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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20-30 % of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T). Here we report a novel MAPT mutation (K298E) in exon 10 in a patient with FTDP-17T. Neuropathological studies of post-mortem brain showed widespread neuronal loss and gliosis and abundant deposition of hyperphosphorylated tau in neurons and glia. Molecular studies demonstrated that the K298E mutation affects both protein function and alternative mRNA splicing. Fibroblasts from a skin biopsy of the proband taken at post-mortem were directly induced into neurons (iNs) and expressed both 3-repeat and 4-repeat tau isoforms. As well as contributing new knowledge on MAPT mutations in FTDP-17T, this is the first example of the successful generation of iNs from skin cells retrieved post-mortem.
    Acta Neuropathologica 11/2013; 127(2). DOI:10.1007/s00401-013-1219-1
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    ABSTRACT: A severe complication of spinal cord injury is loss of bladder function (neurogenic bladder), which is characterized by loss of bladder sensation and voluntary control of micturition (urination), and spontaneous hyperreflexive voiding against a closed sphincter (detrusor-sphincter dyssynergia). A sacral anterior root stimulator at low frequency can drive volitional bladder voiding, but surgical rhizotomy of the lumbosacral dorsal roots is needed to prevent spontaneous voiding and dyssynergia. However, rhizotomy is irreversible and eliminates sexual function, and the stimulator gives no information on bladder fullness. We designed a closed-loop neuroprosthetic interface that measures bladder fullness and prevents spontaneous voiding episodes without the need for dorsal rhizotomy in a rat model. To obtain bladder sensory information, we implanted teased dorsal roots (rootlets) within the rat vertebral column into microchannel electrodes, which provided signal amplification and noise suppression. As long as they were attached to the spinal cord, these rootlets survived for up to 3 months and contained axons and blood vessels. Electrophysiological recordings showed that half of the rootlets propagated action potentials, with firing frequency correlated to bladder fullness. When the bladder became full enough to initiate spontaneous voiding, high-frequency/amplitude sensory activity was detected. Voiding was abolished using a high-frequency depolarizing block to the ventral roots. A ventral root stimulator initiated bladder emptying at low frequency and prevented unwanted contraction at high frequency. These data suggest that sensory information from the dorsal root together with a ventral root stimulator could form the basis for a closed-loop bladder neuroprosthetic.
    Science translational medicine 11/2013; 5(210):210ra155. DOI:10.1126/scitranslmed.3007186
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    ABSTRACT: Pathological aggregation of alpha-synuclein as Lewy-bodies and neurites is a hallmark of a group of neurodegenerative disorders named alpha-synucleinopathies. It is becoming apparent that alpha-synuclein facilitates presynaptic neuronal function in the brain, and events leading to its aggregation produce marked disruption of neurotransmitter release mechanism. We discuss here the literature related to the function of alpha-synuclein at the neuronal synapse in synucleinopathies brains and corresponding animal models.
    CNS & neurological disorders drug targets 09/2013; DOI:10.2174/18715273113129990114
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    ABSTRACT: After spinal cord injury (SCi), re-establishing functional circuitry in the damaged central nervous system (CNS) faces multiple challenges including lost tissue volume, insufficient intrinsic growth capacity of adult neurons, and the inhibitory environment in the damaged CNS. Several treatment strategies have been developed over the past three decades, but successful restoration of sensory and motor functions will probably require a combination of approaches to address different aspects of the problem. Degradation of the chondroitin sulfate proteoglycans with the chondroitinase ABC (ChABC) enzyme removes a regeneration barrier from the glial scar and increases plasticity in the CNS by removing perineuronal nets. its mechanism of action does not clash or overlap with most of the other treatment strategies, making ChABC an attractive candidate as a combinational partner with other methods. in this article, we review studies in rat SCi models using ChABC combined with other treatments including cell implantation, growth factors, myelin-inhibitory molecule blockers, and ion channel expression. We discuss possible ways to optimize treatment protocols for future combinational studies. To date, combinational therapies with ChABC have shown synergistic effects with several other strategies in enhancing functional recovery after SCi. These combinatorial approaches can now be developed for clinical application.
    Neuroscience Bulletin 07/2013; 29(4). DOI:10.1007/s12264-013-1359-2
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    Journal of Neurology 05/2013; 260(6). DOI:10.1007/s00415-013-6947-6
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    ABSTRACT: The early and accurate diagnosis of Parkinson's disease (PD) is the first step towards optimal patient management. The aim of this study was to investigate the major determinants of delayed diagnosis in PD. We recruited a population-representative cohort of 239 newly-diagnosed PD patients who underwent clinical and neuropsychological evaluation. Non-parametric methods were used to define the factors associated with diagnostic delay. The median time from motor symptom onset to primary care physician (PCP) presentation was considerably longer than the time from PCP presentation to PD diagnosis (11 vs. 1 months). Male sex and presenting motor phenotype were independently associated with delayed PCP presentation on Cox regression analysis. Patients presenting with gait disturbance experienced the longest delay, whilst those presenting with tremor had the shortest. In summary, male sex and presenting motor phenotype are key determinants of delayed diagnosis in PD.
    Journal of Neurology 04/2013; DOI:10.1007/s00415-013-6905-3
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    ABSTRACT: Thanks to the development of efficient differentiation strategies, human pluripotent stem cells (HPSC) offer the opportunity for modelling neuronal injury and dysfunction in human neurons in vitro. Critically, the effective use of HPSC-derived neural cells in disease-modelling and potentially cell replacement therapies hinges on an understanding of the biology of these cells, specifically their development, subtype specification and responses to neurotoxic signalling mediators. Here, we generated neurons from human embryonic stem cells and characterized the development of vulnerability to glutamate excitotoxicity, a key contributor to neuronal injury in several acute and chronic neurodegenerative disorders. Over two months of differentiation we observed a gradual increase in responsiveness of neurons to glutamate-induced Ca2+ influx, attributable to NMDA receptor activity. This increase was concomitant with an increase in expression of mRNA encoding NMDA and AMPA receptor subunits. Differentiated neurons were vulnerable to glutamate excitotoxicity in a dose-dependent manner, which was reduced by NMDA receptor antagonists.
    Neuroscience Letters 03/2013; DOI:10.1016/j.neulet.2013.03.010
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    ABSTRACT: Soft bioengineered surfaces offer a route towards modulating the tissue responses to chronically implanted devices and may enhance their functionality. In this communication we fabricate micro-topographically rich and mechanically compliant silicone surfaces for use in soft neural interfaces. We observe the interaction of primary rat microglia and astroglia with arrays of tall and short (4.7μm and 0.5μm) vertically oriented Polydimethylsiloxane (PDMS) micropillars and a flat PDMS surface in vitro. With the pillar size and spacing that we use (1.3μm diameter and 1.6μm edge to edge), glia are found to engulf and bend tall pillars. The cytoskeleton of cells adhering to the pillar arrays lacks actin stress fibers, instead we observe actin ring formations around individual pillars. Tall, but not short pillar arrays are inhibitory to migration and spreading for both microglia and astrocytes. When compared to a flat PDMS surface and short pillar arrays, tall micropillar arrays cause nearly two-fold decrease in proliferation rates for both cell types. The anti-mitotic properties of tall pillar arrays may be useful for reducing the density of the glial capsule around brain implanted devices.
    Acta biomaterialia 03/2013; 9(6). DOI:10.1016/j.actbio.2013.02.048
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    ABSTRACT: Nonmotor symptoms (NMS) are common in patients with established Parkinson disease (PD) but their frequency in early PD has not been extensively studied. Our aim was to determine the frequency of NMS in a cohort of patients with newly diagnosed PD. A total of 159 patients with early PD and 99 healthy controls participated in this study. NMS were screened for using the Nonmotor Symptom Questionnaire. Other assessments included measures of motor disability (Movement Disorders Society-revised Unified Parkinson's Disease Rating Scale [MDS-UPDRS]), disease severity (Hoehn & Yahr staging), depression (Geriatric Depression Scale), and global cognitive function (Mini-Mental State Examination and Montreal Cognitive Assessment). The PD group reported a significantly greater number of NMS compared with controls (8.4 [4.3] vs 2.8 [2.6]). In the PD group, the most commonly experienced NMS were excessive saliva, forgetfulness, urinary urgency, hyposmia, and constipation. Patients with higher MDS-UPDRS III scores and those with the postural instability gait subtype experienced a greater number of NMS. NMS are common in early PD and reflect the multisystem nature of the disorder. Even in the earliest stages of PD, NMS may be detrimental to patients' functional status and sense of well-being.
    Neurology 01/2013; 80(3):276-81. DOI:10.1212/WNL.0b013e31827deb74
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    Journal of Neurology 12/2012; 260(1). DOI:10.1007/s00415-012-6784-z
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