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C O N F E R E N C E R E P O RT S7th World Congress for Neurorehabilitation 2012Conference details: 16-19 May, 2012, Melbourne, Australia Reviewed by: Louise Blakeborough, on behalf of the World Federation for Neurorehabilitation.The WCNR attracted neurorehabilitationclinicians and therapists from 55 countries.More than 1800 health professionalsattended the meeting in Melbourne’s awardwinningCongress Centre, where there were 650submitted abstracts, and over 300 posters.The Congress was held in conjunction with the35th Annual Brain Impairment Congress for theAustralian Society for the Study of BrainImpairment (ASSBI) and the 20th AnnualScientific Meeting of the Australasian Faculty ofRehabilitation Medicine, The Royal College ofAustralasian Physicians (RACP). The Congressincluded 12 half-day workshops, ‘Meet theProfessor’, breakfast sessions and a scientificprogramme covering international research,discovery and innovation in all the major areas ofneurorehabilitation including traumatic braininjury, multiple sclerosis, stroke, spasticity managementand neuro-oncology. In addition there were17 World Federation for NeuroRehabilitation(WFNR) Special Interest Group Meetings takingplace concurrently.In the Opening ceremony, Professor JohnOlver, Convenor and Chairman of the OrganisingCommittee and WFNR Regional Vice-Presidentfor Australia, New Zealand and Oceaniawelcomed delegates. The meeting officiallyopened with The 2nd Michael Barnes Lecture,established in recognition of the visionary leadershipand dedication of the founding Presidentand delivered by Professor Randolph Nudo,Director of the Landon Centre on Aging andProfessor in the Department of Molecular andIntegrative Physiology at the Kansas UniversityMedical Centre, USA. Neuroplasticity occurs ona variety of levels, ranging from cellular changesdue to learning, to large-scale changes involvedin cortical remapping in response to injury. Itprovides the scientific basis for the treatment ofacquired brain injury with goal-directed therapeuticprogrammes in the context of rehabilitation.The adult brain is not ‘hard-wired’ withfixed neuronal circuits. Cortical and subcorticalrewiring of neuronal circuits occurs in responseto training and injury; this active, experiencedependentre-organisation of the synapticnetworks of the brain involves multiple interrelatedstructures including the cerebral cortex.Individual connections within the brain areconstantly being removed or recreated, largelydependent upon how they are used. If there aretwo nearby neurons that often produce animpulse simultaneously, their cortical maps maybecome one. Professor Nudo encapsulated thisconcept by saying “Neurons that fire together,wire together". He outlined animal studiesshowing that if a tiny stroke is produced byblocking the blood flow to a small part of amonkey’s motor cortex, the part of the body thatused to move in response to electrical stimulationof that area of cortex moves when nearbyTracey Mole and Professor Michael Barnes WFNR.areas of the brain are stimulated. Understandingthis interaction between the damaged andundamaged areas provides a basis for bettertreatment plans in stroke patients. Functionalimaging studies have shown that the brain canchange its responses in human stroke patients inways similar to that found in monkeys. This hasalso been shown by experiments using transcranialmagnetic stimulation of the human cortex.“The challenge is to translate these results to theclinic” concluded Professor Nudo.Current neuroprosthetic applicationsinclude Deep Brain Stimulation in Parkinson’sDisease, the Cochlear Implant, Bionic Eye andepidural stimulation post-stroke. ProfessorNudo is currently collaborating with engineersto develop micro-implantable devices forrepairing neural circuits after stroke and traumaticbrain injury.Against the exciting developments in neuroplasticityand neuroprosthetic tools, there arefrustrations due to the limits imposed by thebiology of the brain, and the difficulty in doinghuman experiments that demonstrate the benefitsof therapy. It has proved difficult forresearchers carrying out rehabilitation trials todetermine how much an improvement is due toa particular therapy, how much is placebo andhow much is the ‘normal’ spontaneous partialrecovery that follows stroke or brain injury.Professor Bruce Dobkin, Professor of Neurologyand Director of the Neurologic RehabilitationProgram at the University of California, LosAngeles, USA highlighted the shortcomings ofneurorehabilitation clinical trials. He illustratedhis talk by looking at randomised control trialsof body weight-supported treadmill trainingand robotic-assisted step training which did notproduce better outcomes than a comparabledose of progressive over-ground training orexercise in disabled persons with stroke, spinalcord injury, multiple sclerosis, Parkinson’sdisease and cerebral palsy. Professor Dobkinsuggested that the shortcomings require betterstrategies to assess the conceptual basis, designand outcome measurements for future trials ofpharmacological, cortical stimulation, neuralrepair and other experimental neurorehabilitationinterventions.Professor Robert Teasell, Chair-Chief of theDepartment of Physical Medicine andRehabilitation, University of Western Ontario,Canada pointed out that despite all theevidence available, clinical care for strokepatients is not generally delivered in accordancewith established guidelines and this maynegate the benefits of specialised, organised,interdisciplinary care. Stroke is increasing - it’sa disease of older people – this was the recurringmessage throughout the Congress andProfessor Teasell emphasised “the demographiccrunch that is coming”. The three key principlesfor stroke rehabilitation are a) organisedstroke care, b) the earlier the better and c)intensity of therapy. Evidence is growing thatrehabilitation has a significant impact on functionaloutcomes following stroke with improvementsin discharge disposition and communityreintegration. If the rehabilitation team adhereto guidelines the outcomes are better. “You candiscover all you want but if you don’t transfer itto the patient then it doesn’t matter” saidProfessor Teasell, “the simple existence ofresearch evidence doesn’t automatically resultin alterations in policy or clinical decisions”.Professor Michael Barnes presented the EarlyCareer Development Awards in recognition ofthe most outstanding oral and poster presentationsby a delegate. The Awards, totallingAU$6000, were donated by the MelbourneConvention and Visitors Bureau. The recipients ofthe Poster Awards were Louisa Ng (Australia) andCorina Schuster (Switzerland). The recipients ofthe Oral Presentation Awards were Camila Fiore(Australia) and Mayowa Owolabi (Nigeria).The meeting closed with a presentation byProfessor Anthony Burkitt on the developmentof the Retinal Implant for the Sight Impaired.The ‘Bionic Eye’ works by using electricalcurrents to stimulate nerves at the back of theeye. This Australian technology is targeted attwo forms of vision loss; retinosa pigmentosaand age-related macular degeneration.Commenting at the closing ceremonyProfessors Barnes and Clarke said: “The WFNRneeds to position itself to address the challengesof acute to community rehabilitation sowe can do the best possible rehabilitation forour patients. We should strengthen our teachinginitiatives and awareness raising is key amongstpoliticians and the public”. “In 15 years we havecome a long way and we need to keep movingforwards. The WFNR’s 32 National Societiescover half the world’s population but there’s 400million people who are not getting any rehabilitationat all and we need to address thisthrough education and training. There is reasonableevidence to suggest that low tech aids canprovide some rehabilitation to the masses andwe should work on the concept that somethingis better than nothing”. l36 > ACNR > VOLUME 12 NUMBER 4 > SEPTEMBER/OCTOBER 2012
J O U R N A L R E V I E W SEditor’s ChoiceA mutation for protectionagainst Alzheimer’s diseaseThe perceived importance of amyloid in the pathogenesisof Alzheimer’s disease has fluctuated in thelast 30 years. Deposition of amyloid is a pathologicalhallmark of the disease and suggests a central role forthe protein in the disease. The association of Down’ssyndrome, trisomy 21, with Alzheimer’s made theAmyloid Precursor Protein (APP) gene on chromosome21 an obvious candidate gene for autosomaldominant Alzheimer’s disease. Initial genetic linkagestudies excluded APP as the site of the causativemutation. The subsequent realisation that Alzheimer’sdisease might be caused by more than one gene byJohn Hardy’s group led to a re-examination of linkageresults and the discovery that APP mutations cancause autosomal dominant Alzheimer’s disease. Over20 further pathological mutations in the APP genehave been described, however, APP mutations provedcomparatively rare. Other genes, Presenilin 1 andAPOE, stole much of the limelight. In Alzheimer’sdisease drug development, there was a clear rationaleto developing treatments that influenced amyloidmetabolism or deposition. These treatments havebeen developed and shown initial promise but, so far,have disappointed.This paper is another step in the Alzheimer/amyloid story. Jonsson and colleagues utilised wholegenome data from over 1500 Icelanders to look forsequence changes in the APP gene. They identified acoding mutation (A673T) which confers protectionagainst Alzheimer’s disease in their cohort and showthat this mutation reduces the production ofamyloidogenic peptides in vitro. Their controls wereelderly (over 85 years of age) and had passed acognitive assessment. Jonsson and colleagues foundthat the A673T mutation was also rarer in patientswith less specific “cognitive decline”. The results lookrobust and there seems little reason to suppose thatthey will not apply to a wider population thanIceland, but this remains to be shown. 0.6% of thecontrol Icelandic population carry the mutation sothe effect is significant although the protective allelemay be rarer in other populations. This discovery willalso encourage therapeutic approaches aimed ataltering APP metabolism.It is not surprising that these results apply also topatients with cognitive decline not diagnosed withAD. It highlights the spectrum that exists between the“normal” decline in memory with age, amnestic MildCognitive Impairment and Alzheimer’s disease. Theresult supports the theory that very mild Alzheimer’spathology may be responsible for minor cognitiveproblems as people age. This observation highlightsthe question that already troubles Alzheimer specialists:of when a minor cognitive problem becomes adisease.– Dr Jeremy Brown, Addenbrooke’s Hospital and QueenElizabeth Hospital, King’s Lynn.Jonsson et al. A mutation in APP protects againstAlzheimer's disease and age-related cognitive decline.Nature: 488, 96–99. Date published: (02 August 2012)miRNA and ASO –The initial approachto treating geneticdiseases in a new wayOne of the holy grails of treating geneticdisorders of the CNS is to target theabnormal gene itself and by so doingeffect a cure without having to worryabout off target effects. There have beentwo recent papers which are worth highlightingin this regard – one using amicroRNA approach, the other an antisenseoligonucleotide (ASO) strategyand both involving autosomal dominanttrinucleotide repeat disorders.In the first paper by Miyazaki et al inNature Medicine (with a wonderfullyclear News and Views commentary on itby Christopher Pearson), they concentratedon spinal bulbar muscular atrophy(SBMA) which is a slowly progressivelower motor neuron disorder of men. Thedisease is characterised by a CAG expansionin the androgen receptor, whichthen causes motor neuronal cell dysfunctionand death through translocation ofthe mutant receptor within the cell. Thishas in the past led to attempts to blocktranslocation using anti-androgen agents,although as a clinical therapy this createsobvious problems. In this new paper theauthors looked at a transgenic model ofthis condition and found that oneendogenous microRNAs in particular(the imaginatively named miRNA-196a)was upregulated and that by overexpressingit they could slow down thedisease process. This they did using anAAV delivery system that selectivelytargeted the motoneurons. They thenshowed that miR-196a mediated itseffects on the mutant receptor through aprotein that is involved with mRNAprocessing (CELF2). This beautiful workshows how miRNAs are coming of agenot only in terms of how they regulatenetworks of intracellular processes buthow they can be recruited for treatingdisease.In the second study the disease underattack is Huntington’s disease, which has itsCAG repeat in exon 1 of the huntingtin(htt) gene. This gene product causes extensivecell loss in the CNS but typically notuntil patients are in their 40s, althoughexactly when the disease process beginsrelative to clinical expression remains asubject of great interest (see TRACK-HDand PREDICT-HD studies). Obviouslybeing able to switch off the mutant gene(mthtt) whilst leaving the normal htt to doits job has proven difficult, as has gettingthe silencing agent for the mutant htt in allcells for long period of times. This last pointin particular has vexed the field but arecent paper by Kordasiewicz et al inNeuron (again accompanied by a lovelyPreview by Lu and Yang) suggests that thismight not be necessary as they showedthat transiently knocking down mthttcould have long lasting benefits in animalmodels of disease. This implies that stoppingthe production of mthtt even if onlyfor a short time may allow the cell torecover, regroup and fight another day, andthus whilst repeated injections of ASOsmay be required, the frequency of administrationmay be less than once thought.These papers highlight once more theskill of researchers to get to the heart ofdisease, and their ingenuity in how to dothis. Obviously the challenge still remainsas to how one can translate such findingsinto a much larger, longer living humanpatient – but slowly we are movingtowards therapies that seek to trulyswitch off disease causing genes andtheir products.– Roger Barker, Cambridge Centre for BrainRepair.Pearson CE. Co-opting endogenousmicroRNAs for therapy.NATURE MEDICINE 2012;18:1011-2.Miyazaki Y, Adachi H, Katsuno M et al.Viral delivery of miR-196a amelioratesthe SBMA phenotype via the silencing ofCELF2.NATURE MEDICINE 2012;18:1136-1141.X-H Lu & X.W Yang. “Huntingtin Holiday”:progress toward an antisense therapy forHuntington’s disease.NEURON 2012;74:964-6.Kordasiewicz HB, Stanek LM, Wancewicz EVet al. Sustained Therapeutic Reversal ofHuntington's Disease by TransientRepression of Huntingtin Synthesis.NEURON 2012;74:1031-44.Intramuscularmidazolam for statusepilepticusLarge studies of status epilepticus whichchange practice are hard to come bybut this is one such. The study comparedthe outcome of treatment of statusepilepticus with IM midazolam and IVlorazepam, which has been the goldstandard since 1998. This massive effortincluded 3114 paramedics and 79 hospitals.Children estimated to be over 13Kgand adults were included and weretreated if convulsive seizures had beencontinuing for over five minutes. Patientswere excluded with major trauma, hypoglycaemia,cardiac arrest or HR VOLUME 12 NUMBER 4 > SEPTEMBER/OCTOBER 2012 > 37
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