Combined Socio-Behavioral Evaluation Improves the Differential Diagnosis Between the Behavioral Variant of Frontotemporal Dementia and Alzheimer’s Disease: In Search of Neuropsychological Markers

Abstract

Background:

Current diagnostic criteria for behavioral variant of frontotemporal dementia (bvFTD) and typical Alzheimer’s disease (AD) include a differential pattern of neuropsychological impairments (episodic memory deficit in typical AD and dysexecutive syndrome in bvFTD). There is, however, large evidence of a frequent overlap in neuropsychological features, making the differential diagnosis extremely difficult.

Objectives:

In this retrospective study, we evaluated the diagnostic value of different cognitive and neurobehavioral markers in bvFTD and AD patient groups.

Methods:

We included 95 dementia patients with a clinical and biomarker evidence of bvFTD (n = 48) or typical AD (n = 47) pathology. A clinical 2-year follow-up confirmed clinical classification. Performances at basic cognitive tasks (memory, executive functions, visuo-spatial, language) as well as social cognition skills and neurobehavioral profiles have been recorded. A stepwise logistic regression model compared the neuropsychological profiles between groups and assessed the accuracy of cognitive and neurobehavioral markers in discriminating bvFTD from AD.

Results:

Statistical comparison between patient groups proved social cognition and episodic memory impairments as main cognitive signatures of bvFTD and AD neuropsychological profiles, respectively. Only half of bvFTD patients showed attentive/executive deficits, questioning their role as cognitive marker of bvFTD. Notably, the large majority of bvFTD sample (i.e., 70%) poorly performed at delayed recall tasks. Logistic regression analysis identified social cognition performances, Frontal Behavioral Inventory and Mini-Mental State Examination scores as the best combination in distinguishing bvFTD from AD.

Conclusion:

Social cognition tasks and socio-behavioral questionnaires are recommended in clinical settings to improve the accuracy of early diagnosis of bvFTD.

Keywords

Alzheimer’s disease frontotemporal dementia neurodegenerative disease neuropsychology social skills

INTRODUCTION

The clinical presentation of the behavioral variant of frontotemporal dementia (bvFTD) is characterized by progressive and insidious behavioral alterations variably associated to cognitive impairments, mainly involving executive/generation deficits with relative sparing of memory and visuospatial functions [1]. Although current consensus criteria [1] provide a more flexible combination of clinical features with respect to Neary et al. classification [2], recent evidence supports the presence of a consistent heterogeneity in the presentation of bvFTD syndrome [3 –5], which may not completely fit with Rascovsky et al. criteria [1]. Differential diagnosis may thus be particularly difficult, especially in the early disease phase [6, 7]. It is indeed increasingly recognized that bvFTD results from a variable combination of key symptoms (e.g., social cognition disorders and behavioral changes) and additional cognitive (e.g., executive, memory, or language disorders) or clinical (e.g., parkinsonism or motor neuron dysfunction) features [3 –5]. Thus, valid information from neuropsychological markers becomes urgent as gateway for a better early differential diagnosis and to address to a correct use of second-level biomarkers (e.g., cerebrospinal fluid analysis, FDG- and amyloid-PET imaging).

In recent years, many efforts have been devoted to define reliable neuropsychological markers distinguishing bvFTD from other dementias, and in particular from Alzheimer’s disease (AD). However, up to now, no standardized and shared neuropsychological procedures for the early diagnosis of bvFTD have been identified in clinical settings, and cognitive measures often fail to reliably distinguish bvFTD from AD at presentation [6, 7].

First, bvFTD patients may not present neuropsychological deficits in the very early clinical phase [8]. The prodromal phase of bvFTD is characterized by mild behavioral impairments, identified as persistent behavioral changes and mild psychiatric symptoms, without impairments in basic cognitive functioning (e.g., memory or attention/executive functions) [8]. These domains are usually much more impaired in bvFTD as the disease progresses [5].

Additionally, a subset of bvFTD patients show episodic memory deficits as severe as those observed in typical AD [3 , 9–13], even in case of tasks specifically designed to detect hippocampal dysfunctions [14]. The clinical profile of typical AD is actually strongly characterized by selective episodic memory dysfunction of hippocampal type [15, 16] yet in the prodromal phase. Conversely, attention/executive deficits may characterize an atypical presentation of AD pathology [15, 17]. However, they are also frequently observed in typical AD [18 –21], particularly in those who present widespread prefrontal and medial temporal lobe atrophy [20].

According to the above mentioned cognitive overlap in memory and attentive/executive performances between the two dementia syndromes, recent literature proved that some behavioral/dysexecutive AD patients may actually fit current criteria for bvFTD [22]. This is particularly impressive if we consider the case of dysesecutive AD patients with minimal behavioral changes [19].

In view of the low accuracy of standard neuropsychological measures, clinicians and researchers focused on the investigation of social cognition abilities for the early differential diagnosis of bvFTD [23 –28]. Thus, impaired performances on socio-emotional tasks and altered scores at socio-behavioral questionnaires have been suggested as the possible neuropsychological markers of bvFTD syndrome. They are considered to represent the clinical counterpart of the fronto-limbic neuronal dysfunction occurring in the very early disease phase [29, 30].

Nevertheless, although bvFTD is actually considered one of the best models in neurology to study “social brain” disorders [31], the presence of socio-emotional dysfunctions in non-bvFTD syndromes (e.g., atypical AD and other frontotemporal dementia (FTD) subtypes) [32, 33] crucially questions the accuracy and reliability of social tasks as neuropsychological marker for the differential diagnosis.

In this context, this retrospective study compared cognitive performances and socio-behavioral scores in bvFTD versus typical AD, and assessed the accuracy of different neuropsychological markers in distinguishing these neurodegenerative diseases by means of a logistic regression model.

MATERIALS AND METHODS

Participants

We retrospectively collected information of 95 neurodegenerative dementia patients (i.e., 48 bvFTD (14 women; mean age = 68.24±8.57 years; mean education = 10.02±4.54 years; mean MMSE = 23.53±3.69) and 47 AD (24 women; mean age = 72.98±9.92 years; mean education = 10.15±4.7 years; mean Mini-Mental State Examination (MMSE) = 20.10±3.98)) belonging to the Memory Clinic database of the Clinical Neuroscience Department, San Raffaele Hospital (Milan) to which they were referred for the evaluation of memory or other cognitive impairments in the years between 2010 to 2016 (see Table 1). The criteria for retrospective inclusion were as follows: 1) a clinical diagnosis of probable typical AD or bvFTD, made in accordance with current clinical criteria [1 , 16], thus supported by biomarker evidence (i.e., conventional MRI, FDG-PET and/or CSF); 2) a clinical follow-up of at least 2 years confirming the initial classification.

Table 1

Demographic and clinical data of the sample at baseline clinical evaluation. For each variable, mean±standard deviation are reported

	bvFTD n = 48	AD n = 47	Statistics	Cut-off score
Female/Male ratio	14/34	24/23	p < 0.05	–
Age in years	68.24±8.57	72.98±9.92	n.s.	–
Age range in years	41–83	43–89	–	–
Years of Education	10.02±4.54	10.15±4.7	n.s.	–
Disease duration in months	43.18±31.15	35.19±22.27	n.s.	–
CDR sum of boxes score	5.65±3.38	4.99±2.12	n.s.	–
CDR-FTD sum of boxes score	7.25±3.8	5.81±2.79	n.s.	–
MMSE score	23.53±3.69	20.10±3.98	p < 0.001	23.8^a
FBI score	26±10.57	13.82±8.61	p < 0.001	28.6^a
IRI-EC score	21.24±7.5	25.76±5.2	p < 0.05	17^b
IRI-PT score	13±4.91	18.2±6.3	p < 0.001	12^b
r-SMS score	30.83±8.8	40.65±11.1	p < 0.001	17^b
Social cognition Z score	–0.36±0.89	0.27±0.76	p < 0.01	–
Long-term memory Z score	0.24±0.9	–0.23±0.7	p < 0.05	–
Short-term memory Z score	0.9±0.75	–0.1±0.8	n.s.	–
Attentive/executive Z score	0.001±0.7	–0.07±0.88	n.s.	–
Language production Z score	0.03±0.84	0.006±0.87	n.s.	–
Language comprehension Z score	–0.14±0.55	0.12±0.71	n.s.	–
Visuo-constructive Z score	0.07±0.82	–0.07±1.16	n.s.	–

bvFTD, behavioral variant of frontotemporal dementia; AD, Alzheimer’s disease; CDR, Clinical Dementia Rating scale; FTD, frontotemporal dementia; FBI, Frontal Behavioral Inventory; IRI, Interpersonal Reactivity Index; IRI-EC, Empathic Concern subscale of IRI questionnaire; IRI-PT, Perspective Taking subscale of IRI questionnaire; r-SMS, revised-Self Monitoring Scale; MMSE, Mini-Mental State Examination; n.s., not significant. ^acut-off score obtained according to normative values. ^bcut-off score obtained from the performances of 30 healthy control subjects with a –2 standard deviation approach.

At referral, patients were evaluated by experienced behavioral neurologists and neuropsychologists. Clinical evaluation included a structured clinical interview, a full neurological examination, and a neuropsychological evaluation, including behavioral questionnaires and social scales. Patients with other neuropsychiatric diseases were excluded. According to the standard procedure for the diagnosis of neurodegenerative disorders in our center, we acquired conventional MRI in the large majority of patients (>90% of the whole sample), with the exception of those patients who presented MRI contraindications (e.g., implanted cardiac devices). FDG-PET imaging was acquired in the 65% of patients, while lumbar puncture was performed in 35% of thesample.

All subjects, or their informants/caregivers, gave informed consent to clinical-instrumental examinations according to what approved by the local Ethical Committee.

Neuropsychological markers

The neuropsychological battery included a selection of measures of basic cognitive functions: auditory verbal and visuo-spatial short-term memory (i.e., Digit span forward, Corsi block-tapping test) long-term episodic memory (i.e., Free and Cued Selective Reminding Task-FCSRT, Rey Auditory Verbal List Test-RAVLT, short story recall, Rey-Osterrieth Complex Figure-ROCF recall), attention/executive functions (i.e., attentional matrices, Digit span backward, Raven’s progressive matrices, verbal fluency on phonemic cue), language (i.e., Token test, naming and comprehension tasks of CAGI battery, verbal fluency on semantic cue), and complex visuo-constructive abilities (Rey-Osterrieth Complex Figure-ROCF copy) [34, 35]. For the assessment of social cognition, the battery included the Italian version of the Ekman 60-Faces test- EK-60F [36], the Story-based Empathy Task- SET [37], and the social norms questionnaire-SNQ [38]. Briefly, while the Ek-60F task evaluates the recognition of basic emotions from faces, the SET assesses the attribution of emotions and intentions to other individuals based on a vignette task (see [36, 37] for further details on task procedures). The SNQ is a questionnaire in which subjects are asked to specify whether a behavior would be appropriate in the presence of an acquaintance based on current social norms [38]. We considered the total number of correct answers (i.e., both breaking and over-adherence errors to a perceived social norm were considered) [38].

All patients were evaluated in each cognitive domain (i.e., short-term and long-term memory, attention/executive functions, language production, language comprehension, complex visuo-constructive abilities, and social cognition) with at least one test (see Table S1 for the list of tests included in each cognitive domain).

Behavioral changes were assessed with the Frontal Behavioral Inventory (FBI) scale [39]. Emotional and cognitive facets of empathic skills were evaluated by means of the empathic concern (EC) (e.g., “I often have tender, concerned feelings for people less fortunate than me”) and perspective taking (PT) (e.g., “sometimes I try to understand my friends better by imagining how things looks from their perspective”) subscales of the Interpersonal Reactivity Index (IRI) [40, 41]. Caregivers were asked to rate how well each of 14 statements reflected the behavior of patient on a scale from 1 (does not describe at all) to 5 (describes very well). Finally, the ability to adapt behavior to social context was assessed with the revised version of the Self-Monitoring Scale(r-SMS) [42].

This 13-item scale rates the extent to which people regulate their self-presentation by tailoring their actions in accordance with immediate situational cues on a 5-point Likert scale.

Statistical analyses

In order to investigate cognitive and behavioral profiles of bvFTD and AD groups, we estimated separately for each group: 1) the number of impaired/unimpaired patients (i.e., score below/above the 5th percentile or 2-SD compared to healthy controls scores) in different cognitive domains (i.e., short-term and long-term memory, attention/executive, language production and comprehension, visuo-constructive, and social cognition); 2) the presence/absence of socio-behavioral changes (i.e., FBI score above/below the 5th percentile; IRI and r-SMS scores above/below 2-SD compared to healthy controls scores). See Table 1.

We then compared performances between bvFTD and AD in each cognitive domain (i.e., Student’s t-test on calculated Z scores from each cognitive domain) as well as in scores obtained in socio-behavioral questionnaires (i.e., FBI, IRI, and r-SMS).

We finally performed a logistic regression analysis (i.e., stepwise forward) to assess the accuracy of neuropsychological markers in distinguishing bvFTD from AD, entering in the model only those variables significantly different between groups from t-test comparisons. Statistical correlation analyses (i.e., Pearson ρ) were also performed in each patient group to test the relationship between cognitive scores, global cognitive status (i.e., MMSE score) and changes in behavior and social cognition as reported by scales and questionnaires.

RESULTS

Neuropsychological profiles of bvFTD and AD patients

Global cognitive functioning measured by MMSE was largely preserved in bvFTD group, with less than half of these patients with an impaired MMSE score. Spatial and temporal orientation were relatively spared, while attention/working memory and verbal long-term memory were the most impaired MMSE subtasks.

A defective performance in social cognition tasks was the main cognitive signature of the majority of bvFTD patients (i.e., 81%). Within the social cognition domain, bvFTD patients showed a predominant deficit of emotion recognition (i.e., Ek-60F) and emotion attribution (i.e., subtask of emotion attribution in SET). Recognition of positive and negative emotions was equally impaired. Half of the bvFTD patients were impaired in the recognition of happiness, surprise, fear, sadness, and anger, while 25% of the sample was impaired in disgust recognition. Attention/executive impairments, on the contrary, were present only in half of the bvFTD sample (i.e., 58%). Notably, a high percentage of bvFTD patients (i.e., 72%) showed long-term memory impairment. A minority of them showed additional cognitive disorders involving language production (i.e., 37%), oral comprehension (i.e., 20%), and visuo-constructional abilities (i.e., 35%).The FBI scale failed to identify significant behavioral symptoms, with a majority of patients (i.e., 64%) scoring under the cut-off score [39]. Cognitive (i.e., IRI-PT) and emotional (i.e., IRI-EC) empathy were significantly reduced in 47% and 26% of patients, respectively. Moreover, almost half of the sample (i.e., 46%) showed reduced self-monitoring abilities. See Fig. 1 for details.

Fig.1

Percentage of impaired patients in each cognitive domain and behavioral measure. Statistical comparisons are performed on the comprehensive variables obtained by Z scores. IRI, interpersonal reactivity index; bvFTD, behavioral variant of frontotemporal dementia; AD, Alzheimer’s disease. ^**p < 0.001, ^*p < 0.05.

In contrast, the large majority of AD patients had an impaired performance at the MMSE test, with comparable impairment among the different subtasks. As expected, the cognitive profile of AD patients was strongly characterized by impairments in episodic memory (i.e., all patients showed deficits at the delayed recall tasks). In addition, different combinations of disorders in other cognitive domains were present among AD patients. Short-term memory, attention/executive, visuo-constructive, and social cognition domains were impaired in half of the AD sample, while language production and oral comprehension were affected only in a subset of this group. In the Ek-60F test, AD patients showed a prevalent deficit in the recognition of negative emotions (i.e., sadness was impaired in the 47% of the sample and fear in the 41%). FBI scores were below the cut-off score for frontal syndrome in the majority of AD patients (i.e., only the 7% of AD patients scored above the cut-off score). Moreover, in contrast to bvFTD, IRI sub-scores were significantly reduced only in around 10% of AD patients. Twenty percent of this group also showed difficulties in self-monitoring abilities. See Fig. 1 for details.

Neuropsychological markers of bvFTD

Direct comparisons of cognitive performances between patient groups identified impairments in social cognition and long-term memory as cognitive markers, respectively, of bvFTD and AD (Fig. 1). Overall, bvFTD patients showed lower performances on socio-emotional tasks (t(88) = –3.61, p < 0.01), while AD patients were more impaired in delayed recall tasks (t(88) = 2.5, p < 0.05). No significant differences were found in short-term memory, attention/executive functions, language production and oral comprehension, and visuo-constructional tests. Coherently with the severe social cognition impairments, bvFTD patients were judged by caregivers as less empathic (i.e., IRI-EC: t(81) = –3.18, p < 0.05; IRI-PT: t(81) = –4.19, p < 0.001) and less able to adapt behaviors according to the social situation (i.e., r-SMS: t(93) = –4.43, p < 0.001). As expected, FBI scores were significantly higher in bvFTD compared to AD (i.e., FBI: t(93) = 4.29, p < 0.001) (Fig. 1).

Logistic regression analysis identified social cognition performances, FBI, and MMSE scores as the best combination in accurately distinguishing bvFTD from AD, as they correctly classified the 85% of bvFTD and 90% of AD patients (Fig. 2). A direct comparison of cognitive and behavioral performances in correctly classified bvFTD versus misclassified bvFTD showed lower FBI (t(41) = 2.52, p < 0.05) and MMSE (t(41) = 2.55, p < 0.05) scores, and more preserved social performances (t(41) = –2.08, p < 0.05) in the latter group. Conversely, misclassified AD patients presented higher FBI scores (t(40) = –3.09, p < 0.05) and more impaired social performances (t(40) = 2.16, p < 0.05).

Fig.2

Expected scores for each patient according to the logistic regression equation distinguishing the behavioral variant of frontotemporal dementia (bvFTD, rhombus; in green) from Alzheimer’s disease (AD, circle; in red).

In order to test whether these results depict bvFTD cognitive profiles also in early disease phase, we repeated t-test and linear regression analyses including only bvFTD patients with short disease duration. Preliminarily, according to the median of the disease duration (i.e., period between disease onset and neuropsychological observation) in our bvFTD sample (i.e., 30 months), we sub-grouped bvFTD in short (i.e., below 30 months) and long (i.e., above 30 months) disease duration. Statistical comparisons performed on bvFTD with short disease duration and AD patients confirmed the results obtained in the whole bvFTD sample.

Correlation analyses

Correlation analyses showed significant associations between global cognitive status and basic cognitive domains (i.e., attention/executive functions, long-term memory, and language production) in both patient groups. Additionally, global cognitive status correlated with complex visuo-constructional performances in AD and with oral comprehension in bvFTD patients. Notably, social cognition abilities correlated with global cognitive status only in the AD group. In this group, social cognition abilities were indeed correlated with language production and attention/executive functions. No correlation between social cognition scores and other cognitive performances or global cognitive status was found in bvFTD patients. In bvFTD, social cognition performances were negatively correlated with FBI scores, and positively with r-SMS scores.

See Table 2 and Fig. 3 for details.

Fig.3

Scatterplot matrix showing the correlations between the global cognitive status, cognitive functions and behavioral scales distinguishing behavioral variant of frontotemporal dementia (bvFTD, rhombus; in green) from Alzheimer’s disease (AD, circle; in red). See Table 2 for details on coefficient scores.

Table 2

Correlation analyses between cognitive and socio-behavioral scores in patient sample. Significant correlation values are reported in bold

DISCUSSION

Although in the last decade advances in clinical diagnostic criteria allowed a better diagnosis of bvFTD [1], its early identification in clinical settings is still challenging. Standard neuropsychological batteries proved very low accuracy in the differential diagnosis of this neurodegenerative condition [43]. The presence of normal performances in standard neuropsychological tasks may account for a high level of uncertainty, especially in mild cases, and in a delay in the correct classification of subjects with subtle behavioral symptoms [44]. On the contrary, advanced bvFTD cases may show severe cognitive profiles, hindering the differential diagnosis with AD or with other FTD subtypes [6 , 33].

In our study, we evaluated in a clinical setting the role of combined cognitive and socio-behavioral measures in the differential diagnosis of bvFTD. Some other recent studies attempted to identify specific neuropsychological markers of bvFTD [6 , 45]. They mainly proved that the inclusion in the clinical assessment of bvFTD patients of short social cognition batteries is likely to reduce false negatives [6]. For instance, the mini-SEA developed by Bertoux and colleagues [23] showed a good sensitivity in detecting ventromedial prefrontal dysfunctions in bvFTD, and a better diagnostic performance compared to classic executive tasks (e.g., Go/noGO paradigms), with an accuracy of 85% in distinguishing bvFTD from AD [23]. This approach is supported by our study, which indicates that impaired performances on tasks assessing recognition and processing of socio-emotional cues are consistently present in bvFTD patients and are more frequent than a dysexecutive syndrome. As reported by recent literature [26 , 47], ToM tasks, such as Reading the Mind in the Eye [48], are very useful neuropsychological instruments in FTD and related neurodegenerative disorders, as amyotrophic lateral sclerosis, also from a longitudinal perspective [47]. Consistently, our data support the importance of SET and Ek-60F tasks in the core neuropsychological assessment of bvFTD patients for a better early and differential diagnosis.

Although bvFTD represents a model for thein vivo study of the “social brain” [31], impairments of social cognition abilities may be present in other FTD syndromes, e.g., semantic variant of primary progressive aphasia or corticobasal degeneration [49, 50], as well as in AD dementia [51] or in psychiatric disorders such as bipolar syndrome [38]. Our results confirm that AD patients may show impaired performances on social cognition tasks and scores on socio-behavioral questionnaires comparable to those reported in bvFTD (see Fig. 1). This is particularly true in case of high-complexity mentalizing tasks [32, 52], such as the SET, which according to correlation analyses are likely driven by global cognitive status and in particular by language and attention/executive functions. Moreover, unlike bvFTD, our AD patients showed more severe impairments in basic cognitive functions compared to theory of mind deficits, as previously reported [51].

As expected, behavioral changes largely characterized bvFTD patients whereas only a minority of AD showed severe behavioral disorders (see Table 1). Noteworthy, the majority of bvFTD (i.e., 60%) scored under the FBI cut-off score [39] for the presence of a frontal behavioral syndrome. Although FBI is considered an efficient and accurate scale for the early and differential diagnosis of bvFTD [39, 53], the cut-off score proposed by Alberici et al. [39] was not effective in our sample. This index was indeed calculated in a bvFTD sample with more severe clinical symptoms (MMSE = 14.2±10.5; CDR global score = 1.9±1) compared to our sample (MMSE = 23.53±3.69; CDR global score = 0.9±0.39). In addition, quantitative measures assessing socio-behavioral changes in real-life situations, such as r-SMS, may be a useful addition to current behavioral scales. This questionnaire, as well as FBI scale, well correlated with social cognition performances in our bvFTD sample. Further normative and comparative studies for the reference population are however needed to clarify the usefulness of socio-behavioral scales in clinical settings.

Neuropsychological profiles of bvFTD and AD at basic cognitive tasks may also overlap. In line with literature [3 , 9–12], our bvFTD sample presented with heterogeneous neuropsychological features, including long-term episodic memory and/or language disorders (see Fig. 1). As previously reported [13], delayed recall tests were impaired not only in every AD patient but also in the majority of bvFTD. Impaired long-term memory performances were actually more frequent than attentive/executive dysfunctions, though they are a core diagnostic signature [1]. Thus, while preserved delayed recall performance excludes a typical AD presentation, it does not allow to distinguish AD from bvFTD (i.e., about the 80% of bvFTD patients had impaired delayed recall task). This variable combination of cognitive impairments associated to socio-behavioral changes is the result of differences in the topography and extent of damage to specific neural substrates, i.e., ventromedial and dorsolateral prefrontal cortex, medial temporal and limbic structures [54, 55]. Similarly to what is now fully accepted for AD, in which typical and atypical clinical presentations are known to underlie the same pathological substrates [17], bvFTD is likely to have different clinical-neuropsychological endo-phenotypes [54, 55]. Crucially, the results of our logistic regression analysis suggested a combination of cognitive (i.e., social cognition scores and global cognitive functioning level) and behavioral (i.e., frontal behavioral changes) measures as the best neuropsychological markers for the differential diagnosis. Although socio-behavioral changes are fundamental for an early and accurate identification of bvFTD (i.e., high sensitivity), they may not be sufficient to differentiate this syndrome from other neurodegenerative conditions (i.e., low specificity). Individually, no basic cognitive measure is sufficient to provide useful information for the differential diagnosis. Notwithstanding the well-known limitations of tasks assessing global cognitive status as the MMSE test [56, 57], the discrepancy between bvFTD and AD scores at this test proved to be a useful support for a reliable discrimination between these two clinical syndromes. BvFTD patients usually present with preserved global cognitive functioning, while AD patients show low MMSE scores even in the early disease phase [58].

Finally, a small percentage of patients belonging to both diagnostic groups was misclassified according to the logistic regression analysis, as they presented with a dissonant neuropsychological profile in respect to the majority of patients. This result suggests that probably current neuropsychological and neurobehavioral measures are still not sufficiently accurate to completely discriminate bvFTD from AD patients in clinical settings. Thus, neuropsychological information may only represent a gateway in the diagnostic algorithm of neurodegenerative dementias and the support of instrumental biomarker is certainly needed in order to reach a good level of certainty. MRI and/or FDG-PET imaging may add crucial information in order to better classify patients in the early disease phases [54 , 60].

Some limitations must be acknowledged. The clinical-based design of this study prevents us from having any definite pathological diagnosis for the reference population. However, biomarkers helped to support clinical classification. In particular, no bvFTD case showed temporo-parietal damage in association to frontal involvement, which is the typical pattern of the frontal variant of AD [61]. In addition, the cognitive battery used in this clinical setting includes only a subset of executive measures. For instance, the Wisconsin Card sorting test (WCST) [62] or the Hayling test [63] were not part of the cognitive assessment. While there is no evidence of a better performance at WCST for AD compared to bvFTD [6, 64], the Hayling test showed a better potential [21]. Nevertheless, the here used digit span backward and verbal fluency on phonemic cue presented also good accuracy in differential diagnosis [21, 64]. Finally, the retrospective design of the study prevented us from considering the relative weight of single cognitive tests in each specific cognitive domain.

In conclusion, the present study supports the integration of socio-behavioral evaluation in the neuropsychological batteries in suspicion of bvFTD syndrome. Such neuropsychological measures could represent the best gateway to address to biomarkers as MRI or PET imaging. Biomarker results are certainly needed to complement the contribution of the neuropsychological assessment in order to disentangle ambiguous clinical presentations in dementias especially in view of the correct administration of well-known (e.g., acetylcholinesterase inhibitor) or new (e.g., human monoclonal anti-amyloid antibodies) therapies [65, 66].

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/17-0650r1).

Footnotes

The supplementary material is available in the electronic version of this article: .

References

Rascovsky

, Hodges

, Knopman

, Mendez

, Kramer

, Neuhaus

, van Swieten

, Seelaar

, Dopper

, Onyike

, Hillis

, Josephs

, Boeve

, Kertesz

, Seeley

, Rankin

, Johnson

, Gorno-Tempini

, Rosen

, Prioleau-Latham

, Lee

, Kipps

, Lillo

, Piguet

, Rohrer

, Rossor

, Warren

, Fox

, Galasko

, Salmon

, Black

, Mesulam

, Weintraub

, Dickerson

, Diehl-Schmid

, Pasquier

, Deramecourt

, Lebert

, Pijnenburg

, Chow

, Manes

, Grafman

, Cappa

, Freedman

, Grossman

, Miller

(2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456–2477.

Neary

, Snowden

, Gustafson

, Passant

, Stuss

, Black

, Freedman

, Kertesz

, Robert

, Albert

, Boone

, Miller

, Cummings

, Benson

(1998) Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 51, 1546–1554.

Hornberger

, Piguet

(2012) Episodic memory in frontotemporal dementia: A critical review. Brain 135, 678–692.

Piguet

, Hornberger

, Mioshi

, Hodges

(2011) Behavioural-variant frontotemporal dementia: Diagnosis, clinical staging, and management. Lancet Neurol 10, 162–172.

Cerami

, Cappa

(2013) The behavioral variant of frontotemporal dementia: Linking neuropathology to social cognition. Neurol Sci 34, 1267–1274.

Bertoux

, de Souza

, O’Callaghan

, Greve

, Sarazin

, Dubois

, Hornberger

(2016) Social cognition deficits: The key to discriminate behavioral variant frontotemporal dementia from Alzheimer’s disease regardless of amnesia?. J Alzheimers Dis 49, 1065–1074.

Hutchinson

, Mathias

(2007) Neuropsychological deficits in frontotemporal dementia and Alzheimer’s disease: A meta-analytic review. J Neurol Neurosurg Psychiatry 78, 917–928.

Taragano

, Allegri

, Krupitzki

, Sarasola

, Serrano

, Lon

, Lyketsos

(2009) Mild behavioral impairment and risk of dementia: A prospective cohort study of 358 patients. J Clin Psychiatry 70, 584–592.

Irish

, Graham

, Hodges

, Hornberger

(2012) Differential impairment of source memory in progressive versus non-progressive behavioral variant frontotemporal dementia. Arch Clin Neuropsychol 27, 338–347.

10.

Irish

, Piguet

, Hodges

, Hornberger

(2014) Common and unique gray matter correlates of episodic memory dysfunction in frontotemporal dementia and Alzheimer’s disease. Hum Brain Mapp 35, 1422–1435.

11.

Schubert

, Leyton

, Hodges

, Piguet

(2016) Longitudinal memory profiles in behavioral-variant frontotemporal dementia and Alzheimer’s disease. J Alzheimers Dis 51, 775–782.

12.

Ramanan

, Bertoux

, Flanagan

, Irish

, Piguet

, Hodges

, Hornberger

(2017) Longitudinal executive function and episodic memory profiles in behavioral-variant frontotemporal dementia and Alzheimer’s disease. J Int Neuropsychol Soc 23, 34–43.

13.

Fernandez-Matarrubia

, Matias-Guiu

, Cabrera-Martin

, Moreno-Ramos

, Valles-Salgado

, Carreras

, Matias-Guiu

(2017) Episodic memory dysfunction in behavioral variant frontotemporal dementia: A clinical and FDG-PET study. J Alzheimers Dis 57, 1251–1264.

14.

Bertoux

, de Souza

, Corlier

, Lamari

, Bottlaender

, Dubois

, Sarazin

(2014) Two distinct amnesic profiles in behavioral variant frontotemporal dementia. Biol Psychiatry 75, 582–588.

15.

Dubois

, Feldman

, Jacova

, Hampel

, Molinuevo

, Blennow

, DeKosky

, Gauthier

, Selkoe

, Bateman

, Cappa

, Crutch

, Engelborghs

, Frisoni

, Fox

, Galasko

, Habert

, Jicha

, Nordberg

, Pasquier

, Rabinovici

, Robert

, Rowe

, Salloway

, Sarazin

, Epelbaum

, de Souza

, Vellas

, Visser

, Schneider

, Stern

, Scheltens

, Cummings

(2014) Advancingresearch diagnostic criteria for Alzheimer’s disease: The IWG-2criteria. Lancet Neurol 13, 614–629.

16.

McKhann

, Knopman

, Chertkow

, Hyman

, Jack

Jr. , Kawas

, Klunk

, Koroshetz

, Manly

, Mayeux

, Mohs

, Morris

, Rossor

, Scheltens

, Carrillo

, Thies

, Weintraub

, Phelps

(2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 263–269.

17.

Ossenkoppele

, Pijnenburg

, Perry

, Cohn-Sheehy

, Scheltens

, Vogel

, Kramer

, van der Vlies

, La Joie

, Rosen

, van der Flier

, Grinberg

, Rozemuller

, Huang

, van Berckel

, Miller

, Barkhof

, Jagust

, Scheltens

, Seeley

, Rabinovici

(2015) The behavioural/dysexecutive variant of Alzheimer’s disease: Clinical, neuroimaging and pathological features. Brain 138, 2732–2749.

18.

Possin

, Feigenbaum

, Rankin

, Smith

, Boxer

, Wood

, Hanna

, Miller

, Kramer

(2013) Dissociable executive functions in behavioral variant frontotemporal and Alzheimer dementias. Neurology 80, 2180–2185.

19.

Stopford

, Thompson

, Neary

, Richardson

, Snowden

(2012) Working memory, attention, and executive function in Alzheimer’s disease and frontotemporal dementia. Cortex 48, 429–446.

20.

Wong

, Bertoux

, Savage

, Hodges

, Piguet

, Hornberger

(2016) Comparison of prefrontal atrophy and episodic memoryperformance in dysexecutive Alzheimer’s disease and behavioral-variant frontotemporal dementia. J Alzheimers Dis 51, 889–903.

21.

Hornberger

, Savage

, Hsieh

, Mioshi

, Piguet

, Hodges

(2010) Orbitofrontal dysfunction discriminates behavioral variant frontotemporal dementia from Alzheimer’s disease. Dement Geriatr Cogn Disord 30, 547–552.

22.

Blennerhassett

, Lillo

, Halliday

, Hodges

, Kril

(2014) Distribution of pathology in frontal variant Alzheimer’s disease. J Alzheimers Dis 39, 63–70.

23.

Bertoux

, Funkiewiez

, O’Callaghan

, Dubois

, Hornberger

(2013) Sensitivity and specificity of ventromedial prefrontal cortex tests in behavioral variant frontotemporal dementia., S. Alzheimers Dement 9, 84–94.

24.

Funkiewiez

, Bertoux

, de Souza

, Levy

, Dubois

(2012) The SEA (Social cognition and Emotional Assessment): A clinical neuropsychological tool for early diagnosis of frontal variant of frontotemporal lobar degeneration. Neuropsychology 26, 81–90.

25.

Torralva

, Roca

, Gleichgerrcht

, Bekinschtein

, Manes

(2009) A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia. Brain 132, 1299–1309.

26.

Poletti

, Enrici

, Adenzato

(2012) Cognitive and affective Theory of Mind in neurodegenerative diseases: Neuropsychological, neuroanatomical and neurochemical levels. Neurosci Biobehav Rev 36, 2147–2164.

27.

Schroeter

(2012) Considering the frontomedian cortex in revised criteria for behavioural variant frontotemporal dementia. Brain 135, e213; author reply e214.

28.

Adenzato

, Poletti

(2013) Theory of Mind abilities in neurodegenerative diseases: An update and a call to introduce mentalizing tasks in standard neuropsychological assessments. Clin Neuropsychiatry 10, 226–234.

29.

Eslinger

, Moore

, Anderson

, Grossman

(2011) Social cognition, executive functioning, and neuroimaging correlates of empathic deficits in frontotemporal dementia. J Neuropsychiatry Clin Neurosci 23, 74–82.

30.

Ibanez

, Manes

(2012) Contextual social cognition and the behavioral variant of frontotemporal dementia. Neurology 78, 1354–1362.

31.

Schroeter

, Laird

, Chwiesko

, Deuschl

, Schneider

, Bzdok

, Eickhoff

, Neumann

(2014) Conceptualizing neuropsychiatric diseases with multimodal data-driven meta-analyses - the case of behavioral variant frontotemporal dementia. Cortex 57, 22–37.

32.

Dodich

, Cerami

, Crespi

, Canessa

, Lettieri

, Iannaccone

, Marcone

, Cappa

, Cacioppo

(2016) Differential impairment of cognitive and affective mentalizing abilities in neurodegenerative dementias: Evidence from behavioral variant of frontotemporal dementia, Alzheimer’s disease, and mild cognitive impairment. J Alzheimers Dis 50, 1011–1022.

33.

Hutchings

, Hodges

, Piguet

, Kumfor

, Boutoleau-Bretonniere

(2015) Why should I care? Dimensions of socio-emotionalcognition in younger-onset dementia. J Alzheimers Dis 48, 135–147.

34.

Lezak

(2004) Neuropsychological assessment, Oxford University Press.

35.

Catricala

, Della Rosa

, Ginex

, Mussetti

, Plebani

, Cappa

(2013) An Italian battery for the assessment of semantic memory disorders. Neurol Sci 34, 985–993.

36.

Dodich

, Cerami

, Canessa

, Crespi

, Marcone

, Arpone

, Realmuto

, Cappa

(2014) Emotion recognition from facial expressions: A normative study of the Ekman 60-Faces Test in the Italian population. Neurol Sci 35, 1015–1021.

37.

Dodich

, Cerami

, Canessa

, Crespi

, Iannaccone

, Marcone

, Realmuto

, Lettieri

, Perani

, Cappa

(2015) A novel task assessing intention and emotion attribution: Italian standardization and normative data of the Story-based Empathy Task. Neurol Sci 36, 1907–1912.

38.

Baez

, Herrera

, Villarin

, Theil

, Gonzalez-Gadea

, Gomez

, Mosquera

, Huepe

, Strejilevich

, Vigliecca

, Matthaus

, Decety

, Manes

, Ibanez

(2013) Contextual social cognition impairments inschizophrenia and bipolar disorder. PLoS One 8, e57664.

39.

Alberici

, Geroldi

, Cotelli

, Adorni

, Calabria

, Rossi

, Borroni

, Padovani

, Zanetti

, Kertesz

(2007) The Frontal Behavioural Inventory (Italian version) differentiates frontotemporal lobar degeneration variants from Alzheimer’s disease. Neurol Sci 28, 80–86.

40.

Davis

(1983) Measuring individual differences in empathy: Evidence for a multidimensional approach. J Pers Soc Psychol 44, 113–126.

41.

Rankin

, Kramer

, Miller

(2005) Patterns of cognitive and emotional empathy in frontotemporal lobar degeneration. Cogn Behav Neurol 18, 28–36.

42.

Lennox

, Wolfe

(1984) Revision of the self-monitoring scale. J Pers Soc Psychol 46, 1349–1364.

43.

Rascovsky

, Grossman

(2013) Clinical diagnostic criteria and classification controversies in frontotemporal lobar degeneration. Int Rev Psychiatry 25, 145–158.

44.

Mendez

, Shapira

, McMurtray

, Licht

, Miller

(2007) Accuracy of the clinical evaluation for frontotemporal dementia. Arch Neurol 64, 830–835.

45.

Leslie

, Foxe

, Daveson

, Flannagan

, Hodges

, Piguet

(2016) FRONTIER Executive Screen: A brief executive battery to differentiate frontotemporal dementia and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 87, 831–835.

46.

Burke

, Pinto-Grau

, Lonergan

, Elamin

, Bede

, Costello

, Hardiman

, Pender

(2016) Measurement of social cognition in amyotrophic lateral sclerosis: A population based study. PLoS One 11, e0160850.

47.

Pardini

, Emberti Gialloreti

, Mascolo

, Benassi

, Abate

, Guida

, Viani

, Dal Monte

, Schintu

, Krueger

, Cocito

(2013) Isolated theory of mind deficits and risk forfrontotemporal dementia: A longitudinal pilot study. J NeurolNeurosurg Psychiatry 84, 818–821.

48.

Serafin

, Surian

(2004) Il Test degli Occhi: Uno strumento per valutare la” teoria della mente”. G Ital Psicol 31, 839–862.

49.

Hutchings

, Palermo

, Piguet

, Kumfor

(2017) Disrupted face processing in frontotemporal dementia: A review of the clinical and neuroanatomical evidence. Neuropsychol Rev 27, 18–30.

50.

Rankin

, Gorno-Tempini

, Allison

, Stanley

, Glenn

, Weiner

, Miller

(2006) Structural anatomy of empathy in neurodegenerative disease. Brain 129, 2945–2956.

51.

Bora

, Walterfang

, Velakoulis

(2015) Theory of mind in behavioural-variant frontotemporal dementia and Alzheimer’s disease: A meta-analysis. J Neurol Neurosurg Psychiatry 86, 714–719.

52.

Castelli

, Pini

, Alberoni

, Liverta-Sempio

, Baglio

, Massaro

, Marchetti

, Nemni

(2011) Mapping levels of theory of mind in Alzheimer’s disease: A preliminary study. Aging Ment Health 15, 157–168.

53.

Kertesz

, Davidson

, McCabe

, Munoz

(2003) Behavioral quantitation is more sensitive than cognitive testing in frontotemporal dementia. Alzheimer Dis Assoc Disord 17, 223–229.

54.

Cerami

, Dodich

, Lettieri

, Iannaccone

, Magnani

, Marcone

, Gianolli

, Cappa

, Perani

(2016) Different FDG-PET metabolic patterns at single-subject level in the behavioral variant of fronto-temporal dementia. Cortex 83, 101–112.

55.

Whitwell

, Przybelski

, Weigand

, Ivnik

, Vemuri

, Gunter

, Senjem

, Shiung

, Boeve

, Knopman

, Parisi

, Dickson

, Petersen

, Jack

Jr. , Josephs

(2009) Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: A cluster analysis study. Brain 132, 2932–2946.

56.

Tombaugh

, McIntyre

(1992) The mini-mental state examination: A comprehensive review. J Am Geriatr Soc 40, 922–935.

57.

Trzepacz

, Hochstetler

, Wang

, Walker

, Saykin

(2015) Relationship between the Montreal Cognitive Assessment and Mini-mental State Examination for assessment of mild cognitive impairment in older adults. BMC Geriatr 15, 107.

58.

Pasquier

, Richard

, Lebert

(2004) Natural history of frontotemporal dementia: Comparison with Alzheimer’s disease. Dement Geriatr Cogn Disord 17, 253–257.

59.

Perani

, Cerami

, Caminiti

, Santangelo

, Coppi

, Ferrari

, Pinto

, Passerini

, Falini

, Iannaccone

, Cappa

, Comi

, Gianolli

, Magnani

(2016) Cross-validation of biomarkers for the early differential diagnosis and prognosis of dementia in a clinical setting. Eur J Nucl Med Mol Imaging 43, 499–508.

60.

Seeley

(2008) Selective functional, regional, and neuronal vulnerability in frontotemporal dementia. Curr Opin Neurol 21, 701–707.

61.

Woodward

, Rowe

, Jones

, Villemagne

, Varos

(2015) Differentiating the frontal presentation of Alzheimer’s disease with FDG-PET. J Alzheimers Dis 44, 233–242.

62.

Nelson

(1976) A modified card sorting test sensitive to frontal lobe defects. Cortex 12, 313–324.

63.

Burgess

, Shallice

(1997) The Hayling and Brixton Tests.

64.

Siri

, Benaglio

, Frigerio

, Binetti

, Cappa

(2001) A brief neuropsychological assessment for the differential diagnosis between frontotemporal dementia and Alzheimer’s disease. Eur J Neurol 8, 125–132.

65.

Nardell

, Tampi

(2014) Pharmacological treatments for frontotemporal dementias: A systematic review of randomized controlled trials. Am J Alzheimers Dis Other Demen 29, 123–132.

66.

Sevigny

, Chiao

, Bussiere

, Weinreb

, Williams

, Maier

, Dunstan

, Salloway

, Chen

, Ling

, O’Gorman

, Qian

, Arastu

, Li

, Chollate

, Brennan

, Quintero-Monzon

, Scannevin

, Arnold

, Engber

, Rhodes

, Ferrero

, Hang

, Mikulskis

, Grimm

, Hock

, Nitsch

, Sandrock

(2016) The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 537, 50–56.