Social cognition profile in early Huntington disease: Insight from neuropsychological assessment and structural neuroimaging

Abstract

Background

Huntington's disease (HD) is traditionally associated with motor, cognitive, and neuropsychiatric symptoms. Recent observations suggest that disturbances in social cognition may feature prominently in HD, potentially contributing to behavioral challenges.

Objective

This study aims to explore the onset and neural mechanisms underlying social cognition disturbances in HD, which are not yet well understood despite increasing recognition of these symptoms.

Methods

This study compared 20 individuals in the early stages of HD with 20 healthy controls across a range of cognitive tests, in-depth social cognition assessments, and structural MRI evaluations.

Results

The findings revealed alterations in various aspects of social cognition, particularly cognitive and affective Theory of Mind, in the early HD group. Some of these alterations correlated with the neurodegeneration of the striatum (caudate), suggesting that social cognition deficits may serve as early indicators of disease progression.

Conclusions

This research underscores the importance of integrating social cognition evaluations into the clinical assessment of HD and hints at a complex interplay between these deficits and the broader neuropsychological impact of the disease. The results thus advocate for a more holistic approach to understanding and managing HD, considering the potential interdependencies between social cognition and other cognitive functions.

Keywords

Huntington’s disease social cognition theory of mind structural MRI

Introduction

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms.¹ Motor symptoms are often used to make the formal clinical diagnosis of HD in persons with a positive family history, confirmed by genetic testing. Nevertheless, subtle cognitive and behavioral symptoms, subtended by neuropathological changes, can be observed many years before the diagnosis, even at the pre-symptomatic stage of the disease.^2–4 Cognitive changes occur primarily in the domain of executive functioning.⁵ Concerning behavioral changes, HD patients are often described as self-centered, lacking sympathy and empathy, mentally inflexible, and exhibiting apathy, irritability, and perseveration.⁶ While executive deficits are thought to be major contributors to behavioral changes in HD, several studies have suggested that these behavioral changes may be related to impairments of social cognition.^6–8 Yet, little is known about the deficit in social cognition in HD, their neuroanatomical substrates, and their onset in the course of the disease (for review, see 9).

Social cognition includes numerous processes such as the recognition of emotions, social knowledge, and Theory of Mind (ToM).^10,11 The most widely investigated aspect of HD is the recognition of facial emotions (for reviews, see^12,13). HD was associated with a deficit of recognition of all the negative basic emotions (anger, sadness, fear, and disgust).¹³ Deficits in the recognition of emotions could extend to positive emotions,¹⁴ especially in manifest HD.¹⁵ Despite their considerable role in regulating social behaviors and integrating appropriate behaviors,¹⁶ the treatment of complex emotions (such as embarrassment, pride, and contempt) has not been specifically studied in HD. Furthermore, most studies have evaluated the recognition of emotions from photos, in a static condition, whereas it has been shown that a more ecological material, based on dynamic and non-stereotypical facial expressions, was more suitable to highlight subtle difficulties in HD.¹⁷

To our knowledge, only one study has assessed social knowledge in HD patients, using a task of moral judgment.¹⁸ Social knowledge refers to the understanding of social norms, rules, and roles that guide interactions within a society.¹⁹ The authors found that, compared to Healthy Control (HC) subjects, patients with HD tend to underestimate the severity of immoral behavior in the Moral Behavior Inventory.²⁰ No correlation was observed between the performances at this inventory and the frequency and severity of their behavioral disorders and psychiatric symptoms (Problem Behaviors Assessment-short form).²¹ However, this study was specifically focused on the morality component through a morality scale and no study has focused on social knowledge in a more comprehensive way.

Finally, distinct studies with HD patients have focused on the ToM, i.e., the ability to attribute cognitive (e.g., beliefs, thoughts) and affective (e.g., emotional states of mind, emotion, or feelings) to others and predict behaviors based on their mental states.^22,23 Overall, they reported an impairment of the capacities of cognitive,^24,25 affective,²⁶ or both types of ToM in HD patients.^6,7,27,28 Some studies with pre-manifest cases indicated preservation of ToM abilities,^29–31 while others described impairments in both types of ToM.³² This discrepancy might be partly explained by the different inclusion criteria used to categorize subjects in the pre-manifest phase and the different sensitivity of the social cognition tasks proposed in each study.

The brain damage underlying the changes in social cognition in HD is still poorly defined. Difficulties in the recognition of negative emotions have been related to structural³³ and functional abnormalities in the cortico-thalamo-striatal network, ventromedial prefrontal cortex, amygdala, and insula,^34,35 but also in medial occipital and parietal structures.³⁶ Concerning the deficit in ToM, a link with abnormal connectivity between the amygdala and certain cortical regions (e.g., right fusiform face area) has been demonstrated.³⁷

This study aims to delineate the scope of social cognition deficits in early-stage HD and identify the brain regions implicated in these deficits. By deploying a comprehensive, sensitive, validated, and ecologically grounded social cognition battery, we aim at providing a holistic picture of social cognition anomalies characteristic of early HD.

Methods

Participants

Participants with HD were recruited at the Reference National Center for Neurogenetic Disease at Angers University Hospital, while participants of the control group were recruited from different sources such as advertisements in electronic media or posted in the community. The inclusion criteria for all participants were to be right-handed, native French speakers, aged between 20 and 75 years old (but in our final sample, participants were between 20 and 57 years old), and without contraindications for MRI. The exclusion criteria for the controls included the absence of neurological, psychiatric disorders, or a history of addiction, ensured by a medical examination with a physician from our team. The regional ethics committee (CPP Nord-Ouest III) approved the study and all procedures performed were under the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration. Participants gave their written informed consent before participation and all neuropsychological and neuroimaging examinations were performed within a maximum of 3 months following the signature of the consent.

Participants with HD

Our research protocol was proposed to 20 subjects carrying the genetic mutation of HD (Cytosine–Adenine–Guanine repeats, CAG > 40). This group consisted of participants who received annual medical and neuropsychological monitoring in this hospital department. Based on the Unified Huntington's Disease Rating Scale (UHDRS),¹ 11 were at the early symptomatic phase of the disease (stage 1, motor UHDRS > 5),³⁸ and 9 at the pre-symptomatic stage (motor UHDRS ≤ 5). Demographic and clinical information are reported in Table 1.

Table 1.

Demographic data for HD and HC participants.

	HD	HC	Mann–Whitney U test
N (Women)	20 (9)	20 (9)	−
Age (y)	37.41 ± 8.96	38.49 ± 10.14	U = 188, z = 0.311, p = 0.756
	[21–53]	[20–57]
Education (y)	13.65 ± 3.27	13.9 ± 2.61	U = 183, z = 0.446, p = 0.658
	[9–20]	[11–20]
HD features
CAG	45 ± 2.40	−	−
	[40–49]
UHDRS motor score (max. 124)	9.26 ± 11.23	−	−
	[0–32]
UHDRS functional capacity score (max. 13)	12.58 ± 0.84	−	−
	[11–13]
UHDRS independence (%)	98.68 ± 3.27	−	−
	[90–100]	−	−

Values are mean ± standard deviation and ranges [min-max values].

HD: Huntington's disease; HC: healthy controls; CAG: cytosine adenine guanine; UHDRS: Unified Huntington Disease Rating Scale.

Four of 11 HD participants were under medication to address depression and or anxiety (e.g., Escitalopram) which are commonly observed in HD. Three participants were treated with medication to reduce involuntary movements (e.g., Tetrabenazine) and 2 participants were also treated for epilepsy (e.g., Lamotrigine). Among the 9 HD participants in the pre-symptomatic phase, 4 were under medication for depression and or anxiety, and one of them was also taking sleep medication (e.g., Doxylamine).

Healthy control participants

Each participant in the HD group was matched to one HC subject, for sex, age, and education level.

Neuropsychological assessment

All participants completed a comprehensive assessment of cognitive functions (cognitive UHDRS). It included classical executive tests assessing verbal generativity using a lexical (P, R, and V) and semantic (animal) fluency test,³⁹ mental flexibility with the Trail Making Test (TMT A and B),⁴⁰ inhibition with a Stroop test,⁴¹ selective attention and working memory with the Symbol Digit Modalities Test (SDMT),⁴² and learning and memory was evaluated with the Hopkins Verbal Learning Test (HVLT).⁴³ In addition, the overall cognitive level was estimated with the Mattis Dementia Rating Scale (MDRS).⁴⁴

Social cognition assessment

Original and validated neuropsychological tasks were administered to HD and HC participants to assess the different dimension of social cognition (see Supplemental Figures 1–4).

Figure 1.

Clusters of significant atrophy (uncorrected p < 0.0001 and cluster extent k > 100 mm³). Note. On the color bar, the T-values correspond to the extent of atrophy.

Facial emotions recognition

Emotions recognition was assessed through an original task, the Facial Emotion Recognition Test (FERT), built using the Amsterdam Dynamic Facial Expression Set (ADFES).⁴⁵ The task consisted of the emotional recognition of 100 color faces^25,46 including 50 photographs and 50 short videos (5 to 6 s). The strength of this task resides in the assessment of basic (happiness, surprise, sadness, anger, fear, and disgust) and complex emotions (pride, contempt, and embarrassment), as well as neutral expressions (Supplemental Figure 1), using both static and dynamic facial expressions. Five items were proposed for each emotion and each condition (static and dynamic). Participants had to choose between the 10 possible expressions for each item, with the list of possibilities presented in front of them. To synthesize a comprehensive measure of performance, scores from the static assessments were combined with those from the dynamic assessments, yielding a total possible score out of 100.

Theory of mind

The affective ToM was assessed through the Pierre and Marie task.⁴⁷ It consists of 120 black and white videos featuring 2 characters in everyday life situations (Supplemental Figure 2). For each situation, the participant had to mentally infer the emotion normally felt by one of the two characters (identified by a pink armband) and to reason about it in a first video with a specific context. This emotion could be basic (anger or surprise), complex (pride or embarrassment), or neutral. A second video then showed the actual emotional reaction of the character, the expression in response to the context. Participants had to decide whether the character's reaction was congruent/adapted or not to the situation. An accuracy score was calculated by taking the sum of the correct responses across both conditions and dividing it by the total number of items presented. This ratio provides a measure of the participant's precision in identifying the correct expressions within the given tasks. This task was assessed during a functional MRI.

In addition, cognitive ToM was assessed by the TOM-15 test,⁴⁸ a false belief task, including 15 short stories illustrated each time by comic strips. In this test, 8 items involve first-order mental representations (first-order ToM score, max. 8) and 7 s-order mental representations (second-order ToM score, max. 7). First-order refers to representations of an individual's thoughts that involve adopting the other's perspective (e.g., “I think that Mr A thinks that”), while second-order representations involve simultaneously adopting two perspectives (e.g., “I think that Mr A thinks that Mrs. B thinks that”). Each story was accompanied by a comprehension question, used as a control condition to rule out difficulties in understanding the story (Comprehension score, max 15; see Supplemental Figure 3).

Social norm knowledge

Social Norm Knowledge (SNK) was assessed through another original task allowing the detection of knowledge of social rules in ecological situations and without reference to morality.¹⁹ It includes 44 drawings representing characters in social situations of everyday life (Supplemental Figure 4). Half of them illustrate a character breaking a social rule (for example: to telephone in a church) and the other half show similar behaviors but without breaking a social rule (for example: to telephone in a train station). These later were used as control situations. Participants had to indicate whether the attitude of the characters was adapted to the situation or if a transgression of social norms was performed. A correct detection score (max. 22) and a false alarm score (max. 22; i.e., control situations wrongly identified as involving a transgression) were calculated and combined (max. 44).

MRI data acquisition

All subjects underwent an anatomical MRI on a Philips scanner (Eindhoven, Netherlands) Achieva 3.0 T at the Cyceron Center in Caen (France). Specifically, we acquired a high-resolution T1-weighted images (3D-T1-Fast Field Echo sagittal orientation, SENSE factor = 2, Repetition Time (TR) = 20 ms, Echo Time (TE) = 4.6 ms; flip = 10 °, 180 slices, no gap, slice thickness = 1 mm, field of view (FOV) = 256 × 256 mm2, resolution in the plane = 1 × 1 mm²).

MRI data process

The neuroimaging data set was processed using the Statistical Parametric Mapping Version 12 (SPM12) software implemented in MATLAB 7.4 (The MathWorks, Sherborn, MA). The preprocessing steps of the T1-weighted structural images included segmentation and spatial normalization to the Montreal Neurological Institute (MNI) template. The normalized gray matter images were then modulated by the Jacobian determinants, correcting only the effects of the nonlinear deformation, and smoothed using a Gaussian kernel of 8 mm full width at half maximum.

Statistical analysis

Behavioral comparisons

The cognitive data analysis was conducted using Statistica (Version 13). Non-parametric Mann-Whitney U tests were employed to assess differences between the HD group (comprising both patients and pre-symptomatic participants) and the HC group. Non-parametric tests were preferred due to the small sample size. Subsequently, a Benjamini-Hochberg false discovery rate control was independently applied to each set of assessments, neuropsychological and social cognition, to correct for multiple comparisons in the respective datasets. To better understand the social cognition performance in HD, Spearman correlations were carried out between neuropsychological and social cognition performances. These correlations were limited to areas where deficits in HD participants were previously identified, and a false discovery rate control was applied to the results.

MRI data analysis

We compared voxel-based morphometry between HD and HC groups to identify atrophied regions in HD. We then performed voxelwise regression models to assess the brain region associated with the performances at social cognition tasks in the HD group (symptomatic and pre-symptomatic together). As for the cognitive correlations, our analyses focused on specific scores for which there were significant differences between HDs and HCs. This model allowed us to identify the specific neuronal substrates of each deficit in the whole group of HD. These analyses were masked to include only voxels for which the probability of being gray matter was greater than 0.3 and results were thresholded at p < 0.001 (uncorrected). To control the specificity of our findings and ensure that they didn’t reflect disease severity, we included the MDRS total score as a covariate for each of our statistical models.

Results

Neuropsychological performances

The results of the comprehensive assessment of cognitive functions are summarized in Table 2. Participants diagnosed with HD exhibited significantly lower performance (p < 0.05) than those in the HC group across several measures including the MDRS, semantic verbal fluency, the Dot and Interference conditions of the Stroop test, the TMT-A, and the SDMT. All these differences, with the exception of the MDRS, remained significant after applying the false discovery rate control.

Table 2.

Neuropsychological scores of HD participants (N = 20) compared to their HC group (N = 20).

	HD	HC	Mann–Whitney U test
MDRS (total score /144)	138.55 ± 6.25	142.35 ± 2.13	U = 121. Z = 2.123. p = 0.032
Semantic verbal fluency task (animals score)	28.4 ± 9.52	35.9 ± 6.5	U = 106. Z = 2.529. p = 0.010
Letter verbal fluency task (P. V. and L score)	59.3 ± 33.83	58.75 ± 13.19	U = 182. Z = 0.473. p = 0.639
Stroop
Dot condition (score)	66.15 ± 17.87	83.67 ± 14.68	U = 79.5. z = 2.924. p = 0.002
Word condition (score)	85.32 ± 17.05	106.94 ± 13.78	U = 49.5. z = 3.677. p = 0.588
Interference condition (score)	39.5 ± 14.69	52.5 ± 9.82	U = 89.5. z = 2.631. p = 0.007
TMT
Part A (reaction time s)	47.85 ± 23.06	29.8 ± 8.94	U = 81. Z = −3.205. p < 0.001
Part B (reaction time s)	87.35 ± 58.39	62.95 ± 25.21	U = 168.5. z = −0.839. p = 0.398
HVLT
Total of the three recall (score /36)	25.7 ± 5.28	28.75 ± 4.28	U = 134. Z = 1.772. p = 0.076
Delayed recall (score /12)	9 ± 2.45	9.85 ± 1.53	U = 164.5. z = 0.947. p = 0.340
Recognition (score /12)	11.5 ± 0.89	11.5 ± 1	U = 198. Z = 0.041. p = 0.968
SDMT (score)	44.3 ± 17.45	55.4 ± 9.14	U = 105.5. z = 2.543. p = 0.009

HD: Huntington's disease; HC: healthy controls; MDRS: Mattis Dementia Rating Scale; TMT: Trail Making Test; HVLT: Hopkins Verbal Learning Test; SDMT: Symbol Digit Modalities Test.

Significant comparisons after false discovery rate corrections are in bold.

Social cognition performances

Regarding social cognition scores, HD participants showed deficit performances (p < 0.05) compared to HCs on tasks of cognitive ToM (TOM-15, second-order score) and affective ToM (Pierre and Marie). Only the differences in the TOM-15 persisted after false discovery rate control. No significant differences were observed in TOM-15 (comprehension and first-order scores), emotion recognition (FERT), or the social norms knowledge task (Table 3).

Table 3.

Social cognition scores of HD participants (N = 20) compared to their HC group (N = 20).

	HD	HC	Mann–Whitney U test
FERT (score /100)	73.95 ± 16.81	81.85 ± 9.99	U = 150, z = 1.339, p = 0.182
ToM-15
Comprehension (score /15)	13.7 ± 1.89	14.55 ± 0.6	U = 173.5, z = 0.703, p = 0.477
First order (indice)	0.84 ± 0.26	0.92 ± 0.12	U = 182, z = 0.473, p = 0.639
Second order (indice)	0.63 ± 0.32	0.90 ± 0.10	U = 90, z = 2.962, p = 0.003
P&M score	0.75 ± 0.17^a	0.88 ± 0.07	U = 98, z = 1.958, p = 0.049
SNK score	37.25 ± 4.42	37.25 ± 2.84	U = 182.5, z = 0.460, p = 0.645

Analyses were conducted on 16 participants with Huntington Disease.

Significant comparison after false discovery rate corrections is in bold.

HD: Huntington's disease; HC: healthy controls; FERT: Facial Emotion Recognition Test; P&M: Pierre and Marie test; SNK: Social Norms Knowledge test.

Relationship between neuropsychological and social cognitive impairments

In the correlation analyses, our primary focus was on cognitive test scores that remained significant after a false discovery rate correction to avoid false positives. However, for the sake of comprehensiveness and to ensure we did not miss any potential trends, we also included certain non-significant results after false discovery rate control, such as the correlations between TOM-15 and MDRS, and the Pierre and Marie tests. This approach allows us to highlight trends and relationships that are important for understanding the broader context of our findings.

In the HD group, correlations were specifically conducted between areas of deficit in both neuropsychological and social cognition tasks (Table 4). After applying false discovery rate control, we observed significant correlations between the TOM-15 s-order score and the following: the MDRS (r = 0.508, p = 0.022), the semantic verbal fluency task score (r = 0.708, p < 0.001), the Stroop Dot (r = 0.626, p = 0.003) and Interference condition score (r = 0.547, p = 0.012), the TMT Part A reaction time (r = 0.584, p = 0.006), and the SDMT score (r = 0.733, p < 0.001). However, no correlation was found between the Pierre and Marie test score and the neuropsychological scores.

Table 4.

Spearman correlations between neuropsychological performance deficits and social cognition performance deficits in participants with Huntington disease.

	ToM-15 s order indice	P&M Score
MDRS (total score /144)	n = 20, Rho = 0.508, p = 0.022	n = 17, Rho = 0.171, p = 0.512
Semantic verbal fluency task (animals score)	n = 20, Rho = 0.708, p < 0.001	n = 17, Rho = 0.202, p = 0.436
Stroop dot condition (score)	n = 20, Rho = 0.626, p = 0.003	n = 17, Rho = 0.124, p = 0.634
Stroop interference condition (score)	n = 20, Rho = 0.547, p = 0.012	n = 17, Rho = 0.192, p = 0.460
TMT part A (reaction time s)	n = 20, Rho = −0.584, p = 0.006	n = 17, Rho = −0.009, p = 0.973
SDMT (score)	n = 20, Rho = 0.733, p < 0.001	n = 17, Rho = 0.063, p = 0.809

MDRS: Mattis Dementia Rating Scale; TMT: Trail Making Test; SDMT: Symbol Digit Modalities Test.

Significant correlations after false discovery rate corrections are in bold.

Relationship between social cognitive impairments and neuroimaging

Voxel-based morphometry analyses have revealed bilateral atrophy in the caudate and putamen in individuals with HD when compared to HC, as illustrated in Figure 1 (detailed in Supplemental Table 1).

We report significant associations between gray matter volume and social cognition scores, where notable differences between HD and HC participants emerged (p cluster-level < 0.05 FWE), in Table 5 and Figure 2, with all statistical models adjusted for overall cognitive level (MDRS). Our findings indicate an association between the TOM-15 s-order scores and gray matter volume in the right caudate nucleus (see Figure 2A). Additionally, a distinct dichotomy is observed in the TOM-15 s-order scores between symptomatic HD participants (represented by orange dots) and pre-symptomatic HD participants (depicted as yellow dots) on the correlation scatterplot for these associations.

Figure 2.

Correlations between TOM-15 s-order scores (A; uncorrected p < 0.0001, n = 19) and P&M scores (B; uncorrected p < 0.001, n = 16), with mean gray matter volume signal, p cluster-level <0.05FWE.

Table 5.

Voxel-wise results showing associations between gray matter volume and social cognition scores (uncorrected p < 0.001 and cluster extent k > 100 mm³).

Label	Hemisphere	Cluster size (k)	MNI coordinates			T
Label	Hemisphere	Cluster size (k)	x	y	z
ToM-15 score
Caudate nucleus	Right	187	−15	21	12	6.11
P&M score
Anterior Insula	Right	638	−36	−15	−6	6
Posterior Insula	Right		−46	−12	7	5.57
Rolandic operculum	Right		−51	−1	13	4.64

The bolded clusters represent the most significant findings.

Although the Pierre and Marie test did not show significant differences between groups after false discovery rate control, it showed a trend toward significance before correction. Therefore, we explored the potential associations between this test and gray matter volumes to provide a more comprehensive overview of the observed relationships. Performance for the Pierre and Marie test was also correlated with the volumes of the right anterior and posterior insula, as well as the right Rolandic operculum (Figure 1B).

Discussion

This study investigated the presence and extent of social cognitive impairments in the early stages of HD. We discovered deficits across various aspects of social cognition in individuals with early HD, particularly in the domains of cognitive and affective ToM. Crucially, our analyses indicated that these deficits in cognitive ToM are related to structural changes in the striatum (caudate) and also to overall cognitive and executive functioning. This suggests that some of the observed social cognitive impairments may be partly attributable to broader cognitive deterioration.

In the investigation of cognitive ToM, especially for the second-order representations as assessed by the TOM-15,⁴⁸ our analysis revealed an impairment of the mental representation abilities in these HD subjects, consistent with the literature (for review, see).¹² Interestingly, a strong link was observed between the deficit in the second-order score and performance in executive functions, particularly flexibility (fluency task), inhibition (stroop test) and working memory measures (SDMT) of the UHDRS, executive functions that are well-known to be associated with cognitive ToM.⁴⁹

While our findings indicate significant correlations between second-order cognitive ToM deficits and executive functions, as well as gray matter volume in the caudate nucleus, it is important to consider that these differences may be influenced by general executive dysfunctions. Future studies should investigate the unique contributions of cognitive ToM by using other cognitive tests, such as the SDMT or the categorical fluency test (animals), which have demonstrated significant differences between HD and controls, to further refine the analyses and better understand the specific role of executive functions in cognitive ToM deficits.

Additionally, our visual representation in Figure 2A illustrates the correlation between TOM-15 s-order performance and gray matter volume, spanning various stages of early HD, from presymptomatic to early symptomatic. Data points for symptomatic HD participants cluster at the lower end of the curve, indicating both reduced cognitive function and diminished gray matter volume. In contrast, presymptomatic participants are positioned at the higher end, showing relatively intact cognitive functions and more substantial gray matter volume. This gradient visually encapsulates the progressive nature of social cognition deficits in HD, aligning with both the clinical trajectory of the disease and the accompanying cerebral atrophy, thereby supporting a continuum of decline rather than an abrupt onset. This finding is congruent with the ToM trajectory described in the literature.^50–52

While the HD group exhibited lower performance on the emotion recognition task (FERT) compared to HCs, the differences did not reach statistical significance, even though the task was challenging and encompassed both basic and complex emotions in static and dynamic forms. Given these performance discrepancies and considering the established literature on deficits in emotional recognition (for review, see¹³), it is plausible to suggest that such abilities may deteriorate further and become more noticeable as the disease progresses. The lack of significant differences in emotion recognition between groups in our study may also be influenced by our relatively small sample size, which limits statistical power. Future research with larger samples is needed to more definitively assess these potential differences and their implications for social cognitive dysfunction in HD.

Interestingly, in the Pierre and Marie task, our analysis indicated deficits in affective ToM in HD, albeit to a lesser extent than for cognitive ToM. This result highlights a specific deficit in the ability of individuals with HD to infer emotions from contextual subtleties, in contrast to their relative preserved skill in basic emotional recognition from facial expressions (FERT) which taps into more fundamental cognitive processes. This deficit in affective ToM did not correlate with broader cognitive or executive dysfunctions suggesting a more cognitively independent skill. Although the Pierre and Marie test did not show significant differences between groups after false discovery rate control, it showed a trend towards significance before correction. Therefore, we explored the potential associations between this test and gray matter volumes to provide a more comprehensive overview of the observed relationships.

To date, this is the first time that knowledge of social norms was assessed in HD. We did not evidence significant differences between the HD and control groups. This type of task typically requires notably semantic memory capabilities, which tend to be preserved in HD patients until the later stages of the disease.⁵³ This preservation could, in part, explain the absence of observed deficits in this aspect during the early stages of the pathology. Furthermore, our clinical observations support that knowledge of social norms is preserved in early-stage HD patients. Clinically, it appears that in the early stages, it is not the knowledge of social norms that deteriorates first but rather other aspects of social cognition.

The atrophy in the bilateral caudate and putamen in HD relative to HC is consistent with established patterns observed in early stages of the disease (for a review, see⁵⁴). Interestingly, our analysis also points to the involvement of some of these regions in the deficits in social cognition. Notably, the right caudate nucleus showed a significant correlation with the second-order representations in cognitive ToM, implicating its role beyond motor functions and classical cognitive operations.^55–57 This relationship may reflect a possible damage within a complex cognitive ToM network involving the dorsal parts of the prefrontal regions, the dorsal anterior cingulate cortex, and the striatum.⁵⁸ The early dorsal striatal atrophy (caudate and putamen), a hallmark in HD that our sample corroborates, could be a factor disrupting this intricated network, especially as the caudate represents a key node in the ToM connectivity network.⁵⁹ Regarding affective ToM, our analysis of the Pierre and Marie test indicates a distinct neural underpinning for these deficits, with neuroimaging data highlighting the right insula, a critical hub for emotion processing⁶⁰ and particularly for complex emotions.⁶¹ The particularity of this relationship emphasizes the insula's delicate role in the intricate mosaic of social cognition and its susceptibility in HD's progression.⁵⁷ Regarding the lateralization of our findings, it is noteworthy that only gray matter volume in the right side of the brain was associated with social cognitive test scores. This asymmetry might reflect the right hemisphere's known specialization in social and emotional processing, which has been documented in previous studies.^62,63

The neuroanatomical findings in this study suggest that cognitive ToM abilities in HD are closely tied to general cognitive and executive functions, reflecting a broad neural network engagement. Concerning affective ToM, it is linked to the limbic system, particularly the insula⁶⁴ indicating a dedicated pathway, relatively independent from the cognitive mechanisms in this study. Identifying distinct neural pathways for cognitive and affective processes in HD could provide clear targets for treatments aimed at social cognition deficits. Research indicates that the interplay of cognitive and affective processes is crucial for real-world social cognition, as tasks meant to assess ToM often simultaneously draw on both cognitive and emotional faculties (for meta-analysis, see⁶⁵).

Considering the extensive testing already required during HD clinical visits, prioritizing neuropsychological tasks that provide crucial insights becomes essential. These tasks are not only significant for healthcare professionals and researchers but also for helping families prepare for potential challenges associated with disease progression. Our results highlight the need to consider nonmotor symptoms (for review, see⁹), such as ToM deficits, along with more general cognitive aspects, within the diagnostic framework, advocating for a more comprehensive approach that captures the significant cognitive changes associated with HD. Recognizing that these deficits, deeply linked to executive dysfunctions (cognitive ToM), emerge before the later symptomatic stage, they prove valuable for early detection of cognitive decline. Furthermore, addressing one cognitive domain may have a reciprocal effect on another, reinforcing the benefit of an integrative treatment and care strategy. Therefore, enhancing the UHDRS cognitive battery with dual assessments of cognitive and affective ToM could clarify the onset of social cognition issues, thereby aiding in the more effective management of HD and potentially enhancing patient social engagement.

This study's main limitation arises from the small size of the HD group and the fact that both symptomatic and presymptomatic participants were combined for analysis. While it may seem that the analysis could be influenced more by those in the symptomatic phase, it is recognized that cognitive difficulties develop gradually, not suddenly, across the continuum from presymptomatic to symptomatic stages.^66,67 Consequently, we conducted our neuropsychological and anatomical analyses across the entire spectrum of HD participants to enhance statistical robustness and capture a broader range of variability. Additionally, while the MDRS total score was used to control for overall cognitive function, we did not control for other potential confounding variables such as age, gender, or CAG repeat length due to our limited sample size. We acknowledge that the MDRS score, although a robust and widely used measure of overall cognitive functioning in HD, was not significant after false discovery rate control. This choice was motivated by its comprehensive nature and its ability to capture variability within the HD group. Future studies with larger cohorts should aim to include these factors to provide a more comprehensive analysis. Furthermore, other cognitive tests, such as the SDMT or the categorical fluency test (animals), which have demonstrated significant differences between HD and controls, could be considered to further refine the analyses.

This inclusive approach has enabled us, for the first time, to identify brain regions where volume loss correlates with deficits in social cognition in the early stages of HD and to begin clarifying the extent of cognitive and executive function involvement. To build on these preliminary findings, further extensive research is necessary to fully understand these patterns, to ascertain the co-occurrence of ToM deficits with global cognitive impairments, to determine their onset in the HD progression, and to assess their consistency across the patient population. This refined comprehension is essential for developing tailored interventions and could significantly deepen our insights into the progression and management of HD.

Conclusions

Overall, this research provide new insights into the early impact of HD on social cognition, particularly cognitive and affective ToM. Through a combined approach of neuropsychological assessment and structural neuroimaging, we have uncovered the brain substrates for ToM deficits, particularly in brain areas implicated in HD. This understanding offers a crucial stepping stone for enhancing awareness and fostering better social engagement among those affected by HD, ultimately aiming to support and improve their interpersonal relationships.

Supplemental Material

sj-docx-1-hun-10.1177_18796397241291730 - Supplemental material for Social cognition profile in early Huntington disease: Insight from neuropsychological assessment and structural neuroimaging

Supplemental material, sj-docx-1-hun-10.1177_18796397241291730 for Social cognition profile in early Huntington disease: Insight from neuropsychological assessment and structural neuroimaging by Marie Caillaud, Mickael Laisney, Alexandre Bejanin, Harmony Duclos, Clarisse Scherer-Gagou, Adriana Prundean, Dominique Bonneau, Francis Eustache, Christophe Verny, Béatrice Desgranges and Philippe Allain in Journal of Huntington's Disease

Footnotes

Acknowledgements

This article is dedicated to the memory of our colleague Béatrice Desgranges. For their help with clinical data, the authors are grateful to neurogenetic staff members of the Hospital of Angers, A. Olivier, M. Bost, J. Muller (clinical research associates), and Marie-Anne Guerid (genetic counselor). The authors are also grateful to Dr S. Benbrika, Dr J. Dayan, Dr N. Derache, Dr A. Quillard, Dr F. Viader, and the Cyceron MRI-PET staff members for their help with the imaging examination.

ORCID iDs

Marie Caillaud

Alexandre Bejanin

Harmony Duclos

Francis Eustache

Funding

This research was supported by the France Huntington's Disease Association, Hospital of Angers (France), the French Ministry of Health (PHRC, ID-RCB: 2011-A00681-40), and the French National Institute for Health and Medical Research (INSERM). Independent of this work, AB acknowledges research support from the Fondo de Investigaciones Sanitario, Carlos III Health Institute (CP20/00038, PI22/00307) and the Alzheimer's Association (AARG-22-923680).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability

The data supporting this study's findings are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Supplemental material

Supplemental material for this article is available online.

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