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JNNP Online First, published on January 16, 2015 as 10.1136/jnnp-2014-309445 Cognition

REVIEW

Theory of mind in behavioural-variant frontotemporal dementia and Alzheimer’s disease: a meta-analysis Emre Bora, Mark Walterfang, Dennis Velakoulis ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ jnnp-2014-309445). Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia Correspondence to Dr Emre Bora, Department of Psychiatry, University of Melbourne, Alan Gilbert Building NNF level 3, Carlton, VIC 3053, Australia; [email protected] Received 9 September 2014 Revised 20 November 2014 Accepted 28 December 2014

ABSTRACT Current evidence suggests that neurocognitive testing has limited practical benefit in distinguishing behavioural-variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD). In this meta-analysis of 30 studies, theory of mind (ToM) performances of 784 individuals with bvFTD (n=273) and AD (n=511) were compared with 671 healthy controls. ToM performances of 227 patients with bvFTD and 229 with AD were also compared in studies matched for general cognition. ToM was impaired in both bvFTD (d=1.79) and AD (d=1.15). In bvFTD, patients were particularly impaired in advanced tasks such as recognition of faux pas and sarcasm (d>2.0). In AD, ToM deficits were relatively modest. In studies matched for general cognition, ToM was significantly impaired in bvFTD in comparision to AD (d=1.29), especially for faux pas recognition (d=1.75). ToM dysfunction is a robust and more specific feature of bvFTD. In contrast, ToM deficits are modest compared with level of general cognitive impairment in AD. In both disorders, longer duration of disease and level of general cognitive impairment are related to relatively more severe ToM deficits. Assessment of ToM can be beneficial for early identification of bvFTD.

INTRODUCTION

To cite: Bora E, Walterfang M, Velakoulis D. J Neurol Neurosurg Psychiatry Published Online First: [ please include Day Month Year] doi:10.1136/ jnnp-2014-309445

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are among the most common forms of dementia. Unlike AD, behavioural-variant FTD (bvFTD) is primarily characterised by behavioural problems and changes in social conduct and personality rather than memory problems.1 Accurate and timely differential diagnosis of AD and FTD is important, as there are significant differences in management of these conditions. Most importantly, a number of pharmacological treatments that are temporarily effective in enhancing cognition are available for AD but not for FTD.2 3 Definitive diagnoses of AD and FTD can only be made at autopsy or via genetic testing in familial cases, therefore it is important to develop clinical diagnostic methods that have high specificity and sensitivity in the early phases of dementia. The current diagnostic approach is based on clinical criteria incorporating neuropsychological and brain imaging assessments in addition to behavioural changes. In the international consensus criteria for behavioural bvFTD, neuropsychological criteria suggest that bvFTD is associated with more severe deficits in executive functions, yet relatively preserved memory and visuospatial functions.1

In practice, cognitive testing on its own has been proved to be only modestly helpful in differentiating FTD and AD. Studies using objective neuropsychological tests have yielded inconsistent findings. A meta-analysis of studies comparing neuropsychological differences using traditional testing methods between AD and FTD provided some evidence of differences between groups.4 AD disorder was associated with more severe problems in memory, general cognition and orientation (Cohen D values around 1); whereas FTD was associated with more severe deficit in verbal abilities. Yew et al5 reported that orientation and memory might have modest discriminatory potential between AD and bvFTD. However, there is still a significant overlap between the two groups even for these measures. Moreover, a number of recent studies showed that memory may be substantially impaired in bvFTD as well.6 7 Importantly, there were only small differences between groups for executive function, despite the fact that executive dysfunction is part of current diagnostic criteria of bvFTD. There might be other executive abilities such as inhibition and tasks specifically assessing ventromedial frontal dysfunction as these abilities might be more specifically impaired in bvFTD, but more studies are needed to test these hypotheses.8 Overall, few neuropsychological domains (ie, memory and orientation) have any value (and only to a limited extent) for aiding differentiation of FTD from AD. A potential alternative neuropsychological candidate for differentiating between FTD and AD is social cognition.8 9 Abnormal social and interpersonal functioning, in addition to behavioural disturbances, are more pronounced in bvFTD than in AD.10 11 Such deficits may be early and dominant characteristics of FTD and impaired ability in empathy is among the current behavioural criteria of bvFTD (3). However, assessment of social cognition deficits is not included in current neuropsychological criteria of bvFTD.3 Additionally, social cognition is likely to be more directly related to interpersonal functioning than cognitive abilities measured by standard neuropsychological batteries. Social cognition, especially theory of mind (ToM), has been found to be substantially impaired in a number of conditions that present with significant impairments in social functioning, including autism spectrum disorders and schizophrenia, and evidence suggests that ToM impairment is related to social and behavioural

Bora E, et al. J Neurol Neurosurg Psychiatry 2015;0:1–6. doi:10.1136/jnnp-2014-309445

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Cognition disturbances in these conditions.12–14 While research into ToM is relatively new in FTD compared with in autism and schizophrenia, emerging evidence suggests that ToM is also impaired in FTD. Additionally, the neuroanatomical profile of FTD primarily includes atrophy in regions that have a role in ToM including ventromedial, lateral temporal and frontoinsular cortices.15 16 Therefore, it is possible that ToM deficits may be more specific to FTD, especially in early phases, and may underpin the dominant interpersonal and behavioural dysfunction. This may have implications for early diagnosis of FTD, and in the differentiation of FTD from AD. A number of recent studies examining ToM deficits in FTD and AD have been published.17–19 However, the sample sizes of most of these studies are small and there is significant variability in magnitude of group differences between bvFTD and AD, and controls. There are also inconsistencies regarding discriminatory potential of ToM and most useful ToM measures. A meta-analysis of the ToM findings to date can help clarify findings where statistical power has been inadequate (ie, findings that are not consistent across studies), and also offers the means to examine the influence of demographic confounders, clinical stage and general cognitive deficits. To our knowledge, there is only one recent meta-analysis that examined ToM differences between bvFTD and healthy controls (HC), but no previous meta-analysis has investigated ToM deficits in AD.20 The aforementioned Henry et al20 study calculated a ToM score based on numerous very different ToM tasks. It is important to investigate the diagnostic specificity of particular ToM tasks, as it is likely that some ToM tasks may have a greater capacity to distinguish FTD from AD. It is also crucial to investigate the relationship between neurocognition and ToM deficits. The goal of the current meta-analysis was to compare ToM deficits in FTD and AD by taking into account the general cognitive impairment and ToM task used.

METHODS Study selection PRISMA and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines were used in conducting this meta-analysis.21 22 A literature search was conducted using the databases PubMed, PsycINFO and Scopus to identify the relevant studies ( January 1990 to March 2014 using the combination of keywords as follows: dementia, Alzheimer, frontotemporal, theory of mind, mentalisation and social cognition). Reference lists of published reports were also reviewed for additional studies. Inclusion criteria were studies that: (1) examined ToM abilities; (2) reported sufficient data to calculate the effect size and SE of the ToM measure; and (3) compared the neurocognitive performances of at least two of the following three groups: patients with FTD (frontal/behavioural-variant) (bvFTD), AD and HC. A number of groups had published multiple reports based on overlapping samples; only the study with the largest sample size was included in the current meta-analysis. Reports from Gleichgerrcht et al23 and Torralva et al,24 which were included in the meta-analysis of Henry et al,20 were excluded, as their samples were overlapping with the Torralva et al19 that was included in the Henry et al and the current meta-analyses (personal communication with Dr Torralva). Two new studies from the same group were reported to be based on independent samples and not overlapping with previous studies ( personal communication with Dr Ibanez) were included. A total of 30 studies were included in the current meta-analysis (see online supplementary table S1; see online 2

supplementary figure for flow chart of study selection process). For bvFTD-AD comparisons, studies that were only matched for mini mental state examination (MMSE) or non-MMSE general cognition tests (Addenbrooke’s Cognitive Examination (ACE), Mattis dementia rating scale (MDRS)) were included (see online supplementary table S2). This step was undertaken to ensure that bvFTD and AD groups were matched for cognitive abilities.

BvFTD versus HC Eighteen studies (including 20 bvFTD samples) comparing bvFTD participants (n=334; 64.4% male) and HC (n=391; 44.8% male) were included in the study. There were no significant between-group differences for age (d=0.10, CI −0.20 to 0.41, z=0.66, p=0.51).

AD and controls Twenty studies comparing 402 individuals with AD (44.4% male) and HC (n=421; 34.9% male) were included in the study. Patients with AD were significantly older than the controls (d=0.38, CI 0.08 to 0.67, z=2.51, p=0.01).

AD and bvFTD Thirteen studies consisting of 228 patients with bvFTD (65.3% males) and 229 patients with AD (55.3% males) were included in the meta-analysis. Patients with AD were significantly older than patients with bvFTD (d=0.62, CI 0.35 to 0.89, z=4.51, p0.50 indicate large magnitudes. Tau squared (τ2), an estimate of between study variance was used as measure of heterogeneity in the randomeffects model. The possibility of publication bias was assessed with Egger’s test. In the case of a significant Egger’s test, funnel plots were visualised to see whether the significant Egger’s test related to small study effect. The fail-safe N test was also used. This test involves computing a combined p value for all studies included in the meta-analysis, and calculating how many additional studies with a zero effect (average z of zero) would be necessary to create a non-significant p value. Meta-regression analyses were conducted for age (age of patient group and effect size of between-group difference), gender (male ratio in patient group and effect size of between-group difference), duration of education (effect size of between-group difference), MMSE, global cognition (effect size of between-group difference for ACE or MDRS), ACE (score of Bora E, et al. J Neurol Neurosurg Psychiatry 2015;0:1–6. doi:10.1136/jnnp-2014-309445

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Cognition patient group), executive function (effect size of between-group difference) and duration of disease. Effect size for executive function was calculated based on pooled score of most commonly used individual tasks (Wisconsin Card Sorting Test and letter fluency) or frontal screening tools (frontal assessment battery or INECO frontal screening). Meta-regression analyses (weighted generalised least squares regressions) were conducted using SPSS V.11.0 (SPSS Inc, USA). Meta-regression analyses performed with a random effects model were conducted using the restricted-information maximum likelihood method with a significance level set at p

Theory of mind in behavioural-variant frontotemporal dementia and Alzheimer's disease: a meta-analysis.

Current evidence suggests that neurocognitive testing has limited practical benefit in distinguishing behavioural-variant frontotemporal dementia (bvF...
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