Abstract

We explored the capacity of Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients to recognize facial expressions. Twenty-three consecutive CADASIL patients and 23 age-matched, gender-matched, and education-matched controls were assessed with a semi-structured psychiatric interview, cognitive tests, and the Ekman and Friesen test. Cases and controls (5 males, 18 females) had a mean age (+SD) of 52.4 + 15.7 and 54.0 + 15.3 years, respectively, and a Mini-Mental State Examination (MMSE) mean score of 27.8 + 2.2 and 28.9 + 1.3 (p < .05). Eighteen out of the 23 (78.3%) CADASIL patients and 10 (43.5%) controls were diagnosed as affected by major depression according to DSM-IV criteria (p < .05). The CADASIL patients had an impaired ability of emotion recognition in comparison with controls, particularly for fear expression. This effect was not mediated by depression, cognitive impairment, and MMSE score. Facial affect recognition is reduced in the CADASIL patients and this impairment might represent an early manifestation of the disease.

Introduction

Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) [MIM 125310] is an inherited autosomal-dominant small-vessel disease caused by point mutations in one of the 33 exons of the NOTCH3 gene, localized in chromosome 19p13.1, that codes for a transmembrane receptor protein (Chabriat, Joutel, Dichgans, Tournier-lasserve, & Bousser, 2009; Joutel et al., 1996). CADASIL is clinically characterized by a variable combination of migraine, recurrent transient ischemic attack (TIA) or lacunar strokes, cognitive decline, and mood disturbances (Chabriat et al., 2009; Reyes et al., 2009). Other less frequent clinical manifestations of the disease such as epileptic seizures, visual disturbances, and stroke due to cerebral haemorrhages are also recognized (Chabriat et al., 2009; Choi, Kang, Kang, & Park, 2006; Rufa et al., 2004). Cerebral magnetic resonance imaging (MRI) abnormalities in CADASIL include a diffuse leukoencephalopathy, subcortical lacunar infarcts, and microbleeds (Chabriat et al., 1998). Hyperintense lesions in T2-weighted and FLAIR sequences are confluent in the deep subcortical white matter and particularly involve the anterior part of the temporal lobe and the external capsule (Chabriat et al., 1998). CADASIL is typically considered a subcortical disease, but recent data suggest an involvement of the cortex early in the disease (Jouvent et al., 2008). The cortical changes, such as increase in the depth of cortical sulci, decrease in the cortical thickness and progression of global cerebral atrophy, seem to have a clinical influence (Jouvent et al., 2008, 2011). Particularly, the alterations of global cognitive performance were demonstrated to be related to global brain atrophy, and the worsening of disability to cortical thinning and the reduction of performances in executive function, motor speed, or visuo-spatial skills were found to be significantly associated with the decrease in the sulcal depth. Moreover, the depth and width of cortical sulci, primarily in posterior cingulated, mediofrontal, and orbito-frontal areas was demonstrated to have an independent strong association with apathy (Jouvent et al., 2008, 2011).

Although the clinical expression of CADASIL is mainly neurological, psychiatric disturbances are considered among the cardinal symptoms (Valenti, Poggesi, Pescini, Inzitari, & Pantoni, 2008). Apathy has recently been proposed as a hallmark of the disease (Reyes et al., 2009). We have shown that a structured assessment of psychiatric disorders in CADASIL, particularly mood, is able to reveal frequencies of disturbances higher than previously reported (Valenti et al., 2011). Moreover, many CADASIL patients present with a quite mild phenotype.

Concerning research focused on psychiatric and neurobehavioral aspects, we performed a study aimed at assessing the capacity by CADASIL patients of recognizing facial expressions taken as a marker of the integrity or damage of cortical-subcortical circuits. In other neurological diseases, such as Huntington's and Parkinson's diseases, the impairment of facial affect recognition precedes the full clinical expression of the disease and is proposed as an early sign (Ibarretxe-Bilbao et al., 2009; Johnson et al., 2007). Assessing facial recognition ability in CADASIL might be one step on the way to explore uncovered manifestations of the disease with potential diagnostic outputs and to study correlates of alterations of complex brain circuits.

Methods

The study was approved by the local ethics committee.

We enrolled 23 consecutive patients with a genetically confirmed diagnosis of CADASIL among those followed in our center. NOTCH3 gene analysis was done as previously described (Pantoni et al., 2010). The mutations are available on request. Of these 23 CADASIL patients, 4 were asymptomatic and the diagnosis was made because they were relatives of affected patients.

For each CADASIL patient, a healthy individual (referred to as “control”), matching with the corresponding patient's age (±3 years), gender, and education (±3 years), was paired. Each control was chosen as the first one fitting the matching criteria in the alphabetical list of clients of a general practitioner. For ethical and economic reasons, it was not considered appropriate to submit the controls to genetic investigation and/or magnetic resonance of the brain; therefore, we decided to exclude a possible diagnosis of CADASIL in controls exclusively on a clinical basis: a suggestive family history and the simultaneous presence of two disturbances among stroke or TIA, migraine, and cognitive deterioration.

Exclusion criteria for cases and controls were: dementia; severe co-morbidities with impact on clinical status and prognosis in the short term, such as cancer, chronic disabling neurological and non-neurological diseases; inability to come for the evaluation; refusal. Patients with mild cognitive impairment (MCI) were allowed to participate.

All the following data were collected by board-certified neurologists on enrollment. MCI was defined as the presence of cognitive decline from a previously normal status as reported by a next-of-kin or by the patient and confirmed by objective cognitive impairment on neuropsychological testing. Neuropsychological cognitive performances were judged as impaired if the patient scored at least 1.5 SD below the age- and education-corrected means in at least one cognitive test. Stroke and TIA were defined according to World Health Organization (Hatano, 1976) and the National Institute of Neurological Disorders and Stroke criteria (Special report from the National Institute of Neurological Disorders and Stroke, 1990), respectively. Psychiatric disorders were recorded as present in the case of any of the following: (1) previous diagnosis of a psychiatric disease by a certified specialist (psychiatrist, geriatrician, or neurologist); (2) previous or current use of antipsychotic or antidepressant drugs, or psychotherapy (the sole use of benzodiazepines was not regarded as sufficient); (3) mood or behavior disorders referred by the patient or his/her family, not immediately related to bereavement, and that had interfered for at least 6 months with daily or work activities. Migraine with and without aura was defined according to the Headache Classification Committee of the International Headache Society (Headache Classification Committee of the International Headache Society, 2004). Seizures were defined according to the International League Against Epilepsy (ILAE) Commission Report (Fisher et al., 2005).

The present assessment is part of a study focused on the evaluation of psychiatric and cognitive aspects of the disease the results of which have been partly published (Valenti et al., 2011). Patients and controls were assessed in terms of mood disorders by board-certified psychiatrists using the mood disorder module of the Structured Clinical Interview for the DSM-IV, clinician version (SCID) (validated Italian version) (American Psychiatric Association, 1994; First, Spitzer, Gibbon, & Williams, 1994) to evaluate the presence of major depression (Valenti et al., 2011). For a quantitative measurement of depressive symptoms in depressed participants, the original version of the Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960) was used. Regarding the psychiatric evaluation, the interviewer was blinded with respect to the disease status of the participant examined, not knowing whether he/she was a CADASIL patient or a control. Cases and controls were randomly alternated.

To assess the capacity of recognizing facial expressions, we used the Ekman and Friesen “Pictures of facial affect” test (Ekman & Friesen, 1976). This test comprises 40 black and white photographs of facial expressions of several different basic emotions presented on a computer screen: happiness, sadness, fear, anger, surprise, disgust (six pictures each), and neutral expression (four pictures). The participant has to select the most appropriate affect from a list. For each expression, we recorded the number of correct recognitions.

A functional and cognitive assessment was also carried out using the following scales: Activities of Daily Living (Kuriansky and Gurland, 1976) and Instrumental Activities of Daily Living Scales (Lawton & Brody, 1969), Mini-Mental State Examination (MMSE) (Folstein, Folstein, & McHugh, 1975) for an evaluation of global cognitive status, Color Word Stroop Test (modified version) (Madureira et al., 2006), and Trail Making Test (Trail A, Trail B) (Reitan, 1958). Trail A was used to assess visuo-spatial abilities and psycho-motor speed, Color Word Stroop Test, and Trail B to assess executive functions that are specifically altered in patients with subcortical small-vessel diseases like CADASIL.

Statistical Analysis

A comparison between the CADASIL and the control groups with regard to demographic variables, clinical disturbances, cognitive and functional tests, diagnosis of depression, and HDRS scores was made. For continuous variables, we used independent samples t-test; in the case of dichotomous variables, Pearson χ2 test was used. All p values were two-tailed, and the level of significance was set at p < .05.

Considering the left-skewed distribution of facial expressions test's scores (Kolmogorov–Smirnov test), the data were transformed by the reciprocal function (range 0–1) and for comparison between the two groups nonparametric statistics were used (Mann–Whitney U test). The level of statistical significance was set at p < .05; in case of multiple comparisons, the level of significance was adjusted with the Bonferroni correction (p < .007).

Although the reciprocal transformation of facial expressions test's scores did not result in a complete normalization of data (Kolmogorov–Smirnov test was still significant), two models of multivariate analysis of variance were performed. Model 1 (multivariate ANOVA) was used to evaluate, together with a diagnosis of CADASIL, the influence of major depression and MCI (as independent variables) on affect recognition. Model 2 (multivariate ANCOVA) evaluated the influence of diagnosis of CADASIL on affect recognition, taking into account cognitive performance on the MMSE (Stroop e Trail B did not differ between groups) and depressive symptoms (HRSD score) as covariates. All p values were two-tailed, and the level of significance was set at p < .007 (Bonferroni correction) and, for significant results, effect size measures were reported as partial eta-squared (forumla).

Statistical analyses were performed using SPSS version 17.0 for Windows (SPSS Institute, Inc., Cary, NC).

Results

Of the 31 CADASIL patients followed in our center at the time of the study beginning, eight were not enrolled for the following reasons: four due to dementia or motor disability resulting in incapacity to attend the visit, two because of refusal, and two because they were unable to come for the visit because living outside the region. Considering controls, we excluded 4 individuals with dementia and motor impairment leading to inability to attend the visit, 4 with cancer, 1 with scleroderma, and 11 because of refusal to participate. Each group was composed of 5 males and 18 females. The mean age (±SD) was 52.4 ± 15.7 years for the CADASIL patients and 54.0 ± 15.3 years for controls (t-test p = .73). The mean education level was 10.3 ± 3.7 and 10.9 ± 3.9 years, respectively (t-test, p = .59).

The mean age of onset (±SD) of the disease for the 19 symptomatic CADASIL patients was 48.2 ± 15.5 years (range 22–72). Table 1 shows the frequency of clinical disturbances typical of CADASIL.

Table 1.

Clinical disturbances in CADASIL patients and controls

 CADASIL patients (N = 23) Controls (N = 23) p
Migraine 19 (82.6%) 8 (34.8%) .002 
Stroke 9 (39.1%) 0 (0%) .001 
TIA 5 (21.7%) 0 (0%) .049 
History of psychiatric disturbances 15 (65.2%) 1 (4.3%) <.001 
MCI 8 (34.8%) 0 (0%) .004 
Seizures 2 (8.7%) 0 (0%) .489 
 CADASIL patients (N = 23) Controls (N = 23) p
Migraine 19 (82.6%) 8 (34.8%) .002 
Stroke 9 (39.1%) 0 (0%) .001 
TIA 5 (21.7%) 0 (0%) .049 
History of psychiatric disturbances 15 (65.2%) 1 (4.3%) <.001 
MCI 8 (34.8%) 0 (0%) .004 
Seizures 2 (8.7%) 0 (0%) .489 

Notes: TIA = Transient Ischemic Attacks; MCI = Mild Cognitive Impairment

* χ2 test.

Data about functional and cognitive assessment of cases and controls are reported in Table 2. The CADASIL patients showed slightly worse performances in global cognitive functioning, and lower functional autonomy in instrumental activities of daily living, while significant differences in visuo-spatial abilities and executive functions were not found (Table 2).

Table 2.

Cognitive and functional tests mean scores (±SD) in CADASIL patients and controls

  CADASIL patients (N = 22)a Controls (N = 23) pb 
MMSE 27.8 ± 2.2 28.9 ± 1.3 .037 
ADL (preserved number of items) 5.7 ± 0.9 6.0 ± 0.0 .114 
IADL (preserved number of items) 6.5 ± 2.6 8.0 ± 0.2 .010 
 N = 22a N = 22a  
Stroop test (Interference Score) 44.5 ± 32.2 53.8 ± 55.6 .500 
TMT (Trail B152.9 ± 107.7 104.9 ± 63.1 .079 
TMT (Trail A56.2 ± 36.3 57.2 ± 71.4 .956 
  CADASIL patients (N = 22)a Controls (N = 23) pb 
MMSE 27.8 ± 2.2 28.9 ± 1.3 .037 
ADL (preserved number of items) 5.7 ± 0.9 6.0 ± 0.0 .114 
IADL (preserved number of items) 6.5 ± 2.6 8.0 ± 0.2 .010 
 N = 22a N = 22a  
Stroop test (Interference Score) 44.5 ± 32.2 53.8 ± 55.6 .500 
TMT (Trail B152.9 ± 107.7 104.9 ± 63.1 .079 
TMT (Trail A56.2 ± 36.3 57.2 ± 71.4 .956 

Notes: MMSE = Mini-Mental State Examination; ADL = Activities of Daily Living Scale; IADL = Instrumental Activities of Daily Living Scale; TMT = Trail Making Test.

ªOne patient refused to undergo this evaluation.

bIndependent samples t-test.

According to DSM-IV criteria, a diagnosis of major depressive episode was made in 18 out of the 23 (78.3%) CADASIL patients and 10 (43.5%) controls (χ2 test p < .05). Considering depressed participants, the level of depression as evaluated by HRSD was mild (mean score: 9.1 ± 8.1) for the CADASIL patients and in the normal range (6.1 ± 6.9) for controls (t-test p = .191).

On the Ekman and Friesen test, the CADASIL patients tended to have a correct recognition of facial expressions less frequently than controls (total score: 0.12 ± 0.08 vs. 0.40 ± 0.37, p < .05). Considering the recognition of specific emotions, the only statistically significant difference after Bonferroni correction was for fear (Fig. 1).

Fig. 1.

Test of recognition of facial expressions in CADASIL patients and controls. *Mann–Whitney U test and Bonferroni correction for multiple comparisons.

Fig. 1.

Test of recognition of facial expressions in CADASIL patients and controls. *Mann–Whitney U test and Bonferroni correction for multiple comparisons.

Multivariate analysis, including the diagnoses of CADASIL, major depression, and MCI as independent variables (model 1), confirmed a reduced capacity in recognition of fear (p < .007, forumla) expression in the CADASIL patients in comparison to controls, and showed a significant effect of depression on sadness (p < .007, forumla) recognition: non-depressed patients better recognized sadness. The interaction between diagnosis of CADASIL and major depression yielded no additional effect (Table 3). There was no significant affect of MCI on facial affect recognition ability. The interaction between CADASIL and MCI could not be calculated for the lack of MCI patients in the control group.

Table 3.

Test of recognition of facial expressions in CADASIL patients and controls with or without diagnosis of major depression and mild cognitive impairment

  CADASIL
 
Controls
 
pa (CADASIL vs. controls) pa (MCI vs. not MCI) pa (depression vs. not depression) pa (interaction CADASIL vs. depression) 
Depression
 
Depression
 
Yes No Yes No 
Happiness 0.88 ± 0.23 1.00 ± 0.00 0.95 ± 0.16 0.96 ± 0.14 .504 .334 .559 .223 
Neutral 0.56 ± 0.29 0.84 ± 0.36 0.83 ± 0.27 0.89 ± 0.25 .443 .188 .260 .093 
Surprise 0.75 ± 0.33 0.87 ± 0.30 0.68 ± 0.28 0.82 ± 0.28 .843 .659 .147 .579 
Sadness 0.48 ± 0.31 0.84 ± 0.36 0.63 ± 0.32 0.84 ± 0.30 .373 .622 .006 .976 
Fear 0.31 ± 0.22 0.26 ± 0.08 0.73 ± 0.35 0.84 ± 0.31 .001 .611 .953 .586 
Disgust 0.75 ± 0.33 0.80 ± 0.27 0.85 ± 0.24 0.94 ± 0.18 .733 .117 .823 .400 
Anger 0.44 ± 0.28 0.56 ± 0.41 0.40 ± 0.21 0.70 ± 0.33 .615 .067 .340 .885 
  CADASIL
 
Controls
 
pa (CADASIL vs. controls) pa (MCI vs. not MCI) pa (depression vs. not depression) pa (interaction CADASIL vs. depression) 
Depression
 
Depression
 
Yes No Yes No 
Happiness 0.88 ± 0.23 1.00 ± 0.00 0.95 ± 0.16 0.96 ± 0.14 .504 .334 .559 .223 
Neutral 0.56 ± 0.29 0.84 ± 0.36 0.83 ± 0.27 0.89 ± 0.25 .443 .188 .260 .093 
Surprise 0.75 ± 0.33 0.87 ± 0.30 0.68 ± 0.28 0.82 ± 0.28 .843 .659 .147 .579 
Sadness 0.48 ± 0.31 0.84 ± 0.36 0.63 ± 0.32 0.84 ± 0.30 .373 .622 .006 .976 
Fear 0.31 ± 0.22 0.26 ± 0.08 0.73 ± 0.35 0.84 ± 0.31 .001 .611 .953 .586 
Disgust 0.75 ± 0.33 0.80 ± 0.27 0.85 ± 0.24 0.94 ± 0.18 .733 .117 .823 .400 
Anger 0.44 ± 0.28 0.56 ± 0.41 0.40 ± 0.21 0.70 ± 0.33 .615 .067 .340 .885 

Note: In bold, significant p level (<.007). MCI = Mild Cognitive Impairment.

aMultivariate ANOVA.

In multivariate model 2, including cognitive performances (MMSE score) and a quantitative evaluation of depressive symptoms (HRSD score) as covariates (Table 4), the effect of CADASIL diagnosis on recognition of fear expression remained statistically significant (p < .007, forumla). In this model, the HRSD score influenced the recognition of neutral faces (p < .007, forumla); the higher scores of HDRS corresponded to a decrease in the ability to recognize neutral expression. Cognitive performances did not influence the recognition of any expression.

Table 4.

Test of recognition of facial expressions in CADASIL patients and controls including the influence of cognitive performance (MMSE score) and HDRS score

 CADASIL Controls pa (CADASIL vs. controls) pa (MMSE) pa (HDRS) 
Happiness 0.90 ± 0.22 0.96 ± 0.14 .296 .135 .012 
Neutral 0.64 ± 0.32 0.87 ± 0.26 .092 .014 .001 
Surprise 0.76 ± 0.33 0.76 ± 0.28 .641 .529 .137 
Sadness 0.57 ± 0.35 0.75 ± 0.32 .290 .081 .663 
Fear 0.27 ± 0.12 0.79 ± 0.33 .001 .733 .585 
Disgust 0.75 ± 0.31 0.90 ± 0.21 .264 .048 .387 
Anger 0.47 ± 0.31 0.57 ± 0.32 .591 .305 .253 
 CADASIL Controls pa (CADASIL vs. controls) pa (MMSE) pa (HDRS) 
Happiness 0.90 ± 0.22 0.96 ± 0.14 .296 .135 .012 
Neutral 0.64 ± 0.32 0.87 ± 0.26 .092 .014 .001 
Surprise 0.76 ± 0.33 0.76 ± 0.28 .641 .529 .137 
Sadness 0.57 ± 0.35 0.75 ± 0.32 .290 .081 .663 
Fear 0.27 ± 0.12 0.79 ± 0.33 .001 .733 .585 
Disgust 0.75 ± 0.31 0.90 ± 0.21 .264 .048 .387 
Anger 0.47 ± 0.31 0.57 ± 0.32 .591 .305 .253 

Note: In bold, significant p level (<.007).

aMultivariate ANCOVA.

Discussion

In this study, we have been able to show for the first time that the CADASIL patients have impaired abilities in the recognition of emotions, particularly of fear. This effect was not mediated by depressive symptoms or by cognitive performances as shown in the multivariate analyses. In fact, a prior study has shown that patients affected by depression may have a more severe impairment in facial recognition (Demenescu, Kortekaas, den Boer, & Aleman, 2010). These results represent a first attempt to study disease features that are not immediately appreciable on typical clinical evaluation.

An interesting and speculative aspect of our findings concerns the anatomic basis of impaired recognition of emotions in the CADASIL patients. Similar patterns of face expression processing impairment have been attributed in other diseases to damage in the cortical-subcortical circuits (Ariatti, Benuzzi, & Nichelli, 2008; Ibarretxe-Bilbao et al., 2009) and related to a variable degree of early neuronal changes in specific areas (Assogna, Pontieri, Caltagirone, & Spalletta, 2008; Ibarretxe-Bilbao et al., 2009). A large number of different structures participate in recognizing facial expression of emotions; among them, the occipito-temporal cortex, the amygdala, the orbito-frontal and the prefrontal cortex, the insula, the basal ganglia, and the right parietal cortex and other subcortical structures (Adolphs, Damasio, & Tranel, 2002; Adolphs, 2010; Pessoa & Adolphs, 2010). In relation to our results, several studies have shown that the brain structure responsible for fear recognition is the right amygdala (Adolphs et al., 2002; Adolphs, 2010; Pessoa & Adolphs, 2010). In the CADASIL patients, this impaired ability might depend on the damage of cortico-subcortical circuits caused by the typical subcortical pathological changes of the disease, as in multiple sclerosis (Henry et al., 2009). Of note, in the CADASIL patients, a prominent involvement of the temporal lobes is present like in other conditions in which recognition of emotions is impaired (Bonora et al., 2011). Concerning the specific fear recognition impairment, we could hypothesize a particular involvement of the amygdala among the typical temporal lobe alterations in CADASIL.

Some authors have suggested that deficits in emotion recognition are associated with grey matter volume loss in emotion-relevant areas (Adolphs, 2010; Ariatti et al., 2008; Assogna et al., 2008; Ibarretxe-Bilbao et al., 2009; Johnson et al., 2007). In the CADASIL patients, damage of cortical grey structures has been recently found, and this has been related to cognitive disturbances (O'Sullivan et al., 2008) and, interestingly, to apathy (Jouvent et al., 2011).

None of our CADASIL patients was severely cognitively affected or disabled. This might imply that an impaired recognition of emotions is altered early during the course of the disease. Other apparently nondisabling neuropsychological aspects, such as mood disorders and apathy, have recently been identified in the CADASIL patients and proposed as cardinal features of the disease (Reyes et al., 2009). Our study may add to these findings. In other neurological diseases, particularly Huntington's and Parkinson's diseases, the abnormalities in emotional processing (mainly of negative emotions) begin early in the pre-diagnostic stages (Henley et al., 2008; Ibarretxe-Bilbao et al., 2009; Johnson et al., 2007), and are thought to sustain some aspects of human social behavioral disorders (Henley et al., 2008; Ibarretxe-Bilbao et al., 2009; Johnson et al., 2007). Whether in CADASIL patients the impairment in affect recognition might be used as a pre-clinical marker of the disease, as in other neurological conditions (Adolphs et al., 2002; Adolphs, 2010; Bonora et al., 2011; Henley et al., 2008; Henry et al., 2009; Ibarretxe-Bilbao et al., 2009; Johnson et al., 2007; O'Sullivan et al., 2008; Pessoa & Adolphs, 2010), remains to be elucidated. The issue of specificity, particularly concerning the impairment in the recognition of fear in our sample, needs to be confirmed in larger series.

Limitations of the Study and Possible Future Developments

We recognize some limitations of our study. The lack of functional or volumetric analysis imaging represents a major shortcoming. We plan to perform neuroimaging analyses in our patients in the future. A second limitation is that we examined only a few selective neurobehavioral characteristics, while other aspects were not taken into account. Moreover, tests to assess complex visuo-perceptual abilities, such as facial discrimination (Gur et al., 1993; Meletti et al., 2009), were not performed in our study. However, considering that our patients were not severely cognitively affected and differences in facial recognition are restricted to fear, the findings might not be just a function of differences in perception.

Moreover, the reciprocal transformation of facial expressions test' scores improved normality indexes but did not reach a complete normalization of data; despite these limitations, we decided to perform a multivariate parametric analysis to take into account the simultaneous effect of several factors on facial affect recognition.

A further limitation is the small number of patients, due in part to the low frequency of the disease in the population and by the fact that the study was conducted as a single-center survey. The small sample size reduces the robustness of findings and the results need to be confirmed in larger series to test the potential impact of affect recognition impairment in the CADASIL patients, for example, by seeing whether this alteration could be used as an early marker of the disease. Our sample was also skewed in terms of gender distribution and therefore we cannot exclude that the obtained results were due to some interaction between CADASIL and female gender with regard to fear facial affect recognition.

Additionally, we recognize a high prevalence of major depression also in our control group. Because depression is associated with worse recognition of facial expressions (Demenescu et al., 2010), this might have caused an attenuation of the differences with the CADASIL group (where depression is more represented). Despite high levels of depression in both groups, when depression was included as a covariate, the finding of significant differences in facial recognition remained.

Finally, considering that recognition and processing of emotions are reputed to be a crucial aspect of social behavior and are related to poor social functioning and motivational deficits (Demenescu et al., 2010), it will be interesting to explore the relationship between affect recognition impairment and other features of the disease, such as apathy.

Conflict of Interest

None declared.

Acknowledgement

We wish to thank Professor Paolo Frigio Nichelli (Department of Neurosciences, University of Modena and Reggio Emilia) for useful comments and criticism on the paper.

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