Herva M.E.,Cambridge Center for Brain Repair
Prion | Year: 2012
Prions consist of PrPSc, a misfolded version of the cellular protein PrPC. They occur in a variety of strains that share the amino acid sequence of PrP but differ in phenotypic properties, such as cell tropism and pathogenicity; strain-ness is attributed to the conformation of PrP Sc. To gain insight as to how susceptibility of cells to a given prion strain comes about, we compared amplification of RML prions by PMCA, using cell lysates from related, RML-resistant and RML-susceptible cell lines as substrate. We found that both lysates supported amplification of RML PrP Sc equally well, despite a 280-fold difference in the susceptibility of the cells from which they were derived. Thus, susceptibility is an attribute of the intact cell. © 2012 Landes Bioscience.
Dunn V.J.,University of Cambridge |
Abbott R.A.,University of Cambridge |
Croudace T.J.,University of Cambridge |
Wilkinson P.,University of Cambridge |
And 3 more authors.
BMC Psychiatry | Year: 2011
Background: Adverse family experiences in early life are associated with subsequent psychopathology. This study adds to the growing body of work exploring the nature and associations between adverse experiences over the childhood years.Methods: Primary carers of 1143 randomly recruited 14-year olds in Cambridgeshire and Suffolk, UK were interviewed using the Cambridge Early Experiences Interview (CAMEEI) to assess family-focused adversities. Adversities were recorded retrospectively in three time periods (early and later childhood and early adolescence). Latent Class Analysis (LCA) grouped individuals into adversity classes for each time period and longitudinally. Adolescents were interviewed to generate lifetime DSM-IV diagnoses using the K-SADS-PL. The associations between adversity class and diagnoses were explored.Results: LCA generated a 4-class model for each time period and longitudinally. In early childhood 69% were allocated to a low adversity class; a moderate adversity class (19%) showed elevated rates of family loss, mild or moderate family discord, financial difficulties, maternal psychiatric illness and higher risk for paternal atypical parenting; a severe class (6%) experienced higher rates on all indicators and almost exclusively accounted for incidents of child abuse; a fourth class, characterised by atypical parenting from both parents, accounted for the remaining 7%. Class membership was fairly stable (~ 55%) over time with escape from any adversity by 14 years being uncommon. Compared to those in the low class, the odds ratio for reported psychopathology in adolescents in the severe class ranged from 8 for disruptive behaviour disorders through to 4.8 for depressions and 2.0 for anxiety disorders. Only in the low adversity class did significantly more females than males report psychopathology.Conclusions: Family adversities in the early years occur as multiple rather than single experiences. Although some children escape adversity, for many this negative family environment persists over the first 15 years of life. Different profiles of family risk may be associated with specific mental disorders in young people. Sex differences in psychopathologies may be most pronounced in those exposed to low levels of family adversities. © 2011 Dunn et al; licensee BioMed Central Ltd.
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.
Barker R.A.,Cambridge Center for Brain Repair |
Barrett J.,Institute of Public Health |
Mason S.L.,Cambridge Center for Brain Repair |
Bjorklund A.,Lund University
The 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. © 2013 Elsevier Ltd.
Calder A.J.,MRC Cognition and Brain science Unit |
Keane J.,MRC Cognition and Brain science Unit |
Young A.W.,University of York |
Lawrence A.D.,University of Cardiff |
And 2 more authors.
Neuropsychologia | Year: 2010
Initial reports of emotion recognition in Huntington's disease (HD) found disproportionate impairments in recognising disgust. Not all subsequent studies have found this pattern, and a review of the literature to date shows that marked impairments in recognising anger are also often seen in HD. However, the majority of studies have based their conclusions on a single test of facial expression recognition. In the current study we revisit this issue of emotion recognition in HD to address whether the pattern found on one test of facial expression recognition generalised to another, and to different modalities using tests of emotion recognition from facial expressions, vocal expressions, and short verbal vignettes. The results showed evidence of impairments in recognising anger, fear and disgust across the three domains, with recognition of anger the most severely impaired. Given work identifying different subtypes of disgust that are associated with different facial features, a second study examined the recognition of three disgust expressions that healthy participants reliably associate with unpleasant tastes, unpleasant smells, and a more general elaborated or expanded form of disgust that includes reactions to violations of moral standards. The results showed a disproportionate impairment in recognising faces associated with the expanded form, the subtype most closely aligned with anger. We conclude that the related emotions of disgust and anger associated with social disapproval are frequently impaired in HD and discuss factors that might cause one emotion to show more severe impairments than the other. © 2010 Elsevier Ltd.
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.
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.
Appel E.A.,University of Cambridge |
Rowland M.J.,University of Cambridge |
Loh X.J.,University of Cambridge |
Heywood R.M.,Cambridge Center for Brain Repair |
And 3 more authors.
Chemical Communications | Year: 2012
Temozolomide (TMZ) is the primary chemotherapeutic agent for treatment of glioblastoma multiforme (GBM) yet it has a fast rate of degradation under physiological conditions to the 'active' MTIC, which has poor penetration of the blood-brain barrier and cellular absorption. Herein we have demonstrated binding of TMZ within the cavity of nano-container cucurbituril, resulting in a decreased rate of drug degradation. Prolonging the lifetime of the TMZ under physiological conditions through encapsulation dramatically improved the drug's activity against primary GBM cell lines as more TMZ could be absorbed by the cells before degradation. This work can potentially lead to increases in the drug's propensity for crossing the blood-brain barrier and absorption into the GBM cells, thereby increasing the efficacy of this chemotherapy. © The Royal Society of Chemistry 2012.
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.