Parkinson Disease: Barker RA

Lewis SJ, Barker RA. · Department of Neurology, Royal Prince Alfred Hospital, Sydney 2050, Australia. · J Clin Neurosci. · Pubmed #19285870 No free full text.

Abstract: Parkinson's disease is a common condition with a broad clinical diversity suggesting the existence of distinct subgroups of patients. This paper describes how dopaminergic disruption within basal ganglia circuitry accounts for some of the major features of the disease and examines how the limited repertoire of the output nuclei within these pathways could allow for an element of "cross-talk" between competing inputs. It is proposed that such conditions could lead to an excessive inhibition of the thalamus and pedunculopontine nucleus and account for many of the familiar patterns of clinical phenotype. It is further postulated that this phenomenon may be acting via increased synchronization within the basal ganglia circuitry.

Antoniades CA, Barker RA. · Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB22PY, UK. · Expert Rev Neurother. · Pubmed #19086880 No free full text.

Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily presents with features of bradykinesia, rigidity and tremor, and has, as part of its core pathology, the degeneration of dopaminergic neurons in the substantia nigra pars compacta. There is a great need for the development of a reliable diagnostic tool to improve promptness of diagnosis, definition of disease subtypes, and to monitor disease progression and demonstrate treatment efficacy in the case of disease modifying therapies. Current biomarkers range from objective clinical tools, to neuroimaging, to 'wet' markers involving blood and cerebrospinal fluid. To date, all candidate biomarkers for PD have failed to be developed into a clinically useful tool. Ideally, a combination of sensitive markers will be needed, not only to predict the onset of PD, but also to help in subtype classification and to follow progression. Here, we critically review various PD biomarker studies.

Evans JR, Barker RA. · University of Cambridge, Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, UK. · Expert Opin Ther Targets. · Pubmed #18348680 No free full text.

Abstract: BACKGROUND: The search for therapeutic agents that might alter the disease course in Parkinson's disease (PD) is ongoing. One area of particular interest involves neurotrophic factors (NTFs), with those of the glial cell line-derived neurotrophic factor (GDNF) family showing greatest promise. The safety and efficacy of these therapies has recently come into question. Furthermore, many of the key questions pertaining to such therapies, such as the optimal method of delivery, timing of treatment and selection of patients most likely to benefit, remain unanswered. OBJECTIVE: In this review we sought to evaluate the therapeutic potential of NTFs in the treatment of PD. We appraised the evidence provided by both in vitro and in vivo work before proceeding to a critical assessment of the relevant clinical trial data. METHODS: Relevant literature was identified using a PubMed search of articles published up to October 2007. Search terms included: 'Parkinson's disease', 'Neurotrophic factors', 'BDNF' (Brain-derived neurotrophic factor), 'GDNF' and 'Neurturin'. Original articles were reviewed, and relevant citations from these articles were also appraised. CONCLUSION: NTF therapy has potential in the treatment of nigrostriatal dysfunction in PD but numerous methodological and safety issues will need to be addressed before this approach can be widely adopted. Furthermore PD is now recognized as being more than a pure motor disorder, and one in which neuronal loss is not just confined to the dopaminergic nigrostriatal system. Non-motor symptomatology in PD is unlikely to benefit from therapies that target only the nigrostriatal system, and this must inform our thinking as to the maximal achievable benefit that NTFs are ever likely to provide.

Laguna Goya R, Tyers P, Barker RA. · Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK. · J Neurol Sci. · Pubmed #17936303 No free full text.

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder, characterised by the progressive loss of dopaminergic neurons in the substantia nigra, and typically treated by dopamine replacement. This treatment, although very effective in the early stages of the disease, is not curative and has side-effects. As such there has been a search for a more definitive treatment for this condition, which has mainly concentrated on replacing the lost neurons with neural grafts. Possible cell sources for replacement range from autologous grafts of dopamine secreting cells to allografts of fetal ventral mesencephalon and neural precursor cells derived from fetal tissue or embryonic stem cells. Some of these cells have been the subject of clinical trials, which to date have produced disparate outcomes. Therefore, whilst cell therapies remain a promising treatment for PD, there is need for further refinement of the techniques involved in this experimental procedure, before any new trials in patients are undertaken.

Goya RL, Kuan WL, Barker RA. · Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK. · Expert Opin Biol Ther. · Pubmed #17916042 No free full text.

Abstract: Parkinson's disease (PD) is a common neurological disorder of the brain which has as a part of its core pathology the progressive degeneration of the dopaminergic nigrostriatal pathway. Therefore, cell therapies that aim to restore this degenerated dopaminergic network represent a promising strategy in helping to cure PD. In this review, the authors start by discussing the progress of research on the use of fetal ventral mesencephalic (VM) tissue in transplantation therapies in PD, both from the clinical and experimental perspectives. Then the issues pertinent to its adoption in the clinic are discussed, including the ethical and practical problems with its use, the varied composition of VM tissue that is implanted with the graft and how this may account for some of the problems seen in the clinical trials using this tissue, especially graft-induced dyskinesia. Finally other promising sources of tissue for PD cell therapy are described, including mesenchymal and embryonic stem cells, before concluding on what is the best approach to the cellular repair of the parkinsonian brain.

Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA. · Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK. · Brain. · Pubmed #17535834 links to  free full text

Abstract: We have previously performed detailed clinical and neuropsychological assessments in a community-based cohort of patients with newly diagnosed parkinsonism, and through analysis of a subcohort with idiopathic Parkinson's disease (PD), we have demonstrated that cognitive dysfunction occurs even at the time of PD diagnosis and is heterogeneous. Longitudinal follow-up of the cohort has now been performed to examine the evolution of cognitive dysfunction within the early years of the disease. One hundred and eighty (79%) eligible patients from the original cohort with parkinsonism were available for re-assessment at between 3 and 5 years from their initial baseline assessments. PD diagnoses were re-validated with repeated application of the UKPDS Brain Bank criteria in order to maximize sensitivity and specificity, following which a diagnosis of idiopathic PD was confirmed in 126 patients. Thirteen out of 126 (10%) had developed dementia at a mean (SD) of 3.5 (0.7) years from diagnosis, corresponding to an annual dementia incidence of 30.0 (16.4-52.9) per 1000 person-years. A further 57% of PD patients showed evidence of cognitive impairment, with frontostriatal deficits being most common amongst the non-demented group. However, the most important clinical predictors of global cognitive decline following correction for age were neuropsychological tasks with a more posterior cortical basis, including semantic fluency and ability to copy an intersecting pentagons figure, as well as a non-tremor dominant motor phenotype at the baseline assessment. This work clarifies the profile of cognitive dysfunction in early PD and demonstrates that the dementing process in this illness is heralded by both postural and gait dysfunction and cognitive deficits with a posterior cortical basis, reflecting probable non-dopaminergic cortical Lewy body pathology. Furthermore, given that these predictors of dementia are readily measurable within just a few minutes in a clinical setting, our work may ultimately have practical implications in terms of guiding prognosis in individual patients.

Williams-Gray CH, Foltynie T, Lewis SJ, Barker RA. · Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK. · CNS Drugs. · Pubmed #16734499 No free full text.

Abstract: Parkinson's disease is a neurodegenerative disorder causing not only motor dysfunction but also cognitive, psychiatric, autonomic and sensory disturbances. Symptoms of dementia and psychosis are common: longitudinal studies suggest that up to 75% of patients with Parkinson's disease may eventually develop dementia, and the prevalence of hallucinations ranges from 16-17% in population-based surveys to 30-40% in hospital-based series. These cognitive and behavioural features are important in terms of prognosis, nursing home placement and mortality. The pattern of cognitive deficits in Parkinson's disease is variable, but often includes executive impairment similar to that seen in patients with frontal lesions, as well as episodic memory impairment, visuospatial dysfunction and impaired verbal fluency. The most common manifestation of psychosis in Parkinson's disease is visual hallucinations, but delusions, paranoid beliefs, agitation and florid psychosis can also occur. An understanding of the pathophysiology underlying these symptoms is essential to the development of targeted therapeutic strategies. Post-mortem studies suggest an association between Lewy body deposition and dementia in Parkinson's disease, and indeed Parkinson's disease and dementia with Lewy bodies may form part of the same disease spectrum. Whether Lewy bodies actually play a causative role in cognitive dysfunction, however, is unknown. Deficits in neurotransmitter systems provide more obvious therapeutic targets and dysfunction of dopaminergic, cholinergic, noradrenergic and serotonergic systems have all been implicated; these may each underlie different features of Parkinson's disease dementia, perhaps explaining some of the heterogeneity of the syndrome. Psychosis has traditionally been considered as a dopaminergic drug-induced phenomenon, but factors intrinsic to the disease process itself also cause hallucinations and delusions. These factors may include Lewy body deposition in the limbic system, cholinergic deficits and impairments of primary visual processing. Therapeutic intervention for cognitive and behavioural symptoms in Parkinson's disease currently focuses on two main groups of drugs: cholinesterase inhibitors and atypical antipsychotics. A recent large, randomised, controlled trial suggests that cholinesterase inhibitors can produce a modest improvement in cognitive function, as well as psychotic symptoms, generally without an adverse effect on motor function. Certain atypical antipsychotics allow hallucinations, delusions and behavioural problems to be brought under control with minimal deleterious effects on motor function and cognition, but their safety in elderly patients has recently been called into question. Deep brain stimulation does not appear to be a useful treatment for cognitive and psychiatric dysfunction in patients with Parkinson's disease. Modafinil improves alertness in Parkinson's disease and warrants further investigation to establish its effects on cognitive performance.

Kuan WL, Barker RA. · Cambridge Centre for Brain Repair, Cambridge University, UK. · Neurorehabil Neural Repair. · Pubmed #16093408 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder of the brain and typically presents with a disorder of movement. The core pathological event underlying the condition is the loss of the dopaminergic nigrostriatal pathway with the formation of alpha-synuclein positive Lewy bodies. As a result, drugs that target the degenerating dopaminergic network within the brain work well at least in the early stages of the disease. Unfortunately, with time these therapies fail and produce their own unique side-effect profile, and this, coupled with the more diffuse pathological and clinical findings in advancing disease, has led to a search for more effective therapies. In this review, the authors will briefly discuss the emerging new drug therapies in PD before concentrating on a more detailed discussion on the state of cell therapies to cure PD.

Harrower TP, Michell AW, Barker RA. · Cambridge Centre for Brain Repair, Robinson Way, Cambridge CB22PY, UK. · Exp Neurol. · Pubmed #16023637 No free full text.

This publication has no abstract.

Michell AW, Lewis SJ, Foltynie T, Barker RA. · Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, CB2 2PY, UK. · Brain. · Pubmed #15215212 links to  free full text

Abstract: Biomarkers are characteristics that can be measured as an indicator of a normal biological process, and they have special relevance in Parkinson's disease. Parkinson's disease is a chronic neurodegenerative disorder that is difficult to study, given the site of pathology and because the resultant clinical phenotype fluctuates over time. We currently have no definitive diagnostic test, and thus for the clinician there is hope that biomarkers will help diagnose symptomatic and presymptomatic disease or provide surrogate end-points to demonstrate clinical efficacy of new treatments, such as neuroprotective therapies, and help stratify this heterogeneous disease. No biomarker is likely to fulfil all these functions, so we need to know how each has been validated in order to understand their uses and limitations, and be aware of potential pitfalls. In this review we discuss the current potential biomarkers for Parkinson's disease, highlight the problems with their use, and conclude with a discussion of future alternatives.

Harrower TP, Barker RA. · Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK. · BioDrugs. · Pubmed #15161332 No free full text.

Abstract: Traditionally neural transplantation has had as its central tenet the replacement of missing neurons that have been lost because of neurodegenerative processes, as exemplified by diseases such as Parkinson disease (PD). However, the effectiveness and widespread application of this approach clinically has been limited, primarily because of the poor donor supply of human fetal neural tissue and the incomplete neurobiological understanding of the circuit reconstruction required to normalize function in these diseases. So, in PD the progress from promising neural transplantation in animal models to proof-of-principle, open-labeled clinical transplants, to randomized, placebo-controlled studies of neural transplantation has not been straightforward. The emergence of previously undescribed adverse effects and lack of significant functional advantage in recent clinical studies has been disappointing and has served to cast a new, and perhaps more realistic, perspective on this treatment approach. In fact, there have been calls by some involved in neural transplantation to return to the drawing board before pressing on with further clinical trials, and the return to basic experimentation. This therefore precipitates the question - is there a future for neural transplantation? It is important to remember that there are a number of possible explanations for the disappointing results from the recent clinical trials in PD, ranging from the mode of transplantation to patient selection. Nevertheless, almost irrespective of these reasons for the current trial results, there have always been significant practical and ethical problems with using human fetal tissue, and so a number of alternative cell sources have been investigated. These alternative sources include stem cells, which are attractive for cell-based therapies because of their potential ease of isolation, propagation and manipulation, and their ability in some cases to migrate to areas of pathology and differentiate into specific and appropriate cell types. Furthermore, the availability of stem cells derived from non-embryonic sources (e.g. adult stem cells derived from the sub-ventricular zone) has removed some of the ethical limitations associated with the use of embryonic human tissue. These potentially beneficial aspects of stem cells means that there is a future for neural transplantation as a means of treating patients with a range of neurological disorders, although whether this will ever translate into a truly effective, widely available therapy remains unknown.

Sayles M, Jain M, Barker RA. · Cambridge Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK. · Transpl Immunol. · Pubmed #15157925 No free full text.

Abstract: Damage to the central nervous system was once considered irreparable. However, there is now growing optimism that neural transplant therapies may one day enable complete circuit reconstruction and thus functional benefit for patients with neurodegenerative conditions such as Parkinson's disease (PD), and perhaps even those with more widespread damage such as stroke patients. Indeed, since the late 1980s hundreds of patients with Parkinson's disease have received allografts of dopamine-rich embryonic human neural tissue. The grafted tissue has been shown to survive and ameliorate many of the symptoms of the disease, both in the clinical setting and in animal models of the disease. However, practical problems associated with tissue procurement and storage, and ethical concerns over using aborted human fetal tissue have fuelled a search for alternative sources of suitable material for grafting. In particular, stem cells and xenogeneic embryonic dopamine-rich neural tissue are being explored, both of which bring their own practical and ethical dilemmas. Here we review the progress made in neural transplantation, both in the laboratory and in the clinic with particular attention to the development of stem cell and xenogeneic tissue based therapy.

Barker RA, Foltynie T. · Cambridge Centre for Brain Repair and Department of Neurology, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK. · J Neurol. · Pubmed #15015024 No free full text.

This publication has no abstract.

Lewis SJ, Caldwell MA, Barker RA. · Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK. · Expert Rev Mol Med. · Pubmed #14987395 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder of the brain and typically presents with a disorder of movement. The core pathological event underlying the condition is the loss of the dopaminergic nigrostriatal pathway with the formation of alpha-synuclein-positive Lewy bodies. As a result, drugs that target the degenerating dopaminergic network within the brain work well, at least in the early stages of the disease. Unfortunately, with time, these therapies fail and produce their own unique side-effect profile and this, coupled with the more-diffuse pathological and clinical findings in advancing disease, has led to the search for more-effective therapies. In this review, we discuss the emerging new therapies in PD in terms of neuroprotective agents, drugs designed to control symptoms more effectively, and finally curative cell therapies.

Lazic SE, Barker RA. · Centre for Brain Repair, University of Cambridge, Cambridge CB2 2PY, UK. · J Hematother Stem Cell Res. · Pubmed #14977473 No free full text.

Abstract: Parkinson's disease is a common neurodegenerative disease with a lifetime incidence of 2.5% and a prevalence of at least 2% in individuals over 70 years old. Patients can be effectively treated with drugs that target the dopaminergic nigro-striatal pathway, but over time the efficacy of these medications is limited by the development of profound motor fluctuations and dyskinesias. This has prompted the search for alternative treatments, including the use of cell replacement therapies. Over the last decade, human fetal nigral transplants have demonstrated that dopaminergic neurons can survive and provide clinical benefit for patients with Parkinson's disease. However, there are clearly ethical concerns and a limit to the supply of this tissue as well as more recently anxieties over side effects. As a result, alternative sources of tissue have been investigated, and one such source are stem cells, which provide an attractive renewable tissue supply. In this review, we will discuss the current state-of-the-art and the characteristics of Parkinson's disease that increase its attraction as a target of stem cell therapy against results of current clinical trials using fetal neural grafts. Then we will discuss the various types and sources of stem cells, and some early transplantation results in animal models of Parkinson's disease. Finally we will discuss the prospect of using stem cells to deliver drugs and neurotrophic factors involved in neuroprotective and neuroreparative strategies in Parkinson's disease and other neurodegenerative conditions.

Foltynie T, Sawcer S, Brayne C, Barker RA. · Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #12235301 links to  free full text

Abstract: Although the mechanisms underlying neurodegeneration in Parkinson's disease are not fully understood, considerable evidence suggests that genetic factors can influence susceptibility to the disease. In this article, we critically review this evidence and examine studies estimating patterns of inheritance. In a few families, Parkinson's disease is clearly inherited in a Mendelian fashion, and in some of these the disease causing genes have already been identified. Possible pathogenic mechanisms by which these genes cause Parkinson's disease are discussed. Further candidate genes and systematic efforts to identify genes influencing susceptibility to the disease in general are also summarised. The identification of such susceptibility genes will eventually enable us to more accurately classify this complex disease.

Foltynie T, Brayne C, Barker RA. · Cambridge Centre for Brain Repair, University of Cambridge, UK. · J Neurol. · Pubmed #11985378 No free full text.

Abstract: The diagnosis of Idiopathic Parkinson's disease (IPD) requires post mortem neuropathological confirmation to be secure, since there is marked heterogeneity in the clinical phenotype of these patients. Pathologically confirmed IPD encompasses a spectrum of microscopic appearances with respect to the extent and distribution of Lewy Body deposition, which may reflect the clinical phenotypes observed during life. In this review, we discuss how IPD is currently defined and the purpose and applications of a classification of the disease. We have also performed a systematic review of the literature to present the quantitative evidence on which potential classifications of the disease might be based. This evidence suggests that sub-groups based on age of onset, motor presentation, or subsequent motor phenotype may have some use in predicting disease progression. However, further clinicopathological studies are required to evaluate pathological heterogeneity within these groups. Clinical sub-groups may be related to a variety of as yet unknown risks, including genetic factors for both the familial and sporadic forms of the disease, and may have far reaching consequences for our understanding of disease pathogenesis and treatment strategies.

Barker RA. · Cambridge Centre for Brain Repair, and Department of Neurology, University of Cambridge, Forvie Site, Cambridge, United Kingdom. · Mov Disord. · Pubmed #11921107 No free full text.

This publication has no abstract.

Hurelbrink CB, Barker RA. · Cambridge Centre for Brain Repair, Addenbrooke's Hospital, Cambridge CB2 2PY, UK. · Expert Opin Pharmacother. · Pubmed #11825297 No free full text.

Abstract: Parkinson's disease (PD) is a debilitating neurodegenerative condition that is characterised by a progressive loss of dopaminergic neurones of the substantia nigra pars compacta (SNpc) and the presence of alpha-synuclein cytoplasmic inclusions (Lewy bodies). Cardinal symptoms include tremor, bradykinesia, and rigidity, although cognitive and autonomic disturbances are not uncommon. Pharmacological treatment targeting the dopaminergic network is relatively effective at ameliorating these symptoms, especially in the early stages of the disease, but none of these therapies are curative and they generate their own problems. As dopaminergic neuronal death in PD occurs in a gradual manner, it is amenable to treatments that can either protect remaining dopaminergic neurones or prevent death of those neurones that have begun to die. Use of neurotrophic factors is a potential candidate, as various factors have been shown to increase dopaminergic neuronal survival in culture and promote survival and axonal growth in animal models of PD. Glial cell line-derived neurotrophic factor (GDNF) is currently the most effective substance that has been intensively studied and shown to have a specific 'dopaminotrophic' effect. This review will therefore focus on studies that have investigated GDNF and discuss the potential for neurotrophic factor treatment in PD.

Barker RA. · Cambridge Centre for Brain Repair and Department of Neurology, Addenbrooke's Hospital, Cambridge CB2 2PY, UK. · Expert Opin Pharmacother. · Pubmed #11249498 No free full text.

Abstract: Parkinson's disease (PD) is an incurable neurodegenerative condition of the central nervous system (CNS) that typically presents in the fifth to seventh decade of life, with a movement disorder that consists of a resting tremor, bradykinesia and rigidity. It is a disease that can only be diagnosed with certainty at postmortem when the pathological hallmark is loss of the dopaminergic nigrostriatal pathway and presence of Lewy bodies in the substantia nigra. However, pathological changes, including Lewy body formation, are found outside of the nigrostriatal system and involve other neurotransmitters, which may also account for some of the cognitive, psychiatric and autonomic abnormalities in these patients. To date, the mainstay of treatment for patients with PD has been drugs that activate the dopaminergic network, namely the dopamine precursor L-dopa and dopamine receptor agonists. However, recently interest has turned towards more curative therapies, including the use of grafts of neural tissue to replace dopaminergic neurones that have been lost. This approach has now entered clinical trials and this review will analyse the therapeutic approach of neural grafting in PD.

Barker RA, Kendall AL, Widner H. · Department of Experimental Psychology and Centre for Brain Repair, University of Cambridge, UK. · Cell Transplant. · Pubmed #10811396 No free full text.

Abstract: Embryonic allografted human tissue in patients with Parkinson's disease has been shown to survive and ameliorate many of the symptoms of this disease. Despite this success, the practical problems of using this tissue coupled to the ethical restrictions of using aborted human fetal tissue have lead to an exploration for alternative sources of suitable material for grafting, including xenogeneic embryonic dopaminergic-rich neural tissue. Nevertheless, xenografted neural tissue itself generates a number of practical, ethical, safety, and immunological issues that have to be addressed prior to any clinical xenotransplant program. In this article we review these critical issues and set out the criteria that we consider need to be met in the development of our clinical xenotransplantation research programs. We advocate that these, or similar, criteria should be adopted and made explicit by other centers contemplating similar clinical trials.

Slabosz A, Lewis SJ, Smigasiewicz K, Szymura B, Barker RA, Owen AM. · MRC Cognition and Brain Sciences Unit, Cambridge, England. · Neuropsychology. · Pubmed #16938020 No free full text.

Abstract: In this study, the cognitive and neurochemical factors underlying learned irrelevance, one of the mechanisms thought to be responsible for attentional set-shifting deficits in Parkinson's disease (PD), were investigated. In a visual discrimination learning task, the extent to which a target dimension was irrelevant prior to an extra-dimensional shift was varied. Twenty patients with PD and 22 healthy participants performed the task twice, with patients tested on and off L-dopa. The patients made more errors than control participants in the condition in which the target dimension was completely irrelevant prior to the extradimensional shift, but not when it was partially reinforced. Moreover, L-dopa had no effect on the patients' task performance, despite improving their working memory. These results confirm that learned irrelevance is a significant factor in accounting for attentional set-shifting deficits in patients with PD, although unlike other executive impairments in this group, the phenomenon appears to be unrelated to their central dopaminergic deficit.

Cools R, Lewis SJ, Clark L, Barker RA, Robbins TW. · Department of Experimental Psychology, Behavioural and Clinical Neurosciences Institute, University of Cambridge, Cambridge, UK. · Neuropsychopharmacology. · Pubmed #16841074 links to  free full text

Abstract: Evidence indicates that dopaminergic medication in Parkinson's disease may impair certain aspects of cognitive function, such as reversal learning. We used functional magnetic resonance imaging in patients with mild Parkinson's disease to investigate the neural site at which L-DOPA acts during reversal learning. Patients were scanned both ON and OFF their normal dopamine-enhancing L-DOPA medication during the performance of a probabilistic reversal learning task. We demonstrate that L-DOPA modulated reversal-related activity in the nucleus accumbens, but not in the dorsal striatum or the prefrontal cortex. These data concur with evidence from studies with experimental animals and indicate an important role for the human nucleus accumbens in the dopaminergic modulation of reversal learning.

Lewis SJ, Slabosz A, Robbins TW, Barker RA, Owen AM. · Cambridge Centre for Brain Repair, Forvie Site, Addenbrooke's Hospital, Cambridge CB2 2PY, UK. · Neuropsychologia. · Pubmed #15716155 No free full text.

Abstract: Although Parkinson's disease is a common neurodegenerative disorder characterised by its motoric symptoms, there is an increasing recognition of accompanying impairments in cognition that have a profound impact on the quality of life of these patients. These deficits predominantly affect executive function and impairments of working memory have been frequently reported. However, the underlying neurochemical and pathological basis for these deficits are not well understood. In this study, 20 patients were tested 'on' and 'off' levodopa (L-dopa) medication on a task that allowed different aspects of working memory function such as maintenance, retrieval and manipulation to be tested within the same general paradigm as well as on an unrelated test of attentional set-shifting, which is known to be sensitive to deficits in early Parkinson's disease. Compared to healthy volunteers, PD patients were impaired at manipulation more than maintenance or retrieval of information within working memory. The patients were also impaired at the attentional set-shifting task. However, whereas L-dopa ameliorated the working memory deficit in manipulation (improving both accuracy and cognitive response time), it had no effect on the attentional set-shifting impairment. These results confirm that working memory deficits in PD are both psychologically specific and related to dopamine depletion. It is anticipated that greater understanding of these mechanisms will lead to future therapeutic improvements.

Lewis SJ, Dove A, Robbins TW, Barker RA, Owen AM. · Cambridge Centre for Brain Repair and Department of Neurology, University of Cambridge, Cambridge, United Kingdom CB2 2EF. · J Neurosci. · Pubmed #12867520 links to  free full text

Abstract: Studies in patients with Parkinson's disease (PD) suggest that the characteristic motor symptoms of the disorder are frequently accompanied by impairments in cognition that are most profound in tasks of executive function. Neuropsychological deficits are not an inevitable consequence of the disease, yet the reasons underlying cognitive heterogeneity in PD are not well understood. To determine the underlying neural correlate of these cognitive deficits, we used event-related functional magnetic resonance imaging (fMRI) to compare groups of cognitively impaired and unimpaired patients, matched on all other clinical measures. fMRI revealed significant signal intensity reductions during a working-memory paradigm in specific striatal and frontal lobe sites in patients with cognitive impairment compared with those patients who were not cognitively unimpaired. These results demonstrate that cognitive deficits in PD are accompanied by neural changes that are related to, but distinct from, those changes that underlie motoric deficits in these patients. Furthermore, they suggest that fMRI may provide a valuable tool for identifying patients who may benefit from targeted therapeutic strategies.