# Serum sortilin-derived propeptide concentrations as markers of depression in chronic stroke.

E. Mazella, A. M. Mendyk, B. Accart, M. Borsotto, C. Heurteaux, J. Mazella, Thibaut Dondaine, Regis Bordet

► To cite this version:

E. Mazella, A. M. Mendyk, B. Accart, M. Borsotto, C. Heurteaux, et al. Serum sortilin-derived propeptide concentrations as markers of depression in chronic stroke. J Neurol Sci, 2025, J Neurol Sci, 472, pp.123459. 10.1016/j.jns.2025.123459. hal-05034446

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# Serum sortilin-derived propeptide concentrations as markers of depression in chronic stroke

Estelle Mazella<sup>a</sup>, Anne-Marie Mendyk<sup>b</sup>, Bertrand Accart<sup>b</sup>, Marc Borsotto<sup>a</sup>, Catherine Heurteaux<sup>a</sup>, Régis Bordet<sup>b</sup>, Jean Mazella<sup>a</sup>, Thibaut Dondaine<sup>b,*</sup>

## ARTICLE INFO

**Keywords:**

Sortilin

Post-stroke depression

Propeptide

Biomarker

Diagnosis

## ABSTRACT

**Introduction:** Post-stroke depression is a common and debilitating consequence of stroke that significantly impacts functional recovery and quality of life. Identifying new biological markers and treatments is essential to enhance patient care. This study aimed to assess the relationship between serum levels of the sortilin-derived propeptide and depression scores in the STROKDEM cohort (NCT01330160).

**Methods:** The study enrolled 204 stroke patients and followed them at 6, 12, 36, and 60 months post-stroke. Serum sortilin-derived propeptide levels were measured at each visit, along with comprehensive clinical assessments including depression and anxiety scales.

**Results:** The results showed a significant main effect of serum sortilin-derived propeptide levels on depression scores (p = 0.006). There was also a significant interaction between propeptide levels and follow-up visit (p = 0.05). In contrast, propeptide levels did not have a significant effect on anxiety scores (p = 0.75).

**Discussion:** These findings suggest serum sortilin-derived propeptide could be a useful biomarker for post-stroke depression. This opens up potential new treatment approaches, including the consideration of the drug spadin, which targets this peptide, for managing post-stroke depression in humans.

## 1. Introduction

Stroke poses a severe and unpredictable threat to human health, often leading to either death or, for approximately 65 % of stroke survivors, cognitive and psychiatric disorders, including depression, anxiety, and cognitive deficits [1,2]. Within 5 years, up to one-third of patients may develop post-stroke depression (PSD), which is closely intertwined with post-stroke anxiety [3]. PSD can significantly increase mortality rates, with affected individuals facing up to ten times higher mortality rates compared to stroke patients without PSD [4,5].

Despite the profound impact of post-stroke disorders on patients' lives, research on effective treatments and diagnostic methods for PSD remains notably underexplored and, consequently, is of critical importance. The primary clinical approach for treating PSD involves the use of antidepressants (ADs), particularly selective serotonin reuptake inhibitors (SSRIs), which have shown promise in alleviating depression, anxiety, and neurological impairment symptoms in stroke survivors [6,7]. However, their efficacy is hampered by adverse effects, coupled

with an increased risk of hemorrhagic complications in the gastrointestinal tract, which limits their overall effectiveness and satisfaction as a treatment option [3,8].

Sortilin, a receptor involved in neurotrophic signaling, has been found to be significantly increased in individuals with depression, and is positively correlated with brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) [9]. Sortilin's role in depression may be related to altered activity of neurotrophic factors [10]. Sortilin are involved in the sorting of trophic and dementia-linked proteins, and in the processing and trafficking of amyloid precursor protein [11,12]. In this context, spadin, a synthetic peptide derived from the endogenous propeptide (PE) released during the post-translational maturation of sortilin [13], has displayed significant promise. Spadin not only acts as a potent antidepressant (AD) through its selective antagonist action on the potassium channel TREK-1 [14] but has also shown effectiveness in stroke recovery and alleviating PSD [15]. Spadin's advantages lie in its rapid onset of action as an AD (within four days) and its absence of adverse effects [16]. Consequently, spadin and

<footnote><sup>a</sup> Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, UMR 7275, Université Côte d'Azur, 660, Route Des Lucioles, 06560 Valbonne, France</footnote>

<footnote><sup>b</sup> University Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition, Degenerative and Vascular Cognitive Disorders, Department of Pharmacology, Faculty of Medicine, 1, place de Verdun, 59045 Lille Cedex, France</footnote>

<footnote>* Corresponding author at: Service de pharmacologie, Faculté de Médecine, Pôle Recherche, 1, place de Verdun, 59045 Lille Cedex, France.
E-mail address: thibaut.dondaine2@univ-lille.fr (T. Dondaine).</footnote>
its derivatives are highly recommended as superior alternatives to currently utilized ADs for enhancing neurological and neuropsychiatric recovery following a stroke.

Of note, PE levels are reduced in patients with major depressive disorder (MDD), and normal levels are restored following AD treatments, correlating with clinical improvements in MDD [17]. Furthermore, in treatment-resistant depressed patients, PE levels significantly increase after electroconvulsive therapy, aligning with treatment responders. This observation holds the potential for evaluating the success of therapy [18]. Building upon these findings, the present study aims to investigate whether PE levels may serve as a sensitive indicator of depression following a stroke.

On the basis of previous work, we hypothesize that the PSD is related with the concentration of PE. We also assume that there is a variation in the PSD over time and that it is related to the level of PE concentration.

## 2. Materials and methods

### 2.1. Study population

The current study utilized blood samples obtained from the previously described STROKDEM cohort [19]. The objective of the STROKDEM project was to identify prognostic factors associated with the onset of dementia or cognitive decline following an acute stroke. The procedures of the earlier studies received approval from the local ethics committee and were registered on clinicaltrials.gov (NCT01330160). Following an explanation of the study's goals, approval was obtained, and participants provided written informed consent.

In the STROKDEM cohort, individuals aged 18 years or older, without pre-existing dementia, and admitted for either ischemic or hemorrhagic stroke (with brain lesion evaluation via magnetic resonance imaging (MRI) conducted within 72 h of symptom onset) were consecutively enrolled after providing written informed consent. The exclusion criteria consisted of (i) pre-stroke dementia, defined as an Informant Questionnaire on Cognitive Decline in the Elderly (IQ Code) [20] summed score exceeding 64, (ii) malformed, traumatic, puremeningeal, or intraventricular hemorrhage, (iii) patients under legal guardianship, (iv) contraindications for an MRI, (v) inability to communicate in French, and (vi) neurological deficits, including severe aphasia affecting the understanding of questionnaires and tests.

Upon enrollment, sociodemographic characteristics, vascular risk factors, and medical history data were collected through face-to-face interviews using a structured questionnaire. Etiological information about the stroke (based on imaging, vascular, and cardiac examinations) and blood samples for relevant post-stroke dementia biomarker analysis were also gathered. All patients were scheduled for follow-up assessments at 6, 12, 36, and 60 months. During each of these visits, evaluations were conducted to assess the severity of neurological deficits using the NIH Stroke Scale (NIHSS) [21] and the modified Rankin Scale (mRS) [21], as well as depression (Center for Epidemiologic Studies – Depression Scale; CES) [22] and anxiety (Hamilton Anxiety Rating Scale; HAM-A) [23]. Global cognitive disorders were assessed by Montreal Cognitive Assessment [24]. We also collected histories of smoking and diabetes. We excluded patients who have not received evaluation (including Depression) or/and patients who have not had a blood test. Based on these criteria, we included a total of 157 patients (78 %) in this study. Comparative analyses between included and non-included patients at the inclusion are presented in the supplemental data (Supplementary analyses, Table 1). flow chart of the study is shown in Fig. 1.

A group of patients with (D+) and without depression (D-) were built based on scores of CES. A cut-off ≥ 16 was used to define the two groups [25].

### 2.2. Serum PE concentration

The concentration of serum sortilin-derived

<figure><img src="image_4.png" /><figcaption>Fig. 1. Flowchart of the study.</figcaption></figure>

phosphatidylethanolamine (PE) was assessed in triplicate for each blood sample treated with EDTA, employing AlphaLisaTM technology (Perkin Elmer). This method utilized polyclonal antibodies capable of recognizing various sequences from PE and spadin analogs [17]. In brief, the PE concentration (measured in nM) in the serum samples was determined by calculating the percentage of signal inhibition between donor and acceptor beads in the presence of biotinylated spadin, following the original procedure outlined by Devader and colleagues [17].

### 2.3. Statistics

The results are presented as mean ± standard deviation. Statistical analyses were conducted using R (version 4.1.3) and RStudio (version 2022.2.1). Demographic and clinical characteristics of the patient samples are summarized in Table 1. To compare demographic and clinical features across groups, we utilized Student's t-test and the Chi-square test.

The analysis of CES scores was carried out using a linear mixed model (model 1) including time points (visit), PE concentration and any variable with *p* < 0.20 for comparison in the first step and with participant considered as a random effect. The slope of the correlation

<table><caption>**Table 1**
Demographic and clinical data of stroke patients with (D+) and without (D-) depression at 6 months post-stroke.</caption><thead><tr><th></th><th>D+ (n = 41)</th><th>D- (n = 116)</th><th>t/χ<sup>2</sup></th><th>p</th></tr></thead><tbody><tr><td>Age (years)</td><td>65.71 (13.36)</td><td>64.21 (12.01)</td><td>0.67</td><td>0.51</td></tr><tr><td>Sex (M/F)</td><td>25/16 (11.41)</td><td>78/38 (4.00)</td><td>0.53</td><td>0.47</td></tr><tr><td>Education (years)</td><td>11.56 (4.07)</td><td>0.20</td><td>0.84</td><td></td></tr><tr><td>Medical history</td><td></td><td></td><td></td><td></td></tr><tr><td>Smoking (Y/N)</td><td>10/31 (6.35)</td><td>20/96 (16/100)</td><td>1.00</td><td>0.32</td></tr><tr><td>Diabetes (Y/N)</td><td>1.12 (1.03)</td><td>0.79 (0.91)</td><td>1.92</td><td>0.06</td></tr><tr><td>mRS</td><td>0.95 (1.90)</td><td>0.55 (1.08)</td><td>1.64</td><td>0.10</td></tr><tr><td>NIHSS</td><td>25.18 (4.12)</td><td></td><td></td><td></td></tr><tr><td>MoCA</td><td>26.26 (3.09)</td><td></td><td>1.75</td><td>0.08</td></tr><tr><td>HARS</td><td>5.41 (4.01)</td><td></td><td>4.73</td><td>&lt;0.001</td></tr><tr><td>Antidepressant treatment (Y/N)</td><td>11/30 (4.55)</td><td>14/102</td><td>4.93</td><td>0.03</td></tr></tbody></table>

Values are expressed as number or mean ± standard deviation.

D+ = patients with depression, D- = patients without depression, HARS = Hamilton Anxiety Rating Scale; MoCA = Montreal Cognitive Assessment, mRS modified Rankin Scale, M6 6 months, NIHSS NIH Stroke Scale, t student test, χ² chi-square test.
between CES and PE was calculated at 4 time points (corresponding to follow-up visits): M6, M12, M36, and M60. Pairwise comparisons were conducted to test for differences in slopes between the time points with. *p*-values were adjusted using the Tukey method to account for multiple comparisons using “emtrends” function from “emmeans” package. Significance testing was conducted using the lmerTest package [26], which employs Satterthwaite’s method to estimate degrees of freedom and generate *p*-values for mixed models. As anxiety is very frequently linked to depression, we constructed a second linear mixed model (model 2) including PE concentration and visit and with participant considered as a random effect. We used maximum likelihood estimation (MLE) in our analysis. MLE uses only the available observations to estimate the model parameters, effectively excluding cases with missing values from the analysis. This approach allows us to use all available data while maintaining the integrity of our estimates.

### 3. Results

The demographic and clinical characteristics of the study population are outlined in Table 1. At the time of study initiation, a total of 204 patients were enrolled. Table 2 presents the progression of both the count and percentage of patients falling into different groups, theirs mean and standard deviation of CES and PE concentration based on the timing of patient assessments following a stroke.

Model 1 was conducted on CES scores with PE concentration, visit (M6, M12, M36 and M60), MoCA scores, mRS, HARS and NIHSS scores as the within-subject factor and with participant considered as a random effect. The results indicate that PE has a significant main effect on the CES (F(1, 408.64) = 7.776, *p* = 0.006). This suggests that the level of PE has a meaningful impact on clinical outcomes. Additionally, there is a significant main effect of Visit on CES (F(3, 318.29) = 10.9485, *p* < 0.0001), demonstrating that CES scores vary significantly across different time points), with a significant reduction of the CES score at M60 compared with M6 (*t* = 4.55, *p* < 0.001), M12 (*t* = 4.76; *p* < 0.001). We also observed a significant reduction of the CES score at M36 compared to M6 (*t* = 3.11; *p* = 0.01) and M12 (*t* = 3.35; *p* = 0.005).

Importantly, there is also a significant interaction between PE and Visit (F(3, 326.00) = 2.66, *p* = 0.05), indicating that the effect of PE concentration on CES depends on the specific visit.

The analysis revealed that the slopes of the CES-PE correlation did not differ significantly between the earlier time points. Pairwise comparisons with Tukey corrections for multiple comparisons revealed a significant difference in the effect of PE on CES between M12 and M60 (*t* = -2.76; *p* = 0.05. No other significant differences were observed between the visit timepoints (see Fig. 2).

The results from model 2 with HARS as the outcome variable, and PE and VISIT as the predictors, show that the main effect of PE on HARS is not statistically significant, (F(1, 432.67) = 0.10, *p* = 0.75). This indicates that the level of PE concentration does not have a significant impact on the HARS.

The main effect of visit on HARS is statistically significant, (F(3, 318.59) = 2.68, *p* = 0.05). This suggests that the HARS varies significantly across the different time points or visits but contrasts with Tukey corrections for multiple comparisons did not reveal any significant differences.

The interaction between PE and visit is not statistically significant (F (3, 328.88) = 0.7812, *p* = 0.51). This means that the effect of PE on HARS does not depend on the specific visit.

### 4. Discussion

The aim of this study was to assess the impact of PE concentration on the level of PSD, a peptide that has already been identified as a potential marker for depressive states. This research builds upon our previous studies, which demonstrated that serum PE concentration is sensitive to depression in a cohort of stroke patients. Our results suggest that the effect of PE on clinical endpoints varies over the course of the study, with the strongest negative effect observed 12 months after stroke. These findings highlight the importance of considering temporal dynamics when interpreting the relationship between PE concentration and depression.

We note that the PE concentration is stable for the group of non-depressed patients, whereas it changes during the follow-up for the group of depressed patients. This indicates that serum peptide concentration may be a suitable diagnostic marker. The overall mean PE concentration measured in this study is approximately 14.43 nM, a level comparable to those measured in healthy controls without trauma in two prior studies (approximately 22 nM) [17,18].

A low level of PE has been observed in patients with depression, and treatment with antidepressants has been shown to significantly increase serum PE concentrations [17]. In our current study, no evidence of an impact of antidepressant treatment on serum PE concentration was observed. This finding can be attributed to the large number of patients in all groups who were receiving antidepressant therapy.

Research on post-stroke depression (PSD) has identified several potential biomarkers. PSD becomes a significant concern during the chronic phase of stroke, often diagnosed late and carrying substantial functional consequences. Medicinal and psychotherapeutic approaches for treating PSD are frequently inadequate [27,28]. Recent research from our team, using an animal model, provides initial evidence that the modulation of TREK-1 channels by mini-spadine in both the early and chronic phases of stroke may play a pivotal role in its protective effects on the brain against stroke and PSD [15]. Another recent study conducted in both humans and animals demonstrated that the levels of sortilin following subarachnoid hemorrhage could serve as a promising biomarker for assessing neuronal injury [29]. Other biomarkers associated with PSD include elevated post-dexamethasone cortisol, reduced serum BDNF, smaller amygdala volumes, and decreased brain perfusion [30]. Calcitonin gene-related peptide (CGRP) levels are increased in PSD and may play a role in its pathophysiology [31]. Neuroimaging markers, genetic factors, and neurophysiological changes have also been identified as potential PSD biomarkers [32].

Notably, in our study, the presence of anxiety appeared to have a tendency to elevate PE concentration levels (at M12). This could serve as a marker for distinguishing between these two commonly co-occurring conditions following a stroke. Moreover, it may be instrumental in devising distinct therapeutic strategies aimed at enhancing the management of these disorders.

The pathophysiology of PSD involves inflammation, neurotransmitter dysfunction, and altered neurotrophic signaling [33]. Sortilin, a

<table><caption>**Table 2**
Evolution of the number and proportion of depressed and non-depressed patients, mean and standard deviation of CES scores and PE concentration according the visits.</caption><thead><tr><th rowspan="2"></th><th colspan="2">M6</th><th colspan="2">M12</th><th colspan="2">M36</th><th colspan="2">M60</th></tr><tr><th>D+</th><th>D-</th><th>D+</th><th>D-</th><th>D+</th><th>D-</th><th>D+</th><th>D-</th></tr></thead><tbody><tr><td>n (%)</td><td>41 (26.11)</td><td>116 (73.89)</td><td>44 (30.34)</td><td>101 (69.66)</td><td>27 (24.32)</td><td>84 (75.68)</td><td>11 (19.24)</td><td>45 (80.36)</td></tr><tr><td>CES score (mean (SD))</td><td>22.46 (6.87)</td><td>7.89 (4.52)</td><td>22.89 (7.77)</td><td>6.19 (4.69)</td><td>24.19 (8.70)</td><td>5.64 (4.63)</td><td>22.09 (5.66)</td><td>3.93 (4.24)</td></tr><tr><td>PE concentration (nM;mean (SD))</td><td>13.04 (6.47)</td><td>15.57 (8.33)</td><td>12.88 (5.33)</td><td>15.44 (7.58)</td><td>11.27 (5.35)</td><td>14.56 (6.04)</td><td>11.77 (2.90)</td><td>14.47 (7.87)</td></tr></tbody></table>

CES = Center for Epidemiologic Studies – Depression Scale, D+ = patients with depression, D- = patients with depression, M6 = 6 months, M12 = 12 months, M36 = 36 months, M60 = 60 months.
<figure><img src="image_5.png" /><figcaption>Fig. 2. Relationship between PE concentration and CES scores according to visits (M6, M12, M36, M60).</figcaption></figure>

receptor involved in neurotrophin signaling, shows increased serum levels in depressed individuals [9]. Sortilin-derived peptides could be anti-inflammatory agents and neurotrophic factors due to their roles in regulating neuronal viability and function. Sortilin could act as a receptor for neurotrophic factors and neuropeptides and serves as a co-receptor for cytokine receptors, tyrosine receptor kinases, G-protein coupled receptors, and ion-channels, which are all involved in cellular transport and signaling [34]. Additionally, spadin has been shown to exert potent antidepressant effects in mice without affecting adipocyte physiology, suggesting its potential role in neurotrophic and anti-inflammatory processes [35]. These findings suggest potential new therapeutic targets for PSD, including anti-inflammatory agents, neurotrophic factors, and sortilin-related interventions [15,33].

Our study comes with certain limitations. First, we lack a control group comprising age-matched participants, which would have enabled us to establish the baseline level of PE under non-pathological conditions. The PE levels in our sample exhibit significant heterogeneity, and we included all data points, even those at the extremes that did not fall within the range of normal PE levels. Additionally, many patients were taking antidepressant medication, even those without a diagnosis of depression or anxiety. This medication usage could potentially influence serum PE concentration levels. Notably, a small number of patients exhibited fluctuations in their depressive state during the longitudinal follow-up, which could have implications for the determination of PE concentration across various visits.

In conclusion, our study underscores the value of PE measurement in the context of PSD and opens the door to novel therapeutic avenues. This includes the potential use of spadin for treating PSD in humans, as previously demonstrated in mouse studies [15].

### CRediT authorship contribution statement

**Estelle Mazella:** Writing – original draft. **Anne-Marie Mendyk:** Writing – review & editing, Data curation. **Bertrand Accart:** Writing – review & editing, Data curation. **Marc Borsotto:** Methodology, Formal analysis, Conceptualization. **Catherine Heurteaux:** Writing – review & editing, Validation, Formal analysis, Conceptualization. **Régis Bordet:** Writing – review & editing, Validation, Supervision, Methodology, Conceptualization. **Jean Mazella:** Writing – review & editing, Validation, Supervision, Methodology, Data curation, Conceptualization. **Thibaut Dondaine:** Writing – review & editing, Validation, Methodology, Formal analysis.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jns.2025.123459.

### References

[1] M.F. Folstein, R. Maiberger, P.R. McHugh, Mood disorder as a specific complication of stroke, J. Neurol. Neurosurg. Psychiatry 40 (1977) 1018-1020.

[2] J.M. Gaete, J. Bogousslavsky, Post-stroke depression, Expert. Rev. Neurother. 8 (2008) 75-92.

[3] J.S. Kim, Post-stroke mood and emotional disturbances: pharmacological therapy based on mechanisms, J. Stroke. 18 (2016) 244.

[4] P. Angelelli, S. Paolucci, U. Bivona, L. Piccardi, P. Ciurli, A. Cantagallo, G. Antonucci, L. Fasotti, A. Di Santantonio, M. Grasso, Development of neuropsychiatric symptoms in poststroke patients: a cross-sectional study, Acta Psychiatr. Scand. 110 (2004) 55-63.

[5] G.E. Llorca, L. Castilla-Guerra, M.F. Moreno, S.R. Doblado, M.J. Hernández, Post-stroke depression: an update, Neurol. Engl. Ed. 30 (2015) 23-31.

[6] F. Chollet, J. Tardy, J.-F. Albucher, C. Thalamas, E. Berard, C. Lamy, Y. Bejot, S. Deltour, A. Jaillard, P. Niclot, Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial, Lancet Neurol. 10 (2011) 123-130.

[7] E.L. Miller, L. Murray, L. Richards, R.D. Zorowitz, T. Bakas, P. Clark, S.A. Billinger, Comprehensive overview of nursing and interdisciplinary rehabilitation care of the stroke patient: a scientific statement from the American Heart Association, Stroke 41 (2010) 2402-2448.

[8] C. Coupland, P. Dhiman, R. Morriss, A. Arthur, G. Barton, J. Hippisley-Cox, Antidepressant use and risk of adverse outcomes in older people: population based cohort study, BMJ (2011) 343.

[9] H.N. Buttenschön, D. Demontis, M. Kaas, B. Elfving, S. Mølgaard, C. Gustafsen, L. Kaerlev, C.M. Petersen, A.D. Børglum, O. Mors, et al., Increased serum levels of sortilin are associated with depression and correlated with BDNF and VEGF, Transl. Psychiatry 5 (2015) e677.

[10] J. Mazella, M. Borsotto, C. Heurteaux, The involvement of Sortilin/NTSR3 in depression as the progenitor of Spadin and its role in the membrane expression of TREK-1, Front. Pharmacol. 9 (2019) 1541.

[11] C. Gustafsen, S. Glerup, L.T. Pallesen, D. Olsen, O.M. Andersen, A. Nykjær, P. Madsen, C.M. Petersen, Sortilin and SorLA display distinct roles in processing and trafficking of amyloid precursor protein, J. Neurosci. 33 (2013) 64-71.

[12] L.T. Pallesen, C.B. Vaegter, Sortilin and SorLA regulate neuronal sorting of trophic and dementia-linked proteins, Mol. Neurobiol. 45 (2012) 379-387.

[13] C.M. Petersen, M. Nielsen, C. Jacobsen, J. Tauris, L. Jacobsen, J. Gliemann, S. Moestrup, P. Madsen, Propeptide cleavage conditions sortilin/neurotensin receptor-3 for ligand binding, EMBO J. 18 (1999) 595-604.

[14] J. Mazella, O. Pétrault, G. Lucas, E. Deval, S. Béraud-Dufour, C. Gandin, M. El-Yacoubi, C. Widmann, A. Guyon, E. Chevet, Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design, PLoS Biol. 8 (2010) e1000355.

[15] M. Pietri, A. Djillani, J. Mazella, M. Borsotto, C. Heurteaux, First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides, Neuropharmacology 158 (2019) 107715.
[16] H.M. Ou Maati, J. Veyssiere, F. Labbal, T. Coppola, C. Gandin, C. Widmann, J. Mazella, C. Heurteaux, M. Borsotto, Spadin as a new antidepressant: absence of TREK-1-related side effects, Neuropharmacology 62 (2012) 278-288.

[17] C. Devader, M. Roulot, S. Moréno, A. Minelli, M. Bortolomasi, C. Congiu, M. Gennarelli, M. Borsotto, C. Heurteaux, J. Mazella, Serum sortilin-derived propeptides concentrations are decreased in major depressive disorder patients, J. Affect. Disord. 208 (2017) 443-447.

[18] M. Roulot, A. Minelli, M. Bortolomasi, E. Maffioletti, M. Gennarelli, M. Borsotto, C. Heurteaux, J. Mazella, Increased serum levels of sortilin-derived propeptide after electroconvulsive therapy in treatment-resistant depressed patients, Neuropsychiatr. Dis. Treat. (2018) 2307-2312.

[19] R. Lopes, C. Bournonville, G. Kuchcinski, T. Dondaine, A.-M. Mendyk, R. Viard, J.-P. Pruvo, H. Hénon, M.K. Georgakis, M. Duering, Prediction of long-term cognitive function after minor stroke using functional connectivity, Neurology 96 (2021) e1167-e1179.

[20] A. Jorm, P. Jacomb, The informant questionnaire on cognitive decline in the elderly (IQCODE): socio-demographic correlates, reliability, validity and some norms, Psychol. Med. 19 (1989) 1015-1022.

[21] T. Brott, H.P. Adams Jr., C.P. Olinger, J.R. Marler, W.G. Barsan, J. Biller, J. Spilker, R. Holleran, R. Eberle, V. Hertzberg, Measurements of acute cerebral infarction: a clinical examination scale, Stroke 20 (1989) 864-870.

[22] L.S. Radloff, The CES-D scale: a self-report depression scale for research in the general population, Appl. Psychol. Meas. 1 (1977) 385-401.

[23] M. Hamilton, The assessement of anxiety states by rating, Br. J. Med. Psychol. 32 (1959) 50-55.

[24] Z.S. Nasreddine, N.A. Phillips, V. Bédirian, S. Charbonneau, V. Whitehead, I. Collin, J.L. Cummings, H. Chertkow, The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment, J. Am. Geriatr. Soc. 53 (2005) 695-699.

[25] R.M. Parikh, D.T. Eden, T.R. Price, R.G. Robinson, The sensitivity and specificity of the Center for Epidemiologic Studies Depression Scale in screening for post-stroke depression, Int. J. Psychiatry Med. 18 (1988) 169-181.

[26] A. Kuznetsova, P.B. Brockhoff, R.H.B. Christensen, lmerTest package: tests in linear mixed effects models, J. Stat. Softw. [Internet]. 82 (2017) [cited 2023 May 22].
Available from: http://www.jstatsoft.org/v82/i13/.

[27] W. Cai, C. Mueller, Y.-J. Li, W.-D. Shen, R. Stewart, Post stroke depression and risk of stroke recurrence and mortality: a systematic review and meta-analysis, Ageing Res. Rev. 50 (2019) 102-109.

[28] X. Li, C. Zhang, Comparative efficacy of nine antidepressants in treating Chinese patients with post-stroke depression: a network meta-analysis, J. Affect. Disord. 266 (2020) 540-548.

[29] Y. Wang, J. Wang, Y.-C. Zuo, J. Jiang, T. Tu, X.-X. Yan, F. Liu, Elevation of CSF Sortilin following subarachnoid hemorrhage in patients and experimental model rats, Neuroscience 470 (2021) 23-36.

[30] K. Noonan, L.M. Carey, S.G. Crewther, Meta-analyses indicate associations between neuroendocrine activation, deactivation in neurotrophic and neuroimaging markers in depression after stroke, J. Stroke Cerebrovasc. Dis. 22 (2013) e124-e135.

[31] B. Shao, Y.L. Zhou, H. Wang, Y.S. Lin, The role of calcitonin gene-related peptide in post-stroke depression in chronic mild stress-treated ischemic rats, Physiol. Behav. 139 (2015) 224-230.

[32] O.A. Levada, A.S. Troyan, Poststroke depression biomarkers: a narrative review, Front. Neurol. 9 (2018) 577.

[33] W. Li, S. Ling, Y. Yang, Z. Hu, H. Davies, M. Fang, Systematic hypothesis for post-stroke depression caused inflammation and neurotransmission and resultant on possible treatments, Neuro Endocrinol. Lett. 35 (2014) 104-109.

[34] A. Nykjaer, T.E. Willnow, Sortilin: a receptor to regulate neuronal viability and function, Trends Neurosci. 35 (2012) 261-270.

[35] C. Hivelin, J. Mazella, T. Coppola, Sortilin derived propeptide regulation during adipocyte differentiation and inflammation, Biochem. Biophys. Res. Commun. 482 (2017) 87-92.