Disrupted Rich Club Network in Behavioral Variant Frontotemporal Dementia and Early-Onset Alzheimer s Disease

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1 Human Bain Mapping 37: (2016) Disupted Rich Club Netwok in Behavioal Vaiant Fontotempoal Dementia and Ealy-Onset Alzheime s Disease Madelaine Daianu, 1,2 Adam Mezhe, 1 Maio F. Mendez, 3 Neda Jahanshad, 1 Elvia E. Jimenez, 3 and Paul M. Thompson 1,3,4 * 1 Imaging Genetics Cente, Mak & May Stevens Neuoimaging & Infomatics Institute, Univesity of Southen Califonia, Maina del Rey, Califonia 2 Depatment of Neuology, UCLA School of Medicine, Los Angeles, Califonia 3 Depatment of Neuology, Behavioal Neuology Pogam, UCLA, Los Angeles, Califonia 4 Depatments of Neuology, Psychiaty, Radiology, Engineeing, Pediatics, and Ophthalmology, Univesity of Southen Califonia, Los Angeles, Califonia Abstact: In netwok analysis, the so-called ich club descibes the coe aeas of the bain that ae moe densely inteconnected among themselves than expected by chance, and has been identified as a fundamental aspect of the human bain connectome. This is the fist in-depth diffusion imaging study to investigate the ich club along with othe oganizational changes in the bain s anatomical netwok in behavioal fontotempoal dementia (bvftd), andamatchedcohotwithealyonset Alzheime s disease (EOAD). Ou study sheds light on how bvftd and EOAD affect connectivity of white matte fibe pathways in the bain, evealing diffeences and commonalities in the connectome among the dementias. To analyze the beakdown in connectivity, we studied thee goups: 20 bvftd, 23 EOAD, and 37 healthy eldely contols. All paticipants wee scanned with diffusion-weighted magnetic esonance imaging (MRI), and based on whole-bain pobabilistic tactogaphy and cotical pacellations, we analyzed the ich club of the bain s connectivity netwok. This evealed distinct pattens of disuptioninbothfomsofdementia.intheconnectome, we detected less disuption oveall in EOAD than in bvftd [false discovey ate (FDR) citical P pem , 10,000 pemutations], with moe involvement of ichly inteconnected aeas of the bain (chi-squaed P ) pedominantly posteio cognitive alteations. In bvftd, we found a geate spead of disuption including the ich club (FDR citical P pem ), but especially moe peipheal alteations (chi-squaed P ), paticulaly in medial fontal aeas of the bain, in line with the known behavioal socioemotional deficits seen in these patients. Hum Bain Mapp 37: , VC 2015 The Authos. Human Bain Mapping Published by Wiley Peiodicals, Inc. Additional Suppoting Infomation may be found in the online vesion of this aticle. Contact gant sponso: The NIBIB; Contact gant numbes: R01 EB and R01 EB (Algoithm development and image analysis fo this study wee funded; PT); Contact gant sponsos: The NIA, NIBIB, NIMH, The National Libay of Medicine, and The National Cente fo Reseach Resouces; Contact gant numbes: AG016570, AG040060, EB01651, MH097268, LM05639, and RR (PT); Contact gant sponso: NIH; Contact gant numbe: 5R01 AG (Data collection and shaing fo this poject was funded); Contact gant sponso: Consotium gant fom the NIH Institutes; Contact gant numbes: U54 EB [Big Data to Knowledge (BD2K) Initiative] and R01 EB *Coespondence to: Paul M. Thompson; Imaging Genetics Cente, Mak & May Stevens Neuoimaging & Infomatics Institute, Keck School of Medicine of USC, Univesity of Southen Califonia, 2001 N. Soto Steet, SSB1-102, Los Angeles, CA pthomp@usc.edu Received fo publication 28 July 2015; Revised 5 Novembe 2015; Accepted 18 Novembe DOI: /hbm Published online 17 Decembe 2015 in Wiley Online Libay (wileyonlinelibay.com). VC 2015 The Authos. Human Bain Mapping Published by Wiley Peiodicals, Inc. This is an open access aticle unde the tems of the Ceative Commons Attibution License, which pemits use, distibution and epoduction in any medium, povided the oiginal wok is popely cited.

2 Disupted Rich Club Netwok in bvftd and EOAD Key wods: ealy onset Alzheime s disease; behavioal vaiant fontotempoal dementia; ich club; diffusion tenso imaging; connectome INTRODUCTION AD bvftd FA FDR FTD EOAD DMN DTI DWI E LOAD MD MRI NS k ROI U w U n SD SN TE TI TR Abbeviations Alzheime s disease behavioal vaiant fontotempoal dementia factional anisotopy false discovey ate fontotempoal dementia ealy-onset Alzheime s disease default mode netwok diffusion tenso imaging diffusion-weighted imaging numbe of edges in netwok late-onset Alzheime s disease mean diffusivity magnetic esonance imaging not significant nodal degee egion of inteest weighted ich club nomalized weighted ich club standad deviation salience netwok echo time invesion time elaxation time The human nevous system is a netwok of connections that suppots complex communication between numeous bain egions. Hundeds of billions of densely inteconnected neuons ae involved in disseminating, tansfoming, and pocessing signals though hundeds of tillions of synapses. Using emeging netwok-sensitive neuoimaging techniques, such as diffusion-weighted imaging (DWI), we ae able to econstuct the goss oganization of the human bain as a stuctual netwok of connections that make up the connectome, evealing the achitectual popeties of the nevous system. Studies of the human connectome have advanced neuoscience by shedding light on the cognitive and behavioal chaacteistics [Toga and Thompson, 2013] of the healthy and diseased living bain. Neuodegeneative diseases may taget specific neual netwoks with a chaacteistic pofile of anatomical pogession [Baak and Baak, 1991; Zhou et al., 2012]. Fo instance, in late-onset Alzheime s disease (LOAD), pathology may emege fist in the moe cental and inteconnected aeas of the bain s netwok, known as hubs [Buckne et al., 2005]. Netwok hubs fom a highcapacity cental coe, o ich club, and ich club connections play a key ole in global integation of infomation among egions of the bain [van den Heuvel and Spons, 2011]. Many connectivity studies hypothesize eithe that disease may taget cetain connections in the ich club netwok [Cossley et al., 2014], o that netwok disuptions in the ich club have the most significant impact on cognition. One plausible hypothesis of neuodegeneative disease pogession elates to tansneuonal spead, which may involve pion-like mechanisms [Fost and Diamond, 2010], that pomote and popagate the tansfe of toxic agents between the inteconnected components of the connectome [Zhou et al., 2012]. In line with this, anothe ecently poposed disease model in neuodegeneation was based on the diffusive spead of disease causing agents (i.e., tau, amyloid) intepeted though longitudinal stuctual netwoks. This model was found to ecapitulate classic pattens of alteations in Alzheime s disease (AD) and behavioal vaiant fontotempoal dementia (bvftd) [Raj et al., 2012]. In this wok, we used diffusion imaging to econstuct the bain s stuctual connectome in 20 patients with bvftd, 23 age-matched patients with ealy-onset Alzheime s disease (EOAD) and compaed both goups to 37 age-matched cognitively healthy contols. This is the fist study to combine these two unique foms of disease and analyze thei netwok distubances within the ich club famewok. bvftd and EOAD ae pototypical neuodegeneative diseases compaable in age and onset that tend to affect patially distinct neuoanatomical egions and aise due to diffeent pocesses [Daianu et al., 2015d]. Afte AD, FTD is the second most common fom of neuodegeneative dementia [Koedam et al., 2010], while bvftd one of the subtypes of FTD, is associated with fontal, tempoal, and insula degeneation [Seeley, 2008]. bvftd patients typically pesent with deficits in emotion, social conduct, and insight [Ca et al., 2015; Mendez and Shapia, 2011]. bvftd is known to begin focally with diffeent foci depending on the subtype, affecting neighboing egions in the bain. Meanwhile, EOAD a elatively ae fom of AD, pesents with slightly diffeent pattens of degeneation fom LOAD, affecting moe posteio egions of the bain, including the posteio cingulate and pecuneus [Kaas et al., 2007]. Pominent and pesenting symptoms of EOAD involve cognitive domains, such as language and visuospatial skills [Fisoni et al., 2007; Ishii et al., 2005; Kaas et al., 2007], athe than memoy. Hee, we futhe analyzed potential global disuptions in the ich club oganization of the bain in bvftd and EOAD, in elation to the white matte integity of the fibes linking vaious egions in the connectome. To 869

3 Daianu et al. TABLE I. Demogaphic infomation fo 37 healthy contols, 20 bvftd, and 23 EOAD patients Contols bvftd EOAD Total Age SD SD SD SD Sex 17M/20F 8M/12F 10M/13F 35M/45F MMSE SD SD SD SD The mean age, beakdown by sex and Mini Mental State Examination (MMSE) scoes ae listed fo each diagnostic goup obtain a compehensive landscape of disuptions, we econstucted ou netwoks using infomation fom DTI metics factional anisotopy and mean diffusivity, in addition to commonly studied fibe density-based netwoks. Fom a egional appoach, we defined centally located nodes among the hubs of each netwok in conjunction with moe peipheal aeas of the bain. Moeove, we assessed the alteed popotion of white matte connections leading to alteed infomation tansfe between hub and nonhub egions. We easoned that the key hubs in the ich club would be located in the main sites of atophy in the two diseases pedominantly in the fontal lobe in bvftd and paietal lobe in EOAD patients. We aimed to eveal distinct pattens of disuption in the netwoks of bvftd and EOAD, highlighting key nodes and connections within the ich club netwok, o among its peipheal egions, that may enable the spead of pathological pocesses leading to stuctual and functional consequences of bain disease. METHODS Paticipants and Image Pepocessing Twenty bvftd patients (60.7 yeas SD), 23 agematched EOAD patients (59.6 yeas SD) and 37 cognitively healthy individuals (59.4 yeas SD) wee scanned with whole-bain stuctual T1-weighted magnetic esonance imaging (MRI) and diffusion-weighted MRI (Table I). Paticipants with bvftd and with EOAD wee ecuited fom an outpatient behavioal neuology clinic in an academic univesity medical cente. bvftd paticipants met citeia fo pobable bvftd based on Intenational Consensus Citeia [Rascovsky et al., 2011] and fontotempoal changes on neuoimaging. While it is not possible to absolutely ule out atypical AD pathology among those who meet clinical citeia fo pobable bvftd, these citeia have a epoted specificity fo fontotempoal loba degeneation pathology close to 95% [Hais et al., 2013; Lamae et al., 2013]. The bvftd cohot was easonably homogeneous with pominent apathy, episodic disinhibition, steeotypical behavios, emotional blunting, and cabohydate caving. The eason fo the geate homogeneity elates, in pat, to the absence of patients with any of the known mutations. Paticipants with EOAD wee diagnosed accoding to the National Institute of Aging-Alzheime s citeia fo clinically pobable AD [McKhann et al., 2011]. Given the usual pesenile onset of bvftd, to have age-matched goups, only EOAD patients with ealy-onset disease (<65 yeas of age) wee included in the compaison goup. On pesentation, most of the EOAD patients had pedominant memoy impaiment, fou had visuospatial deficits, and five had language impaiment, howeve, they all had simila AD biomake changes in the ceebospinal fluid. All of the EOAD patients wee nonfamilial, that is, thee was no histoy of autosomal dominant tansmission o affected family membes with EOAD. All of the EOAD patients had the diagnosis of AD confimed by the pesence of low b42-amyloid and high total tau and phospho-tau on ceebospinal fluid analysis. None of the EOAD patients had a pio histoy of a psychiatic disode o neuological disease and none was at the time taking medications that could impact pefomance on the neuological exam. In addition, thee wee no bvftd o EOAD patients with clinical o neuoimaging evidence of comobid neuological disodes such as dementia with Lewy bodies. PET imaging with flobetapi o othe amyloid-binding adioligands was not available at the date of most MRI scan acquisitions. Acoss all thee goups, individuals with majo medical illnesses (except hypetension o diabetes) wee excluded. All 80 study paticipants undewent MRI scanning on the 1.5-Tesla Siemens Avanto scanne at the MRI Cente at the Univesity of Califonia Los Angeles (UCLA). Standad anatomical T1-weighted sequences wee collected ( matix; voxel size mm 3 ;TI5 900 ms; TR 5 2,000 ms; TE ms; flip angle 5 408), and DWIs using singleshot multisection spin-echo echo-plana pulse sequence ( matix; voxel size: mm 3 ;TR5 9,800 ms; TE 5 97 ms; flip angle 5 908; scan time 5 5 min 38 s). Thityone sepaate images wee acquied fo each DWI seies: one T2-weighted image with no diffusion sensitization (b 0 image) and 30 DWI volumes (b 5 1,000 s/mm 2 ). To coect fo head motion and eddy cuent distotions, all aw DWI volumes wee aligned to the b 0 image using FSL ( To ensue alignment in space, the skull-stipped T1-weighted images wee linealy aligned to the standad Colin27 template (Holmes et al., 1998] using the FLIRT function in FSL with 9 degees of feedom to account fo tanslation, otation and scaling in 3D [Jahanshad et al., 2012]. Then, we coected fo echo- 870

4 Disupted Rich Club Netwok in bvftd and EOAD Image pocessing steps. (A) A subject s T1-weighted anatomical image was segmented into N (i.e., 68) distinct ROIs, to define the netwok nodes in the connectome. These wee combined with white matte tactogaphy fom the DWIs, factional anisotopy (FA) and mean diffusivity (MD) maps to detemine the numbe of detected fibes that inteconnected a pai of nodes and the FA and MD values associated with them. (B) The inteconnecting fibes wee stoed as N 3 N connectivity matices descibing the fibe density, aveage FA and aveage MD values Figue 1. among connections that linked pais of nodes in the bain. (C) These connections can be epesented as netwoks of nodes and edges that make up the human connectome. Based on the numbe and type of nodes that they pass though, edges can be defined as ich club edges that link ich club nodes to othe ich club nodes, feede edges, that link ich club nodes to nonich club nodes and local edges that link nonich club nodes to othe nonich club nodes. [Colo figue can be viewed in the online issue, which is available at wileyonlinelibay.com.] plana imaging (EPI)-induced distotions, which can cause atifacts at fluid-tissue intefaces and may lead to patial volume effects. We did this by linealy and elastically aligning the skull-stipped b 0 images to thei coesponding T1-weighted stuctual images using invese consistent egistation with a mutual infomation cost function [Leow et al., 2005]. The esulting defomation fields wee applied to all 30 diffusion volumes befoe computing factional anisotopy (FA) and mean diffusivity (MD) maps. Using FeeSufe vesion 5.3 ( havad.edu/) [Fischl, 2004], we automatically extacted 34 cotical labels [Desikan et al., 2006] pe hemisphee fom the T1-weighted stuctual scans. All pacellations wee closely inspected and edited as needed. Resulting cotical labels and T1-weighted images wee downsampled to the space of the linealy aligned DWIs using neaest neighbo intepolation to avoid intemixing of labels [Jahanshad et al., 2012]. Finally, to ensue that econstucted fibe tacts would intesect labeled cotical boundaies, we dilated the labels with a voxel isotopic box kenel. In this study, we did not include subcotical pacellations. We expect that the analysis of additional egions would edefine the oganization of the netwok and the ich club might include subcotical labels. Fo now, in line with seveal othe studies assessing netwoks, we chose to focus on cotical netwok connectivity, howeve, we intend to include the subcotical pacellations in ou futue wok. N 3 N Connectivity Matix Computation Using the linealy aligned DWIs, we an pobabilistic tactogaphy using a global appoach based on the Hough tansfom [Aganj et al., 2011] and ecoveed 40,000 usable fibes (3-D cuves) fo each paticipant. Tenso econstuction was based on the diffusion tenso imaging (DTI) model. Duing pocessing, we filteed out fibes that wee <20 mm in length, as they ae moe likely to be false positive fibes, and emoved all duplicates. The 3-D elastic defomation field obtained fom the EPI distotion coections wee applied to the tacts coodinates. Next, fo each subject, we ceated thee distinct connectivity matices by combining fibe tactogaphy with the downsampled cotical labels fom FeeSufe to map the bain s goss fibe connections (Fig. 1). These we enumeated in a connectivity matix with 34 egions of inteest (ROIs) in each hemisphee. In this aticle, we use the wod fibe to denote a single cuve, o steamline, extacted via tactogaphy; if no paticipants had detected fibes connecting two egions (i.e., all paticipants had a 0 count at a specific matix element), then that connection 871

5 Daianu et al. was not included in the analysis. The thee distinct connectivity matices fo each paticipant descibed (1) nomalized fibe density of connections, (2) aveage FA, and (3) aveage MD along the tacts connecting a pai of ROIs. Finally, we used the connectivity matices to define each paticipant s bain netwok as a set of nodes (ROIs) and edges (fibe pathways). Computing the Weighted Rich Club Coefficient The matices allowed us to detect the ich club oganization of a netwok whee high-degee nodes ae moe inteconnected among themselves than pedicted by chance [Colizza et al., 2006]. The weighted ich club (U w ) incopoates the weight of the edges within each netwok and is a function of nodal degee, k defined as the sum of all the white matte connections that pass though an ROI. U w is computed as the atio between the sum of weights of a subnetwok of connections with nodal degee >k, E >k, and the sum of stongest weights of top connections in the whole netwok [van den Heuvel and Spons, 2011] (moe details in Suppoting Infomation). We nomalized U w using 500 andom netwoks of the same size and simila nodal distibution to the netwoks fom the paticipants in the study, to help detemine if the obseved connectivity densities exceeded those pedicted by a andom null distibution [Colizza et al., 2006]. A ich club phenomenon is said to be pesent if the nomalized U w,o U n,is> 1 at distinct nodal levels, k. Using the Bain Connectivity Toolbox [Spons, 2011], we computed the nomalized weighted ich club coefficients as functions of the fibe density, FA- and MD-weighted connectivity matices. Fo simplicity, we will efe to these as U w f, U w FA, and U w MD. Netwok Nodes and Edges We defined the ich club netwok at a peviously epoted nodal level of k > 15, sepaating the netwok into low- and high-nodal degee ich club egimes [Daianu et al., 2014; 2015a). This ich club theshold has been peviously poposed by studies using pacellation schemes of simila esolution [Daianu et al., 2015b; van den Heuvel and Spons, 2011; van den Heuvel et al., 2013]. To futhe explain, at k516, each node in the subnetwok is equied to connect to at least anothe 24% of the 67 nodes in the whole bain s netwok (16/ %, while at 100% one node connects to 67 nodes). We also anked the most inteconnected nodes at the afoementioned ich club theshold and selected the top 12% of the most consistently inteconnected nodes acoss all diagnostic goups. This was in line with pevious wok by van den Heuvel et al. [2013]. The nodes that made up the top most inteconnected subnetwoks wee included in the ich club netwok (see the Results section). Based on the oganization and inteconnectedness of nodes in the netwok, edges (E) wee defined as ich club, feede, and local connections (Fig. 1C). Rich club connections linked ich club nodes to othe ich club nodes, feede connections linked ich club nodes to nonich club nodes and local connections linked nonich club nodes to othe nonich club nodes [Ball et al., 2014; van den Heuvel et al., 2013]. We illustate these edges in the fom of connectogams using softwae developed by Iimia and Van Hon [2014], Iimia et al. [2012], and Van Hon et al. [2012]. Statistical Analyses We pefomed two analyses to chaacteize bain connectivity at global and nodal level. Fo ou global analyses, we tested fo goup diffeences (i.e., in U w f, U w FA, U w MD, E, ich club, feede, and local connections) between patients and healthy contols and between the two patient goups. To do this, we an a linea egession (coding disease status as 1 and contols as 0) on the esiduals of the global measues afte emoving age, sex, and bain volume effects. Pemutation testing was used to andomize the independent vaiable of inteest (i.e., disease status) while maintaining the esiduals of the global measues tue to the subject. We pefomed m 5 10,000 pemutations and geneated pemutation-coected P values using the following fomula: P 5 (b11)/(m11), whee b is the numbe of andomized test statistics t pem found to have a geate magnitude than the obseved test statistic t obs. FDR coection [Benjamini and Hochbeg, 1995] (q < 0.05) was applied to the P values to coect fo multiple compaisons acoss all k values. Fo ou nodal analyses, we tested fo diagnostic goup diffeences in the connectivity matices and sepaately, nodal degee, using the esidual values as descibed above. To detemine if the affected edges in the goup diffeences wee dispopotionally distibuted among ich club, feede, o local edges, we pefomed a chi-squaed (v 2 ) test between the expected popotions of edges in each diagnostic goup (i.e., known numbe of aveage ich club, feede, and local edges) and the obseved popotions (i.e., alteed edges). Similaly, we tested fo the distibution of alteed ich club vesus nonich club nodes in each goup. In the Results section, we will only epot popotion of affected nodes and edges that wee diffeently distibuted than expected. Finally, to detemine if thee wee any changes in the nodal and global netwok measues with cognitive decline, we tested fo associations between MMSE scoes and each netwok measue (U w f, U w FA, U w MD, E, ich club, feede, and local connections). Fo this, we an a linea egession on the esidual values as descibed above in all 80 paticipants and covaied fo disease status. Pemutation testing was also pefomed. 872

6 Disupted Rich Club Netwok in bvftd and EOAD RESULTS Global Analysis A ich club oganization was detected in the bain netwoks of patients and healthy contols. Patients had a significantly educed connectivity (see fewe edges inteconnecting ROIs in Fig. 2) and alteed ich club oganization (Fig. 3A), compaed to contols: Global Analysis: bvftd vesus Contols In bvftd, the U w f cuve was highe than in healthy contols (FDR citical P pem , 10,000 pemutations) at k (Fig. 3A), accompanied by a significant dop in E (P pem ) in the whole bain netwoks, suggesting disupted oganization fo the fibe density netwok. If in paticula nodal degee, and theefoe, fibe density, ae lowe in patients (see next section), then due to nomalization (when the netwok components ae equally distibuted), the ich club density would go up as obseved in Suppoting Infomation, Eq. (S3), athe than down. To explain futhe, both the tue and andom U w ae < 1 as the k-level inceases; yet natually, andom U w < tue U w especially when andom U w is constucted based on a lowe degee diseased netwok, leading to lage atios fo the nomalized U w. Suppoting this, the U w FA cuve was also highe in bvftd compaed to contols (FDR citical P pem ) at k , while the U w MD cuve, expected to have an opposing effect (in neuodegeneation when FA deceases, MD inceases), was lowe in bvftd, elative to contols (FDR citical P pem ), at k Relative to healthy contols, bvftd patients also had a significant dop in the numbe of edges among ich club (P pem ), feede (P pem ) and local (P pem ) connections in the netwok. Global Analysis: EOAD vesus Contols The U w f cuve inceased in EOAD, elative to contols (FDR citical P pem ), only in the high k-value egime, at k (Fig. 3A). U w FA and U w MD wee not significantly diffeent between EOAD paticipants and contols, but the total E dopped significantly in EOAD, compaed to contols (P pem ). Rich club (P pem ) and feede (P pem ) connections also deceased in EOAD, elative to contols. Local connections wee not detectably diffeent between EOAD and contols. Global Analysis: bvftd vesus EOAD Between the two patient goups, bvftd paticipants had a significantly diffeent netwok than EOAD paticipants. bvftd had a highe U w f cuve than EOAD (FDR citical P pem ) at k , and a significantly lowe E (P pem ). bvftd also had a highe U w FA cuve at k (FDR citical P pem ) and lowe U w MD cuve than EOAD at k 5 5, 6, 8, 10, 11, (FDR citical P pem ). In addition, bvftd patients had a significant lowe numbe of edges in the feede (P pem ) and local (P pem ) connections, than EOAD. Node and Edge Analysis The fibe density in ou DTI netwoks had a fat-tailed distibution, following an exponentially tuncated powe law [Clauset et al., 2009; Cossley et al., 2014]. This indicates the pesence of stongly inteconnected hub nodes (Fig. 3B). The most inteconnected nodes of the ich club netwok wee, as peviously documented in Spons et al. [2007], the ight and left hemisphee pecuneus, posteio cingulate, supeio paietal, supeio fontal, and insula (on aveage, thei nodal degee 37 out of 68 possible egions in healthy contols and most patients). Although these constitute highly connected epicentes in the connectome, they only add up to 6% of the connectome. To be consistent with pevious wok that selected the top 12% most consistently inteconnected nodes in each bain netwok [van den Heuvel et al., 2013], we included additional nodes with equivalently high aveage nodal degee (30): the ight and left isthmus of the cingulate, fusifom, infeio tempoal, lateal obitofontal, lingual, paahippocampal, pecental and ostal anteio cingulate. The only exceptions to these wee the ight fusifom and medial obitofontal (nodal degee < 30) but we included them in the ich club fo consistency. Oveall, we analyzed 26 ich club bilateal nodes and 42 nonich club nodes (Fig. 3C). Nodal Analysis: bvftd vesus Contols The nodal degee was significantly lowe in bvftd patients, elative to contols in 53 egions (FDR citical P pem ; Fig. 4A). Some of the most affected aeas wee pedominantly in the fontal lobe, as well as tempoal and paietal (Table S1, Suppoting Infomation). Twenty-one of the affected nodes (21/ %) wee pat of the ich club netwok and 32 (32/ %) wee in the nonich club (Table II). The fibe density was lowe in bvftd, than contols (FDR citical P pem ), at 18 distinct connections in the connecome. Futhemoe, FA connectivity analysis detected deceased FA (FDR citical P pem ) acoss 158 connections; the popotion of affected connections was diffeently distibuted than expected among the thee edge categoies in bvftd: 29 wee ich club connections out of a total aveage of 179 (Fig. 3D), 78/390 feede and 51/173 local connections (v 2 P ; Fig. 5D). In paticula, the popotion of local connections was moe alteed than the ich club connections in bvftd (v 2 P ), and than the feede connections (v 2 P ). Meanwhile, MD connectivity inceased at 112 connections (FDR citical P pem ; Fig. 5A). 873

7 Daianu et al. Figue 2. Connectogams depicting the aveage pattens of bain connectivity in healthy contols, bvftd and EOAD patients. This pacellation scheme was based on the Desikan-Killiany atlas povided with FeeSufe, which is boken down into 34 cotical ROIs fo the left and ight hemisphees (LH and RH). Colo coded ROIs ae listed in the bottom ight quadant, and the nodal degee at each ROI is depicted by the inne ing (gay pallet, with dake squaes indicating highe degee). [Colo figue can be viewed in the online issue, which is available at wileyonlinelibay.com.] 874

8 Disupted Rich Club Netwok in bvftd and EOAD Figue 3. Rich club cuves, stength distibution, ich club nodes and netwok edges. (A) Aveage nomalized ich club cuves (Un) computed as a function of fibe density (Uwf), FA (UwFA) and MD connectivity (UwMD) in healthy contols (blue), bvftd (ed), and EOAD patients (geen). The ange of significantly (*) alteed ich club measues is indicated (i.e., FTD < CTL*), as well as the zoomed in cuves fo k (in ed boxes). bvftd patients had a highe Uwf and UwFA acoss the low and high k-value egime and lowe UwMD cuves in the low egime than seen in contols, eflecting lowe levels of connectivity in the bain connectome; EOAD had a highe Uwf cuve than contols in the high k-value egime. (B) Fat-tailed distibution of stength in the DTI netwoks of each diagnostic goup and coesponding andom netwoks indicating highe pobability of hubs than in the andom distibution. (C) Bain netwoks delineating 13 distinct egions (26 bilateal) included in the ich club netwok (light blue); figue to the ight shows the 3D glass bain pojected on top of an axial slice with FeeSufe pacellations. (D) Aveage netwok connections and thei standad deviation acoss the thee diagnostic goups wee defined as ich club, feede, and local edges. All thee classes of connections wee lowe in the diagnostic goups, elative to contols, except the local connections in EOAD patients. [Colo figue can be viewed in the online issue, which is available at wileyonlinelibay.com.] 875

9 Daianu et al. Figue 4. Aveage netwoks indicating nodal degee diffeences between diagnostic goups inteconnected by alteed ich club (light blue), feede (light geen) and local connections (dak blue). (A) Deceases in nodal degee in bvftd, vesus contols, at 53 distinct nodes popotionally distibuted among ich club (light blue) and nonich club (dak blue) nodes; note that most significantly alteed nodes wee in the fontal lobe. (B) Deceases in nodal degee in EOAD, vesus contols, acoss 19 nodes with lagest popotion of these nodes located in the ich club netwok. (C) Deceases in nodal degee in bvftd, vesus EOAD, at 24 popotionally distibuted ich club and nonich club nodes. (D) Only the lingual aea in EOAD pesented with a deceased nodal degee, compaed to bvftd. All affected edges fom goup compaisons assessing deceases in fibe density, FA and MD connectivity matices (also shown in Fig. 5) wee added onto the aveage netwoks in bvftd (A, C) and EOAD (B, D). These show existing connections between significantly alteed nodes that may allow the disease popagation between egions of the bain. The size of the nodes is popotional to the magnitude of the Pobs (the geate the sphee, the moe significant Pobs). [Colo figue can be viewed in the online issue, which is available at wileyonlinelibay.com.] 876

10 Disupted Rich Club Netwok in bvftd and EOAD TABLE II. Goup diffeences fo bvftd vesus contols, EOAD vesus contols and bvftd vesus EOAD fo assessing changes in nodal degee, fibe density, FA and MD connectivity. Nodal degee Fibe Density Connectivity FA Connectivity MD Connectivity bvftd < Contols FDR ct. P pem /68 affected nodes NS (v 2 P > 0.05) FDR ct. P pem /742 affected edges NS (v 2 P > 0.05) FDR ct. P pem /742 affected edges local < RC (v 2 P ) local < feede (v 2 P50.013) FDR ct. P pem /742 affected edges NS (v 2 P > 0.05) EOAD < Contols FDR ct. P pem /68 affected nodes RC < non-rc (v 2 P ) FDR ct. P pem /843 affected edges RC < feede (v 2 P ) RC < local (v 2 P ) NS (P pem > 0.05) FDR ct. P pem /843 affected edges NS (v 2 P > 0.05) bvftd < EOAD FDR ct. P pem /68 affected nodes NS (v 2 P > 0.05) FDR ct. P pem /742 affected edges local < RC (v 2 P50.016) FDR ct. P pem /742 affected edges NS (v 2 P > 0.05) NS (P pem > 0.05) EOAD < bvftd FDR ct. P pem /68 affected nodes NS (v 2 P > 0.05) FDR ct. P pem /843 affected edges RC < feede (v 2 P ) RC < local (v 2 P ) NS (P pem > 0.05) NS (P pem > 0.05) We detemined the popotion of affected (obseved) ich club (RC) vesus nonich club nodes among the significant findings, in addition to the distibution of alteed edges among ich club, feede and local edges in the bain netwoks; these ae listed as pat of the existing (expected) nodes and edges aveaged acoss each diagnostic goup (i.e., 158/742 edges in bvftd). Results ae illustated in Figue 5. Oveall, among the alteed connections the popotion of local edges in bvftd (when compaed to contols and EOAD) wee moe affected than thei ich club and feede connections; wheeas fo EOAD, the popotion of ich club nodes and edges wee moe affected than thei nonich club nodes, feede o local edges. NS5not significant; < 5moe alteed node/connection; ct. 5citical. Nodal Analysis: EOAD vesus Contols Nodal degee also deceased in EOAD, elative to contols (FDR citical P pem ) at 19 ROIs (Fig. 4B). Some of the most significant deficits wee found in the left and ight hemisphee pecental egions, left lingual, left and ight pecuneus, and posteio cingulate among othe egions (Table S2, Suppoting Infomation). Thiteen of the affected nodes in EOAD wee in the ich club (13/ %) and 6 wee nonich club netwok (6/ %). The popotion of ich club nodes was moe seveely affected than the nonich club nodes (v 2 P ). Fibe density was lowe in EOAD, vesus contols (FDR citical P pem ) at 38 diffeent connections. Twenty-thee affected connections out of a total of 195 aveage EOAD edges wee among ich club connections, 12/442 wee feede, and 4/206 local (Fig. 5B). The popotion of affected connections was diffeently distibuted than expected (v 2 P ), with ich club connections moe seveely affected than both feede (v 2 P ) and local edges (v 2 P ) (Fig. 5D). MD connectivity was highe acoss 158 distinct connections in EOAD, elative to contols (FDR citical P pem ). Thee wee no diffeences detected in FA connectivity. Nodal Analysis: bvftd vesus EOAD bvftd patients had a lowe nodal degee, elative to EOAD in 24 aeas of the bain (FDR citical P pem ; Fig. 4C and Table II) mostly in the fontal lobe (Table S1, Suppoting Infomation); only the left lingual pesented with lowe nodal degee in EOAD patients, elative to bvftd. Fibe density deceased in bvftd, elative to EOAD (FDR citical P pem ), at 25 connections (5/179 ich club, 9/390 feede, 11/173 local; Fig. 5C) and the popotion of connections among the thee categoies of edges was significantly diffeent (v 2 P ), with local connections moe seveely affected than ich club edges (v 2 P ), but not feede (v 2 P 5 0.1); fibe density also deceased in EOAD, elative to bvftd (FDR citical P pem ), 877

11 Figue 5. Diagnostic goup diffeences in the N 3 N connectivity matices fo fibe density (FD), FA and MD between: (A) bvftd and healthy contols; (B) EOAD and healthy contols; and (C) bvftd and EOAD. Blue edges indicate deceasing pattens fo coesponding measues, while ed edges indicate inceasing pattens all suggestive of alteations in connectivity. (D) Popotion (%, yaxis) of significantly alteed connections (100% 3 obseved/ expected) illustated as ich club, feede, o local edges. In bvftd, the popotion of local edges was moe affected among the alteed connections when compaed to contols and sepaately, EOAD; while in EOAD, the popotion of ich club edges was moe affected among the alteed connections when compaed to contols and bvftd. < indicates that a paticula diagnostic goup pesented with moe alteations than the othe; * denotes whee a significantly highe popotion of edges than expected was alteed as descibed by the v2 test. [Colo figue can be viewed in the online issue, which is available at wileyonlinelibay.com.]

12 Disupted Rich Club Netwok in bvftd and EOAD at 24 connections diffeently distibuted among ich club, feede, and local connections than expected (14/195 ich club, 7/442 feede, 3/206 local; v 2 P ). As seen in EOAD vesus contols, the popotion of ich club edges in EOAD was moe affected than the feede (v 2 P ) and local connections (v 2 P ). FA connectivity deceased in bvftd paticipants, elative to EOAD at 63 distinct connections (FDR citical P pem ). MD connectivity did not detect significant diffeences. Changes in Connectivity with Cognitive Decline Among the global measues, MMSE scoes deceased with the numbe of edges fo the ich club connections (P pem ). At local netwok level, MMSE scoes deceased with inceasing MD connectivity at 115 connections (FDR citical P pem ) (29/196 ich club, 58/436 feede, and 28/196 local). Hee, the affected connections wee tested against the aveage numbe of connections within each diagnostic goup and wee popotionally distibuted among the ich club, feede, and local connections. The affected connections tavesed all lobes of the bain, especially the paietal lobe (infeio and supeio segments, and pecuneus) and the tempoal lobe (infeio, middle and supeio segments) bilateally with pefeential involvement of the left hemisphee. Futhemoe, no othe significant associations wee detected between the emaining global and nodal netwok measues and cognitive decline. This may be because a lage sample is needed to pick up associations o MMSE scoes ae less sensitive than othe moe specific cognitive tests to changes in connectivity in the eldely. DISCUSSION As hypothesized, we found disupted levels of connectivity in patients with dementia, bvftd, and EOAD (Fig. 2), based on an in-depth analysis of the weighted ich club oganization of the bain. In addition to the commonly studied fibe density metic, we also analyzed connectome changes in tems of standad diffusion tenso imaging (DTI) measues FA and MD expected to decease and incease simultaneously, indicating stuctual disuptions in the white matte. bvftd and EOAD Affect the Global Netwok Oganization of the Connectome Fom ou global analyses, we found that the fibe density and FA ich club cuves wee affected acoss both low and high degee nodes in bvftd, vesus contols, while MD only detected diffeences in the low nodal degee egime possibly indicating that bvftd pedominantly affects the peipheal (local) nodes of the netwok (Fig. 3A). The low k-value egime includes low degee nodes that fom locally clusteed and segegated communities of the connectome and povide a communication elay that aids the global integation of infomation in the bain [de Reus and van den Heuvel, 2013; Spons, 2011]. Meanwhile, in EOAD, only the fibe density ich club cuves detected alteations in the high k-value egime tageting the ich club netwok nodes (Fig. 3A). The high k-value egime etains only the most densely inteconnected nodes of the connectome and defines the ich club that futhe eflects the integation of hubs in the netwok. Communication among these cental nodes is achieved though long distance pathways and is cucial fo efficient global infomation tansfe in the healthy bain [van den Heuvel et al., 2009]. Although we show that the weighted ich club netwok is affected in both types of dementia, futhe investigation is needed to distinguish whethe the ich club netwoks ae moe affected puely due to thei high topological value (i.e., high nodal degee) o because thee ae disease pocesses that oiginate fom o popagate to centally located nodes. Nodal Analysis Reveals a 78% Alteed Netwok in bvftd and 28% in EOAD In addition to studying the global ich club oganization, we also analyzed the integity of the connections that tansfe infomation between hub and nonhub egions of the bain. The bain exhibits densely inteconnected netwoks in which communication hubs and nonhubs opeate collectively, athe than as individual entities [Daianu et al., 2014; van den Heuvel and Spons, 2011]. In ou nodal analyses, we showed that in bvftd, elative to healthy paticipants (Figs. 4A and 5A) and sepaately, EOAD (Figs. 4C and 5C), most pominent eductions wee detected within popotionally distibuted ich club and nonich club nodes acoss the cotex. Pedominantly, the local connections that linked these egions wee most affected among all connections in the netwok. Convesely, in the EOAD vesus contols (Figs. 4B and 5B), and sepaately bvftd (Figs. 4D and 5C), disconnections wee most obvious among the ich club nodes of the connectome and the ich club connections that linked them (Figs. 4B and 5B, D). Although ich club nodes wee affected in EOAD, thei nodal degee did not decease below the ich club nodal degee equiement (30), unlike seen in bvftd whee the ight and left lateal and medial obitofontal egions (ich club egions in contols and EOAD) dopped out of the ich club subnetwok. This might indicate that the global ich club communication backbone in EOAD emains elatively peseved [Daianu et al., 2015a,b,c] despite the nodal diffeences detected by the weighted analyses. These findings ae in line with ou knowledge of the pathology of bvftd and EOAD. Pattens of anatomical changes do vay in bvftd, and elate to the behavioal pofile of the patients, but taditionally, bvftd is associated with lagely symmetical atophy of the fontal lobes [Whitwell et al., 2009]. Recent studies divide bvftd into 879

13 Daianu et al. sepaate anatomical goups fontal-dominant, tempoaldominant, fontotempoal, and fontotempoalpaietal [Whitwell et al., 2009]. In this study, we found the disuption in connectivity to be moe consistent with the fontotempoalpaietal pathology in bvftd. Ninety-six pecent of the bilateal fontal lobe nodes pesented with a deceased nodal degee, compaed to contols, and 70% of these wee nonich club nodes possibly explaining why most alteations wee located among the local connections in bvftd (Fig. 4A). Ninety-thee pecent of the bipaietal nodes and 72% of the tempoal nodes had a lowe nodal degee in bvftd, compaed to contols. The nodes in the fontal, paietal, and tempoal lobes wee faily symmetically affected acoss the two hemisphees. The occipital lobe in bvftd was elatively spaed; only the ight hemisphee cuneus had a lowe nodal degee than seen in contols. The insula, especially in the ight hemisphee, also contibuted to the disconnection obseved in bvftd. Moeove, the buden of pathology in EOAD has been associated with bipaietal and fontal lobe dysfunction [Mashall et al., 2007] and left geate than ight hemispheic tempoal lobe atophy [Koedam et al., 2010]. Unlike LOAD, EOAD often pesents with pominent visual dysfunction [Koedam et al., 2010]. Hee, we found consideable suppoting evidence fo a disupted connectome in EOAD, vesus contols, in aeas elevant to disease that wee pedominantly located among the ich club netwok nodes. The nodes with a lowe nodal degee that dove this phenomenon wee located in the bipaietal lobe (57% of paietal lobe was affected; Fig. 4B); some of these alteations wee in the pecuneus, posteio cingulate, and isthmus of the cingulate egions known to show pofound atophy in AD [Daianu et al., 2013; Thompson et al., 2003]. Twenty-seven pecent of the fontal lobe nodes had a lowe nodal degee, including the supeio fontal, caudal anteio, and middle cingulate affected pedominantly in the left hemisphee. The infeio tempoal and fusifom wee affected in the left tempoal lobe aeas of the bain that ae esponsible fo identifying objects and face peception [Goss, 1994]. The nodes on the peicalcaine cotex (anatomical location of pimay visual cotex [Bedny, 2011]) and lingual aeas pesented with a lowe nodal degee in the left hemisphee occipital lobe. This is indicative of the visual impaiment that is pevalent in EOAD [Koedam et al., 2010]. Many diseases may affect the bain in a netwok-elated spatial patten that might closely elate to functional intinsic connectivity netwoks [Buckne et al., 2005; Zhou et al., 2012]. Although this wok did not assess functional connectivity, ou stuctual findings ae in line with epots on an atophied salience netwok (SN) in bvftd and an atophied posteio default mode netwok (DMN) in AD [Zhou et al., 2010]. bvftd patients pesented with affected stuctual egions that ovelap with aeas that ae pat of the SN and include the anteio cingulate cotex and fontoinsula connections. One of the most affected nodes in the bvftd connectome was the ight hemisphee ostal anteio cingulate (Fig. 4A), also a ich club node, which plays a majo ole in the SN and is involved in emotion and decision-making. This node may also be associated with a high level of nodal stess and could affect, possibly though tansneuonal spead, its neighboing nodes including the ight lateal obitofontal anothe seveely affected ich club node that is pat of the SN and is concened with decision-making [Kingelbach, 2005]. The ight and left supeio fontal, pat of the DMN and involved in self-awaeness [Goldbeg et al., 2006], wee geatly affected in both bvftd and EOAD. The supeio fontal is one of the most cental ich club nodes in the connectome poviding a communication elay fo many neighboing nodes which might possibly make it moe vulneable to disease pocesses. In addition, the pecuneus and posteio cingulate, hubs in the DMN, wee also affected in EOAD. The pecuneus contols visuospatial functioning [Kaas et al., 2007] while the posteio cingulate has a cental ole in the DMN, possibly in suppoting intenally diected cognition [Leech and Shap, 2014]. Oveall, these nodes that ae actively involved in the SN and DMN, constitute netwok-specific hubs in bvftd and EOAD, which may o may not be sites of initial injuy, but ae closely elated to the clinical deficits defining each fom of dementia. Anothe impotant aspect involves the impact of gay matte atophy on netwok analysis. Atophy is commonly epoted in patients with bvftd, especially in the fontal lobe as found by a ecent meta-analysis fom 11 voxelbased analysis studies acoss 237 bvftd patients and 297 healthy contols [Pan et al., 2012]. Widespead gay matte changes wee also found in EOAD patients in the paietal and occipital lobes, as well as in aeas of the neocotex [Fisoni et al., 2007]. Gay matte loss can lead to seconday changes in the white matte stuctue, fo example, though Walleian degeneation [Thompson et al., 1998], as suggested by the alteed connectivity in this study. Although the gay matte effects on the white matte stuctue ae not well undestood, lesions in the gay matte, as seen in taumatic bain injuy, can affect the integation and segegation popeties of bain netwoks [Iimia and Van Hon, 2014]. Paticulaly, lesions in the fontopola and supeio fontal cotex may lead to alteations in segegation popeties [Iimia and Van Hon, 2014] a local popety of the netwok, and can be associated with changes in behavio and pesonality, as seen in bvftd. This is futhe suppoted by the pominent local disuption among components of the bvftd netwok shown in this study and could imply that gay matte deficits may contibute to these alteations. Fontal lobe lesions may only minimally affect integation popeties, but injuy to the medial paietal and supeio tempoal cotices may cause dastic alteations in netwok-wide integation [Iimia and Van Hon, 2014] an impotant chaacteistic of the connectome that gives it the capacity 880

14 Disupted Rich Club Netwok in bvftd and EOAD to engage in global inteactions. The paietal lobe was found to be most alteed in ou EOAD patients and is also one of the egions with geatest connectivity in humans [Hagmann, 2008]. It, theefoe, has majo involvement in the ich-club netwok. The bain may also be moe sensitive to injuies in egions with moe basic pimay sensoy functions citical to the suvival of the individual, and moe esilient to injuies among the highe ode functions (i.e., fontal pole egions) [Iimia and Van Hon, 2014]. Limitations and Concluding Remaks A limitation of this study is the DTI econstuction that was used to ecove fibes in the white matte stuctue. Unlike high angula esolution imaging (HARDI), DTI is not always able to accuately econstuct the axonal banching, including cossing fibes, within a single image voxel [Daianu et al., 2015c]. This might lead to an undeepesentation of the white matte fibe populations in the human connectome [van den Heuvel and Spons, 2011] and might esult in false-positive esults, and false negatives. In ou nodal analyses, we found unexpected inceases in fibe density and FA connectivity in the dementia goups, compaed to contols, pimaily pojecting though the insula. Although the micostuctual aspects of abnomal inceases in connectivity ae not fully undestood, thee may be micoscopic deficits at axonal level, as well as deceases in packing density and banching o deceases in axonal diamete [Beaulieu, 2002; Hoeft et al., 2007] that might lead to such esults. Connectivity measues of fibe density, FA and MD ae indiect makes of white matte integity, yet they povide valuable infomation about the alteed connectivity pattens in disease. Impotantly, FA and MD metics wee sensitive to a lage ange of alteations and led to fewe abnomal inceases (than found fo fibe density), possibly suggesting moe eliable outcomes in compaing healthy to diseased goups. Anothe limitation of ou study may be the low esolution pacellation scheme used to segment the bain into 68 cotical egions. Including moe egional components may help bette distinguish between functionally heteogeneous egions and possibly bette undestand nodes that paticipate in multiple netwoks. Howeve, the oganizational pinciples of the stuctue and function of the connectome might be independent of the pacellation paadigm [de Reus and van den Heuvel, 2013] although the quantification of gaph theoy measues could change between lowto lage-esolution netwoks. Anatomical templates segment the bain into egions, wheeas many significantly lage pacellations schemes ae designed to poduce hundeds o thousands of pacels of appoximately equal size [de Reus and van den Heuvel, 2013]. Nonetheless, it emains open fo debate if athe unifomly sized bain egions have an advantage ove anatomically delineated templates. In this study, we epot on a seveely disupted connectome in bvftd affecting 78% of the netwok nodes, including both ich club and peipheal (local) components. Distinctly, the local connections that linked these components wee most seveely affected in bvftd unlike what we found in EOAD, whee 28% of the connectome nodes wee affected and pedominated among the ich club nodes and thei ich club connections. Longitudinal studies ae needed to chaacteize the tansneuonal degeneation acoss the netwok-like oganization of the bain, but an impotant step is undestanding the elements of the netwok, as shown hee, that may enable dysfunction to spead between linked egions of the connectome. REFERENCES Aganj I, Lenglet C, Jahanshad N, Yacoub E, Hael N, Thompson PM, Sapio G (2011): A Hough tansfom global pobabilistic appoach to multiple-subject diffusion MRI tactogaphy. 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