title: Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study.
abstract: Parkinson's disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the 'Dual Syndrome' hypothesis for cognitive impairment in Parkinson's disease, which distinguishes an executive syndrome (affecting the frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson's disease cohort (n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms associated with cognitive change in Parkinson's disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii) rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-ε2, 3, 4. We identified performance deficits in all three cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations in Parkinson's disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson's disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson's disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson's disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson's disease.
authors: 1 John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK dra.cristinanombela@gmail.com.
authors: Cristina
authors: C
authors: Nombela
authors: 2 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK 3 Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, UK 4 Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK.
authors: James B
authors: JB
authors: Rowe
authors: 1 John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors: Sophie E
authors: SE
authors: Winder-Rhodes
authors: 5 Computational, Cognitive and Clinical Neuroscience Laboratory, Imperial College London, London, UK.
authors: Adam
authors: A
authors: Hampshire
authors: 6 Brain and Mind Institute, University of Western Ontario, London, Canada 7 Department of Psychology, University of Western Ontario, London, Canada.
authors: Adrian M
authors: AM
authors: Owen
authors: 1 John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors: David P
authors: DP
authors: Breen
authors: 8 Institute for Ageing and Health, Newcastle University, Newcastle, UK.
authors: Gordon W
authors: GW
authors: Duncan
authors: 9 Griffith Health Institute and School of Medicine, Griffith University, Gold Coast, Australia.
authors: Tien K
authors: TK
authors: Khoo
authors: 8 Institute for Ageing and Health, Newcastle University, Newcastle, UK.
authors: Alison J
authors: AJ
authors: Yarnall
authors: 8 Institute for Ageing and Health, Newcastle University, Newcastle, UK.
authors: Michael J
authors: MJ
authors: Firbank
authors: 10 Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
authors: Patrick F
authors: PF
authors: Chinnery
authors: 4 Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK.
authors: Trevor W
authors: TW
authors: Robbins
authors: 11 Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors: John T
authors: JT
authors: O'Brien
authors: 12 Imperial College London, London, UK 13 Department of Clinical Medicine, Positron Emission Tomography Centre, Aarhus University, Denmark.
authors: David J
authors: DJ
authors: Brooks
authors: 8 Institute for Ageing and Health, Newcastle University, Newcastle, UK.
authors: David J
authors: DJ
authors: Burn
authors: 1 John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors: Roger A
authors: RA
authors: Barker
mesh_terms: D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000503:physiopathology*; D002394:Catechol O-Methyltransferase / Q000235:genetics; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000209:etiology / Q000523:psychology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007092:Imagination / Q000502:physiology; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008568:Memory / Q000502:physiology; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D059906:Neuroimaging; D009483:Neuropsychological Tests; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology*; D011597:Psychomotor Performance / Q000502:physiology; D012399:Rotation; D013028:Space Perception / Q000502:physiology; D016875:tau Proteins / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D016875:tau Proteins; D002394:Catechol O-Methyltransferase; D020928:Mitogen-Activated Protein Kinases
keywords: Parkinson’s disease; cognition; functional MRI; genetics