On the right side? A longitudinal study of left- versus right-lateralized semantic dementia

doi:10.1093/brain/awv387 BRAIN 2016: 139; 986 998 986 On the right side? A longitudinal study of left- versus right-lateralized semantic dementia Fiona Kumfor, 1,2,3 Ramon Landin-Romero, 1,3 Emma Devenney, 1,3,4 Rosalind Hutchings, 1,2,3 Roberto Grasso, 1 John R. Hodges 1,2,3 and Olivier Piguet 1,2,3 The typical presentation of semantic dementia is associated with marked, left predominant anterior temporal lobe atrophy and with changes in language. About 30% of individuals, however, present with predominant right anterior temporal lobe atrophy, usually accompanied by behavioural changes and prosopagnosia. Here, we aimed to establish whether these initially distinct clinical presentations evolve into a similar syndrome at the neural and behavioural level. Thirty-one patients who presented with predominant anterior temporal lobe atrophy were included. Based on imaging, patients were categorized as either predominant left (n = 22) or right (n = 9) semantic dementia. Thirty-three Alzheimer s disease patients and 25 healthy controls were included for comparison. Participants completed the Addenbrooke s Cognitive Examination, a Face and Emotion Processing Battery and the Cambridge Behavioural Inventory, and underwent magnetic resonance imaging annually. Longitudinal neuroimaging analyses showed greater right temporal pole atrophy in left semantic dementia than Alzheimer s disease, whereas right semantic dementia showed greater orbitofrontal and left temporal lobe atrophy than Alzheimer s disease. Importantly, direct comparisons between semantic dementia groups revealed that over time, left semantic dementia showed progressive thinning in the right temporal pole, whereas right semantic dementia showed thinning in the orbitofrontal cortex and anterior cingulate. Behaviourally, longitudinal analyses revealed that general cognition declined in all patients. In contrast, patients with left and right semantic dementia showed greater emotion recognition decline than Alzheimer s disease. In addition, left semantic dementia showed greater motivation loss than Alzheimer s disease. Correlational analyses revealed that emotion recognition was associated with right temporal pole, right medial orbitofrontal and right fusiform integrity, while changes in motivation were associated with right temporal pole cortical thinning. While left and right semantic dementia show distinct profiles at presentation, both phenotypes develop deficits in emotion recognition and behaviour. These findings highlight the pervasive socio-emotional deficits in frontotemporal dementia, even in patients with an initial language presentation. These changes reflect right anterior temporal and orbitofrontal cortex degeneration, underscoring the role of these regions in social cognition and behaviour. 1 Neuroscience Research Australia, Sydney, Australia 2 School of Medical Sciences, the University of New South Wales, Sydney, Australia 3 ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia 4 Prince of Wales Clinical School, the University of New South Wales, Sydney, Australia Correspondence to: Dr Fiona Kumfor, Neuroscience Research Australia, PO Box 1165, Randwick, Sydney, NSW, 2031, Australia E-mail: f.kumfor@neura.edu.au Keywords: frontotemporal dementia; temporal lobe; social cognition; behaviour Abbreviations: ACE = Addenbrooke s Cognitive Examination; CBI = Cambridge Behavioural Inventory; LME = linear mixed effects; SD = semantic dementia Received September 14, 2015. Revised October 21, 2015. Accepted November 6, 2015. Advance Access publication January 25, 2016 ß The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Left- versus right-lateralized SD BRAIN 2016: 139; 986 998 987 Introduction The clinical manifestation of dementia varies widely, depending on the pattern of initial brain changes and the spread of pathology with disease progression. Frontotemporal dementia is characterized by a progressive neurodegeneration of the frontal and/or temporal lobes. Disproportionate atrophy of the temporal lobe is usually associated with a generalized loss of semantic knowledge, and is clinically known as semantic-variant primary progressive aphasia (Gorno-Tempini et al., 2011) or semantic dementia (SD) (Snowden et al., 1989; Hodges et al., 1992). The primary complaint in patients with SD is a loss of memory for words/anomia, with this profound loss of semantic knowledge evident irrespective of the modality of testing (Hodges et al., 1992). Typically, individuals diagnosed with SD show a bilateral but asymmetric pattern of brain atrophy, where the left anterior temporal lobe regions are markedly more affected than the right (Mion et al., 2010). Studies of these patients with typical, left predominant SD have directly influenced our understanding of the representation of semantic knowledge in humans, and identified the unique contribution of the left anterior temporal lobe in the representation of language (Lambon Ralph et al., 2001; Patterson et al., 2007). Importantly, in a proportion (30%) of patients, the anterior temporal lobe involvement is reversed, whereby atrophy is more pronounced in the right than the left anterior temporal lobe region (Chan et al., 2009). The clinical presentation of these predominant right SD cases is heterogeneous and includes inappropriate behaviour, prosopagnosia and/or semantic deficits (Chan et al., 2009; Josephs et al., 2009). Indeed, differentiating patients with right SD from the behavioural-variant of frontotemporal dementia is challenging, with the nosology of right SD remaining unclear (Josephs et al., 2009; Whitwell et al., 2009; Kamminga et al., 2015). One of the key unresolved issues is whether left and right SD represent distinct clinicopathological entities (Seeley et al., 2005; Josephs et al., 2009) and the extent that these syndromes evolve into a similar profile with disease progression. Longitudinal studies are scant but existing evidence suggests that, over time, individuals with right SD develop language features, whereas individuals with left SD may exhibit behavioural changes (Seeley et al., 2005). These reports, however, relied on clinical case reviews to determine the presence and nature of symptoms, which were not objectively measured. The authors proposed that the apparent evolution of behavioural and language features may reflect spreading of disease into the contralateral temporal lobe (Seeley et al., 2005). Neuroimaging data, however, were not available to explore this hypothesis. Few studies have attempted to quantify patterns of atrophy change in left SD over time. In one, the mean rate of volume loss over an 18-month period was reported to be significantly greater in the right temporal lobe and right hippocampus specifically, when compared to these structures in the left hemisphere (Rohrer et al., 2008). Atrophy progression in left SD, however, is not always restricted to the right hemisphere with changes in the left hemisphere also observed over time (Brambati et al., 2015), some even reporting greater left than right hemisphere degeneration (Rogalski et al., 2014). Thus, existing longitudinal studies of left SD have yielded mixed findings about the pattern of disease progression. In right SD, case studies have suggested that atrophy progresses from the right fusiform and parahippocampal gyrus anteriorly to the right temporal pole as well as the left anterior temporal regions, albeit to a lesser extent than the right (Joubert et al., 2004; Henry et al., 2012). To our knowledge, only one group study has investigated progressive grey matter atrophy in six patients with right SD and 13 patients with left SD (Brambati et al., 2009). Over a 1- year period, both groups showed atrophy in the hemisphere contralateral to that predominantly affected at presentation (Brambati et al., 2009). Patterns of atrophy between left and right SD, however, were not directly compared. Furthermore, how atrophy progresses in these individuals beyond 1 year remains unknown. Thus, while some evidence suggests that these syndromes may evolve into a similar clinical phenotype over time, comprehensive longitudinal clinical and neurological examination of these syndromes is lacking. Moreover, comparisons with other neurodegenerative brain disorders have not been conducted, and thus the extent that these changes are specific to left and right SD is unknown. The comparison of right and left SD is not only of interest from a clinical and nosological perspective, but may also help shed light on the function of the right temporal lobe. Damage to the right temporal lobe has been variably associated with impaired visual recognition (Milner, 1968), visual learning deficits (Helmstaedter et al., 1991), musical timbre discriminations (Samson and Zatorre, 1994), recognition of famous tunes (Hsieh et al., 2011) and memory for complex visual scenes (Pigott and Milner, 1993). More recently, however, a potential role in social cognition has been put forward (Olson et al., 2007, 2013). How the right temporal lobe supports social behaviour and how it interacts with other regions of the social brain such as the amygdala and orbitofrontal cortex is yet to be fully elucidated. Here, we aimed to longitudinally examine a group of individuals who presented with predominant anterior temporal lobe atrophy (either left of right) and map the pattern of progression using a combination of neuroimaging and behavioural measures, with respect to a group of patients with Alzheimer s disease and healthy controls. The Alzheimer s disease group was included as a disease control group, and to demonstrate that even in a state of advanced neurodegeneration, SD and Alzheimer s disease remain entities that are clinically and neurologically distinct. Direct comparisons with healthy matched controls were conducted at baseline to determine patterns of neurodegeneration and behavioural impairment, specific to each patient group.

988 BRAIN 2016: 139; 986 998 F. Kumfor et al. Our first aim was to determine the common and divergent baseline and longitudinal patterns of atrophy in these syndromes. The second aim was to longitudinally examine general cognition, face perception, emotion processing and behaviour, to understand how these abilities become affected over time. We hypothesized that left and right SD are essentially manifestations of the same pathological disorder and that over time their initially asymmetrical cortical thinning would extend into parallel structures in the contralateral hemisphere to create equivalent patterns of atrophy. Behaviourally, we hypothesized that individuals with right SD would show greater social cognition and behavioural impairment than left SD and Alzheimer s disease at baseline. Longitudinally, we predicted left SD would also develop social cognition and behavioural deficits. Materials and methods Participants Thirty-one dementia cases that presented to FRONTIER, the frontotemporal dementia research clinic in Sydney, with predominant anterior temporal lobe atrophy were included in this study. Twenty-two patients were classified as left SD and nine patients as right SD (Supplementary material). These individuals were compared with 33 age- and education-matched Alzheimer s disease patients and 25 healthy matched controls. All patients were assessed by the multidisciplinary team and diagnosis was reached by consensus according to current clinical diagnostic criteria (Gorno-Tempini et al., 2011; McKhann et al., 2011; Rascovsky et al., 2011) following a comprehensive clinical assessment including: neurological examination, neuropsychological assessment, structural brain MRI, informant report and independent review of the clinical files by an experienced behavioural neurologist (E.D. or J.R.H.). The Frontotemporal Dementia Rating Scale (FRS) was used to measure disease severity/functioning (Mioshi et al., 2010). Controls were recruited from the Neuroscience Research Australia Volunteer database and local community clubs. Controls scored 588/100 on the Addenbrooke s Cognitive Examination-Revised (ACE-revised) (Mioshi et al., 2006) and 0 on the sum of boxes score of the Clinical Dementia Rating scale (Morris, 1993). Exclusion criteria for patients and controls included concurrent psychiatric disturbance, other neurodegenerative conditions or neurological disorders and/or history of substance abuse. The South Eastern Sydney Local Health District and the University of New South Wales ethics committees approved the study. Participants or their person responsible provided informed consent in accordance with the Declaration of Helsinki. Participants volunteered their time and were reimbursed for travel costs. MRI acquisition Twenty-seven patients with SD (19 left SD and eight right SD), 32 patients with Alzheimer s disease and 25 controls underwent whole-brain structural MRI with a 3 T Phillips scanner using a standard 8-channel head coil. Three dimensional high-resolution turbo field echo T 1 -weighted sequences were acquired with the following parameters: coronal orientation, matrix 256 256, 200 slices, 1 mm 2 in-plane resolution, slice thickness 1 mm, echo time/repetition time 2.6/5.8 ms, flip angle a =19. Among the study participants, 24 patients with SD (17 left SD and seven right SD) and 25 patients with Alzheimer s disease underwent annual MRI (range 1 4 years, median number of MRI scans = 2). A total of 76 SD (54 left SD and 22 right SD) and 92 Alzheimer s disease consecutive scans were included in the study (Table 1). MRI scans were obtained on average within 2 months of the behavioural assessment. Classification of patients The baseline MRI scans of the SD participants were rated using a previously validated MRI rating scale by two trained raters (E.D., R.G.), blind to clinical diagnosis (Kipps et al., 2007; Davies et al., 2009). Inter-rater reliability was high for both raters (Cronbach s a = 0.9). The region of interest selected was the anterior temporal lobe. To reduce potential bias in ratings, all MRI scans were rated in both the correct orientation and a mirror image, and the left and right hemispheres were rated separately. Then, the average score for each rater on the correct and mirror image scans were averaged. Finally, the two raters scores were averaged and the participant was classified as predominantly left- or right-lateralized according to the side with greater atrophy. Research MRI scan was unavailable for four patients (one had pacemaker in situ, three had other metallic implants which prevented MRI scanning). For these individuals, classification into left or right SD group was established based on clinical magnetic resonance or CT images (see Supplementary material for additional information). Preprocessing of baseline and longitudinal imaging data Before analyses, the two T 1 volumes were merged and averaged to increase the signal-to-noise ratio and the grey matter white matter contrasts in brain structures. Freesurfer software, version 5.3.0 (http://surfer.nmr.mgh.harvard.edu) was used for surface-based cortical processing (Dale et al., 1999; Fischl et al., 1999) using standard methods (Fischl and Dale, 2000). Cortical thickness was automatically extracted for each hemisphere at each time point. For the longitudinal processing, an unbiased within-subject template (Reuter and Fischl, 2011) was created using robust, inverse consistent registration between the available time points for each individual (Reuter et al., 2010). Several preprocessing steps, such as skull stripping, Talairach transformations, atlas registration, as well as spherical surface maps and parcellations were initialized with common information from the within-subject template, significantly increasing reliability and statistical power (Reuter et al., 2012). Cortical thickness was smoothed with a 20 mm full-width at half-height Gaussian kernel. This level of blurring kernel was chosen to reduce the impact of imperfect alignment between cortices and thereby improve the signal-to-noise ratio (Lerch and Evans, 2005). All the resulting

Left- versus right-lateralized SD BRAIN 2016: 139; 986 998 989 Table 1 Demographics at baseline in left SD, right SD and Alzheimer s disease compared with controls Left SD n =22 Right SD n =9 AD n =33 Controls n =25 F P-value Post hoc M:F 13:9 5:4 21:12 12:13 1.465 # ns Age (years) 62.2 6.2 62.3 7.5 65.1 7.8 64.3 4.0 1.143 ns Education (years) 12.5 3.0 11.6 3.7 12.3 3.4 13.7 2.6 1.482 ns Disease duration (years) a 4.1 1.9 4.3 2.1 3.1 3.1 1.435 ns FRS (Rasch score) b 1.2 1.4 0.8 1.4 1.2 1.3 0.370 ns Number of behavioural visits 3.0 1.8 2.0 1.1 2.5 1.5 4.395 0.013 right SD 5 left SD; left SD = AD Number of MRI scans 2.2 1.2 2.1 1.2 2.2 1.2 0.063 ns Values are mean standard deviation. ns = P 4 0.05. # Chi-square value. AD = Alzheimer s disease; FRS = Frontotemporal Dementia Rating Scale. Missing data: a Date of onset missing for one Alzheimer s disease participant; b FRS score missing for one left SD participant. images were visually inspected and manually corrected in the event of tissue segmentation errors. Subjects who had excessive surface segmentation errors after manual correction were excluded from the subsequent baseline (one control, one Alzheimer s disease patient) and follow-up (two Alzheimer s disease patients) statistical analyses. Neuropsychological and behavioural assessment All patients were assessed at least twice and, where possible, followed up annually. All data were included until the point of drop out. The outcome variables were obtained approximately annually. The ACE was used to assess general cognition, with the total score /100. Recently, the ACE-revised (Mioshi et al., 2006) has been updated (ACE-III) (Hsieh et al., 2013). Because the two versions are largely equivalent, we analysed either the ACErevised (R) score or the ACE-III score, to maximize the available data. We analysed both the total score, as a measure of general cognitive ability, as well as performance on the five subtests embedded within the ACE tapping into specific cognitive domains (attention/orientation, memory, language, visuospatial function, fluency). In addition, we examined language function with the Sydney Language Battery (SYDBAT) (Savage et al., 2013), focusing on the Naming, Comprehension and Semantic Association subtests. Finally, we used the copy of the Rey Complex Figure (Rey, 1941) to examine visuospatial ability. We used the Face and Emotion Processing Battery to assess socio-emotional function, which has been described previously (Miller et al., 2012; Kumfor et al., 2014). This battery assesses face perception and emotion decoding ability and consists of four subtests (i.e. Face-Perception, Face- Matching, Emotion-Matching, Emotion-Selection). During the Face-Perception task, individuals are shown 40 pairs of faces and are required to determine whether the images are identical or different. The remaining three tasks consist of 42 trials each. In the Face-Matching task, again, participants view pairs of faces expressing different emotions and are asked to determine whether the faces are the same person. In the Emotion-Matching task, participants view pairs of faces of different people and are asked to determine whether they are expressing the same emotion. Finally, in the Emotion-Selection task, individuals view an array of seven faces showing the six basic emotions (i.e. sadness, surprise, anger, disgust, fear, happiness) and a neutral expression and are asked to point to the face expressing the emotion that corresponds to the emotional label given verbally by the examiner. Images are from the NimStim stimulus set (www. mac-brain.org) and were cropped to remove any non-facial information (e.g. hair). All images are presented in greyscale. Responding is untimed and no feedback is provided. Behavioural change was assessed using the Cambridge Behavioural Inventory-Revised informant questionnaire (Wear et al., 2008; Wedderburn et al., 2008). This questionnaire assesses 10 domains of behaviour (e.g. mood, motivation, abnormal behaviour). For each item the informant reports how frequent the behaviour is on a 5-point scale from never (0) to constantly (4). Here, we focused on the subscales relevant to social function: abnormal behaviour (e.g. Shows socially embarrassing behaviour, Finds humour or laughs at things others do not find funny ), motivation (e.g. Shows reduced affection, Fails to maintain motivation to keep in contact with friends and family ), and stereotypical behaviour (e.g. Is rigid and fixed in her/his ideas, Develops routines from which s/he cannot easily be discouraged ). Statistical analyses Baseline and longitudinal comparisons of cortical thickness Baseline comparisons of cortical thickness between groups were performed using a vertex-wise general linear model (GLM) including cortical thickness as a dependent factor and group (healthy controls, left SD, right SD and Alzheimer s disease) as an independent factor, to identify patterns of neurodegeneration in each disease syndrome with respect to healthy controls. For the longitudinal analyses of cortical thinning, vertexwise comparisons of annual rate of change of cortical thickness among patient groups (left SD, right SD and Alzheimer s disease) were analysed using the Spatiotemporal Linear Mixed Effects (LME) Matlab tools (FreeSurfer version 5.2.0 onwards) (Bernal-Rusiel et al., 2013a, b). We assumed minimal change in brain integrity in our control group over time, and therefore did not include them in the longitudinal analyses. LME models provide a powerful and flexible approach for analysing longitudinal data while handling variable missing rates, nonuniform timing and making use of subjects with a single time point to characterize population-level regionally specific differences in cortical thickness (Bernal-Rusiel et al., 2013a).

990 BRAIN 2016: 139; 986 998 F. Kumfor et al. The mean response trends over time among the diagnostic groups (left SD, right SD and Alzheimer s disease) across the cortex were plotted. Visual inspection of the plots revealed linear trajectories over time for the three groups so we fitted a spatiotemporal LME model of cortical atrophy with two random effects: (i) the intercept; and (ii) time from baseline MRI acquisition (expressed in days). As the groups were matched at baseline in age, sex, disease duration and education, no covariates were included in the model. The null hypotheses of no change in cortical thickness over time and no Group Time interaction (i.e. group-specific atrophy rate) were tested. The significance maps for each contrast were written for visualization and postprocessing using tksurfer included in the Freesurfer software suite. We used the two-stage adaptive false discovery rate (FDR) procedure with an array of q- values (Benjamini et al., 2006) to control for multiple comparisons and the results were thresholded at a corrected P-value of 50.05. Baseline and longitudinal behavioural analyses Analyses were conducted using SPSS Statistics, version 22.0 (IBM). One-way analyses of variance were conducted to examine demographic variables as well as the outcome variables at baseline (ACE-R, Face and Emotion Processing Battery, CBI). Categorical variables were analysed using chi-square analyses. Post hoc analyses were corrected for multiple comparisons using a Sidak adjustment. For the baseline analyses, we compared the left and right SD groups with the Alzheimer s disease and control groups, to determine patterns of cognitive and social impairment across disease groups, with respect to a well-characterized older adult population. LME models were used to model the change in outcome variable according to diagnosis over time. The fixed effects in the model included diagnosis, follow-up time, and the interaction between diagnosis and follow-up time. The only random effect included was the individual variability associated with the patient at baseline (where we used the random intercept model). Residual errors of the model and the random intercepts for each participant at baseline were assumed to be normally distributed. All participants were assumed to be independent. The longitudinal analyses compared left SD, right SD and Alzheimer s disease patients, as we assumed minimal change in cognition and social functioning in our control group over time. Finally, to determine the relationship between cortical thinning and behavioural performance we calculated weighted correlation coefficients for each individual, to enable examination of correlations between subjects across repeated observations (Bland and Altman, 1995). Pearson two-tailed correlational analyses were then conducted with Bonferroni correction for multiple comparisons P 5a=k = 0.00278. Results Demographics As shown in Table 1, no significant differences in basic demographics, including age, sex and education, were observed across diagnostic groups (all P-values 4 0.05). All patient groups were matched for disease duration and functional ability as measured by the FRS (P-values 4 0.05). A difference in the number of followup visits between patient groups was, however, observed with the right SD cases having on average one follow-up visit fewer than the left SD group (P = 0.02). Baseline neuroimaging findings The baseline neuroimaging findings in each patient group compared to controls are reported in the Supplementary material. In brief, these analyses confirmed the typical profiles of cortical thinning with left SD showing bilateral asymmetrical cortical thinning with the left temporal pole more affected than the right. The right SD group showed a similar pattern but lateralized to the right temporal pole. Finally, patients with Alzheimer s disease showed extensive cortical thinning in the posterior lateral and medial surfaces bilaterally. Next, we compared patterns of cortical thinning between patient groups at baseline (Fig. 1). Compared with Alzheimer s disease, left SD showed relatively circumscribed cortical thinning in the bilateral anterior temporal lobes, with the left temporal lobe more affected than the right (shown in red-yellow), whereas the Alzheimer s disease group (shown in blue) showed greater precuneus/posterior cingulate and bilateral posterior parietal cortical thinning compared to left SD. Right SD showed cortical thinning in the right anterior temporal lobe on both the medial and lateral surfaces, with similar but less extensive regions identified in the left temporal lobe compared with Alzheimer s disease (shown in red-yellow). In contrast, compared with right SD, the Alzheimer s disease group showed a few small clusters of cortical thinning in the left posterior cingulate (shown in blue). Critically, comparisons between left and right SD confirmed that although these groups showed bilateral temporal cortical thinning, significant differences in the pattern and degree of cortical thinning were present between groups. Specifically, left SD showed greater left anterior temporal thinning on both the lateral and medial surfaces of the temporal lobe than right SD (shown in redyellow), whereas right SD showed greater cortical thinning in the right anterior temporal lobe than left SD (shown in blue) (Fig. 1). Longitudinal neuroimaging findings Within-group longitudinal changes from baseline are depicted in Fig. 2A. In left SD, progressive cortical thinning was observed in the temporal lobes bilaterally, with more widespread thinning in the left temporal lobe extending posteriorly into the left temporoparietal junction. In addition, progressive thinning was observed in the left superior orbitofrontal and superior frontal cortices. In right SD, extensive cortical thinning was observed across the lateral surface of the right hemisphere,

Left- versus right-lateralized SD BRAIN 2016: 139; 986 998 991 Figure 1 Baseline neuroimaging findings showing regions of cortical thinning between diagnostic groups. 4 denotes the group with greater cortical thinning. AD = Alzheimer s disease. together with somewhat more circumscribed thinning in the left lateral temporal lobe, anterior temporal pole and the bilateral cingulate and orbitofrontal cortex. In Alzheimer s disease, progressive cortical thinning was observed in the bilateral parietal and occipital regions, together with the posterior cingulate/precuneus and the inferior temporal gyri. Next, we compared the differential patterns of longitudinal cortical thinning across patient groups (Fig. 2B). Compared with Alzheimer s disease, left SD showed disproportionate cortical thinning in the right anterior temporal pole only, whereas Alzheimer s disease showed greater thinning in the right posterior cingulate/precuneus compared with left SD. In contrast, right SD showed greater cortical thinning in the left middle temporal gyrus extending into the superior temporal gyrus, together with the bilateral orbitofrontal cortices than Alzheimer s disease. In the right hemisphere, greater widespread cortical thinning was present across the lateral surface including the superior temporal gyrus, medial orbitofrontal cortex, and middle frontal gyrus, compared with Alzheimer s disease. No regions of greater cortical thinning were observed in Alzheimer s disease when compared with right SD. Finally, direct comparisons between left SD and right SD revealed distinct patterns of cortical thinning according to group. The patients with left SD showed greater cortical thinning in the right inferior temporal gyrus extending into the right fusiform when compared with right SD. In contrast, right SD showed greater thinning in the right medial orbitofrontal cortex and cingulate, right superior temporal gyrus and right middle frontal gyrus, when compared with left SD. Additional regions of cortical thinning were also identified in the right pre- and postcentral gyri and the right supramarginal gyrus in right SD compared to left SD. Importantly, these differences in progression do not appear to be due to a delayed diagnosis in the right SD group. A follow-up analysis comparing a subset of the patients with more severe left SD with the right SD group showed remarkably consistent findings as the overall analysis (Supplementary material). Baseline behavioural findings Cognition We investigated how these patterns of cortical thinning manifested clinically at baseline and over time across syndromes. At baseline, all patient groups showed overall cognitive impairment on the ACE-R compared to controls (all P-values 5 0.001), with left SD also impaired on this task compared to Alzheimer s disease (P 5 0.001) (Table 2). Detailed cognitive assessment indicated that left SD showed impaired performance in language, fluency, memory and attention on the ACE, as well as on the SYDBAT measures compared with both healthy controls and Alzheimer s disease. Right SD also showed impaired language, fluency and memory on the ACE and impaired naming, comprehension and semantic association on the SYDBAT, compared with controls and Alzheimer s disease. Alzheimer s disease patients in contrast showed impaired attention and memory, with fluency reduced compared to controls, but to a lesser extent than left SD. Alzheimer s disease also showed impaired visuospatial function on the RCF copy compared with controls but no impairments on the SYDBAT were observed (Supplementary material). Social function A significant effect of diagnosis was observed on the Face- Perception task (P = 0.045), with patients with right SD performing worse than controls (P = 0.037), whereas left SD and Alzheimer s disease performed within normal limits (P-values 4 0.05). On the Face-Matching task,

992 BRAIN 2016: 139; 986 998 F. Kumfor et al. Figure 2 Longitudinal changes in cortical thickness according to diagnostic group. (A) Within-group and (B) between-group longitudinal changes in cortical thickness in left SD, right SD and Alzheimer s disease (AD) patients. 4 denotes the group with greater cortical thinning. again a significant effect of diagnosis was observed (P = 0.002) with right SD (P = 0.002) impaired on this task, while the left SD (P = 0.242) and Alzheimer s disease groups (P = 0.062) performed within normal limits. A main effect of diagnosis was again present on the Emotion-Matching task (P 5 0.001). Here, right SD (P = 0.002) and left SD (P = 0.001) were impaired, while patients with Alzheimer s disease performed similarly to controls (P = 0.200). No significant differences were present between patient groups (all P-values 4 0.05). Finally, all patient groups performed worse than controls on the Emotion-Selection task, (all P-values 4 0.001). Notably, right SD also performed significantly worse than the Alzheimer s disease group on this task (P = 0.001) and tended to also perform worse than left SD (P = 0.056). No difference between left SD and Alzheimer s disease was observed (P = 0.569). On the CBI Abnormal Behaviour subscale, the right SD group showed more frequent abnormal behaviour than the Alzheimer s disease group (P = 0.015). No difference was observed between left and right SD (P = 0.634), although a trend for more frequent abnormal behaviour in left SD than Alzheimer s disease was observed (P = 0.059). Right SD also exhibited decreased motivation compared to Alzheimer s disease (P = 0.022). No difference in motivation was reported between right and left SD (P = 0.311) or left SD and Alzheimer s disease groups (P = 0.378). Finally, no difference in the level of stereotypical behaviour amongst patient groups was observed at baseline (P = 0.105) (Table 2).

Left- versus right-lateralized SD BRAIN 2016: 139; 986 998 993 Table 2 Baseline performance on the primary behavioural outcome variables according to diagnostic group Left SD n =22 Right SD n =9 AD n =33 Control n =25 F P-value Post hoc ACE Total 61.3 14.0 67.3 16.2 76.2 11.5 95.6 3.3 39.677 50.001 Patients 5 controls; left SD 5AD Face-perception a 96.8 7.8 89.7 16.2 95.2 6.9 98.4 3.0 2.819 0.045 Right SD 5 controls Face-matching a 78.2 22.6 65.5 8.1 76.6 8.9 86.7 9.4 5.519 0.002 Right SD 5 controls Emotion-matching a 79.7 8.0 78.0 8.8 83.5 4.8 87.1 4.5 7.603 50.001 Left SD, right SD 5 controls Emotion-selection a 74.1 15.5 61.3 12.3 79.3 11.2 92.0 6.7 18.225 5 0.001 Patients 5 controls; right SD 5AD CBI-abnormal behaviour b 22.1 24.5 30.6 31.9 9.2 9.4 5.315 0.008 Right SD 4AD CBI-motivation b 31.5 27.6 47.2 31.6 21.9 20.6 3.837 0.027 Right SD 4AD CBI-stereotypical behaviour b 34.8 33.9 39.6 32.3 21.1 22.2 2.347 ns Values are mean standard deviation. AD = Alzheimer s disease. Missing data: a Baseline scores on the Face and Emotion Processing subtests include individuals with at least one follow-up. Data available for: 19 left SD, eight right SD, 26 Alzheimer s disease and 25 controls. b Baseline scores on the CBI include individuals who had at least one follow-up on this measure: Data available for: 21 left SD, nine right SD and 32 Alzheimer s disease. Controls did not complete the CBI. Longitudinal behavioural performance Cognition The modelled trajectories for performance on the ACE, SYDBAT and RCF are reported in the Supplementary material. In brief, the only significant Time Diagnosis interaction on the ACE was on the language subtest (P = 0.002), with left SD (P 5 0.001) declining more over time compared with Alzheimer s disease. Right SD also declined compared with Alzheimer s disease, but not significantly so (P = 0.326). On the SYDBAT Naming, Comprehension and Semantic Association subtests both left and right SD declined more than Alzheimer s disease (all P-values 5 0.05). In contrast, on the RCF copy, patients with Alzheimer s disease declined significantly more than left SD (P = 0.003), but not right SD (P = 0.113) (Supplementary material). Social function The modelled trajectories for performance on the Face and Emotion Processing Battery and the CBI in left SD, right SD and Alzheimer s disease are shown in Table 3. These analyses revealed a significant change in performance over time on all tasks (P-values ranging between 0.021 and 50.001), with the exception of the Face-Matching task (P = 0.278). Absence of significant interactions between time and diagnosis on the ACE, Face-Perception task, Emotion-Matching task and the Abnormal Behaviour subscale of the CBI indicated that all patient groups declined at a similar rate on these measures. In contrast, a significant interaction between time and diagnosis was observed on the Emotion-Selection task (P =0.004), the CBI Motivation subscale (P = 0.026) and the CBI Stereotypical Behaviour subscale (P 5 0.001) (Fig. 3). On the Emotion-Selection task, both left SD (P = 0.003) and right SD (P = 0.028) declined at a faster rate than Alzheimer s disease. The left SD group showed greater changes in motivation over time than patients with Alzheimer s disease (P = 0.008), whereas the rate of change in right SD did not differ significantly from Alzheimer s disease (P = 0.228). Both left (P 5 0.001) and right (P = 0.002) SD groups showed significantly increased stereotypical behaviours with disease progression, compared with Alzheimer s disease. Correlations between cortical thinning and behavioural performance Finally, we investigated the associations between the behavioural variables (Emotion-Selection, CBI-motivation, CBIstereotypical) and the regions of cortical thinning (medial orbitofrontal cortex, temporal pole, fusiform cortex), which showed a significant Time Diagnosis interaction. Across all patients, correlational analyses revealed that emotion recognition ability was positively associated with cortical thickness of the right fusiform gyrus (r = 0.517, P 5 0.0001) and the right temporal pole (r = 0.450, P = 0.0002), with association with the right medial orbitofrontal cortex approaching significance (r = 0.354, P = 0.0048) (Table 4). In addition, reduced cortical thickness in the right temporal pole was associated with increased motivational difficulties (r = 0.409, P = 0.0008) and increased stereotypical behaviour (r = 0.354, P = 0.0041) as measured by the CBI. Correlation between the left temporal pole and motivation (r = 0.354, P = 0.0041) approached significance. Correlations separated by group did not reach statistical significance following correction for multiple comparisons. Correlations between cortical thinning and cognitive variables are reported in the Supplementary material. Discussion This study aimed to investigate longitudinal cortical changes in patients with SD with either predominant leftor right-lateralized temporal atrophy at initial presentation, and performance on aspects of social cognition and behaviour over time. Our results revealed divergent patterns of neurodegeneration both at baseline and longitudinally. Importantly, while left SD and right SD initially showed

994 BRAIN 2016: 139; 986 998 F. Kumfor et al. Table 3 Longitudinal analyses of outcome variables in left SD, right SD and Alzheimer s disease Follow-up time Diagnosis follow-up time interaction Parameter estimation coefficients F P-value F P-value Left SD Right SD AD ACE total 133.550 50.001 1.978 0.142 7.5 6.8 6.0 Face-perception 5.478 0.021 2.620 0.078 0.2 1.3 2.1 Face-matching 1.188 0.278 1.749 0.179 1.0 0.9 3.0 Emotion-matching 5.758 0.018 0.874 0.420 0.4 2.5 1.2 Emotion-selection 30.094 50.001 5.994 0.004 4.7 5.5 1.3 CBI abnormal behaviour 19.351 5 0.001 1.516 0.223 4.0 5.4 2.1 CBI motivation 25.292 5 0.001 3.720 0.026 8.2 7.6 3.3 CBI stereotypical behaviour 36.714 5 0.001 13.609 50.001 8.0 9.7 0.8 Data available on at least two time points for 22 left SD, nine right SD and 33 Alzheimer s disease on the ACE; 19 left SD, eight right SD and 26 Alzheimer s disease on the Face and Emotion Processing Battery; and 21 left SD, nine right SD and 32 Alzheimer s disease on the CBI. Note, higher positive scores on the CBI indicate greater behavioural abnormalities. The parameter estimation coefficients represent the estimated rate of annual percentage change according to diagnostic group. Figure 3 Longitudinal performance on the behavioural variables with significant Time Diagnosis interaction. Markers represent individuals. Lines represent line of best fit according to diagnosis using linear regression. Baseline (Day 0) is determined with respect to the first neurology appointment and ACE assessment. predominantly asymmetric anterior temporal lobe involvement, involvement of the contralateral hemisphere became apparent with disease progression. Notably, direct comparisons between left and right SD revealed progressive degeneration of the right anterior temporal lobe in left SD, while right SD showed right orbitofrontal and anterior cingulate changes, together with diffuse lateral cortical thinning with disease progression. These patterns were in contrast to that seen in Alzheimer s disease, with cortical thinning affecting primarily posterior brain regions bilaterally in this group. Behaviourally, the most significant findings were a change in the rate of degradation of emotion recognition and social behaviour across patients over time. Here, we discuss how our findings inform the characterization of these subtypes of frontotemporal dementia, with respect to syndrome-specific patterns of atrophy and current understanding of the role of the right anterior temporal lobe and orbitofrontal cortex in social cognition. Our findings revealed that in left SD, progressive cortical thinning of the temporal lobes bilaterally occurred over time, in line with prior studies (Brambati et al., 2007, 2009, 2015; Lam et al., 2014). Importantly, here, we have demonstrated for the first time a disproportionate degradation of the right anterior temporal pole and right fusiform gyrus in this group compared to right SD and Alzheimer s disease. At the behavioural level, this manifested as decline across the majority of social cognition and behavioural measures, with significantly faster decline in emotion recognition and greater social behaviour changes than Alzheimer s disease. Moreover, we found a significant association between right temporal pole integrity and emotion recognition and behaviour. While individuals with left SD typically present with semantic impairment, recent studies have reported impaired emotion processing in these patients (Rosen et al., 2002; Kumfor and Piguet, 2012; Kumfor et al., 2013a), in addition to the relatively circumscribed and slowly progressing changes in language (Leyton et al., 2013). Our neuroimaging and behavioural findings support the view that involvement of the right anterior temporal lobe is responsible for the emergence of social cognition deficits in these patients (see also Irish et al., 2014). The functions of the right temporal lobe

Left- versus right-lateralized SD BRAIN 2016: 139; 986 998 995 Table 4 Correlations between regions of cortical thinning and social functioning in patient groups Medial OFC Left Temporal pole Right Fusiform Medial OFC Temporal pole Fusiform Emotion-selection a 0.123 0.259 0.293 0.354* 0.450** 0.517** CBI-motivation b 0.306 0.354* 0.249 0.203 0.409** 0.244 CBI- stereotypical b 0.222 0.310 0.228 0.093 0.354* 0.217 OFC = orbitofrontal cortex. Data missing: Emotion Selection test one left SD and two Alzheimer s disease; CBI for one left SD. **P 5 Bonferroni a/k = 0.00278; *P 5 0.01 a degrees of freedom = 60; b degrees of freedom = 62. continue to be somewhat elusive to neuroscientists (Olson et al., 2007, 2013), with its primary role still contentious (Gainotti, 2015). Some argue that this region is necessary for representation of non-verbal information (with verbal information primarily subserved by the left temporal lobe), whilst others have suggested that the right temporal lobe is specialized for social cognition (for review of these arguments see Gainotti, 2015). Indeed, this region has been previously associated with abnormal emotional responses in the behavioural-variant of frontotemporal dementia and in clinical Alzheimer s disease (Kumfor et al., 2013a; Sturm et al., 2013; Lee et al., 2014). Our results align with the proposition that social cognition is lateralized to the right anterior temporal lobe. In right SD, our findings revealed widespread bilateral cortical thinning with disease progression. Importantly, compared to both Alzheimer s disease and left SD, right SD showed significant cortical thinning in the right orbitofrontal cortex and anterior cingulate. Until now, the pattern of pathological spreading in right SD has been relatively unclear (see also Brambati et al., 2009). Behaviourally our right SD cohort exhibited widespread impairments in social cognition and behaviour at first presentation, including aspects of basic face and identity recognition, emotion perception and behavioural change, findings that concur with recent studies (Irish et al., 2013; Kumfor et al., 2015; Kamminga et al., 2015). Importantly, our findings revealed that with disease progression, individuals with right SD continue to decline significantly faster across most aspects of social cognition and behaviour, than patients with Alzheimer s disease. In addition, patients with right SD show additional loss of language abilities with disease progression. The continuing decline of social function converges with the documented cortical thinning in the right orbitofrontal cortex and right anterior cingulate in these patients. The degradation of the orbitofrontal cortex has been reliably associated with the manifestation of socioemotional disturbance in frontotemporal dementia, especially in individuals with the behavioural variant (Viskontas et al., 2007; Kumfor et al., 2013b; Hutchings et al., 2015). Indeed, here we found an association between right medial orbitofrontal cortex integrity and emotion recognition. The orbitofrontal cortex is thought to be involved in emotion processing, reward and decision-making (Bechara et al., 2000; Rolls, 2004) and may be particularly important for tagging the emotional nature of stimuli (Kumfor et al., 2013b). Our results suggest that while degradation of the right temporal pole likely underpins the manifestation of the initial symptoms in right SD, including prosopagnosia, with disease progression, encroachment into the right orbitofrontal cortex leads to further disintegration of social function in these patients. Of relevance here are the dense connections between the orbitofrontal cortex and the anterior temporal pole, via the uncinate fasciculus (Von Der Heide et al., 2013). How pathology spreads across different neuropathological syndromes still remains poorly understood (Fletcher and Warren, 2011). The pattern of progression in both left and right SD observed here, together with the previously reported degree of bilateral involvement in both these syndromes (Galton et al., 2001; Mion et al., 2010), however, point towards pathology spreading between functionally connected regions via commissural fibres (Fletcher and Warren, 2011). Fine-grained assessment of these syndromes with a focus on the ongoing degradation of social function and behaviour will be key to further unravelling the organization and function of the social brain. In Alzheimer s disease, social cognition and behaviour remained relatively spared despite the pervasive atrophy and progressive decline in general cognitive ability. These findings closely reflect anecdotal and clinical reports of maintained social graces in Alzheimer s disease even in the moderate disease stages (for review see Kumfor and Piguet, 2013). In contrast to the current findings, one study reported decline in emotion recognition over a 40- month period in seven patients with Alzheimer s disease (Lavenu and Pasquier, 2005). Here, with a large and well-characterized sample, we demonstrate minimal decline in social cognition and behaviour in Alzheimer s disease. This encouraging finding suggests that novel behavioural interventions may be able to harness this spared ability to improve the quality of life of Alzheimer s disease patients and their families (Kumfor et al., 2013b). Pathologically the vast majority of left SD patients have frontotemporal lobar degeneration with TAR DNA binding protein 43 (FTLD-TDP) pathology (Chare et al., 2014) but few studies have examined the pathological basis of right SD to date. A recent case study reported FTLD-TDP

996 BRAIN 2016: 139; 986 998 F. Kumfor et al. pathology in an individual who initially presented with right SD, pointing towards a common pathological basis for these two clinical phenotypes (Henry et al., 2012), in keeping with previous studies (Hodges et al., 2004; Davies et al., 2005). Other reports, however, have suggested that only a subset of right SD cases with co-occurring semantic deficits have FTLD-TDP pathology, whereas those with a behavioural presentation were associated with tau mutations (Josephs et al., 2009). Future studies combining longitudinal clinical, neuroimaging and pathological findings will be essential to further understand the pathophysiological basis of these related syndromes. A further caveat is that our study included a relatively small number of right SD cases. Nevertheless, here the data were maximized using LME modelling. This approach handles unbalanced data (with variable missing rates across time points and imperfect timing), utilizes participants with a single assessment to characterize inter-subject variation and allows the representation of the group mean trajectory and covariance structure between serial measurements. Compared to alternative approaches, LME models offer superior statistical power in detecting longitudinal group differences (Bernal-Rusiel et al., 2013a), which is important when examining these rare clinical syndromes. In conclusion, our findings provide support for the hypothesis that, over time, left and right SD evolve into a similar clinical profile, with social cognition affected in both these phenotypes, despite showing divergent patterns of cortical thinning at baseline and with disease progression. Our findings also offer novel insights into the social brain, providing convergent evidence that both the right anterior temporal pole and orbitofrontal cortex are key players in the successful engagement in and contribution to complex human social interactions. These findings are important for clinicians to bear in mind when considering the disease course and prognosis of individuals with left and right SD and demonstrate the importance of studying these dementia syndromes to uncover new insights into brain-behaviour relationships. Acknowledgements The authors are grateful to the participants and their families for supporting our research. Funding This work was supported by a National Health and Medical Research Council of Australia (NHMRC) Research Project Grant (510106) and by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the NHMRC (APP1037746) and the Australia Research Council (ARC) Centre of Excellence in Cognition and its Disorders Memory Node (CE11000102). F.K. is supported by an Alzheimer s Australia Dementia Research Foundation Postdoctoral Fellowship. E.D. is supported by a UNSW PhD scholarship and the Motor Neuron Disease Association UK. R.H. is supported by an Australia Postgraduate Award. O.P. is supported by an NHMRC Career Development Fellowship (APP1022684). Supplementary material Supplementary material is available at Brain online. References Bechara A, Damasio H, Damasio AR. Emotion, decision making and the orbitofrontal cortex. Cereb Cortex 2000; 10: 295 307. Benjamini Y, Krieger AM, Yekutieli D. 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