http://www.dspace.cam.ac.uk:80/handle/1810/227520 Mon, 20 May 2013 12:56:07 GMT 2013-05-20T12:56:07Z http://www.dspace.cam.ac.uk:80/handle/1810/241739 Title: Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk Authors: Bettens, Karolien; Brouwers, Nathalie; Engelborghs, Sebastiaan; Lambert, Jean-Charles; Rogaeva, Ekaterina; Vandenberghe, Rik; Le Bastard, Nathalie; Pasquier, Florence; Vermeulen, Steven; Van Dongen, Jasper; Mattheijssens, Maria; Peeters, Karin; Mayeux, Richard; St George-Hyslop, Peter; Amouyel, Philippe; De Deyn, Peter P; Sleegers, Kristel; Van Broeckhoven, Christine Abstract: Abstract Background We have followed-up on the recent genome-wide association (GWA) of the clusterin gene (CLU) with increased risk for Alzheimer disease (AD), by performing an unbiased resequencing of all CLU coding exons and regulatory regions in an extended Flanders-Belgian cohort of Caucasian AD patients and control individuals (n = 1930). Moreover, we have replicated genetic findings by targeted resequencing in independent Caucasian cohorts of French (n = 2182) and Canadian (n = 573) origin and by performing meta-analysis combining our data with previous genetic CLU screenings. Results In the Flanders-Belgian cohort, we identified significant clustering in exons 5-8 of rare genetic variations leading to non-synonymous substitutions and a 9-bp insertion/deletion affecting the CLU β-chain (p = 0.02). Replicating this observation by targeted resequencing of CLU exons 5-8 in 2 independent Caucasian cohorts of French and Canadian origin identified identical as well as novel non-synonymous substitutions and small insertion/deletions. A meta-analysis, combining the datasets of the 3 cohorts with published CLU sequencing data, confirmed that rare coding variations in the CLU β-chain were significantly enriched in AD patients (ORMH = 1.96 [95% CI = 1.18-3.25]; p = 0.009). Single nucleotide polymorphisms (SNPs) association analysis indicated the common AD risk association (GWA SNP rs11136000, p = 0.013) in the 3 combined datasets could not be explained by the presence of the rare coding variations we identified. Further, high-density SNP mapping in the CLU locus mapped the common association signal to a more 5' CLU region. Conclusions We identified a new genetic risk association of AD with rare coding CLU variations that is independent of the 5' common association signal identified in the GWA studies. At this stage the role of these coding variations and their likely effect on the β-chain domain and CLU protein functioning remains unclear and requires further studies. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Mon, 16 Jan 2012 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/241739 2012-01-16T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/241663 Title: Communicating oscillatory networks: Frequency Domain Analysis Authors: Ihekwaba, Adaoha E C; Sedwards, Sean Abstract: Abstract Background Constructing predictive dynamic models of interacting signalling networks remains one of the great challenges facing systems biology. While detailed dynamical data exists about individual pathways, the task of combining such data without further lengthy experimentation is highly nontrivial. The communicating links between pathways, implicitly assumed to be unimportant and thus excluded, are precisely what become important in the larger system and must be reinstated. To maintain the delicate phase relationships between signals, signalling networks demand accurate dynamical parameters, but parameters optimised in isolation and under varying conditions are unlikely to remain optimal when combined. The computational burden of estimating parameters increases exponentially with increasing system size, so it is crucial to find precise and efficient ways of measuring the behaviour of systems, in order to re-use existing work. Results Motivated by the above, we present a new frequency domain-based systematic analysis technique that attempts to address the challenge of network assembly by defining a rigorous means to quantify the behaviour of stochastic systems. As our focus we construct a novel coupled oscillatory model of p53, NF-kB and the mammalian cell cycle, based on recent experimentally verified mathematical models. Informed by online databases of protein networks and interactions, we distilled their key elements into simplified models containing the most significant parts. Having coupled these systems, we constructed stochastic models for use in our frequency domain analysis. We used our new technique to investigate the crosstalk between the components of our model and measure the efficacy of certain network-based heuristic measures. Conclusions We find that the interactions between the networks we study are highly complex and not intuitive: (i) points of maximum perturbation do not necessarily correspond to points of maximum proximity to influence; (ii) increased coupling strength does not necessarily increase perturbation; (iii) different perturbations do not necessarily sum and (iv) overall, susceptibility to perturbation is amplitude and frequency dependent and cannot easily be predicted by heuristic measures. Our methodology is particularly relevant for oscillatory systems, though not limited to these, and is most revealing when applied to the results of stochastic simulation. The technique is able to characterise precisely the distance in behaviour between different models, different systems and different parts within the same system. It can also measure the difference between different simulation algorithms used on the same system and can be used to inform the choice of dynamic parameters. By measuring crosstalk between subsystems it can also indicate mechanisms by which such systems may be controlled in experiments and therapeutics. We have thus found our technique of frequency domain analysis to be a valuable benchmark systems-biological tool. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Thu, 22 Dec 2011 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/241663 2011-12-22T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/238111 Title: Cerebrovascular pressure-reactivity in normal pressure hydrocephalus Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Thu, 23 Dec 2004 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/238111 2004-12-23T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/238110 Title: Reasons for shunting and reasons for revision: a survey based on data from the UK Shunt Registry Abstract: Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Thu, 23 Dec 2004 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/238110 2004-12-23T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/238109 Title: Neuropsychological profile of patients with normal pressure hydrocephalus and Alzheimer's disease Abstract: Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Thu, 23 Dec 2004 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/238109 2004-12-23T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/238079 Title: Resistance to CSF outflow depends upon duration of symptoms in patients with Normal Pressure Hydrocephalus Abstract: Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Fri, 30 Dec 2005 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/238079 2005-12-30T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/238055 Title: Programmable hydrocephalus shunt which cannot be unwillingly re-adjusted even in 3T MRI magnet Abstract: Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Thu, 21 Dec 2006 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/238055 2006-12-21T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/238039 Title: Laboratory study on intracranial hypotension created by pumping the chamber of a hydrocephalus shunt Authors: Bromby, Adam; Czosnyka, Zofia; Allin, David M; Richards, Hugh K; Pickard, John D; Czosnyka, Marek Abstract: Abstract Background It has been reported that pumping a shunt in situ may precipitate a proximal occlusion, and/or lead to ventricular over-drainage, particularly in the context of small ventricles. In the laboratory we measured the effect of pumping the pre-chamber of hydrocephalus shunts on intracranial hypotension. Materials and methods A simple physical model of the CSF space in a hydrocephalic patient was constructed with appropriate compliance, CSF production and circulation. This was used to test eleven different hydrocephalus shunts. The lowest pressure obtained, the number of pumps needed to reach this pressure, and the maximum pressure change with a single pump, were recorded. Results All models were able to produce negative pressures ranging from -11.5 mmHg (Orbis-Sigma valve) to -233.1 mmHg (Sinu-Shunt). The number of pumps required reaching these levels ranged from 21 (PS Medical LP Reservoir) to 315 (Codman Hakim-Programmable). The maximum pressure change per pump ranged from 0.39 mmHg (Orbis-Sigma valve) to 23.1 (PS Medical LP Reservoir). Conclusion Patients, carers and professionals should be warned that 'pumping' a shunt's pre-chamber may cause a large change in intracranial pressure and predispose the patient to ventricular catheter obstruction or other complications. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Sun, 25 Mar 2007 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/238039 2007-03-25T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/237917 Title: Visualising disease progression on multiple variables with vector plots and path plots Authors: Lazic, Stanley E; Mason, Sarah L; Michell, Andrew W; Barker, Roger A Abstract: Abstract Background It is often desirable to observe how a disease progresses over time in individual patients, rather than graphing group averages; and since multiple outcomes are typically recorded on each patient, it would be advantageous to visualise disease progression on multiple variables simultaneously. Methods A variety of vector plots and a path plot have been developed for this purpose, and data from a longitudinal Huntington's disease study are used to illustrate the utility of these graphical methods for exploratory data analysis. Results Initial and final values for three outcome variables can be easily visualised per patient, along with the change in these variables over time. In addition to the disease trajectory, the path individual patients take from initial to final observation can be traced. Categorical variables can be coded with different types of vectors or paths (e.g. different colours, line types, line thickness) and separate panels can be used to include further categorical or continuous variables, allowing clear visualisation of further information for each individual. In addition, summary statistics such as mean vectors, bivariate interquartile ranges and convex polygons can be included to assist in interpreting trajectories, comparing groups, and detecting multivariate outliers. Conclusion Vector and path plots are useful graphical methods for exploratory data analysis when individual-level information on multiple variables over time is desired, and they have several advantages over plotting each variable separately. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Tue, 26 May 2009 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/237917 2009-05-26T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/237882 Title: Acute dosing of latrepirdine (DimebonTM), a possible Alzheimer therapeutic, elevates extracellular amyloid-beta levels in vitro and in vivo Authors: Steele, John W; Kim, Soong Ho; Cirrito, John R; Verges, Deborah K; Restivo, Jessica L; Westaway, David; Fraser, Paul; St George Hyslop, Peter; Sano, Mary; Bezprozvanny, Ilya; Ehrlich, Michelle E; Holtzman, David M; Gandy, Sam Abstract: Abstract Background Recent reports suggest that latrepirdine (Dimebon™, dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-β (Aβ) peptide in the brain, and Aβ-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of latrepirdine on levels of extracellular Aβ using in vitro and in vivo experimental systems. Results We evaluated extracellular levels of Aβ in three experimental systems, under basal conditions and after treatment with latrepirdine. Mouse N2a neuroblastoma cells overexpressing Swedish APP were incubated for 6 hr in the presence of either vehicle or vehicle + latrepirdine (500pM-5 μM). Synaptoneurosomes were isolated from TgCRND8 mutant APP-overexpressing transgenic mice and incubated for 0 to 10 min in the absence or presence of latrepirdine (1 μM or 10 μM). Drug-naïve Tg2576 Swedish mutant APP overexpressing transgenic mice received a single intraperitoneal injection of either vehicle or vehicle + latrepirdine (3.5 mg/kg). Picomolar to nanomolar concentrations of acutely administered latrepirdine increased the extracellular concentration of Aβ in the conditioned media from Swedish mutant APP-overexpressing N2a cells by up to 64% (p = 0.01), while a clinically relevant acute dose of latrepirdine administered i.p. led to an increase in the interstitial fluid of freely moving APP transgenic mice by up to 40% (p = 0.01). Reconstitution of membrane protein trafficking and processing is frequently inefficient, and, consistent with this interpretation, latrepirdine treatment of isolated TgCRND8 synaptoneurosomes involved higher concentrations of drug (1-10 μM) and led to more modest increases in extracellular Aβx-42 levels (+10%; p = 0.001); of note, however, was the observation that extracellular Aβx-40 levels did not change. Conclusions Here, we report the surprising association of acute latrepirdine dosing with elevated levels of extracellular Aβ as measured in three independent neuron-related or neuron-derived systems, including the hippocampus of freely moving Tg2576 mice. Given the reported association of chronic latrepirdine treatment with improvement in cognitive function, the effects of chronic latrepirdine treatment on extracellular Aβ levels must now be determined. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Thu, 17 Dec 2009 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/237882 2009-12-17T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/237729 Title: Investigation of the hydrodynamic properties of a new MRI-resistant programmable hydrocephalus shunt Authors: Allin, David M; Czosnyka, Marek; Richards, Hugh K; Pickard, John D; Czosnyka, Zofia Abstract: Abstract Background The Polaris valve is a newly released hydrocephalus shunt that is designed to drain cerebrospinal fluid (CSF) from the brain ventricles or lumbar CSF space. The aim of this study was to bench test the properties of the Polaris shunt, independently of the manufacturer. Methods The Polaris Valve is a ball-on-spring valve, which can be adjusted magnetically in vivo. A special mechanism is incorporated to prevent accidental re-adjustment by an external magnetic field. The performance and hydrodynamic properties of the valve were evaluated in the UK Shunt Evaluation Laboratory, Cambridge, UK. Results The three shunts tested showed good mechanical durability over the 3-month period of testing, and a stable hydrodynamic performance over 45 days. The pressure-flow performance curves, operating, opening and closing pressures were stable. The drainage rate of the shunt increased when a negative outlet pressure (siphoning) was applied. The hydrodynamic parameters fell within the limits specified by the manufacturer and changed according to the five programmed performance levels. Hydrodynamic resistance was dependant on operating pressure, changing from low values of 1.6 mmHg/ml/min at the lowest level to 11.2 mmHg/ml/min at the highest performance level. External programming proved to be easy and reliable. Even very strong magnetic fields (3 Tesla) were not able to change the programming of the valve. However, distortion of magnetic resonance images was present. Conclusion The Polaris Valve is a reliable, adjustable valve. Unlike other adjustable valves (except the Miethke ProGAV valve), the Polaris cannot be accidentally re-adjusted by an external magnetic field. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Sun, 20 Apr 2008 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/237729 2008-04-20T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/237670 Title: A Cre-lox approach for transient transgene expression in neural precursor cells and long-term tracking of their progeny in vitro and in vivo. Authors: Geoffroy, Cedric G; Raineteau, Olivier Abstract: Abstract Background Neural precursor cells (NPCs) can be isolated from various regions of the postnatal central nervous system (CNS). Manipulation of gene expression in these cells offers a promising strategy to manipulate their fate both in vitro and in vivo. In this study, we developed a technique that allows the transient manipulation of single/multiple gene expression in NPCs in vitro, and the long-term tracking of their progeny both in vitro and in vivo. Results In order to combine the advantages of transient transfection with the long-term tracking of the transfected cells progeny, we developed a new approach based on the cre-lox technology. We first established a fast and reliable protocol to isolate and culture NPCs as monolayer, from the spinal cord of neonatal transgenic Rosa26-YFP cre-reporter mice. These cells could be reliably transfected with single/multiple plasmids by nucleofection. Nucleofection with mono- or bicistronic plasmids containing the Cre recombinase gene resulted in efficient recombination and the long-term expression of the YFP-reporter gene. The transient cre-expression was non-toxic for the transfected cells and did not alter their intrinsic properties. Finally, we demonstrated that cre-transfected cells could be transplanted into the adult brain, where they maintained YFP expression permitting long-term tracking of their migration and differentiation. Conclusion This approach allows single/multiple genes to be manipulated in NPCs, while at the same time allowing long-term tracking of the transfected cells progeny to be analyzed both in vitro and in vivo. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Mon, 14 May 2007 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/237670 2007-05-14T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/237259 Title: The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) Trial protocol and baseline cohort characteristics: an open-label pre-test : post-test study with blinded outcome assessments Authors: Connick, Peter; Kolappan, Madhan; Patani, Rickie; Scott, Michael A; Crawley, Charles; He, Xiao-ling; Richardson, Karen; Barber, Kelly; Webber, Daniel J; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; Samson, Rebecca S; Thomas, David L; Du, Ming-Qing; Luan, Shi L; Michell, Andrew W; Altmann, Daniel R; Thompson, Alan J; Miller, David H; Compston, Alastair; Chandran, Siddharthan Abstract: Abstract Background No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach". Methods/design MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Results Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. Conclusions In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability. Trial registration ClinicalTrials.gov (NCT00395200). Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Wed, 02 Mar 2011 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/237259 2011-03-02T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/236604 Title: Local relationships between restricted water diffusion and oxygen consumption in the ischaemic human brain Authors: Guadagno, Joseph V; Simon Jones, P; Fryer, Tim D; Barret, Olivier; Aigbirhio, Franklin I; Carpenter, T. Adrian; Price, Christopher J; Gillard, Jonathan H; Warburton, Elizabeth A; Baron, Jean-Claude Abstract: Background and Purpose— MR is widely used to depict still ischemic but viable tissue in acute stroke. However, the relationship between the apparent diffusion coefficient (ADC) and energy failure from reduced oxygen supply are unknown in man.; Methods— Acute carotid-territory stroke patients were studied prospectively with both diffusion tensor–imaging and back-to-back steady-state 15O-PET. Substantial numbers of voxels with oxygen extraction fraction >0.70 (ie, significant ongoing hypoxia) were identified in 3 patients (imaged at 7, 16 and 21 hours after stroke onset). In this voxel population, the quantitative relationships between the ADC and cerebral metabolic rate of oxygen (CMRO2), and ADC and cerebral blood flow (CBF), were assessed.; Results— The ADC remained essentially unchanged until CBF reached values 20 mls/100g per min, beyond which it declined linearly. In contrast, except when severely reduced, the ADC was a poorer predictor of CMRO2. For both CBF and CMRO2, however, the relationship with ADC became steeper with longer times since onset, ie, the same ADC reflected lower perfusion and CMRO2 with elapsed time.; Conclusions— Despite the small sample and late times from stroke onset, the findings indicate that the degree of restricted water diffusion reliably reflects the severity of oxygen deprivation below the penumbral threshold but is less strongly related to metabolic disruption, which may explain why the ADC does not reliably predict tissue outcome. However, the same degree of diffusion restriction may correspond to greater severity of tissue disruption with elapsing time, which has relevance for stroke therapy. Time elapsed since stroke onset should be taken into account when interpreting ADC declines and in voxel-based infarct prediction models. Description: Corrections to the article are appended in a separate file Wed, 07 Jun 2006 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/236604 2006-06-07T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/236603 Title: Dynamics of Motor Network Overactivation After Striatocapsular Stroke. A Longitudinal PET Study Using a Fixed-Performance Paradigm Authors: Calautti, Cinzia; Guincestre, Jean-Yves; Leroy, François; Baron, Jean-Claude Abstract: Background and Purpose—Although excessive brain activation during affected hand motion after stroke is well documented, its time course has been rarely studied, and when studied, this has either been with passive movement or with active but cognitively complex task and uncontrolled performance over time, complicating interpretation.; Methods—According to a prospective and longitudinal design, we studied 5 right-handed patients with right-sided hemiparesis due to first-ever left striatocapsular infarction. Three-dimensional PET H2O15 studies were performed twice ( 7 and 31 weeks after stroke [PET1 and PET2, respectively]) during right thumb-to-index tapping executed at the same rate in both studies (1.26 Hz, auditory cued). With SPM96 software, significant group and individual overactivations (P 0.05, corrected for multiple comparisons) were computed by comparison with a group of 7 healthy age-matched right-handed control subjects performing the same task.; Results—Motor recovery was significant from PET1 to PET2. Both the group and individual analyses revealed striking overactivations at PET1, affecting notably the cortical hand area and the whole motor network bilaterally. These overactivations were less prominent at PET2 over both hemispheres, not only in terms of Z score but also in terms of spatial extent (almost reaching statistical significance in the affected hemisphere for the latter, P 0.09). However, new overactivations were found at PET2 in the left prefrontal areas, the putamen, and the premotor cortex.; Conclusions—This study is the first to document that to perform the same simple movement of the paretic fingers, the brain with subcortical infarction shows less overactivations at the late than at the early timepoint, especially on the affected side, suggesting reduced recruitment of affected-hemisphere motor networks. However, unaffected-hemisphere prefrontal, premotor, and putaminal overactivations, observed at PET2 only, may suggest late-appearing compensatory reorganization. Mon, 01 Jan 2001 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/236603 2001-01-01T00:00:00Z