title: Cerebral pathological and compensatory mechanisms in the premotor phase of leucine-rich repeat kinase 2 parkinsonism.
abstract: Compensatory cerebral mechanisms can delay motor symptom onset in Parkinson's disease. We aim to characterize these compensatory mechanisms and early disease-related changes by quantifying movement-related cerebral function in subjects at significantly increased risk of developing Parkinson's disease, namely carriers of a leucine-rich repeat kinase 2-G2019S mutation associated with dominantly inherited parkinsonism. Functional magnetic resonance imaging was used to examine cerebral activity evoked during internal selection of motor representations, a core motor deficit in clinically overt Parkinson's disease. Thirty-nine healthy first-degree relatives of Ashkenazi Jewish patients with Parkinson's disease, who carry the leucine-rich repeat kinase 2-G2019S mutation, participated in this study. Twenty-one carriers of the leucine-rich repeat kinase 2-G2019S mutation and 18 non-carriers of this mutation were engaged in a motor imagery task (laterality judgements of left or right hands) known to be sensitive to motor control parameters. Behavioural performance of both groups was matched. Mutation carriers and non-carriers were equally sensitive to the extent and biomechanical constraints of the imagined movements in relation to the current posture of the participants' hands. Cerebral activity differed between groups, such that leucine-rich repeat kinase 2-G2019S carriers had reduced imagery-related activity in the right caudate nucleus and increased activity in the right dorsal premotor cortex. More severe striatal impairment was associated with stronger effective connectivity between the right dorsal premotor cortex and the right extrastriate body area. These findings suggest that altered movement-related activity in the caudate nuclei of leucine-rich repeat kinase 2-G2019S carriers might remain behaviourally latent by virtue of cortical compensatory mechanisms involving long-range connectivity between the dorsal premotor cortex and posterior sensory regions. These functional cerebral changes open the possibility to use a prospective study to test their relevance as early markers of Parkinson's disease.
authors.affiliation: Department of Neurology (935), Radboud University Nijmegen Medical Centre, PO Box 9 101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Bart F L
authors.initials: BF
authors.lastname: van Nuenen
authors.forename: Rick C
authors.initials: RC
authors.lastname: Helmich
authors.forename: Murielle
authors.initials: M
authors.lastname: Ferraye
authors.forename: Avner
authors.initials: A
authors.lastname: Thaler
authors.forename: Talma
authors.initials: T
authors.lastname: Hendler
authors.forename: Avi
authors.initials: A
authors.lastname: Orr-Urtreger
authors.forename: Anat
authors.initials: A
authors.lastname: Mirelman
authors.forename: Susan
authors.initials: S
authors.lastname: Bressman
authors.forename: Karen S
authors.initials: KS
authors.lastname: Marder
authors.forename: Nir
authors.initials: N
authors.lastname: Giladi
authors.forename: Bart P C
authors.initials: BP
authors.lastname: van de Warrenburg
authors.forename: Bastiaan R
authors.initials: BR
authors.lastname: Bloem
authors.forename: Ivan
authors.initials: I
authors.lastname: Toni
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001696:Biomechanical Phenomena; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000098:blood supply / Q000473:pathology*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D005998:Glycine / Q000235:genetics; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007092:Imagination / Q000502:physiology*; D007599:Judaism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D009434:Neural Pathways / Q000098:blood supply / Q000502:physiology; D010100:Oxygen / Q000097:blood; D020734:Parkinsonian Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011930:Reaction Time / Q000502:physiology; D012399:Rotation; D012694:Serine / Q000235:genetics
chemical_list: D012694:Serine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D010100:Oxygen; D005998:Glycine