Publications by authors named "Richard J E Armstrong"

12 Publications

  • Page 1 of 1

Superficial siderosis following spontaneous intracranial hypotension.

Pract Neurol 2015 Oct 2;15(5):382-4. Epub 2015 Jul 2.

Department of Clinical Neurosciences, University of Oxford, Oxford, UK Department of Neurology, Royal Berkshire Hospital, Reading, UK.

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http://dx.doi.org/10.1136/practneurol-2015-001169DOI Listing
October 2015

Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development.

PLoS Genet 2012 6;8(12):e1003074. Epub 2012 Dec 6.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.
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http://dx.doi.org/10.1371/journal.pgen.1003074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516553PMC
May 2013

Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.

Ann Neurol 2011 May 17;69(5):892-900. Epub 2011 Mar 17.

Department of Clinical Neurology, Oxford University, Oxford, UK.

Objective: To describe a distinctive seizure semiology that closely associates with voltage-gated potassium channel (VGKC)-complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE).

Methods: Twenty-nine patients were identified by the authors (n = 15) or referring clinicians (n = 14). The temporal progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission tomography/single photon emission computed tomography, and VGKC-complex antibodies was studied.

Results: Videos and still images showed a distinctive adult-onset, frequent, brief dystonic seizure semiology that predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS). All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in 89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients (24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2 signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs) were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast, immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency.

Interpretation: Recognition of FBDS should prompt testing for VGKC-complex/Lgi1 antibodies. AEDs often produce adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral atrophy and cognitive impairment.
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http://dx.doi.org/10.1002/ana.22307DOI Listing
May 2011

De novo relapsing-remitting multiple sclerosis following autologous stem cell transplantation.

Neurology 2010 Jul;75(1):89-91

Department of Clinical Neurology, University of Oxford, Oxford OX3 9DU, UK.

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http://dx.doi.org/10.1212/WNL.0b013e3181e6215dDOI Listing
July 2010

The survival of neural precursor cell grafts is influenced by in vitro expansion.

J Anat 2005 Sep;207(3):227-40

School of Biosciences, Cardiff University, UK.

Embryonic neural precursor cells (ENPs) provide a potential alternative for transplantation in neurodegenerative diseases, as they can be expanded in culture, avoiding many of the practical obstacles that limit the application of transplanting primary neurones. However, grafts of ENPs into animal models show variable survival and limited differentiation into neurones. The effect of expansion time on their ability to survive and differentiate may be an important factor in this and has not been examined directly. In these experiments, murine and human ENPs were expanded for short (4 weeks) and long (20 weeks) periods before transplantation into the adult rat striatum. Whereas grafts of both short- and long-term expanded human ENPs survived for 4 weeks following transplantation, by 20 weeks all long-term expanded grafts had disappeared. Murine ENPs behaved similarly: only grafts of short-term expanded ENPs survived at 12 weeks following transplantation. RT-PCR analysis of ENP cultures after 4 and 20 weeks of expansion demonstrated changes in expression of a number of different groups of genes. We conclude that long-term expansion of ENPs profoundly impairs their ability to survive long-term after transplantation into the adult brain. This has implications for the potential use of these cells for neural transplantation strategies.
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http://dx.doi.org/10.1111/j.1469-7580.2005.00449.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571534PMC
September 2005

Decreased hippocampal cell proliferation in R6/1 Huntington's mice.

Neuroreport 2004 Apr;15(5):811-3

Centre for Brain Repair, University of Cambridge, Cambridge CB2 2PY, UK.

In order to ascertain whether disturbances of neurogenesis occur in chronic neurodegenerative disorders, we assessed hippocampal cell proliferation in the R6/1 transgenic mouse model of Huntington's disease (HD). Using BrdU labelling for dividing cells at two different time points (5 and 20 weeks) in transgenic and wild type control mice, we have shown that cell proliferation in the hippocampus was similar in younger asymptomatic R6/1 mice and wild type controls, but that older R6/1 mice had significantly fewer BrdU cells than controls. Such a decrease in cell proliferation may be relevant to some of the deficits seen in these mice, although further work is needed to prove this.
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http://dx.doi.org/10.1097/00001756-200404090-00014DOI Listing
April 2004

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.

Cell Transplant 2003 ;12(7):687-95

Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK.

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.
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http://dx.doi.org/10.3727/000000003108747307DOI Listing
July 2004

Migration and differentiation of transplanted human neural precursor cells.

Neuroreport 2003 Jul;14(9):1257-62

Cambridge University Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, UK.

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.
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http://dx.doi.org/10.1097/00001756-200307010-00014DOI Listing
July 2003

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

Exp Neurol 2003 Jul;182(1):113-23

Cambridge University Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK.

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.
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http://dx.doi.org/10.1016/s0014-4886(03)00055-4DOI Listing
July 2003

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

Exp Brain Res 2003 Jul 3;151(2):204-17. Epub 2003 Jun 3.

Cambridge Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, CB2 2PY, Cambridge, UK.

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.
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http://dx.doi.org/10.1007/s00221-003-1491-8DOI Listing
July 2003

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

Exp Neurol 2002 May;175(1):98-111

Cambridge Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 2PY, United Kingdom.

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.
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http://dx.doi.org/10.1006/exnr.2002.7889DOI Listing
May 2002

Neural cells from primary human striatal xenografts migrate extensively in the adult rat CNS.

Eur J Neurosci 2002 Apr;15(7):1255-66

Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK.

Primary neural cells do not appear to migrate significantly following transplantation into the adult rodent CNS, which is in contrast to expanded neural precursor cells where migration is well-documented. However, most transplant studies of primary neural tissue have been performed in an allograft situation in which it is difficult to identify graft-derived cells. We have, therefore, used a xenograft paradigm to investigate the potential for cells derived from grafts of primary human fetal striatal tissue (gestational age of 66-72 days) to migrate following intrastriatal transplantation in an athymic adult rat model of Huntington's disease. The use of an antibody specific to human nuclear antigen enabled clear identification of graft-derived cells within the host brain, and specific neural phenotypes were determined using human-specific tau for neurons, glial fibrillary acidic protein for mature astrocytes and Ki67 for proliferative cells. At 6 weeks, the graft mass was very dense with a high proliferative index, few cells had migrated away from the graft, and the cells that had differentiated both within and away from the graft were mainly neurons. In contrast, at 6 months, the graft core was dispersed significantly more and a large number of graft-derived cells had migrated throughout the brain as far rostral as the olfactory bulb and as caudal as the substantia nigra. Cells had differentiated into both neurons and astrocytes and the level of proliferation was significantly lower within the graft. These results demonstrate that primary neural xenografts contain proliferative cells that possess the ability to migrate and differentiate into both neurons and astrocytes, and suggest that these cells could contribute to normal graft function. This property may be a consequence of the xenograft situation and could potentially be exploited to provide the opportunity to target regions of distant pathology in neurodegenerative diseases using xenotransplantation of embryonic neural tissue.
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http://dx.doi.org/10.1046/j.1460-9568.2002.01959.xDOI Listing
April 2002