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Parkinson Disease: HELP
Articles by Trevor W. Robbins
Based on 23 articles published since 2008
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Between 2008 and 2019, Trevor W. Robbins wrote the following 23 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Review Cognitive deficits in Parkinson's disease: a cognitive neuroscience perspective. 2014

Robbins, Trevor W / Cools, Roshan. ·Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom. ·Mov Disord · Pubmed #24757109.

ABSTRACT: Progress in characterization of the nature, neural basis, and treatment of cognitive deficits in Parkinson's disease is reviewed from the perspective of cognitive neuroscience. An initial emphasis on fronto-striatal executive deficits is surveyed along with the discoveries of disruption as well as remediation of certain impairments by dopaminergic mediation and their association with theories of reinforcement learning. Subsequent focus on large cohorts has revealed considerable heterogeneity in the cognitive impairments as well as a suggestion of at least two distinct syndromes, with the dopamine-dependent fronto-striatal deficits being somewhat independent of other signs commonly associated with Parkinson's disease dementia. The utility is proposed of a new, integrated cognitive neuroscience approach based on combining genetic and neuroimaging methodologies with neuropsychological and, ultimately, psychopharmacological approaches.

2 Review Parkinson's disease--the debate on the clinical phenomenology, aetiology, pathology and pathogenesis. 2013

Jenner, Peter / Morris, Huw R / Robbins, Trevor W / Goedert, Michel / Hardy, John / Ben-Shlomo, Yoav / Bolam, Paul / Burn, David / Hindle, John V / Brooks, David. ·Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King's College, London, UK. peter.jenner@kcl.ac.uk ·J Parkinsons Dis · Pubmed #23938306.

ABSTRACT: The definition of Parkinson's disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article--widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic perspective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include--Parkinson's syndrome, Parkinson's syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA).

3 Review Cognitive impairment in Parkinson's disease: the dual syndrome hypothesis. 2013

Kehagia, Angie A / Barker, Roger A / Robbins, Trevor W. ·School of Psychology, University of St. Andrews, St. Andrews, UK. ·Neurodegener Dis · Pubmed #23038420.

ABSTRACT: Research into the heterogeneous nature of cognitive impairment documented in patients with Parkinson's disease (PD) has focused on disentangling deficits that vary between individuals, evolve and respond differentially to pharmacological treatments, and relate differentially to PD dementia (PDD). We summarise studies conducted in our laboratory over the last 2 decades, outlining the incremental development of our hypotheses, the starting point for which is our early work on executive deficits mirroring fronto-striatal dysfunction. We present subsequent findings linking these deficits to a model of dopaminergic function that conforms to an inverted curvilinear function. We review studies that investigated the range of dopamine-independent attentional and visuospatial memory deficits seen in PD, demonstrating that abnormalities in these domains more accurately predict PDD. We conclude with an exposition of the dual syndrome hypothesis, which distinguishes between dopaminergically mediated fronto-striatal executive impairments and a dementia syndrome with distinctive prodromal visuospatial deficits in which cholinergic treatments offer some clinical benefits.

4 Review Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson's disease. 2010

Kehagia, Angie A / Barker, Roger A / Robbins, Trevor W. ·Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK; Department of Experimental Psychology, University of Cambridge, UK. · Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, UK. · Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK; Department of Experimental Psychology, University of Cambridge, UK. Electronic address: twr2@cam.ac.uk. ·Lancet Neurol · Pubmed #20880750.

ABSTRACT: Cognitive impairment in patients with Parkinson's disease is gaining increased clinical significance owing to the relative success of therapeutic approaches to the motor symptoms of this disorder. Early investigations contributed to the concept of subcortical dementia associated with bradyphrenia and cognitive rigidity. For cognition in parkinsonian disorders, this notion developed into the concept of mild cognitive impairment and fronto-executive dysfunction in particular, driven mainly by dopaminergic dysmodulation and manifesting as deficits in flexibility, planning, working memory, and reinforcement learning. However, patients with Parkinson's disease could also develop a syndrome of dementia that might depend on non-dopaminergic, cholinergic cortical dysfunction. Recent findings, supplemented by advances in neuroimaging and genetic research, reveal substantial heterogeneity in the range of cognitive deficits in patients with Parkinson's disease. Remediation and management prospects for these cognitive deficits are based on neuropharmacological and cognitive rehabilitation approaches.

5 Review Personality, addiction, dopamine: insights from Parkinson's disease. 2009

Dagher, Alain / Robbins, Trevor W. ·Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada. alain.dagher@mcgill.ca ·Neuron · Pubmed #19249271.

ABSTRACT: In rare instances, patients with Parkinson's disease (PD) may become addicted to their own medication or develop behavioral addictions such as pathological gambling. This is surprising because PD patients typically have a very low incidence of drug abuse and display a personality type that is the polar opposite of the addictive personality. These rare addictive syndromes, which appear to result from excessive dopaminergic medication use, illustrate the link between dopamine, personality, and addiction. We describe the clinical phenomena and attempt to relate them to current models of learning and addiction. We conclude that persistently elevated dopaminergic stimulation promotes the development and maintenance of addictive behaviors.

6 Article Atomoxetine restores the response inhibition network in Parkinson's disease. 2016

Rae, Charlotte L / Nombela, Cristina / Rodríguez, Patricia Vázquez / Ye, Zheng / Hughes, Laura E / Jones, P Simon / Ham, Timothy / Rittman, Timothy / Coyle-Gilchrist, Ian / Regenthal, Ralf / Sahakian, Barbara J / Barker, Roger A / Robbins, Trevor W / Rowe, James B. ·1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK 2 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, CB2 7EF, UK. · 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK. · 3 Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, 04107, Germany. · 4 Behavioural and Clinical Neuroscience Institute, Cambridge, CB2 3EB, UK 5 Department of Psychiatry, University of Cambridge, CB2 0SZ, Cambridge, UK. · 4 Behavioural and Clinical Neuroscience Institute, Cambridge, CB2 3EB, UK 6 Department of Experimental Psychology, University of Cambridge, CB2 3EB, Cambridge, UK. · 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK 2 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, CB2 7EF, UK 4 Behavioural and Clinical Neuroscience Institute, Cambridge, CB2 3EB, UK james.rowe@mrc-cbu.cam.ac.uk. ·Brain · Pubmed #27343257.

ABSTRACT: Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease.

7 Article Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease. 2016

Borchert, Robin J / Rittman, Timothy / Passamonti, Luca / Ye, Zheng / Sami, Saber / Jones, Simon P / Nombela, Cristina / Vázquez Rodríguez, Patricia / Vatansever, Deniz / Rae, Charlotte L / Hughes, Laura E / Robbins, Trevor W / Rowe, James B. ·Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. · National Research Council, Institute of Bioimaging and Molecular Physiology, Catanzaro, Italy. · Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China. · Systems and Automatic Control Engineering, Technical University of Cartagena, Cartagena, Spain. · Division of Anaesthesia, University of Cambridge, Cambridge, UK. · Sackler Centre for Consciousness Science, University of Sussex, Brighton, UK. · Department of Psychiatry, Brighton and Sussex Medical School, Brighton, UK. · MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK. · University of Cambridge Behavioural and Clinical Neuroscience Institute, Cambridge, UK. ·Neuropsychopharmacology · Pubmed #26837463.

ABSTRACT: Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest ('task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems.

8 Article Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures. 2016

Ye, Zheng / Rae, Charlotte L / Nombela, Cristina / Ham, Timothy / Rittman, Timothy / Jones, Peter Simon / Rodríguez, Patricia Vázquez / Coyle-Gilchrist, Ian / Regenthal, Ralf / Altena, Ellemarije / Housden, Charlotte R / Maxwell, Helen / Sahakian, Barbara J / Barker, Roger A / Robbins, Trevor W / Rowe, James B. ·Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom. · Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China. · Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom. · Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany. · Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. · Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom. · Department of Psychology, University of Cambridge, Cambridge, United Kingdom. ·Hum Brain Mapp · Pubmed #26757216.

ABSTRACT: Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double-blind randomized three-way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion-weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave-one-out cross-validation (LOOCV) to predict patients' responses in terms of improved stopping efficiency. We identified two optimal models: (1) a "clinical" model that predicted the response of an individual patient with 77-79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion-weighted imaging scan; and (2) a "mechanistic" model that explained the behavioral response with 85% accuracy for each drug, using drug-induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features.

9 Article Association between MAPT haplotype and memory function in patients with Parkinson's disease and healthy aging individuals. 2015

Winder-Rhodes, Sophie E / Hampshire, Adam / Rowe, James B / Peelle, Jonathan E / Robbins, Trevor W / Owen, Adrian M / Barker, Roger A. ·Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King's College London, UK. Electronic address: sophie.winder-rhodes@doctors.org.uk. · MRC Cognition and Brain Sciences Unit, Cambridge, UK; The Division of Brain Sciences, Department of Medicine, Imperial College, London, UK. · Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; MRC Cognition and Brain Sciences Unit, Cambridge, UK; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. · Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO, USA. · Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. · MRC Cognition and Brain Sciences Unit, Cambridge, UK; The Brain and Mind Institute, The University of Western Ontario, London Ontario, Canada. · Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. Electronic address: rab46@cam.ac.uk. ·Neurobiol Aging · Pubmed #25577413.

ABSTRACT: Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene (MAPT) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of MAPT haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was associated with impaired picture recognition memory in PD patients and control subjects. These impairments in the H1 homozygotes were accompanied by an altered blood-oxygen level-dependent response in the medial temporal lobe during successful memory encoding. Additional age-related differences in blood-oxygen level-dependent response were observed in the medial temporal lobes of H1 homozygotes with PD. These results suggest that common variation in MAPT is not only associated with the dementia of PD but also differences in the neural circuitry underlying aspects of cognition in normal aging.

10 Article Iowa gambling task impairment in Parkinson's disease can be normalised by reduction of dopaminergic medication after subthalamic stimulation. 2015

Castrioto, Anna / Funkiewiez, Aurélie / Debû, Bettina / Cools, Roshan / Lhommée, Eugénie / Ardouin, Claire / Fraix, Valérie / Chabardès, Stephan / Robbins, Trevor W / Pollak, Pierre / Krack, Paul. ·Movement Disorder Unit, Department of Psychiatry and Neurology, CHU de Grenoble, Joseph Fourier University, Grenoble, France INSERM, Unité 836, Grenoble Institut des Neurosciences, Grenoble, France Clinica Neurologica, Università degli Studi di Perugia, Perugia, Italy. · Movement Disorder Unit, Department of Psychiatry and Neurology, CHU de Grenoble, Joseph Fourier University, Grenoble, France INSERM-UPMC UMRS 975, IMMA, Fédération de Neurologie, AP-HP Hôpital de la Pitié-Salpêtrière, Paris, France. · Movement Disorder Unit, Department of Psychiatry and Neurology, CHU de Grenoble, Joseph Fourier University, Grenoble, France INSERM, Unité 836, Grenoble Institut des Neurosciences, Grenoble, France. · Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging Nijmegen, Nijmegen, The Netherlands Department of Psychology, Behavioural, and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. · INSERM, Unité 836, Grenoble Institut des Neurosciences, Grenoble, France Neurosurgery Department, CHU de Grenoble, Joseph Fourier University, Grenoble, France. · Department of Psychology, Behavioural, and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. · Movement Disorder Unit, Department of Psychiatry and Neurology, CHU de Grenoble, Joseph Fourier University, Grenoble, France Service de Neurologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland. ·J Neurol Neurosurg Psychiatry · Pubmed #24860137.

ABSTRACT: BACKGROUND: Impulse control disorders (ICD), including pathological gambling, are common in Parkinson's disease (PD) and tend to improve after subthalamic (STN) stimulation after a marked reduction of dopaminergic medication. In order to investigate the effect of STN stimulation on impulsive decision making, we used the Iowa Gambling task (IGT). METHODS: We investigated IGT performance in 20 patients with PD before STN surgery with and without dopaminergic treatment and in 24 age-matched controls. All patients underwent an extensive neuropsychological interview screening for behavioural disorders. Assessment in patients was repeated 3 months after surgery without dopaminergic treatment with and without stimulation. RESULTS: Chronic antiparkinsonian treatment was drastically reduced after surgery (-74%). At baseline, on high chronic dopaminergic treatment 8/20 patients with PD presented with pathological hyperdopaminergic behaviours, which had resolved in 7/8 patients 3 months after surgery on low chronic dopaminergic treatment. Preoperative performance on the IGT was significantly impaired compared to after surgery. CONCLUSIONS: Dopaminergic medication likely contributes to the impairment in decision making underlying ICDs. Deep brain stimulation allows drastic reduction of dopaminergic medication and, thus, concomitant remediation of medication-induced impairment in decision making.

11 Article Improving response inhibition in Parkinson's disease with atomoxetine. 2015

Ye, Zheng / Altena, Ellemarije / Nombela, Cristina / Housden, Charlotte R / Maxwell, Helen / Rittman, Timothy / Huddleston, Chelan / Rae, Charlotte L / Regenthal, Ralf / Sahakian, Barbara J / Barker, Roger A / Robbins, Trevor W / Rowe, James B. ·Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom. · Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Cognition Ltd, University of Cambridge, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute , University of Cambridge, Cambridge, United Kingdom. · Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom. · Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom. · Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany. · Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom. · Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom. · Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom. Electronic address: James.Rowe@mrc-cbu.cam.ac.uk. ·Biol Psychiatry · Pubmed #24655598.

ABSTRACT: BACKGROUND: Dopaminergic drugs remain the mainstay of Parkinson's disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. METHODS: This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. RESULTS: Patients with Parkinson's disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. CONCLUSIONS: This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson's disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson's disease.

12 Article Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study. 2014

Nombela, Cristina / Rowe, James B / Winder-Rhodes, Sophie E / Hampshire, Adam / Owen, Adrian M / Breen, David P / Duncan, Gordon W / Khoo, Tien K / Yarnall, Alison J / Firbank, Michael J / Chinnery, Patrick F / Robbins, Trevor W / O'Brien, John T / Brooks, David J / Burn, David J / Anonymous710802 / Barker, Roger A. ·1 John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK dra.cristinanombela@gmail.com. · 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. · 1 John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK. · 5 Computational, Cognitive and Clinical Neuroscience Laboratory, Imperial College London, London, UK. · 6 Brain and Mind Institute, University of Western Ontario, London, Canada 7 Department of Psychology, University of Western Ontario, London, Canada. · 8 Institute for Ageing and Health, Newcastle University, Newcastle, UK. · 9 Griffith Health Institute and School of Medicine, Griffith University, Gold Coast, Australia. · 10 Institute of Genetic Medicine, Newcastle University, Newcastle, UK. · 4 Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK. · 11 Department of Psychiatry, University of Cambridge, Cambridge, UK. · 12 Imperial College London, London, UK 13 Department of Clinical Medicine, Positron Emission Tomography Centre, Aarhus University, Denmark. ·Brain · Pubmed #25080285.

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.

13 Article Targeting impulsivity in Parkinson's disease using atomoxetine. 2014

Kehagia, Angie A / Housden, Charlotte R / Regenthal, Ralf / Barker, Roger A / Müller, Ulrich / Rowe, James / Sahakian, Barbara J / Robbins, Trevor W. ·1 Department of Neuroimaging, Institute of Psychiatry, King's College London, London SE5 8AF, UK angie.kehagia@gmail.com. · 2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK3 Cambridge Cognition Limited, Cambridge, UK4 Department of Psychiatry, University of Cambridge, Cambridge, UK. · 5 Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Germany. · 6 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. · 2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK4 Department of Psychiatry, University of Cambridge, Cambridge, UK7 Adult ADHD Service, Cambridgeshire and Peterborough NHS Foundation Trust, UK. · 2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK6 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK8 MRC Cognition and Brain Sciences Unit, Cambridge, UK. · 2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK4 Department of Psychiatry, University of Cambridge, Cambridge, UK. · 2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK9 Department of Psychology, University of Cambridge, Cambridge, UK. ·Brain · Pubmed #24893708.

ABSTRACT: Noradrenergic dysfunction may play a significant role in cognition in Parkinson's disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson's disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P = 0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R(2) = 0.23, F(1,16) = 5.83, P = 0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R(2) = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P = 0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson's disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder.

14 Article Selective serotonin reuptake inhibition modulates response inhibition in Parkinson's disease. 2014

Ye, Zheng / Altena, Ellemarije / Nombela, Cristina / Housden, Charlotte R / Maxwell, Helen / Rittman, Timothy / Huddleston, Chelan / Rae, Charlotte L / Regenthal, Ralf / Sahakian, Barbara J / Barker, Roger A / Robbins, Trevor W / Rowe, James B. ·1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. ·Brain · Pubmed #24578545.

ABSTRACT: Impulsivity is common in Parkinson's disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic 'overdose' and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson's disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson's disease (46-76 years old, 11 male, Hoehn and Yahr stage 1.5-3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54-74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson's disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson's Disease Rating Scale motor score). The behavioural effect correlated with the citalopram-induced enhancement of prefrontal activation and the strength of preserved structural connectivity between the frontal and striatal regions. In conclusion, the behavioural effect of citalopram on response inhibition depends on individual differences in prefrontal cortical activation and frontostriatal connectivity. The correlation between disease severity and the effect of citalopram on response inhibition may be due to the progressive loss of forebrain serotonergic projections. These results contribute to a broader understanding of the critical roles of serotonin in regulating cognitive and behavioural control, as well as new strategies for patient stratification in clinical trials of serotonergic treatments in Parkinson's disease.

15 Article Multiple modes of impulsivity in Parkinson's disease. 2014

Nombela, Cristina / Rittman, Timothy / Robbins, Trevor W / Rowe, James B. ·Department of Clinical Neurosciences, Cambridge University, Cambridge, United Kingdom. · Department of Psychology, Cambridge University, Cambridge, United Kingdom ; Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom. · Department of Clinical Neurosciences, Cambridge University, Cambridge, United Kingdom ; Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom ; Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, United Kingdom. ·PLoS One · Pubmed #24465678.

ABSTRACT: Cognitive problems are a major factor determining quality of life of patients with Parkinson's disease. These include deficits in inhibitory control, ranging from subclinical alterations in decision-making to severe impulse control disorders. Based on preclinical studies, we proposed that Parkinson's disease does not cause a unified disorder of inhibitory control, but rather a set of impulsivity factors with distinct psychological profiles, anatomy and pharmacology. We assessed a broad set of measures of the cognitive, behavioural and temperamental/trait aspects of impulsivity. Sixty adults, including 30 idiopathic Parkinson's disease patients (Hoehn and Yahr stage I-III) and 30 healthy controls, completed a neuropsychological battery, objective behavioural measures and self-report questionnaires. Univariate analyses of variance confirmed group differences in nine out of eleven metrics. We then used factor analysis (principal components method) to identify the structure of impulsivity in Parkinson's disease. Four principal factors were identified, consistent with four different mechanisms of impulsivity, explaining 60% of variance. The factors were related to (1) tests of response conflict, interference and self assessment of impulsive behaviours on the Barrett Impulsivity Scale, (2) tests of motor inhibitory control, and the self-report behavioural approach system, (3) time estimation and delay aversion, and (4) reflection in hypothetical scenarios including temporal discounting. The different test profiles of these four factors were consistent with human and comparative studies of the pharmacology and functional anatomy of impulsivity. Relationships between each factor and clinical and demographic features were examined by regression against factor loadings. Levodopa dose equivalent was associated only with factors (2) and (3). The results confirm that impulsivity is common in Parkinson's disease, even in the absence of impulse control disorders, and that it is not a unitary phenomenon. A better understanding of the structure of impulsivity in Parkinson's disease will support more evidence-based and effective strategies to treat impulsivity.

16 Article Characterizing mild cognitive impairment in incident Parkinson disease: the ICICLE-PD study. 2014

Yarnall, Alison J / Breen, David P / Duncan, Gordon W / Khoo, Tien K / Coleman, Shirley Y / Firbank, Michael J / Nombela, Cristina / Winder-Rhodes, Sophie / Evans, Jonathan R / Rowe, James B / Mollenhauer, Brit / Kruse, Niels / Hudson, Gavin / Chinnery, Patrick F / O'Brien, John T / Robbins, Trevor W / Wesnes, Keith / Brooks, David J / Barker, Roger A / Burn, David J / Anonymous5370779. ·From the Institute for Ageing and Health (A.J.Y., G.W.D., M.J.F., D.J.B.), Industrial Statistics Research Unit (S.Y.C.), and Institute of Genetic Medicine (G.H., P.F.C.), Newcastle University · John van Geest Centre for Brain Repair (D.P.B., J.R.E., R.A.B.), Department of Clinical Neurosciences (C.N., S.W.-R., J.B.R.), Behavioural and Clinical Neuroscience Institute (C.N., S.W.-R., J.B.R., T.W.R.), MRC Cognition and Brain Sciences Unit (C.N., S.W.-R., J.B.R.), Departments of Psychiatry (J.T.O.) and Psychology (T.W.R.), University of Cambridge, UK · School of Medicine (T.K.K.), Griffith University, Australia · Paracelsus-Elena-Klinik (B.M.), Kassel, and Göttingen University · Institute for Neuropathology (N.K.), Prion and Dementia Research Unit, University Medical Centre Göttingen, Germany · Centre for Human Psychopharmacology (K.W.), Swinburne University, Melbourne, Australia · and Department of Medicine (D.J.W.), Imperial College London, UK. ·Neurology · Pubmed #24363137.

ABSTRACT: OBJECTIVE: To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers. METHODS: Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria. RESULTS: The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1-42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1-42 and 1-40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold. CONCLUSIONS: In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1-42 and 1-40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.

17 Article Revisiting the effects of Parkinson's disease and frontal lobe lesions on task switching: the role of rule reconfiguration. 2014

Kehagia, Angie A / Barker, Roger A / Robbins, Trevor W. ·Institute of Psychiatry, King's College London, UK; Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK. ·J Neuropsychol · Pubmed #23279799.

ABSTRACT: This study investigated the hypothesis that rule reconfiguration in task switching can isolate aspects of intact and impaired control at different stages of Parkinson's disease (PD) by comparing switches between concrete naming rules pertaining to stimulus selection, to switches between abstract rules which allocate categorization responses to these stimuli. Based on previous findings, it was hypothesized that attentional switches, where task set competition emerges at the stimulus but not response set level, highlights striatal dopaminergic function. Conversely, increasing the degree of task set competition to encompass reconfiguration of response set when switching between abstract rules, represents a condition which engages the prefrontal cortex (PFC) and renders this manipulation sensitive to frontal damage. To this end, we investigated task switching with concrete and abstract rules in unilaterally (Hoehn & Yahr stage I) and bilaterally (Hoehn & Yahr stage II) affected PD patients, as well as striatally intact frontal lesion patients. As predicted, frontal lesion patients demonstrated switching deficits only with abstract categorization rules, where switching engendered complete task set reconfiguration and a new response, as did stage II PD patients with presumed frontal cortical pathology. Replicating previous findings, stage I PD patients with relatively circumscribed striatal pathology demonstrated no such impairment. Disease severity also impacted on attentional switching indexed by naming rules, since medicated stage II but not stage I patients demonstrated switching deficits emerging from stimulus set reconfiguration, suggesting that the ameliorative efficacy of dopaminergic medication is inversely related to the severity of the striatal deficit. These findings illustrate that the nature of the rules that are switched, and its implication in terms of reconfiguring different task set elements, highlights different neural characters of cognitive flexibility. These manipulations may help decipher the differential effects of progressive neurodegeneration on parkinsonian cognition, and provide a framework in which to conceptualize the contributions of cortical and subcortical regions to cognitive control.

18 Article The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort. 2013

Williams-Gray, Caroline H / Mason, Sarah L / Evans, Jonathan R / Foltynie, Thomas / Brayne, Carol / Robbins, Trevor W / Barker, Roger A. ·John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. ·J Neurol Neurosurg Psychiatry · Pubmed #23781007.

ABSTRACT: BACKGROUND: Prognosis in Parkinson's disease (PD) remains poorly understood due to a lack of unbiased data on the natural history of treated PD. The CamPaIGN study has been the first to prospectively track disease evolution from diagnosis in an unselected population-representative incident cohort. We now report the 10-year follow-up data, focusing on three key irreversible milestones: postural instability (Hoehn and Yahr 3), dementia and death. METHODS: The cohort was collected between December 2000 and 2002. Those meeting diagnostic criteria (n=142) were followed-up until 1 January 2012. Clinical, neuropsychological and genetic testing were performed. Progression to key milestones was evaluated using Kaplan-Meier and Cox regression survival analyses. RESULTS: At 10 years, 55% had died, 68% had postural instability and 46% dementia. 23% had a good outcome at 10 years (surviving free of dementia/postural instability). Death rate was comparable with the UK population (standardised mortality ratio 1.29 (0.97-1.61)). Death certificates indicated PD was a substantial contributor in only 20%, with pneumonia being the commonest cause of death. Age, non-tremor-dominant motor phenotype and comorbidity predicted earlier postural instability. Baseline predictors of dementia were age, motor impairment, 'posterior-cortical' cognitive deficits and MAPT genotype. CONCLUSIONS: (1) outlook in PD is heterogeneous, with most dying or developing dementia or postural instability by 10 years from diagnosis, but a quarter still doing well, with preserved mobility and intact cognition; (2) death is not directly related to PD in the majority; (3) baseline clinical and genetic variables are predictive of outcome and may be helpful in selecting patients for clinical trials.

19 Article The catechol-O-methyltransferase Val(158)Met polymorphism modulates fronto-cortical dopamine turnover in early Parkinson's disease: a PET study. 2012

Wu, Kit / O'Keeffe, Deirdre / Politis, Marios / O'Keeffe, Grainne C / Robbins, Trevor W / Bose, Subrata K / Brooks, David J / Piccini, Paola / Barker, Roger A. ·Centre for Neuroscience, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, UK. kit.wu@imperial.ac.uk ·Brain · Pubmed #22843413.

ABSTRACT: Cognitive deficits occur in up to 30% of patients with early Parkinson's disease, some of which are thought to result from dysfunction within the fronto-striatal dopaminergic network. Recently, it has been shown that a common functional polymorphism (Val(158)Met) in the catechol-O-methyltransferase (COMT) gene is associated with changes in executive performance in tasks that have a fronto-striatal basis. This is thought to relate to changes in cortical dopamine levels as catechol-O-methyltransferase is the main mode of inactivation for dopamine in frontal areas. However to date, no study has investigated dopamine turnover as a function of this genetic polymorphism in Parkinson's disease. We, therefore, set out to investigate in vivo changes in presynaptic dopamine storage in patients with idiopathic Parkinson's disease as a function of the catechol-O-methyltransferase Val(158)Met polymorphism using (18)F-DOPA positron emission tomography. Twenty patients with Parkinson's disease (10 homozygous for Val/Val and 10 for Met/Met catechol-O-methyltransferase polymorphisms) underwent (18)F-DOPA positron emission tomography using a prolonged imaging protocol. The first dynamic scan was acquired from 0 to 90 min (early), and the second scan (late) from 150 to 210 min post-intravenous radioligand administration. Patients were matched for age, sex, verbal IQ, disease duration and severity of motor features. (18)F-DOPA influx constants (Ki) were calculated and compared for frontal and striatal regions. Late scan mean frontal and striatal Ki values were significantly reduced in both Parkinson's disease groups relative to early scan Ki values. Met/Met patients had significantly higher late scan Ki values compared with their Val/Val counterparts in anterior cingulate, superior frontal and mid-frontal regions but early frontal Ki values were not different between the two groups. As late Ki values reflect rates of dopamine metabolism to 3,4-dihydroxyphenylacetic acid and homovanillic acid, our results indicate that Met homozygotes have higher presynaptic dopamine levels in frontal regions than Val homozygotes, which may help to explain how this genotypic variation may influence the fronto-striatal cognitive deficits of Parkinson's disease.

20 Article The natural history of treated Parkinson's disease in an incident, community based cohort. 2011

Evans, Jonathan R / Mason, Sarah L / Williams-Gray, Caroline H / Foltynie, Thomas / Brayne, Carol / Robbins, Trevor W / Barker, Roger A. ·Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK. jonathanevans@doctors.org.uk ·J Neurol Neurosurg Psychiatry · Pubmed #21593513.

ABSTRACT: BACKGROUND: Our understanding of the natural history of idiopathic Parkinson's disease (PD) remains limited. In the era of potential disease modifying therapies, there is an urgent need for studies assessing the natural evolution of treated PD from onset so that relevant outcome measures can be identified for clinical trials. No previous studies have charted progression in unselected patients followed from the point of diagnosis. METHODS: A representative cohort of 132 PD patients was followed from diagnosis for up to 7.9 years (mean 5.2 years). Comprehensive clinical and neuropsychological evaluations were performed every 18 months. Disease progression was evaluated using well validated clinical measures (motor progression and development of dyskinesia on the Unified PD Rating Scale and Hoehn-Yahr scale, dementia onset according to DSM-IV criteria). Multi-level linear modelling was used to chart the nature and rate of progression in parkinsonian symptoms and signs over time. The prognostic importance of baseline demogr‘aphic, clinical and genetic variables was evaluated using survival analysis. RESULTS: Axial (gait and postural) symptoms evolve more rapidly than other motor features of PD and appear to be the best index of disease progression. Conversely, conventional outcome measures are relatively insensitive to change over time. Earlier onset of postural instability (Hoehn-Yahr stage 3) is strongly associated with increased age at disease onset and has a significant impact on quality of life. CONCLUSIONS: Dementia risk is associated with increased age, impaired baseline semantic fluency and the MAPT H1/H1 genotype. The efficacy of disease modifying therapies may be more meaningfully assessed in terms of their effects in delaying the major milestones of PD, such as postural instability and dementia, since it is these that have the greatest impact on patients.

21 Article Top-down attentional control in Parkinson's disease: salient considerations. 2010

Cools, Roshan / Rogers, Robert / Barker, Roger A / Robbins, Trevor W. ·Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Centre, The Netherlands. roshan.cools@donders.ru.nl ·J Cogn Neurosci · Pubmed #19320545.

ABSTRACT: Cognitive dysfunction in Parkinson's disease (PD) has been hypothesized to reflect a failure of cortical control. In keeping with this hypothesis, some of the cognitive deficits in PD resemble those seen in patients with lesions in the lateral pFC, which has been associated with top-down attentional control. However, there is no direct evidence for a failure of top-down control mechanisms in PD. Here we fill this gap by demonstrating disproportionate control by bottom-up attention to dimensional salience during attentional set shifting. Patients needed significantly more trials to criterion than did controls when shifting to a low-salient dimension while, remarkably, needing significantly fewer trials to criterion than did controls when shifting to a high-salient dimension. Thus, attention was captured by bottom-up attention to salient information to a greater extent in patients than in controls. The results provide a striking reinterpretation of prior set-shifting data and provide the first direct evidence for a failure of top-down attentional control, resembling that seen after catecholamine depletion in the pFC.

22 Article The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. 2009

Williams-Gray, Caroline H / Evans, Jonathan R / Goris, An / Foltynie, Thomas / Ban, Maria / Robbins, Trevor W / Brayne, Carol / Kolachana, Bhaskar S / Weinberger, Daniel R / Sawcer, Stephen J / Barker, Roger A. ·Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK. chm27@cam.ac.uk ·Brain · Pubmed #19812213.

ABSTRACT: Cognitive abnormalities are common in Parkinson's disease, with important social and economic implications. Factors influencing their evolution remain unclear but are crucial to the development of targeted therapeutic strategies. We have investigated the development of cognitive impairment and dementia in Parkinson's disease using a longitudinal approach in a population-representative incident cohort (CamPaIGN study, n = 126) and here present the 5-year follow-up data from this study. Our previous work has implicated two genetic factors in the development of cognitive dysfunction in Parkinson's disease, namely the genes for catechol-O-methyltransferase (COMT Val(158)Met) and microtubule-associated protein tau (MAPT) H1/H2. Here, we have explored the influence of these genes in our incident cohort and an additional cross-sectional prevalent cohort (n = 386), and investigated the effect of MAPT H1/H2 haplotypes on tau transcription in post-mortem brain samples from patients with Lewy body disease and controls. Seventeen percent of incident patients developed dementia over 5 years [incidence 38.7 (23.9-59.3) per 1000 person-years]. We have demonstrated that three baseline measures, namely, age >or=72 years, semantic fluency less than 20 words in 90 s and inability to copy an intersecting pentagons figure, are significant predictors of dementia risk, thus validating our previous findings. In combination, these factors had an odds ratio of 88 for dementia within the first 5 years from diagnosis and may reflect the syndrome of mild cognitive impairment of Parkinson's disease. Phonemic fluency and other frontally based tasks were not associated with dementia risk. MAPT H1/H1 genotype was an independent predictor of dementia risk (odds ratio = 12.1) and the H1 versus H2 haplotype was associated with a 20% increase in transcription of 4-repeat tau in Lewy body disease brains. In contrast, COMT genotype had no effect on dementia, but a significant impact on Tower of London performance, a frontostriatally based executive task, which was dynamic, such that the ability to solve this task changed with disease progression. Hence, we have identified three highly informative predictors of dementia in Parkinson's disease, which can be easily translated into the clinic, and established that MAPT H1/H1 genotype is an important risk factor with functional effects on tau transcription. Our work suggests that the dementing process in Parkinson's disease is predictable and related to tau while frontal-executive dysfunction evolves independently with a more dopaminergic basis and better prognosis.

23 Article Switching between abstract rules reflects disease severity but not dopaminergic status in Parkinson's disease. 2009

Kehagia, Angie A / Cools, Roshan / Barker, Roger A / Robbins, Trevor W. ·Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK. ak423@cam.ac.uk ·Neuropsychologia · Pubmed #19166864.

ABSTRACT: This study sought to disambiguate the impact of Parkinson's disease (PD) on cognitive control as indexed by task set switching, by addressing discrepancies in the literature pertaining to disease severity and paradigm heterogeneity. A task set is governed by a rule that determines how relevant stimuli (stimulus set) map onto specific responses (response set). Task set switching may entail reconfiguration in either or both of these components. Although previous studies have shown that PD patients are impaired at switching between stimuli, in the present study not all patients were impaired at switching entire task sets, that is, both stimulus and response sets: compared with controls, patients with unilateral signs (Hoehn & Yahr Stage I) demonstrated intact switching, even following withdrawal from dopaminergic medication, while bilaterally affected Stage II patients were impaired. The parametric measure of Unified Parkinson's Disease Rating Scale (UPDRS) score predicted increasing switch costs within the patient group. These findings suggest that switching entire task sets may be a function of extrastriatal, possibly non-dopaminergic pathology which increases as the disease progresses.