Positron emission tomography neuroimaging in amyotrophic lateral sclerosis: what is new?
11
344 THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING December 2014 motor cortex, brainstem, and spinal cord, 2 but also astrocytes and microglia, which contribute to the spread of the initial damage and disease progres- sion. 3-5 The neuropathological hallmark of ALS is, along with corticospinal tract degeneration, a selec- tive loss of the anterior horns cells of the spinal cord and of cells in lower motor cranial nerve nuclei. In two-thirds of patients the onset is at the spinal level (with hypotrophy and weakness of upper or lower limbs muscles); in one-third of patients dysphagia and dysarthria are the first symptoms (bulbar onset). The latter group shows in a variable percent of cases a moderately to severe impairment in frontal lobe functions. 3 The main clinical variants of ALS include Primary Muscular Atrophy (PMA), Primary Lateral Sclerosis (PLS), and Progressive Bulbar Palsy (PBP). 6 Diagnostic work-up is very complex and should include clinical history and examination, 7 electro- diagnostic tests (such as conventional electromy- 1 Nuclear Medicine Unit Department of Biomedical Sciences and of Morphologic and Functional Images University of Messina, Italy 2 Nuclear Medicine and Molecular Imaging Department of Imaging and Pathology KU Leuven and University Hospital Leuven Leuven, Belgium 3 Positron Emission Tomography Centre IRMET S.p.A., Euromedic Inc., Turin, Italy 4 PET Pediatric AIMN InterGroup, Turin Italy 5 Institute of Cognitive Sciences and Technologies CNR, Rome, Italy 6 Department of Nuclear Medicine Karolinska Hospital, Stockholm, Sweden Q J NUCL MED MOL IMAGING 2014;58:344-54 N. QUARTUCCIO 1 , D. VAN WEEHAEGHE 2 , A. CISTARO 3, 4, 5 , C. JONSSON 6 , K. VAN LAERE 2 , M. PAGANI 5, 6 Positron emission tomography neuroimaging in amyotrophic lateral sclerosis: what is new? Amyotrophic lateral sclerosis (ALS) is a neurodegene- rative disease involving upper and lower motor neu- rons, extra-motor neurons, microglia and astrocytes. The neurodegenerative process results in progressive muscle paralysis and even in cognitive impairment. Within the complex diagnostic work-up, positron emission tomography (PET) represents a valuable ima- ging tool in the assessment of patients with ALS. PET, by means of different radiotracers (i.e. 18 F-fluorode- oxyglucose, 6-[ 18 F]fluoro-L-dopa, [ 11 C]flumazenil) can assess the status of the wide range of brain regions and neural circuits, which can be affected by ALS. Fur- thermore, experimental radiocompounds have been developed for the evaluation of white matter, which plays a role in the progression of the disease. Here we present a comprehensive review including in different sections the most relevant PET studies: studies investi- gating ALS and ALS-mimicking conditions (especially primary lateral sclerosis and other neurodegenerative diseases), articles selecting specific subsets of patients (with bulbar or spinal onset), studies investigating pa- tients with familial type of ALS, studies evaluating the role of the white matter in ALS and papers evaluating the diagnostic sensitivity of PET in ALS patients. KEY WORDS: Amyotrophic lateral sclerosis - Positron-emis- sion tomography - Bulbar - Spinal. A myotrophic lateral sclerosis (ALS), is a neuro- degenerative process characterized by a pro- gressive impairment of motor function at the bulbar and spinal levels with a not yet fully understood aetiology, resulting in progressive muscle paralysis. 1 ALS involves motor neurons allocated in primary Corresponding author: M. Pagani, MD, PhD, Institute of Cognitive Sciences and Technologies, CNR, via Palestro 32, 00185 Rome, Italy. E-mail: [email protected] MINERVA MEDICA COPYRIGHT® This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
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Transcript of Positron emission tomography neuroimaging in amyotrophic lateral sclerosis: what is new?
344 THEQUARTERLYJOURNALOFNUCLEARMEDICINEANDMOLECULARIMAGING December2014
motorcortex,brainstem,andspinalcord,2butalsoastrocytes and microglia, which contribute to thespread of the initial damage and disease progres-sion.3-5 The neuropathological hallmark of ALS is,alongwithcorticospinaltractdegeneration,aselec-tivelossoftheanteriorhornscellsofthespinalcordandofcellsinlowermotorcranialnervenuclei.Intwo-thirdsofpatientstheonsetisatthespinallevel(withhypotrophyandweaknessofupperorlowerlimbsmuscles); inone-thirdofpatients dysphagiaanddysarthriaarethefirstsymptoms(bulbaronset).Thelattergroupshowsinavariablepercentofcasesamoderately to severe impairment in frontal lobefunctions.3ThemainclinicalvariantsofALSincludePrimary Muscular Atrophy (PMA), Primary LateralSclerosis(PLS),andProgressiveBulbarPalsy(PBP).6
Diagnosticwork-upisverycomplexandshouldinclude clinical history and examination,7 electro-diagnostic tests (such as conventional electromy-
1Nuclear Medicine Unit Department of Biomedical Sciences
and of Morphologic and Functional Images University of Messina, Italy
2Nuclear Medicine and Molecular Imaging Department of Imaging and Pathology
KU Leuven and University Hospital Leuven Leuven, Belgium
3Positron Emission Tomography Centre IRMET S.p.A., Euromedic Inc., Turin, Italy
4PET Pediatric AIMN InterGroup, Turin Italy5 Institute of Cognitive Sciences and Technologies
CNR, Rome, Italy6Department of Nuclear Medicine
Karolinska Hospital, Stockholm, Sweden
QJNUCLMEDMOLIMAGING2014;58:344-54
N.QUARTUCCIO1,D.VANWEEHAEGHE2,A.CISTARO3,4,5,C.JONSSON6,K.VANLAERE2,M.PAGANI5,6
Positron emission tomography neuroimaging in amyotrophic lateral sclerosis: what is new?
Amyotrophic lateral sclerosis (ALS) is a neurodegene-rative disease involving upper and lower motor neu-rons, extra-motor neurons, microglia and astrocytes. The neurodegenerative process results in progressive muscle paralysis and even in cognitive impairment. Within the complex diagnostic work-up, positron emission tomography (PET) represents a valuable ima-ging tool in the assessment of patients with ALS. PET, by means of different radiotracers (i.e. 18F-fluorode-oxyglucose, 6-[18F]fluoro-L-dopa, [11C]flumazenil) can assess the status of the wide range of brain regions and neural circuits, which can be affected by ALS. Fur-thermore, experimental radiocompounds have been developed for the evaluation of white matter, which plays a role in the progression of the disease. Here we present a comprehensive review including in different sections the most relevant PET studies: studies investi-gating ALS and ALS-mimicking conditions (especially primary lateral sclerosis and other neurodegenerative diseases), articles selecting specific subsets of patients (with bulbar or spinal onset), studies investigating pa-tients with familial type of ALS, studies evaluating the role of the white matter in ALS and papers evaluating the diagnostic sensitivity of PET in ALS patients.Key words: Amyotrophic lateral sclerosis -Positron-emis-siontomography-Bulbar-Spinal.
Amyotrophic lateral sclerosis (ALS), is a neuro-degenerative process characterized by a pro-
gressiveimpairmentofmotorfunctionatthebulbarand spinal levels with a not yet fully understoodaetiology,resultinginprogressivemuscleparalysis.1ALS involves motor neurons allocated in primary
Corresponding author:M.Pagani,MD,PhD, InstituteofCognitiveSciences andTechnologies, CNR, via Palestro 32, 00185Rome, Italy.E-mail:[email protected]
Anno: 2014Mese: DecemberVolume: 58No: 4Rivista: THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGINGCod Rivista: Q J NUCL MED MOL IMAGING
Lavoro: 2775-JNUtitolo breve: PET neuroimaging in ALSprimo autore: QUARTUCCIOpagine: 344-54
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Lavoro: 2775-JNUtitolo breve: PET neuroimaging in ALSprimo autore: QUARTUCCIOpagine: 344-54
PET studies in patients with ALS-mimicking conditions
[18F]FDG-PET has not been used yet in clinicalroutinefortheevaluationofpatientswithALS,buthasrecentlybeenproposedasapotentialbiomarkerofthedisease.26,27
NeurodegenerationinALSinvolvesalsoextra-mo-torcerebralneurons,includingfrontalandtemporallobes.Cognitive impairment inALSshowsclinical,pathologicalandgeneticoverlapwithfrontotempo-raldementia (FTD).10Abrahams et al.3, 18 assessedthe cerebral blood flow (rCBF), during activationstudies performed by word generation and wordrepetition(TableI).TheauthorsdemonstratedthatALS patients with cognitive impairment show re-ducedactivationincorticalandsubcorticalregionsinvolvingthedorsolateralprefrontal,premotor,me-dial prefrontal, and insular cortices aswell as theanteriorthalamicnuclearcomplex.Conversely,non-dementedALSpatientspresentedarelativelynormalpatternofactivation.Thesedataareexpressionofanextramotorneuronalinvolvementinsomenon-dementedALSpatientsthatdevelopsprobablyalongathalamo-frontalassociationpathway.
Renardet al.31 investigatedthe[18F]FDG-PETfind-ingsin10patients:6ALSand4ALS-FTDsubjects.Theauthorsreportedhypometabolismintheprerolandicmedialfrontalandorbitofrontalcorticesaswellasintheanterior temporal lobeof theALSpatients.TheanterolateralareawasthemostpreservedpartofthefrontallobeinALSpatients,comparedtoALS-FTDpa-tients.ConverselyintheALS-FTDsubgroups,frontalandtemporalregionswerehighlyhypometabolicwithrelatively spared perirolandicmetabolism.Hypome-tabolism resulted unrelated to the disease duration.No differences were evidenced at [18F]FDG-PET re-gardingmetabolismbetweenpatientswithsymptomonsetinthelimbsandpatientswithbulbaronset.31
The group of Turku 32 reported on a patient, inwhomclinicalevaluation,MRIand[18F]FDG-PETfailedtodifferentiatebetweenFTDandAlzheimer’sdisease(AD), whereas a subsequent [11-C]-Pittsburgh com-poundB([11C]PIB-PET)investigationwasnegativeforamyloidpathology.Thepatient laterdevelopedALSsymptoms, and post-mortem neuropathological ex-aminationwasdiagnosticofFTD-ALS.Noteworthy,ageneticC9Orf72expansionwasdetected.Theauthorssuggested that [11C]PIB-PET may facilitate the earlydifferentialdiagnosisbetweenADandFTD,includingAD versus C9Orf72-FTD/ALS. Further confirmation
ography,nerveconductionstudies),8neuroimagingincludingcomputed tomography(CT)ormagneticresonance imaging (MRI) of the brain and spinalcordmyelogram,9,10clinicallaboratorytests,muscleand/ornervebiopsy,andgenetictesting.6
Appropriate investigations are needed to distin-guishALSfromitsvariants,especiallyPLS11,12andPMA13,14orfromdiseasesasfrontotemporaldemen-tia (FTD) with similar cognitive symptomatology.Unrelateddisorders,suchasmultifocalmotorneu-ropathy,Kennedy’sdiseaseorX-linkedspinobulbarmuscularatrophy,maypresentclinicalfeaturessimi-lartoALSoritsvariants6,15andareconsideredtoberesponsiblefordiagnosticerrorin5-10%ofcases.16
Combinationofuppermotorneuron(UMN)andlowermotorneuron(LMN)impairmentthatcannotbeexplainedbyanyotherdiseaseprocessbymeansof the diagnostic work-up, together with progres-sion,issuggestiveofALS.15
In the last decades, neuroimaging by PositronEmissionTomography(PET)hascontributedtotheknowledgeoffunctionalchangesoccurringinALSincombinationwithbothcognitiveandmotor im-pairment.17SeveralstudiesontheuseofPETinALShavebeenpublishedsofar,mainlyusing18F-fluor-odeoxyglucose ([18F]FDG-PET).18-24 Most imagingstudiesfocusingonALSusednormalcontrolsasacomparisongrouptohighlightdiseaseneuropatho-physiology, which is essential to validate specificALS relatedmetabolicpatterns.3, 16, 18, 20, 21, 25-27 Pa-tients with ALS usually demonstrate at PET a dif-fuselydecreased[18F]FDGuptakeinprimarymotorcortex,premotorcorticesandsupplementarymotorareas, but eventually also in parietal andoccipitallobes.26-28Clustersofrelativehypermetabolismhavebeen demonstrated in the mesiotemporal regionsbutalsointheoccipitalcortex,cerebellum,andup-perbrain stemofpatientswithALS, compared tonormal controls.20, 26, 27 All these findings reflect acomplex neuropathophysiology of the disease in-volving degeneration of gray matter and areas ofreactivemicroglialactivation.29,30
Wewill review the scientific literature reportingPETstudiesinALSpatientsdiscussingthefindingsin five separate sections: i) studies aiming to dif-ferentiate ALS from ALS-mimicking conditions; ii)studies focusingonALSpatientswithspinalonsetandiii)studiesfocusingonALSpatientswithbulbaronset; iv)studiesinvestigatingtheimpactofwhitematteronthediseaseprogressionv)papersevaluat-ingthediagnosticsensitivityofPETinALSpatients.
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sporadicorfamilialALS(homozygousforthe‘D90A’mutation).24Thedifferentiation,accordingtoPringleet al.,isbasedonthefactthatPLSpatientsshowamoremarkedneurodegenerationthanALSpatientsoftheneuronslocatedintheprimarymotorcortex,with theexceptionof the footarea.35Besides,pa-tientswithPLSdemonstratetheadditionalinvolve-mentof theanteriorcingulategyrus.24,34Lastly, intheirlarge-cohort[18F]FDG-PETstudy,VanLaereet al.alsodescribedmoreseverehypometabolismintheprefrontalandposteriorcingulatecortexofpa-tientswithALSthaninpatientswithPLS.27
PET studies on patients with spinal ALS
Patientswithspinalonsetrepresentthemoststud-iedsubgroupofALSpatientssofar.17,20,21,26,27,36-38Dalakas et al.38 firstly indicated that hypometabo-
regardingtheutilityofamyloidtracershasbeengivenbyYamakawaet al., inatwocase-studyofpatientswithdementia(FTDandAD,respectively)associatedwithMND.InthepatientwithFTD,the[11C]PIB-PETwas negative,while in theADpatient [11C]PIB-PETdocumentedpresenceofamyloidaccumulation.33
Using11C-Flumazenil,bindingtothesubunitoftheGABAAreceptor,LeForestieret al.34firstlydescribedareductionofthesynapticbrainfunctionandare-ducedneuronaldensity in theprimarymotor andanterior cingulate cortex in patientswith PLS andALS.SincePLSandALShavefeaturesincommoninrespect tothecorticaldysfunction,34PETcanbeauseful toolalsoindiscriminatingthetwodiseases.Even though [11C]flumazenilpatternsaresimilar inALS and PLS patients when compared to healthysubjects,differencescanbedemonstratedbyadi-rect comparisonbetween the [11C]flumazenil bind-ingpatternofPLSsubjectsandbothpatientswith
Table I.—�Summary of studies evaluating PET in patients with ALS-mimicking conditions.
Authors Year Patients(N.=) Controls(N.=)
Diseaseduration(months) Reduceduptake Increaseduptake
Pringle et al.35 1992 3PLS NA 140±55.4 Pericentralcortex. NAAbrahamset al.18 1996 6ALSci
6ALSu 6 ALSci:22.7±15.0
ALScu:25.7±17.0ALScivs.ALSci/HC:premotorcortex,dorsolateralPFC,temporalandparietalcortices.ALScivs.HC:dorsolateralPFC,insularcortexandthalamus
NA
LeForestieret al.34 2001 5PLS NA 91.2±39.6 ReducedCBFandBZRbindinginPMC,prefrontalandACC.
NA
Turneret al.24 2007 4PLS24ALS10ALS-D90A-SOD1
24 PLS:51±24ALS:27±19
ALS-D90A-SOD:68±59
PLSvs HC:reducedBZRinPMC,temporal,parietalcortexandACC.ALS/ALS-D90A-SODvsPLS:decreasedbindinginfrontalcortex.
NA
Renardet al.31 2011 4ALS-FTD NA 12-24 PFC,temporalandparietalcortex. NAYamakawaet al.33 2012 2ALS-AD/FTD NA 18±8.5 ALS-FTD:frontalandtemporal
cortex.ALS-AD:frontal,temporalandparietalcortex,PCCandprecuneus.
NA
Martikainenet al.32 2014 2C9ORF72-ALS-FTD NA 24 Frontal,temporalandparietalcortex.
NA
VanLaereet al.27 2014 70ALS7PLS4PMA
20 ALS:15.2±10.7PLS:52.3±52.1PMA:12.5±5.7
PLSvs HC:reducedmetabolisminPFC,ACC,pericentralcortexandthalamus.ALSvsPLS:morepronouncedhypometabolisminALSinPFCandPCC;morepronouncedhypometabolisminPLSinsensorymotorcortex.
PLSvs HC:cerebellumandoccipitalcortex.
PLS:primarylateralsclerosis;NA:notavailable;ALSci:ALSpatientswithcognitiveimpairment;ALScu:ALSpatientswithoutcognitiveimpairment;PFC:prefrontalcortex;CBF:cerebralbloodflow;BZR:benzodiazepinereceptor;PMC:primarymotorcortex;ACC:anteriorcingulatecortex;HC:healthycontrol;FTD:frontotemporaldementia;AD:Alzheimerdementia;PCC:posteriorcingulatecortex;PMA:primarymuscularatrophy.
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withthediseaseduration,21otherauthorsfoundnocorrelations.31,37,40Thesecontrastingfindingsmaybe related to the small sampleof the investigatedpatientsandcontrols.
Cistaroet al.20describedin2012theclinicaland[18F]FDG-PET findings of 19 patients with spinalonset part of a group of 32 ALS patients. Whencompared to healthy controls, the subgroup withspinalonsetdemonstratedrelativehypometabolisminsmallclustersinbilaterallingualandinrightfusi-formgyrianddemonstrated less severehypomet-abolic imaging pattern than patients with bulbaronset.Directcomparisonbetweenspinalandbul-bar patients showed a less dramatic involvementof prefrontal, frontal and parietal regions in theformergroupsuggestingadifferentmetabolicstatebetweenthetwoconditions.20Furthermore,relativehypermetabolismwasdescribedintheupperbrainstemmainlyinpatientwithspinalonset.VanLaerereplicatedthehypermetabolicfindingsinthepos-terior regions, including the cerebellum, occipitallobe,brainstem,andmesialtemporalcortices.27
Lastly,in2014,furtherconfirmationofthisputa-tiveALSmetabolicpatterncamefromthestudyofPaganiet al.,whorecruited136patientswithspinalALS.Theauthorsevidenced,aspreviouslydescribedinformerstudies,arelativehypermetabolisminbi-lateralmidbrain,superiortemporalgyrus,andrightcerebellumofpatientswith spinal-onset26 aswellashypometabolicareasinbilateralprimaryandas-sociativevisualcortexandinbilateralprefrontalandpremotorcortex.
lismat[18F]FDG-PETimagingisasignofaneuronalmalfunctioninginALSpatients(TableII).Hypome-tabolismappearedtoextendbeyondtheexpectedregions (primarymotorcortex), includingalso thesurroundinghealthyneurons.Laterstudiescorrob-orated thefindingsofDalakas,demonstrating thatPET abnormalities, besides affecting the primarymotor cortex, involve an extensive range of brainregionsincludingthefrontal3,18andprefrontalre-gions3,18,26,27parietal,39andtemporalcortex27andeven occipital lobe.26 Hatazawa et al.21 showed acorrelation between altered [18F]FDG metabolismandlengthofdiseaseinALSpatients.Ametabolicasymmetrybetweenrightandleftlobe,butwithoutpreferentialside,wasobservedinpatientswithALSwithupper and lowermotor neuron involvement,whereasanormalornearnormal[18F]FDGactivitywasnotedinfourALSpatients,whopresentedwithonlylowermotorneuroninvolvement.21
Another importanthallmarkofALS is thecorre-lationbetweenhypometabolismat[18F]FDG-PETinmotorcortexandthecharacteristicclinicalfeaturesofthedisease(progressivemuscularweaknessandtendon reflex changes). In this respect an inversecorrelationhasbeenobservedbetweenmetabolisminmiddlefrontalgyrusandseverityofneurologicalsigns.40
Discrepant results have been reported betweenseverity of hypometabolism and disease duration.WhileHatazawa et al. reported the degree of hy-pometabolisminthemotor-sensorycortex,assessedin a small groupofALSpatients, tobe correlated
Table II.—�Summary of studies evaluating PET in ALS patients with spinal onset.
Authors Year Patients(N.=)
Controls(N.=)
Diseaseduration(months) Reduceduptake Increaseduptake
Dalakaset al.38 1987 12 11 12-45 Cerebralcortexandbasalganglia. NAHatazawaet al.21 1988 12 11 12-45 Motor-sensorycortex,extra-motor
cortexandputamen.NA
Ludolphet al.37 1992 18 12 16.4±10.5 Entirecortexandregionallyinfrontal,frontobasalandsuperioroccipitalcortex.
NA
Cistaroet al.20 2012 19 20 17.8±16.0 Occipitalcortex. Ponsandmidbrain.Paganiet al.26 2013 136 40 4.1 Premotorcortex,PFCandoccipital
cortexMidbrain,cerebellumandtemporalcortex
Cistaroet al.36 2014 30 40 12.1±8.8 Frontal,superiortemporalandinsularcortex,ACC,PCC,caudateandthalamus.
Premotorcortex,post-central,temporalcortex,midbrainandoccipitalcortex.
VanLaereet al.27 2014 48 20 15.2±10 PMC,PFC,lateralfrontalcortex,ACCandthalamus.Nodifferencesreportedbetweenspinalandbulbarpatients.
Cerebellum,brainstem,occipitalandmedialtemporalcortex.Nodifferencesreportedbetweenspinalandbulbarpatients.
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QUARTUCCIO PETNEUROIMAGINGINALS
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bulbar onset. Furthermore, relative hypermetabo-lismwasdescribedintheupperbrainstemalsoinpatientswithbulbaronsettoughlessevidentthaninspinalpatients.InALSpatientswithbulbaronset,asignificantrelativedecreasedmetabolismwasfoundin large prefrontal, frontal and parietal regions ascomparedwithpatientswithspinalonset,suggest-ingadifferentialneuropsychologicalandmetabolicstate between the two subgroups of patients. Ontheotherhand,anormalornearnormalfrontopa-rietal[18F]FDGactivitywasobservedinALSpatientswithaspinalonset.Oncethepatientsnumberwassubstantially increased,26 the bulbar subgroup (59patients) showed, as compared to controls, severemetabolicdeficitinmotor,premotor,andprefrontalcortex.Suchhypometabolicclusterwasalsofoundinthecomparisonwithspinalpatients,thoughlessextended and with a lesser statistical significance.Theseverehypometabolisminfrontalandprefron-tal regionswas confirmed inanother recent studyinwhich59sporadicALSpatientswereinvestigated(Figure1)butwherenodifferencesinmetabolismwerefoundbetweenpatientswithspinalandbulbaronset.27Thesefindingsspeakinfavourofadifferentmetabolicdistributioninbulbarandspinalpatients,stressing an association between frontal hypome-tabolismandtheprodromalorfullblowncognitivedeclineintheformergroup.
PET studies in ALS patients carrying specific mutations
In2014,Cistaroet al.36evaluatedthe[18F]FDG-PETpatternin15patientswithfamilialALScarryingtheGGGGCC hexanucleotide repeat expansion in the
PET studies on patients with bulbar ALS
In 1993,Kew et al.41 performed a15OPET acti-vation studyaiming tomeasure the regional cere-bral bloodflow (rCBF) in 12patientswithALS, 7of them with bulbar onset, comparing them to 6age-matchedcontrols(TableIII).Patientsandcon-trols underwent PET at rest and during executionofstereotypedandfreelyselectedmovementsofajoystick.TheALSpatientshowedanincreasedacti-vationinprimarysensorimotorcortexduringactiva-tiontasks,whereasdecreaseduptakewasdetectedatrestinthesensorimotorandlateralpremotorcor-tices,supplementarymotorarea,anteriorcingulatecortex,paracentrallobule,superiorandinferiorpa-rietalcortex.Noteworthy,greateractivationwasob-servedinALSpatientsintheventralthird(facearea)of thecontralateralprimarysensorimotorareaandin the adjacent contralateral ventral premotor andparietal association regions during freely selectedjoystickmovements.ThemagnitudeofrCBFchang-es in the contralateral face area during activationwasrobustlycorrelatedwiththeresponsetimeandthe presence of spasticity. The authors argumentthattimeofresponseispartiallydependentoncon-ductionvelocityalongthecentralmotorpathways.Beingspasticityaclinicalmanifestationofdamagedpathways,therelationshipofthesetwoparameterswithrCBFchangesinthefaceareasuggeststhatacorticaladaptationtopyramidaltractdisruptionmayberesponsiblefortherecruitmentofthisarea.41
Cistaroet al.20alsoevaluated,amongthe32pa-tientswithALS,13patientswithbulbaronsetcom-paringthemto19spinalALSpatientsand22controls.Patientswithspinalonsetshowedhigherscoresinneuropsychologicalexaminationthanpatientswith
Table III.—�Summary of studies evaluating PET in ALS patients with bulbar onset.
Authors Year Patients(N.=)
Controls(N.=)
Diseaseduration(months)
Reduceduptake Increaseduptake
Kewet al.41 1993 7 6 23 Sensorimotor,lateralpremotorcortex,SMA,parietalcortexandACC.
Uponactivation:PMC,insulaandACC.
Cistaroet al.20 2012 13 20 17.8±16.0 Inferior,middleandsuperiorfrontalcortex,ACCandinsula.
Amygdala,pons,midbrain.
Paganiet al.26 2013 59 40 4.1 PMC,premotorcortexandPFC. Midbrain.VanLaereet al.27 2014 21 20 15.2±10 PMC,PFC,lateralfrontalcortex,ACC
andthalamus.Nodifferencesreportedbetweenspinalandbulbarpatients.
Cerebellum,brainstem,occipitalandmedialtemporalcortex.Nodifferencesreportedbetweenspinalandbulbarpatients.
SMA:supplementarymotorarea.
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PETNEUROIMAGINGINALS QUARTUCCIO
Vol.58-No.4 THEQUARTERLYJOURNALOFNUCLEARMEDICINEANDMOLECULARIMAGING 349
ture. Sincegenetic testinghasbecomepartof thediagnosticworkup,alsoatypical casesbeyond thecommonALSphenotypehavebeenidentified.Adeliet al.42 reported on an atypical case of C9Orf72-FTD/ALS,withdetailedlongitudinalfollow-up.ThepatientpresentedmildcognitiveimpairmentwhichevolvedintoAlzheimer’sdisease(AD)andlaterde-velopmentofALS,withoutbehaviouralorpersonal-itychanges inhiscourse, followedbymotorneu-rondysfunction about six years after theonset ofcognitivedysfunction.ThefirstPET studyatpres-entationhad showedmildhypometabolism in themedial frontal and lateral temporal cortices (withmoreprominentinvolvementoftheleftside),whichbecamemoresevereduringfollow-up.42
PreviousstudieshavealsodealtwithALSpatientscarrying mutation of SOD1, a gene encoding theenzymecopper,zincsuperoxidedismutaseprotein(Cu/Zn-SOD).24,43-45Cu/Zn-SOD,widelyexpressedinnumeroussubsetsofcellsofcentralandperipher-alnervoussystems,playsafundamentalroleinpro-tectingcellsagainst reactiveoxygenspecies,46andmutatedformsoftheproteincanresultinapoptoticdeath ofmotor neuron cells.47With regard to theevidence that spinalmotorneuronsanddopamin-ergic neurons are among the cells with the high-est expression of Cu/Zn-SOD,48 Przedborski et al.postulatedasubliclinicalnigrostriataldysfunctioninSOD1-mutatedpatients43andinvestigatedby6-[18F]fluoro-L-dopa ([18F]FDOPA) PET 14 familial ALS(FALS)patients(7withand7withoutSOD1-muta-tion).Despitetheabsenceofstatisticallysignificant
C9Orf72 gene (Table IV). The authors comparedthe15patientswithfamilialALSwithagroupof12patients with ALS and comorbid FTD without theC9Orf72 expansion (ALS-FTD),with 30 cognitivelynormal ALS patients and wth 40 normal controls.Amongthe4groups,patientscarryingtheC9Orf72mutation showed the more severe involvement ofthecentralnervoussystem,withsignificanthypome-tabolismintheanteriorandposteriorcingulatecor-tex, insula, caudate, certices thalamus and the leftfrontalandsuperiortemporalcertices,andhyperme-tabolism in themidbrain, bilateral occipital cortex,globuspallidus,andleftinferiortemporalcortex.36
In the same year Van Laere 27 investigated thepossible presence of specific metabolic signatureat [18F]FDG-PET imaging in a large group (N.=81)of patients with suspected diagnosis of ALS. Thediagnosis of pure ALS was made in seventy sub-jects,amongwhich11carriedtheC9orf72mutation.Whereasoverallhypometabolismwasevidencedintheperirolandicregionandwithvariabledegreeintheprefrontalcortexinthemajorityofpatients,pa-tientswithC9orf72mutationdemonstratedgreaterrelative hypometabolism in the thalamus, prefron-talandposteriorcingulatecerticeswhencomparedwithC9orf72-negativeALSpatients.27
Taken together these studies concordantly sug-gestamoreseverecentralnervoussysteminvolve-ment inpatients carrying theC9orf72mutation ascompared to both sporadicALS andALS-FTDpa-tientsunderscoringthecorrelationbetweenchangesat[18F]FDG-PETandtheseverityoftheclinicalpic-
Figure1.—PETfindingsin119ALSpatientscomparedwith30controls.Statisticallysignificantdifferences(P<0.05FDR)arehighlightedonaMRIT1template.Hypermetabolism:left:sagittalview;centerandright:coronalviews.Significantcorrectedclustersareseeninmidbrain,medialtemporallobesandcortispinaltracts.
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QUARTUCCIO PETNEUROIMAGINGINALS
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ter of decreased of [11C]flumazenil binding at theleft-frontotemporaljunction,whichhenamed“theclinicalhorizon”,possiblyreflectingcorticalmodi-ficationsappearingbeforetheonsetoftheclinicalsigns.44 There is evidence that patients with spo-radic ALS demonstrate a relative reduced corticalinhibitionat[11C]flumazenil-PETadetectableinmo-tor andmotor associative areas, compared to pa-tientswithD90Amutation45supportingtheroleofexcitotoxicpathogenicmechanismsindeterminingthedifferentsurvivalbetweenthetwogroups.45,51ThediversecorticalvulnerabilityofD90A-mutatedpatientswasalsoexploredinacomparativestudywithasmallgroupofPLSpatients,highlightingarelative decreased [11C]flumazenil binding patternintheanteriorandorbito-frontalregionsofD90A-mutatedpatients.24
Studies on the impact of white matter and neuroinflammation on
the evolution of ALS disease
There aremanydata in literature suggesting anactiveroleofwhitematterintheprogressionofALSdisease.Someauthorshavepostulatedthat the in-creased number of astrocytes found in ALS brainmaybeduetothecolonizationoftheemptyspaces
differencesbetweenthetwogroupsofpatientsre-garding thestriato-occipital ratios(SOR),fiveFALSpatients showed abnormal [18F]FDOPA uptake,confirmed at post-mortem by nigrostriatal degen-eration.Twooutof5patientswithabnormal [18F]FDOPA-PET imaging presented clinical features ofParkinson’sdisease(bradykinesia),and2/5patientswithoutclinicalsignsshowedSORvalueswithintherangeofearlyParkinson’sdisease.Furthermore,theauthorsdidnotfindanycorrelationbetweenabnor-malSORvalues,ageatonsetordurationofsymp-toms.This lastfinding is incontrastwith thoseofTakahashiet al.49whofoundaninversecorrelationbetween reduced [18F]FDOPAuptake anddurationof symptomsbut in apopulationof sporadicALSpatients.
Among the several known SOD1 gene muta-tions,46 the ‘D90A’ mutation is associated with aslowerprogressionthanusualofthediseaseandalongersurvival.50PatientswithD90Amutationseemto show a different pattern of cortical neuronallossordysfunctionat[11C]flumazenilPETimaging,compared to patients with sporadic ALS (premo-torandmotorcorticesandposteriormotorassocia-tiveareas).44Turnerdetectedadecreaseduptakeinthe frontal lobe of the dominant hemisphere andin anterior cingulategyrus in 10 symptomaticpa-tientscarryingD90Amutationanda smallerclus-
Table IV.—�Summary of PET studies in ALS patients carrying specific mutations.
Authors Year Patients(N.=) Controls(N.=)
Diseaseduration(months) Reduceduptake Increaseduptake
Przedborskiet al.43 1996 14 14 45.36±28.7 7fALSwithoutSOD-1mutation:putamen.5fALSwithSOD-1mutation:caudateandputamen.
NA
Turneret al.44 2005 10 24 68±59 FrontallobeandACC NATurneret al.45 2005 9 NA 65±57 PMCandSMA. NATurneret al.24 2007 10ALS-D90A-SOD1
24ALSPLS
24 53±12 ALS/ALS-D90A-SODvsPLS:decreasedbindinginfrontalcortex.
NA
Adeliet al.42 2014 Ú1 NA 24 Pre-anddorsolateralfrontalandtemporalcortex
NA
Cistaroet al.36 2014 15C9orf72-positive 40 10.1±7.3 Frontal,superiortemporalandinsularcortex,ACC,PCC,caudateandthalamus
Midbrainandoccipitalcortex
VanLaereet al.27 2014 11C9orf72-positive59C9orf72-negative
20 C9orf72-positive13.8±10.2
C9orf72-negative15±10.6
C9orf72-positiveALSvs.HC=bilaterallyinthethalamus,posteriorcingulateandprecuneusC9orf72-positiveALSvs.C9orf72-negativeALS:thalamusandPCC.
NA
fALS:familialALS.
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leftbythedeadneurons,22,52whereasafewstudieshaveshowedalinkbetweenincreasedastrocytosisinareasofneurodegeneration inALSpatientsanddiseaseprogression.19,53
Thesefindingsareinagreementwiththeevidencethatglucoseisnotconsumedonlybyneuronsandthatitsuptakethereforedoesnotexclusivelyreflectneural activity. Conversely astrocytes also play animportant role in the regulationofglucoseutiliza-tionbeingthemajor[18F]FDGuptakedeterminantintheastrocyte-neuronfunctionalunit.54,55
Turner et al.23 performed a study in 10 patientswithALSanddemonstratedanextensivemicroglialactivation by means of 11C-(R)-PK11195, a ligandfor the18kDatranslocatorprotein(TSPO)(formerlyknown as the peripheral benzodiazepine bindingsite),expressedonthemitochondrialmembraneofactivatedmicroglia(TableV).Uptakewasfoundinthemotorcortex,ponsandthalamus,andappearedtoberelatedwiththeburdenofuppermotorneuronclinical signs.23 The group of Johansson providedevidence thatastrocytosismaybedepicted in vivoinALSpatientsandhighlightedtheutilityof11C-(L)-deprenyl-D2 (DED), targeting the enzymeMAO-B,primarilylocatedinastrocytes.56Theauthorsdocu-menteduptakeofDEDinponsandwhitematterin7ALSpatientsandemphasizedtheneedoffuturestud-iescombining[11C](R)-PK11195and[11C]DEDPETtoclarifythespatialandtemporalrelationshipbetweenmicroglialactivationandastrocytosisinALS.
AfurtherstudywithaglialtracerwasperformedbyCorciaet al.57whoevaluatedneuroinflammationinALSpatientsusing[18F]-DPA-714,amorerecentlydeveloped TSPO radioligand with high signal-to-noiseratio.Asignificantincreaseofdistributionvol-umeratiovalues,correspondingtomicroglialactiva-tion,wasshownintheprimaryandsupplementarymotor and temporal cortices, thus suggesting theuseofthistracerasapromisingbiomarkerofneu-roinflammation.57
Figure2.—Three-dimensionalrenderingshowingthoseregionsinwhich[18F]FDGuptakewassignificantlyhigherinCTR(N.=20)ascomparedwithALSpatients(N.=59)(thresholdP<0.0001uncorrected).Toprowleft:medialleftview;toprowright:medialrightview;secondrowleft:posteriorview;secondrowright: frontalview;third row left: right-side view; third row right: left-side view;bottomrowleft:viewfrombelow;bottomrowright:viewfromabove.
Table V.—�Summary of PET studies evaluating white matter in ALS patients.
Authors Year Patients(N.=)
Controls(N.=) Diseaseduration(months) Reduceduptake Increaseduptake
Turneret al.23 2004 10 14 25.3±11.6 NA PMC,pons,dorsolateralPFC,thalamus.
Johanssonet al.56 2007 7 7 27.6±13.6 NA PonsandWM.
Corciaet al.57 2012 10 7 11.7;5-27 NA PMC,SMAandtemporallobe.
WM:whitematter.
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Future perspectives and conclusions
Despite the lackofmulticentrestudies toevalu-ate the utility of neuroimaging in differentiatingALS from ALS-mimicking conditions, an appropri-ateassessmentofsensitivityandspecificityof [18F]FDG-PETisnowpossibleduetothelargepatientscohorts recruitedby someof the centres involvedinALSresearch.26,27AhighaccuracyindiagnosingASLpatientsandpossiblydiscriminatingthemfromALS-mimickingdiseasespatientswillbeessentialtorecruitappropriatesubjectsforclinicaltrials,tode-velopnewtherapiesandtoidentifypossiblediseasefamiliarityallowingearlyinterventions.
Functional imaging is likely to increment in thenextfutureitsroleintheevaluationofpatientsaf-fected byALS and probably [18F]FDG-PET/CTwillcontinuetobeanimagingtoolofoutstandingim-portanceintheevaluationofALSinthenextdec-ade.Lastbutnotleast,theintroductionofPET/MRIscannersinclinicalsettingwouldcontributetobet-terunderstandtheALSpathophysiologycombiningmorphological and functional information, whichmayalsoincludenovelmarkersforneuroinflamma-tionoreffectsonneurotransmission.61
References
1. RowlandLP.Amyotrophiclateralsclerosis:humanchallengeforneuroscience.ProcNatlAcadSciUSA1995;92:1251-3.
2. Chio A, Logroscino G, Hardiman O, Swingler R, Mitchell D,BeghiE et al.PrognosticfactorsinALS:Acriticalreview.Amyo-trophLateralScler2009;10:310-23.
3. AbrahamsS,GoldsteinLH,SucklingJ,NgV,SimmonsA,ChitnisX et al. Frontotemporal white matter changes in amyotrophiclateralsclerosis.JNeurol2005;252:321-31.
4. Hall ED, Oostveen JA, Gurney ME. Relationship of microglialandastrocyticactivationtodiseaseonsetandprogressioninatransgenicmodeloffamilialALS.Glia1998;23:249-56.
5. ZhangJ,YinX,ZhaoL,EvansAC,SongL,XieB et al.Regionalalterations in cortical thickness and white matter integrity inamyotrophiclateralsclerosis.JNeurol2014;261:412-21.
6. RowlandLP,ShneiderNA.Amyotrophiclateralsclerosis.NEnglJMed2001;344:1688-700.
7. TraynorBJ,CoddMB,CorrB,FordeC,FrostE,HardimanOM.ClinicalfeaturesofamyotrophiclateralsclerosisaccordingtotheElEscorial andAirlieHousediagnostic criteria:Apopulation-basedstudy.ArchNeurol2000;57:1171-6.
8. deCarvalhoM,DenglerR,EisenA,EnglandJD,KajiR,KimuraJ et al.ElectrodiagnosticcriteriafordiagnosisofALS.ClinNeuro-physiol2008;119:497-503.
9. BrooksBR,MillerRG,SwashM,MunsatTL,WorldFederationofNeurologyResearchGrouponMotorNeuronD.ElEscorialrevisited:revisedcriteriaforthediagnosisofamyotrophiclateralsclerosis.AmyotrophLateralSclerOtherMotorNeuronDisord2000;1:293-9.
10. TurnerMR,AgostaF,BedeP,GovindV, LuleD,VerstraeteE.
Ontheotherhand,bothCistaroet al.20andPa-gani et al.26 speculated that the hypermetabolismfoundinmidbrainandcorticospinaltracts(Figure2)mightbeduetoastrocytosisresultinginarelativelyhigherglucoseuptakeascompared to thenormalconditioninwhichtheamountofastrocytesinsuchtwostructuresisverylimited.
Diagnostic sensitivity analyses
Asinotherneurodegenerativedisease,58theuseofmachinelearningtoolsisrapidlyincreasing,inor-dertodifferentiateALSfrommimickingsyndromes.Machinelearningidentifiescomplexpatternsauto-maticallyandmayhelpnuclearmedicinephysiciansmake intelligent decisions on the analysis of PETimages,whichmaybecombinedwithother infor-mation (structural, clinical, genetical), also knownasradiomics.59
In2010,Filippiniet al.usedinaMRIstudydis-criminantanalysis,combiningradialdiffusivity,frac-tionalanisotropyandvoxel-basedmorphometry,ina group of ALS patients reporting 92% sensitivity,88%specificity,and90%accuracy.60
Only two studies analyzed the diagnostic per-formanceofPETinALSpatientsduetotherarityofdiseaseandthesmallsampleinmoststudies.
VanLaereet al.27evaluatedthediagnosticabilityof[18F]FDG-PETinalargecohortof81patientswithsuspecteddiagnosisofALS.Withouta prioriknowl-edgePETcorrectlyclassified100%ofcontrols,89%ofALSpatientsand71%patientswithPLS.27AdirectcomparisonbetweenALSandPLS,usingasupportvectormachine approach and 88VOIs, showed ahighaccuracy(89.7%),theprefrontalcortex,thala-mus,posteriorcingulate,andanteriorcingulatebe-ingthemostdiscriminatingregions.
RecentlyPagani,et al.26reportedfor[18F]FDG-PETimplementing the generalized linear discriminantmodelasensitivityof95%andaspecificityof83%indiscriminatingALSpatientsfromhealthycontrolsinthelargeststudypublishedsofar,including195ALS subjects and 40 controls. The study analyseswerebaseon51corticalandsubcorticalpredefinedvolumesofinterestanddocumentedamixedhyper-metabolic-hypometabolicpattern,wherebymarkedhypometabolismwasdemonstrated in frontal,pre-motor, and occipital cortices,whereas relative hy-permetabolismwasdescribedinthemidbrain,supe-riortemporalgyrusandhippocampus.
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reat
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of d
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isno
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rmitt
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t is
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mitt
ed t
o re
mov
e, c
over
, ov
erla
y, o
bscu
re,
bloc
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r ch
ange
any
cop
yrig
ht n
otic
es o
r te
rms
of u
se w
hich
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Pub
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r m
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rtic
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PETNEUROIMAGINGINALS QUARTUCCIO
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31. RenardD,CollombierL,CastelnovoG,FourcadeG,KotzkiPO,LaBaugeP.BrainFDG-PETchangesinALSandALS-FTD.ActaNeurolBelg2011;111:306-9.
32. MartikainenMH,GardbergM, Jansson L, RoyttaM,Rinne JO,KaasinenV.Brain(1)(8)F-FDGand(1)(1)C-PiBPETfindingsintwosiblingswithFTD/ALSassociatedwiththeC9ORF72repeatexpansion.Neurocase2014;20:150-7.
33. YamakawaY,ShimadaH,AtakaS,TamuraA,MasakiH,NakaH et al.Twocasesofdementiaswithmotorneurondiseaseevalu-atedbyPittsburghcompoundB-positronemissiontomography.NeurolSci2012;33:87-92.
34. LeForestierN,MaisonobeT,SpelleL,LesortA,SalachasF,La-comblezL et al.Primarylateralsclerosis:furtherclarification.JNeurolSci2001;185:95-100.
35. Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF,EbersGC.Primary lateral sclerosis.Clinical features, neuropa-thologyanddiagnosticcriteria.Brain1992;115(Pt2):495-520.
36. CistaroA,PaganiM,MontuschiA,CalvoA,MogliaC,CanosaA et al.ThemetabolicsignatureofC9ORF72-relatedALS:FDGPETcomparisonwithnonmutatedpatients.EurJNuclMedMolImaging2014;41:844-52.
37. LudolphAC,LangenKJ,RegardM,HerzogH,KemperB,KuwertT et al. Frontal lobe function in amyotrophic lateral sclerosis:a neuropsychologic and positron emission tomography study.ActaNeurolScand1992;85:81-9.
38.DalakasMC,HatazawaJ,BrooksRA,DiChiroG.Loweredcer-ebral glucose utilization in amyotrophic lateral sclerosis. AnnNeurol1987;22:580-86.
39. LloydCM,RichardsonMP,BrooksDJ,Al-ChalabiA,LeighPN.ExtramotorinvolvementinALS:PETstudieswiththeGABA(A)ligand[(11)C]flumazenil.Brain2000;123(Pt11):2289-96.
40. HoffmanJM,MazziottaJC,HawkTC,SumidaR.Cerebralglucoseutilizationinmotorneurondisease.ArchNeurol1992;49:849-54.
41. KewJJ,LeighPN,PlayfordED,PassinghamRE,GoldsteinLH,FrackowiakRS et al.Corticalfunctioninamyotrophiclateralscle-rosis.Apositronemissiontomographystudy.Brain1993;116(Pt3):655-80.
42. AdeliA, SavicaR, LoweVJ,VemuriP,KnopmanDS,Dejesus-HernandezM et al.TheGGGGCCrepeatexpansioninC9ORF72in a casewithdiscordant clinical andFDG-PETfindings:PETtrumpssyndrome.Neurocase2014;20:110-20.
43. PrzedborskiS,DhawanV,DonaldsonDM,MurphyPL,McKen-na-YasekD,MandelFS et al.Nigrostriataldopaminergicfunctioninfamilialamyotrophiclateralsclerosispatientswithandwith-out copper/zinc superoxide dismutase mutations. Neurology1996;47:1546-51.
44. Turner MR, Hammers A, Al-Chalabi A, Shaw CE, AndersenPM,BrooksDJ et al.Distinct cerebral lesions in sporadic and‘D90A’ SOD1 ALS: studies with [11C]flumazenil PET. Brain2005;128:1323-9.
45. TurnerMR,Osei-LahAD,HammersA,Al-ChalabiA,ShawCE,AndersenPM et al.AbnormalcorticalexcitabilityinsporadicbutnothomozygousD90ASOD1ALS.JNeurolNeurosurgPsychia-try2005;76:1279-85.
46. ValentineJS,DoucettePA,ZittinPotterS.Copper-zincsuperox-idedismutaseandamyotrophiclateralsclerosis.AnnuRevBio-chem2005;74:563-93.
47. NishitohH,KadowakiH,NagaiA,MaruyamaT,YokotaT,Fuku-tomiH et al.ALS-linkedmutant SOD1 inducesER stress- andASK1-dependent motor neuron death by targeting Derlin-1.GenesDev2008;22:1451-64.
48. PardoCA,XuZ,BorcheltDR,PriceDL,SisodiaSS,ClevelandDW. Superoxide dismutase is an abundant component in cellbodies,dendrites,andaxonsofmotorneuronsandinasubsetofotherneurons.ProcNatlAcadSciUSA1995;92:954-8.
49. TakahashiH, SnowBJ, BhattMH, Peppard R, EisenA, CalneDB. Evidence for a dopaminergic deficit in sporadic amyo-trophic lateral sclerosisonpositronemission scanning. Lancet1993;342:1016-8.
Neuroimaging in amyotrophic lateral sclerosis. Biomark Med2012;6:319-37.
11. Kuipers-UpmeijerJ,deJagerAE,HewJM,SnoekJW,vanWeer-den TW. Primary lateral sclerosis: clinical, neurophysiological,andmagneticresonancefindings.JNeurolNeurosurgPsychiatry2001;71:615-20.
12. TartagliaMC,RoweA,FindlaterK,OrangeJB,GraceG,StrongMJ.Differentiationbetweenprimarylateralsclerosisandamyo-trophiclateralsclerosis:examinationofsymptomsandsignsatdiseaseonsetandduringfollow-up.ArchNeurol2007;64:232-6.
13. CosottiniM,GiannelliM, SicilianoG, Lazzarotti G,MichelassiMC,DelCoronaA et al.Diffusion-tensorMRimagingofcorti-cospinal tract in amyotrophic lateral sclerosis andprogressivemuscularatrophy.Radiology2005;237:258-64.
14. SachM,WinklerG,GlaucheV,LiepertJ,HeimbachB,KochMA et al.DiffusiontensorMRIofearlyuppermotorneuroninvolve-mentinamyotrophiclateralsclerosis.Brain2004;127:340-50.
15. WijesekeraLC,LeighPN.Amyotrophiclateralsclerosis.Orphan-etJRareDis2009;4:3.
16. PatronasNJ,DiChiroG,SmithBH,DeLaPazR,BrooksRA,MilamHL et al.Depressedcerebellarglucosemetabolisminsu-pratentorialtumors.BrainRes1984;291:93-101.
17. CistaroA,CuccurulloV,QuartuccioN,PaganiM,ValentiniMC,MansiL.RoleofPETandSPECT in thestudyofamyotrophiclateralsclerosis.BiomedResInt2014;2014:237437.
18. AbrahamsS,GoldsteinLH,KewJJ,BrooksDJ,LloydCM,FrithCD et al.Frontallobedysfunctioninamyotrophiclateralsclero-sis.APETstudy.Brain1996;119(Pt6):2105-20.
19. AquiloniusSM,JossanSS,EkblomJG,AskmarkH,GillbergPG.Increasedbindingof3H-L-deprenylinspinalcordsfrompatientswithamyotrophiclateralsclerosisasdemonstratedbyautoradi-ography.JNeuralTransmGenSect1992;89:111-22.
20. CistaroA,ValentiniMC,ChioA,NobiliF,CalvoA,MogliaC et al.Brainhypermetabolisminamyotrophiclateralsclerosis:aFDGPETstudyinALSofspinalandbulbaronset.EurJNuclMedMolImaging2012;39:251-9.
21. HatazawaJ,BrooksRA,DalakasMC,MansiL,DiChiroG.Corti-calmotor-sensoryhypometabolisminamyotrophiclateralscle-rosis:aPETstudy.JComputAssistTomogr1988;12:630-6.
22. MarikJ,OgasawaraA,Martin-McNultyB,RossJ,FloresJE,GillHS et al. PET of glial metabolism using 2-18F-fluoroacetate. JNuclMed2009;50:982-90.
23. Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE,BrooksDJ et al.Evidenceofwidespreadcerebralmicroglialacti-vationinamyotrophiclateralsclerosis:an[11C](R)-Pk11195posi-tronemissiontomographystudy.NeurobiolDis2004;15:601-9.
24. Turner MR, Hammers A, Al-Chalabi A, Shaw CE, AndersenPM,BrooksDJ et al.Corticalinvolvementinfourcasesofpri-mary lateral sclerosis using [(11)C]-flumazenil PET. J Neurol2007;254:1033-6.
25. JeongY,ParkKC,ChoSS,KimEJ,KangSJ,KimSE et al.Patternof glucose hypometabolism in frontotemporal dementia withmotorneurondisease.Neurology2005;64:734-6.
26. PaganiM,ChioA,ValentiniMC,Oberg J,NobiliF,CalvoA et al.FunctionalpatternofbrainFDG-PETinamyotrophiclateralsclerosis.Neurology2014;83:1067-74.
27. VanLaereK,VanheeA,VerschuerenJ,DeCosterL,DriesenA,Dupont P et al. Value of 18fluorodeoxyglucose-positron-emis-siontomographyinamyotrophiclateralsclerosis:aprospectivestudy.JAMANeurol2014;71:553-61.
28. ChiòA,PaganiM,AgostaF,CalvoA,CistaroA,FilippiM.Neu-roimaging inAmyotrophic Lateral Sclerosis: insight into struc-turalandfunctionalchanges.LancetNeurology2014;13:1228-40.
29. BoilleeS,YamanakaK,LobsigerCS,CopelandNG,JenkinsNA,KassiotisG et al.Onsetandprogressionin inheritedALSdeter-minedbymotorneuronsandmicroglia.Science2006;312:138992.
30. PhilipsT,RobberechtW.Neuroinflammationinamyotrophiclat-eral sclerosis: roleofglialactivation inmotorneurondisease.LancetNeurol2011;10:253-63.
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tosisinALSdemonstratedby[11C](L)-deprenyl-D2PET.JNeurolSci2007;255:17-22.
57. CorciaP,TauberC,VercoullieJ,ArlicotN,PrunierC,PralineJ et al.Molecularimagingofmicroglialactivationinamyotrophiclateralsclerosis.PLoSOne2012;7:e52941.
58. WangS,SummersRM.Machinelearningandradiology.MedIm-ageAnal2012;16:933-51.
59. AertsHJ,VelazquezER,LeijenaarRT,ParmarC,GrossmannP,Cavalho S et al. Decoding tumour phenotype by noninvasiveimagingusingaquantitativeradiomicsapproach.NatCommun2014;5:4006.
60. FilippiniN,DouaudG,MackayCE,Knight S,TalbotK,Turn-erMR.Corpuscallosuminvolvement isaconsistent featureofamyotrophiclateralsclerosis.Neurology2010;75:1645-52.
61. BedeP,HardimanO.LessonsofALSimaging:Pitfallsandfuturedirections-Acriticalreview.NeuroimageClin2014;4:436-43.
Conflicts of interest.—Theauthorscertifythatthereisnoconflictofinterestwithanyfinancialorganizationregardingthematerialdiscussedinthemanuscript.
EpubaheadofprintonNovember6,2014.
50. Andersen PM, Forsgren L, Binzer M, Nilsson P, Ala-Hurula V,KeranenML et al.Autosomalrecessiveadult-onsetamyotroph-ic lateral sclerosis associatedwith homozygosity forAsp90AlaCuZn-superoxidedismutasemutation.Aclinicalandgenealogi-calstudyof36patients.Brain1996;119(Pt4):1153-72.
51. Leigh PN, Meldrum BS. Excitotoxicity in ALS. Neurology1996;47:S221-7.
52. YuI,InajiM,MaedaJ,OkauchiT,NariaiT,OhnoK et al.Glialcell-mediateddeteriorationandrepairofthenervoussystemaf-tertraumaticbraininjuryinaratmodelasassessedbypositronemissiontomography.JNeurotrauma2010;27:1463-75.
53. YamanakaK,ChunSJ,BoilleeS,Fujimori-TonouN,YamashitaH,GutmannDH et al.Astrocytesasdeterminantsofdiseasepro-gressionininheritedamyotrophiclateralsclerosis.NatNeurosci2008;11:251-3.
54. Magistretti PJ.Neuron-gliametabolic coupling andplasticity. JExpBiol2006;209:2304-11.
55. PellerinL,MagistrettiPJ.Glutamateuptakeintoastrocytesstimu-latesaerobicglycolysis:amechanismcouplingneuronalactivitytoglucoseutilization.ProcNatlAcadSciUSA1994;91:10625-9.
56. JohanssonA,EnglerH,BlomquistG et al.Evidenceforastrocy-
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