Disease-related cortical thinning in presymptomatic granulin mutation carriers

Neu oImage: Clinical 29 (2021) 102540 A ailable online 29 Decembe 2020 2213-1582/© 2020 The Au ho s. Published by Else ie Inc. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/). Disease- ela ed co ical hinning in p esymp oma ic g anulin mu a ion ca ie s Se gi Bo ego-´ Ecija a , 1 , Rose Sala-Llonch b , 1 , John an Swie en c , Ba ba a Bo oni d , Fe mín Mo eno e , Ma io Masellis , Ca mela Ta aglia g , Ca oline G a h , Daniela Galimbe i i , j , Robe La o ce J k , James B Rowe l , Elizabe h Finge m , Rik Vandenbe ghe n , Fab izio Taglia ini o , Alexand e de Mendonça p , Isabel San ana q , Ma his Syno zik , s , Simon Ducha me , u , Johannes Le in , w , x , Ad ian Danek , Alex Ge ha d y , Ma kus O o z , Ch is Bu le aa , Gio anni F isoni bb , cc , Sand o So bi dd , ee , Ca olin Helle , Ma ina Bocche a , Da id M Cash , Rhian S Con e y , Ka ina M Moo e , Jona han D Roh e , Raquel Sanchez-Valle a , b , * , on behal o he Gene ic FTD Ini ia i e GENFI a Alzheime ’s disease and O he Cogni i e Diso de s Uni , Neu ology Se ice, Hospi al Clinic, Ins i u d’In es igacions Biom` ediques Augus Pi I Sunye , Ba celona, Spain b Depa amen de Biomedicina, Ins i u e o Neu oscience, Uni e si y o Ba celona, Ins i u e o Biomedical Resea ch Augus Pi i Sunye (IDIBAPS), Biomedical Resea ch Ne wo king Cen e in Bioenginee ing, Bioma e ials and Nanomedicine (CIBER-BBN), Spain c Depa men o Neu ology, E asmus Medical Cen e, Ro e dam, Ne he lands d 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 e 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 LC Campbell Cogni i e Neu ology Resea ch Uni , Sunnyb ook Resea ch Ins i u e, Uni e si y o To on o, To on o, On a io, Canada g To on o Wes e n Hospi al, Tanz Cen e o Resea ch in Neu odegene a i e Diseases, Uni e si y o To on o, To on o, On a io, Canada h Depa men o Ge ia ic Medicine, Ka olinska Uni e si y Hospi al-Huddinge, S ockholm, Sweden i Biomedical, Su gical and Den al Sciences, Uni e si y o Milan, Cen o Dino Fe a i, Milan, I aly j Fondazione IRCCS Ca’ G anda, Ospedale Policlinico, Neu odegene a i e Diseases Uni , Milan, I aly k Clinique In e disciplinai e de M´ emoi e, D´ epa emen des Sciences Neu ologiques, Uni e si ´ e La al, Qu´ ebec, Canada l Depa men o Clinical Neu osciences and Medical Resea ch Council, Cogni ion and B ain Sciences Uni , Uni e si y o Camb idge, Camb idge, Uni ed Kingdom m Depa men o Clinical Neu ological Sciences, Uni e si y o Wes e n On a io, London, On a io, Canada n Labo a o y o Cogni i e Neu ology, Depa men o Neu osciences, KU Leu en, Leu en, Belgium o 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 p Facul y o Medicine, Uni e si y o Lisbon, Lisbon, Po ugal q Facul y o Medicine, Uni e si y o Coimb a, Coimb a, Po ugal 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 Tübingen, Tübingen, Ge many s Ge man Cen e o Neu odegene a i e Diseases (DZNE), Tübingen, Ge many Depa men o Psychia y, McGill Uni e si y Heal h Cen e, McGill Uni e si y, Mon eal, Qu´ ebec, Canada u McConnell B ain Imaging Cen e, Mon eal Neu ological Ins i u , McGill Uni e si y, Mon eal, Qu´ ebec, Canada Depa men o Neu ology, Ludwig-Maximilians-Uni e si y, Munich, Ge many w Ge man Cen e o Neu odegene a i e Diseases (DZNE), Si e Munich, Munich, Ge many x SyNe gy, Munich Clus e o Sys ems Neu ology, Munich, Ge many y Facul y o Medical and Human Sciences, Ins i u e o B ain, Beha iou and Men al Heal h, Uni e si y o Manches e , Manches e , UK z Depa men o Neu ology, Uni e si y o Ulm, Ulm, Ge many aa Depa men o Clinical Neu ology, Uni e si y o Ox o d, Ox o d, Uni ed Kingdom bb Is i u o di Rico e o e Cu a a Ca a e e Scien i ico (IRCCS) Is i u o Cen o San Gio anni di Dio Fa ebene a elli, B escia, I aly cc Memo y Clinic LANVIE-Labo a o y o Neu oimaging o Aging, Uni e si y Hospi als and Uni e si y o Gene a, Gene a, Swi ze land dd Depa men o Neu oscience, Psychology, D ug Resea ch, and Child Heal h, Uni e si y o Flo ence, Flo ence, I aly ee Is i u o di Rico e o e Cu a a Ca a e e Scien i ico (IRCCS) Don Ca lo Gnocchi, Flo ence, I aly Demen ia Resea ch Cen e, Depa men o Neu odegene a i e Disease, Queen Squa e UCL Ins i u e o Neu ology, London, UK * Co esponding au ho a : Alzheime ’s disease and o he cogni i e diso de s Uni , Hospi al Clinic, Ins i u d’In es igacions Biom` ediques Augus Pi I Sunye (IDIBAPS), Uni e si y o Ba celona, Villa oel, 170 08036 Ba celona, Spain. E-mail add ess: [email p o ec ed] (R. Sanchez-Valle). 1 These au ho s con ibu ed equally. Con en s lis s a ailable a ScienceDi ec Neu oImage: Clinical jou nal homepage: www.else ie .com/loca e/ynicl h ps://doi.o g/10.1016/j.nicl.2020.102540 Recei ed 23 June 2020; Recei ed in e ised o m 14 Decembe 2020; Accep ed 15 Decembe 2020 Neu oImage: Clinical 29 (2021) 102540 2 ARTICLE INFO Keywo ds: F on o empo al demen ia Co ical hickness GRN P esymp oma ic Gene ic mu a ions ABSTRACT Mu a ions in he g anulin gene (GRN) cause amilial on o empo al demen ia. Unde s anding he s uc u al b ain changes in p esymp oma ic GRN ca ie s would en o ce he use o neu oimaging bioma ke s o ea ly diagnosis and moni o ing. We s udied 100 p esymp oma ic GRN mu a ion ca ie s and 94 nonca ie s om he Gene ic F on o empo al demen ia ini ia i e (GENFI), wi h MRI s uc u al images. We analyzed 3T MRI s uc u al images using he F eeSu e pipeline o calcula e he whole b ain co ical hickness (CTh) o each subjec . We also pe o m a e ex-wise gene al linea model o assess di e ences be ween g oups in he ela ionship be ween CTh and di e se co a iables as gende , age, he es ima ed yea s o onse and educa ion. We also explo ed di e ences acco ding o TMEM106B geno ype, a possible disease modi ie . Whole b ain CTh did no di e be ween ca ie s and nonca ie s. Bo h g oups showed age- ela ed co ical hinning. The g oup-by-age in e ac ion analysis showed ha his age- ela ed co ical hinning was signi ican ly g ea e in GRN ca ie s in he le supe io on al co ex. TMEM106B did no signi ican ly in luence he age- ela ed co ical hinning. Ou esul s alida e and expand p e ious indings sugges ing an inc eased CTh loss associa ed wi h age and es ima ed p oximi y o symp oms onse in GRN ca ie s, e en be o e he disease onse . 1. In oduc ion F on o empo al demen ia (FTD) is a clinically, gene ically and pa hologically he e ogeneous g oup o neu odegene a i e diseases cha ac e ized by beha io al and language impai men . FTD is a highly he i able diso de , wi h mu a ions in se e al genes causing gene ic o ms o he disease. Mu a ions in he p og anulin (GRN) gene we e iden i ied in 2006 as a cause o amilial FTD wi h TAR-DNA binding p o ein 43 (TDP-43) inclusions (Bake e al., 2006; C u s e al., 2006). The p e alence o GRN mu a ions has been es ima ed a 6% o all FTD pa ien s and 20% o amilial FTD (C u s and Van B oeckho en, 2008). The majo i y o FTD due o GRN mu a ions pa ien s p esen a beha io al a ian FTD, non- luen p ima y p og essi e aphasia o co icobasal synd ome (Moo e e al., 2019). In 2010, a genome-wide associa ion s udy e ealed ansmemb ane p o ein 106B (TMEM106B) gene as a isk ac o o FTD wi h TDP-43 inclusions (Van Dee lin e al., 2010). Fu he s udies had eplica ed hese indings, showing an ex emely low p esence o he TMEM106B mino allele in homozygosis in GRN pa ien s, indica ing ha indi iduals who a e homozygous o he mino TMEM106B allele a e less likely o de elop symp oms (Finch e al., 2011; Nicholson and Rademake s, 2016). P e ious wo k using s uc u al MRI e ealed ha symp oma ic GRN mu a ion ca ie s ypically show a widesp ead bu asymme ic pa e n o g ey ma e (GM) loss, a ec ing on al, empo al and pa ie al lobes (Beck e al., 2008; Fumagalli e al., 2018; Whi well e al., 2009). S udies in p esymp oma ic GRN mu a ions ca ie s ha e shown di e gen e- sul s, wi h many o hem epo ing no signi ican b ain s uc u al di - e ences compa ed wi h nonca ie s (Bo oni e al., 2012, 2008; Ca oppo e al., 2015; Cash e al., 2018; Olm e al., 2018; Panman e al., 2019; Pie ani e al., 2014; Roh e e al., 2015). TMEM106B a ian s ha e also been s udied in he gene al popula ion using neu oimaging, wi h he isk allele being ela ed o educed olume o he le empo al lobe in non-demen ed subjec s (Adams e al., 2014). In his line, and complemen ing he s uc u al indings, P emi e . al. used unc ional MRI and ound ha , in GRN ca ie s, he TMEM106B isk haplo ype was associa ed wi h dec eased unc ional connec i i y in he le on opa - ie al ne wo k (P emi e al., 2014). In a p e ious c oss-sec ional s udy wi h a limi ed numbe o subjec s, we obse ed ha p esymp oma ic GRN mu a ion ca ie s p esen ed g ea e loss o co ical hickness (CTh) by age in empo al a eas compa ed o nonca ie s (Mo eno e al., 2013). He e, we aimed o expand hese p e ious indings by in es iga ing he change in CTh in a much la ge coho o p esymp oma ic mu a ion ca ie s using da a om he Gene ic F on o empo al Demen ia Ini ia i e (GENFI). We also aimed o in es iga e he po en ial in luence o he TMEM106B geno ype in he g ey ma e loss in GRN ca ie s. 2. Me hods 2.1. Pa icipan s We analyzed c oss-sec ional da a om he GENFI s udy (Roh e e al., 2015), Da a F eeze 3. The GENFI coho includes subjec s a isk o gene ic FTD, om cen es ac oss Eu ope and Canada (h ps://www. gen i.o g/). Subjec s in he coho unde go a s anda dized clinical and neu opsychological assessmen as well as an MRI exam once a yea (Roh e e al., 2013). Ou wo k included he baseline da a om 100 p esymp oma ic mu a ion ca ie s and 94 nonca ie s om 54 di e en amilies. Fo each subjec , sex, age, es ima ed yea s o onse (EYO) and educa ion we e ob ained om he GENFI da abase. The EYO was compu ed conside ing he di e ence be ween he subjec ’s age and he a e age amilial age o symp om onse . Asymp oma ic s a us was asce ained based on ela i e’s in e iew, neu ological examina ion and no mali y on beha io al scales and neu opsychological es s. Local e hics commi ees a each si e app o ed he s udy and all pa icipan s p o ided w i en in o med consen . 2.2. TMEM106B gene ic analysis TMEM106B s1990622 (C/T) single nucleo ide polymo phism was pe o med acco ding o s anda d p ocedu es (P emi e al., 2014) in 90 subjec s: 46 p esymp oma ic GRN ca ie s and 44 nonca ie s. 2.3. Demog aphic and clinical s a is ical analysis Di e ences in he clinical and demog aphic da a be ween ca ie s and p esymp oma ic ca ie s we e assessed using - es o con inuous a iables and chi-squa ed es was used o dicho omous da a. Di e - ences in demog aphics be ween TMEM106B geno ypes we e assessed wi h non-pa ame ic es s (Fishe Tes o dicho omous da a and K uskall-Wallis Tes o con inuous da a). 2.4. Image acquisi ion and p ocessing Pa icipan s unde wen a 1.1-mm iso opic esolu ion olume ic T1 MR imaging on a 3 T using he sequences de ined wi hin he GENFI conso ium. MRI images o all subjec s we e downloaded om GENFI da abase and p ocessed using F eeSu e e sion 6.0 (h p://su e .nm .mgh.ha a d.edu/), wi h he main goal o compu ing indi idual CTh su ace maps. B ie ly, he F eeSu e pipeline includes skull s ipping (S´ egonne e al., 2004), segmen a ion o he subco ical whi e ma e and deep g ay ma e olume ic s uc u es (Fischl e al., 2004, 2002), essella ion o bounda ies, and de ini ion o he ansi ion be ween issue classes. Then, CTh is calcula ed as he closes dis ance om he g ay/whi e bounda y o he g ay/ce eb ospinal luid bounda y a each e ex (Dale e al., S. Bo ego-´ Ecija e al. Neu oImage: Clinical 29 (2021) 102540 3 1999; Fischl and Dale, 2000). Indi idual CTh maps we e isually inspec ed o de ec and co ec p ocessing e o s. F om an ini ial sample o 114 p esymp oma ic mu- a ion ca ie s and 101 nonca ie s, 21 subjec s we e excluded due o bad econs uc ion o o he F eeSu e p ocessing e o s, esul ing in he inal sample o 100 p esymp oma ic ca ie s and 94 nonca ie s. Su ace maps we e egis e ed o he s anda d a e age space and smoo hed wi h a Full Wid h a Hal Maximum (FWHM) o 15 mm. 2.5. Image-based s a is ics We i s ob ained whole b ain CTh o each subjec , calcula ed as he a e age CTh ac oss all e ices (i.e., weigh ed a e age be ween he wo hemisphe es). This measu e was co ela ed using Pea son’s coe icien wi h age o in es iga e global age- ela ed ajec o ies in he wo g oups. Linea and non-linea eg ession models we e explo ed in he whole g oup as showed in he Supplemen a y ma e ial o de e mine he asso- cia ion be ween he whole CTh and age (Supplemen a y ma e ial). Due he lack o di e ence be ween linea and non-linea models, we used e ex-wise gene al linea models as implemen ed in F eeSu e o es di e ences be ween ca ie s and nonca ie s as well as in e ac ion wi h age a he egional le el. We added sex, educa ion and he scanne used as co a ia es. Homoscedas ici y o he samples we e assessed by he Non-Cons an Va iance Tes . In addi ion o ch onological age, we also assessed he e ec on CTh o he EYO. All maps we e co ec ed o mul iple compa isons using p ecompu ed Mon e Ca lo pe mu a ions wi h a signi icance h eshold o p <0.05 ( o bo h h esholding and clus e signi icance), as implemen ed in F eesu e . To s udy whe he he e we e di e ences in asymp oma ic ca ie s as hey app oached he p edic ed symp oms onse , we epea ed he g oup compa ison analysis (i.e., ca ie s s non-ca ie s) using only he sub- g oup o subjec s ha we e close o he disease onse (i.e. hose wi h EYO >-10 yea s). Finally, we epea ed he mul iple linea eg ession adding he TMEM106B geno ype as co a iable. Fo his analysis, we assess he ROIs ound signi ican di e en in he p e ious analyses. 3. Resul s 3.1. Demog aphic and gene ic esul s The demog aphic and gene ic da a o he 194 subjec s a e desc ibed in Table 1. The mean age a onse o he 54 di e en amilies included was 60.1 yea s ( ange 43 – 74.5 yea s). The e we e no di e ences in age, EYO, sex o educa ion be ween g oups. On a e age, p esymp oma ic mu a ion ca ie s p esen ed an EYO o −13.0 yea s. No signi ican di - e ences we e ound in TMEM106B haplo ypes be ween g oups. In bo h g oups, he homozygosi y o he p o ec i e geno ype (C/C) we e a e (6.8% in nonca ie s ca ie s and 6.2% in p esymp oma ic ca ie s). No di e ences in gende , age, EYO o educa ion we e ound be ween he di e en TMEM106B geno ypes. 3.2. G oup di e ences in co ical hickness The e we e no di e ences in CTh a he g oup le el when compa ing p esymp oma ic mu a ion ca ie s and nonca ie s g oups, nei he wi h global measu es no wi h e ex-wise analyses. We hypo hesized ha his lack o di e ence migh be consequence o he inclusion o subjec s a om he p edic ed age a onse , and we also pe o med he whole- b ain e ex-wise analysis be ween ca ie s and nonca ie s in he sub- g oup o subjec s nea es o he expec ed onse (EYO >-10), bu no signi ican di e ences a ose. 3.3. Co ela ion be ween co ical hickness and age When we e alua ed he CTh co ela ion wi h age a he whole-b ain le el, bo h p esymp oma ic mu a ion ca ie s and nonca ie s showed a pa e n o co ical hinning associa ed wi h age ( = − 0.59 s = − 0.53, bo h signi ican wi h p <0.001), bu no signi ican di e ences we e obse ed di e ences be ween hem a he whole b ain le el (p =0.272) (Fig. 1). 3.4. Ve ex-wise gene al linea models When compa ing ca ie s and nonca ie s a he e ex-wise le el wi h an in e ac ion model, we iden i ied a clus e wi h signi ican esul s (co ec ed p <0.05) in he le supe io on al co ex (Fig. 2A). Age, gende , educa ion and scanne we e included as co a ia es. When s udying he ajec o ies sepa a ely o each g oup wi hin he signi ican ROI, we ound ha p esymp oma ic ca ie s showed a signi ican nega i e co ela ion be ween age and CTh ( = − 0.57, p <0.001), while nonca ie s did no ( = − 0.12, p =0.265) (Fig. 2B). Addi ionally, we pe o med a mul iple linea eg ession model wi hin he ROI o quan i y he e ec o age educa ion and gende in o his esul . Only Age and Age ×g oup in e ac ion we e signi ican (p <0.001, see Table 2). 3.5. Co ela ions be ween co ical hickness and EYO Due o he p esence o di e en GRN mu a ions ha may p esen di e en ages o onse , we epea ed he in e ac ion analysis using EYO ins ead o ac ual age. We iden i ied a clus e wi h signi ican di e ences be ween ca ie s and nonca ie s (co ec ed p <0.05) co e ing he igh empo al co ex, he banks o supe io empo al sulcus, he in e i- o pa ie al and he sup ama ginal gy us. I is no iceable ha hese e- gions also appea ed in he analysis wi h age, howe e hey did no su i e mul iple compa isons. Again, we pe o med mul iple linea eg ession models o p edic he ROI-CTh o hese a eas conside ing EYO (ins ead he age), we ound simila esul s, wi h p esymp oma ic ca ie s p esen ing signi ican highe CTh loss by age han nonca ie s (p < 0.01). Fig. 3 shows he co ela ion be ween CTh and EYO in bo h g oups. ( = − 0.65 o ca ie s s = − 0.33 o nonca ei s, p <0.01) (Fig. 3). 3.6. In luence o he TMEM106B geno ype in he CTh – Age ela ionship We did no ind signi ican esul s a he e ex-wise le el o he TMEM106B analyses o any o he compa isons es ed. The e o e, we pe o med a hypo hesis-d i en s udy by ocusing on he egion ha esul ed signi ican in he age ×g oup in e ac ion. We di ided he GRN ca ie s in g oups acco ding hei TMEM106B geno ype we ound a signi ican nega i e co ela ion in he T/C ca ie s ( = − 0.52, p <0.01) and he T/T ca ie s ( = − 0.47, p <0.05), bu no in he h ee subjec s wi h he C/C geno ype ( =–0.365, p =0.762; Fig. 4). Only he co e- la ion o he T/C ca ie s was signi ican and showed s a is ical Table 1 Demog aphic cha ac e is ics and TMEM106B geno ype. EYO: Es ima ed Yea s o Onse , SD: s anda d de ia ion; ns: no signi ican , TMEM106B: ansmemb ane p o ein 106B. Nonca ie s n =94 GRN p esymp oma ic ca ie s n =100 G oup di e ences p alue Age, yea s mean (SD) 47.5 (13.2) 46.8 (12.2) 0.595 EYO, yea s mean (SD) −13.2 (14.9) −13.0 (12.2) 0.967 Sex male/ emale 51/43 65/35 0.141 Educa ion, yea s mean (SD) 14.2 (3.8) 14.6 (3.6) 0.658 TMEM106B ( s1990622) n ¼44 n ¼46 C/C (%) 3 (6.8%) 3 (6.5%) 0.889 C/T (%) 27 (61.4%) 26 (56.5%) T/T (%) 14 (31.8%) 17 (37.0%) S. Bo ego-´ Ecija e al. Neu oImage: Clinical 29 (2021) 102540 4 di e ences wi h he nonca ie s g oup (p <0.05). When we added he TMEM106B geno ype as co a ia e o he mul iple linea eg ession analysis we did no ind any in luence o his o e he CTh, nei he o p esymp oma ic ca ie s no he nonca ie s. 4. Discussion In his s udy, we used da a om he GENFI coho o e alua e CTh in p esymp oma ic GRN mu a ion ca ie s. Al hough we did no ind di - e ences be ween ca ie s and nonca ie s a he g oup-wise compa ison, we ound di e ences in he in luence o aging and es ima ed yea s o onse in CTh, sugges ing a g ea e co ical loss in p esymp oma ic ca - ie s as hey app oach he clinical onse . Se e al c oss-sec ional and longi udinal s udies ha e e alua ed GM loss in p esymp oma ic GRN mu a ion ca ie s wi h di e en me hod- ologies, wi h pa ially di e gen esul s. Ou s udy, as mos p e ious c oss-sec ional s udies using s uc u al MRI, did no ind g ay ma e co ical hickness di e ences be ween p esym oma ic GRN mu a ion ca ie s and con ols (Bo oni e al., 2012, 2008; Ca oppo e al., 2015; Cash e al., 2018; Doppe e al., 2013; Fumagalli e al., 2018; Mo eno e al., 2013; Panman e al., 2019). By con as , ew s udies ound g ay ma e a ophy pa e n in p esymp oma ic ca ie s: Pie ani and col- leagues ound g ea e GM loss in on al a eas, (Pie ani e al., 2014) while Roh e e . al. ound signi ican di e ences be ween ca ie s and Fig. 1. Sca e plo showing co ela ion be ween whole CTh and age in p esymp oma ic GRN ca ie s ( ed) and nonca ie s (blue). No s a is ical di e ences be ween ajec o ies we e ound. CTh: Co ical Thickness. (Fo in e p e a ion o he e e ences o colou in his igu e legend, he eade is e e ed o he web e sion o his a icle.) Fig. 2. Rela ionship be ween CTh and age in he selec ed a ea o he co ex whe e signi ican di e ences be ween ca ie s and nonca ie s whe e ound: A) B ain maps showing he a ea wi h s a is ical di e ences be ween p esymp oma ic ca ie s and nonca ie s (p <0.05). B) Sca e plo showing ela ionship be ween CTh and age in p esymp oma ic GRN ca ie s ( ed) and nonca ie s (blue) in he selec ed a ea. Lines ep esen es ima ed linea eg ession models o bo h g oups. (Fo in e p e a ion o he e e ences o colou in his igu e legend, he eade is e e ed o he web e sion o his a icle.) Table 2 Mul iple linea eg ession model o p edic CTh based on he p esence o GRN mu a ion (p esymp oma ic ca ie s s nonca ie s) and age. Sex and educa ion we e added as co a ia es. β (95% CI) alue p alue In e cep 3.021 (2.857, 3.185) 36.82 <0.001 GRN Nonca ie s s ca ie s 0.019 (−0.025, 0.063) 0.85 0.393 Age (yea s) −0.008 (−0.010, −0.005 −6.03 <0.001 Educa ion (yea s) 0.050 (−0.001, 0.011) 1.68 0.094 Gende Male s emale −0.001 (−0.046, 0.043) −0–05 0.956 Age ×GRN 0.006 (0.003, 0.010) 3.50 <0.001 S. Bo ego-´ Ecija e al. Neu oImage: Clinical 29 (2021) 102540 5 nonca ie s in he insula 15 yea s be o e he expec ed onse , and in he empo al and pa ie al lobes 10 yea s be o e he expec ed onse (Roh e e al., 2015). These disc epancies in he quan i ica ion o GM loss in p esymp oma ic GRN mu a ion ca ie s di e om he ex ensi e GM a ophy obse ed in symp oma ic mu a ion ca ie s, e en wi h a isual inspec ion. Se e al explana ions ha e been p oposed o explain his di e gence o esul s. Fi s , in a g oup c oss-sec ional compa ison, sub- jec s a om symp om onse a e mixed wi h subjec s close o disease onse ; i CTh loss in GRN mu a ion ca ie s accele a es a ound he ime o symp oms onse , mixing subjec s a di e en in e als om symp om onse could cancel any appa en di e ences wi h nonca ie s. In addi- ion, he asymme ic pa e n o a ophy in GRN mu a ion ca ie s migh limi he di e ences in g oup-wise neu oimaging analyses. In a p e ious s udy, in a sample o 13 p esymp oma ic GRN mu a ion ca ie s we obse ed ha p esymp oma ic ca ie s p esen ed g ea e age- ela ed co ical hinning in he empo al a eas when compa ed wi h con ols (Mo eno e al., 2013). In he p esen s udy, we expand hese p e ious esul s in a much la ge coho o subjec s a isk o FTD due o mu a ions in GRN. We ound ha bo h, p esymp oma ic GRN ca ie s and nonca ie s showed a nega i e co ela ion o hei CTh wi h age, wi h olde subjec s p esen ing lesse CTh. Wi h he in e ac ion analysis, we ound a g oup-by-age e ec in he le supe io on al co ex. In addi ion, he esul s o he mul iple linea model o ou s udy showed ha , in his a ea, he p esymp oma ic ca ie s showed signi ican ly g ea e loss o CTh wi h age han nonca ie s. I migh sugges ha p esym oma ic GRN ca ie s su e a g ea e neu onal loss in his a ea due o neu odegene a ion a he han no mal aging. This is an a ea pa icula ly a ec ed in symp oma ic pa ien s (Cash e al., 2018) ha ha e also been ound o ha e inc eased a es o a ophy in longi udinal s udies wi h p esymp oma ic ca ie s (Ca oppo e al., 2015; Chen e al., 2019). Recen wo k sugges s ha EYO has limi ed alue in GRN amilies, due o a weak co ela ion be ween he indi idual age a onse and amily age a onse (Moo e e al., 2019) bu be e p edic i e ma ke s o he disease age o onse a e s ill lacking. Thus, as he p esen sample in- cludes di e en GRN mu a ions, we also in es iga e he e ec o EYO in Fig. 3. Rela ionship be ween CTh and EYO: (A) B ain maps showing a eas wi h s a is ical di e ences be ween ca ie s and nonca ie s. B) Sca e plo illus a es he ela ionship be ween CTh and EYO in ca ie s and nonca ie s. The X-axis ep esen s he EYO. The Y-axis ep esen s he mean CTh o he ROI co e ing all a eas wi h signi ican di e ences be ween ca ie s and nonca ie s. CTh: Co ical Thickness; EYO: es ima ed yea s o onse ; ROI: Region o In e es . Fig. 4. Sca e plo showing ela ionship be ween CTh and age in GRN ca ie s acco ding hei TMEM106B geno ype and nonca ie s in he le supe io on- al co ex. S. Bo ego-´ Ecija e al. Neu oImage: Clinical 29 (2021) 102540 6 CTh in addi ion o he e ec o he ch onological age. When we s udy he co ela ion be ween CTh alues and EYO, we ound signi ican di e - ences be ween p esymp oma ic GRN ca ie s and nonca ie s in he igh sup ama ginal gy us and he banks o he igh supe io empo al sulcus, simila o he a ea ound in a p e ious wo k using only subjec s wi h he same GRN mu a ion (Mo eno e al., 2013) and hus, ch ono- logical age was in e changeable wi h EYO. E en i he localiza ion o he signi ican clus e s we e no he same when EYO was used in he in e ac ion analysis ins ead o age, we belie e ha bo h he do so- on al and he sup ama ginal/ empo al gy us a eas a e impo an in he disease, as hey bo h appea a he unco ec ed le el. Howe e , he ac ha he magni ude o he e ec s is small he inclusion o a la ge numbe o co a ia es migh hide some esul s when we co ec ed o mul iple compa isons. Va ian s in he TMEM106B gene ha e been hypo hesized o be a gene ic modula o o isk o GRN ca ie s. P e ious wo ks sugges s ha TMEM106B mino allele in homozygosis (C/C in s1990622) is p o ec- i e o migh delay he onse in indi iduals wi h pa hogenic GRN mu- a ions. On his basis, we e alua e he in luence o he TMEM106B geno ype in ou esul s. Despi e he ac ha we did no ind di e ences be ween he di e en TMEM106B geno ypes, we ound a end sug- ges ing ha C/C ca ie s migh p esen a lowe loss o CTh by age han he T/C and T/T ca ie s in he le supe io on al co ex. The absence o s a is ical di e ences in hese analyses may be consequence o he small sample o subjec s ca ying he C/C geno ype in ou se ies. This would be in consonance wi h p e ious wo ks wi h unc ional MRI ha ound dec eased b ain connec i i y wi hin he middle on al gy us and he le on opa ie al ne wo k in GRN ca ie s wi h he isk TMEM106B allele in on hose wi h he p o ec i e allele (P emi e al., 2014). The main s eng h o his s udy lies in he la ge sample o p e- symp oma ic subjec s ca ying mu a ions in GRN. We also acknowledge some limi a ions. Fi s , ou age- ela ed esul s a e based on c oss- sec ional a he han longi udinal da a. Al hough ou analysis sugges s a as e a ophy in p esymp oma ic ca ie s, u he s udies wi h longi- udinal da a a e needed o co obo a e his hypo hesis. Ano he limi a- ion is he ac ha ou s udy includes di e en GRN mu a ions which may p esen di e en ages a symp om onse , and EYO was used in some o he analysis o o e come his limi a ion. Finally, he TMEM106B haplo ype was no a ailable in all subjec s. This ac , combined wi h he low equency o he C/C haplo ype in ou se ies, limi he alidi y o s a is ical analysis pe o med o e alua e he in luence o he TMEM106B gene in GRN ca ie s. 5. Conclusions In conclusion, despi e no di e ences in CTh we e ound a he whole- g oup compa ison, he p oposed linea model showed ha p e- sym oma ic GRN ca ie s p esen a signi ican ly g ea e loss o CTh wi h age and p oximi y o expec ed disease onse . These indings sugges a as e p ocess o neu onal loss in ca ie s, suppo ing ha s uc u al neu oimaging migh be use ul o moni o he e ec o disease-modi ying he apies e en in p esymp oma ic phases o he disease. Role o he unding sou ce The unding sou ces ha e no ole in he design o his s udy, i s execu ion, analyses, in e p e a ion o he da a, o he decision o submi esul s. Decla a ion o Compe ing In e es The au ho s decla e ha hey ha e no known compe ing inancial in e es s o pe sonal ela ionships ha could ha e appea ed o in luence he wo k epo ed in his pape . Acknowledgmen s The au ho s hank all he olun ee s o hei pa icipa ion in his s udy. SBE is a ecipien o he Rio-Ho ega pos - esidency g an om he Ins i u o de Salud Ca los III, Spain. This s udy was pa ially unded by Fundaci´ o Ma a ´ o de TV3, Spain (g an no. 20143810 o RSV). The GENFI s udy has been suppo ed by he Medical Resea ch Council UK, he I alian Minis y o Heal h and he Canadian Ins i u es o Heal h Resea ch as pa o a Cen es o Excellence in Neu odegene a ion g an , as well as o he indi idual unding o in es iga o s. KM has ecei ed unding om an Alzheime ’s Socie y PhD s uden ship. JDR acknowl- edges suppo om he Na ional Ins i u e o Heal h Resea ch (NIHR) Queen Squa e Demen ia Biomedical Resea ch Uni and he Uni e si y College London Hospi als Biomedical Resea ch Cen e, he Leona d Wol son Expe imen al Neu ology Cen e, he UK Demen ia Resea ch Ins i u e, Alzheime ’s Resea ch UK, he B ain Resea ch T us and he Wol son Founda ion. JC S was suppo ed by he Dio aph e Founda ion g an 09-02-03-00, he Associa ion o F on o empo al Demen ias Resea ch G an 2009, The Ne he lands O ganiza ion o Scien i ic Resea ch (NWO) g an HCMI 056-13-018, ZonMw Memo abel (Del a- plan Demen ie, p ojec numbe 733 051 042), Alzheime Nede land and he Blue ield p ojec . CG ha e ecei ed unding om JPND-P e on als VR Dn 529-2014-7504, VR: 2015-02926, and 2018-02754, he Swed- ish FTD Ini ia i e-Sch¨ o ling Founda ion, Alzheime Founda ion, B ain Founda ion and S ockholm Coun y Council ALF. DG has ecei ed sup- po om he EU Join P og amme – Neu odegene a i e Disease Resea ch (JPND) and he I alian Minis y o Heal h (P eF on ALS) g an 733051042. JBR is unded by he Wellcome T us (103838) and he Na ional Ins i u e o Heal h Resea ch (NIHR) Camb idge Biomedical Resea ch Cen e. MM has ecei ed unding om a Canadian Ins i u es o Heal h Resea ch ope a ing g an and he Wes on B ain Ins i u e and On a io B ain Ins i u e. RV has ecei ed unding om he Mady B o- waeys Fund o Resea ch in o F on o empo al Demen ia. EF has ecei ed unding om a CIHR g an #327387. JDR is an MRC Clinician Scien is (MR/M008525/1) and has ecei ed unding om he NIHR Ra e Dis- eases T ansla ional Resea ch Collabo a ion (BRC149/NS/MH), he Blue ield P ojec and he Associa ion o F on o empo al Degene a ion. 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