Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study

TY - JOUR

T1 - Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease

T2 - ICICLE-PD study

AU - Nombela, Cristina

AU - Rowe, James B

AU - Winder-Rhodes, Sophie E

AU - Hampshire, Adam

AU - Owen, Adrian M

AU - Breen, David P

AU - Duncan, Gordon W

AU - Khoo, Tien K

AU - Yarnall, Alison J

AU - Firbank, Michael J

AU - Chinnery, Patrick F

AU - Robbins, Trevor W

AU - O'Brien, John T

AU - Brooks, David J

AU - Burn, David J

AU - Barker, Roger A

AU - ICICLE-PD Study Group

N1 - © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2014/10

Y1 - 2014/10

N2 - 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.

AB - 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.

KW - Aged

KW - Apolipoproteins E

KW - Brain

KW - Catechol O-Methyltransferase

KW - Cognition

KW - Cognition Disorders

KW - Cohort Studies

KW - Female

KW - Humans

KW - Image Processing, Computer-Assisted

KW - Imagination

KW - Longitudinal Studies

KW - Magnetic Resonance Imaging

KW - Male

KW - Memory

KW - Middle Aged

KW - Mitogen-Activated Protein Kinases

KW - Neuroimaging

KW - Neuropsychological Tests

KW - Parkinson Disease

KW - Psychomotor Performance

KW - Rotation

KW - Space Perception

KW - tau Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/brain/awu201

DO - 10.1093/brain/awu201

M3 - Article

C2 - 25080285

VL - 137

SP - 2743

EP - 2758

JO - Brain

JF - Brain

SN - 1460-2156

IS - 10

ER -