Institute of Clinical Neurosciences

United Kingdom

Institute of Clinical Neurosciences

United Kingdom
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Kemp K.,Institute of Clinical Neurosciences | Gordon D.,Institute of Clinical Neurosciences | Mallam E.,Institute of Clinical Neurosciences | Hartfield E.,University of Bristol | And 3 more authors.
Neuropathology and Applied Neurobiology | Year: 2011

Aims: We explored whether cellular fusion and heterokaryon formation between human and rodent cells in the cerebellum of mice occurs after intravenous injection of human bone marrow-derived mesenchymal stem cells (MSCs). The influence of central nervous system inflammation on this process was also assessed. In addition, we examined whether tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, factors associated with inflammation, increase cellular fusion between human MSCs and rodent cerebellar neurons in vitro. Methods and results: Human MSCs were intravenously injected into mice with experimental autoimmune encephalomyelitis (EAE) and control mice. After 22 days, mouse Purkinje cells expressing human Golgi Zone were found within the Purkinje cell layer of the cerebellum, indicating that fusion and heterokaryon formation had occurred. The numbers of heterokaryons in the cerebellum were markedly increased in mice with EAE compared with control mice. Rodent cerebellar neuronal cells labelled with enhanced green fluorescent proteinin vitro were co-cultured with human bone marrow-derived MSCs in the presence of TNF-alpha and/or IFN-gamma to determine their influence on fusion events. We found that fusion between MSCs and cerebellar neurons did occur in vitro and that the frequency of cellular fusion increased in the presence of TNF-alpha and/or IFN-gamma. Conclusions: We believe that this is the first paper to define fusion and heterokaryon formation between human MSCs and rodent cerebellar neurons in vivo. We have also demonstrated that fusion between these cell populations occurs in vitro. These findings indicate that MSCs may be potential therapeutic agents for cerebellar diseases, and other neuroinflammatory and neurodegenerative disorders. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.


Miners J.S.,Institute of Clinical Neurosciences | Clarke P.,Institute of Clinical Neurosciences | Love S.,Institute of Clinical Neurosciences
Brain Pathology | Year: 2016

Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid-β (Aβ) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene (CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology-mid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH), and regions with little or no pathology-thalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of Aβ. It was significantly higher in AD than controls, and correlated positively with Aβ42 and insoluble Aβ40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy, and in MF and PC regions was highest in APOE e(open)4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with Aβ level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble Aβ42; however, the molar ratio of clusterin: Aβ42 declined with insoluble Aβ42 level in a region-dependent manner, being lowest in regions with predilection for Aβ plaque pathology. Under physiological conditions, clusterin reduces aggregation and promotes clearance of Aβ. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant Aβ, but because the increase does not match the rising level of Aβ42, the molar ratio of clusterin: Aβ42 in those regions falls, probably contributing to Aβ deposition within the tissue. © 2016 International Society of Neuropathology.


Abhinav K.,Institute of Clinical Neurosciences | Park N.D.,Institute of Clinical Neurosciences | Prakash S.K.,Institute of Clinical Neurosciences | Love-Jones S.,Institute of Clinical Neurosciences | Patel N.K.,Institute of Clinical Neurosciences
Neuromodulation | Year: 2013

Objectives Occipital nerve stimulation (ONS), an established treatment for medically intractable headache syndromes, has lead migration rates quoted up to 24%. In a series of patients with ideal characteristics for this treatment modality, we describe an operative technique for ONS involving the novel use of narrow paddle electrodes: "S8 Lamitrode" (St. Jude Medical [SJM], St. Paul, MN, USA). Materials and Methods Five patients (occipital neuralgia [ON] = 4; chronic migraine [CM] = 1) were treated with ONS between 2010 and 2011. All patients had a successful trial of peripheral neurostimulation (Algotec Ltd, Crawley, UK) therapy. Operative technique involved the use of a park-bench position, allowing simultaneous exposure of the occipital and infraclavicular regions. Through a retromastoid/occipital incision just beneath the external occipital protruberance, exposing the extrafascial plane, the S8 Lamitrode is implanted to intersect both greater occipital nerves for bilateral pain or unilateral greater and lesser occipital nerves for unilateral ON or with significant component of the pain relating to the lesser occipital nerve. Results Over the median follow-up of 12 months, there were no episodes of lead migration or revision. There also was significant improvement in symptoms in all patients. Conclusions This is the first reported use of S8 Lamitrode electrode for ONS. This narrow electrode is suited for this role leading to minimal trauma during surgical placement, facilitates resolution of problems with lead migration, and optimizes effect with stimulation focused more in direction of the occipital nerves without skin involvement. To date, the SJM Genesis neurostimulation system, with percutaneous electrodes only, is CE mark approved in Europe for peripheral nerve stimulation of the occipital nerves for the management of pain and disability for patients diagnosed with intractable CM. Further developments and studies are required for better devices to suit ONS, thereby avoiding frequently encountered problems and which may clarify the role of paddle leads in ONS. © 2012 International Neuromodulation Society.


Prineas J.W.,Institute of Clinical Neurosciences | Prineas J.W.,University of Sydney | Parratt J.D.E.,Institute of Clinical Neurosciences | Parratt J.D.E.,Royal North Shore Hospital
Annals of Neurology | Year: 2012

There is little agreement among neuropathologists regarding the timing and nature of oligodendrocyte loss in multiple sclerosis (MS). This review describes changes that accompany acute oligodendrocyte loss in new lesions. Included is a description of the immunopathology of new lesions in 23 severe early cases selected from a bank of 300 MS autopsies. Oligodendrocytes in prephagocytic lesions exhibit cytopathic changes that include apoptosis of oligodendrocytes immunoreactive for caspase 3, phagocytosis of apoptotic oligodendrocytes, swelling of cells with abnormal nuclei, complement deposition, and lysis. These are nonspecific changes that provide no clue as to the cause of oligodendrocyte injury. Associated changes include the presence of enlarged immunoglobulin (IgG) + microglia and early macrophages, the presence nearby of a focus of inflammatory demyelination, an open blood-brain barrier, and the presence of rare CD8 T cells. Myelin contacted by IgG + macrophages is immunoreactive for complement but not for IgG. It is likely that macrophage activity in evolving white and gray matter plaques is scavenging activity directed at nonvital myelin secondary to oligodendrocytes loss. One feature of MS that is not understood is the extraordinarily close resemblance the disease shows pathologically to neuromyelitis optica (NMO), including that demyelination in both is secondary to a loss of caspase 3-positive apoptotic oligodendrocytes. These similarities raise the possibility that like NMO, MS is an autoimmune disease in which oligodendrocyte apoptosis is determined by injury to some other glial or mesenchymal component. © 2012 American Neurological Association.


PubMed | Institute of Clinical Neurosciences
Type: Journal Article | Journal: Neuropathology and applied neurobiology | Year: 2011

we explored whether cellular fusion and heterokaryon formation between human and rodent cells in the cerebellum of mice occurs after intravenous injection of human bone marrow-derived mesenchymal stem cells (MSCs). The influence of central nervous system inflammation on this process was also assessed. In addition, we examined whether tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, factors associated with inflammation, increase cellular fusion between human MSCs and rodent cerebellar neurons in vitro.human MSCs were intravenously injected into mice with experimental autoimmune encephalomyelitis (EAE) and control mice. After 22 days, mouse Purkinje cells expressing human Golgi Zone were found within the Purkinje cell layer of the cerebellum, indicating that fusion and heterokaryon formation had occurred. The numbers of heterokaryons in the cerebellum were markedly increased in mice with EAE compared with control mice. Rodent cerebellar neuronal cells labelled with enhanced green fluorescent proteinin vitro were co-cultured with human bone marrow-derived MSCs in the presence of TNF-alpha and/or IFN-gamma to determine their influence on fusion events. We found that fusion between MSCs and cerebellar neurons did occur in vitro and that the frequency of cellular fusion increased in the presence of TNF-alpha and/or IFN-gamma.we believe that this is the first paper to define fusion and heterokaryon formation between human MSCs and rodent cerebellar neurons in vivo. We have also demonstrated that fusion between these cell populations occurs in vitro. These findings indicate that MSCs may be potential therapeutic agents for cerebellar diseases, and other neuroinflammatory and neurodegenerative disorders.


PubMed | Institute of Clinical Neurosciences
Type: Journal Article | Journal: Journal of cognitive neuroscience | Year: 2012

Perception of known patterns results from the interaction of current sensory input with existing internal representations. It is unclear how perceptual and mnemonic processes interact when visual input is dynamic and structured such that it does not allow immediate recognition of obvious objects and forms. In an fMRI experiment, meaningful visual motion stimuli depicting movement through a virtual tunnel and indistinct, meaningless visual motion stimuli, achieved through phase scrambling of the same stimuli, were presented while participants performed an optic flow task. We found that our indistinct visual motion stimuli evoked hippocampal activation, whereas the corresponding meaningful stimuli did not. Using independent component analysis, we were able to demonstrate a functional connectivity between the hippocampus and early visual areas, with increased activity for indistinct stimuli. In a second experiment, we used the same stimuli to test whether our results depended on the participants task. We found task-independent bilateral hippocampal activation in response to indistinct motion stimuli. For both experiments, psychophysiological interaction analysis revealed a coupling from posterior hippocampus to dorsal visuospatial and ventral visual object processing areas when viewing indistinct stimuli. These results indicate a close functional link between stimulus-dependent perceptual and mnemonic processes. The observed pattern of hippocampal functional connectivity, in the absence of an explicit memory task, suggests that cortical-hippocampal networks are recruited when visual stimuli are temporally uncertain and do not immediately reveal a clear meaning.

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