Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort

Beha iou al Neu ology Social cogni ion impai men in gene ic on o empo al demen ia wi hin he GENFI coho Lucy L. Russell a , Ca oline V. G ea es a , Ma ina Bocche a a , Jenni e Nicholas b,c , Rhian S. Con e y a , Ka ina Moo e a , Da id M. Cash a,d , John an Swie en e , Lize Jiskoo a,e , Fe min Mo eno , Raquel Sanchez-Valle g , Ba ba a Bo oni h , Robe La o ce J . i , Ma io Masellis j , Ma ia Ca mela Ta aglia k , Ca oline G a l , Emanuela Ro ondo m , Daniela Galimbe i m,n , James B. Rowe o , Elizabe h Finge p , Ma his Syno zik q , Rik Vandenbe ghe , Alexand e de Mendonc¸a s , Fab izio Taglia ini , Isabel San ana u , Simon Ducha me , Ch is Bu le w , Alex Ge ha d x,y , Johannes Le in z , Ad ian Danek z , Ma kus O o aa , Jason D. Wa en a and Jona han D. Roh e a,* , on behal o he Gene ic FTD Ini ia i e, GENFI 1 a Demen ia Resea ch Cen e, Depa men o Neu odegene a i e Disease, London, UK b Depa men o Medical S a is ics, London School o Hygiene and T opical Medicine, London, UK c Ins i u e o P ion Disease, UCL Queen Squa e Ins i u e o Neu ology, London, UK d Cen e o Medical Image Compu ing, Depa men o Medical Physics and Biomedical Enginee ing, Uni e si y College London, London, UK e Depa men o Neu ology, E asmus Medical Cen e, Ro e dam, Ne he lands Cogni i e Diso de s Uni , Depa men o Neu ology, Donos ia Uni e si y Hospi al, San Sebas ian, Gipuzkoa, Spain g Alzheime 's Disease and O he Cogni i e Diso de s Uni , Neu ology Se ice, Hospi al Clı´nic, Ba celona, Spain h Cen e o Neu odegene a i e Diso de s, Neu ology Uni , Depa men o Clinical and Expe imen al Sciences, Uni e si y o B escia, B escia, I aly i Clinique In e disciplinai e de M emoi e, D epa emen des Sciences Neu ologiques du CHU de Qu ebec, Uni e si  e La al, Qu ebec, Canada j Sunnyb ook Heal h Sciences Cen e, Sunnyb ook Resea ch Ins i u e, Uni e si y o To on o, To on o, Canada k Tanz Cen e o Resea ch in Neu odegene a i e Diseases, Uni e si y o To on o, To on o, Canada l Depa men o Ge ia ic Medicine, Ka olinska Uni e si y Hospi al-Huddinge, S ockholm, Sweden m Uni e si y o Milan, Cen o Dino Fe a i, Milan, I aly n Fondazione Ca’ G anda, IRCCS Ospedale Policlinico, Milan, I aly o Depa men o Clinical Neu osciences, Uni e si y o Camb idge, Camb idge, UK p Depa men o Clinical Neu ological Sciences, Uni e si y o Wes e n On a io, London, On a io, Canada q Depa men o Neu odegene a i e Diseases, He ie-Ins i u e o Clinical B ain Resea ch and Cen e o Neu ology, Uni e si y o Tu ¨bingen, Tu ¨bingen, Ge many *Co esponding au ho . Demen ia Resea ch Cen e, Depa men o Neu odegene a i e Disease, UCL Ins i u e o Neu ology, Queen Squa e, London, WC1N 3BG, UK. E-mail add ess: [email p o ec ed] (J.D. Roh e ). 1 Lis o GENFI conso ium au ho s is lis ed in Appendix sec ion. A ailable online a www.sciencedi ec .com ScienceDi ec Jou nal homepage: www.else ie .com/loca e/co ex co ex 133 (2020) 384e398 h ps://doi.o g/10.1016/j.co ex.2020.08.023 0010-9452/©2020 The Au ho (s). Published by Else ie L d. This is an open access a icle unde he CC BY license (h p:// c ea i ecommons.o g/licenses/by/4.0/). Labo a o y o Cogni i e Neu ology, Depa men o Neu osciences, KU Leu en, Leu en, Belgium s Facul y o Medicine, Uni e si y o Lisbon, Lisbon, Po ugal Fondazione Is i u o di Rico e o e Cu a a Ca a e e Scien i ico Is i u o Neu ologica Ca lo Bes a, Milano, I aly u Facul y o Medicine, Uni e si y o Coimb a, Coimb a, Po ugal Depa men o Psychia y, McGill Uni e si y, Mon eal, Qu ebec, Canada w Depa men o Clinical Neu ology, Uni e si y o Ox o d, Ox o d, UK x Di ision o Neu oscience and Expe imen al Psychology, Wol son Molecula Imaging Cen e, Uni e si y o Manches e , Manches e , UK y Depa men s o Ge ia ic Medicine and Nuclea Medicine, Uni e si y o Duisbu g- Essen, Ge many z Depa men o Neu ology, Ludwig-Maximilians-Uni e si y, Munich, Ge many aa Depa men o Neu ology, Uni e si y o Ulm, Ulm, Ge many a icle in o A icle his o y: Recei ed 31 Ma ch 2020 Re iewed 11 May 2020 Re ised 6 July 2020 Accep ed 22 Augus 2020 Ac ion edi o B ad Dicke son Published online 26 Sep embe 2020 Keywo ds: F on o empo al demen ia Theo y o mind Emo ion p ocessing Faux pas Facial emo ion ecogni ion C9o 72 P og anulin MAPT abs ac A key symp om o on o empo al demen ia (FTD) is di icul y in e ac ing socially wi h o he s. Social cogni ion p oblems in FTD include impai ed emo ion p ocessing and heo y o mind di icul ies, and whils hese ha e been s udied ex ensi ely in spo adic FTD, ew s udies ha e in es iga ed hem in amilial FTD. Facial Emo ion Recogni ion (FER) and Faux Pas (FP) ecogni ion es s we e used o s udy social cogni ion wi hin he Gene ic F on o- empo al Demen ia Ini ia i e (GENFI), a la ge amilial FTD coho o C9o 72, GRN, and MAPT mu a ion ca ie s. 627 pa icipan s unde ook a leas one o he asks, and we e sepa a ed in o mu a ion-nega i e heal hy con ols, p esymp oma ic mu a ion ca ie s (spli in o ea ly and la e g oups) and symp oma ic mu a ion ca ie s. G oups we e compa ed using a linea eg ession model wi h boo s apping, adjus ing o age, sex, educa ion, and o he FP ecogni ion es , language. Neu al co ela es o social cogni ion de ici s we e explo ed using a oxel-based mo phome y (VBM) s udy. All h ee o he symp oma ic gene ic g oups we e impai ed on bo h asks wi h no signi ican di e ence be ween hem. Howe e , p io o onse , only he la e p esymp oma ic C9o 72 mu a ion ca ie s on he FER es we e impai ed compa ed o he con ol g oup, wi h a subanalysis showing di e ences pa icula ly in ea and sadness. The VBM analysis e ealed ha impai ed social cogni ion was mainly associa ed wi h a le hemisphe e p edominan ne wo k o egions in ol ing pa icula ly he s ia um, o bi o on al co ex and insula, and o a lesse ex en he in e omedial empo al lobe and o he a eas o he on al lobe. In conclusion, heo y o mind and emo ion p ocessing abili ies a e impai ed in amilial FTD, wi h ea ly changes occu ing p io o symp om onse in C9o 72 p esymp oma ic mu a ion ca ie s. Fu u e wo k should in es iga e how pe o mance changes o e ime, in o de o gain a clea e insigh in o social cogni i e impai men o e he cou se o he disease. ©2020 The Au ho (s). Published by Else ie L d. This is an open access a icle unde he CC BY license (h p://c ea i ecommons.o g/licenses/by/4.0/). 1. In oduc ion The impai men o social skills is one o he mos p ominen symp oms expe ienced by people wi h on o empo al de- men ia (FTD) (Adenza o, Ca allo, &En ici, 2010;Kum o and Pigue , 2012). The di e en neu al p ocesses ha unde lie such skills a e gene ally g ouped oge he wi hin he e m ‘social cogni ion’ (Adolphs, 2009), and include a numbe o abili ies ha ha e been shown o be impai ed in FTD, including ecogni ion o o he s'emo ions, and ‘ heo y o mind’, he abili y o unde s and ha o he s ha e hough s and belie s (G ego y e al., 2002;Lough and Hodges, 2002;Rosen e al., 2006;Adenza o e al., 2010;Oma , Roh e , Hails one, & Wa en, 2011;Kum o and Pigue , 2012). Whils he e ha e been a numbe o s udies explo ing hese skills in spo adic FTD, ew ha e ocused on people wi h he gene ic o ms o FTD, cha ac e ized usually by mu a ions in he p og anulin (GRN), au (MAPT) and ch omosome 9 open eading ame 72 (C9o 72) genes (Jiskoo e al., 2016,2018, Che an e al., 2019). So a , hese s udies ha e been ela i ely small and o en ocused on one (Che an e al., 2019)o wo (Jiskoo e al., 2016,2018) o he gene ic g oups, showing change only in speci ic ques ionnai es, o when g oups we e ollowed longi udinally. The Gene ic FTD Ini ia i e (GENFI) is an in e na ional ge- ne ic FTD coho s udy, aimed a in es iga ing ea ly bio- ma ke s, including measu es o cogni ion (Roh e e al., 2015). Using his coho we he e o e aimed o assess emo ion p ocessing and heo y o mind abili ies in a la ge co ex 133 (2020) 384e398 385 coho o p esymp oma ic and symp oma ic indi iduals wi h mu a ions in he C9o 72,GRN and MAPT genes, wi h he hypo hesis ha social cogni i e de ici s would become appa en only la e in he p esymp oma ic pe iod o when symp oma ic. 2. Me hods We epo how we de e mined ou sample size, all da a ex- clusions (i any), all inclusion/exclusion c i e ia, whe he in- clusion/exclusion c i e ia we e es ablished p io o da a analysis, all manipula ions, and all measu es in he s udy. 2.1. Pa icipan s Pa icipan s we e ec ui ed om he ou h da a eeze o he GENFI s udy including si es in he UK, Canada, Sweden, Ne he lands, Belgium, Spain, Po ugal, I aly and Ge many. O he 680 pa icipan s consecu i ely en olled in he s udy, 627 unde ook a leas one es o social cogni ion: 246 who es ed nega i e o he mu a ion wi hin he amily, and he e o e ac ed as he con ols, 159 C9o 72 expansion ca ie s, 155 GRN mu a ion ca ie s, and 67 MAPT mu a ion ca ie s (Table 1). Mu a ion ca ie s we e classi ied as ei he symp oma ic o p esymp oma ic based on clinician judgemen . Pa icipan s we e only classi ied as symp oma ic i he clinician judged ha symp oms we e p esen , consis en wi h a diagnosis o a degene a i e diso de , and p og essi e in na u e (Table S1). The p esymp oma ic ca ie s we e u he spli in o hose u he han i e yea s om es ima ed symp om onse (based on he mean age a onse in he amily), called he ‘ea ly’ g oup, and hose wi hin i e yea s o es ima ed onse , called he ‘la e’ g oup. Diagnoses in he symp oma ic g oup we e as ollows: MAPT mu a ion ca ie s, 17 b FTD, 1 o he ; GRN mu- a ion ca ie s, 15 b FTD, 16 p ima y p og essi e aphasia (PPA), 1 o he ; C9o 72 expansion ca ie s, 38 b FTD, 10 FTD wi h amyo ophic la e al scle osis, 1 PPA, 1 p og essi e sup anuclea palsy and 3 o he . All pa icipan s unde wen he s anda dized GENFI clinical assessmen including medical his o y, physical examina ion, he Mini-Men al S a e Examina ion (MMSE), and he Clinical Demen ia Ra ing Scale wi h he Na ional Alzheime Coo di- na ing Cen e FTLD sum o boxes sco e (FTLD-CDR-SOB). De- mog aphics a e shown in Table 1. The e was a signi ican di e ence in sex be ween he g oups (p¼.018): he symp- oma ic C9o 72 mu a ion ca ie s had a signi ican ly highe pe cen age o men han he ea ly and la e C9o 72 mu a ion ca ie s and he con ol g oup (p¼.013, p¼.002 and p¼.001 espec i ely). The e was also a signi ican di e ence in age be ween he g oups: all ea ly p esymp oma ic mu a ion ca - ie s we e signi ican ly younge han he con ol g oup (all p<.001), and all la e p esymp oma ic mu a ion ca ie s and symp oma ic mu a ion ca ie s we e signi ican ly olde han con ols (all p<.001) excep o he la e MAPT mu a ion ca - ie s in which no di e ence was obse ed (p¼.239). The e we e also di e ences be ween he g oups in educa ion: he symp oma ic C9o 72 and GRN mu a ion ca ie s had signi i- can ly lowe le els o educa ion han he con ol g oup did (p¼.007 and p<.001 espec i ely). No signi ican di e ences in disease se e i y we e obse ed be ween he symp oma ic gene ic g oups o be ween he la e p esymp oma ic g oups, based on hei FTLD-CDR-SOB. Howe e , he ea ly GRN p e- symp oma ic mu a ion ca ie did ha e a signi ican ly lowe FTLD-CDR-SOB sco es han he o he wo ea ly g oups. 2.2. Tes ing o social cogni ion Social cogni ion was es ed in he GENFI coho using he sho ened e sion o he Social Cogni ion and Emo ional Assessmen , known as he mini-SEA (Be oux e al., 2012; Funkiewiez, Be oux, de Souza, L e y, &Dubois, 2012) which consis s o a es o acial emo ion ecogni ion and a es o heo y o mind. I was designed speci ically o people wi h FTD, wi h ini ial s udies showing de ici s in FTD compa ed wi h heal hy con ols, wi h people wi h Alzheime 's disease, and also hose wi h majo dep essi e diso de (Gue a a e al., 2015;Na me, Mou as, Roussel, De ende ille, &Gode oy, 2013;To al a, Gleichge ch , To es A dila, Roca, &Manes, 2015). 2.2.1. Expe imen 1: acial emo ion ecogni ion (FER) es The FER es is a sho ened e sion o he s anda d Ekman aces ask (Ekman, Ellswo h, F iesen, Golds ein, &K asne , 1972), wi h pa icipan s asked o ecognise whe he aces a e showing one o ei he six uni e sal emo ions (happiness, su p ise, ange , ea , disgus and sadness) o a neu al exp ession. Pa icipan s a e p esen ed wi h 35 di e en aces ( i e i ems o each emo ion) and a e equi ed o selec he co ec emo ional label ha ma ches he emo ion o he ace. 2.2.2. Expe imen 2: aux pas (FP) ecogni ion es The FP ecogni ion es con ains a se ies o 10 sho ca oon s o ies desc ibing scena ios in ol ing social incon eniences, known as ‘ aux pas’; i e o he s o ies con ain a aux pas, he o he i e do no . The ask equi es indi iduals o be able o in e ano he 's hough s o belie s. A s uc u ed ques ionnai e asks how and why he social aux pas has occu ed. Pa ici- pan s can sco e a maximum o 40 on his ask, 10 poin s o he con ol s o ies and 30 poin s o he aux pas s o ies. 2.3. S a is ical analysis In he con ol g oup, we explo ed he ela ionship o he FER and FP ecogni ion es s o age (Spea man ank co ela ion), sex (ManneWhi ney U es ) and yea s o educa ion (Spea man ank co ela ion). Fo he FP ecogni ion es , we explo ed he e ec o he di e en language e sions using a linea eg ession. Sco es on he wo social cogni i e es s (and he indi idual emo ion sco es on he FER es ) we e compa ed be ween he g oups using linea eg ession, adjus ing o age, sex and ed- uca ion (and language o he FP ecogni ion es ) wi h 95% bias-co ec ed boo s apped con idence in e als wi h 1000 epe i ions (as he da a was no no mally dis ibu ed). A subanalysis o he e ec o pheno ype was also pe - o med using he same me hodology as he main analysis: sco es on he wo social cogni i e es s we e compa ed co ex 133 (2020) 384e398386 Table 1 eDemog aphics and sco es o he Facial Emo ion Recogni ion (FER) and Faux Pas (FP) ecogni ion es s. N is he numbe o pa icipan s. Mean (s anda d de ia ion) shown o age, educa ion and cogni i e es sco es. As a sligh ly di e en numbe o pa icipan s a emp ed each es in some o he subg oups, he mean (s anda d de ia ion) sex, age, educa ion, MMSE and FTLD-CDR a ied be ween hose ha did he FER es and hose ha did he FP ecogni ion es e hese a e shown unde nea h in i alics o he FP ecogni ion es i di e en . N (FER)/(FP) Sex (% male) Age (yea s) Educa ion (yea s) MMSE (/30) FTLD-CDR (Sum o boxes) FER es sco e (/35) FER subsco es by emo ion (each sco e ou o 5) FP ecogni ion es sco e (/40) Neu al Happy Su p ise Disgus Fea Ange Sadness Heal hy con ols 246/245 42 46.0 (12.8) 14.3 (3.5) 29.4 (1.2) .2 (.6) 28.5 (3.3) 4.8 (.5) 5.0 (.2) 4.5 (.9) 4.0 (1.0) 3.0 (1.4) 3.9 (.9) 3.5 (1.3) 35.1 (4.6) C9o 72 Ea ly p esymp oma ic 81/81 41 41.7 (10.1) 14.8 (2.5) 29.4 (1.0) .3 (.6) 29.0 (2.9) 4.9 (.4) 5.0 (.0) 4.6 (.8) 3.8 (1.1) 3.1 (1.3) 3.9 (1.0) 3.8 (1.2) 35.0 (5.2) La e p esymp oma ic 25/24 36 56.3 (8.3) 56.5 (8.4) 13.2 (3.9) 13.1 (3.9) 28.7 (1.3) 28.7 (1.4) .4 (.9) 26.3 (3.5) 4.8 (.5) 5.0 (.0) 4.2 (1.2) 3.6 (1.2) 2.3 (1.2) 3.7 (1.1) 2.7 (1.4) 31.9 (7.5) Symp oma ic 53/45 64 62 62.3 (8.0) 63.0 (8.0) 13.0 (3.6) 13.0 (3.7) 24.7 (4.9) 24.9 (5.2) 9.3 (5.6) 9.2 (5.3) 18.7 (6.9) 3.5 (1.8) 4.4 (1.2) 3.0 (1.6) 2.4 (1.5) 1.4 (1.3) 2.3 (1.5) 1.9 (1.5) 22.0 (9.9) GRN Ea ly p esymp oma ic 93/93 35 41.3 (9.1) 15.0 (3.7) 29.5 (.8) .1 (.2) 29.3 (3.2) 4.9 (.4) 5.0 (.0) 4.6 (.9) 4.0 (1.0) 3.2 (1.3) 3.9 (1.0) 3.8 (1.2) 36.3 (4.3) La e p esymp oma ic 29/30 48 60.5 (6.6) 60.3 (6.5) 14.4 (3.2) 14.3 (3.1) 29.2 (1.1) .2 (.6) 28.4 (4.2) 4.8 (.7) 5.0 (.2) 4.5 (.7) 3.8 (1.2) 2.9 (1.3) 3.9 (1.2) 3.6 (1.1) 35.6 (3.7) Symp oma ic 32/22 53 41 64.2 (8.4) 62.9 (7.9) 11.6 (3.6) 11.4 (3.2) 21.8 (6.3) 21.8 (7.1) 8.6 (5.5) 8.6 (5.6) 20.0 (7.2) 3.2 (1.8) 4.4 (.9) 3.1 (1.4) 3.0 (1.7) 2.0 (1.7) 2.9 (1.4) 1.9 (1.6) 18.7 (12.2) MAPT Ea ly p esymp oma ic 37/37 35 36.1 (8.0) 14.8 (2.7) 29.7 (.8) .3 (.6) 29.5 (3.0) 4.8 (.4) 5.0 (.0) 4.5 (.9) 4.1 (.9) 3.5 (1.6) 3.9 (1.0) 3.6 (1.3) 35.2 (4.5) La e p esymp oma ic 12/12 42 51.2 (10.2) 14.0 (3.4) 29.3 (1.0) .2 (.6) 29.4 (2.2) 4.8 (.4) 5.0 (.0) 4.8 (.5) 4.0 (1.2) 3.2 (1.2) 4.2 (.7) 3.5 (.8) 34.7 (4.5) Symp oma ic 18/12 56 50 59.8 (6.0) 59.7 (5.7) 14.6 (3.6) 15.1 (4.0) 23.2 (6.5) 25.8 (3.3) 9.0 (5.3) 8.5 (5.5) 22.3 (6.6) 4.3 (1.6) 4.8 (.5) 3.3 (1.6) 2.6 (1.7) 2.1 (1.5) 2.6 (1.6) 2.7 (1.1) 29.2 (7.0) co ex 133 (2020) 384e398 387 be ween he di e en clinical synd omes wi hin he symp- oma ic mu a ion ca ie s as well as wi h con ols. 2.4. Imaging analysis Pa icipan s unde wen olume ic T1-weigh ed MRI using he GENFI p o ocol. A a ie y o 3T scanne s we e used ac oss he si es: Siemens T io, Siemens Sky a, Siemens P isma, Phillips and Gene al Elec ic. The scan p o ocols we e designed a he s a o he GENFI s udy o ensu e ha he e was adequa e ma ching be ween he scanne s and he quali y o he images. All scans we e quali y checked and hose wi h mo emen s o a e ac s we e emo ed. Fu he mo e, i any pa icipan s displayed mode a e o se e e ascula disease o any o he b ain lesions, hey we e also excluded om he analysis. Voxel-based mo phome y (VBM) was pe o med using S a is ical Pa ame ic Mapping (SPM) 12 so wa e, e sion 6685 (www. il.ion.ucl.ac.uk/spm), unning unde Ma lab R2014a (Ma hwo ks, USA). The T1-weigh ed images we e no malized and segmen ed in o g ey ma e (GM), whi e ma e (WM) and ce eb ospinal luid (CSF) p obabili y maps, by using s anda d p ocedu es and he as -di eomo phic image egis a ion algo i hm (DARTEL) (Ashbu ne , 2007). GM segmen a ions we e a ine ans o med in o he Mon eal Neu ological Ins i u e (MNI) space, modula ed and smoo hed using a Gaussian ke nel wi h 6 mm ull-wid h a hal maximum be o e analysis. Finally, a mask was applied as e- po ed in Ridgway e al., 2009. S udy-speci ic empla es we e c ea ed based on he subjec s included in he speci ic analysis. A each s age, all segmen a ions we e e iewed isually. To al in ac anial olume (TIV) was calcula ed using SPM (Malone e al., 2015). In o de o explo e he ela ionship be ween pe o mance on he es s and GM densi y, mul iple eg ession models o each gene ic g oup we e used o co ela e he GM issue maps o he FER and FP pe o mance in mu a ion ca ie s (bo h symp oma ic and p esymp oma ic indi iduals com- bined). 319 scans we e used o he FER analysis and 309 scans we e used o he FP analysis (C9o 72 expansion ca - ie s: FER ¼132, FP ¼128, GRN mu a ion ca ie s: FER ¼132, FP ¼129, and MAPT mu a ion ca ie s: FER ¼55, FP ¼52) we e included in he imaging analysis. Con ol pa icipan s we e no included in any o he analysis. Age, sex, scanne ype and TIV we e included as nuisance co a ia es. The Family- Wise E o (FWE) a e o mul iple compa isons co ec ion was se a .05. I he e we e no indings a ha s ic le el o co ec ion, esul s we e e iewed a an unco ec ed p alue o .001. No pa o he s udy p ocedu e o analyses we e p e- egis e ed p io o he esea ch being conduc ed. The condi- ions o ou e hics app o al do no pe mi public a chi ing o indi idual anonymised da a. Reade s seeking access o he da a should con ac he co esponding au ho . Access will be g an ed o named indi iduals in acco dance wi h e hical p ocedu es go e ning he euse o sensi i e da a, including comple ion o a da a sha ing ag eemen . All s imuli and s a- is ical code ha e been a chi ed a : h ps://os .io/m8yp7/? iew_only¼949ba796b549 4b7b87d37766ad 840b . 3. Resul s 3.1. Expe imen 1: acial emo ion ecogni ion (FER) es 3.1.1. Heal hy con ols FER es sco e was no signi ican ly co ela ed wi h ei he age ( ho ¼.12, p¼.063) (Table S2) o educa ion ( ho ¼.13, p¼.051) (Table S3) wi hin he con ols. Howe e , he e was a signi ican e ec o sex (p¼.031): mean (s anda d de ia ion) sco e o e all in con ols was 28.5 (3.3), wi h a highe sco e o 29.1 (3.1) in emales (n ¼143), compa ed wi h 28.2 (3.2) in males (n ¼103). O e all, con ols sco ed be ween 19 and 34 ou o a o al possible sco e o 35, wi h cumula i e equency shown in Table S4. A cu -o sco e below he 5 h pe cen ile is commonly conside ed o be abno mal: o he FER es a sco e o below 23 would he e o e be conside ed ou side he no mal ange, wi h a sco e o 23 conside ed bo de line abno mal. 3.1.2. Mu a ion ca ie s All o he h ee symp oma ic mu a ion ca ie g oups sco ed signi ican ly lowe on he FER es compa ed wi h con ols (Table 1,Table S4,Fig. 1): C9o 72 mean 18.7 (s anda d de ia- ion 6.9), GRN 20.0 (7.2) and MAPT 22.3 (6.6), wi h no signi ican di e ence be ween he disease g oups. Wi hin each gene ic g oup, sco es we e signi ican ly lowe in he symp oma ic g oup compa ed wi h bo h he ea ly and la e p esymp oma ic g oups (Table 1,Table S5,Fig. 1). The C9o 72 la e p esymp oma ic g oup pe o med signi i- can ly lowe han bo h he C9o 72 ea ly p esymp oma ic g oup and he con ols (Table 1,Table S5,Fig. 1): la e p e- symp oma ic g oup 26.3 (3.5), ea ly p esymp oma ic g oup 29.0 (2.9). No signi ican di e ences we e seen be ween he o he p esymp oma ic g oups and con ols. 3.1.3. Pheno ypic analysis All pheno ypic g oups [b FTD (19.6 {6.3}), PPA (22.0 {6.4}) and an FTD-ALS/ALS g oup (18.4 {8.1})] we e signi ican ly impai ed on he FER es compa ed wi h con ols, wi h no signi ican di e ences be ween any o he clinical synd omes (Table S6 and Table S7). 3.1.4. Imaging analysis In C9o 72 mu a ion ca ie s, FER es sco e was posi i ely associa ed wi h bila e al insula in ol emen , as well as a o- phy in he le on al lobe (middle on al gy us and o bi o- on al co ex), le basal ganglia (pu amen and cauda e) and igh amygdala (Table S8,Fig. 2). Fo he GRN mu a ion ca ie s, pe o mance was posi i ely co ela ed wi h a le hemisphe e p edominan ne wo k o a eas in ol ing he insula, on al lobe, in e omedial empo al lobe, cingula e, basal ganglia (pu amen and cauda e) and halamus (Table S8,Fig. 2). In he MAPT mu a ion g oup FER es sco e posi i ely co ela ed wi h wo small clus e s, one in he le basal ganglia and one in he le o bi o on al co ex when co ec ing o mul iple compa isons. A an unco ec ed p alue o <.001, he e was also an associa ion wi h he le insula and co ex 133 (2020) 384e398388 Fig. 1 eFacial Emo ion Recogni ion es sco es in each g oup. Signi ican di e ences om con ols and wi hin each gene ic g oup a e s a ed. Di e ences ac oss gene ic g oups a e no shown. Fig. 2 eNeu al co ela es o pe o mance on he Facial Emo ion Recogni ion es . Resul s o C9o 72 and GRN g oups a e shown a p<.05, co ec ed o Family Wise E o whils he esul s o he MAPT g oup a e shown a p<.001 unco ec ed (wi h he egions ci cled ha a e signi ican a p<.05 co ec ed o Family Wise E o ). Resul s a e shown on a s udy-speci ic T1-weigh ed MRI empla e in MNI space. Colou ba s ep esen T- alues. co ex 133 (2020) 384e398 389 in e omedial empo al lobe as well as bila e al supe io on al and o bi o on al egions (Table S8,Fig. 2). 3.1.5. Subanalysis o pe o mance on indi idual emo ions Iden i ica ion o nega i e emo ions ( ea , ange , sadness and disgus ) was in gene al wo se han he ecogni ion o posi i e ones (happiness and su p ise) in each o he g oups (including con ols). In almos all o he emo ions, he symp oma ic g oups sco ed wo se han con ols (Table 1,Fig. 3). Only in he symp oma ic MAPT mu a ion g oup o happiness and ea was he e no signi ican di e ence. In he p esymp oma ic g oups, he C9o 72 la e p esymp- oma ic g oup sco ed signi ican ly lowe han con ols on bo h ea and sadness, bu no on he o he emo ions (Fig. 3). No o he signi ican di e ences we e seen in he p esymp oma ic g oups compa ed wi h con ols. 3.2. Expe imen 2: aux pas (FP) ecogni ion es 3.2.1. Heal hy con ols As he FP ecogni ion es was pe o med in eigh di e en language e sions, we ini ially compa ed he pe o mance in con ols ac oss hese language g oups (Table S9). Signi ican di e ences we e seen be ween he languages when adjus ing o age, sex and educa ion and he e o e language was used as a co a ia e in he analysis. FP ecogni ion es sco e co ela ed wi h age ( ho ¼.21, p<.001) (Table S10) and educa ion ( ho ¼.18, p¼.005) (Table S11) wi hin he con ols and he e was an e ec o sex (p¼.006): mean (s anda d de ia ion) sco e o e all in con ols was 35.1 (4.6), wi h a highe sco e o 35.7 (4.7) in emales (n ¼142), compa ed wi h 34.3 (4.7) in males (n ¼103). O e all, con ols sco ed be ween 19 and 40 ou o a o al possible sco e o 40, wi h cumula i e equency shown in Table S12. A cu -o sco e below he 5 h pe cen ile is commonly conside ed o be abno mal: o he FP ecogni ion es a sco e o below 26 would he e o e be conside ed ou side he no mal ange, wi h a sco e o 26 conside ed bo de line abno mal. We also compa ed pe o mance in con ols (n ¼245) ac oss he FER and FP ecogni ion es s, whe e he e was a signi ican bu weak co ela ion: ho ¼.20, p¼.002. 3.2.2. Mu a ion ca ie s All o he h ee symp oma ic mu a ion ca ie g oups sco ed signi ican ly lowe on he FP ecogni ion es compa ed wi h con ols (Table 1,Table S13,Fig. 4): C9o 72 22.0 (9.9), GRN 18.7 (12.2) and MAPT 29.2 (7.0), wi h signi ican ly wo se pe o - mance in he C9o 72 and GRN g oups compa ed wi h he MAPT g oup. Wi hin each gene ic g oup, sco es we e signi ican ly lowe in he symp oma ic g oup compa ed wi h bo h he ea ly and la e p esymp oma ic g oups (Table 1,Table S13,Fig. 4). No signi ican di e ences we e seen be ween any o he p esymp oma ic g oups and con ols. 3.2.3. Pheno ypic analysis All pheno ypic g oups [b FTD (23.1 {10.0}), PPA (21.8 {14.6}) and an FTD-ALS/ALS g oup (21.1 {12.1})] we e signi ican ly impai ed on he FP ecogni ion es compa ed wi h con ols, wi h no signi ican di e ences be ween any o he clinical synd omes (Table S14 and Table S15). 3.2.4. Imaging analysis In he C9o 72 mu a ion ca ie s, FP ecogni ion es sco e was posi i ely co ela ed wi h g ey ma e densi y in he le su- pe io on al gy us, middle empo al gy us, p ecuneus and lingual gy us, as well as he insula and empo al lobe in he igh hemisphe e (Table S16,Fig. 5). Fo he GRN mu a ion ca ie s, pe o mance on he FP ask was posi i ely co ela ed wi h g ey ma e densi y in a p e- dominan ly le -sided ne wo k o egions including he basal ganglia, on al lobe (o bi o on al co ex, supe io and in e- io on al gy i), insula, and empo al lobe (bo h medial i.e. amygdala and hippocampus, and o he egions). In he MAPT mu a ion ca ie s, he e we e no signi ican co ela ions when co ec ed o mul iple compa isons. A an unco ec ed p- alue <.001, FP ecogni ion es sco e was associa ed wi h a ophy in he le basal ganglia and le mo e han igh o bi o on al co ex mainly. 4. Discussion In his s udy we ha e demons a ed ha bo h he FER and FP ecogni ion es s a e able o de ec social cogni ion de ici s in amilial o ms o FTD du ing he symp oma ic pe iod, bu only he FER es was able o de ec p esymp oma ic de ici s (pa icula ly in he nega i e emo ions o ea and sadness), speci ically wi hin C9o 72 expansion ca ie s in p oximi y o symp om onse . Neu al co ela es a ied ac oss he di e en gene ic g oups wi h a le hemisphe e p edominan basal ganglia-o bi o on al-insula ne wo k implica ed ac oss all h ee gene ic g oups on bo h asks, excep in he C9o 72 g oup on he FP ecogni ion es . In es iga ion o mu a ion-nega i e membe s o amilies wi hin he GENFI coho has allowed us o s udy he pe o - mance o he mini-SEA in a la ge heal hy con ol popula ion han p e iously, gene a ing no ma i e da a ac oss age, sex and educa ion ha can be used in o he s udies. We show a signi ican decline in pe o mance wi h age wi h he heo y o mind ask consis en wi h he p e ious li e a u e (Maylo , Moulson, Munce , &Taylo , 2002;Pa dini &Nichelli, 2009; Wang &Su, 2006). P io s udies ha e also shown an age- ela ed decline in emo ion p ocessing (Mill, Allik, Realo, & Valk, 2009;Sulli an, Ru man, &Hu on, 2007, pp. P53eP60; Wes e al., 2012), al hough in ou s udy he co ela ion was weak wi h only a end o signi icance (p¼.063). A simila pa e n was shown in he co ela ion wi h educa ion (wo se sco e wi h less yea s o educa ion) wi h a weak bu signi ican co ela ion on he FP ecogni ion es and only a end o sig- ni icance in he FER es . Clea e di e ences we e seen when co ex 133 (2020) 384e398390 Fig. 3 eFacial Emo ion Recogni ion es indi idual emo ion subsco es, shown as a pe cen age o he mean con ol sco e. Signi ican di e ences om con ols a e shown wi h a s a a he op o he ba . Di e ences wi hin each gene ic g oup a e shown wi h a b acke and s a . Di e ences ac oss gene ic g oups a e no shown. co ex 133 (2020) 384e398 391 Fig. 4 eFaux Pas ecogni ion es sco es in each g oup. Signi ican di e ences om con ols and wi hin each gene ic g oup a e s a ed. Di e ences ac oss gene ic g oups a e no shown. Fig. 5 eNeu al co ela es o pe o mance on he Faux Pas ecogni ion es . Resul s o C9o 72 and GRN g oups a e shown a p<.05, co ec ed o Family Wise E o whils he esul s o he MAPT g oup a e shown a p<.001 unco ec ed. Resul s a e shown on a s udy-speci ic T1-weigh ed MRI empla e in MNI space. Colou ba s ep esen T- alues. co ex 133 (2020) 384e398392