title: Reorganization of corticostriatal circuits in healthy G2019S LRRK2 carriers.
abstract: OBJECTIVE
  We investigated system-level corticostriatal changes in a human model of premotor Parkinson disease (PD), i.e., healthy carriers of the G2019S LRRK2 mutation that is associated with a markedly increased, age-dependent risk of developing PD.
  
  
  METHODS
  We compared 37 asymptomatic LRRK2 G2019S mutation carriers (age range 30-78 years) with 32 matched, asymptomatic nonmutation carriers (age range 30-74 years). Using fMRI, we tested the hypothesis that corticostriatal connectivity in premotor PD shifts from severely affected to less affected striatal subregions, as shown previously in symptomatic PD. Specifically, we predicted that in premotor PD, the shift in corticostriatal connectivity would follow the same gradient of striatal dopamine depletion known from overt PD, with the dorsoposterior putamen being more affected than the ventroanterior putamen.
  
  
  RESULTS
  The known parallel topology of corticostriatal loops was preserved in each group, but the topography of putamen connectivity shifted. In LRRK2 G2019S mutation carriers, the right inferior parietal cortex had reduced functional connectivity with the dorsoposterior putamen but increased connectivity with the ventroanterior putamen, as compared with noncarriers. This shift in functional connectivity increased with age in LRRK2 G2019S mutation carriers.
  
  
  CONCLUSIONS
  Asymptomatic LRRK2 G2019S mutation carriers show a reorganization of corticostriatal circuits that mirrors findings in idiopathic PD. These changes may reflect premotor basal ganglia dysfunction or circuit-level compensatory changes.
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY. rick.helmich@radboudumc.nl.
authors.forename: Rick C
authors.initials: RC
authors.lastname: Helmich
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.
authors.forename: Avner
authors.initials: A
authors.lastname: Thaler
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.
authors.forename: Bart F L
authors.initials: BF
authors.lastname: van Nuenen
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.
authors.forename: Tanya
authors.initials: T
authors.lastname: Gurevich
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.
authors.forename: Anat
authors.initials: A
authors.lastname: Mirelman
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Marder
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.
authors.forename: Susan
authors.initials: S
authors.lastname: Bressman
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.
authors.forename: Avi
authors.initials: A
authors.lastname: Orr-Urtreger
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.
authors.forename: Nir
authors.initials: N
authors.lastname: Giladi
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.
authors.forename: Bastiaan R
authors.initials: BR
authors.lastname: Bloem
authors.affiliation: From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.
authors.forename: Ivan
authors.initials: I
authors.lastname: Toni
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D005260:Female; D059907:Functional Neuroimaging; D006579:Heterozygote; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009434:Neural Pathways / Q000503:physiopathology; D010296:Parietal Lobe / Q000503:physiopathology*; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D062706:Prodromal Symptoms; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011699:Putamen / Q000503:physiopathology*
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases