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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.

SUBMITTER: Nombela C

PROVIDER: S-EPMC4163033 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mild cognitive impairment in Parkinson's disease is associated with progression to dementia (Parkinson's disease dementia) in a majority of patients. Determining structural imaging biomarkers associated with prodromal Parkinson's disease dementia may allow for the earlier identification of those at risk, and allow for targeted disease modifying therapies. One hundred and five non-demented subjects with newly diagnosed idiopathic Parkinson's disease and 37 healthy matched controls had serial 3 T structural magnetic resonance imaging scans with clinical and neuropsychological assessments at baseline, which were repeated after 18 months. The Movement Disorder Society Task Force criteria were used to classify the Parkinson's disease subjects into Parkinson's disease with mild cognitive impairment (n = 39) and Parkinson's disease with no cognitive impairment (n = 66). Freesurfer image processing software was used to measure cortical thickness and subcortical volumes at baseline and follow-up. We compared regional percentage change of cortical thinning and subcortical atrophy over 18 months. At baseline, cases with Parkinson's disease with mild cognitive impairment demonstrated widespread cortical thinning relative to controls and atrophy of the nucleus accumbens compared to both controls and subjects with Parkinson's disease with no cognitive impairment. Regional cortical thickness at baseline was correlated with global cognition in the combined Parkinson's disease cohort. Over 18 months, patients with Parkinson's disease with mild cognitive impairment demonstrated more severe cortical thinning in frontal and temporo-parietal cortices, including hippocampal atrophy, relative to those with Parkinson's disease and no cognitive impairment and healthy controls, whereas subjects with Parkinson's disease and no cognitive impairment showed more severe frontal cortical thinning compared to healthy controls. At baseline, Parkinson's disease with no cognitive impairment converters showed bilateral temporal cortex thinning relative to the Parkinson's disease with no cognitive impairment stable subjects. Although loss of both cortical and subcortical volume occurs in non-demented Parkinson's disease, our longitudinal analyses revealed that Parkinson's disease with mild cognitive impairment shows more extensive atrophy and greater percentage of cortical thinning compared to Parkinson's disease with no cognitive impairment. In particular, an extension of cortical thinning in the temporo-parietal regions in addition to frontal atrophy could be a biomarker in therapeutic studies of mild cognitive impairment in Parkinson's disease for progression towards dementia.

Project description:BackgroundThe immune system is a promising therapeutic target for disease modification in Parkinson's disease (PD), but appropriate immune-related biomarkers must be identified to allow patient stratification for trials and tracking of therapeutic effects. The objective of this study was to investigate whether immune markers in peripheral blood are candidate prognostic biomarkers through determining their relationship with disease progression in PD.MethodsSerum samples were collected in incident PD cases and age-matched controls. Subjects were clinically evaluated at baseline and 18 and 36 months. Ten cytokines and C-reactive protein were measured, with data reduction using principal-component analysis, and relationships between component scores and motor (MDS Unified Parkinson's Disease Rating Scale - part 3) and cognitive (Mini Mental State Examination [MMSE]) measures of disease severity/progression were investigated.ResultsTNF-?, IL1-?, IL-2, and IL-10 were higher in PD (n = 230) than in controls (n = 93), P ? 0.001). Principal-component analysis of log-transformed data resulted in a 3-component solution explaining 51% of the variance. Higher "proinflammatory" and lower "anti-inflammatory" component scores were associated with more rapid motor progression over 36 months (P < 0.05), and higher "proinflammatory" component scores were associated with lower MMSE at all times (P < 0.05). Multiple linear regression analysis with adjustment for covariates confirmed "anti-inflammatory" component score was the strongest predictor of slower motor progression (? = -0.22, P = 0.002), whereas proinflammatory cytokines were associated with lower baseline MMSE (? = -0.175, P = 0.007).ConclusionsSerum immune marker profile is predictive of disease progression in PD and hence a potential prognostic biomarker. However, interventional trials are needed to clarify whether peripheral immune changes causally contribute to the progression of PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Project description:ObjectiveThe objective of this study was to develop valid prognostic models to predict mortality, dependency, and "death or dependency" for use in newly diagnosed Parkinson's disease (PD).MethodsThe models were developed in the Parkinsonism Incidence in North-East Scotland study (UK, 198 patients) and validated in the ParkWest study (Norway, 192 patients), cohorts that attempted to identify and follow-up all new PD cases in the study area. Dependency was defined using the Schwab & England scale. We selected variables measured at time of diagnosis to include in the models. Internal validation and external validation were performed by calculating C-statistics (discrimination) and plotting observed versus predicted risk in quantiles of predicted risk (calibration).ResultsOlder age, male sex, increased severity of axial features, and Charlson comorbidity index were independent prognostic factors in the mortality model. Increasing age, higher smoking history, increased severity of axial features, and lower MMSE score were independent predictors in the models of dependency and "death or dependency." Each model had very good internal calibration and very good or good discrimination (internal and external C-statistics for the models were 0.73-0.75 and 0.68-0.78, respectively). Although each model clearly separated patients into groups according to risk, they tended to overestimate risk in ParkWest. The models were recalibrated to the baseline risk in the ParkWest study and then calibrated well in this cohort.ConclusionsWe have developed prognostic models for predicting medium-term risk of important clinical outcomes in newly diagnosed PD. These models have validity for use for stratification of randomization, confounder adjustment, and case-mix correction, but they are inadequate for individualized prognostication. © 2017. The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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

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