Genotypic Influences on Network Progression in Parkinson's Disease

NCT04228172 | Active Not Recruiting

• 1 other identifier: MJFF grant 16325
• Study Type: observational
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

In this longitudinal study, the investigators will follow Parkinson's disease (PD) patients with and without glucocerebrosidase (GBA) mutations. The investigators hypothesize that the rate of increase in brain network activity over time (network progression rate) is faster in patients with GBA gene mutations.

Conditions

Parkinson's Disease

Keywords

GBA; genetic; progression; PD; glucocerebrosidase

Outcome Measures

Primary Outcomes (2)

• Increase in PD related metabolic pattern expression

  Changes in PD related and PD cognition related pattern expression in 18F-2-fluoro-2-deoxy-D-glucose (FDG) PET scans

  Baseline and 18 months later

• Increase in PD related functional pattern expression

  Changes in PD related and PD cognition related pattern expression in resting state functional magnetic resonance imaging (rs-fMRI)

  Baseline and 18 months later

Secondary Outcomes (2)

• Change in motor function

  Baseline and 18 months later

• Change in cognitive function

  Baseline and 18 months later

Study Arms (2)

Parkinson's disease (PD) glucocerebrosidase (GBA) carriers

Parkinson's disease subjects with GBA mutation

Genetic: DNA/GeneticTesting; Radiation: FDG PET scan; Other: MRI scan; Other: Clinical and neuropsychological assessments

Parkinson's disease (PD) non glucocerebrosidase (GBA) carriers

Parkinson's disease subjects without GBA mutation

Genetic: DNA/GeneticTesting; Radiation: FDG PET scan; Other: MRI scan; Other: Clinical and neuropsychological assessments

Interventions

DNA/GeneticTesting GENETIC

Subjects will be tested for GBA and LRRK2 mutation status at baseline.

Parkinson's disease (PD) glucocerebrosidase (GBA) carriers; Parkinson's disease (PD) non glucocerebrosidase (GBA) carriers

FDG PET scan RADIATION

18F-Fluoro-2-deoxy-glucose (FDG) PET scan is a nuclear medicine test that measures glucose metabolism (energy) in your brain at baseline and 18 months later.

Parkinson's disease (PD) glucocerebrosidase (GBA) carriers; Parkinson's disease (PD) non glucocerebrosidase (GBA) carriers

MRI scan OTHER

Magnetic Resonance Imaging (MRI) is a noninvasive scan which produces detailed pictures of the brain using a magnetic field. In addition, a special type of MRI, called resting state functional MRI (rs-fMRI), will measure and map brain activity. Conducted at baseline and 18 months later.

Parkinson's disease (PD) glucocerebrosidase (GBA) carriers; Parkinson's disease (PD) non glucocerebrosidase (GBA) carriers

Clinical and neuropsychological assessments OTHER

Investigator will evaluate subjects according to the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the standard clinical tool used to measure the severity and progression of PD. Neuropsychological evaluation will assess how one's brain functions (via pencil and paper testing), which indirectly yields information about the structural and functional integrity of the brain. Conducted at baseline and 18 months later.

Parkinson's disease (PD) glucocerebrosidase (GBA) carriers; Parkinson's disease (PD) non glucocerebrosidase (GBA) carriers

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Study population will be recruited through local movement disorders centers in the tri-state area, prior PD studies, The Michael J. Fox Trial Finder, community outreach

You may qualify if:

• Diagnosis of PD made according to United Kingdom (UK) Parkinson's Disease Society Brain Bank Criteria
• Ability to provide written informed consent
• Age 40-75
• Stable dose of antiparkinsonian medication for \>1 month prior to study entry

You may not qualify if:

• Subjects with pathogenic mutations in LRRK2 related PD mutations (subjects with variants of uncertain significance (VUS) are eligible
• History of known causative factors such as encephalitis or neuroleptic treatment
• Patients with dementia (defined as Mini-Mental Status Exam score \<24 or a Telephone Interview for Cognitive Status score \<26)
• Atypical parkinsonian features including oculomotor abnormalities, incontinence, ataxia, sensory loss, or pyramidal signs
• Known structural brain lesions
• Patients with history of stroke, head injury, high intracranial pressure or severe headaches
• Psychiatric disorder, including a history of major depression in the past 36 months
• Pregnant or breastfeeding women (female subjects of child-bearing potential will be screened for pregnancy before imaging).

Sponsors & Collaborators

• Northwell Health: lead
• Michael J. Fox Foundation for Parkinson's Research: collaborator

Study Sites (1)

Feinstein Institutes for Medical Research

Manhasset, New York, 11030, United States

Location

Related Publications (22)

• Davis MY, Johnson CO, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, Van Deerlin VM, Quinn JF, Chung KA, Peterson-Hiller AL, Rosenthal LS, Dawson TM, Albert MS, Goldman JG, Stebbins GT, Bernard B, Wszolek ZK, Ross OA, Dickson DW, Eidelberg D, Mattis PJ, Niethammer M, Yearout D, Hu SC, Cholerton BA, Smith M, Mata IF, Montine TJ, Edwards KL, Zabetian CP. Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol. 2016 Oct 1;73(10):1217-1224. doi: 10.1001/jamaneurol.2016.2245.

  PMID: 27571329 BACKGROUND

• Cilia R, Tunesi S, Marotta G, Cereda E, Siri C, Tesei S, Zecchinelli AL, Canesi M, Mariani CB, Meucci N, Sacilotto G, Zini M, Barichella M, Magnani C, Duga S, Asselta R, Solda G, Seresini A, Seia M, Pezzoli G, Goldwurm S. Survival and dementia in GBA-associated Parkinson's disease: The mutation matters. Ann Neurol. 2016 Nov;80(5):662-673. doi: 10.1002/ana.24777. Epub 2016 Oct 3.

  PMID: 27632223 BACKGROUND

• Sidransky E, Lopez G. The link between the GBA gene and parkinsonism. Lancet Neurol. 2012 Nov;11(11):986-98. doi: 10.1016/S1474-4422(12)70190-4.

  PMID: 23079555 BACKGROUND

• Schindlbeck KA, Eidelberg D. Network imaging biomarkers: insights and clinical applications in Parkinson's disease. Lancet Neurol. 2018 Jul;17(7):629-640. doi: 10.1016/S1474-4422(18)30169-8.

  PMID: 29914708 BACKGROUND

• Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009 Jul;132(Pt 7):1783-94. doi: 10.1093/brain/awp044. Epub 2009 Mar 13.

  PMID: 19286695 BACKGROUND

• Winder-Rhodes SE, Evans JR, Ban M, Mason SL, Williams-Gray CH, Foltynie T, Duran R, Mencacci NE, Sawcer SJ, Barker RA. Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort. Brain. 2013 Feb;136(Pt 2):392-9. doi: 10.1093/brain/aws318.

  PMID: 23413260 BACKGROUND

• Alcalay RN, Levy OA, Waters CC, Fahn S, Ford B, Kuo SH, Mazzoni P, Pauciulo MW, Nichols WC, Gan-Or Z, Rouleau GA, Chung WK, Wolf P, Oliva P, Keutzer J, Marder K, Zhang X. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain. 2015 Sep;138(Pt 9):2648-58. doi: 10.1093/brain/awv179. Epub 2015 Jun 27.

  PMID: 26117366 BACKGROUND

• Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul 8;146(1):37-52. doi: 10.1016/j.cell.2011.06.001. Epub 2011 Jun 23.

  PMID: 21700325 BACKGROUND

• McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AH. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain. 2014 May;137(Pt 5):1481-95. doi: 10.1093/brain/awu020. Epub 2014 Feb 25.

  PMID: 24574503 BACKGROUND

• Sardi SP, Clarke J, Viel C, Chan M, Tamsett TJ, Treleaven CM, Bu J, Sweet L, Passini MA, Dodge JC, Yu WH, Sidman RL, Cheng SH, Shihabuddin LS. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3537-42. doi: 10.1073/pnas.1220464110. Epub 2013 Jan 7.

  PMID: 23297226 BACKGROUND

• Feigin A, Kaplitt MG, Tang C, Lin T, Mattis P, Dhawan V, During MJ, Eidelberg D. Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson's disease. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19559-64. doi: 10.1073/pnas.0706006104. Epub 2007 Nov 27.

  PMID: 18042721 BACKGROUND

• Niethammer M, Eidelberg D. Metabolic brain networks in translational neurology: concepts and applications. Ann Neurol. 2012 Nov;72(5):635-47. doi: 10.1002/ana.23631. Epub 2012 Aug 31.

  PMID: 22941893 BACKGROUND

• Eidelberg D. Metabolic brain networks in neurodegenerative disorders: a functional imaging approach. Trends Neurosci. 2009 Oct;32(10):548-57. doi: 10.1016/j.tins.2009.06.003. Epub 2009 Sep 16.

  PMID: 19765835 BACKGROUND

• Vo A, Sako W, Fujita K, Peng S, Mattis PJ, Skidmore FM, Ma Y, Ulug AM, Eidelberg D. Parkinson's disease-related network topographies characterized with resting state functional MRI. Hum Brain Mapp. 2017 Feb;38(2):617-630. doi: 10.1002/hbm.23260. Epub 2016 May 21.

  PMID: 27207613 BACKGROUND

• Schindlbeck, K.A. et al., Multicenter validation of disease-related Parkinson's disease pattern with resting state fMRI. 21st International Congress of Parkinson's Disease and Movement Disorders, June 8, 2018, Vancouver, Canada

  BACKGROUND

• Schindlbeck, K.A. et al., Cognition-related Parkinson's disease pattern with functional MRI - Validation and clinical correlates. 62nd Congress of the German Society for Clinical Neurophysiology and Functional Imaging (DGKN), Berlin, Germany, March 15, 2018

  BACKGROUND

• Huang C, Tang C, Feigin A, Lesser M, Ma Y, Pourfar M, Dhawan V, Eidelberg D. Changes in network activity with the progression of Parkinson's disease. Brain. 2007 Jul;130(Pt 7):1834-46. doi: 10.1093/brain/awm086. Epub 2007 Apr 30.

  PMID: 17470495 BACKGROUND

• Tang CC, Poston KL, Dhawan V, Eidelberg D. Abnormalities in metabolic network activity precede the onset of motor symptoms in Parkinson's disease. J Neurosci. 2010 Jan 20;30(3):1049-56. doi: 10.1523/JNEUROSCI.4188-09.2010.

  PMID: 20089913 BACKGROUND

• Niethammer M, Tang CC, LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Sarkar A, Siddiqui MS, Tatter SB, Schwalb JM, Poston KL, Henderson JM, Kurlan RM, Richard IH, Sapan CV, Eidelberg D, During MJ, Kaplitt MG, Feigin A. Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson's disease. JCI Insight. 2017 Apr 6;2(7):e90133. doi: 10.1172/jci.insight.90133.

  PMID: 28405611 BACKGROUND

• Spetsieris PG, Ko JH, Tang CC, Nazem A, Sako W, Peng S, Ma Y, Dhawan V, Eidelberg D. Metabolic resting-state brain networks in health and disease. Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2563-8. doi: 10.1073/pnas.1411011112. Epub 2015 Feb 9.

  PMID: 25675473 BACKGROUND

• Mattis PJ, Tang CC, Ma Y, Dhawan V, Eidelberg D. Network correlates of the cognitive response to levodopa in Parkinson disease. Neurology. 2011 Aug 30;77(9):858-65. doi: 10.1212/WNL.0b013e31822c6224. Epub 2011 Aug 17.

  PMID: 21849641 BACKGROUND

• Tang CC, Feigin A, Ma Y, Habeck C, Paulsen JS, Leenders KL, Teune LK, van Oostrom JC, Guttman M, Dhawan V, Eidelberg D. Metabolic network as a progression biomarker of premanifest Huntington's disease. J Clin Invest. 2013 Sep;123(9):4076-88. doi: 10.1172/JCI69411. Epub 2013 Aug 29.

  PMID: 23985564 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Potential subjects may undergo DNA testing for GBA and LRRK2 PD mutations.

MeSH Terms

Conditions

Parkinson Disease; Disease Progression

Interventions

Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• David Eidelberg, MD

  Head, Center for Neurosciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor & Head, Feinstein Center for Neurosciences, Feinstein Institutes for Medical Research

Study Record Dates

• First Submitted: January 7, 2020
• First Posted: January 14, 2020
• Study Start: February 24, 2020
• Primary Completion: April 6, 2026
• Study Completion (Estimated): October 6, 2026
• Last Updated: April 13, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)