Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis: C9orf72 Repeats

摘要: Amyotrophiclateralsclerosis(ALS) isadevastatingdiseaseofthe motornervoussystem.Whilemost casesare sporadic, approximately5%to10%ofcasesare familial andresult frommutation in1ofmorethan25knownALS genes.Thesegenesspanasurprisingly broad range of molecular functions, including RNA metabolism, oxidative stress, axonal transport, autophagy, excitability, and immunity.Oneof thegreatmysteries in the field is thatmotorneurondiseaseresultsasaconvergentphenotypefrommutations this diverse group genes. Understanding puzzle likely keytooptimizingbothclinicaltrialsandpatienttreatmentbecause differentdrugsmayultimatelybenecessaryfortargetingspecific disease variants. Despitethemolecularheterogeneity, theclinicalmotorneuronphenotypesresultingfromthevariousgeneticmutationsand sporadic casesdifferonlymodestly. So toohasbeen thecaseon theneurophysiological level, inwhichBaeandcolleagues1have performedanimpressiveassemblyofstudiesshowingaxonaland cortical hyperexcitability ALS. Lowermotor neuron studies useaspecializednerveconductionstudyprotocolcalled threshold tracking,whichwasdevelopedbyMogyoroset al.2Changes instimulus intensitynecessarytogeneratecompoundmotoractionpotentialsofapredeterminedamplitudearemonitoredduring course a recording, andprepulses recovery cycle analysisareusedtomeasuredifferentcomponentsofaxonalexcitability.Cortical inALShasbeen repeatedly demonstrated using transcranial magnetic stimulation (TMS), bothusing traditional constant stimulus technique toelicit motor-evokedpotentials (MEPs)andbyadaptingthethresholdtracking approach to TMS. Inthis issueofJAMANeurology,Geevasingaandcolleagues3 extendedtheirobservationstoshowcorticalhyperexcitability patients with ALS due chromosome 9 open reading frame72(c9orf72)hexanucleotidegenerepeatexpansion,which themost commongenetic causeofALSand responsible for about5%ofapparentsporadicALSand40%offamilialALScases. The findings are quite similar those superoxidedismutase(SOD1)genefamilialALS,with increasedexcitabilitymanifestedmost clearlyusingpaired testing. Short intracortical inhibitionreferstotheincreaseinMEPthreshold(ordecrease inMEPamplitude) resulting fromaconditioningprepulsea few millisecondsbefore test pulse. In contrast, facilitationisthereductioninthreshold(orincreaseinMEPamplitude) whentheconditioningprepulseprecedesthetestpulsebyabout 15milliseconds.4The reduction short inhibition increase facilitationare2of themostprominentTMSfindings inALS.Otherdisease featuressharedbyboth sporadicandc9orf72 familialALS includereducedrestingmotor threshold, increased MEP amplitude, decreased silent periodduration, centralmotor conduction time. Thecorticalandaxonalexcitabilitystudieshaveshownaremarkableconsistencyof inbothpatientswithsporadic ALSandpatientswithfamilialALSand,thus,raisequestionsabout how different mechanisms converge produce changes inneuronalexcitability inALSandwhether researchers can leverage consistent neurophysiological hyperexcitabilityphenotypetoreveal informationandpotential targetsthatare broadlyrelevantacrossALSvariants.Theclinical resultssuggest anopportunitytoreexaminehyperexcitabilityusinganimalmodelsandmore-reductionistsystemstoaddressexcitabilitymechanisms.Suchworkcouldpotentially reveal specific ionchannels or cellular pathways that underlie phenotype.Thecomplexityofdifferentneuronal andnonneuronal cellularsubtypesthatgiverisetoandmodulatethedifferentTMS nerve study measurements justify additional basic exploration.However, technical considerationshave limited theuseof techniques inmice, both regard challenges inperforming tests aswell as artifacts owing sedation interpreting results. animalmodels SOD1 ALS, most have supported motor neuronactivity5;however,others, includingastudyusinginvivo recordings specificmotor pools, not.6 Inmotor neuronsmadefromALS-inducedpluripotent stemcells,hyperexcitability ispresentbut thendecreaseswith longcultureperiods, potentially because worsening neuronal health depolarization-inducedblockofmotorneuronfiring.7-9 Invitro identified roles persistent sodium currents delayed-rectifierpotassiumcurrents increasingmotorneuron excitability Futurework channelmodifiers may help elucidate channels, receptors, andmolecular scaffolding underlying clinical hyperexcitability. Webelievethebulkoftheevidencesupportshyperexcitability aprimaryprocess inALSasopposed toanadaptiveone.10 Thepresenceofsignsofhyperexcitability,suchasfasciculations, beforeotherclinicalsymptomsismoreconsistentwithaprimary roleforhyperexcitability.Similarly,thehyperexcitabilityobserved inbothprenatalSOD1motorneuronsandALSstemcell–derived motorneuronsofmultiplegeneticvariants, inwhichdecreasing improvesmotorneuronsurvival andreducesendoplasmicreticulumstressinvitro,bothsupportaprimaryupstream Author Audio Interview at jamaneurology.com