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An increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinson's disease is appealing, but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in Parkinson's disease, a multi-arm platform trial must also specifically consider the heterogeneous nature of the disease, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm; however, in Parkinson's disease there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of predefined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of Parkinson's disease patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinson's disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Current research does not provide a clear explanation for why some patients with Parkinson's Disease (PD) develop psychotic symptoms. The 'aberrant salience hypothesis' of psychosis has been influential and proposes that dopaminergic dysregulation leads to inappropriate attribution of salience to irrelevant/non-informative stimuli, facilitating the formation of hallucinations and delusions. The aim of this study is to investigate whether non-motivational salience is altered in PD patients and possibly linked to the development of psychotic symptoms., Methods: We investigated salience processing in 14 PD patients with psychotic symptoms, 23 PD patients without psychotic symptoms and 19 healthy controls. All patients were on dopaminergic medication for their PD. We examined emotional salience using a visual oddball fMRI paradigm that has been used to investigate early stages of schizophrenia spectrum psychosis, controlling for resting cerebral blood flow as assessed with arterial spin labelling fMRI., Results: We found significant differences between patient groups in brain responses to emotional salience. PD patients with psychotic symptoms had enhanced brain responses in the striatum, dopaminergic midbrain, hippocampus and amygdala compared to patients without psychotic symptoms. PD patients with psychotic symptoms showed significant correlations between the levels of dopaminergic drugs they were taking and BOLD signalling, as well as psychotic symptom scores., Conclusion: Our study suggests that enhanced signalling in the striatum, dopaminergic midbrain, the hippocampus and amygdala is associated with the development of psychotic symptoms in PD, in line with that proposed in the 'aberrant salience hypothesis' of psychosis in schizophrenia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: A wealth of evidence implicates both central and peripheral immune changes as contributing to the pathogenesis of Parkinson's disease (PD). It is critical to better understand this aspect of PD given that it is a tractable target for disease-modifying therapy. Age-related changes are known to occur in the immune system (immunosenescence) and might be of particular relevance in PD given that its prevalence rises with increasing age. We therefore sought to investigate this with respect to T cell replicative senescence, a key immune component of human ageing., Methods: Peripheral blood mononuclear cells were extracted from blood samples from 41 patients with mild PD (Hoehn and Yahr stages 1-2, mean (SD) disease duration 4.3 (1.2) years) and 41 age- and gender-matched controls. Immunophenotyping was performed with flow cytometry using markers of T lymphocyte activation and senescence (CD3, CD4, CD8, HLA-DR, CD38, CD28, CCR7, CD45RA, CD57, CD31). Cytomegalovirus (CMV) serology was measured given its proposed relevance in driving T cell senescence., Results: Markers of replicative senescence in the CD8+ population were strikingly reduced in PD cases versus controls (reduced CD57 expression (p = 0.005), reduced percentage of 'late differentiated' CD57 lo CD28 hi cells (p = 0.007) and 'TEMRA' cells (p = 0.042)), whilst expression of activation markers (CD28) was increased (p = 0.005). This was not driven by differences in CMV seropositivity. No significant changes were observed in the CD4 population., Conclusions: This study demonstrates for the first time that the peripheral immune profile in PD is distinctly atypical for an older population, with a lack of the CD8+ T cell replicative senescence which characterises normal ageing. This suggests that 'abnormal' immune ageing may contribute to the development of PD, and markers of T cell senescence warrant further investigation as potential biomarkers in this condition.

Objective: To assess reductions of cerebral glucose metabolism in Parkinson's disease (PD) with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and their associations with cognitive decline., Methods: FDG-PET was performed on a cohort of 79 patients with newly diagnosed PD (mean disease duration 8 months) and 20 unrelated controls. PD participants were scanned while on their usual dopaminergic medication. Cognitive testing was performed at baseline, and after 18 months using the Cognitive Drug Research (CDR) and Cambridge Neuropsychological Test Automated Battery (CANTAB) computerised batteries, the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA). We used statistical parametric mapping (SPM V.12) software to compare groups and investigate voxelwise correlations between FDG metabolism and cognitive score at baseline. Linear regression was used to evaluate how levels of cortical FDG metabolism were predictive of subsequent cognitive decline rated with the MMSE and MoCA., Results: PD participants showed reduced glucose metabolism in the occipital and inferior parietal lobes relative to controls. Low performance on memory-based tasks was associated with reduced FDG metabolism in posterior parietal and temporal regions, while attentional performance was associated with more frontal deficits. Baseline parietal to cerebellum FDG metabolism ratios predicted MMSE (β=0.38, p=0.001) and MoCA (β=0.3, p=0.002) at 18 months controlling for baseline score., Conclusions: Reductions in cortical FDG metabolism were present in newly diagnosed PD, and correlated with performance on neuropsychological tests. A reduced baseline parietal metabolism is associated with risk of cognitive decline and may represent a potential biomarker for this state and the development of PD dementia., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background and Purpose: To determine whether iron deposition in deep brain nuclei assessed using high-pass filtered phase imaging plays a role in motor disease severity in Parkinson's disease (PD)., Methods: Seventy patients with mild to moderate PD and 20 age- and gender-matched healthy volunteers (HVs) underwent susceptibility-weighted imaging on a 3 T magnetic resonance imaging scanner. Phase shifts (radians) in deep brain nuclei were derived from high-pass filtered phase images and compared between groups. Analysis of clinical laterality and correlations with motor severity (Unified Parkinson's Disease Rating Scale, Part III, UPDRS-III) were performed. Phase shifts (in radians) were compared between HVs and three PD subgroups divided according to UPDRS-III scores using analysis of covariance, adjusting for age and regional area., Results: Parkinson's disease patients had significantly (P < 0.001) higher radians than HVs bilaterally in the putamen, globus pallidus and substantia nigra (SN). The SN contralateral to the most affected side showed higher radians (P < 0.001) compared to the less affected side. SN radians positively correlated with UPDRS-III and bradykinesia-rigidity subscores, but not with tremor subscores. ancova followed by post hoc Bonferroni-adjusted pairwise comparisons revealed that SN radians were significantly greater in the PD subgroup with higher UPDRS-III scores compared to both lowest UPDRS-III PD and HV groups (P < 0.001)., Conclusions: Increased nigral iron accumulation in PD appears to be stratified according to disease motor severity and correlates with symptoms related to dopaminergic neurodegeneration. This semi-quantitative in vivo iron assessment could prove useful for objectively monitoring PD progression, especially in clinical trials concerning iron chelation therapies., (© 2016 EAN.)

Background: Parkin related Parkinson's disease (PD) is differentiated from idiopathic PD by absent or sparse Lewy bodies, and preserved olfaction. The significance of single Parkin mutations in the pathogenesis of PD is debated., Objectives: To assess olfaction results according to Parkin mutation status. To compare the prevalence of Parkin single heterozygous mutations in patients diagnosed with PD to the rate in healthy controls in order to establish whether these single mutations could be a risk factor for developing PD., Methods: Parkin gene mutation testing was performed in young onset PD (diagnosed <50 years old) to identify three groups: Parkin homozygous or compound heterozygote mutation carriers, Parkin single heterozygote mutation carriers, and non-carriers of Parkin mutations. Olfaction was tested using the 40-item British version of the University of Pennsylvania smell identification test (UPSIT)., Results: Of 344 young onset PD cases tested, 8 (2.3%) were Parkin compound heterozygotes and 13 (3.8%) were Parkin single heterozygotes. Olfaction results were available in 282 cases (eight compound heterozygotes, nine single heterozygotes, and 265 non-carriers). In Parkin compound heterozygotes, the median UPSIT score was 33, interquartile range (IQR) 28.5-36.5, which was significantly better than in single Parkin heterozygotes (median 19, IQR 18-28) and non-carriers (median score 22, IQR 16-28) (ANOVA P < 0.001). These differences persisted after adjusting for age, disease duration, gender, and smoking (P < 0.001). There was no significant difference in UPSIT scores between single heterozygotes and non-carriers (P = 0.90)., Conclusions: Patients with Parkin compound heterozygous mutations have relatively preserved olfaction compared to Parkin single heterozygotes and non-carriers. The prevalence of Parkin single heterozygosity is similar to the 3.7% rate reported in healthy controls., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

It has been recognized for many years that a number of chronic neurodegenerative diseases of the CNS are characterized by the development of intracellular inclusion bodies, but it is only relatively recently that the core proteins defining these pathologies have been defined. One such protein is alpha synuclein, that was found to be the main component of Lewy bodies in the late 1990s, and this discovery reinforced the emerging view that alpha synuclein was intimately linked to diseases characterized by this type of pathology--namely Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Furthermore at around this time, this same protein was also found within the glial inclusion bodies of patients dying with multiple system atrophy (MSA). These three disorders constitute the majority of patients with an 'alpha synucleinopathy', although there are a number of rarer conditions that can also cause this pathology including inherited metabolic disorders such as Gaucher's disease (GD). In this review, we will concentrate on PD, the commonest alpha synucleinopathy, and its associated dementia (PDD), as well as discussing DLB and MSA and will highlight how the clinical features of these conditions vary as a function of pathology., (© 2016 British Neuropathological Society.)

Human cytomegalovirus (HCMV) encodes abundant numbers of microRNAs (miRNAs) and other non-coding RNAs (ncRNAs) whose functions are presently under intense investigation. In this chapter, we discuss the function of one of the more well characterised virus-encoded ncRNAs, derived from the viral major early gene (Beta2.7). This RNA plays an anti-apoptotic role during infection by directly interacting with mitochondrial complex I to help maintain high levels of ATP production and by preventing the stress induced re-localisation of retinoid/interferon-induced mortality-19 protein, GRIM-19. We then go on to describe how an 800 nucleotide sub-domain of the Beta2.7 transcript, p137, has been exploited in the development of a novel therapeutic for the treatment of Parkinson's disease., (Copyright © 2015. Published by Elsevier B.V.)

Objective: This study investigated the predictive value of various coping processes for the psychological and disease specific aspects of health-related quality of life (HRQoL) in Parkinson's disease (PD)., Method: Cross-sectional study of 85 participants with PD using the Ways of Coping Questionnaire (WCQ), Depression, Anxiety, and Stress Scale (DASS-21), quality of life (PDQ-39), and socio-demographic and clinical variables., Results: Greater use of planful problem solving coping was found to be significantly associated with better HRQoL in relation to cognitive impairment, communication and bodily discomfort. In addition to greater disease duration, greater use of escape-avoidance coping processes were identified as significant predictors of poorer HRQoL outcomes in the domains of mood and emotional well-being., Conclusion: Psychological interventions such as mindfulness training, aimed at reducing the use of escape-avoidance copying, may help to improve HRQoL in PD., (Copyright © 2010 John Wiley & Sons, Ltd.)

Background: In studies of mild cognitive impairment (MCI) in Parkinson disease (PD), patients without dementia have reported variable prevalences and profiles of MCI, likely to be due to methodologic differences between the studies., Objective: The objective of this study was to determine frequency and the profile of MCI in a large, multicenter cohort of well-defined patients with PD using a standardized analytic method and a common definition of MCI., Methods: A total of 1,346 patients with PD from 8 different cohorts were included. Standardized analysis of verbal memory, visuospatial, and attentional/executive abilities was performed. Subjects were classified as having MCI if their age- and education-corrected z score on one or more cognitive domains was at least 1.5 standard deviations below the mean of either control subjects or normative data., Results: A total of 25.8% of subjects (95% confidence interval [CI] 23.5-28.2) were classified as having MCI. Memory impairment was most common (13.3%; 11.6-15.3), followed by visuospatial (11.0%; 9.4-13.0) and attention/executive ability impairment (10.1%; 8.6-11.9). Regarding cognitive profiles, 11.3% (9.7-13.1) were classified as nonamnestic single-domain MCI, 8.9% (7.0-9.9) as amnestic single-domain, 4.8% (3.8-6.1) as amnestic multiple-domain, and 1.3% (0.9-2.1) as nonamnestic multiple-domain MCI. Having MCI was associated with older age at assessment and at disease onset, male gender, depression, more severe motor symptoms, and advanced disease stage., Conclusions: MCI is common in patients with PD without dementia, affecting a range of cognitive domains, including memory, visual-spatial, and attention/executive abilities. Future studies of patients with PD with MCI need to determine risk factors for ongoing cognitive decline and assess interventions at a predementia stage.

Dynamic causal modelling (DCM) of functional magnetic resonance imaging (fMRI) data offers new insights into the pathophysiology of neurological disease and mechanisms of effective therapies. Current applications can be used both to identify the most likely functional brain network underlying observed data and estimate the networks' connectivity parameters. We examined the reproducibility of DCM in healthy subjects (young 18-48 years, n=27; old 50-80 years, n=15) in the context of action selection. We then examined the effects of Parkinson's disease (50-78 years, Hoehn and Yahr stage 1-2.5, n=16) and dopaminergic therapy. Forty-eight models were compared, for each of 90 sessions from 58 subjects. Model-evidences clustered according to sets of structurally similar models, with high correlations over two sessions in healthy older subjects. The same model was identified as most likely in healthy controls on both sessions and in medicated patients. In this most likely network model, the selection of action was associated with enhanced coupling between prefrontal cortex and the pre-supplementary motor area. However, the parameters for intrinsic connectivity and contextual modulation in this model were poorly correlated across sessions. A different model was identified in patients with Parkinson's disease after medication withdrawal. In "off" patients, action selection was associated with enhanced connectivity from prefrontal to lateral premotor cortex. This accords with independent evidence of a dopamine-dependent functional disconnection of the SMA in Parkinson's disease. Together, these results suggest that DCM model selection is robust and sensitive enough to study clinical populations and their pharmacological treatment. For critical inferences, model selection may be sufficient. However, caution is required when comparing groups or drug effects in terms of the connectivity parameter estimates, if there are significant posterior covariances among parameters., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

We investigated whether the val(158)met functional polymorphism of catechol-o-methyltransferase influenced age-related changes in grey matter density and volume, both in healthy individuals (n=80, ages 18-79) and those with Parkinson's disease (n=50). Global grey matter volumes and voxelwise estimates of grey matter volume and density were determined from structural magnetic resonance images at 3T. Male and female ValVal homozygotes (low prefrontal cortical dopamine) had more grey matter in early adulthood, but this difference disappeared with increasing age. The insula and ventral prefrontal cortex had higher grey matter volume in younger, but not older, ValVal homozygotes. Conversely, the dominant premotor cortex revealed genotypic differences in grey matter density in later life. There were no global or local interactions between Parkinson's disease and COMT val(158)met genotype on morphometry. Since the val(158)met polymorphism is associated with differences in cortical dopamine metabolism, our data suggest a role for dopamine in cortical development followed by differential vulnerability to cortical atrophy across the adult life span., (Copyright 2008 Elsevier Inc. All rights reserved.)

Background: Levodopa induced dyskinesias (LID) are a common problem which ultimately limit the effective treatment of patients with Parkinson's disease (PD). There is accumulating evidence that LID develop due to abnormal synaptic plasticity, which is in turn influenced by the release of brain derived neurotrophic factor (BDNF)., Methods: The influence of a common functional polymorphism of the BDNF gene on the risk of developing dyskinesias in a large cohort of patients with PD (n = 315), who were independently and variably treated with levodopa and/or other dopaminergic treatments, was investigated., Results: Patients with the met allele of BDNF, associated with lower activity dependent secretion of BDNF, were at significantly higher risk of developing dyskinesias earlier in the course of treatment with dopaminergic agents (hazard ratio for each additional met allele 2.12, p = 0.001), which persisted following adjustment for potential confounding variables., Conclusion: This functional polymorphism may help predict which individuals are most at risk of LID and is consistent with the known actions of BDNF on synaptic plasticity in the striatum.

Cognitive deficits are very common in Parkinson's disease particularly for 'executive functions' associated with frontal cortico-striatal networks. Previous work has identified deficits in tasks that require attentional control like task-switching, and reward-based tasks like gambling or reversal learning. However, there is a complex relationship between the specific cognitive problems faced by an individual patient, their stage of disease and dopaminergic treatment. We used a bimodality continuous performance task during fMRI to examine how patients with Parkinson's disease represent the prospect of reward and switch between competing task rules accordingly. The task-switch was not separately cued but was based on the implicit reward relevance of spatial and verbal dimensions of successive compound stimuli. Nineteen patients were studied in relative 'on' and 'off' states, induced by dopaminergic medication withdrawal (Hoehn and Yahr stages 1-4). Patients were able to successfully complete the task and establish a bias to one or other dimension in order to gain reward. However the lateral prefrontal cortex and caudate nucleus showed a non-linear U-shape relationship between motor disease severity and regional brain activation. Dopaminergic treatment led to a shift in this U-shape function, supporting the hypothesis of differential neurodegeneration in separate motor and cognitive cortico-striato-thalamo-cortical circuits. In addition, anterior cingulate activation associated with reward expectation declined with more severe disease, whereas activation following actual rewards increased with more severe disease. This may facilitate a change in goal-directed behaviours from deferred predicted rewards to immediate actual rewards, particularly when on dopaminergic treatment. We discuss the implications for investigation and optimal treatment of this common condition at different stages of disease.

We investigated the utility of the Cambridge Behavioural Inventory (CBI), a carer-completed questionnaire, in a large cohort with Parkinson's disease (PD) (n = 215). In a sub-cohort of 112 patients with PD, the CBI was found to be a valid instrument compared with the Neuropsychiatric Inventory, PDQ-39 and UPDRS, with high internal consistency. Furthermore, in the whole cohort, the CBI was sensitive to changes in behaviour with disease progression. Comparison between CBI scores in PD and other neurodegenerative diseases, including Huntington's disease (HD) (n = 75), Alzheimer's disease (AD) (n = 96) and frontal variant frontotemporal dementia (fvFTD) (n = 64), revealed distinct profiles for each disease. Predominant deficits were "sleep"' and "self care" in PD; "memory" in HD and AD; and "motivation" and "stereotypic behaviours" in fvFTD. The CBI is a robust, easy-to-use and valid instrument, which has the capacity to discriminate between neurodegenerative diseases, and may be of value in monitoring therapeutic interventions.

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.

Given the known roles of TGFbeta2 in both regulating the immune system and promoting the survival of dopaminergic neurons, it is feasible that genetic variations in TGFB2 might play an aetiological role in neurological diseases such as Multiple Sclerosis (MS) and Parkinson's disease (PD). Hence we performed an indirect association analysis of TGFB2 using 8 haplotype-tagging SNPs in a population of 937 MS patients, 538 PD cases and 2022 controls. We found no evidence for association with susceptibility or progression of MS, but have demonstrated a trend towards association of the 5' region of the gene with susceptibility to PD. Further analysis of TGFB2 is warranted in other PD cohorts.

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.

Alpha-Synuclein is thought to play an important role in the pathology of Parkinson's disease (PD). Truncated forms of this protein can be found in PD brain extracts, and these species aggregate faster and are more susceptible to oxidative stress than the full-length protein. We investigated the effect of truncated alpha-synuclein on dopaminergic cells using a transgenic mouse expressing alpha-synuclein (1-120) driven by the rat tyrosine hydroxylase promoter on a mouse alpha-synuclein null background. We found a selective reduction in the yield of dopaminergic cells from transgenic embryonic ventral mesencephalic cell cultures. However, in vivo the substantia nigra/ventral tegmentum dopaminergic cell counts were not reduced in transgenics, although these mice are known to have reduced striatal dopamine. When transplanted to the striatum in the unilateral 6-hydroxydopamine-lesioned mouse model of PD, dopaminergic cells derived from transgenic embryonic ventral mesencephala were significantly smaller at 6 weeks, and showed a trend towards being less effective at ameliorating rotational asymmetry than those from control alpha-synuclein null mice. These results suggest that alpha-synuclein (1-120) renders dopaminergic cells more susceptible to stress, which may have important implications as to how this truncated protein might contribute to dopaminergic cell death in sporadic PD.

Parkinson's disease (PD) is associated with a loss of central dopaminergic pathways in the brain leading to an abnormality of movement, including saccades. In PD, analysis of saccadic latency distributions, rather than mean latencies, can provide much more information about how the neural decision process that precedes movement is affected by disease or medication. Subject to the constraints of intersubject variation and reproducibility, latency distribution may represent an attractive potential biomarker of PD. Here we report two studies that provide information about these parameters, and demonstrate a novel effect of dopamine on saccadic latency, implying that it influences the neural decision process itself. We performed a detailed cross-sectional study of saccadic latency distributions during a simple step task in 22 medicated patients and 27 age-matched controls. This revealed high intersubject variability and an overlap of PD and control distributions. A second study was undertaken on a different population specifically to investigate the effects of dopamine on saccadic latency distributions in 15 PD patients. L-dopa was found to prolong latency, although the magnitude of the effect varied between subjects. The implications of these observations for the use of saccadic latency distributions as a potential biomarker of PD are discussed, as are the effects of L-dopa on neural decision making, where it is postulated to increase the criterion level of evidence required before the decision to move is made.

The LRRK2 G2019S mutation is the commonest genetic cause of Parkinson's disease (PD) identified to date, although estimates of its prevalence in idiopathic disease vary considerably. Our objectives were to determine G2019S mutation frequency in an unselected, community based cohort of idiopathic PD cases from the UK and to describe phenotypic characteristics among carriers. The mutation was present in two of 519 cases (0.4%) and none of 887 control individuals. The true prevalence of the mutation in idiopathic disease, its penetrance, and the phenotypic heterogeneity of associated cases have important implications for genetic screening in the clinical field.

Objective: The UCHL-1 gene is widely cited as a susceptibility factor for sporadic Parkinson's disease (PD). The strongest evidence comes from a meta-analysis of small studies that reported the S18Y polymorphism as protective against PD, after pooling studies of white and Asian subjects. Here, we present data that challenge this association., Methods: In a new large case-control study in white individuals (3,023 subjects), the S18Y variant was not protective against PD under any genetic model of inheritance. Similarly, a more powerful haplotype-tagging approach did not detect other associated variants., Results: Finally, in an updated S18Y-PD meta-analysis (6,594 subjects), no significant association was observed under additive, recessive, or dominant models (odds ratio = 1.00 [95% confidence interval: 0.74-1.33]; odds ratio = 1.01 [95% confidence interval: 0.76-1.35]; and odds ratio = 0.96 [95% confidence interval: 0.86-1.08], respectively), and a cumulative meta-analysis showed a trend toward a null effect., Interpretation: Based on the current evidence, the UCHL-1 gene does not exhibit a protective effect in PD.

It has been suggested that Parkinson's disease (PD) impairs the ability to learn on the basis of reward or reinforcing feedback i.e., by trial-and-error. In many learning tasks, particular 'dimensions' of stimulus information are relevant whilst others are irrelevant; therefore, efficient performance depends on identifying the dimensions of these 'compound' stimuli and selecting the relevant dimension for further processing. We investigated the ability of patients with PD, as well as patients with Huntington's disease and patients with frontal or temporal lobe lesions, to learn visual discriminations which required either a number of associations to be learned concurrently (the 'eight-pair' task) or the selection of information from compound stimuli (the 'five-dimension' task), both tasks being learned by trial-and-error. None of the basal ganglia disorder patient groups was impaired on the eight-pair task, militating against a crucial role for these brain structures in trial-and-error learning per se. Patients with mild, medicated PD, but not unmedicated PD patients, were impaired at identifying all five feature dimensions in the five-dimension task, implying dopaminergic 'overdosing' of the ability to analyse compound stimuli in terms of their component dimensions. Temporal lobe lesion patients performed similarly, suggesting that the temporal lobe may be the site of the medication overdose effect. Patients with severe, medicated PD were impaired at compound discrimination learning on the five-dimension task in the absence of an underlying impairment in identifying component stimulus dimensions; this pattern resembled that seen in Huntington's disease and frontal lobe lesion patients, implying that fronto-striatal circuitry is involved in the formation of rules based upon selected stimulus dimensions.

Porcine fetal neural tissue has been considered as an alternative source to human allografts for transplantation in neurodegenerative disorders by virtue of the fact that it can overcome the ethical and practical difficulties using human fetal neural tissue. However, primary porcine neural xenografts are rejected while porcine expanded neural precursor neural cells (PNPCs) seem to be less immunogenic and thus survive better [Armstrong, R.J., Harrower, T.P., Hurelbrink, C.B., McLaughin, M., Ratcliffe, E.L., Tyers, P., Richards, A., Dunnett, S.B., Rosser, A.E., Barker, R.A., 2001a. Porcine neural xenografts in the immunocompetent rat: immune response following grafting of expanded neural precursor cells. Neuroscience 106, 201-216]. In this study, we extended these observations to investigate the long-term survival of such transplants in immunosuppressed rats. Unilateral 6 OHDA lesioned rats received grafts into the dopamine denervated striatum of either primary porcine fetal neural tissue dissected from the E26 cortex or cortically derived neural stem cells which had been derived from the same source but expanded in vitro for 21 days. All cortically derived neural stem cell grafts survived up to 5 months in contrast to the poor survival of primary porcine xenografts. Histological analysis demonstrated good graft integration with fibers extending into the surrounding host tissue including white matter with synapse formation, and in addition there was evidence of host vascularization and myelinated fibers within the graft area. This study has therefore shown for the first time the reliable long-term survival of grafts derived from porcine expanded neural precursors in a rat model of PD, with maturation and integration into the host brain. This demonstrates that such xenografted cells may be able to recreate the damaged circuitry in PD although strategies for dopaminergic differentiation of the porcine neural precursor cell remain to be refined.

Objectives: The aetiology of the cognitive changes seen in Parkinson's disease (PD) is multifactorial but it is likely that a significant contribution arises from the disruption of dopaminergic pathways. This study aimed to investigate the contribution of the dopaminergic system to performance on two executive tasks using (18)F-6-fluorodopa positron emission tomography ((18)F-dopa PET) in PD subjects with early cognitive changes., Methods: 16 non-demented, non-depressed PD subjects were evaluated with the Tower of London (TOL) spatial planning task, a verbal working memory task (VWMT) and (18)F-dopa PET, all known to be affected in early PD. Statistical parametric mapping (SPM) localised brain regions in which (18)F-dopa uptake covaried with performance scores. Frontal cortical resting glucose metabolism was assessed with (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET., Results: SPM localised significant covariation between right caudate (18)F-dopa uptake (Ki) and TOL scores and between left anterior putamen Ki and VWMT performance. No significant covariation was found between task scores and (18)F-dopa Ki values in either limbic or cortical regions. Frontal cortical glucose metabolism was preserved in all cases., Conclusions: These findings support a causative role of striatal dopaminergic depletion in the early impairment of executive functions seen in PD. They suggest that spatial and verbal executive tasks require integrity of the right and left striatum, respectively, and imply that the pattern of cognitive changes manifest by a patient with PD may reflect differential dopamine loss in the two striatal complexes.

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.

There is increasing evidence that genetic variants of mitochondrial DNA have an important role in the cause of idiopathic Parkinson's disease. We determined the mitochondrial DNA haplogroup of 455 Parkinson's disease cases, 185 Alzheimer's disease cases, and 447 healthy English control subjects. The UKJT haplogroup cluster was associated with a 22% reduction in population-attributable risk for Parkinson's disease. There was no association between individual haplogroups or the UKJT cluster and Alzheimer's disease, confirming that the association with Parkinson's disease was disease specific and not a general effect seen in all neurodegenerative diseases.

Objective: To investigate the heterogeneity of idiopathic Parkinson's disease (PD) in a data driven manner among a cohort of patients in the early clinical stages of the disease meeting established diagnostic criteria., Methods: Data on demographic, motor, mood, and cognitive measures were collected from 120 consecutive patients in the early stages of PD (Hoehn and Yahr I-III) attending a specialist PD research clinic. Statistical cluster analysis of the data allowed the existence of the patient subgroups generated to be explored., Results: The analysis revealed four main subgroups: (a) patients with a younger disease onset; (b) a tremor dominant subgroup of patients; (c) a non-tremor dominant subgroup with significant levels of cognitive impairment and mild depression; and (d) a subgroup with rapid disease progression but no cognitive impairment., Conclusions: This study complements and extends previous research by using a data driven approach to define the clinical heterogeneity of early PD. The approach adopted in this study for the identification of subgroups of patients within Parkinson's disease has important implications for generating testable hypotheses on defining the heterogeneity of this common condition and its aetiopathological basis and thus its treatment.

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.

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.

Previous research on cognitive set shifting in patients with Parkinson's disease has often been confounded by concept formation, rule learning, working memory and/or general slowing of cognitive processes. To circumvent this problem, the present study used the task-set switching procedure in which good performance was independent of rule learning, and in which working memory load was reduced by explicitly cueing the task switches. Our results provide strong evidence for a specific cognitive set shifting deficit in patients with mild Parkinson's disease in a non-learning context, which also cannot be explained by general slowing of cognitive processes. Moreover, the deficit was robust in a small sample of patients at the earliest stages of the disease. Finally, the impairment in task-set switching was only apparent when competing information was present, i.e. when the load on selection mechanisms was increased.

We investigated how dopamine (DA) systems contribute to cognitive performance in the domain of learning and attentional flexibility by examining effects of withdrawing DA-ergic medication in patients with Parkinson's disease (PD). Medication remediated impairments in switching between two tasks, thought to depend on circuitry connecting the dorsolateral prefrontal cortex and the posterior parietal cortex to the dorsal caudate nucleus, which is profoundly DA-depleted in PD. By contrast, the same medication impaired probabilistic reversal learning that implicates orbitofrontal cortex- ventral striatal circuitry, which is relatively spared of DA loss in PD. Hence, DA-ergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of DA function in underlying cortico-striatal circuitry.

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.

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.

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.

Parkinson's disease (PD) is a common condition that, in the majority of cases, is idiopathic in origin. The loss of central dopaminergic pathways is well-known and in this paper a theory is presented that this is brought about by an autoimmune process. The lack of any HLA association or familial clumping for the disease does not exclude such a theory, as a common etiological agent may exist that we do not yet recognize, e.g., infection, or drugs. Several autoantibodies and disturbances in T-cell function have been found in PD. The theory proposes that the production of autoantibodies and T-cell activation are important in the pathogenesis of idiopathic PD by an action on the substance P striatonigral pathway and its input to the dopaminergic nigrostriatal pathway. The autoimmune destruction of the substance P input leads to a secondary loss of the dopaminergic system and hence PD.

Parkinson's disease (PD) is a common condition that is thought to result from a marked degeneration of dopaminergic neurones of midbrain origin. Here I present evidence to show that PD may result from a primary loss of active tachykinin, probably substance P (SP) in the substantia nigra (SN), and that this loss leads to a secondary degeneration of the dopaminergic neurones. This raises the possibility of treating and curing patients with PD by giving them SP agonsts.