Brain Imaging and Behavior DOI 10.

1007/s11682-013-9261-0

BRIEF COMMUNICATION

Neural correlates of the mini-SEA (Social cognition and Emotional Assessment) in behavioral variant frontotemporal dementia
M. Bertoux & E. Volle & L. C. de Souza & A. Funkiewiez & B. Dubois & M. O. Habert

# Springer Science+Business Media New York 2013

Abstract Although Frontotemporal Dementia (FTD) is the second most common form of dementia after Alzheimers disease, its diagnosis remains particularly challenging today. This is particularly true for the behavioral variant (bvFTD), the most common phenotype of FTD, which is characterised by dramatic changes in personal and social conduct. Novel clinical cognitive tests have been recently proposed to diagnose and assess these patients. Among them, the mini-SEA (Social cognition & Emotional Assessment) has shown promising results. This quick clinical tool evaluates emotion recognition and theory of mind deficits, both recognized as hallmark features of bvFTD. In this study, we investigated the neural correlates of the mini-SEA in twenty bvFTD patients, using single photon emission computed tomography (SPECT) and focusing on the mPFC. Results showed that

detection of faux pas during a theory of mind evaluation was related to rostral mPFC perfusion (BA 10) while recognition of emotion involved more dorsal regions within the mPFC (BA 9). As significant and early dysfunction of the mPFC has been extensively described in bvFTD, this study supports the use of the mini-SEA in evaluation and diagnosis purposes in bvFTD. Keywords Frontotemporal dementia . bvFTD . Theory of mind . Emotion . Mini-SEA

Introduction The Social cognition and Emotional Assessment (SEA) has been recently proposed to improve the clinical diagnosis of the behavioral variant frontotemporal dementia (bvFTD) (Funkiewiez et al. 2012). This young-onset disease, second to Alzheimers disease in prevalence, is characterized by early alterations in behavior and personality, loss of insight, disinhibition, social inappropriateness and emotional blunting (Piguet et al. 2011). The purpose of this neuropsychological battery is to assess the cognitive dysfunctions that may be responsible for the behavioral impairments observed in bvFTD in order to provide an objective evaluation of behavioral deficit that are classically assessed by clinical scales such as the Cambridge Behavioural Inventory (Wedderburn et al., 2008) or the Neuropsychiatric Inventory (Kertesz et al. 2000) that require the help of a carer. Through its five subtests, the SEA was designed to assess motivation, theory of mind, emotion recognition, behavioral control and reversal learning impairments, that all have been recognized as hallmark features of bvFTD (Neary et al. 2005; Piguet et al. 2011). In order to fit to the time and material constraints of a standard clinical assessment, a reduced version of the SEA (mini-SEA) was proposed. The mini-SEA

M. Bertoux (*) : E. Volle : L. C. de Souza : B. Dubois Centre de Recherche de lInstitut du Cerveau et de la Moelle pinire (CRICM), Universit Pierre et Marie-Curie (UPMC), INSERM UMRS 975, Paris, France e-mail: maximeL.bertoux@gmail.com M. Bertoux : A. Funkiewiez : B. Dubois Centre de Rfrence Dmences Rares, Paris, France M. O. Habert INSERM, UMR-S 678, Universit Pierre et Marie Curie-Paris 6, 75013 Paris, France M. Bertoux : E. Volle : L. C. de Souza : A. Funkiewiez : B. Dubois Institut de la Mmoire et de la Maladie dAlzheimer, Pavillon Franois Lhermite, GHU Hospitalier de la Piti-Salptrire, 47 boulevard de lHpital., 75013 Paris, France M. O. Habert Service de mdecine nuclaire, GHU Hospitalier de la Piti-Salptrire, 47 boulevard de lHpital., 75013 Paris, France

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allows a quick and easy assessment of social-cognition and emotional processing through a reduced version of the theory of mind test (TOM; the ability to attribute mental states to others), and a facial emotion recognition test. This tool has showed a good discrimination power to differentiate bvFTD patients from its two main differential diagnoses: Alzheimers disease and major depression (Bertoux et al. 2012a, b). Neural correlates of the mini-SEA subtests have been recently investigated through voxel-based morphometry (VBM) in bvFTD (Bertoux et al. 2012c). Results have shown an association between its two subtests and the rostral and dorsal medial prefrontal cortex (mPFC), which is concordant with previous neuroimaging investigations of these functions (Frith and Frith 2006; Shamay-Tsoory et al. 2005; Hornak et al. 2003). Given that symptoms of bvFTD have been mostly related to progressive dysfunctions of frontal and temporopolar regions (Agosta et al. 2011; Schroeter et al. 2008), especially in the mPFC, cognitive tests tapping into this region such as the mini-SEA, could be very useful for evaluation and diagnosis purposes. The aim of the current study was to investigate the neural correlates of the mini-SEA through brain perfusion imaging, using single photon emission computed tomography (SPECT). Based on converging evidences from literature and previous VBM results (Bertoux et al. 2012c), we hypothesized that scores at both subtests are correlated to regional perfusion in specific areas within the anterior mPFC.

Descriptions of the test design, instructions and scoring are detailed in a previous study (Funkiewiez et al. 2012). Faux-pas test We used a short (ten stories) version of the Faux-Pas Test (Stone et al. 1998) to evaluate TOM. We calculated a detection of faux-pas score, the ability to detect a social inconvenience in the stories. Emotions recognition test Thirty-five faces from Ekman pictures (Ekman and Friesen 1975) were presented. Patients had to identify which emotion was being expressed (among a list of seven different emotions presented in the top of the screen). They had to choose between fear, sadness, disgust, surprise, anger, happiness and neutral. A general recognition percentage was calculated. Brain perfusion SPECT acquisition and pre-processing Brain SPECT was performed while patients rested in quiet surroundings, with eyes closed, after intravenous injection of 740900 MBq of 99mTc-ECD. One hundred and twenty projections were acquired over 360, using a triple-head gamma camera equipped with a high resolution and low-energy parallel collimators (IRIX, Philips). Projections were reconstructed with an interactive algorithm, and filtered using a low-pass filter (cut-off frequency 0.4 cycle/pixel). Attenuation correction was performed using ellipses outer-line approximation and Changs method (coefficient of 0.12/cm). All images were converted and processed using SPM8 (Wellcome Department of Cognitive Neurology, University College, London) running under Matlab R2011a (Mathworks Inc., Sherborn, MA). Images were spatially normalized to the Montreal Neurological Institute space using the SPECT template provided in SPM and a 12-parameter affine and non-linear transformations. Each normalized scan was visually checked for intensity or shape artefacts. Normalized images were smoothed using an isotropic 12 mm Gaussian kernel to remove high-frequency noise and to minimize inter-individual differences. Dimensions of the resulting voxel were 222mm. We removed differences in global cerebral activity between subjects by scaling the activity in each voxel with reference to the averaged cerebellar activity. Region of interest (ROI) analysis We looked for correlations between mini-SEA performance and a priori anatomical ROI, based on converging evidence from the literature. Anatomical ROI were defined as follows. TOM functioning has been reliably related to mPFC, and particularly to the

Method Patients Twenty bvFTD patients were recruited via the National Reference Center for Rare Disease of the Piti-Salptrire Hospital in Paris (France). Demographics and neuropsychological data are presented in Table 1. All patients fulfilled diagnostic criteria for bvFTD (Rascovsky et al. 2011) and had no additional neurological (such as amyotrophic lateral sclerosis) or psychiatric disorder. All patients were extensively evaluated with clinical, neuropsychological and neuroimaging exams. Furthermore, all patients had at least 18 months of clinical follow-up in a clinical centre with expertise in the field of FTD. According to French legislation, explicit informed consent for patients was waived. It is important to note that the current patient group is an independent sample from the previous VBM study. Mini-SEA All patients underwent the mini-SEA within 6 months of SPECT. We briefly describe below each subtest and how raw scores used in the imaging analysis were calculated.

Brain Imaging and Behavior Table 1 Demographic and neuropsychological data of bvFTD patients. Pathological threshold were established according to each test normative data. Control scores from Bertoux et al. (2012a, b, c) were used as comparative data for the mini-SEA subscores. Mean (SD) [Range]

Demographics Age Gender Educational level Duration of disease (year) Neuropsychological assessment

63.5 (10.4) [4784] 4 F/16 M 4.7 (1.9) [27] 3.7 (2.4) [0.59] Patients scores Number of patient with pathological score 9 8 7

Mini mental state examination (/30) Frontal assessment battery (/18) Mattis Dementia Rating Scale (/144) Modified WCST Number of criteria (/6) Perseveration errors Words denomination (/12) Free and cued selective reminding test Encoding (/16) Free recall (/48) Total recall (/48) Mini-SEA Emotions recognition general percentage Faux-Pas test detection score (/20)

24.2 (4.6) [1029] 13.1 (3.9) [218] 125.2 (13.3) [94 138] 3.3 (1.9) [16] 7.6 (6.6) [024] 11.7 (0.8) [912] 14.2 (2.2) [916] 20.7 (5.5) [1130] 42.9 (5.8) [2948] Patients scores 64.2 (13.7) [28.677] 12.7 (1.8) [915]

10 N.A. 2 6 5 5 Control scores 84.3 (7.4) [6897] 18.8 (1.4) [1620]

median anterior part of Brodmann Area (BA) 10 (Frith and Frith 2006; Shamay-Tsoory et al. 2005; Roca et al. 2011). One ROI thus included medial BA10. Emotion recognition has also found to be related with median prefrontal cortex, particularly with median BA 9 (Hornak et al. 2003; Ruby and Decety 2004; Fusar-Poli et al. 2009). The second ROI included medial BA9. Finally, using the mini-SEA, a previous study from our team with structural imaging have also linked TOM with BA 10 and emotion recognition with BA 9 in bvFTD patients (Bertoux et al. 2012c). Each ROI was built from BA provided by the wfu_pickatlas tool for Matlab (http://www. fmri.wfubmc.edu/download.htm). We entered the pre-processed images and the mini-SEA subscores into multiple regression analysis in order to explore relationships between local perfusion decrease in these ROI and performance at mini-SEA subtests. Age and MMSE were covaried out. SPM(T) maps were calculated for correlation between a given mini-SEA subscore and perfusion of the corresponding region of interest, using Small volume correction (SVC), with a threshold of p <0.05 FWE-corrected for multiple comparison, and a minimal cluster size extent of 0 voxels. We performed separate SVC analyses for each of the subtests and their corresponding region of interest. Thus, BA 10 was used for Faux-Pas test (detection score) and BA 9 was used for emotion test (recognition percentage). Five patients did not undergo the Faux-Pas test due to an extreme fatigability; the size of the group for this analyse was thus 15 patients.

In addition to the small volume correction analyses, individual adjusted values were extracted for each significant maxima (defined as 2x2x2mm box centered on cluster maxima) using the MarsBar region of interest toolbox for SPM (http://marsbar.sourceforge.net). Correlations between the mean perfusion in each of these maxima and cognitive scores were then evaluated using a non-parametric Spearman R test. The aim of this analysis was to better describe the effects observed in the SPM analysis.

Results Significant positive correlation (pFWE <.05; T =6.74) was found between the faux-pas detection score and a cluster (78 voxels) localized in the left median BA 10 (coordinates: 6 68 2) within the median BA 10 ROI (Fig. 1a). Perfusion in this region correlated with the Faux-Pas subtest (R =0.57; p <0.05) but not with the emotion recognition subtest. Significant positive correlation (pFWE < .05; T = 4.02) was also found between emotion recognition percentage and a cluster (23 voxels) in the left median BA 9 (coordinates: 4 52 38) within the median BA 9 ROI (Fig. 1b). Perfusion in this region correlated with the emotion recognition subtest (R =0.46; p <0.05) but not with the FauxPas subtest.

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Discussion The aim of this study was to determine, using SPECT imaging, brain regions associated with each component of the mini-SEA. During the TOM evaluation, the ability to detect the presence of a social inconvenience in verbal stories (Faux-Pas Test) was correlated with perfusion in the left mPFC (BA 10). This result is consistent with our previous study in structural imaging that has also revealed a correlation between Faux-Pas Test and atrophy in this particular region in bvFTD (Bertoux et al. 2012c). While results from Lee et al. (2010) suggest that this Faux-pas detection impairment could be not specific to a medial frontal lesion, it brings another evidence that the integrity of rostral mPFC is critical for TOM abilities. Links between this metacognitive process and BA 10 has been previously shown through lesion or functional imaging studies (ShamayTsoory et al. 2005; Frith and Frith 2006). mPFC is indeed involved in 93 % of neuroimaging studies on theory of mind

together with OFC (Carrington and Bailey 2009) and is considered as a key structure that integrates social information to determine explicit representations of other peoples mental states (Adenzato et al. 2010). The performance in identification of facial emotions test was correlated with perfusion in the left mPFC (BA 9). The link between emotions recognition and mPFC (BA 9) has been highlighted through functional imaging studies in normal subjects when they had to identify or attribute an emotion to a face or a person (Lane et al. 1997; Ochsner et al. 2004). Alterations of facial emotions recognition and subjective emotional state after surgical lesions of BA 9 have also been shown by Hornak et al. (2003). According to Peelen et al. (2010), mPFC (BA 9) carries processes information about emotion categories regardless of the specific sensory cues and it seems to integrate supramodal emotion representations. Interrogations could be raised concerning the specificity of the correlations we observed. For each of the regions that

Fig. 1 Correlation between brain perfusion and (a ) detection of faux-pas score; (b ) emotion recognition percentage in bvFTD at a threshold of p <0.05 FWE-corrected for multiple comparison and plots of the normalized perfusion values for significant maxima in the left BA10 (a ) and left BA 9 (b )

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correlated significantly with a given subtest, we looked for correlation with the other mini-SEA subtest. No other correlation was found. We think this is a valuable argument to reinforce the assumption that the mini-SEA evaluates two different and distinct cognitive functions, associated with different cerebral areas. In addition, twenty subjects is a minimum for a correlation study and the small size of the group probably negatively biases significance thresholds and the force of the link we observed. However, since we a priori hypothesized to find correlations between perfusion decrease in the anterior mPFC, a ROI analysis with SPM was conducted. We defined two ROI based on converging evidences of the literature and from a previous study using structural imaging in bvFTD. Significant correlation between the Faux-Pas Test and perfusion in the rostral medial PFC, and between the Emotion recognition test and perfusion in more dorsal part of the medial PFC were observed. These findings are consistent with previous structural imaging results in bvFTD that have reported similar results (Bertoux et al. 2012c) and could be linked to recent metaanalyses indicating that both hypometabolism and atrophy compromise mainly the mPFC in the early stages of bvFTD (Schroeter et al. 2008; Adenzato et al. 2010; Agosta et al. 2011). Despite the recent advances in brain imaging, neuropsychology and genetics, the diagnosis of behavioral variant of frontotemporal dementia (bvFTD) is, still today, particularly challenging. Except genetic mutations, no blood or cerebrospinal fluid markers are available for the diagnosis of bvFTD, and thus, the diagnosis remains clinical in most of the cases. Moreover, recent studies have showed that patients with bvFTD can present with similar episodic memory deficits that those suffering from Alzheimer s disease on neuropsychological testing (Hornberger et al. 2010), which clearly complicate the diagnosis. Taken together, these last points highlight the need of novel clinical tests tapping into the cognitive functions that are specifically impaired in bvFTD and that are linked to the cerebral areas that are early and specifically involved in the neurodegeneration process, such as the mPFC (Schroeter et al. 2008). In this context, the mini-SEA, which was proposed as a fast and useful clinical tool to assess social cognition in bvFTD, showed encouraging results. Given that this tool showed high specificity and sensitivity to differentiate bvFTD from AD (Bertoux et al. 2012a) and that another evidence of its link with mPFC dysfunction in bvFTD was brought in this study, the use of the mini-SEA appears relevant to help the diagnosis processing in bvFTD.

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Conflict of interest The authors declare that they have no conflict of interest.

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