Genotypiske påvirkninger på nettverksprogresjon ved Parkinsons sykdom
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.
Studieoversikt
Status
Forhold
Intervensjon / Behandling
Detaljert beskrivelse
Parkinson's disease (PD) patients with mutations in the glucocerebrosidase gene (GBA) tend to have a more aggressive disease course. GBA may therefore provide a target for disease modifying therapies in mutation carriers. Using positron emission tomography (PET) and magnetic resonance imaging (MRI) brain imaging to measure network progression rates in mutation carriers will allow for the assessment of the potential disease modifying effects of new anti-GBA therapies.
The investigators will also determine whether magnetic resonance imaging (MRI) network methods, which are less invasive and more broadly available than positron emission tomography (PET), produce comparable network progression measurements in individual patients. These determinations will be critical for the design of clinical trials of new disease-modifying drugs.
Studietype
Registrering (Faktiske)
Kontakter og plasseringer
Studiesteder
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New York
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Manhasset, New York, Forente stater, 11030
- Feinstein Institutes for Medical Research
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Deltakelseskriterier
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
Tar imot friske frivillige
Kjønn som er kvalifisert for studier
Prøvetakingsmetode
Studiepopulasjon
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
Beskrivelse
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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).
Studieplan
Hvordan er studiet utformet?
Designdetaljer
- Observasjonsmodeller: CASE_CONTROL
- Tidsperspektiver: PROSPECTIVE
Kohorter og intervensjoner
Gruppe / Kohort |
Intervensjon / Behandling |
|---|---|
|
Parkinson's disease (PD) glucocerebrosidase (GBA) carriers
Parkinson's disease subjects with GBA mutation |
Subjects will be tested for GBA and LRRK2 mutation status at baseline. 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. 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. 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) non glucocerebrosidase (GBA) carriers
Parkinson's disease subjects without GBA mutation |
Subjects will be tested for GBA and LRRK2 mutation status at baseline. 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. 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. 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. |
Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
|
Increase in PD related metabolic pattern expression
Tidsramme: Baseline and 18 months later
|
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
|
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Increase in PD related functional pattern expression
Tidsramme: Baseline and 18 months later
|
Changes in PD related and PD cognition related pattern expression in resting state functional magnetic resonance imaging (rs-fMRI) |
Baseline and 18 months later
|
Sekundære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
|
Change in motor function
Tidsramme: Baseline and 18 months later
|
Change in motor function assessed with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III (The sum score ranges between 0-132 points. Higher scores indicate more severe impairment) |
Baseline and 18 months later
|
|
Change in cognitive function
Tidsramme: Baseline and 18 months later
|
Change in cognitive function assessed with neuropsychological testing |
Baseline and 18 months later
|
Samarbeidspartnere og etterforskere
Sponsor
Samarbeidspartnere
Etterforskere
- Hovedetterforsker: David Eidelberg, MD, Head, Center for Neurosciences
Publikasjoner og nyttige lenker
Generelle publikasjoner
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Studierekorddatoer
Studer hoveddatoer
Studiestart (Faktiske)
Primær fullføring (Faktiske)
Studiet fullført (Faktiske)
Datoer for studieregistrering
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Først innsendt som oppfylte QC-kriteriene
Først lagt ut (Faktiske)
Oppdateringer av studieposter
Sist oppdatering lagt ut (Faktiske)
Siste oppdatering sendt inn som oppfylte QC-kriteriene
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Begreper knyttet til denne studien
Nøkkelord
Ytterligere relevante MeSH-vilkår
- Synukleinopatier
- Hjernesykdommer
- Sykdommer i sentralnervesystemet
- Sykdommer i nervesystemet
- Patologiske prosesser
- Sykdomsattributter
- Nevrodegenerative sykdommer
- Bevegelsesforstyrrelser
- Parkinsonlidelser
- Basal ganglia sykdommer
- Patologiske tilstander, tegn og symptomer
- Sykdomsprogresjon
- Parkinsons sykdom
- Undersøkelsesteknikker
- Kjemisteknikker, analytisk
- Spektrumanalyse
- Magnetisk resonansspektroskopi
Andre studie-ID-numre
- MJFF grant 16325
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