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.

Keywords: Parkinson’s disease; cognition; functional MRI; genetics.

Figure 1

Statistical parametric maps contrasting activity in active versus baseline conditions rendered into a canonical brain in standard anatomic space. (A) Activity during planning minus control condition on Tower of London Task across all groups. (B) Activity during rotations minus baseline on Spatial Rotations Task across all groups. (C) Activity during encoding (pictures seen once) minus baseline on the Encoding Memory Task across all groups. Figures show areas of signal change above a threshold of P = 0.05 after FDR correction for the whole brain volume.

Figure 2

Behavioural performance by groups on (A) Tower of London (planning items) where difficulty is manipulated by the number of movements required; (B) Spatial Rotations Task (rotation items), where difficulty is manipulated by the complexity of the items to rotate; and (C) Encoding Memory Task, where difficulty is manipulated by the number of expositions in the memory task. A1 and B1 show response latency against the three level of difficulty for patients and controls. A2 and B2 show results in accuracy (the number of correct responses) against levels of difficulty for patients and controls. C1 shows the number of correct, incorrect and unseen responses during the post-scan test for patients and controls. C2 shows the number of correct responses for patients and controls, against exposure fold. (once versus twice). *Significant interaction between condition and difficulty (A1 and A2), significant interaction between disease and difficulty (B1 and B2), significant exposure effect (C1) and disease effect (C2), P < 0.05. PD = Parkinson’s disease.

Figure 3

For the Tower of London Task (top left), the activation in regions of interest is presented separately by COMT genotype and LEDD in patients (bottom). The y-axis of each graph represents the mean activation in terms of average parameter estimates. The data are subdivided by a median split of LEDD (above versus below 275 mg/day) for each region of interest (top right). *P < 0.05.

Figure 4

Behavioural responses in the Spatial Rotations Task, showing the number of correct responses during experimental (left) and control (right) conditions, respectively. Repeated-measures ANOVA indicated a significant interaction between MAPT (H1/H1 versus H2 carriers) and difficulty at rotation condition during the Spatial Rotations Task. *P < 0.05. Difficulty is manipulated by the complexity of the items to rotate in the Spatial Rotation Task.

Figure 5

For the Spatial Rotations Task (top left), the activation within each region of interest (top right) is plotted separately for H1 patient homozygotes and H2 patient carriers. The y-axes represent the mean parameter estimate, in arbitrary scaled units. See text for details of the gene by region interaction. Post hoc t-test analysis indicated that region of interest and MAPT genotype interaction occurred at marked areas (bottom). *P < 0.05.

Figure 6

Regional activation during encoding of items in the Encoding Memory Task (top left), illustrating the significant interaction between regional activation and APOE genotype in Parkinson’s disease patients (see text for details). The y-axes represent the mean parameter estimate, in arbitrary scaled units. Post hoc t-test analysis indicated that region of interest and APOE genotype interaction occurred at marked areas (bottom). *P < 0.05. TPO = temporo-parieto-occipital.