Bridges, LR

Clark, CN

Holton, JL

MacKinnon, AD

Nirmalananthan, N

Pereira, AC

Quaegebeur, A

Revesz, T

English

UCL Discovery

Foix%Chavany%Marie/ syndrome/ due/ to/ type/ E/ TDP43/pathology!Authors:/CN/Clark1,/*/PhD/MRCP,/A/Quaegebeur2,/*/MD/PhD,/N/Nirmalananthan1/PhD/FRCP,/Andrew/ D/ MacKinnon3/ MD/ FRCR,/ Tamas/ Revesz4/ MD/ PhD/ FRCPath,/ JL/ Holton2/ PhD/FRCPath,/LR/Bridges5/MD/FRCPath,/AC/Pereira1/MD/FRCP/1Neurology!department,!Atkinson!Morley!Regional!Neuroscience!Centre,!St!George's!University!Hospitals!NHS!Foundation!Trust,!London,!UK!!2Division!of!Neuropathology,!National!Hospital!for!Neurology!and!Neurosurgery,!University!College!London!Hospitals!NHS!Foundation!Trust,!London,!UK!!3Department!of!Neuroradiology,!Atkinson!Morley!Regional!Neuroscience!Centre,!St!George's!University!Hospitals!NHS!Foundation!Trust,!London,!UK.!4Queen!Square!Brain!Bank!for!Neurological!Disorders!and!Department!of!Neurodegenerative!Disease,!UCL,!Queen!Square!!Institute!of!Neurology,!London,!UK.!!5St!George's!University!Hospitals!NHS!Foundation!Trust,!Department!of!Cellular!Pathology,!St!George's!Hospital,!Blackshaw!Road,!London!SW17!0QT!!*!joint!first!authors!as!contributed!equally!to!final!manuscript!Corresponding/author:!!Anthony!Pereira!!!!St!George’s!Hospital!!Blackshaw!Road!London!SW17!0QT!Phone:!020!8725!4322!Fax:!020!8725!4700!anthony.pereira@stgeorges.nhs.uk!!Study/funding//CN!Clark!reports!no!disclosures!!A!Quaegebeur!reports!no!disclosures!N!Nirmalananthan!reports!no!disclosures!AD!MacKinnon!reports!no!disclosures!T!Revesz!is!supported!by!the!Karin!&!Sten!Morstedt!CBD!Solutions!AB!and!the!National!Institute!for!Health! Research! (NIHR)! Queen! Square! Biomedical! Reseach! Unit! in! Dementia! based! at! University!College!London!Hospitals!(UCLH),!University!College!London!JL! Holton! is! supported! by! the! Multiple! System! Atrophy! Trust! and! Karin! &! Sten! Mortstedt! CBD!Solutions.!!LR!Bridges!reports!no!disclosures!AC!Pereira!reports!no!disclosures!This!research!was!supported!by!the!National!Institute!for!Health!Research!University!College!London!Hospitals!Biomedical!Research!Centre.!The!Editors!of!Neuropathology!and!Applied!Neurobiology!are!committed! to! peercreview! integrity! and! upholding! the! highest! standards! of! review.! As! such,! this!article!was!peercreviewed!by! independent,!anonymous!expert! referees,!and!the!authors! (including!JH)!had!no!role!in!either!the!editorial!decision!or!the!handling!of!the!paper.!!!Character!count!for!title:!57!Abstract:!N/A!Word!count!main!text:!1067!Figures:!1!!References:!10!!!Author/Contributions/CN!Clark:!Drafting!manuscript!and!reviewing!patient!notes.!A!Quaegebeur:!Drafting!manuscript!and!neuropathological!diagnosis!N!Nirmalananthan:!Clinical!management!and!diagnosis!of!patient!in!life,!manuscript!review!AD!MacKinnon:!Selection!and!review!of!MR!images!and!editing!of!legend,!manuscript!Review!T!Revesz:!neuropathological!diagnosis!and!manuscript!review!JL!Holton:!neuropathological!diagnosis!and!manuscript!review!!LR!Bridges:!!neuropathological!diagnosis!and!manuscript!review!AC!Pereira:!Clinical!management,!critical!revision!of!text!and!images!for!intellectual!comment.!Search! terms:! FoixcChavanycMarie,! opercular! syndrome,! primary! progressive! aphasia,! PPA,! FTLD,!frontotemporal! lobar! degeneration,! TDP43! pathology,! FTLDcTDP! type! E,! granulofilamentous!neuronal!inclusions,!GFNI!! !We! present! a! 78cyearcold! lady! with! a! clinical! and! radiological! diagnosis! of! anterior! opercular!syndrome! or! FoixcChavanycMarie! syndrome! (FCMS)! and! an! autopsy! diagnosis! of! type! E! TDP43!pathology.! The! neurodegenerative! form!of! FCMS! presents!with! articulation! difficulty,! dysprosody,!orofacial!and!speech!apraxia!and!can!mimic!but!is!distinct!from!primary!progressive!aphasia!(PPA)!(1,!2).!It!was!suggested!that!the!progressive!form!of!FCMS!should!be!included!with!frontotemporal!lobar!degenerations! (FTLD)! (3).! However,! its! neuropathological! substrates! are! poorly! understood.! This!case!reveals!a!rare!pattern!of!TDP43!pathology!as!neurodegenerative!cause!of!FCMS.!The! patient! presented! with! falls! and! a! rapidly! progressive! dysarthria! on! a! background! of!hypertension.!Within! 4!months! she! was! fed! via! nasogastric! tube.! She! became! rapidly! cognitively!impaired!(not!formally!quantified!owing!to!unintelligibility!of!speech).!There!was!minimal!voluntary!facial!movement!(closing!eyes/smiling!to!command)!with!preserved!involuntary!movements!(blink!to!threat/!spontaneous! laughter).!Palatal!elevation!was!normal!with!no!tongue!wasting!or!fibrillation.!There! was! mild! wasting! and! weakness! of! her! hands! but! no! significant!wasting! or! fasciculations!elsewhere.!Power!generally!was!good.!She!walked!slowly,!but!unaided.!Reflexes!(including!facial,!jaw!and!trapezius)!were!normal.!MR!brain!imaging!showed!widening!of!the!Sylvian!fissures!and!frontocparietal! sulci,! with! rightcsided! predominance! (Figure! 1).! !A! tentative! diagnosis! of! motor! neuron!disease!(MND)!was!initially!entertained!but!without!EMG!support,!the!clinicocradiological!diagnosis!was!of!anterior!opercular!syndrome!secondary!to!neurodegeneration.!No!other!specific!radiological!abnormalities!were!identified.!CT!thorax,!abdomen!and!pelvis!showed!no!malignancy.!Repeat!EMG/NCS!one!month!later!demonstrated!mild!corticospinal!tract!dysfunction!with!small!potentials!from!hands!and!feet!on!transcranial!magnetic!stimulation.!EMG!showed!mild!neurogenic!changes!in!the!limb!muscles!and!tongue.!Therefore,!despite!evidence!of!upper!and!lower!motor! neurone! dysfunction,! the! absence! of! evidence! of! denervation! and! reinnervation! in! the!muscles!failed!to!support!the!diagnosis!of!MND!neurophysiologically,!despite!a!high!clinical!index!of!suspicion.!!Videofluoroscopy!showed!abnormal!contraction!of!the!posterior!pharyngeal!wall.!A! radiologically! guided! gastrostomy! was! inserted.! A! trial! of! steroids! did! not! demonstrate!improvement.!!She!became!increasingly!weak!(4/5!upper! limbs!and!3/5! lower! limbs!on!MRC!scale)!with! hyperreflexia.! Within! 6! months! of! presentation,! she! developed! chronic! type! 2! respiratory!failure!and!was!palliated.!At! autopsy,! the! brain! weighed! 1318g! and! showed! atrophy! of! the! inferior! frontal! and! superior!temporal! gyri.! Histologically! there!was! superficial! spongiosis! and!mild! neuronal! loss! in! the! frontal!and! temporal! lobes! in! keeping! with! frontotemporal! lobar! degeneration! (FTLD).! The! other! lobes,!medial! temporal! lobe! structures,! deep! grey! nuclei! and! hindbrain! showed! preserved!cytoarchitecture.! Immunostaining! for! phosphorylated! TDP43! showed! finely! granular! neuronal!cytoplasmic! inclusions! (NCIs)!with! fine!grainclike! inclusions!and!short! threads! in! the!neuropil!of!all!cortical!layers!of!the!temporal!and!frontal!cortices!with!emphasis!on!the!superficial!layers.!Compact!NCIs!were!rare!and!neuronal!nuclear!inclusions!were!not!identified.!Grey!and!white!matter!showed!scattered!glial!cytoplasmic! inclusions!(figure!1).!This!pattern!did!not!conform!to!the!well!described!subtypes!of!TDP43!pathology!(type!AcD)!(4)!but!was!similar!to!the!morphology!of!inclusions!observed!in! the! recently! proposed! FTLDcTDP! type! E! (5).! TDP43! pathology!was!more! severe! in! the! affected!cortical!regions!of!the!right!cerebral!hemisphere,!similar!to!the!asymmetry!found!on!MRI!(table!1).!TDP43!pathology!in!the!hippocampus!was!sparse.!Rare!NCIs!were!observed!in!the!hypoglossal!nuclei!and! increased! microglial! activation! was! noted! in! the! pyramids! indicative! of! corticospinal! tract!degeneration.!In!addition!to!TDP43!pathology!there!was!evidence!of!low!level!of!Alzheimer’s!disease!pathological! change! (6)! with! amyloidcbeta! pathology! corresponding! to! Thal! phase! 3! and!neurofibrillary!tangle!and!thread!pathology!not!exceeding!Braak&Braak!stage!I.!Vascular!comorbidity!was! limited! to! presence! of! mild! hyaline! arteriosclerosis! affecting! the! deep! grey! nuclei! and! both!cerebral!and!cerebellar!white!matter.!Overall! the!most! significant!neuropathological! findings!were!those!of!FTLD!due!to!TDP43!proteinopathy,!Type!E.!The! neuropathological! study! of! FCMS! is! limited! to! a! handful! of! reports! (7c10)! all! showing! focal!cortical!degenerative!pathology!in!keeping!with!FTLD.!A!single!study!described!a!clinical!presentation!of!opercular!syndrome!in!a!patient!carrying!a!P332S!MAPT!mutation!(9)!and!showing!tauopathy!with!Pickclike! bodies! on! autopsy.! A! further! study! described! the! pathology! in! a! patient! with! FCMS! as!TDP43cpositive! NCIs! in! frontal! and! temporal! lobes! along! with! involvement! of! motor! cortex! and!hypoglossal! nucleus! (8)! in! keeping! with! FTLDcTDP! with! MND.! The! pattern! of! TDP43! pathology!described!most!likely!corresponds!to!type!A.!Others!found!degeneration!in!keeping!with!FTLD!with!tau! negative,! ubiquitincpositive! neuronal! cytoplasmic! inclusions,! diagnosed! as! FTLDcU! (10).! TDP43!staining! was! not! performed,! but! one! may! speculate! that! this! might! have! been! a! case! of! TDP43!proteinopathy.! Finally,! two! cases! were! described! with! focal! frontal! cortical! atrophy! (7)! with!Immunostaining!for!tau!and!ubiquitin!described!as!“insignificant”!in!one!case!and!showing!“a!certain!number”! of! neuronal! inclusions! in! the! other.! Whilst! both! cases! seem! consistent! with! FTLD! the!precise!pathologies!are!unclear!in!today’s!terms.!The! morphology! and! distribution! of! the! TDP43! inclusions! in! this! case! is! unusual,! resembling! a!recently!proposed!subtype!of!TDP43!pathology,!FTLDcTDP!type!E!(5).!This!study!described!7!cases!of!FTLDcTDP! showing!a!distinct!pattern!of! TDP43!pathology!not! corresponding! to! any!of! the!existing!TDP43! pathology! subtypes,! comprising! granulofilamentous! inclusions,! abundant! grains! and!oligodendroglial! inclusions.! All! cases! presented! clinically! with! behavioural! variant! of! FTD! with! a!single!case!showing!additional!motor!neuron!disease.!Whilst!in!the!latter!patient!a!C9orf72!mutation!was! detected,! no! other! known! mutations! were! identified.! In! our! case! genetic! testing! was! not!available,! however,! the! absence! of! p62cpositive,! TDP43cnegative! inclusions! in! hippocampus! and!cerebellum! argued! against! a! C9orf72! repeat! expansion! mutation.! Of! interest,! the! short! disease!duration!in!our!case!(6!months)!is! in!line!with!the!rapidly!progressive!disease!course!characterising!the!previously!described!TDP43!type!E!cases!(5).!!To!summarise,!a!78cyearcold!lady!with!rapidly!progressive!pseudobulbar!dysarthria!with!automaticcvoluntary!dissociation!and!cognitive! impairment! together!with!radiological!evidence!of!an!anterior!opercular! syndrome! was! found! to! have! a! rare! pattern! of! TDP43! pathology! corresponding! to! the!newly!proposed!category!of!FTLDcTDP!type!E.!Not!only!do!our!findings!expand!the!clinical!spectrum!encountered! in! this!distinct! type!of!TDP43!pathology! to!anterior!opercular! syndrome,!but!also!we!describe!one!of! the! very! few!pathologically! proven! cases! of! neurodegenerative! FCMS!highlighting!that!TDP43!pathology!should!be!included!in!the!differential!diagnosis.!!!!!!Figure!1:!Radiological!and!histopathological! features.!MRI!brain! images! (AcC).!A:!Coronal!T1! image!showing! right! predominant! Sylvian! fissure! (white! arrow)! widening! secondary! to! atrophy! of! the!inferior!frontal!and!superior!temporal!gyri;!B:!Sagittal!T2!image!showing!widening!of!right!precentral!sulcus! (black!arrow)!and!atrophy!of! right!anterior! frontal!operculum! (dotted!arrow);!C:! Sagittal!T2!image! showing! less! pronounced! left! anterior! frontal! opercular! atrophy! (dotted! arrow).!Immunohistochemical! staining! for! phosphorylated! TDP43! (DcI).! DcF:! Finely! granular! neuronal!cytoplasmic! inclusions! (arrow)! on! a! background! of! short! threads! and! fine! grainclike! inclusions!(dotted! arrow)! in! the! neocortex! of! the! right! superior! temporal! gyrus;! occasional! glial! cytoplasmic!inclusions! (dashed! arrow)! are! also! present.! G:! Glial! cytoplasmic! inclusion! in!white!matter! of! right!superior! temporal! gyrus.! HcI:! TDP43! pathology! in! right! (H)! and! left! (I)! inferior! frontal! gyrus!highlighting! leftcright! asymmetry! in! TDP43! pathology.! Orientation! in! panel! H! and! I! demonstrate!superficial!cortex!on!the!left!and!deep!cortex!on!the!right!aspect.!Bar!in!(D)!represents!120µm!in!(H,!I),!60µm!in!(D),!30µm!in!(E)!and!20!µm!in!(F,G).!Table!1:!Severity!of!TDP43!pathology!across!different!brain!regions!Brain!region! Right! Left!Superior!frontal!gyrus! +++! ++!Inferior!frontal!gyrus! +++! ++!Insula! ++! +!Superior!temporal!gyrus! ++! +!Inferior!temporal!gyrus! +++! +!Occipital!! c! c!Hippocampus! +! +!!+++:!frequent;!++:!occasional;!+:!sparse;!c:!absent!!/Acknowledgements:/JLH!is!supported!by!the!Multiple!System!Atrophy!Trust!and!Karin!&!Sten!Mortstedt!CBD!Solutions.!TR!is!supported!by!the!Karin!&!Sten!Morstedt!CBD!Solutions!AB!and!the!National!Institute!for!Health!Research!(NIHR)!Queen!Square!Biomedical!Reseach!Unit!in!Dementia!based!at!University!College!London!Hospitals!(UCLH),!University!College!London.!This!research!was!supported!by!the!National!Institute!for!Health!Research!University!College!London!Hospitals!Biomedical!Research!Centre.!/ /References/1.! Uttner! I,! Brettschneider! J,! Unrath! A,! Riecker! A.! Slowly! progressive! 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Foix–Chavany–Marie syndrome due to type E TDP43 pathology

https://discovery.ucl.ac.uk/10086071/1/FCMS_Clark%20and%20Quaegebeur%20et%20al_accepted.pdf

Foix–Chavany–Marie syndrome due to type E TDP43 pathology

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