Received: 11 May 2022 | Accepted: 14 July 2022 DOI: 10.1111/ene.15513 ORIGINAL ARTICLE Clinical and structural brain correlates of hypomimia in early-­ stage Parkinson's disease Frederic Sampedro1,2,3 | Saul Martínez-­Horta1,2,3 | Andrea Horta-­Barba1,2,3 | 1,4 1,4 1,4 Michel J. Grothe | Miguel A. Labrador-­Espinosa | Silvia Jesús | 1,4 5 1,2,3 Astrid Adarmes-­Gomez | Fatima Carrillo | Arnau Puig-­Davi | 6 7 7 Florinda Roldan-­Lora | Miquel Aguilar-­Barbera | Pau Pastor | Sonia Escalante Arroyo8 | Berta Solano Vila9 | Anna Cots-­Foraster9 | Javier Ruiz-­Martínez10 | Francisco Carrillo-­Padilla11 | Mercedes Pueyo-­Morlans11 | Isabel Gonzalez-­Aramburu12 | Jon Infante-­Ceberio12 | Jorge Hernandez-­Vara13 | Oriol de Fabregues-­Boixar13 | Teresa de Deus Fonticoba14 | Asuncion Avila15 | 16 1,2,3 Juan Carlos Martínez-­Castrillo | Helena Bejr-­Kasem | Antonia Campolongo1,2,3 | Berta Pascual-­Sedano1,2,3 | Pablo Martínez-­Martín1 | Diego Santos-­García17 | 1,4 18 Pablo Mir | COPPADIS Study Group | Pedro J. Garcia-­Ruiz | Jaime Kulisevsky1,2,3 1 Centro de Investigacion Biomedica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain 2 Unidad de Trastornos del Movimiento, Servicio de Neurología, Hospital de Sant Pau, Barcelona, Spain 3 Instituto de Investigacion del Hospital de Sant Pau, Barcelona, Spain 4 Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain 5 Movement Disorders Unit, Neurology Department, Hospital Universitario Virgen del Rocío, Seville, Spain 6 Unidad de Radiodiagnostico, Hospital Universitario Virgen del Rocío, Seville, Spain 7 Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain 8 Hospital de Tortosa Verge de la Cinta (HTVC), Tortosa, Tarragona, Spain 9 Institut Catala de la Salud (Girona), Institut d'Assistencia Sanitaria (IAS), Girona, Spain 10 Instituto de Investigacion Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain 11 Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain 12 Unidad de Trastornos del Movimiento, Servicio de Neurología, Hospital Universitario Marques de Valdecilla, Santander, Spain 13 Neurology Department and Neurodegenerative Diseases Research Group, Vall d'Hebron Universitary Campus, Barcelona, Spain 14 Complejo Hospitalario Universitario de Ferrol (CHUF), Hospital Arquitecto Marcide, Ferrol, Spain 15 Consorci Sanitari Integral, Hospital General de L'Hospitalet, L'Hospitalet de Llobregat, Barcelona, Spain 16 Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain 17 Complejo Hospitalario Universitario de A Coruña (CHUAC), A Coruña, Spain 18 Department of Neurology, Fundación Jimenez Diaz, Madrid, Spain Frederic Sampedro and Saul Martínez-­Horta contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial-­NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-­commercial and no modifications or adaptations are made. © 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. Eur J Neurol. 2022;00:1–8.  wileyonlinelibrary.com/journal/ene | 1 2 | SAMPEDRO et al. Correspondence Abstract Jaime Kulisevsky, Movement Disorders Unit, Neurology Department, Hospital de Background and purpose: Reduced facial expression of emotions is a very frequent symp- la Santa Creu i Sant Pau, Mas Casanovas tom of Parkinson's disease (PD) and has been considered part of the motor features of 90, 08041 Barcelona, Spain. Email: jkulisevsky@santpau.cat the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non-­motor symptoms of PD are poorly understood. Funding information Fundaci oacute;n Curemos el Parkinson Methods: The clinical and structural brain correlates of hypomimia were studied. For this (https://curemoselparkinson.org/) purpose, cross-­sectional data from the COPPADIS study database were used. Age, dis- ease duration, levodopa equivalent daily dose, Unified Parkinson's Disease Rating Scale part III (UPDRS-­III), severity of apathy and depression and global cognitive status were collected. At the imaging level, analyses based on gray matter volume and cortical thick- ness were used. Results: After controlling for multiple confounding variables such as age or disease dura- tion, the severity of hypomimia was shown to be indissociable from the UPDRS-­III speech and bradykinesia items and was significantly related to the severity of apathy (β = 0.595; p < 0.0001). At the level of neural correlates, hypomimia was related to motor regions brodmann area 8 (BA 8) and to multiple fronto-­temporo-­parietal regions involved in the decoding, recognition and production of facial expression of emotions. Conclusion: Reduced facial expressivity in PD is related to the severity of symptoms of apathy and is mediated by the dysfunction of brain systems involved in motor control and in the recognition, integration and expression of emotions. Therefore, hypomimia in PD may be conceptualized not exclusively as a motor symptom but as a consequence of a multidimensional deficit leading to a symptom where motor and non-­motor aspects converge. KEYWORDS hypomimia, neural, neuroimage, non-­motor symptoms, Parkinson's disease I NTRO D U C TI O N and voluntary facial expression of emotions are not comparable to other systems of motor control. Moreover, in contrast to limb Hypomimia, a reduced degree of facial expression for sponta- bradykinesia, it has been suggested that hypomimia is not usually neous and emotional movements, is a classical and very frequent asymmetrical, although some studies found that the most expres- symptom of Parkinson's disease (PD) [1, 2]. Lack of or reduced fa- sive face side is usually the less affected body side in terms of cial expression of emotions has a substantial impact on patients, bradykinesia [6, 11, 12]. partners and caregivers. For all of them, hypomimia arises as a Thus, the question arises as to whether hypomimia is a pure stigma that significantly impacts quality of life [3], social wellbeing motor disorder [11, 13] or if, in contrast, this symptom is a con- and interpersonal relationships, and that gradually increases social sequence of a more complex set of defective neural, cognitive isolation [2, 4, 5]. and affective mechanisms. Preliminary evidence supporting hy- Hypomimia is typically considered to be a form of bradykinesia pomimia as a non-­m otor symptom of PD comes from studies as- of the facial muscles and to be primarily mediated by motor basal sociating hypomimia to impairment in facial emotion recognition ganglia dysfunction [4]. Accordingly, hypomimia is rated as a motor [14, 15]. Facial emotion recognition deficits are more pronounced sign for which its gradation is associated with the severity of the in PD patients with apathy [16] and in PD patients with cognitive disease [6, 7]. Therefore, hypomimia can improve with dopamine-­ impairment [17]. Moreover, in PD there is also an association be- replacement treatment, an effect possibly mirroring the changes tween impairment in posing facial expressions of emotions and observed in axial motor symptoms induced by treatment with deficits in facial emotion recognition [13]. A recent study showed levodopa [8]. However, the evolutionary particularities of human that patients with hypomimia had more severe apathy and axial facial expression and the multiplicity of functions of facial mus- signs than patients without hypomimia, but that they did not dif- cles, compared to limb muscles, make facial muscle innervation fer in terms of depression, anxiety and neuropsychological per- and control unique [9, 10]. The mechanisms involved in involuntary formance [8]. CORRELATES OF HYPOMIMIA IN PD | 3 Less is known about the association between hypomimia and Statistical analyses cognition in PD. One recent study in a relatively small sample of patients observed that the severity of hypomimia was positively First, simple correlational analyses were performed to explore the correlated with axial symptoms and negatively correlated with association between hypomimia and age, disease duration, LEDD, cognitive performance [11]. Similar results indicating that more UPDRS-­III scores, depressive symptoms, apathy and cognitive per- severe hypomimia was associated with worse cognitive scores formance. To more deeply address the association between hy- independently of motor severity were obtained using a larger pomimia and all the other UPDRS-­III items, a univariate regression sample of untreated PD patients from the Parkinson's Progression analysis was first performed between the facial expression item and Markers Initiative [18]. the total UPDRS-­III score minus facial expression, using disease du- In the present study, associations between hypomimia, motor ration and LEDD as covariates. In a second step, to better disentan- symptoms, apathy and cognition in a large observational cohort gle the specific items of the UPDRS-­III associated with hypomimia, study of already treated non-­demented PD patients were examined, the data were subjected to a second univariate regression analysis and the neural correlates of the severity of hypomimia as assessed including all the UPDRS-­III items as fixed factors and using disease by multimodal magnetic resonance imaging (MRI) acquisitions were duration, age and LEDD as covariates. further assessed. To explore the association between hypomimia and other clinical variables, separate univariate regression analyses were conducted between hypomimia and depression, apathy and cognitive status, M ATE R I A L S A N D M E TH O D S using as covariates all the UPDRS-­III items minus those that appeared to be indissociable from hypomimia in the previous analysis. Finally, Sample and assessments a binary logistic regression analysis was performed with participants classified as with and without clinically relevant apathetic symptoms Cross-­s ectional data from the Cohort of Patients with Parkinson's (NPI apathy ≥2) [25] and hypomimia, age, disease duration, LEDD Disease in Spain (COPPADIS) study (database released in May and UPDRS-­III items minus those involved in hypomimia as predic- 2019) were used [19]. Details regarding the methods used in tors. Given that previous studies have supported that asymmetry of the COPPADIS study can be found in the original publications facial expression occurs in PD and is related to asymmetry of motor [19]. A total of 506 PD participants were included for whom impairment [12, 13], the analyses were repeated after controlling for the following variables were available: age, disease duration, motor laterality. For these analyses, the SPSS statistical package was levodopa equivalent daily dose (LEDD), the Unified Parkinson's used, and p <0.05 was considered significant. Disease Rating Scale part III (UPDRS-­I II) [7], the apathy item of The data that support the findings of this study are available on the Neuropsychiatric Inventory (NPI) [20], Beck’s Depression request from the corresponding author. The data are not publicly Inventory [21] and the Parkinson's Disease—­C ognitive Rating available due to privacy or ethical restrictions. Scale (PD-­CRS) [22]. The severity of hypomimia was rated through the UPDRS-­I II facial expression item which grades eye-­b link frequency, masked Neuroimaging add-­on study facies or loss of facial expression, spontaneous smiling, and part- ing of lips from 0, normal, to 1, slight; 2, mild; 3, moderate; and A subset of 132 patients had T1-­MRI available. These data were 4, severe. Global motor status was rated with all the components used to explore the structural neuroimaging correlates of facial ex- of the UPDRS-­I II. To further explore the association between hy- pression in PD. Details about the image acquisition protocols in the pomimia and other clinical and imaging parameters controlling the COPPADIS cohort have been reported previously [19]. effect of other motor symptoms, a secondary motor score derived Regarding neuroimaging preprocessing, two procedures were from the total Movement Disorder Society UPDRS-­I II score minus applied to quantify gray matter integrity. On the one hand, to as- the facial expression score was also computed. The bradykinesia sess cortical atrophy, a standard surface-­based cortical thickness subscore of the UPDRS was also computed (sum of items 2, 4–­9 (Cth) pipeline using FreeSurfer 6.0 was used to obtain vertexwise and 14) [23]. Cth data for each patient. These Cth maps were normalized to a The severity of apathetic symptoms and the severity of depres- standard fsaverage space and smoothed using a Gaussian kernel of sive symptoms were respectively rated with the apathy item of 15 mm full-­width at half-­maximum (FWHM). the NPI and Beck's Depression Inventory. Global cognitive status On the other hand, subcortical differences in gray matter volume was rated with the PD-­CRS. Cut-­off scores for mild cognitive im- (GMV) were assessed by a standard GMV voxel-­based morphome- pairment (PD-­MCI) and for dementia (PDD) were used to identify try pipeline using the SPM12 toolbox. Briefly, voxelwise GMV maps participants with normal cognition, PD-­MCI or PDD [22, 24]. The were obtained by probabilistic tissue-­based segmentation normal- frontal-­subcortical and posterior-­cortical PD-­CRS summary scores ized to the standard MNI space and smoothed using an isotropic and the scores from performance in each PD-­CRS subtest were also kernel of 8 mm FWHM. This voxel-­based morphometry analysis was collected. restricted to subcortical regions. 4 | SAMPEDRO et al. Neuroimaging regression analyses were performed to study the In a simple correlational analysis, the direct association between GMV and Cth correlates of facial expression, using age as a nuisance hypomimia and age, disease duration, LEDD, UPDRS-­III scores, covariate. To do this, a global map was first obtained from the re- depressive symptoms, apathy and cognitive performance was ex- gression using the UPDRS-­III total score. For the latter neuroimag- plored. As expected, associations were found between hypomimia ing analyses, only the set of clusters surviving p < 0.05 and multiple and disease duration (r = 0.167; p < 0.0002), LEDD (r = 0.223; comparison correction (Monte Carlo with 10,000 repeats for Cth p < 0.0001) and UPDRS-­III (hypomimia item excluded) (r = 0.516; and small-­volume random field theory for GMV) were considered p < 0.0001). Significant associations were also found between hypo- significant. mimia and severity of depressive symptoms (r = 0.139; p = 0.002), The sets of GMV and Cth maps obtained were then used to apathy (r = 0.169; p < 0.0001) and cognitive status as measured with explore the specific association between hypomimia and distinct the PD-­CRS total score (r = −0.233; p < 0.0001). clusters of GMV and Cth. Thus, to delimit those clusters in associa- Focusing on the exploration of the association between hypo- tion with hypomimia without the collinear contribution of the other mimia and other motor symptoms, a univariate regression analysis UPDRS-­III items, LEDD or disease duration, a univariate regression was performed using disease duration and LEDD as covariates. analysis was conducted using hypomimia and related UPDRS-­III This first step showed a moderate association between hypomimia items as dependent variables and all the other UPDRS-­III scores, age, and UPDRS-­III minus hypomimia score (r2 = 0.349; F(1,53) = 3.83; disease duration and LEDD as covariates. p < 0.0001). In a second step, to better disentangle the specific items of the UPDRS-­III associated with hypomimia, the data were subjected to R E S U LT S a second univariate regression analysis including all the UPDRS-­III items as fixed factors and using disease duration, age and LEDD as The sample was composed of 506 PD participants from the covariates. This analysis showed that the main UPDRS-­III items asso- COPPADIS study with mean age 62.3 ± 9.1 years, mean disease du- ciated with hypomimia were speech (F(1,53) = 20.05; p < 0.0001) and ration 5.5 ± 4.3 years and mean UPDRS-­III = 23.4 ± 11.4. Table 1 bradykinesia-­hypokinesia (F(1,53) = 4.01; p = 0.003). Thus, these two shows the sociodemographic and clinical characteristics of the factors (speech and bradykinesia-­hypokinesia) were assumed not as sample. Bradykinesia was found to be more severe on the left side confounders but as inherent to hypomimia. (t(506) = −2.6; p = 0.008). In the sample, according to the PD-­CRS Thirdly, the association between hypomimia and other clinical total score, 71.1% (n = 360) were cognitively preserved, 22.1% symptoms that appeared as directly correlated in the simple cor- (n = 112) were classified as PD-­MCI and 6.7% (n = 34) were classi- relational analysis was explored. A separate univariate regression fied as PDD. analysis was conducted between hypomimia and depression, apa- thy and cognitive status, using as covariates all the UPDRS-­III items minus those assumed to be hypomimia or part of them (speech and TA B L E 1 Clinical and sociodemographic characteristics of the bradykinesia-­hypokinesia), disease duration and LEDD. This analy- sample sis showed an absence of association between depression, cogni- Mean (SD) Range tive status and hypomimia, but a significant, albeit relatively low, association between hypomimia and apathy severity (F(1,53) = 2.01; Age (years) 62.2 (9.1) 30–­75 p = 0.043). Following this finding, a binary logistic regression analy- Disease duration 5.5 (4.3) 0–­3 0 sis was performed with participants classified as presenting with and UPDRS-­III total 23.4 (11.4) 2–­78 without clinically relevant apathetic symptoms (NPI apathy sever- Hypomimia 1.2 (0.7) 0–­3 ity ≥2) and hypomimia, age, disease duration, LEDD and UPDRS-­III Bradykinesia 8.9 (5.1) 0–­28 items minus those involved in hypomimia as predictors. This analysis Left side 4.6 (3.2) 0–­14 showed a strong association between hypomimia and clinically rel- Right side 4.2 (2.9) 0–­14 evant apathy (β = 0.595; p < 0.0001). These associations remained LEDD 576.4 (418.5) 0–­ significant after controlling for motor asymmetry. To further explore 2220 the possible relationship between the severity of hypomimia and the BDI-­II 9.5 (7.3) 0–­37 laterality of bradykinesia, another binary logistic regression analysis NPI—­Apathy 1.3 (2.3) 0–­12 was performed. No significant relationship was found between lat- PD-­CRS total 91.1 (16.3) 44–­141 erality of bradykinesia and severity of hypomimia. Frontal-­subcortical 63.6 (14.8) 25–­111 In the neuroimaging analysis, a whole series of cortical and GMV Posterior-­cortical 27.4 (3.4) 11–­38 maps was obtained. The obtained maps represented the main neuro- anatomical correlates of the whole UPDRS-­III scores. Then, to delimit Abbreviations: BDI-­II, Beck's Depression Inventory; LEDD, levodopa those clusters in association with hypomimia without the collinear equivalent daily dose; NPI, Neuropsychiatric Inventory; PD-­CRS, Parkinson's Disease—­Cognitive Rating Scale; UPDRS-­III, Unified contribution of the other UPDRS-­III items, LEDD or disease duration, Parkinson's Disease Rating Scale part III. a univariate regression analysis was conducted using hypomimia, CORRELATES OF HYPOMIMIA IN PD | 5 speech and bradykinesia-­hypokinesia as independent variables of expected that patients do not present a single motor symptom but interest and all the other UPDRS-­III scores, age, disease duration a combination of these symptoms whose severity is related. In this and LEDD as covariates. This analysis showed an independent asso- sense, collinearity between motor symptoms will always be a com- ciation of hypomimia and lower Cth in the left rostral middle fron- mon finding. Nevertheless, our results indicate that, regardless of tal cortex (r = −0.257; p = 0.004), in the left superior frontal gyrus age, disease duration and pharmacological treatment, the severity (r = −0.208; p = 0.020), in the left superior parietal gyrus (r = −0.250; of hypomimia specifically correlates with a few specific motor items p = 0.005), left middle temporal cortex (r = −0.201; p = 0.025), the of the UPDRS-­III, namely speech and bradykinesia-­hypokinesia. This right rostral middle frontal gyrus (r = −0.212; p = 0.018) and the relationship was not considered to be the result of a collinearity right inferior parietal gyrus (r = −0.210; p = 0.019). Equivalent asso- effect since it is maintained by controlling for the effect of all the ciations were found between all these brain regions and the other other motor symptoms. In contrast, it is considered that it may re- UPDRS-­III items that appeared as contributors to hypomimia such flect the expression of the same cluster of symptoms whose causal as speech and bradykinesia-­hypokinesia. Specifically, a significant mechanisms could be the same. Secondly, no relationship between association was found between the left (r = 0.317; p < 0.001) and the severity of hypomimia and the severity of anxiety or cognitive right (r = 0.258; p = 0.004) rostral middle frontal gyrus thickness and impairment was found. Moreover, the clinical and neuroimaging the bradykinesia-­hypokinesia score. Regarding the analysis of sub- correlates of hypomimia were not significantly influenced by motor cortical GMV, the only region that showed a significant correlation laterality. In contrast, a clear relationship between the severity of with hypomimia was the posterior portion of the mesencephalon hypomimia and the severity of apathy was observed, as well as be- (r = −0.192; p = 0.028). The neuroimaging correlates of hypomimia tween the severity of hypomimia and the frequency with which pa- were not significantly altered after controlling for motor laterality tients express apathy in a clinically significant range. These results (Figure 1). do not allow the directionality of this relationship to be clarified. Previous studies have shown a relationship between predominantly rigid-­akinetic phenotypes of PD and a higher prevalence of apathy DISCUSSION [26, 27]. In this sense, it could be considered that patients with more rigid-­akinetic symptomatology and who therefore score higher on The main results of the present study indicate a relationship of hy- bradykinesia-­hypokinesia will have not only more severe hypomimia pomimia with few and specific motor and non-­motor symptoms of but also more severe apathy. PD. The correlates of hypomimia with other motor symptoms, neu- Another possibility has to do with the effect that apathy itself ropsychiatric symptoms, cognitive performance as well as neuroim- could have as a modulator of the intensity of facial expression. aging data were addressed in a prospective sample of PD patients Apathy in PD is a common and multidimensional symptom character- in the early stages. Although hypomimia represents a very frequent ized by a decrease in goal-­oriented behaviors, often accompanied by symptom of PD, there are few studies that have explored the clinical emotional flattening, loss of initiative and reactivity, and decreased and neural correlates of this symptom in a representative sample. self-­activation. As an accompanying feature, several studies have The results highlight different facets that deserve to be con- pointed to disturbances of facial expression in patients with apathy, sidered. First, as anticipated, the severity of hypomimia appeared with lack of emotional expression being the most representative inseparable from the severity of other motor symptoms. It is to be feature. Interestingly, facial emotion recognition is also significantly F I G U R E 1 Regions exhibiting a significant pattern of cortical thinning and reduced subcortical gray matter volume in association with hypomimia 6 | SAMPEDRO et al. impaired in PD with isolated apathy compared to non-­apathetic and editing (equal). Sa uuml;l Martinez-­Horta: Conceptualization patients [28]. Taken together, these data point to the possible in- (equal); formal analysis (equal); investigation (equal); methodol- volvement of mechanisms and processes related to the expression ogy (equal); project administration (equal); writing –­ original draft and recognition of facial emotions in the genesis of hypomimia and (equal); writing –­ review and editing (equal). Andrea Horta-­Barba: related apathetic symptoms in PD. Data curation (equal); investigation (equal); writing –­ review and From a neuroimaging perspective, with the exception of the mid- editing (equal). Michel J. Grothe: Conceptualization (equal); in- dle frontal gyrus at the intersection with the precentral gyrus form- vestigation (equal); methodology (equal); project administra- ing the frontal eye fields (BA 8), the regions that appear most closely tion (equal); writing –­ review and editing (equal). Miguel Angel related to the severity of hypomimia were not regions that play a Labrador-­E spinosa: Investigation (equal); methodology (equal); central role in motor control. All the other fronto-­temporo-­parietal project administration (equal); writing –­review and editing (equal). regions highlighted in the analysis are known to participate both in Silvia Jesus: Conceptualization (equal); investigation (equal); meth- the recognition and production of facial expressions of emotions [29, odology (equal); project administration (equal); writing –­ review 30]. Specifically, the middle and superior frontal cortex, and proxi- and editing (equal). Astrid Adarmes: Investigation (equal); meth- mal territories such as the dorsal-­lateral prefrontal cortex and the odology (equal); project administration (equal); writing –­ review frontal pole, appeared previously associated with the expression and and editing (equal). Fatima Carrillo: Investigation (equal); method- imitation of different types of facial expressions. Similarly, superior ology (equal); project administration (equal); writing –­ review and parietal and middle temporal regions strongly contribute to decod- editing (equal). Arnau Puig-­Davi: Investigation (equal); methodol- ing and processing facial expressions [29, 30]. In this sense, it would ogy (equal); ­project administration (equal); writing –­ review and be interesting to explore the role of these structures in the context editing (equal). Florinda Roldan-­Lora: Investigation (equal); meth- of hypomimia associated with PD in studies based on dynamic facial odology (equal); project administration (equal); writing –­ review expression and recognition processes, and not only in a static con- and editing (equal). Miquel Aguilar: Conceptualization (equal); text as in the present study. investigation (equal); methodology (equal); project administra- As limitations of the study, it should be noted that it is a cross-­ tion (equal); writing –­ review and editing (equal). Pau Pastor: sectional study that does not allow conclusions to be drawn regard- Investigation (equal); methodology (equal); project administra- ing the possible causal relationship between hypomimia and the tion (equal); writing –­ review and editing (equal). Sonia Escalante: risk of cognitive impairment. In this sense, longitudinal studies are Conceptualization (equal); investigation (equal); methodology needed to answer this question. A main limitation of this study is (equal); project administration (equal); writing –­ review and edit- the use of a single-­item-­based scoring of hypomimia and apathy. ing (equal). Berta Solano-­V ila: Investigation (equal); methodology Future work using more comprehensive scales should delve into (equal); project administration (equal); writing –­ review and edit- the characterization of their subdomains. Finally, it is evident that ing (equal). Anna Cots-­Foraster: Investigation (equal); methodol- some of the associations found at the level of correlation analysis ogy (equal); project administration (equal); writing –­ review and are weak and their replication deserves to be taken into account in editing (equal). Javier Ruiz-­Martinez: Investigation (equal); meth- future studies. odology (equal); project administration (equal); writing –­ review Taken together, these results confirm that, in addition to being a and editing (equal). Francisco Carrillo: Conceptualization (equal); rigid-­akinetic symptom, hypomimia in PD may be partly mediated by investigation (equal); methodology (equal); project administration the dysfunction of brain systems involved in the recognition, inte- (equal); writing –­ review and editing (equal). Mercedes Pueyo-­ gration and expression of emotions. Consequently, hypomimia in PD Morlans: Investigation (equal); methodology (equal); project ad- may be conceptualized not exclusively as a motor symptom but as ministration (equal); writing –­ review and editing (equal). Isabel a consequence of a multidimensional deficit involving motor-­action Gonz aacute;lez-­A ramburu: Investigation (equal); methodology control deficits and dysfunction of high-­order cognitive processes (equal); project administration (equal); writing –­review and editing related to the expression and recognition of emotions. Therefore, (equal). Jon Infante-­Ceberio: Investigation (equal); methodology the mechanisms participating in the development of hypomimia are (equal); project administration (equal); writing –­review and editing partially overlapping with those contributing to the expression and (equal). Jorge Hernandez-­Vara: Investigation (equal); methodology recognition of emotion and mood, providing a biologically plausible (equal); project administration (equal); writing –­ review and edit- explanation regarding the association between hypomimia and ap- ing (equal). Oriol De Fabregues: Investigation (equal); methodol- athy in PD. Further prospective and longitudinal research should ogy (equal); project administration (equal); writing –­ review and explore whether hypomimia should be taken as an early indicator editing (equal). Teresa de Deus: Investigation (equal); methodol- of apathy in PD. ogy (equal); project administration (equal); writing –­ review and editing (equal). Asuncion Avila: Investigation (equal); methodology AU T H O R C O N T R I B U T I O N S (equal); project administration (equal); writing –­review and editing Frederic Sampedro: Data curation (equal); formal analysis (equal); (equal). Juan Carlos Mart iacute;nez Castrillo: Conceptualization investigation (equal); methodology (equal); validation (equal); visu- (equal); investigation (equal); methodology (equal); project ad- alization (equal); writing –­ original draft (equal); writing –­ review ministration (equal); writing –­ review and editing (equal). Helena CORRELATES OF HYPOMIMIA IN PD | 7 Bejr-­kasem: Investigation (equal); methodology (equal); project ad- ORCID ministration (equal); writing –­ review and editing (equal). Antonia Frederic Sampedro https://orcid.org/0000-0002-3933-1355 Campolongo: Investigation (equal); methodology (equal); project Saul Martínez-­Horta https://orcid.org/0000-0003-0125-7249 administration (equal); writing –­ review and editing (equal). Berta Andrea Horta-­Barba https://orcid.org/0000-0003-0050-5466 Pascual-­Sedano: Investigation (equal); methodology (equal); pro- Arnau Puig-­Davi https://orcid.org/0000-0001-8883-4947 ject administration (equal); writing –­ review and editing (equal). Asuncion Avila https://orcid.org/0000-0001-8357-0751 Pablo Martinez-­Martin: Conceptualization (equal); investiga- Juan Carlos Martínez-­Castrillo https://orcid. tion (equal); methodology (equal); project administration (equal); org/0000-0001-7744-6850 writing –­ review and editing (equal). Diego Santos-­G arc iacute;a: Helena Bejr-­Kasem https://orcid.org/0000-0001-8828-5976 Conceptualization (equal); funding acquisition (equal); investiga- Diego Santos-­García https://orcid.org/0000-0002-3126-5111 tion (equal); methodology (equal); project administration (equal); Pablo Mir https://orcid.org/0000-0003-1656-302X resources (equal); supervision (equal); validation (equal); writing Pedro J. Garcia-­Ruiz https://orcid.org/0000-0001-6194-672X –­ original draft (equal); writing –­ review and editing (equal). Pablo Mir: Conceptualization (equal); data curation (equal); investiga- REFERENCES tion (equal); methodology (equal); project administration (equal); 1. Goetz CG. The history of Parkinson's disease: early clinical descrip- resources (equal); writing –­ original draft (equal); writing –­ review tions and neurological therapies. Cold Spring Harb Perspect Med. 2011;1:a008862. and editing (equal). Pedro J Garcia-­Ruiz: Conceptualization (equal); 2. Jankovic J. Parkinson's disease: clinical features and diagnosis. J investigation (equal); methodology (equal); project administration Neurol Neurosurg Psychiatry. 2008;79:368-­376. (equal); writing –­original draft (equal); writing –­review and editing 3. Ma HI, Gunnery SD, Stevenson MT, Saint-­Hilaire M, Thomas CA, (equal). Jaime Kulisevsky: Conceptualization (equal); formal analy- Tickle-­Degnen L. 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