Center for Brain Research
Center for Brain Research
Stinear C.M.,University of Auckland |
Stinear C.M.,Center for Brain Research |
Byblow W.D.,Center for Brain Research |
Ackerley S.J.,University of Auckland |
And 6 more authors.
Stroke | Year: 2017
Background and Purpose-Several clinical measures and biomarkers are associated with motor recovery after stroke, but none are used to guide rehabilitation for individual patients. The objective of this study was to evaluate the implementation of upper limb predictions in stroke rehabilitation, by combining clinical measures and biomarkers using the Predict Recovery Potential (PREP) algorithm. Methods-Predictions were provided for patients in the implementation group (n=110) and withheld from the comparison group (n=82). Predictions guided rehabilitation therapy focus for patients in the implementation group. The effects of predictive information on clinical practice (length of stay, therapist confidence, therapy content, and dose) were evaluated. Clinical outcomes (upper limb function, impairment and use, independence, and quality of life) were measured 3 and 6 months poststroke. The primary clinical practice outcome was inpatient length of stay. The primary clinical outcome was Action Research Arm Test score 3 months poststroke. Results-Length of stay was 1 week shorter for the implementation group (11 days; 95% confidence interval, 9-13 days) than the comparison group (17 days; 95% confidence interval, 14-21 days; P=0.001), controlling for upper limb impairment, age, sex, and comorbidities. Therapists were more confident (P=0.004) and modified therapy content according to predictions for the implementation group (P<0.05). The algorithm correctly predicted the primary clinical outcome for 80% of patients in both groups. There were no adverse effects of algorithm implementation on patient outcomes at 3 or 6 months poststroke. Conclusions-PREP algorithm predictions modify therapy content and increase rehabilitation efficiency after stroke without compromising clinical outcome. Clinical Trial Registration-URL: http://anzctr.org.au. Unique identifier: ACTRN12611000755932. © 2017 American Heart Association, Inc.
Mollersen L.,University of Oslo |
Rowe A.D.,University of Oslo |
Illuzzi J.L.,U.S. National Institute on Aging |
Hildrestrand G.A.,University of Oslo |
And 6 more authors.
Human Molecular Genetics | Year: 2012
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by trinucleotide repeat (TNR) expansions. We show here that somatic TNR expansions are significantly reduced in several organs of R6/1 mice lacking exon 2 of Nei-like 1 (Neil1) (R6/1/Neil1-/-), when compared with R6/1/Neil1+/+ mice. Somatic TNR expansion is measured by two different methods, namely mean repeat change and instability index. Reduced somatic expansions are more pronounced in male R6/1/Neil1-/- mice, although expansions are also significantly reduced in brain regions of female R6/1/Neil1-/- mice. In addition, we show that the lack of functional Neil1 significantly reduces germline expansion in R6/1 male mice. In vitro, purified human NEIL1 protein binds and excises 5-hydroxycytosine in duplex DNA more efficiently than in hairpin substrates. NEIL1 excision of cytosine-derived oxidative lesions could therefore be involved in initiating the process of TNR expansion, although other DNA modifications might also contribute. Altogether, these results imply that Neil1 contributes to germline and somatic HD CAG repeat expansion. © The Author 2012. Published by Oxford University Press. All rights reserved.
PubMed | Auckland City Hospital and Center for Brain Research
Type: | Journal: Scientific reports | Year: 2016
Microglia, the resident macrophages of the central nervous system play vital roles in brain homeostasis through clearance of pathogenic material. Microglia are also implicated in neurological disorders through uncontrolled activation and inflammatory responses. To date, the vast majority of microglial studies have been performed using rodent models. Human microglia differ from rodent counterparts in several aspects including their response to pharmacological substances and their inflammatory secretions. Such differences highlight the need for studies on primary adult human brain microglia and methods to isolate them are therefore required. Our procedure generates microglial cultures of >95% purity from both biopsy and autopsy human brain tissue using a very simple media-based culture procedure that takes advantage of the adherent properties of these cells. Microglia obtained in this manner can be utilised for research within a week. Isolated microglia demonstrate phagocytic ability and respond to inflammatory stimuli and their purity makes them suitable for numerous other forms of in vitro studies, including secretome and transcriptome analysis. Furthermore, this protocol allows for the simultaneous isolation of neural precursor cells during the microglial isolation procedure. As human brain tissue is such a precious and valuable resource the simultaneous isolation of multiple cell types is highly beneficial.
Heraud-Farlow J.E.,Center for Brain Research |
Heraud-Farlow J.E.,University of Vienna |
Sharangdhar T.,Ludwig Maximilians University of Munich |
Li X.,University of Toronto |
And 18 more authors.
Cell Reports | Year: 2013
RNA-binding proteins play crucial roles in directing RNA translation to neuronal synapses. Staufen2 (Stau2) has been implicated in both dendritic RNA localization and synaptic plasticity in mammalian neurons. Here, we report the identification of functionally relevant Stau2 target mRNAs in neurons. The majority of Stau2-copurifying mRNAs expressed in the hippocampus are present in neuronal processes, further implicating Stau2 in dendritic mRNA regulation. Stau2 targets are enriched for secondary structures similar to those identified in the 3' UTRs of Drosophila Staufen targets. Next, we show that Stau2 regulates steady-state levels of many neuronal RNAs and that its targets are predominantly downregulated in Stau2-deficient neurons. Detailed analysis confirms that Stau2 stabilizes the expression of one synaptic signaling component, the regulator of G protein signaling 4 (Rgs4) mRNA, via its 3' UTR. This study defines the global impact of Stau2 on mRNAs in neurons, revealing a role in stabilization of the levels of synaptic targets. © 2013 The Authors.
Gassner M.,Center for Brain Research |
Leitner J.,Center for Brain Research |
Gruber-Schoffnegger D.,Center for Brain Research |
Forsthuber L.,Center for Brain Research |
Sandkuhler J.,Center for Brain Research
European Journal of Pain (United Kingdom) | Year: 2013
Background: Nerve injury leads to Aβ-fibre-mediated mechanical allodynia that is in part due to an impaired GABAergic inhibition in the spinal cord dorsal horn. The properties and function of GABAergic neurons in spinal cord lamina III, an area where low-threshold mechanosensitive Aβ-fibres terminate are, however, largely unknown. Methods: We used transgenic mice, which express enhanced green fluorescent protein (EGFP) under control of the promoter GAD67. The morphology and neurochemical characteristics of GABAergic, EGFPexpressing neurons were characterized. We assessed active and passive membrane properties of spinal lamina III GABAergic neurons in naïve animals and animals with a chronic constriction injury (CCI) of the sciatic nerve. Results: EGFP-expressing neurons in lamina III were predominantly islet cells (47%), whereas non-EGFP-expressing neurons were largely inverted stalked cells (40%). EGFP-expressing neurons accounted for about 25% of GABAergic neurons in lamina III. Forty-four percent co-expressed glycine, 10% neuronal nitric oxide synthase and 3% co-expressed parvalbumin. We found costaining with protein kinase CβII in 42% of EGFP-expressing neurons but no expression of protein kinase Cγ. Membrane properties and excitability of EGFP-and non-EGFP-expressing neurons from naïve and neuropathic animals were indistinguishable. The most frequent firing pattern was tonic firing (naïve: 35%, neuropathic: 37%) followed by gap firing (naïve: 33%, neuropathic: 25%). Delayed, initial burst and single-spike firing patterns made up the remainder in both groups. Conclusion: A change in membrane excitability or discharge pattern of this group of lamina III GABAergic neurons is unlikely the cause for mechanical allodynia in animals with CCI. © 2013 Medical University of Vienna, Center.
Maccarrone M.,Biomedical University of Rome |
Maccarrone M.,Center for Brain Research |
Bab I.,Hebrew University of Jerusalem |
Biro T.,Debrecen University |
And 9 more authors.
Trends in Pharmacological Sciences | Year: 2015
In 1964, the psychoactive ingredient of Cannabis sativa, Δ9-tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide) (AEA) in 1992 and 2-arachidonoylglycerol (2-AG) in 1995. Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize, and degrade them and that together form the eCB system (ECS). eCBs control basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation. Unsurprisingly, in the past two decades eCBs have been recognized as key mediators of several aspects of human pathophysiology and thus have emerged to be among the most widespread and versatile signaling molecules ever discovered. Here some of the pioneers of this research field review the state of the art of critical eCB functions in peripheral organs. Our community effort is aimed at establishing consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes. © 2015 Elsevier Ltd. All rights reserved.
Bauer J.,Center for Brain Research |
Vezzani A.,Mario Negri Institute for Pharmacological Research |
Bien C.G.,Hospital Mara
Brain Pathology | Year: 2012
Seizures are a prominent clinical feature of encephalitis. Recent data suggest the adaptive as well as innate immune system to be involved directly in the pathomechanism of epileptogenesis. Cytotoxic T-cells and antibody-mediated complement activation are major components of the adaptive immune system, which can induce neurodegeneration, thereby probably contributing to epileptic encephalitis. The innate immune system operates via interleukin-1 and toll-like receptor-associated mechanisms and was shown to play a direct role in epileptogenesis. Here, we review neuropathology hallmarks of various encephalitis conditions such as Rasmussen encephalitis (RE) but also introduce the more recently discovered antibody-associated voltage-gated potassium channel complex (VGKC), N-methyl-D-aspartate receptor (NMDAR) or glutamic acid decarboxylase (GAD) 65 encephalitides. Neuropathological investigations are used to determine specific cellular components and molecular mechanisms used by the immune system to provoke neurodegeneration and to promote epileptogenesis. Based on recent findings, we propose concepts for the stratification of epileptic encephalitis. Knowledge of the role of the innate immunity has already translated into clinical treatment strategies and may help to discover novel drug targets for these epileptic disorders. © 2012 The Authors; © 2012 International Society of Neuropathology.
Castelo-Branco G.,Karolinska Institutet |
Stridh P.,Karolinska Institutet |
Guerreiro-Cacais A.O.,Karolinska Institutet |
Adzemovic M.Z.,Karolinska Institutet |
And 8 more authors.
Neurobiology of disease | Year: 2014
Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS) in young adults. Chronic treatments with histone deacetylase inhibitors (HDACis) have been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, by targeting immune responses. We have recently shown that the HDAC inhibition/knockdown in the presence of thyroid hormone (T3) can also promote oligodendrocyte (OL) differentiation and expression of myelin genes in neural stem cells (NSCs) and oligodendrocyte precursors (OPCs). In this study, we found that treatment with an HDACi, valproic acid (VPA), and T3, alone or in combination, directly affects encephalitogenic CD4+ T cells. VPA, but not T3, compromised their proliferation, while both molecules reduced the frequency of IL-17-producing cells. Transfer of T3, VPA and VPA/T3 treated encephalitogenic CD4+ T cells into naïve rats induced less severe EAE, indicating that the effects of these molecules are persistent and do not require their maintenance after the initial stimuli. Thus, we investigated the effect of acute treatment with VPA and l-thyroxine (T4), a precursor of T3, on myelin oligodendrocyte glycoprotein-induced EAE in Dark Agouti rats, a close mimic of MS. We found that a brief treatment after disease onset led to sustained amelioration of EAE and prevention of inflammatory demyelination in the CNS accompanied with a higher expression of myelin-related genes in the brain. Furthermore, the treatment modulated immune responses, reduced the number of CD4+ T cells and affected the Th1 differentiation program in the brain. Our data indicate that an acute treatment with VPA and T4 after the onset of EAE can produce persistent clinically relevant therapeutic effects by limiting the pathogenic immune reactions while promoting myelin gene expression. Copyright © 2014. Published by Elsevier Inc.
PubMed | University of Auckland and Center for Brain Research
Type: Journal Article | Journal: Immunology and cell biology | Year: 2016
The homeostatic chemokine CCL21 has a pivotal role in lymphocyte homing and compartment localisation within the lymph node, and also affects adhesion between immune cells. The effects of CCL21 are modulated by its mode of presentation, with different cellular responses seen for surface-bound and soluble forms. Here we show that plasmin cleaves surface-bound CCL21 to release the C-terminal peptide responsible for CCL21 binding to glycosaminoglycans on the extracellular matrix and cell surfaces, thereby generating the soluble form. Loss of this anchoring peptide enabled the chemotactic activity of CCL21 and reduced cell tethering. Tissue plasminogen activator did not cleave CCL21 directly but enhanced CCL21 processing through generation of plasmin from plasminogen. The tissue plasminogen activator inhibitor neuroserpin prevented processing of CCL21 and blocked the effects of soluble CCL21 on cell migration. Similarly, the plasmin-specific inhibitor
News Article | November 11, 2016
The sensation of pain occurs when neural pathways conduct excitation generated by tissue damage to the spinal cord, where the nociceptive information is extensively pre-processed. From there, the information is transmitted to the human brain, where the sensation of "pain" is finally created. This is the general belief. However, researchers from the Division of Neurophysiology at MedUni Vienna's Center for Brain Research have now discovered that pain is not just a matter of nerves but that non-neuronal cells, the glial cells, are also involved in clinically relevant pain models and their activation is sufficient to amplify pain. The study has now been published in the leading journal "Science." Glial cells are the commonest type of cells in the human brain and spinal cord. They surround neurons but are distinct from them and play an important supporting role -- for example, in material transport and metabolism or the fluid balance in the brain and spinal cord. At the same time, however, when they are activated -- by pain processes, for example - glial cells are themselves able to release messenger substances, such as inflammatory cytokines. Glial cells therefore have two modes: a protective and a pro-inflammatory mode. "The activation of glial cells results in a pain-amplifying effect, as well as spreading the pain to previously unaffected parts of the body. For the very first time, our study provides a biological explanation for this and for other hitherto unexplained pain phenomena in medicine," says Jürgen Sandkühler, Head of the Division of Neurophysiology at MedUni Vienna's Center for Brain Research. Over-activation of glial cells in the spinal cord can, for example, be caused by strong pain stimuli from a wound or surgical intervention, or even by opiates. Sandkühler: "This could also explain why opiates are initially very good at relieving pain but then often cease to be effective. Another example is the phenomenon of "withdrawal" in drug addicts, where activated glial cells cause severe pain throughout the body." According to Sandkühler, neuroinflammatory diseases of the brain, environmental factors and even the person's own lifestyle can lead to activation of glial cells. Examples from the current literature are: depression, anxiety disorders and chronic stress, multiple sclerosis or Alzheimer's and diabetes, as well as lack of exercise and poor diet. Sandkühler: "Glial cells are an important factor in ensuring the equilibrium of a person's neuroinflammatory system." The study results give grounds for speculation that improvements in a person's lifestyle could have a beneficial impact upon this system and ensure that they generally suffer less pain or "minor niggles," says Sandkühler: "It is therefore in our own hands: thirty minutes of moderate exercise three or four times a week, a healthy diet and avoiding putting on excess weight can make a huge difference."