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Biomedical subjects

Roger A Barker

Publications and source records attributed to Roger A Barker.

At least 55 records · Page 3Linked to original sources
PubMed2004

Random number generation in patients with symptomatic and presymptomatic Huntington's disease.

Random number generation (RNG), which involves producing lists of numbers at random, requires response selection and inhibition, which are aspects of executive function mediated by the frontal lobe. This study examined RNG performance in a group of mild to moderate Huntington's disease (HD) patients, asymptomatic gene-positive HD patients, and controls. The HD symptomatic group was significantly less random in their choices than controls. The gene-positive asymptomatic HD patients also showed a tendency toward abnormal RNG measures compared with controls, although this did not reach statistical significance after correction for multiple comparisons. However, analyzing the HD group as a whole showed that the frequency of errors, preferential selection of favorite numbers, and counting in 1's correlated significantly with the degree of symptom severity. Furthermore, counting in 1's correlated with degree of vulnerability to symptoms. A subset of patients and controls were retested 6 months later, and all RNG measures showed high correlations over time, highlighting the robust reliability of this test. The data therefore suggest that RNG is a useful, brief and reliable test of executive function and may be of value in studies investigating the longitudinal effects of disease-modifying treatment in HD.

Adult↗
PubMed2003

The cognitive ability of an incident cohort of Parkinson's patients in the UK. The CamPaIGN study.

We have used multiple sources to identify a population-representative cohort of newly diagnosed patients with parkinsonism and Parkinson's disease in the UK over a 2-year period. All patients have been invited to participate in a detailed clinical assessment either at home or in an outpatient clinic. These assessments have been used to refine clinical diagnoses of parkinsonism using established criteria, and describe some of the phenotypic variability of Parkinson's disease at the time of diagnosis. The crude incidence of Parkinson's disease was 13.6/10(5yr-1) [confidence interval (CI) 11.8-15.6 and of parkinsonism was 20.9/10(5yr-1) (CI 18.7-23.3). Age-standardized to the 1991 European population, the incidence figures become 10.8/10(5yr-1) (CI 9.4-12.4) for Parkinson's disease and 16.6/10(5yr-1) (CI 14.8-18.6) for parkinsonism. Thirty-six per cent of the Parkinson's disease patients had evidence of cognitive impairment based on their performance in the Mini-Mental State Examination, a pattern recognition task, and the Tower of London task. The pattern of cognitive deficits seen among these patients using these and further cognitive tasks suggests that sub-groups of patients based on cognitive ability might be identifiable even in the early stages of disease, which may reflect regional differences in the underlying neuropathological processes.

Adult↗
PubMed2003

Cognitive impairments in early Parkinson's disease are accompanied by reductions in activity in frontostriatal neural circuitry.

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

Adult↗
PubMed2003

Migration and differentiation of transplanted human neural precursor cells.

In this study we have examined the migration and phenotypic differentiation of human expanded neural precursors (hENPs) when transplanted into the intact adult rat brain. Primary human embryonic cortical cells and hENPs derived from the same source but expanded epigenetically in culture for two different time periods were transplanted into the rodent striatum and hippocampus. Histological analysis showed that overall the number of neurons decreased with time spent in culture prior to transplantation within the core of the graft regardless of site of implantation. Furthermore, transplanted cells migrated away from the graft to a similar extent irrespective of time in culture and site of implantation, although significantly more migrated cells were of a neuronal phenotype following transplantation into the hippocampus.

Animals↗
PubMed2003

Task-set switching deficits in early-stage Huntington's disease: implications for basal ganglia function.

Executive functions are likely mediated by interconnected circuits including frontal lobe and basal ganglia structures. We assessed the executive function of task switching in patients with early-stage Huntington's disease (HD), a neurodegenerative disease affecting the basal ganglia. In two experiments, the HD patients had greater difficulty when switching than when repeating a task than matched controls, and this was true even when scaling for the overall slowing of the patients. In the first experiment, HD patients had a switching deficit even in a "pure" condition where they had to switch, predictably, and with substantial preparation time, between stimuli having only one possible response, indicating a switching deficit different from that for patients with Parkinson's disease or frontal lobe trauma, and possibly relating to inadequate activation of stimulus-response links or "response set." In the more elaborate second experiment, we could not account for the switching deficit of the patients in terms of inadequate preparation in advance of a switch, deficient suppression of task-set processing from the preswitch trial, or impaired suppression of interference due to the presence of a competing task set. Instead, we found that part of the switching deficit was due to elevated reaction time and errors on switch trials for a repeated response (same button press as on preswitch trial) relative to an alternated response (different button press from preswitch trial). We argue that this elevated "repetition effect" for the HD patients is due to excessive inhibition of the just-performed response in advance of a switch. Alterations in the "response-setting" process alone (Experiment 1) and both the response-setting and "response inhibition" process (Experiment 2) probably arise from striatal pathology in HD, thus accounting for the task-switching deficits and showing how basal ganglia implemented response processes may underpin executive function.

Adult↗
PubMed2003

Transplantation of expanded neural precursor cells from the developing pig ventral mesencephalon in a rat model of Parkinson's disease.

Neural precursor cell populations can be expanded in vitro under the influence of growth factors, and may be of use to replace cells lost to neurodegenerative conditions such as the dopaminergic neurons in Parkinson's disease (PD). We explore here whether expanding neural precursor cells from the region in which nigral dopaminergic neurones emerge in normal development renders them more likely to differentiate into TH-positive neurones when transplanted in a rat model of PD. Embryonic neural precursor cells (ENPs) were isolated from the developing pig ventral mesencephalon (VM) at two different gestational ages and were implanted into the striatum or the substantia nigra of cyclosporin A-immunosuppressed, 6-hydroxydopamine-lesioned rats, which were sacrificed 9 or 18 weeks later. The properties of ENPs varied according to the gestational age of the donor: ENPs that expanded robustly and survived transplantation could be derived from E22 VM, but not from E27 VM. ENPs developed into neurones that displayed diffuse fibre projections, including those appropriate for the implantation site. However, behaviourally significant numbers of TH-positive neurones were not seen. A rejection response was apparent in most animals by 18 weeks. These data show that donor age is an important variable when deriving ENPs for transplantation. Furthermore, derivation of ENPs from the VM at the time of normal dopaminergic neurogenesis is inadequate to ensure functional dopaminergic grafts on transplantation.

Animals↗
PubMed2003

Modern therapeutic approaches in Parkinson's disease.

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

Antiparkinson Agents↗
PubMed2003

GABAergic immunoreactivity is predominant in neurons derived from expanded human neural precursor cells in vitro.

Neural precursor cells have been previously isolated from the developing human nervous system and their properties studied both in vitro and in transplantation paradigms in vivo. However, their ability to differentiate into neurons of different neurochemical phenotypes remains poorly defined. In this study, the default in vitro neuronal differentiation of hENPs derived from five different regions of the human embryonic brain (cerebral cortex, striatum, cerebellum, ventral mesencephalon, and spinal cord) was studied after varying periods of time in culture. The results were directly compared to those from similarly prepared murine ENPs. hENPs prepared from all five regions showed a significant reduction in the number of neurons generated at each passage, such that by passage 4 only between 5 and 10% of cells spontaneously adopted a neuronal phenotype after differentiation in vitro. A similar observation was obtained with murine ENPs. hENPs prepared from more caudal parts of the developing neuroaxis generated fewer neurons compared to the more rostral regions. The only neuronal phenotype identified in these cultures was GABA, with 15-60% of the neurons immunopositive for this neurotransmitter. Thus there appears to be important differences between hENPs dependent on region of origin and time in vitro under standard culture conditions, forming decreasing numbers of neurons with increasing time in culture and more caudal sites of harvest, and with the major identifiable neurotransmitter being GABA. Such characterisation is important in the process of learning how to manipulate the neuronal phenotype of these cells.

Animals↗
PubMed2003

Using executive heterogeneity to explore the nature of working memory deficits in Parkinson's disease.

Idiopathic Parkinson's disease (IPD) is characterised by a triad of motor symptoms, namely bradykinesia, rigidity and resting tremor, although cognitive impairment is a common feature of the disease and has been accepted as one of the strong predictors of quality of life in such patients. Neuropsychological testing in Parkinson's disease often reveals a pattern of cognitive impairment similar to that observed in patients with frontal lobe lesions, although clear differences between the two groups have also often been reported. This apparent inconsistency in the literature may reflect heterogeneity among different groups of patients with Parkinson's disease, although to date this possibility has not been formally addressed. In this study, two groups of patients with Parkinson's disease were assessed on a novel verbal memory task, which allowed different aspects of working memory function such as maintenance, retrieval and manipulation to be tested within the same general paradigm. The two groups were selected according to either good or bad performance on a 'standard', visuospatial test of executive function (The Tower of London Task), but were well matched on all other demographic and cognitive measures tested. The sub-group of Parkinson's disease patients with Tower of London defined executive deficit were specifically impaired at manipulating information within verbal working memory, both compared to controls and to the group of patients with no predefined executive impairments. In contrast, the three groups did not differ in their ability to maintain or retrieve information within verbal working memory. Given the known preferential role of the dorsolateral frontal cortex in higher executive functions, (including both planning and the manipulation of information within working memory), these results suggest that, in a subset of Parkinson's disease patients, it is the frontostriatal circuitry involving this region which is primarily affected, while other components of this circuitry may be relatively spared. The results also suggest that performance on the Tower of London task may prove to be a useful discriminant variable in defining the nature of cognitive heterogeneity in Parkinson's disease.

Aged↗
PubMed2003

L-Dopa medication remediates cognitive inflexibility, but increases impulsivity in patients with Parkinson's disease.

In the current study we investigated the role of dopamine in attentional and socio-emotional functioning by examining effects of withdrawing dopaminergic medication in patients with Parkinson's disease (PD). Patients "on" medication exhibited abnormal betting strategies on a task of decision-making, reflecting impulsive behaviour and/or delay aversion, whilst the same patients "off" medication exhibited abnormally increased switch costs when switching between two tasks, reflecting attentional inflexibility. Hence, these data replicate and extend previous findings that dopaminergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of dopamine function in underlying cortico-striatal circuitry.

Aged↗
PubMed2003

A case of unilateral neglect in Huntington's disease.

Unilateral neglect, an attentional deficit in detecting and acting on information coming from one side of space, is a relatively common consequence of right hemisphere stroke. Although neglect has been observed following damage to a variety of brain structures, to date no reports exist of neglect phenomena arising from Huntington's Disease (HD). However, reports in the animal and human literature suggest that neglect is possible following damage to a primary site for Huntington's pathology, the basal ganglia. Here we present a patient (BG) with genetically proven HD who, in the context of the mild intellectual, executive and attentional impairments associated with the disorder, showed a remarkably severe and stable neglect for left space. MRI and electrophysiological results make it unlikely that the spatial bias could be accounted for by basic sensory loss. In addition, behavioural investigation indicated that, although BG's neglect operated in a very striking manner along body-centred co-ordinates (missing almost all information presented to her left), more general limitations in visual attention were apparent to the left-side of information presented entirely to the right of the body midline. Further evidence is presented showing that the neglect was manifest on tactile and auditory tasks as well as those presented in the visual domain. The presence of neglect in HD in this case is novel and somewhat puzzling, particularly as flourodeoyglucose positron emission tomography revealed bilateral caudate hypoperfusion. Reducing the statistical threshold on this analysis revealed a potential frontal hypometabolism that was more marked in the right than left hemisphere. However, as this was only apparent at a threshold below that normally considered acceptable (due to the resulting number of false positives), this possible account of the neglect must be viewed very cautiously.

Attention↗
PubMed2003

The future of cell-based transplantation therapies for neurodegenerative disorders.

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

Animals↗
PubMed2003

Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study.

We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.

Adult↗
PubMed2003

Long-term hibernation of human fetal striatal tissue does not adversely affect its differentiation in vitro or graft survival: implications for clinical trials in Huntington's disease.

Transplantation of human fetal CNS tissue is a promising therapy for neurodegenerative conditions such as Huntington's disease (HD), but its widespread adoption is limited by restricted tissue availability. One method of overcoming this problem would be to store the tissue in hibernation medium, an approach that we reported previously for human fetal striatal tissue stored for up to 24 h. We now demonstrate the feasibility of storing such tissue for up to 8 days in hibernation medium. When either fresh or 8-day hibernated striatal cells were cultured under standard conditions for 4 days, the proportion of DARPP-32-positive neurons did not differ significantly, although the total number of cells was significantly less from tissue that had been hibernated. Six weeks after transplantation into cyclosporin A-immunosuppressed unilateral quinolinic acid-lesioned rats, there was no significant difference between fresh and hibernated grafts, both in terms of graft volume and extent of striatal phenotypic markers. This study therefore clearly demonstrates that hibernation of human fetal striatal tissue for up to 8 days is not deleterious to its differentiation in culture or survival following transplantation, and is therefore an appropriate method of storage for this tissue.

Animals↗
PubMed2002

The potential for circuit reconstruction by expanded neural precursor cells explored through porcine xenografts in a rat model of Parkinson's disease.

Neural precursors with the properties of neural stem cells can be isolated from the developing brain, can be expanded in culture, and have been suggested as a potential source of cells for neuronal replacement therapies in degenerative disorders such as Parkinson's disease (PD). Under such conditions an improved spectrum of functional benefit may be obtained through homotypic reconstruction of degenerated neural circuitry, and to this end we have investigated the potential of expanded neural precursor cells (ENPs) to form long axonal projections following transplantation in the 6-hydroxydopamine-lesioned rat model of PD. ENPs have been isolated from the embryonic pig, since implantation in a xenograft environment is thought to favor axonal growth. These porcine ENPs possessed similar properties in vitro to those described in other species: they proliferated in response to epidermal and fibroblast growth factor-2, expressed the neuroepithelial marker nestin, and differentiated into neurons, astrocytes, and occasional oligodendrocytes on mitogen withdrawal. The use of pig-specific markers following xenotransplantion into cyclosporin A-immunosuppressed rats revealed that many cells differentiated into neurons and displayed extensive axogenesis, such that when placed in the region of the substantia nigra fibers projected throughout the striatal neuropil. These neurons were not restricted in the targets to which they could project since following intrastriatal grafting fibers were seen in the normal striatal targets of the pallidum and substantia nigra. Staining for a pig-specific synaptic marker suggested that synapses were formed in these distant sites. A small number of these cells differentiated spontaneously to express a catecholaminergic phenotype, but were insufficient to mediate behavioral recovery. Our results suggest that when the efficiency of neurochemical phenotype induction is increased, ENP-derived neurons have the potential to be a uniquely flexible source of cells for therapeutic cell replacement where anatomical reconstruction is advantageous.

Amphetamines↗
PubMed2002

The heterogeneity of idiopathic Parkinson's disease.

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

Age of Onset↗
PubMed2002

Verbal fluency in Huntington's disease: a longitudinal analysis of phonemic and semantic clustering and switching.

Two underlying components of verbal fluency tasks have been identified as clustering (the ability to generate successive words within a sub-category) and switching (the ability to shift from one sub-category to another). Selective impairment of switching ability occurs in patients with frontostriatal pathology, whilst clustering ability is compromised with temporal lobe dysfunction. Letter fluency tasks have been shown to be especially sensitive to frontostriatal deficits, whereas, category fluency tasks tend to be compromised by temporal lobe pathology. This study examined two types of verbal fluency task (letter fluency and category fluency) using two levels of analysis (phonemic and semantic) for clustering and switching measures. The performance of 21 frontostriatally compromised Huntington's disease (HD) patients was followed over an average of 3.5 annual follow-up visits. HD patients showed a significant reduction of correctly generated words over time, together with a significant increase in word repetitions. Phonemic switching decreased significantly over time for both letter and category fluency. Semantic switching, however, remained stable over time for both verbal fluency tasks. Clustering (both semantic and phonemic) likewise remained stable and did not vary longitudinally for either letter or category fluency. Hence, phonemic switching alone drove verbal fluency performance and this selective impairment can be explained by the progressive involvement of frontostriatal circuitry in the natural progression of HD.

Adult↗