors (LEGSys™, BioSensics LLC, Newton, MA USA) while performing the Timed Up and Go, 5 × sit-to-stand, and 2-min walk tests. PSPRS and MDS-UPDRS scores were collected virtually or during routine clinical visits., Results: Between November, 2021- November, 2022, 27 participants were screened of whom 3 were excluded because of technological difficulties. Eleven PSP and 12 PD participants enrolled, of whom 10 from each group had complete analyzable data. Demographics were well-matched (PSP mean age = 67.6 ± 1.3 years, 40% female; PD mean age = 70.3 ± 1.8 years, 40% female) while disease duration was significantly shorter in PSP (PSP 14 ± 3.5 months vs PD 87.9 ± 16.9 months). Gait parameters showed significant group differences with effect sizes ranging from d = 1.0 to 2.27. Gait speed was significantly slower in PSP: 0.45 ± 0.06 m/s vs. 0.79 ± 0.06 m/s in PD (d = 1.78, p < 0.001)., Conclusion: Our study demonstrates the feasibility of measuring gait in PSP and PD remotely using wearable sensors. The study provides insight into digital biomarkers for both neurodegenerative diseases., Trial Registration: ClinicalTrials.gov Identifier: NCT04753320, first posted Febuary 15, 2021., (© 2023. The Author(s).)
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- 2023
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11. Utilizing speech analysis to differentiate progressive supranuclear palsy from Parkinson's disease.
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Kang K, Nunes AS, Sharma M, Hall AJ, Mishra RK, Casado J, Cole R, Derhammer M, Barchard G, Najafi B, Vaziri A, Wills AM, and Pantelyat A
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- Humans, Speech, Dysarthria diagnosis, Dysarthria etiology, Sensitivity and Specificity, Parkinson Disease complications, Parkinson Disease diagnosis, Supranuclear Palsy, Progressive diagnosis
- Abstract
Introduction: Distinguishing Parkinson's disease (PD) from Progressive supranuclear palsy (PSP) at early disease stages is important for clinical trial enrollment and clinical care/prognostication., Methods: We recruited 21 participants with PSP(n = 11) or PD(n = 10) with reliable caregivers. Standardized passage reading, counting, and sustained phonation were recorded on the BioDigit Home tablet (BioSensics LLC, Newton, MA USA), and speech features from the assessments were analyzed using the BioDigit Speech platform (BioSensics LLC, Newton, MA USA). An independent t-test was performed to compare each speech feature between PSP and PD participants. We also performed Spearman's correlations to evaluate associations between speech measures and clinical scores (e.g., PSP rating scales and MoCA). In addition, the model's performance in classifying PSP and PD was evaluated using Rainbow passage reading analysis., Results: During Rainbow passage reading, PSP participants had a significantly slower articulation rate (2.45(0.49) vs 3.60(0.47) words/minute), lower speech-to-pause ratio (2.33(1.08) vs 3.67(1.18)), intelligibility dynamic time warping (DTW, 0.26(0.19) vs 0.53(0.26)), and similarity DTW (0.43(0.27) vs 0.67(0.13)) compared to PD participants. PSP participants also had longer pause times (17.24(5.47) vs 8.45(3.13) sec) and longer total signal times (52.44(6.67) vs (36.67(6.73) sec) when reading the passage. In terms of the phonation 'a', PSP participants showed a significant higher spectral entropy, spectral centroid, and spectral spread compared to PD participants and no differences were found for phonation 'e'. PD participants had more accurate reverse number counts than PSP participants (14.89(3.86) vs 7.36(4.67)). PSP Rating Scale (PSPRS) dysarthria (r = 0.79, p = 0.004) and bulbar item scores (r = 0.803, p = 0.005) were positively correlated with articulation rate in reverse number counts. Correct reverse number counts were positively correlated with total Montreal Cognitive Assessment scores (r = 0.703, p = 0.016). Machine learning models using passage reading-derived measures obtained an AUC of 0.93, and the sensitivity/specificity in correctly classifying PSP and PD participants were 0.95 and 0.90, respectively., Conclusion: Our study demonstrates the feasibility of differentiating PSP from PD using a digital health technology platform. Further multi-center studies are needed to expand and validate our initial findings., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ram Kinker Mishra, Jose Casado, Rylee Cole, Adonay S. Nunes, Marc Derhammer, Gregory Barchard and Ashkan Vaziri are employees of BioSensics LLC. Bijan Najafi, a co-author of this paper, serves as a consultant for BioSensics LLC. However, he did not participate in patient recruitment, and his contribution to the study was limited to interpreting data and providing guidance on data analysis. Anne-Marie Wills has research funding from NIA/NIHSBIR Award R44AG080861, from the Parkinson's Foundation, has participated in clinical trials funded by Sanofi/Genzyme, Roche/Genentech, Biogen/Denali, Bial, Transposon therapeutics and received consultant payments from Accordant, CVS/Caremark, Genentech, Amylyx Pharmaceuticals and Ono Pharmaceutical. Alexander Pantelyat serves as a consultant for MedRhythms, Inc, Ono Pharma and Ferrer. He receives research funding from the National Institutes of Health (NINDS U01 NS102035; NIA K23 AG059891)., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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12. Providing genetic testing and genetic counseling for Parkinson's disease to the community.
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Cook L, Verbrugge J, Schwantes-An TH, Schulze J, Beck JC, Naito A, Hall A, Chan AK, Casaceli CJ, Marder K, Nance M, Schwarzschild MA, Simuni T, Wills AM, and Alcalay RN
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- Humans, Pilot Projects, Genetic Testing methods, Alleles, Genetic Counseling methods, Parkinson Disease diagnosis, Parkinson Disease genetics
- Abstract
Purpose: To evaluate the feasibility and impact of offering genetic testing and counseling to patients with Parkinson's disease (PD), with the potential to enroll in gene-targeted clinical trials and improve clinical care., Methods: A multicenter, exploratory pilot study at 7 academic hospital sites in the United States tracked enrollment and randomized participants to receive results and genetic counseling at local sites or by genetic counselors, remotely. Follow-up surveys measured participant/provider satisfaction, knowledge, and psychological impact., Results: From September 5, 2019 to January 4, 2021, 620 participants were enrolled and 387 completed outcome surveys. There were no significant differences in outcomes between local and remote sites, with both arms reporting high knowledge and satisfaction scores (>80%). Notably, 16% of those tested had reportable PD gene variants (pathogenic/likely pathogenic/risk allele)., Conclusion: Local clinicians, as well as genetic counselors, with educational support as needed, can effectively return genetic results for PD as we observed favorable outcome measures in both groups. Increasing access to PD genetic testing and counseling is urgent; this can inform future efforts to integrate genetic testing and counseling into clinical care for all those with PD., Competing Interests: Conflict of Interest Lola Cook received partial funding of salaries from the Michael J. Fox Foundation (MJFF) and Parkinson’s Foundation; Jennifer Verbrugge received partial funding of salaries from the Michael J. Fox Foundation (MJFF) and Parkinson’s Foundation and received travel funding for Movement Disorders Society International Congress, Madrid, Spain September 2022, abstract and poster presentation PD GENEration Clinical Phase: Genetic Diagnostic Yield and Clinical Characteristics by the Parkinson’s Foundation and paid to Indiana University School of Medicine; Tae-Hwi Schwantes-An, no disclosures; Jeanine Schulze received partial funding of salaries from the MJFF and Parkinson’s Foundation; James C. Beck is employed by the Parkinson’s Foundation, and receives funding for grants through their institution from NIH; Anna Naito is employed by the Parkinson’s Foundation; Anne Hall is a research advocate and received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member; Amanda K. Chan, no disclosures; Cynthia J. Casaceli, no disclosures; Karen Marder received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, receives funding of grants from NIH, MJ FOX, CHDI, HSG, HDSA, Prilenia, Novartis, Roche, Springer, receives consulting fees from Novartis, and receives funding for leadership on Enroll HD Oversight Committee (CHDI) and HSG steering committee; Martha Nance received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, received payment for presentation at Parkinson’s Foundation and Parkinson Study Group conferences, received support for attending Parkinson Study Group conference, and is the Chair of Genetics and Environment Working Group for Parkinson Study Group; Michael A. Schwarzschild received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, receives funding of grants or conference support from NIH, MJFF, Farmer Family Foundation, Sergey Brin Family Foundation, American Parkinson’s Disease Association, Cure Parkinson’s, Parkinson’s Foundation, Harvard School of Public Health (NIH, DoD), GSK, GE Healthcare, receives consulting fees through Parkinson Study Group for PSG advisory services (including to Bial, Biogen [LUMA/LIGHTHOUSE trials global SC], UCB [ORHCESTRA trial PSG SC]) and through Sutter Health (NIA), Northwestern Univ (NINDS), Cure Parkinson’s for Steering Committee services (for TOPAZ and SPARX3), International Linked Clinical Trial Committee (CP), participates on an Alzheimer’s drug trial Data Monitoring Committee services for Eli Lilly & Co., and is Chair, Exec. Committee for Parkinson Study Group; Tanya Simuni received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, receives funding of manuscript by MJFF for Parkinson’s Research, receives funding of grants by Amneal, Biogen, Roche, Neuroderm, Sanofi, Prevail and UCB, is an investigator for NINDS, MJFF, Parkinson’s Foundation studies, receives consulting fees from 4D Pharma, Acadia, AcureX, AskBio, Amneal, Blue Rock Therapeutics, Caraway Therapeutics, Critical Path for Parkinson's Consortium (CPP), Denali, MJFF, Neuroderm, Sanofi, Sinopia, Sunovion, Roche, Takeda, UCB, Vanqua Bio and Voyager, and is on the advisory board for Acadia, AcureX, AskBio, Amneal, Denali, Sunovion, Roche, and on the Scientific Advisory Board for 4D Pharma, Neuroderm, Sanofi and UCB; Anne-Marie Wills received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, and receives funding of grants by NIA/NIH, Roche/Genentech, Biogen, and their institution participates on Data Safety Monitoring Board or Advisory Board for Ono Pharmaceuticals and Amylyx Pharmaceuticals; Roy N. Alcalay received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, receives funding from NIH, Department of Defense, MJFF, the Silverstein Foundation for GBA/PD and received consulting fees from Sanofi, Ono Therapeutics, Avrobio, Takeda, Gain Therapeutics, Merck, GSK, Caraway., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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13. Randomized trial of inosine for urate elevation in amyotrophic lateral sclerosis.
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Walk D, Nicholson K, Locatelli E, Chan J, Macklin EA, Ferment V, Manousakis G, Chase M, Connolly M, Dagostino D, Hall M, Ostrow J, Pothier L, Lieberman C, Gelevski D, Randall R, Sherman AV, Steinhart E, Walker DG, Walker J, Yu H, Wills AM, Schwarzschild MA, Beukenhorst AL, Onnela JP, Berry JD, Cudkowicz ME, and Paganoni S
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- Humans, Uric Acid, Retrospective Studies, Inosine therapeutic use, Double-Blind Method, Amyotrophic Lateral Sclerosis drug therapy
- Abstract
Introduction/aims: Higher urate levels are associated with improved ALS survival in retrospective studies, however whether raising urate levels confers a survival advantage is unknown. In the Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (SURE-ALS) trial, inosine raised serum urate and was safe and well-tolerated. The SURE-ALS2 trial was designed to assess longer term safety. Functional outcomes and a smartphone application were also explored., Methods: Participants were randomized 2:1 to inosine (n = 14) or placebo (n = 9) for 20 weeks, titrated to serum urate of 7-8 mg/dL. Primary outcomes were safety and tolerability. Functional outcomes were measured with the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). Mobility and ALSFRS-R were also assessed by a smartphone application., Results: During inosine treatment, mean urate ranged 5.68-6.82 mg/dL. Treatment-emergent adverse event (TEAE) incidence was similar between groups (p > .10). Renal TEAEs occurred in three (21%) and hypertension in one (7%) of participants randomized to inosine. Inosine was tolerated in 71% of participants versus placebo 67%. Two participants (14%) in the inosine group experienced TEAEs deemed related to treatment (nephrolithiasis); one was a severe adverse event. Mean ALSFRS-R decline did not differ between groups (p = .69). Change in measured home time was similar between groups. Digital and in-clinic ALSFRS-R correlated well., Discussion: Inosine met pre-specified criteria for safety and tolerability. A functional benefit was not demonstrated in this trial designed for safety and tolerability. Findings suggested potential utility for a smartphone application in ALS clinical and research settings., (© 2023 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)
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- 2023
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14. Using Downgaze Palsy Progression Rate to Model Survival in Progressive Supranuclear Palsy-Richardson Syndrome.
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Xie T, Wills AM, Liao C, Dale ML, Ramsden DB, Padmanaban M, Abou Chaar W, Pantelyat A, and Golbe LI
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- Humans, Disease Progression, Supranuclear Palsy, Progressive diagnosis, Movement Disorders complications, Deglutition Disorders
- Abstract
Background: Rapid development of downgaze palsy, the most specific symptom of progressive supranuclear palsy (PSP), has been associated with shorter survival in small studies., Objective: We hypothesized that the progression rate of downgaze palsy and other disease features could predict survival if assessed soon after the onset of downgaze palsy in a large data set., Methods: We used a longitudinal database of 414 patients with probable PSP-Richardson syndrome from 1994 to 2020. The data set comprised demographics and, for each visit, 28 PSP Rating Scale (PSPRS) items and PSP stage scores. We calculated the rate of progression of each PSPRS item as its item score when the downgaze item first reached 1 or more (on a 0-4 scale) divided by disease duration at that point. Multivariate Cox regression was applied to identify variables independently associated with survival. We also explored the progression pattern of total PSPRS and downgaze palsy scores with disease course., Results: Independently associated with shorter survival were older onset age and faster progression of downgaze palsy, dysphagia for liquids, difficulty in returning to seat, and PSP stage. Patients with survival duration within 1 year of the median survival (6.58 years) showed approximately linear progression of the PSPRS score and downgaze palsy score during years 2 through 6 of the disease course., Conclusions: Older onset age and faster progression of downgaze palsy and several axial features are associated with shorter survival. The disease typically progresses in approximately linear fashion during years 2 through 6. These results may aid study design and patient counseling. © 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.)
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- 2023
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15. ALSUntangled #63: ketogenic diets.
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Bedlack R, Barkhaus PE, Barnes B, Beauchamp M, Bertorini T, Bromberg MB, Carter GT, Chaudry V, Cudkowicz M, Jackson C, Levitsky G, Lund I, McDermott C, Novella S, Olby N, Ostrow L, Pattee GL, Heiman-Patterson T, Ratner D, Salmon K, Steves S, Terrelonge M, Wicks P, and Wills AM
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- Animals, Humans, Mice, Disease Models, Animal, Amyotrophic Lateral Sclerosis diet therapy, Diet, Ketogenic
- Abstract
ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.
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- 2023
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16. Mitochondrial haplogroups and cognitive progression in Parkinson's disease.
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Liu G, Ni C, Zhan J, Li W, Luo J, Liao Z, Locascio JJ, Xian W, Chen L, Pei Z, Corvol JC, Maple-Grødem J, Campbell MC, Elbaz A, Lesage S, Brice A, Hung AY, Schwarzschild MA, Hayes MT, Wills AM, Ravina B, Shoulson I, Taba P, Kõks S, Beach TG, Cormier-Dequaire F, Alves G, Tysnes OB, Perlmutter JS, Heutink P, van Hilten JJ, Barker RA, Williams-Gray CH, and Scherzer CR
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- Humans, Haplotypes, Mitochondria genetics, DNA, Mitochondrial genetics, Disease Progression, Cognition, Parkinson Disease genetics, Parkinson Disease epidemiology
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Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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17. Recommendations for Virtual Administration of the PSP Rating Scale.
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Wills AM, Golbe LI, Lang AE, Xie T, Dale ML, Espay A, Tartaglia MC, Fox SH, Parashos SA, McFarland NR, Schneider RB, Rodriguez-Porcel F, Gunzler SA, and Pantelyat A
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- Humans, Psychiatric Status Rating Scales, Supranuclear Palsy, Progressive
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- 2022
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18. Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson's disease.
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Karayel O, Virreira Winter S, Padmanabhan S, Kuras YI, Vu DT, Tuncali I, Merchant K, Wills AM, Scherzer CR, and Mann M
- Subjects
- Biomarkers cerebrospinal fluid, Heterozygote, Humans, Proteome metabolism, Proteomics methods, Parkinson Disease diagnosis
- Abstract
Parkinson's disease (PD) is a growing burden worldwide, and there is no reliable biomarker used in clinical routines to date. Cerebrospinal fluid (CSF) is routinely collected in patients with neurological symptoms and should closely reflect alterations in PD patients' brains. Here, we describe a scalable and sensitive mass spectrometry (MS)-based proteomics workflow for CSF proteome profiling. From two independent cohorts with over 200 individuals, our workflow reproducibly quantifies over 1,700 proteins from minimal CSF amounts. Machine learning determines OMD, CD44, VGF, PRL, and MAN2B1 to be altered in PD patients or to significantly correlate with clinical scores. We also uncover signatures of enhanced neuroinflammation in LRRK2 G2019S carriers, as indicated by increased levels of CTSS, PLD4, and HLA proteins. A comparison with our previously acquired urinary proteomes reveals a large overlap in PD-associated changes, including lysosomal proteins, opening up new avenues to improve our understanding of PD pathogenesis., Competing Interests: Declaration of interests The authors declare no conflicts of interest related to this work., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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19. A Modified Progressive Supranuclear Palsy Rating Scale for Virtual Assessments.
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Wills AM, Pantelyat A, Espay A, Chan J, Litvan I, Xie T, Dale ML, Gunzler SA, Tartaglia MC, Fox SH, Rodriguez-Porcel F, Sharma M, Lang AE, Boxer AL, and Golbe LI
- Subjects
- Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Humans, Reproducibility of Results, Supranuclear Palsy, Progressive diagnosis
- Abstract
Background: The reliability of the Progressive Supranuclear Palsy Rating Scale (PSPRS) using teleneurology has not been assessed., Objectives: To test whether removing items inadequately assessed by video would impact measurement of PSP severity and progression., Methods: We performed secondary analyses of two data sets: the phase 2/3 trial of Davunetide in PSP and a large single-center cohort. We examined two modifications of the PSPRS: (1) removing neck rigidity, limb rigidity, and postural stability (25 items; mPSPRS-25) and (2) also removing three ocular motor items and limb dystonia (21 items; mPSPRS-21). Proportional agreement relative to the possible total scores was measured using the intraclass correlation coefficient, compared to the original PSPRS baseline values and change over 6 and 12 months. We examined the ability of both scales to predict survival in the single-center cohort using proportional hazards models., Results: The mPSPRS-25 showed excellent agreement (0.99; P < 0.001) with the original PSPRS at baseline, 0.98 (P < 0.001) agreement in measuring change over 6 months, and 0.98 (P < 0.001) over 12 months. The mPSPRS-21 showed agreement of 0.94 (P < 0.001) with the original PSPRS at baseline, 0.92 (P < 0.001) at 6 months, and 0.95 (P < 0.001) at 12 months. Baseline and 6-month change in both modified scales were highly predictive of survival in the single-center cohort., Conclusions: Modified versions of the PSPRS which can be administered remotely show excellent agreement with the original scale and predict survival in PSP. The mPSPRS-21 should facilitate clinical care and research in PSP via teleneurology. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)
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- 2022
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20. Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.
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Liu G, Peng J, Liao Z, Locascio JJ, Corvol JC, Zhu F, Dong X, Maple-Grødem J, Campbell MC, Elbaz A, Lesage S, Brice A, Mangone G, Growdon JH, Hung AY, Schwarzschild MA, Hayes MT, Wills AM, Herrington TM, Ravina B, Shoulson I, Taba P, Kõks S, Beach TG, Cormier-Dequaire F, Alves G, Tysnes OB, Perlmutter JS, Heutink P, Amr SS, van Hilten JJ, Kasten M, Mollenhauer B, Trenkwalder C, Klein C, Barker RA, Williams-Gray CH, Marinus J, and Scherzer CR
- Subjects
- Apolipoprotein E4 genetics, Cognition Disorders genetics, Genetic Predisposition to Disease, Glucosylceramidase genetics, Humans, Longitudinal Studies, Mutation genetics, Parkinson Disease physiopathology, Proportional Hazards Models, Risk Factors, Survival Analysis, Cognition, Disease Progression, Genetic Loci, Genome-Wide Association Study, Multifactorial Inheritance genetics, Parkinson Disease genetics, Parkinson Disease pathology, Synapses genetics
- Abstract
A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10
-11 ), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10-8 ) and WWOX (HR = 2.12, P = 2.37 × 10-8 ) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.- Published
- 2021
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21. Accelerating diagnosis of Parkinson's disease through risk prediction.
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Yuan W, Beaulieu-Jones B, Krolewski R, Palmer N, Veyrat-Follet C, Frau F, Cohen C, Bozzi S, Cogswell M, Kumar D, Coulouvrat C, Leroy B, Fischer TZ, Sardi SP, Chandross KJ, Rubin LL, Wills AM, Kohane I, and Lipnick SL
- Subjects
- Gait physiology, Gait Analysis, Humans, Machine Learning, Retrospective Studies, Risk Assessment, Tremor, Parkinson Disease diagnosis
- Abstract
Background: Characterization of prediagnostic Parkinson's Disease (PD) and early prediction of subsequent development are critical for preventive interventions, risk stratification and understanding of disease pathology. This study aims to characterize the role of the prediagnostic period in PD and, using selected features from this period as novel interception points, construct a prediction model to accelerate the diagnosis in a real-world setting., Methods: We constructed two sets of machine learning models: a retrospective approach highlighting exposures up to 5 years prior to PD diagnosis, and an alternative model that prospectively predicted future PD diagnosis from all individuals at their first diagnosis of a gait or tremor disorder, these being features that appeared to represent the initiation of a differential diagnostic window., Results: We found many novel features captured by the retrospective models; however, the high accuracy was primarily driven from surrogate diagnoses for PD, such as gait and tremor disorders, suggesting the presence of a distinctive differential diagnostic period when the clinician already suspected PD. The model utilizing a gait/tremor diagnosis as the interception point, achieved a validation AUC of 0.874 with potential time compression to a future PD diagnosis of more than 300 days. Comparisons of predictive diagnoses between the prospective and prediagnostic cohorts suggest the presence of distinctive trajectories of PD progression based on comorbidity profiles., Conclusions: Overall, our machine learning approach allows for both guiding clinical decisions such as the initiation of neuroprotective interventions and importantly, the possibility of earlier diagnosis for clinical trials for disease modifying therapies.
- Published
- 2021
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22. Expediting telehealth use in clinical research studies: recommendations for overcoming barriers in North America.
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Naito A, Wills AM, Tropea TF, Ramirez-Zamora A, Hauser RA, Martino D, Turner TH, Rafferty MR, Afshari M, Williams KL, Vaou O, McKeown MJ, Ginsburg L, Ezra A, Iansek R, Wallock K, Evers C, Schroeder K, DeLeon R, Yarab N, Alcalay RN, and Beck JC
- Published
- 2021
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23. Implementation of high-cadence cycling for Parkinson's disease in the community setting: A pragmatic feasibility study.
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McKee KE, Johnson RK, Chan J, and Wills AM
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- Exercise, Exercise Therapy, Feasibility Studies, Humans, Pilot Projects, Parkinson Disease
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Background: Efficacy of exercise to improve motor symptoms in Parkinson's Disease (PD) has been established in multiple clinical trials. The Pedaling for Parkinson's ™ (PFP) program is an existing community-based cycling intervention for individuals with PD. Although PFP program design was informed by in-laboratory efficacy studies, the implementation and effectiveness of the program in the community have not been studied. This feasibility study explores implementation and effectiveness of PFP utilizing the RE-AIM implementation evaluation framework., Methods: This was a pragmatic open-label multi-site study. First, community-based gyms were recruited to implement the PFP protocol with enhanced multi-modal training and support. Second individuals with Hoehn and Yahr stage I-III idiopathic PD were recruited to participate. Reach, effectiveness (both clinical scores and participant enjoyment), adoption, implementation (gym and participant fidelity, cost), and maintenance (sustainability) were assessed. Tracking of adverse events was used to monitor safety of the intervention., Results: Reach was moderate: 59% of participants who expressed interest opted to participate. No effectiveness outcomes demonstrated a significant change from pre to post; however, the program was highly enjoyable (96% of participants who started classes enjoyed the program and 87% wished to continue). Adoption was poor with only four out of 34 gyms participating. The program had poor gym and moderate participant fidelity. The program was maintained for at least 4 months across all sites. The program was implemented safely., Conclusion: Barriers to implementation of nonpharmacologic interventions such as exercise protocols limit reach and availability of these interventions to patients. Pilot studies are needed to inform and direct further implementation efforts. Our pilot study suggests the PFP cycling intervention should be modified prior to attempts at widespread implementation. Modifications made by gyms in this study suggest adaptations to the protocol that may increase fidelity and effectiveness., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)
- Published
- 2021
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24. β-Glucocerebrosidase activity in GBA -linked Parkinson disease: The type of mutation matters.
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Huh YE, Chiang MSR, Locascio JJ, Liao Z, Liu G, Choudhury K, Kuras YI, Tuncali I, Videnovic A, Hunt AL, Schwarzschild MA, Hung AY, Herrington TM, Hayes MT, Hyman BT, Wills AM, Gomperts SN, Growdon JH, Sardi SP, and Scherzer CR
- Subjects
- Aged, Aged, 80 and over, Cognition Disorders etiology, Cross-Sectional Studies, Female, Follow-Up Studies, Genetic Association Studies, Glucosylceramidase blood, Humans, Male, Middle Aged, Neurologic Examination, Parkinson Disease enzymology, Parkinson Disease physiopathology, Parkinson Disease psychology, Quantitative Trait Loci, Severity of Illness Index, Glucosylceramidase genetics, Mutation, Parkinson Disease genetics
- Abstract
Objective: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and β-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies., Methods: A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants ( GBA -PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years)., Results: β-Glucocerebrosidase activity was low in blood of patients with GBA -PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS ( p < 0.001) and PDBP ( p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual β-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in β-glucocerebrosidase activity during a median 2 years of follow-up ( p = 0.02)., Conclusions: Residual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically., (© 2020 American Academy of Neurology.)
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- 2020
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25. Genetic testing for Parkinson disease: current practice, knowledge, and attitudes among US and Canadian movement disorders specialists.
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Alcalay RN, Kehoe C, Shorr E, Battista R, Hall A, Simuni T, Marder K, Wills AM, Naito A, Beck JC, Schwarzschild MA, and Nance M
- Subjects
- Attitude of Health Personnel, Canada epidemiology, Female, Genetic Counseling, Genetic Predisposition to Disease, Humans, Male, Mutation genetics, Parkinson Disease diagnosis, Parkinson Disease epidemiology, Precision Medicine standards, Surveys and Questionnaires, United States epidemiology, Genetic Testing standards, Glucosylceramidase genetics, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics, Parkinson Disease genetics
- Abstract
Purpose: Genetic testing for Parkinson disease (PD) has not been widely used in clinical practice. In preparation for upcoming precision medicine-designed clinical trials for GBA and LRRK2, we evaluated movement disorders specialists' current practice, knowledge, attitudes, and barriers to genetic testing in PD., Methods: An anonymous questionnaire was sent to movement disorders specialists at 146 Parkinson Study Group (PSG) sites in the United States (n = 131) and Canada (n = 15) to assess their knowledge and attitudes about genetic testing for PD., Results: One hundred seventy-eight (47.6%) PSG clinicians completed the questionnaire. Forty-one percent of respondents had not referred any PD patients for genetic testing in the last year and >80% reported referring fewer than 11 patients over the same period. Most common reasons for not referring for genetic testing included lack of insurance coverage/cost to the patient and lack of perceived utility. On a scale of 0-100, the mean level of comfort in respondents' own ability to genetically counsel PD patients on GBA and LRRK2 was 52 (SD = 28). Sixty percent of clinicians correctly answered all questions about the inheritance and penetrance of GBA and LRRK2 variants., Conclusions: There is an urgent need to increase knowledge and reduce practical barriers to genetic counseling and testing in PD.
- Published
- 2020
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26. Cerebrospinal fluid proteomics implicates the granin family in Parkinson's disease.
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Rotunno MS, Lane M, Zhang W, Wolf P, Oliva P, Viel C, Wills AM, Alcalay RN, Scherzer CR, Shihabuddin LS, Zhang K, and Sardi SP
- Subjects
- Aged, Biomarkers cerebrospinal fluid, Female, Humans, Male, Middle Aged, Proteomics, Tandem Mass Spectrometry, Chromogranins cerebrospinal fluid, Parkinson Disease cerebrospinal fluid
- Abstract
Parkinson's disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Better understanding of the underlying disease mechanism(s) is an urgent need for the development of disease-modifying therapeutics. Limited studies have been performed in large patient cohorts to identify protein alterations in cerebrospinal fluid (CSF), a proximal site to pathology. We set out to identify disease-relevant protein changes in CSF to gain insights into the etiology of Parkinson's disease and potentially assist in disease biomarker identification. In this study, we used liquid chromatography-tandem mass spectrometry in data-independent acquisition (DIA) mode to identify Parkinson's-relevant biomarkers in cerebrospinal fluid. We quantified 341 protein groups in two independent cohorts (n = 196) and a longitudinal cohort (n = 105 samples, representing 40 patients) consisting of Parkinson's disease and healthy control samples from three different sources. A first cohort of 53 Parkinson's disease and 72 control samples was analyzed, identifying 53 proteins with significant changes (p < 0.05) in Parkinson's disease relative to healthy control. We established a biomarker signature and multiple protein ratios that differentiate Parkinson's disease from healthy controls and validated these results in an independent cohort. The second cohort included 28 Parkinson's disease and 43 control samples. Independent analysis of these samples identified 41 proteins with significant changes. Evaluation of the overlapping changes between the two cohorts identified 13 proteins with consistent and significant changes (p < 0.05). Importantly, we found the extended granin family proteins as reduced in disease, suggesting a potential common mechanism for the biological reduction in monoamine neurotransmission in Parkinson's patients. Our study identifies several novel protein changes in Parkinson's disease cerebrospinal fluid that may be exploited for understanding etiology of disease and for biomarker development.
- Published
- 2020
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27. Correction: Genetic testing for Parkinson disease: current practice, knowledge, and attitudes among US and Canadian movement disorders specialists.
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Alcalay RN, Kehoe C, Shorr E, Battista R, Hall A, Simuni T, Marder K, Wills AM, Naito A, Beck JC, Schwarzschild MA, and Nance M
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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28. Loss of appetite in amyotrophic lateral sclerosis is associated with weight loss and decreased calorie consumption independent of dysphagia.
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Mezoian T, Belt E, Garry J, Hubbard J, Breen CT, Miller L, Levine-Weinberg M, Nalipinski P, Sullivan S, Chan J, and Wills AM
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- Aged, Diet, Female, Humans, Male, Middle Aged, Nutritional Status, Surveys and Questionnaires, Amyotrophic Lateral Sclerosis complications, Deglutition Disorders complications, Energy Intake, Feeding and Eating Disorders etiology, Weight Loss
- Abstract
Background: Loss of appetite has been reported to affect up to half of people with amyotrophic lateral sclerosis (ALS) and to be associated with weight loss. We wished to test whether loss of appetite correlates with reduced dietary intake independent of dysphagia., Methods: Appetite was measured repeatedly using the Council on Nutrition Appetite Questionnaire (CNAQ) in participants in the Electronic health Application To Measure Outcomes REmotely study. Dietary intake and weight were compared to appetite, ALS Functional Rating Scale-Revised total and bulbar scores (dysphagia)., Results: The average baseline CNAQ score was 30.4 (n = 61; SD = 3.9) with 18.0% scoring <28 points (severe loss of appetite). Lower CNAQ scores correlated with greater weight loss since diagnosis (Pearson correlation coefficient, r = -0.34; P = 0.009) and lower baseline energy intake (P = 0.007), independent of dysphagia., Conclusions: Our results support an association between loss of appetite and decreased calorie intake and weight in ALS which is independent of dysphagia., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2020
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29. Associations of Lower Caffeine Intake and Plasma Urate Levels with Idiopathic Parkinson's Disease in the Harvard Biomarkers Study.
- Author
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Bakshi R, Macklin EA, Hung AY, Hayes MT, Hyman BT, Wills AM, Gomperts SN, Growdon JH, Ascherio A, Scherzer CR, and Schwarzschild MA
- Subjects
- Aged, Biomarkers metabolism, Case-Control Studies, Cross-Sectional Studies, Eating, Female, Humans, Male, Middle Aged, Parkinson Disease blood, Sex Factors, Caffeine administration & dosage, Parkinson Disease metabolism, Uric Acid blood
- Abstract
Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson's disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these 'reduced risk' factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean difference -125 mg/day, p < 0.001) but not in females (mean difference -30 mg/day, p = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference -0.46 mg/dL, p = 0.017) and females (mean difference -0.45 mg/dL, p = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD.
- Published
- 2020
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30. Nutritional counseling with or without mobile health technology: a randomized open-label standard-of-care-controlled trial in ALS.
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Wills AM, Garry J, Hubbard J, Mezoian T, Breen CT, Ortiz-Miller C, Nalipinski P, Sullivan S, Berry JD, Cudkowicz M, Paganoni S, Chan J, and Macklin EA
- Subjects
- Adult, Female, Humans, Male, Quality of Life, Amyotrophic Lateral Sclerosis diet therapy, Counseling methods, Telemedicine methods
- Abstract
Background: Nutritional status is an important prognostic factor in Amyotrophic Lateral Sclerosis (ALS). We wished to study the safety, tolerability and efficacy of nutritional counseling with or without an mHealth application to maintain or increase body weight in ALS, compared to standard care., Methods: In this randomized open-label, standard-of-care-controlled, single-center clinical trial, we randomly assigned adults with ALS to one of three nutritional interventions: counseling by their physician or nurse ("standard care"), counseling by a registered dietitian (RD) ("in-person"), or counseling supported by a mHealth app ("mHealth"). Both intervention arms received tailored nutrition recommendations and recorded dietary intake and weight biweekly (mHealth) or monthly (in-person). The primary outcome of weight and secondary and tertiary outcomes of calorie intake, ALSFRS-R, and quality of life (QOL) were recorded at each clinic visit and analyzed in an ITT mixed model analysis., Results: A total of 88 participants were enrolled of whom 78 were included in this analysis. The three arms were well-balanced except for excess males in the mHealth arm and greater weight lost at baseline in the in-person arm. Participants in the mHealth arm increased their calorie intake at month 3 to an average of 94% (95% CI: 85, 103) of recommended calories, compared to 81% (95% CI: 72, 91, p = 0.06 vs. mHealth) in the standard care arm. After 6 months, calorie intake was not different among the three arms. Overall weight was stable across all three groups. QOL scores in the mHealth arm were stable over 3 months (0.3 points, 95% CI: - 1.7, 2.2) compared to worsening in standard care (- 2.1 points, 95% CI: - 4.0, - 0.2, p = 0.09 vs. mHealth), but all scores declined by 6 months. ALSFRS-R total scores declined by an average of - 2.6 points (95% CI: - 5.1, - 0.1) over 6 months in the mHealth arm (p = 0.13 vs. standard care) compared to - 5.8 points (95% CI: - 8.2, - 3.4, p = 0.74 vs. standard care) in the in-person and - 5.2 points (95% CI: - 7.6, - 2.9) in the standard care arm., Conclusions: Nutritional counseling by a registered dietitian (with or without support by an mHealth app) is safe but did not maintain weight significantly better than standard care in ALS patients., Trial Registration: https://clinicaltrials.gov/ identifier NCT02418546. Registered April 16, 2015.
- Published
- 2019
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31. Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis.
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Nicholson K, Chan J, Macklin EA, Levine-Weinberg M, Breen C, Bakshi R, Grasso DL, Wills AM, Jahandideh S, Taylor AA, Beaulieu D, Ennist DL, Andronesi O, Ratai EM, Schwarzschild MA, Cudkowicz M, and Paganoni S
- Abstract
Objective: To test the safety, tolerability, and urate-elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS)., Methods: This was a pilot, open-label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre-specified time points to elevate serum urate levels to 7-8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12-week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS-R scores., Results: Twenty-four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow-up. Serum urate rose to target levels in 6 weeks. No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period. Observed changes in ALSFRS-R did not differ from baseline predictions., Interpretation: Inosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease-modifying therapy for ALS.
- Published
- 2018
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32. Vitamin D levels are associated with gross motor function in amyotrophic lateral sclerosis.
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Paganoni S, Macklin EA, Karam C, Yu H, Gonterman F, Fetterman KA, Cudkowicz M, Berry J, and Wills AM
- Subjects
- Aged, Amyotrophic Lateral Sclerosis physiopathology, Biomarkers blood, Female, Humans, Male, Middle Aged, Prospective Studies, Amyotrophic Lateral Sclerosis blood, Amyotrophic Lateral Sclerosis diagnosis, Disease Progression, Motor Skills physiology, Vitamin D blood
- Abstract
Introduction: The objective of this study was to determine whether serum vitamin D [25(OH)D] levels are associated with disease progression in amyotrophic lateral sclerosis (ALS)., Methods: 25(OH)D was measured in subjects enrolled in a multicenter study for validation of ALS biomarkers. Baseline 25(OH)D levels were correlated with baseline ALSFRS-R scores. Average 25(OH)D levels from baseline and month 6 visits (seasonally asynchronous) were used to predict subsequent rate of change in ALSFRS-R from month 6 to month 18., Results: Most subjects had either insufficient or deficient 25(OH)D levels. Lower 25(OH)D was associated with lower ALSFRS-R gross motor scores, but not lower ALSFRS-R total scores at baseline. Levels of 25(OH)D were not predictive of disease progression over the next 12 months., Conclusion: 25(OH)D was associated with baseline gross motor ALSFRS-R scores but did not predict the rate of disease progression. Vitamin D levels may reflect poor mobility in patients with ALS. Muscle Nerve, 2017 Muscle Nerve 56: 726-731, 2017., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
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33. Predictors of weight loss in early treated Parkinson's disease from the NET-PD LS-1 cohort.
- Author
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Wills AM, Li R, Pérez A, Ren X, and Boyd J
- Subjects
- Age Factors, Antiparkinson Agents adverse effects, Antiparkinson Agents therapeutic use, Creatine adverse effects, Creatine therapeutic use, Disease Progression, Dopamine Agents adverse effects, Dopamine Agents therapeutic use, Double-Blind Method, Female, Follow-Up Studies, Humans, Linear Models, Longitudinal Studies, Male, Middle Aged, Parkinson Disease diagnosis, Prognosis, Sex Factors, Parkinson Disease drug therapy, Parkinson Disease physiopathology, Weight Loss
- Abstract
Weight loss is a common symptom of Parkinson's disease and is associated with impaired quality of life. Predictors of weight loss have not been studied in large clinical cohorts. We previously observed an association between change in body mass index and change in Unified Parkinson's Disease Rating Scale (UPDRS) motor and total scores. In this study, we performed a secondary analysis of longitudinal data (1-6 years) from 1619 participants in the NINDS Exploratory Trials in PD Long-term Study-1 (NET-PD LS1) to explore predictors of weight loss in a large prospective clinical trial cohort of early treated Parkinson's disease. The NET-PD LS1 study was a double-blind randomized placebo controlled clinical trial of creatine monohydrate 10 gm/day in early treated PD (within 5 years of diagnosis and within 2 years of starting dopaminergic medications). Linear mixed models were used to estimate the effect of baseline clinical covariates on weight change over time. On average, participants lost only 0.6 kg per year. Higher age, baseline weight, female gender, higher baseline UPDRS scores, greater postural instability, difficulty eating and drinking, lower cognitive scores and baseline levodopa use (compared to dopamine agonists) were all associated with weight loss. Surprisingly baseline difficulty swallowing, dyskinesia, depression, intestinal hypomotility (constipation) and self-reported nausea/vomiting/anorexia were not significantly associated with weight loss in this cohort of early treated Parkinson's disease patients. On average, participants with Parkinson's disease experience little weight loss during the first 1-6 years after starting dopaminergic replacement therapy, however levodopa use and postural instability were both predictors of early weight loss. Trial Registration clinicaltrials.gov identifier# NCT00449865.
- Published
- 2017
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34. Factors associated with falling in early, treated Parkinson's disease: The NET-PD LS1 cohort.
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Chou KL, Elm JJ, Wielinski CL, Simon DK, Aminoff MJ, Christine CW, Liang GS, Hauser RA, Sudarsky L, Umeh CC, Voss T, Juncos J, Fang JY, Boyd JT, Bodis-Wollner I, Mari Z, Morgan JC, Wills AM, Lee SL, and Parashos SA
- Subjects
- Activities of Daily Living, Aged, Cohort Studies, Datasets as Topic statistics & numerical data, Disease Progression, Female, Humans, Logistic Models, Male, Middle Aged, Risk Factors, Severity of Illness Index, Time Factors, Accidental Falls, Dopamine Agents therapeutic use, Parkinson Disease drug therapy, Parkinson Disease physiopathology
- Abstract
Background: Recognizing the factors associated with falling in Parkinson's disease (PD) would improve identification of at-risk individuals., Objective: To examine frequency of falling and baseline characteristics associated with falling in PD using the National Institute of Neurological Disorders and Stroke (NINDS) Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1) dataset., Methods: The LS-1 database included 1741 early treated PD subjects (median 4year follow-up). Baseline characteristics were tested for a univariate association with post-baseline falling during the trial. Significant variables were included in a multivariable logistic regression model. A separate analysis using a negative binomial model investigated baseline factors on fall rate., Results: 728 subjects (42%) fell during the trial, including at baseline. A baseline history of falls was the factor most associated with post-baseline falling. Men had lower odds of post-baseline falling compared to women, but for men, the probability of a post-baseline fall increased with age such that after age 70, men and women had similar odds of falling. Other baseline factors associated with a post-baseline fall and increased fall rate included the Unified PD Rating Scale (UPDRS) Activities of Daily Living (ADL) score, total functional capacity (TFC), baseline ambulatory capacity score and dopamine agonist monotherapy., Conclusion: Falls are common in early treated PD. The biggest risk factor for falls in PD remains a history of falling. Measures of functional ability (UPDRS ADL, TFC) and ambulatory capacity are novel clinical risk factors needing further study. A significant age by sex interaction may help to explain why age has been an inconsistent risk factor for falls in PD., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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35. Caffeine, creatine, GRIN2A and Parkinson's disease progression.
- Author
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Simon DK, Wu C, Tilley BC, Lohmann K, Klein C, Payami H, Wills AM, Aminoff MJ, Bainbridge J, Dewey R, Hauser RA, Schaake S, Schneider JS, Sharma S, Singer C, Tanner CM, Truong D, Wei P, Wong PS, and Yang T
- Subjects
- Aged, Caffeine metabolism, Disease Progression, Female, Gene-Environment Interaction, Genotype, Humans, Longitudinal Studies, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Caffeine therapeutic use, Creatine therapeutic use, Genetic Predisposition to Disease genetics, Parkinson Disease drug therapy, Parkinson Disease genetics, Receptors, N-Methyl-D-Aspartate genetics
- Abstract
Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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36. Blockade of the neurite outgrowth inhibitor Nogo-A in amyotrophic lateral sclerosis.
- Author
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Wills AM
- Subjects
- Humans, Neuronal Outgrowth, Amyotrophic Lateral Sclerosis, Nogo Proteins
- Published
- 2017
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- View/download PDF
37. Association Between Body Mass Index and Parkinson Disease-Reply.
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Wills AM, Boyd J, and Pérez A
- Subjects
- Humans, Obesity, Risk Factors, Body Mass Index, Parkinson Disease
- Published
- 2016
- Full Text
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38. Association Between Change in Body Mass Index, Unified Parkinson's Disease Rating Scale Scores, and Survival Among Persons With Parkinson Disease: Secondary Analysis of Longitudinal Data From NINDS Exploratory Trials in Parkinson Disease Long-term Study 1.
- Author
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Wills AM, Pérez A, Wang J, Su X, Morgan J, Rajan SS, Leehey MA, Pontone GM, Chou KL, Umeh C, Mari Z, and Boyd J
- Subjects
- Aged, Female, Humans, Male, Middle Aged, National Institute of Neurological Disorders and Stroke (U.S.), Randomized Controlled Trials as Topic, United States, Body Mass Index, Disease Progression, Parkinson Disease mortality, Parkinson Disease physiopathology, Severity of Illness Index
- Abstract
Importance: Greater body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) is associated with improved survival among persons with Huntington disease or amyotrophic lateral sclerosis. Weight loss is common among persons with Parkinson disease (PD) and is associated with worse quality of life., Objective: To explore the association between change in BMI, Unified Parkinson's Disease Rating Scale (UPDRS) motor and total scores, and survival among persons with PD and to test whether there is a positive association between BMI at randomization and survival., Design, Setting, and Participants: Secondary analysis (from May 27, 2014, to October 13, 2015) of longitudinal data (3-6 years) from 1673 participants who started the National Institute of Neurological Disorders and Stroke Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1). This was a double-blind randomized placebo-controlled clinical trial of creatine monohydrate (10 g/d) that was performed at 45 sites throughout the United States and Canada. Participants with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) PD were enrolled from March 2007 to May 2010 and followed up until September 2013., Main Outcomes and Measures: Change across time in motor UPDRS score, change across time in total UPDRS score, and time to death. Generalized linear mixed models were used to estimate the effect of BMI on the change in motor and total UPDRS scores after controlling for covariates. Survival was analyzed using Cox proportional hazards models of time to death. A participant's BMI was measured at randomization, and BMI trajectory groups were classified according to whether participants experienced weight loss ("decreasing BMI"), weight stability ("stable BMI"), or weight gain ("increasing BMI") during the study., Results: Of the 1673 participants (mean [SD] age, 61.7 [9.6] years; 1074 [64.2%] were male), 158 (9.4%) experienced weight loss (decreasing BMI), whereas 233 (13.9%) experienced weight gain (increasing BMI). After adjusting for covariates, we found that the weight-loss group's mean (SE) motor UPDRS score increased by 1.48 (0.28) (P < .001) more points per visit than the weight-stable group's mean (SE) motor UPDRS score. The weight-gain group's mean (SE) motor UPDRS score decreased by -0.51 (0.24) (P = .03) points per visit, relative to the weight-stable group. While there was an unadjusted difference in survival between the 3 BMI trajectory groups (log-rank P < .001), this was not significant after adjusting for covariates., Conclusions and Relevance: Change in BMI was inversely associated with change in motor and total UPDRS scores in the NET-PD LS-1. Change in BMI was not associated with survival; however, these results were limited by the low number of deaths in the NET-PD LS-1., Trial Registration: clinicaltrials.gov Identifier: NCT00449865.
- Published
- 2016
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39. Caffeine and Progression of Parkinson Disease: A Deleterious Interaction With Creatine.
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Simon DK, Wu C, Tilley BC, Wills AM, Aminoff MJ, Bainbridge J, Hauser RA, Schneider JS, Sharma S, Singer C, Tanner CM, Truong D, and Wong PS
- Subjects
- Central Nervous System Stimulants adverse effects, Drug Interactions, Female, Humans, Male, Middle Aged, Caffeine adverse effects, Creatine therapeutic use, Disease Progression, Parkinson Disease drug therapy
- Abstract
Objective: Increased caffeine intake is associated with a lower risk of Parkinson disease (PD) and is neuroprotective in mouse models of PD. However, in a previous study, an exploratory analysis suggested that, in patients taking creatine, caffeine intake was associated with a faster rate of progression. In the current study, we investigated the association of caffeine with the rate of progression of PD and the interaction of this association with creatine intake., Methods: Data were analyzed from a large phase 3 placebo-controlled clinical study of creatine as a potentially disease-modifying agent in PD. Subjects were recruited for this study from 45 movement disorders centers across the United States and Canada. A total of 1741 subjects with PD participated in the primary clinical study, and caffeine intake data were available for 1549 of these subjects. The association of caffeine intake with rate of progression of PD as measured by the change in the total Unified Parkinson Disease Rating Scale score and the interaction of this association with creatine intake were assessed., Results: Caffeine intake was not associated with the rate of progression of PD in the main analysis, but higher caffeine intake was associated with significantly faster progression among subjects taking creatine., Conclusions: This is the largest and longest study conducted to date that addresses the association of caffeine with the rate of progression of PD. These data indicate a potentially deleterious interaction between caffeine and creatine with respect to the rate of progression of PD.
- Published
- 2015
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40. Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease.
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Locascio JJ, Eberly S, Liao Z, Liu G, Hoesing AN, Duong K, Trisini-Lipsanopoulos A, Dhima K, Hung AY, Flaherty AW, Schwarzschild MA, Hayes MT, Wills AM, Shivraj Sohur U, Mejia NI, Selkoe DJ, Oakes D, Shoulson I, Dong X, Marek K, Zheng B, Ivinson A, Hyman BT, Growdon JH, Sudarsky LR, Schlossmacher MG, Ravina B, and Scherzer CR
- Subjects
- Aged, Cognition Disorders etiology, Cognition Disorders genetics, Dopamine Plasma Membrane Transport Proteins metabolism, Female, Gene Expression Regulation, Genetic Testing, Humans, Male, Microarray Analysis, Middle Aged, Neuroimaging, Parkinson Disease complications, Parkinson Disease diagnostic imaging, RNA, Messenger metabolism, Radionuclide Imaging, Severity of Illness Index, Tropanes, Parkinson Disease genetics, Parkinson Disease pathology, alpha-Synuclein blood, alpha-Synuclein genetics
- Abstract
There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
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41. Sex Differences in Clinical Features of Early, Treated Parkinson's Disease.
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Augustine EF, Pérez A, Dhall R, Umeh CC, Videnovic A, Cambi F, Wills AM, Elm JJ, Zweig RM, Shulman LM, Nance MA, Bainbridge J, and Suchowersky O
- Subjects
- Adult, Aged, Aged, 80 and over, Creatine metabolism, Double-Blind Method, Female, Humans, Male, Middle Aged, Parkinson Disease metabolism, Severity of Illness Index, Sex Characteristics, Parkinson Disease pathology
- Abstract
Introduction: To improve our understanding of sex differences in the clinical characteristics of Parkinson's Disease, we sought to examine differences in the clinical features and disease severity of men and women with early treated Parkinson's Disease (PD) enrolled in a large-scale clinical trial., Methods: Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between men and women using t-test statistics. Sex differences in clinical features were evaluated, including: symptoms at diagnosis (motor) and symptoms at randomization (motor, non-motor, and daily functioning)., Results: 1,741 participants were enrolled (62.5% male). No differences were detected in mean age at PD onset, age at PD diagnosis, age at randomization, motor symptoms, or daily functioning between men and women. Differences in non-motor symptoms were observed, with women demonstrating better performance compared to men on SCOPA-COG (Z = 5.064, p<0.0001) and Symbol Digit Modality measures (Z = 5.221, p<0.0001)., Conclusions: Overall, men and women did not demonstrate differences in clinical motor features early in the course of PD. However, the differences observed in non-motor cognitive symptoms suggests further assessment of the influence of sex on non-motor symptoms in later stages of PD is warranted.
- Published
- 2015
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42. Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.
- Author
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Kieburtz K, Tilley BC, Elm JJ, Babcock D, Hauser R, Ross GW, Augustine AH, Augustine EU, Aminoff MJ, Bodis-Wollner IG, Boyd J, Cambi F, Chou K, Christine CW, Cines M, Dahodwala N, Derwent L, Dewey RB Jr, Hawthorne K, Houghton DJ, Kamp C, Leehey M, Lew MF, Liang GS, Luo ST, Mari Z, Morgan JC, Parashos S, Pérez A, Petrovitch H, Rajan S, Reichwein S, Roth JT, Schneider JS, Shannon KM, Simon DK, Simuni T, Singer C, Sudarsky L, Tanner CM, Umeh CC, Williams K, and Wills AM
- Subjects
- Aged, Antiparkinson Agents adverse effects, Creatine adverse effects, Creatine blood, Disease Progression, Double-Blind Method, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Medication Adherence, Middle Aged, Treatment Outcome, Antiparkinson Agents therapeutic use, Creatine therapeutic use, Parkinson Disease drug therapy
- Abstract
Importance: There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies., Objective: To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease., Design, Setting, and Patients: The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013., Interventions: Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years)., Main Outcomes and Measures: The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes., Results: The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system., Conclusions and Relevance: Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease., Trial Registration: clinicaltrials.gov Identifier: NCT00449865.
- Published
- 2015
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43. No sex differences in use of dopaminergic medication in early Parkinson disease in the US and Canada - baseline findings of a multicenter trial.
- Author
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Umeh CC, Pérez A, Augustine EF, Dhall R, Dewey RB Jr, Mari Z, Simon DK, Wills AM, Christine CW, Schneider JS, and Suchowersky O
- Subjects
- Aged, Canada, Dopamine Agents administration & dosage, Female, Humans, Levodopa administration & dosage, Levodopa therapeutic use, Male, Middle Aged, Parkinson Disease diagnosis, Severity of Illness Index, Sex Factors, Treatment Outcome, United States, Dopamine Agents therapeutic use, Parkinson Disease drug therapy
- Abstract
Background: Sex differences in Parkinson disease clinical features have been reported, but few studies have examined sex influences on use of dopaminergic medication in early Parkinson disease. The objective of this study was to test if there are differences in the type of dopaminergic medication used and levodopa equivalent daily dose between men and women with early Parkinson disease enrolled in a large multicenter study of Creatine as a potential disease modifying therapy - the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease Long-Term Study-1., Methods: Baseline data of 1,741 participants from 45 participating sites were analyzed. Participants from the United States and Canada were enrolled within five years of Parkinson Disease diagnosis. Two outcome variables were studied: type of dopaminergic medication used and levodopa equivalent daily dose at baseline in the Long-Term Study-1. Chi-square statistic and linear regression models were used for statistical analysis., Results: There were no statistically significant differences in the frequency of use of different types of dopaminergic medications at baseline between men and women with Parkinson Disease. A small but statistically significant difference was observed in the median unadjusted levodopa equivalent daily dose at baseline between women (300 mg) and men (325 mg), but this was not observed after controlling for disease duration (years since Parkinson disease diagnosis), disease severity (Unified Parkinson's Disease Rating Scale Motor and Activities of Daily Living Scores), and body weight., Conclusions: In this large multicenter study, we did not observe sex differences in the type and dose of dopaminergic medications used in early Parkinson Disease. Further research is needed to evaluate the influence of male or female sex on use of dopaminergic medication in mid- and late-stage Parkinson Disease.
- Published
- 2014
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44. Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial.
- Author
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Wills AM, Hubbard J, Macklin EA, Glass J, Tandan R, Simpson EP, Brooks B, Gelinas D, Mitsumoto H, Mozaffar T, Hanes GP, Ladha SS, Heiman-Patterson T, Katz J, Lou JS, Mahoney K, Grasso D, Lawson R, Yu H, and Cudkowicz M
- Subjects
- Adult, Aged, Amyotrophic Lateral Sclerosis blood, Cholesterol blood, Diet, High-Fat adverse effects, Diet, High-Fat methods, Double-Blind Method, Energy Intake, Enteral Nutrition adverse effects, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Pilot Projects, Amyotrophic Lateral Sclerosis therapy, Enteral Nutrition methods
- Abstract
Background: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition., Methods: In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983., Findings: Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0.06; HC/HC vs control, p=0.06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0.0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0.03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group., Interpretation: Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease., Funding: Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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45. Weakness, SR function and stress in gastrocnemius muscles of aged male rats.
- Author
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Russ DW, Wills AM, Boyd IM, and Krause J
- Subjects
- Aging metabolism, Aging pathology, Animals, Autophagy physiology, Body Weight physiology, Calcium metabolism, Male, Muscle Contraction physiology, Muscle Weakness metabolism, Muscle Weakness pathology, Muscle, Skeletal pathology, Myosin Heavy Chains metabolism, Organ Size physiology, Rats, Rats, Inbred F344, Sarcoplasmic Reticulum metabolism, Aging physiology, Muscle Weakness physiopathology, Muscle, Skeletal physiopathology, Sarcoplasmic Reticulum physiology
- Abstract
Aging is associated with a decline in muscle force that exceeds loss of muscle mass, suggesting that factors other than sarcopenia affect age-related muscle weakness. Here, we investigate in situ muscle force and sarcoplasmic reticulum (SR) properties in gastrocnemius muscles of adult (6-8 months) and aged (24 months) rats. Despite minimal loss of muscle mass, peak tetanic force was significantly reduced (-28%) in aged muscles. Adjusting for differences in muscle cross-sectional area mitigated the age difference (-23%), but it remained significant. The SR calcium release function was also impaired (-17%) with aging, although calcium uptake was not, and SR-associated glycogen increased (+30%) with aging. Western blotting revealed age related increases in Grp78, serinepalmitoyltransferase and neutral sphingomyelinase, suggesting that age increased the stress response and ceramide metabolism in the SR. In contrast Parkin, a protein associated with autophagic signaling, was reduced in the aged SR. These findings are consistent with a hypothesis that age-related impairments of the SR, possibly due to impaired autophagy and/or altered membrane metabolism, contribute to age-related muscle weakness, independent of changes in muscle mass., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
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46. Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker Study.
- Author
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Ding H, Dhima K, Lockhart KC, Locascio JJ, Hoesing AN, Duong K, Trisini-Lipsanopoulos A, Hayes MT, Sohur US, Wills AM, Mollenhauer B, Flaherty AW, Hung AY, Mejia N, Khurana V, Gomperts SN, Selkoe DJ, Schwarzschild MA, Schlossmacher MG, Hyman BT, Sudarsky LR, Growdon JH, and Scherzer CR
- Subjects
- Aged, Biomarkers metabolism, Case-Control Studies, Cross-Sectional Studies, Female, Humans, Longitudinal Studies, Male, Middle Aged, Prevalence, Severity of Illness Index, Vitamin D Deficiency diagnosis, Cholecalciferol deficiency, Parkinson Disease etiology, Parkinson Disease metabolism, Vitamin D Deficiency complications
- Abstract
Objective: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD)., Methods: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study., Results: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson's Disease Rating Scale scores at baseline and during follow-up., Conclusions: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D-deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.
- Published
- 2013
- Full Text
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47. High-fat and ketogenic diets in amyotrophic lateral sclerosis.
- Author
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Paganoni S and Wills AM
- Subjects
- Amyotrophic Lateral Sclerosis epidemiology, Amyotrophic Lateral Sclerosis mortality, Animals, Disease Models, Animal, Humans, Mice, Amyotrophic Lateral Sclerosis diet therapy, Diet, High-Fat methods, Diet, Ketogenic methods
- Abstract
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. Epidemiologic data suggest that malnutrition is a common feature in amyotrophic lateral sclerosis and being overweight or obese confers a survival advantage in this patient population. In amyotrophic lateral sclerosis mouse models, a high-fat diet has been shown to lead to weight gain and prolonged survival. However, little research has been conducted to test whether nutritional interventions might ameliorate the disease course in humans. Here we review the currently available evidence supporting the potential role of dietary interventions as a therapeutic tool for amyotrophic lateral sclerosis. Ultimately, determining whether a high-fat or ketogenic diet could be beneficial in amyotrophic lateral sclerosis will require large randomized, placebo-controlled clinical trials.
- Published
- 2013
- Full Text
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48. Caffeine consumption and risk of dyskinesia in CALM-PD.
- Author
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Wills AM, Eberly S, Tennis M, Lang AE, Messing S, Togasaki D, Tanner CM, Kamp C, Chen JF, Oakes D, McDermott MP, and Schwarzschild MA
- Subjects
- Adenosine A2 Receptor Antagonists metabolism, Aged, Caffeine metabolism, Cohort Studies, Dose-Response Relationship, Drug, Double-Blind Method, Dyskinesia, Drug-Induced etiology, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Parkinson Disease drug therapy, Pramipexole, Proportional Hazards Models, Retrospective Studies, Risk, Adenosine A2 Receptor Antagonists administration & dosage, Antiparkinson Agents adverse effects, Benzothiazoles adverse effects, Caffeine administration & dosage, Dyskinesia, Drug-Induced prevention & control, Levodopa adverse effects
- Abstract
Background: Adenosine A2A receptor antagonists reduce or prevent the development of dyskinesia in animal models of levodopa-induced dyskinesia., Methods: We examined the association between self-reported intake of the A2A receptor antagonist caffeine and time to dyskinesia in the Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson's Disease (CALM-PD) and CALM Cohort extension studies, using a Cox proportional hazards model adjusting for age, baseline Parkinson's severity, site, and initial treatment with pramipexole or levodopa., Results: For subjects who consumed >12 ounces of coffee/day, the adjusted hazard ratio for the development of dyskinesia was 0.61 (95% CI, 0.37-1.01) compared with subjects who consumed <4 ounces/day. For subjects who consumed between 4 and 12 ounces/day, the adjusted hazard ratio was 0.73 (95% CI, 0.46-1.15; test for trend, P = .05)., Conclusions: These results support the possibility that caffeine may reduce the likelihood of developing dyskinesia., (Copyright © 2013 Movement Disorder Society.)
- Published
- 2013
- Full Text
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49. Survey of current enteral nutrition practices in treatment of amyotrophic lateral sclerosis.
- Author
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Zhang M, Hubbard J, Rudnicki SA, Johansen CS, Dalton K, Heiman-Patterson T, Forshew DA, and Wills AM
- Abstract
Background and Aims: Enteral nutrition (EN) is commonly prescribed for dysphagia and weight loss in amyotrophic lateral sclerosis (ALS), but there are currently no ALS-specific EN guidelines. We aimed to survey current practices prescribing EN to ALS patients., Methods: An online survey was distributed using list servers administered by the Academy of Nutrition and Dietetics (AND), Muscular Dystrophy Association (MDA), and ALS Association (ALSA)., Results: A total of 148 dietitians, nurses, and physicians participated in the survey, of whom 50% were dietitians and 68% were associated with an ALS clinic. Only 47% of respondents reported their patients to be fully compliant with EN recommendations. Side effects (fullness, diarrhea, constipation, and bloating) were the most important reason for patient noncompliance, followed by dependence on caregivers. By contrast, only 3% of providers rated depression/hopelessness as the most important reason for noncompliance. Half of those surveyed reported that more than 25% of patients continued to lose weight after starting EN., Conclusions: Our survey results show a high frequency of gastrointestinal side effects and weight loss in ALS patients receiving EN. These findings may be limited by sampling error and non-response bias. Prospective studies are needed to help establish EN guidelines for ALS.
- Published
- 2013
- Full Text
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50. Uric acid levels predict survival in men with amyotrophic lateral sclerosis.
- Author
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Paganoni S, Zhang M, Quiroz Zárate A, Jaffa M, Yu H, Cudkowicz ME, and Wills AM
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Neuroprotective Agents, Proportional Hazards Models, Survival Analysis, Amyotrophic Lateral Sclerosis blood, Amyotrophic Lateral Sclerosis mortality, Sex Characteristics, Uric Acid blood
- Abstract
Elevated uric acid levels have recently been found to be associated with slower disease progression in Parkinson's disease, Huntington's disease, multiple system atrophy, and mild cognitive impairment. The aim of this study is to determine whether serum uric acid levels predict survival in amyotrophic lateral sclerosis (ALS). A total of 251 people with ALS enrolled in two multicenter clinical trials were included in our analysis. The main outcome measure was survival time, which was calculated as time to death, tracheostomy, or permanent assistive ventilation, with any event considered a survival endpoint. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching a survival endpoint according to baseline uric acid levels after adjusting for markers of disease severity (FVC, total ALSFRS-R score, time since symptom onset, diagnostic delay, BMI, bulbar vs. spinal onset, age, and riluzole use). There was a dose-dependent survival advantage in men, but not women, with higher baseline uric acid levels (logrank test: p = 0.018 for men, p = 0.81 for women). There was a 39% reduction in risk of death during the study for men with each 1 mg/dl increase in uric acid levels (adjusted HR: 0.61, 95% CI 0.39-0.96, p = 0.03). This is the first study to demonstrate that serum uric acid is associated with prolonged survival in ALS, after adjusting for markers of disease severity. Similar to previous reports in Parkinson's disease, this association was seen in male subjects only.
- Published
- 2012
- Full Text
- View/download PDF
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