Barker R.A.,Cambridge Center for Brain Repair
Lancet neurology | Year: 2013
Clinical use of allografts of fetal ventral mesencephalic tissue as a treatment to replace dopaminergic neurons in patients with Parkinson's disease was first done more than 20 years ago. Since then, many patients have received transplants, with variable results. During this time, our knowledge of Parkinson's disease has changed and the nature and extent of problems associated with the disorder have been better defined. Our understanding on how best to implement this cell-replacement strategy for patients has grown, but gaining this insight has entailed critical reappraisal of data from transplant trials that have already been undertaken. Copyright © 2013 Elsevier Ltd. All rights reserved.
A Wnt1 regulated Frizzled-1/β-catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection
L'Episcopo F.,OASI Institute for Research and Care on Mental Retardation and Brain Aging |
Serapide M.F.,University of Catania |
Tirolo C.,OASI Institute for Research and Care on Mental Retardation and Brain Aging |
Testa N.,OASI Institute for Research and Care on Mental Retardation and Brain Aging |
And 5 more authors.
Molecular Neurodegeneration | Year: 2011
Background: Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. Results: In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT) expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH +) neurons and [ 3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP +. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH + neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH + neuroprotection. In vivo experiments document Fzd-1 co-localization with TH + neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd/β-catenin antagonist within the SN induces reactive astrocytosis and acutely inhibits TH + neuron survival in ipsilateral SNpc, an effect efficiently prevented by pharmacological activation of β-catenin signaling within the SNpc. Conclusion: These results defining a novel Wnt1/Fzd-1/β- catenin astrocyte-DA autoprotective loop provide a new mechanistic inside into the regulation of pro-survival processes, with potentially relevant consequences for drug design or drug action in Parkinson's disease. © 2011 L'Episcopo et al; licensee BioMed Central Ltd.
Rowe J.B.,University of Cambridge |
Rowe J.B.,Medical Research Council Cognition and Brain science Unit |
Hughes L.E.,University of Cambridge |
Hughes L.E.,Medical Research Council Cognition and Brain science Unit |
And 3 more authors.
NeuroImage | Year: 2010
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. © 2009 Elsevier Inc.
Kehagia A.A.,University of St. Andrews |
Barker R.A.,Cambridge Center for Brain Repair |
Robbins T.W.,Behavioural and Clinical Neuroscience Institute |
Robbins T.W.,University of Cambridge
Neurodegenerative Diseases | Year: 2013
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. Copyright © 2012 S. Karger AG, Basel.
Goodyer I.M.,University of Cambridge |
Croudace T.,University of Cambridge |
Dudbridge F.,London School of Hygiene and Tropical Medicine |
Ban M.,University of Cambridge |
Herbert J.,Cambridge Center for Brain Repair
British Journal of Psychiatry | Year: 2010
Background: There is increasing evidence for genetic effects on the hypothalamic-pituitary axis system. More than one gene is likely to moderate corticoid-mediated activity. Aims: To investigate whether the brain-derived neurotrophic factor (BDNF) polymorphism (rs6265, Val66Met) is associated with morning waking salivary cortisol and moderates the corticoid-mediated risk for subsequent depressive episode onset independently of the known effects of 5-HTTLPR (the serotonin transporter gene promoter). Method: High-risk adolescents (n = 401) were genotyped for Val66Met BDNF and 5-HTTLPR. Salivary samples were obtained on four consecutive school days within 1 h of waking. There were 365 (91%) remaining participants reassessed at 12 months for episodes of psychiatric disorder in the follow-up period. Of these, 357 (89%) had complete data for multivariate modelling. Results: There were 41 (11.2%) individuals who reported a new episode of clinical depression over the follow-up period. Increased risk for subsequent depression was found in carriers of the Val66Val genotype in BDNF with higher morning waking cortisol. This remained present when the known interaction between carriers of a short allele of 5-HTTLPR with higher morning salivary cortisol was taken into account. Conclusions: Both BDNF and 5-HTTLPR genes show evidence of modifying the risk of a subsequent new depressive episode associated with elevated morning salivary cortisol. In adolescents morning salivary cortisol levels may constitute a biomarker for some forms of unipolar depression.