# Non-motor Subtypes in Candidates for Subthalamic Deep Brain Stimulation for Parkinson's Disease

Hélène Ducrocq, Salomé Puisieux, Lucie Hopes, Solène Frismand, Sophie Colnat-Coulbois, Maéva Kyheng, Anne Sophie Rolland, Caroline Moreau, Caroline Giordana, Teodor Danaila, et al.

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## To cite this version:

Hélène Ducrocq, Salomé Puisieux, Lucie Hopes, Solène Frismand, Sophie Colnat-Coulbois, et al. "Non-motor Subtypes in Candidates for Subthalamic Deep Brain Stimulation for Parkinson's Disease. Parkinsonism & Related Disorders, 2025, pp.107945. 10.1016/j.parkreldis.2025.107945. hal-05185361

HAL Id: hal-05185361

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# Non-motor subtypes in candidates for subthalamic deep brain stimulation for Parkinson's disease

Hélène Ducrocq<sup>a</sup>, Salomé Puisieux<sup>b, *, c</sup>, Lucie Hopes<sup>b, c</sup>, Solène Frismand<sup>b</sup>, Sophie Colnat-Coulbois<sup>c</sup>, Maeva Kyheng<sup>d</sup>, Anne Sophie Rolland<sup>e, d</sup>, Caroline Moreau<sup>e</sup>, Caroline Giordana<sup>f</sup>, Teodor Danaila<sup>g, d</sup>, David Maltête<sup>h, i</sup>, Margherita Fabbri<sup>j</sup>, Isabelle Benatru<sup>k, l</sup>, Ana Marques<sup>m</sup>, Ouhaid Lagha Boukbiza<sup>n, o</sup>, Cecile Hubsch-Bonneaud<sup>p</sup>, Tiphaine Rouaud<sup>q</sup>, Alexandre Eusebio<sup>r</sup>, Sophie Drapier<sup>s</sup>, Elodie Hainque<sup>t</sup>, Melissa Tir<sup>v</sup>, Béchir Jarraya<sup>w</sup>, Jean-Christophe Corvol<sup>t, u</sup>, David Devos<sup>e</sup>, PREDISTISM study group

## ARTICLE INFO

### Keywords:

Parkinson's disease endophenotypes

Non-motor symptoms

Prognosis

PREDISTIM

MDS-UPDRS

## ABSTRACT

**Introduction:** Patients with Parkinson's Disease (PD) vary markedly in terms of non-motor symptoms (NMS) as the disease progresses. To improve PD management and clinical-trial assessment, we aimed to determine NMS endotypes in a cohort of patients with advanced PD.

**Methods:** We conducted an ancillary cluster analysis of the 2013–2018 cohort (n = 722) of PREDISTIM. In this French multicenter interventional cohort, consecutive candidates for subthalamic deep brain stimulation undergo thorough assessment of motor symptoms (MS) and NMS at the inclusion visit. The NMS data are based on the MDS-UPDRS, Montreal Cognitive Assessment (MoCA), and several psychiatric scales: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), and Lille Apathy Rating Scale (LARS). Cluster analysis with 17 NMS was conducted to identify groups with homogenous NMS profiles.

<footnote><sup>a</sup> Department of Neurology, Hospital of Mercy, CHR of Metz-Thionville, University of Lorraine, Ars Laquenexy, 57530, France</footnote>

<footnote><sup>b</sup> Department of Neurology, University Hospital of Nancy, University of Lorraine, 54000, Nancy, France</footnote>

<footnote><sup>c</sup> Department of Neurosurgery, University Hospital of Nancy, University of Lorraine, 54000, Nancy, France</footnote>

<footnote><sup>d</sup> CHU of Lille, Univ. Lille, ULR 2694 - METRICS: Health Technology and Medical Practice Assessment, 59000, Lille, France</footnote>

<footnote><sup>e</sup> Univ. Lille, CHU of Lille, Lille Neuroscience & Cognition Inserm UMRS_1172, Licend, Department of Medical Pharmacology, Neurology and Movement Disorders
Department, Expert Center of Parkinson's Disease, NS-Park Network, F-59000, Lille, France</footnote>

<footnote><sup>f</sup> Department of Neurology, University Hospital of Nice, University of Nice, Nice, France</footnote>

<footnote><sup>g</sup> Neurologic Hospital Pierre Wertheimer / Hospices Civils de Lyon, Expert Center of Parkinson's Disease, Lyon, France</footnote>

<footnote><sup>h</sup> Department of Neurology, Rouen University Hospital and University of Rouen, France</footnote>

<footnote><sup>i</sup> INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Mont-Saint-Aignan, France</footnote>

<footnote><sup>j</sup> Department of Clinical Pharmacology and Neurosciences, Toulouse Parkinson Expert Center, Toulouse NeuroToul Center of Excellence in Neurodegeneration (COEN) and the French NS-Park/F-CRIN Network, University of Toulouse 3, CHU of Toulouse, INSERM, Toulouse, France</footnote>

<footnote><sup>k</sup> Department of Neurology, University Hospital of Poitiers, Poitiers, France</footnote>

<footnote><sup>l</sup> INSERM, CHU de Poitiers, University of Poitiers, Centre d'Investigation Clinique CIC1402, Poitiers, France</footnote>

<footnote><sup>m</sup> Department of Neurology, CHU of Clermont-Ferrand, University of Clermont Auvergne, CNRS, IGCNC, Institut Pascal, Clermont-Ferrand, France</footnote>

<footnote><sup>n</sup> Department of Neurology, CHU of Strasbourg, Hospital of Hautepierre, 67098, Strasbourg Cedex, France</footnote>

<footnote><sup>o</sup> Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, Strasbourg, France</footnote>

<footnote><sup>p</sup> Department of Neurology, Hospital Fondation Ophtalmologique Adolphe de Rothschild, NS-PARK/F-CRIN Network, France</footnote>

<footnote><sup>q</sup> Department of Neurology, University Hospital of Nantes, CHU of Nantes, 44 093, Nantes Cedex, France</footnote>

<footnote><sup>r</sup> Department of Neurology, NS-PARK/F-CRIN, Assistance Publique - Hôpitaux de Marseille (APHM), Timone University Hospital and Institut de Neurosciences de la Timone, Marseille, France</footnote>

<footnote><sup>s</sup> Department of Neurology, NS-PARK/F-CRIN, University Hospital of Rennes, Rennes, France</footnote>

<footnote><sup>t</sup> Department of Neurology, NS-PARK/F-CRIN, Assistance Publique - Hôpitaux de Paris (APHP), Pitié-Salpêtrière Hospital, Paris, France</footnote>

<footnote><sup>u</sup> Sorbonne Universités, Assistance Publique - Hôpitaux de Paris (APHP), Inserm, CNRS, Institut du Cerveau et de la Moelle (ICM), Paris, France</footnote>

<footnote><sup>v</sup> Department of Neurology, NS-PARK/FCRIN, Amiens University Hospital, Amiens, France</footnote>

<footnote><sup>w</sup> Neuroscience Pole, NS-PARK/F-CRIN, Hôpital Foch, Suresnes, University of Versailles Paris-Saclay, INSERM-CEA NeuroSpin, Saclay, France</footnote>

<footnote>* Corresponding author. Service de Neurologie, CHRU de Nancy, France.</footnote>

<footnote>E-mail address: s.puisieux@chru-nancy.fr (S. Puisieux).</footnote>
*Results:* Three distinct NMS clusters were identified. The largest had mild MS. The smallest had moderate MS and the most severe NMS, including cognitive and psychiatric dysfunction. The middle-large group had moderate MS and NMS but was distinguished by having the worst sleeping problems. The clusters did not differ in onset age or patient age and may be underpinned by disparate patterns of anatomical brain damage.

*Conclusion:* The mainly-motor (Cluster 1), mainly non-motor (Cluster 3), and intermediate (Cluster 2) NMS endophenotypes must be replicated in an independent cohort but may help stratify patients for management (pharmacological, deep-brain stimulation, and non-pharmacological treatments) and inclusion and assessment in clinical trials.

# 1. Introduction

Parkinson's disease (PD) is a progressive neurodegenerative disorder. The clinical L-dopa-responsive symptoms of akinesia, rigidity, and tremor associate with degeneration of dopaminergic neurons in the nigro-striatal pathway. However, the degeneration then variably extends to dopaminergic neurons of the ventral tegmental area (mesolimbic and meso-cortical system) and non-dopaminergic neurons (e.g. noradrenergic, serotoninergic, and cholinergic) [1]. Consequently, patients with PD exhibit considerable heterogeneity in terms of clinical manifestations, including motor symptoms (MS), non-motor symptoms (NMS), disease onset, and progression rates. While the research to date has focused largely on the mechanisms that lead to MS and the treatments [2], it is now clear that NMS also play a key role in PD: they are present at all stages of PD, including the prodromal and advanced stages, and they can have a greater impact on health-related quality of life than MS [3,4]. A better understanding of NMS may promote more individualized care that is better adapted to each patient profile.

Over the last 15 years, the identification of PD subtypes has been a high priority research goal in PD. Given the large variation in non-motor presentation, it has been hypothesized that there are different NMS subtypes of PD. This is plausible given the early identification of MS subtypes of PD, including tremor-dominant and bradykinesia/rigidity/postural instability and gait disorders (PIGD)-dominant subtypes [5,6]. This is also supported by several studies that found different MS subtypes are characterized by disparate NMS characteristics [5,7,8]. For example, PIGD not only often associates with more NMS [7] (e.g. depression [5]), it is also characterized by more severe fatigue, sleep impairment, and urinary symptoms [8]. However, only a few studies have sought to define the clinical NMS subtypes to date. They include several cluster analysis studies on large cohorts of newly diagnosed untreated PD patients that suggested that there are NMS-dominant or NMS-only subtypes as well as mild and severe NMS subtypes. The subtypes identified by these studies differed in number and in terms of NMS combinations depending on whether the subtypes were defined according to NMS burden or disease progression [9,10]. One study found that cognitive-related symptoms associated with a high NMS burden [11]. Another study observed more rapid disease progression in a diffuse/malignant cluster characterized by mild cognitive impairment, orthostatic hypotension and sleep impairment (REM Behavior Disorder) [12]. Yet another study found that age of onset contributed to non-motor subtypes [13].

The identification of NMS-dominated subtypes led several authors to suggest that there are different pathways of neuronal degeneration and spread of pathology: this may explain why certain symptoms tend to aggregate in specific clusters [14,15]. Indeed, on the basis on published evidence, clinical observational studies [16,17], and clinical and imaging biomarkers, Sauerbier et al. recently proposed that there are several different pathophysiological pathways, namely, a brainstem subtype that is characterized by autonomic and sleeping dysfunction, a limbic variant that is characterized by depression, anxiety, pain, and fatigue, and a neocortical subtype that is characterized by cognitive impairment and apathy [18]. However, these subtypes are not universally accepted and must be substantiated by large-scale real-life studies.

To improve PD management and clinical-trial assessment, we sought

to define the NMS endophenotypes that associate with PD prognosis. Thus, we conducted an ancillary study of the PREDISTIM cohort database. PREDISTIM is a large (n > 722) multicentric cohort of French patients with PD who were candidates for subthalamic nucleus-deep brain stimulation (STN-DBS) in 2013–2019. The study aims to identify preoperative factors that predict the quality of life (QoL) of these patients. Here, we subjected the preoperative visit data of the PREDISTIM cohort to cluster analysis to identify the preoperative non-motor subtypes in the cohort. To our knowledge, such studies have not been conducted previously with this type of cohort.

# 2. Methods

## 2.1. Study design and ethics

This study is an ancillary cluster analysis of the prospective French interventional multicenter cohort study called PHRC-N PREDISTIM (Predictive Factors and Subthalamic Stimulation in Parkinson's). The PREDISTIM study was registered on [ClinicalTrials.gov](http://ClinicalTrials.gov) (NCT02360683). The details of this study have been reported previously [19]. Briefly, it involves 17 PD referral centers and started in 2013 and is ongoing. Eligible patients have idiopathic PD, are aged 18–75 years, have had the disease for >5 years, and are indicated for STN-DBS, as defined by the International Parkinson's disease and Movement Disorders Society [20]. Patients are scheduled for a follow-up visit 1, 3, and 5 years after STN-DBS. The study was conducted in accordance with the 1975 Declaration of Helsinki. It was approved by the local ethics committee of the Lille University Hospital (Personal Protection Committee Nord-Ouest IV No. 13/23, delivered on April 09, 2013). Patients gave written informed consent before entering the study.

## 2.2. Patient selection and clinical data

The present study included all patients who were enrolled in PREDISTIM in January 2013–October 2018. The study focused on variables that were recorded at the preoperative examination: patient age; sex; disease duration (defined relative to diagnosis date); onset age (defined as age at diagnosis); and clinical assessments with the following scales and questionnaires, all conducted in a clinical ON state except for the Hoehn and Yahr (H-Y) Scale and Motor Disease Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III: both were tested in the OFF condition.

### 2.2.1. Motor symptoms

MS severity was measured with total MDS-UPDRS-III score (OFF state) [21] and the Freezing-Of-Gait-Questionnaire (FOG-Q). The total MDS-UPDRS-III score range is 0–136. Cutoffs for mild/moderate and moderate/severe MS severity are 32/33 and 58/59, respectively [21]. The FOG-Q score range is 0–64. A global score >32 may reflect moderate impairment, considering that a score of 2 for each item corresponds to moderate impairment. This scale has been validated as being more sensitive for detecting the severity of freezing than the simple 2.13 sub-score of MDS-UPDRS. Motor complications were assessed with total MDS-UPDRS-IV (score range 0–240). Cutoffs for mild/moderate and moderate/severe motor complications are 4/5 and 12/13, respectively
[21]. Dyskinesia duration was measured with MDS-UPDRS-IV.1 (score range 0–4, where none = 0, slight = 1, mild = 2, moderate = 3, and severe = 4) [21]. The ability of Levodopa to reduce motor symptoms was calculated with MDS-UPDRS-III.

### 2.2.2. Disease impact

Disease impact was determined with the H-Y scale in the OFF state [22] (score range 0–5(18)), and total MDS-UPDRS-II score (score range 0–52; mild/moderate and moderate/severe score cutoffs are 12/13 and 29/30, respectively). The latter evaluates activities of daily living (ADL) [21]. QoL was measured with the total Parkinson Disease Questionnaire (PDQ-39) score (score range, 0–100 %) [23].

### 2.2.3. Non-motor symptoms

Eighteen NMS were assessed. Thirteen were the 13 subscores of MDS-UPDRS-I (subscore range 0–4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe), namely, MDS-UPDRS-1.1 for cognition, MDS-UPDRS-1.2 for hallucinations, MDS-UPDRS-1.3 for depression, MDS UPDRS-1.4 for anxiety, MDS-UPDRS-1.5 for apathy, MDS-UPDRS-1.6 for dopaminergic dysregulation syndrome, MDS-UPDRS-1.7 for sleep disturbances, MDS-UPDRS-1.8 for excessive daytime sleepiness, MDS-UPDRS-1.9 for pain, MDS-UPDRS-1.10 for urinary troubles, MDS-UPDRS-1.11 for constipation, MDS-UPDRS-1.12 for light headedness on standing, and MDS-UPDRS-1.13 for fatigue [21]. Total MDS UPDRS-I score (score range 0–52; scores of 10/11 and 21/22 signify mild/moderate and moderate/severe NMS, respectively) [21] was also determined.

The remaining four NMS were determined with specific scales. Anxiety was measured with the Hamilton Anxiety Rating Scale (HAM-A) (scores of <8, 8–14, 15–23, and 24–56 respectively indicate no, mild, moderate, and severe anxiety) [24,25]. Depression was measured with the Hamilton Depression Rating Scale (HAM-D) (scores of <8, 8–16, 17–23, and ≥24 indicate no, mild, moderate, and severe depression, respectively) [26,27]. Apathy was measured with the Lille Apathy Rating Scale (LARS) (a score of > -22 indicates apathy) [28]. Global cognition status was measured with the Montreal Cognitive Assessment (MoCA) (a score of ≥26/30 indicates normal cognitive status) [29].

## 2.3. Statistical analyses

Normality of continuous variable distribution was assessed with the Shapiro-Wilk test. Normally and non-normally distributed continuous variables were expressed as mean ± standard deviation (SD) and median (interquartile range [IQR]), respectively. Categorical variables were expressed as *n* (%). To classify the patients into subgroups, principal component analysis (PCA) followed by hierarchical clustering analysis (HCA) were conducted with 17 of the 18 NMS variables (total MDS-UPDRS-I score was not used). Since the data of the 28 baseline variables were missing for 0–149 patients (mean 62 patients; 8.5 % of the cohort), the missing data were imputed for PCA/HCA analysis with a regression-switching approach (chained equations with m = 1) under the missing-at-random assumption: the predictive mean matching method was used for continuous variables while multinomial or binary logistic regression models were used for categorical variables. The data shown in the tables are non-imputed data; however, the data after imputation were similar (data not shown). After standardization with z-scores, the distributions of the 17 variables in the three clusters were presented on a radar graph. The three clusters were compared in terms of demographic, MS, and NMS variables (unimputed data) by Chi-square tests or Kruskall-Wallis tests; the latter was followed by post-hoc Dunn's tests with Bonferroni correction if the p-value was <0.05. All statistical analyses were conducted at the two-tailed α-leveled of 0.05. Data were analyzed using the SAS software version 9.4 (SAS-Institute, Cary, NC). P values < 0.05 were considered significant.

# 3. Results

## 3.1. Baseline demographic, motor, and non-motor characteristics of the cohort

In total, 722 PD patients who were eligible to undergo STN-DBS were enrolled in the PREDISTIM study in 2013–2018. Mean age, onset age, and disease duration were 60, 51, and 9 years, respectively, and 65 % were male. In terms of motor characteristics, median total MDS-UPDRS-III was 40.0 [31.0–53.0], FOG-Q was 15.0 [6.0–25.0], total MDS-UPDRS-IV was 1.0 [1.0–2.0], and Levodopa reduced MS by 74 % (Table 1A). In terms of disease impact, median H-Y was 2.5 [2.0–3.0], total MDS-UPDRS-II was 5.0 [2.0–9.0], and QoL was 51/100 (Table 1B).

In terms of non-motor characteristics, mean and median total MDS-UPDRS-I scores were 10.5 ± 6.2 and 10.0 [6.0–15.0]. Most patients had sleep problems (82 %), pain/other sensations (82 %), and fatigue (79 %). Two-thirds reported a risk of daytime sleepiness (MDS-UPDRS item 1.8 ≥ 1) (68 %), urinary problems (57 %), and constipation (57 %). Sixty-four percent had no cognitive impairment (MoCA ≥26) and 36 % of patients had a MoCA score **strictly between 24 and 26** (i.e., ≥24 and < 26). Twenty-seven percent had a HAM-D score ≥8, indicating the presence of depressive symptoms. Thirty-one percent reported a sensation of orthostatic hypotension upon standing on MDS-UPDRS-I.12. Sixteen percent had apathy symptoms according to the LARS scale, and 24 % showed signs of dopaminergic dysregulation on MDS-UPDRS-I.6. The prevalence of anxiety varied substantially depending on the assessment scale, with 33 % of patients showing anxiety symptoms on the HAM-A scale and 64.5 % on item 1.4 of the MDS-UPDRS Part I. Hallucinations/psychosis were relatively rare (21 %) (Table 1C).

## 3.2. NMS subtypes at baseline

### 3.2.1. Cluster analysis

PCA followed by HCA with the 17 NMS characteristics elucidated three patient clusters (Supplementary Figs. 1 and 2). The discrimination index which refers to the degree to which different samples are distinguished from each other along the 17 NMS characteristics was 74 %. This result indicated a very good ability of the NMS characteristics to differentiate between groups. Kruskal-Wallis tests comparing the three clusters showed significant differences for all NMS variables. Pairwise comparisons showed that key differences related to MoCA, HAM-D-measured depression, HAM-A-measured anxiety, LARS-measured apathy, sleep problems, pain, urinary problems, constipation, and fatigue (Table 2 and Supplementary Table 1).

The first and largest cluster consisted of 344 patients (48 % of the cohort) and was characterized by very slight non-motor impairment: median MoCA was 27.0 [25–28], HAM-D was 3.0 [1,5–5.0], HAM-A was 3.0 [2.0–6.0], LARS was -29.0 [-32; -25], sleep problems was 1.0 [0.0–2.0], pain was 1.0 [0.0–2.0], urinary problems was 0.0 [0.0–1.0], constipation was 0.0 [0.0–1.0], and fatigue was 1.0 [0.0–1.0] (Table 2 and Supplementary Table 1).

The second cluster consisted of 249 patients (34 %) and was characterized by intermediate non-motor impairment and predominant sleep problems: compared to Cluster 1, MoCA (27.0 [25–28]) and LARS (-30.0 [-32; -26]) were similar but HAM-D (5.0 [3.0–7.0]), HAM-A (6.0 [3.0–9.0]), pain (2.0 [1.0–3.0]), urinary problems (1.0 [0.0–2.0]), constipation (1.0 [0.0–2.0]), fatigue (2.0 [1.0–3.0]), and especially sleep problems (3.0 [2.0–3.0]) were worse (Table 2 and Supplementary Table 1).

The third cluster was the smallest (n = 129, 18 %). Compared to Clusters 1 and 2, it had the most severe MoCA (25 [23–28]), HAM-D (10.0 [8.0–14.0]), HAM-A 12.0 [9.0–17.0], and LARS (-24 [-28; -18]). It had less severe sleep problems (2.0 [2.0–3.0]) than Cluster 2 but similar pain, urinary problems, constipation, and fatigue (Table 2 and Supplementary Table 1).

The radar plot (Fig. 1) confirmed that Cluster 1 had the mildest
<table><caption>**Table 1**

Baseline demographic and motor characteristics (A), impact of the disease (B) and non-motor characteristics (C).</caption><thead><tr><th>Demographic or motor characteristic</th><th>Mean ± SD</th><th>Median [interquartile range]</th><th>Prevalence n (%)</th></tr></thead><tbody><tr><td>Age</td><td>60.4 ± 7.1</td><td>62.0 [56.0-66.0]</td><td>—</td></tr><tr><td>Male sex</td><td>—</td><td>—</td><td>469 (65)</td></tr><tr><td>Age at onset</td><td>51.0 ± 7.4</td><td>52.0 [47.0-56.0]</td><td>—</td></tr><tr><td>Disease duration</td><td>9.4 ± 4.0</td><td>9.0 [7.0-12.0]</td><td>—</td></tr><tr><td>Total MDS-UPDRS-III OFF (motor severity)<sup>a</sup></td><td>42.6 ± 16.0</td><td>40.0 [31.0-53.0]</td><td>—</td></tr><tr><td>FOG-Q (motor severity)<sup>b</sup></td><td>16.5 ± 11.8</td><td>15 [6.0-25.0]</td><td>—</td></tr><tr><td>Total MDS-UPDRS-IV (motor complications)<sup>c</sup></td><td>7.7 ± 4.3</td><td>8.0 [5.0-11.0]</td><td>—</td></tr><tr><td>MDS-UPDRS-IV.1 (% dyskinesias)<sup>d</sup></td><td>1.2 ± 0.9</td><td>1.0 [1.0-2.0]</td><td>—</td></tr><tr><td>Levodopa-reduced MS<sup>e</sup></td><td>74.0 ± 13.9</td><td>67.3 [64.7-84.3]</td><td>—</td></tr><tr><th>Impact of the disease</th><th>Mean ± SD</th><th>Median [interquartile range]</th><th>Prevalence n (%)</th></tr><tr><td>Hoehn and Yahr Score OFF<sup>f</sup></td><td>2.6 ± 0.9</td><td>2.5 [2.0-3.0]</td><td>—</td></tr><tr><td>0 no disability</td><td></td><td></td><td></td></tr><tr><td>1 unilateral disability</td><td>—</td><td>—</td><td>28 (3.9)</td></tr><tr><td>1.5 unilateral and axial disab.</td><td>—</td><td>—</td><td>28 (3.9)</td></tr><tr><td>2 bilateral disab. without gait disorder</td><td>—</td><td>—</td><td>225 (31.2)</td></tr><tr><td>2.5 bilat mild disab. with postural reflex</td><td>—</td><td>—</td><td>175 (24.2)</td></tr><tr><td>3 bilateral mild-mod. disab. with postural instab</td><td>—</td><td>—</td><td>148 (20.5)</td></tr><tr><td>4 severe disability, can walk/stand</td><td>—</td><td>—</td><td>91 (12.6)</td></tr><tr><td>5 confined to bed/wheelchair</td><td>—</td><td>—</td><td>27 (3.7)</td></tr><tr><td>Total MDS UPDRS-II ON (ADL)<sup>g</sup></td><td>6.6 ± 6.3</td><td>5.0 [2.0-9.0]</td><td>—</td></tr><tr><td>PDQ-39 (QoL)<sup>h</sup></td><td>49.9 ± 23.8</td><td>51.0 [34.0-67.0]</td><td>—</td></tr><tr><th>Non-motor characteristic<sup>i</sup></th><th>Mean ± SD</th><th>Median [interquartile range]</th><th>Prevalence n (%)</th></tr><tr><td>MDS-UPDRS-I.1 cognitive impairment</td><td>0.5 ± 0.7</td><td>0.0 [0.0-1.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>286 (39 %)</td></tr><tr><td>MoCA cognitive impairment<sup>j</sup></td><td>26.0 ± 3.2</td><td>27.0 [25.0-28.0]</td><td>—</td></tr><tr><td>Normal ≥26</td><td>—</td><td>—</td><td>466 (64.5 %)</td></tr><tr><td>Not normal <26</td><td>—</td><td>—</td><td>256 (35.4 %)</td></tr><tr><td>MDS-UPDRS-I.2 hallucinations/psychosis</td><td>0.2 ± 0.4</td><td>0.0 [0.0-0.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>115 (21.4 %)</td></tr><tr><td>MDS-UPDRS-I.3 depressed mood</td><td>0.6 ± 0.8</td><td>0.0 [0.0-1.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>306 (42.3 %)</td></tr><tr><td>HAM-D depressed mood<sup>k</sup></td><td>5.5 ± 4.3</td><td>4.0 [2.0-8.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>198 (27 %)</td></tr><tr><td>MDS-UPDRS-I.4 anxious mood</td><td>1.0 ± 1.0</td><td>1.0 [0.0-1.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>467 (64.5 %)</td></tr><tr><td>HAM-A anxious mood<sup>l</sup></td><td>6.5 ± 5.6</td><td>5.0 [2.0-9.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>238 (32.9 %)</td></tr><tr><td>MDS-UPDRS-I.5 apathy</td><td>0.4 ± 0.7</td><td>0.0 [0.0-0.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>177 (24.5 %)</td></tr><tr><td>LARS apathy<sup>m</sup></td><td>-27.4 ± 6.4</td><td>-29.0 [-32.0-24.0]</td><td>—</td></tr><tr><td>MDS-UPDRS-I.6 DDS</td><td>0.3 ± 0.7</td><td>0.0 [0.0-0.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>176 (24.3 %)</td></tr><tr><td>MDS-UPDRS-I.7 sleep problems</td><td>1.9 ± 1.2</td><td>2.0 [1.0-3.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>594 (82 %)</td></tr><tr><td>MDS-UPDRS-I.8 daytime sleepiness</td><td>1.3 ± 1.0</td><td>1.0 [0.0-2.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>443 (68 %)</td></tr><tr><td>MDS-UPDRS-I.9 pain/other sensations</td><td>1.7 ± 1.2</td><td>2.0 [1.0-3.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>591 (81.8 %)</td></tr><tr><td>MDS-UPDRS-I.10 urinary problems</td><td>0.9 ± 1.0</td><td>1.0 [0.0-1.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>410 (56.7 %)</td></tr><tr><td>MDS-UPDRS-I.11 constipation</td><td>0.9 ± 1.0</td><td>1.0 [0.0-2.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>408 (56.5 %)</td></tr><tr><td>MDS-UPDRS-I.12 light-headedness on standing</td><td>0.5 ± 0.8</td><td>0.0 [0.0-1.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>224 (31 %)</td></tr><tr><td>MDS-UPDRS-I.13 fatigue</td><td>1.5 ± 1.1</td><td>1.0 [1.0-2.0]</td><td>—</td></tr><tr><td>Total any</td><td>—</td><td>—</td><td>569 (78.8 %)</td></tr><tr><td>Total MDS-UPDRS-I<sup>n</sup></td><td>10.5 ± 6.2</td><td>10.0 [6.0-15.0]</td><td>—</td></tr></tbody></table>

To simplify this table, patients without symptoms are not included. The total will always be 722 since it is the post-imputation data. The frequencies of each scale severity are shown in Supplementary Table 1.

ADL, activities of daily living; disab., disability; DDS, dysregulation dopaminergic syndrome; HAM-A, Hamilton anxiety rating scale; HAM-D, Hamilton depression rating scale; LARS, Lille apathy rating scale; MoCA, Montreal cognitive assessment; mod., moderate; MDS-UPDRS, Movement Disorder Society Unified Parkinson's Disease Rating Scale; SD, standard deviation.

<footnote>a Total MDS-UPDRS-III score range = 0-136; mild/moderate and moderate/severe cutoffs = 32/33 and 58/59, respectively [21].</footnote>

<footnote>b FOG-Q score range = 0-64; a global score >32 may favor moderate impairment, considering that a score of 2 for each item corresponds to moderate impairment. However, validation studies of FOG-Q have not reached agreement regarding severity intervals. This scale has been validated as being more sensitive for detecting the severity of freezing than the simple 2.13 sub-score of MDS-UPDRS.</footnote>

<footnote>c Total MDS-UPDRS-IV score range = 0-24; mild/moderate and moderate/severe cutoffs = 4/5 and 12/13, respectively [21].</footnote>

<footnote>d MDS-UPDRS-IV.1 score range = 0-4; none = 0, slight = 1; mild = 2, moderate = 3, severe = 4.</footnote>

<footnote>e Levodopa-induced reduction of MS was calculated as [1 - (UPDRS-III Best ON/UPDRS-III OFF**)] x 100, where ** = MDS-UPDRS-III score after taking DOPA (BEST ON)/MDS UPDRS-III score before taking DOPA (OFF).</footnote>

<footnote>f Hoehn-Yahr scale OFF state score range = 0-5 [22].</footnote>
<sup>g</sup> Total MDS-UPDRS-II score range = 0–52; mild/moderate and moderate/severe score cutoffs = 12/13 and 29/30, respectively [21].

<sup>h</sup> PDQ-39 is a 39-item score that ranges from 0 to 100 %, where 100 is the maximum level of problems [23].

<sup>i</sup> Each of the 13 subscores of MDS-UPDRS-I ranges from 0 to 4; none = 0, slight = 1; mild = 2, moderate = 3, severe = 4.

<sup>j</sup> MoCA score range = 0–30; score of ≥26/30 indicates a normal cognitive status [29].

<sup>k</sup> HAM-D score range = 0–52; scores of <8, 8–16, 17–23, and ≥24 indicate no, mild, moderate, and severe depression, respectively [26,27].

<sup>l</sup> HAM-A score range = 0–56; scores of <8, 8–14, 15–23, and 24–56 indicate no, mild, moderate, and severe anxiety, respectively [24,25].

<sup>m</sup> LARS score range = 0–42; scores of ≥22 indicate apathy [28].

<sup>n</sup> Total MDS-UPDRS-1 subscore range = 0–52; mild/moderate and moderate/severe score cutoffs = 10/11 and 21/22, respectively [21].

<table><caption>**Table 2**

Baseline non-motor characteristics of the three non-motor subtypes.</caption><thead><tr><th>Non-motor symptom</th><th>Cluster 1 n = 344</th><th>Cluster 2 n = 249</th><th>Cluster 3 n = 129</th><th>P<sup>a</sup></th><th>P<sup>b</sup><br>1 v. 2</th><th>P<sup>b</sup><br>1 v. 3</th><th>P<sup>b</sup><br>2 v. 3</th></tr></thead><tbody><tr><td>MDS-UPDRS-I.1</td><td>0.3 ± 0.5</td><td>0.6 ± 0.7</td><td>1.0 ± 1.0</td><td></td><td></td><td></td><td></td></tr><tr><td>cognitive impair</td><td>0.0 [0.0–0.0]</td><td>0.0 [0.0–1.0]</td><td>1.0 [0.0–2.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td></tr><tr><td>MoCA cognition</td><td>26.4 ± 2.9<br>27.0 [25.0–28.0]</td><td>26.3 ± 2.6<br>27.0 [25.0–28.0]</td><td>24.8 ± 3.9<br>25.0 [23.0–28.0]</td><td>&lt;0.001</td><td>0.66</td><td>&lt;0.001</td><td>&lt;0.001</td></tr><tr><td>MDS-UPDRS-I.2</td><td>0.0 ± 0.2</td><td>0.2 ± 0.4</td><td>0.5 ± 0.7</td><td></td><td></td><td></td><td></td></tr><tr><td>halluc./psychosis</td><td>0.0 [0.0–0.0]</td><td>0.0 [0.0–0.0]</td><td>0.0 [0.0–1.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td></tr><tr><td>MDS-UPDRS-I.3</td><td>0.2 ± 0.4</td><td>0.5 ± 0.6</td><td>1.5 ± 0.9</td><td></td><td></td><td></td><td></td></tr><tr><td>depressed mood</td><td>0.0 [0.0–0.0]</td><td>0.0 [0.0–1.0]</td><td>1.0 [1.0–2.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td></tr><tr><td>HAM-D</td><td>3.6 ± 2.7</td><td>5.4 ± 3.2</td><td>11.2 ± 4.7</td><td></td><td></td><td></td><td></td></tr><tr><td>depressed mood</td><td>3.0 [1.5–5.0]</td><td>5.0 [3.0–7.0]</td><td>10.0 [8.0–14.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td></tr><tr><td>MDS-UPDRS-I.4</td><td>0.6 ± 0.7</td><td>1 ± 0.8</td><td>2.1 ± 1.0</td><td></td><td></td><td></td><td></td></tr><tr><td>anxious mood</td><td>1.0 [0.0–1.0]</td><td>1.0 [0.0–1.0]</td><td>2.0 [1.0–3.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td></tr><tr><td>HAM-A</td><td>4.1 ± 3.4</td><td>6.3 ± 4.3</td><td>13.6 ± 6.2</td><td></td><td></td><td></td><td></td></tr><tr><td>anxious mood</td><td>3.0 [2.0–6.0]</td><td>6.0 [3.0–9.0]</td><td>12.0 [9.0–17.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td></tr><tr><td>MDS-UPDRS-I.5</td><td>0.2 ± 0.4</td><td>0.3 ± 0.6</td><td>1.1 ± 1.2</td><td></td><td></td><td></td><td></td></tr><tr><td>Apathy</td><td>0.0 [0.0–0.0]</td><td>0.0 [0.0–0.0]</td><td>1.0 [0.0–2.0]</td><td>&lt;0.001</td><td>0.011</td><td>&lt;0.001</td><td>&lt;0.001</td></tr><tr><td>LARS</td><td>-28.1 ± 5.5</td><td>-28.8 ± 4.9</td><td>-22.5 ± 8.4</td><td></td><td></td><td></td><td></td></tr><tr><td>Apathy</td><td>-29.0 [-32.0–25.0]</td><td>-30.0 [-32.0–26.0]</td><td>-24.0 [-28.0–18]</td><td>&lt;0.001</td><td>0.45</td><td>&lt;0.001</td><td>&lt;0.001</td></tr><tr><td>MDS-UPDRS-I.6</td><td>0.2 ± 0.5</td><td>0.4 ± 0.8</td><td>0.6 ± 0.9</td><td></td><td></td><td></td><td></td></tr><tr><td>DDS</td><td>0.0 [0.0–0.0]</td><td>0.0 [0.0–1.0]</td><td>0.0 [0.0–1.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>0.66</td></tr><tr><td>MDS-UPDRS-I.7</td><td>1.3 ± 1.1</td><td>2.6 ± 1.1</td><td>2.2 ± 1.1</td><td></td><td></td><td></td><td></td></tr><tr><td>sleep problems</td><td>1.0 [0.0–2.0]</td><td>3.0 [2.0–3.0]</td><td>2.0 [2.0–3.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>0.002</td></tr><tr><td>MDS-UPDRS-I.8</td><td>0.8 ± 0.9</td><td>1.8 ± 0.9</td><td>1.5 ± 1.0</td><td></td><td></td><td></td><td></td></tr><tr><td>daytime sleep.</td><td>1.0 [0.0–2.0]</td><td>2.0 [1.0–2.0]</td><td>2.0 [1.0–2.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>0.042</td></tr><tr><td>MDS-UPDRS-I.9</td><td>1.1 ± 0.9</td><td>2.2 ± 1.2</td><td>2.0 ± 1.2</td><td></td><td></td><td></td><td></td></tr><tr><td>pain/other sens.</td><td>1.0 [0.0–2.0]</td><td>2.0 [1.0–3.0]</td><td>2.0 [1.0–3.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>0.16</td></tr><tr><td>MDS-UPDRS-I.10</td><td>0.6 ± 0.8</td><td>1.1 ± 1.0</td><td>1.2 ± 1.1</td><td></td><td></td><td></td><td></td></tr><tr><td>urinary problems</td><td>0.0 [0.0–1.0]</td><td>1.0 [0.0–2.0]</td><td>1.0 [0.0–2.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>0.74</td></tr><tr><td>MDS-UPDRS-I.11</td><td>0.6 ± 0.8</td><td>1.1 ± 0.9</td><td>1.4 ± 1.1</td><td></td><td></td><td></td><td></td></tr><tr><td>constipation</td><td>0.0 [0.0–1.0]</td><td>1.0 [0.0–2.0]</td><td>1.0 [0.0–2.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>0.053</td></tr><tr><td>MDS-UPDRS-I.12</td><td>0.0 [0.0–1.0]</td><td>1.0 [0.0–2.0]</td><td>1.0 [0.0–2.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>0.053</td></tr><tr><td>light-headed</td><td>0.3 ± 0.6</td><td>0.5 ± 0.8</td><td>0.7 ± 1.0</td><td></td><td></td><td></td><td></td></tr><tr><td>MDS-UPDRS-I.13</td><td>0.9 ± 0.8</td><td>2.0 ± 1.1</td><td>2.1 ± 1.2</td><td></td><td></td><td></td><td></td></tr><tr><td>Fatigue</td><td>1.0 [0.0–1.0]</td><td>2.0 [1.0–3.0]</td><td>2.0 [1.0–3.0]</td><td>&lt;0.001</td><td>&lt;0.001</td><td>&lt;0.001</td><td>0.20</td></tr></tbody></table>

The data are expressed as mean ± standard deviation or median [interquartile range].

DDS, Dysregulation dopaminergic syndrome; HAM-A, Hamilton anxiety rating scale; HAM-D, Hamilton depression rating scale; LARS, Lille apathy rating scale; MDS-UPDRS, Movement Disorder Society Unified Parkinson's Disease Rating Scale; MOCA, Montreal cognitive assessment.

<sup>a</sup> P values were obtained by Kruskal-Wallis test.

<sup>b</sup> Pairwise comparisons were conducted on the medians with Dunn's tests with Bonferroni correction if the Kruskal-Wallis test p-value was <0.05. Chi-square test was conducted on sex.

scores for all NMS except for MoCA cognitive impairment and LARS apathy, which were similarly low in Cluster 2. However, compared to Cluster 1, Cluster 2 had higher scores for all other NMS, including MDS-UPDRS cognition and apathy. It also had the most severe sleeping problems and daytime sleepiness of the three clusters. It was similar to Cluster 3 in terms of pain, urinary problems, constipation, and fatigue, as well as in DDS and light-headedness on standing. However, Cluster 3 had the worst scores for cognitive impairment, hallucinations/psychosis, depression, anxiety, and apathy (Fig. 1).

Thus, Cluster 1 had the mildest NMS with near complete absence of cognitive, autonomic, and psychiatric symptoms. Cluster 2 generally had moderate NMS but the worst sleep-related problems. While Cluster 3 resembled Cluster 2 in half of the NMS, it had the most severe non-motor impairment in other NMS, including cognitive impairment and psychiatric symptoms. Nonetheless, the NMS in Cluster 3 were still quite mild (Table 2, Supplementary Table 1, and Fig. 1).

### 3.2.2. Demographic and MS characteristics of the three NMS subtypes

Clusters 1, 2, and 3 did not differ in sex ratio (60–67 % male), mean age (60–62 years), onset age (51–52 years), disease duration (9–10 years), response to Levodopa (73–75 %), or dyskinesia burden. However, motor severity (total MDS-UPDRS-III) was lowest in Cluster 1, followed by Cluster 3 and then Cluster 2. Cluster 1 also had fewer motor complications (total MDS-UPDRS-IV) than Clusters 2 and 3, which had similar motor complications. Notably, Cluster 3 exhibited significantly more freezing than Cluster 1 (p = 0.023) and tended to show more freezing than Cluster 2 (p = 0.084) (Table 3A).

The disease had an impact on ADL in all clusters, but it was lowest for Cluster 1. Cluster 1 had the best QoL followed by Cluster 2 and then Cluster 3 (Table 3B).

## 4. Discussion

Our study defined three main NMS-severity endophenotypes in
<figure><img src="image_5.png" /><figcaption>**Fig. 1.** A radar plot showing the distributions of the NMS scores in the three NMS clusters. DDS, Dopaminergic Dysregulation Syndrome; EDS, excessive daytime sleepiness; HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; Hallu, hallucinations and psychosis; LARS, Lille Apathy Rating Scale; MOCA, Montreal Cognitive Assessment Scale; UPDRS, Movement Disorder Society-Unified Parkinson's Disease Rating Scale.</figcaption></figure>

patients with advanced PD. Cluster 1 seems to involve few NMS and MS, while Cluster 3 has moderate-severe NMS and similar MS as Cluster 2 but worse freezing. Thus, the clusters can be described as a low NMS/ relatively low MS subset (Cluster 1), a moderate NMS/moderate MS subset (Cluster 2), and a high NMS/moderate MS subset (Cluster 3). For simplification, we will henceforth call them the mainly-motor (Cluster 1), mainly non-motor (Cluster 3) and intermediate (Cluster 2) subsets (Supplementary Fig. 2).

The average age of our patients was 60 years, 65 % were male, onset age was 51 years, and disease duration was 9 years. These baseline characteristics are in the range seen in other STN-DBS-treated cohorts, including randomized clinical trial cohorts [30–33]. However, given the current trend to offer surgery early, average onset age (51 years) was younger than in the general PD population (60 years) [34].

Notably, age at onset is a major determinant of previously identified PD subtypes: for example, several studies have shown that there are “older-age-at-onset with rapid disease progression” and “younger-age- at-onset with slow progression” subtypes [6,35]. Preferential Lewy body deposition in the brainstem in young onset PD versus a cortical dominant pathology in late onset PD has been described [36]. It is important to note that since our three clusters all had the same age at onset, the different phenotypes we observed are not shaped by this variable.

The overall non-motor impairment in our cohort was relatively moderate (total MDS-UPDRS-I score of 10) [21].

The mainly-motor group (Cluster 1) had slight NMS, mild motor impairment, and the least impact on ADL/QoL. Cognitive and psychi- atric symptoms were largely absent. It was also the largest cluster. These features indicate patients with advanced PD who have few neuropsy- chiatric symptoms.

However, at the other extreme is our mainly non-motor group (Cluster 3). It was the smallest cluster (18 %). While it was similar to Cluster 2 in terms of MS (moderate), it was the most impaired cluster in terms of global NMS, and also presented with more freezing. It was mainly characterized by two NMS, namely, cognitive and psychiatric

dysfunction. However, these symptoms were not severe despite the advanced stage of the disease. Nonetheless, these patients were clearly different to those in Clusters 1 and 2 (Supplementary Fig. 2).

It should be noted that mild cognitive impairment (MCI) may be relatively common in STN-DBS candidates. For example, Yamamoto et al. showed that the baseline MoCA score of 31 STN-DBS-eligible Japanese patients was 25.45, which is similar to the MoCA score of Cluster 3 (score = 25). Moreover, Abboud et al. showed that 80 % of 130 patients who underwent STN-DBS exhibited MCI in terms of five cognitive domains [37]. This is higher than has been observed for PD cohorts in general (30–40 %) [38]. It should be noted that Dujardin et al. found a link between apathy and cognitive impairment [39]. Thus, it is not clear whether the MCI in Cluster 3 is a true cognitive disorder or whether it reflects the more pronounced psychiatric symptomatology in this group, namely, anxiety, depression, and apathy.

Sauerbier et al. recently proposed that there are three pathophysio- logical subtypes of non-motor PD, namely, the brainstem (autonomic and sleeping dysfunction), limbic (depression, anxiety, pain, and fa- tigue), and neocortical (cognitive impairment and apathy) subtypes [18]. The three NMS subtypes we identified are somewhat different to these proposed subtypes. Since Cluster 3 has cognitive and psychiatric impairment and dysautonomia, it thus comprises all three phenotypes. This disparity from Sauerbier et al. may reflect the selected nature of our cohort. Nonetheless, our finding suggests that Cluster 3 has the most severe disease that is probably characterized by diffuse anatomical damage throughout the whole brain.

Given that the three clusters had similar onset ages (and a relatively young onset age) and disease durations, the fact that Cluster 3 had more severe cognitive problems than Clusters 1 and 2 suggests that it is a fundamental PD phenotype that is characterized by faster progression of cognitive dysfunction [17], probably because of more rapid propagation or more extensive lesions of the pathology to all brain regions. This may explain why freezing is more prevalent in this subset. By contrast, the pathology in Cluster 1 may be restricted to the brainstem and peripheral nervous system, probably because of slow progression and less extensive
<table><caption>**Table 3**
Baseline demographic and motor characteristics (A) and disease impact of the three non-motor subtypes (B).</caption><thead><tr><th colspan="2">(A) Demographic or motor characteristic</th><th>Cluster I</th><th>Cluster 2</th><th>Cluster 3</th><th>P<sup>a</sup></th><th>P<sup>b</sup> 1 vs. 2</th><th>P<sup>b</sup> 1 vs. 3</th><th>P<sup>b</sup> 2 vs. 3</th></tr></thead><tbody><tr><td rowspan="2">Sex</td><td>Male</td><td>225 (67.2)</td><td>157 (63.6)</td><td>75 (59.5)</td><td rowspan="2">0.29</td><td rowspan="2">-</td><td rowspan="2">-</td><td rowspan="2">-</td></tr><tr><td>Female</td><td>110 (32.8)</td><td>90 (36.4)</td><td>51 (40.5)</td></tr><tr><td rowspan="2">Age, years</td><td></td><td>n = 327</td><td>n = 242</td><td>n = 123</td><td rowspan="2">0.078</td><td rowspan="2">-</td><td rowspan="2">-</td><td rowspan="2">-</td></tr><tr><td></td><td>60.3 ± 7.5</td><td>59.8 ± 7.2</td><td>61.6 ± 6.2</td></tr><tr><td rowspan="2">Age at onset, years</td><td></td><td>n = 326</td><td>n = 244</td><td>n = 123</td><td rowspan="2">0.35</td><td rowspan="2">-</td><td rowspan="2">-</td><td rowspan="2">-</td></tr><tr><td></td><td>50.8 ± 7.3</td><td>50.6 ± 7.5</td><td>51.7 ± 7.3</td></tr><tr><td rowspan="2">Disease duration, years</td><td></td><td>n = 323</td><td>n = 240</td><td>n = 122</td><td rowspan="2">0.14</td><td rowspan="2">-</td><td rowspan="2">-</td><td rowspan="2">-</td></tr><tr><td></td><td>9.5 ± 3.8</td><td>9.2 ± 4.0</td><td>10.0 ± 4.1</td></tr><tr><td rowspan="2">Total MDS-UPDRS<br/>-III OFF(motor severity)</td><td></td><td>n = 316</td><td>n = 242</td><td>n = 123</td><td rowspan="2">0.016</td><td rowspan="2">0.010</td><td rowspan="2">0.59</td><td rowspan="2">0.46</td></tr><tr><td></td><td>40.9 ± 15.9</td><td>44.5 ± 15.9</td><td>42.9 ± 16.9</td></tr><tr><td rowspan="2">FOG-Q(motor severity)</td><td></td><td>n = 344</td><td>n = 249</td><td>n = 129</td><td rowspan="2">&lt;0.001</td><td rowspan="2">0.023</td><td rowspan="2">&lt;0.001</td><td rowspan="2">0.084</td></tr><tr><td></td><td>6.9 ± 4.3</td><td>8.3 ± 3.8</td><td>8.7 ± 4.5</td></tr><tr><td rowspan="2">Total MDS-UPDRS-IV (motor complications)</td><td></td><td>n = 303</td><td>n = 229</td><td>n = 119</td><td rowspan="2">&lt;0.001</td><td rowspan="2">&lt;0.001</td><td rowspan="2">&lt;0.001</td><td rowspan="2">0.40</td></tr><tr><td></td><td>1.2 ± 0.9</td><td>1.2 ± 0.9</td><td>1.3 ± 1.0</td></tr><tr><td rowspan="2">MDS-UPDRS-IV.1(daily dyskinesia duration, %)</td><td></td><td>n = 303</td><td>n = 229</td><td>n = 119</td><td rowspan="2">0.22</td><td rowspan="2">-</td><td rowspan="2">-</td><td rowspan="2">-</td></tr><tr><td></td><td>1.2 ± 0.9</td><td>1.2 ± 0.9</td><td>1.3 ± 1.0</td></tr><tr><td rowspan="2">Levodopa-induced<br/>MS reduction<sup>c</sup></td><td></td><td>n = 303</td><td>n = 229</td><td>n = 119</td><td rowspan="2">0.26</td><td rowspan="2">-</td><td rowspan="2">-</td><td rowspan="2">-</td></tr><tr><td></td><td>74.7 ± 14.7</td><td>73.8 ± 12.9</td><td>72.9 ± 14</td></tr><tr><td rowspan="2">(B) Disease impact</td><td></td><td>Cluster I n = 344</td><td>Cluster 2 n = 249</td><td>Cluster 3 n = 129</td><td>P<sup>b</sup></td><td>P<sup>b</sup> 1 vs. 2</td><td>P<sup>b</sup> 1 vs. 3</td><td>P<sup>b</sup> 2 vs. 3</td></tr><tr><td>Hoehn and Yahr</td><td>n = 304</td><td>n = 239</td><td>n = 116</td><td rowspan="4">0.007</td><td rowspan="4">0.41</td><td rowspan="4">0.005</td><td rowspan="4">0.10</td></tr><tr><td>Score OFF<br/>(motor severity)</td><td>2.6 ± 0.9</td><td>2.7 ± 0.9</td><td>2.8 ± 0.8</td></tr><tr><td>Total MDS-UPDRS-<br/>II ON (ADL)</td><td>2.5 (2.0-3.0)</td><td>2.5 (2.0-3.0)</td><td>2.5 (2.0-3.0)</td></tr><tr><td></td><td>n = 300</td><td>n = 228</td><td>n = 115</td></tr><tr><td rowspan="3">PDQ-39 (QoL)</td><td>5.2 ± 5.3</td><td>7.2 ± 5.7</td><td>9.2 ± 8.6</td><td rowspan="3">&lt;0.001</td><td rowspan="3">&lt;0.001</td><td rowspan="3">&lt;0.001</td><td rowspan="3">0.14</td></tr><tr><td>4.0 (1.0-7.0)</td><td>6.0 (3.0-10.0)</td><td>8.0 (3.0-12.0)</td></tr><tr><td>n = 344</td><td>n = 249</td><td>n = 129</td></tr><tr><td rowspan="2"></td><td>41.5 ± 21.9</td><td>53.6 ± 20.6</td><td>65.3 ± 25.3</td><td rowspan="2">&lt;0.001</td><td rowspan="2">&lt;0.001</td><td rowspan="2">&lt;0.001</td><td rowspan="2">&lt;0.001</td></tr><tr><td>41.0 (27.0-56.5)</td><td>55.0 (41.0-68.0)</td><td>69.0 (54.0-83.0)</td></tr></tbody></table>

The data are expressed as mean ± standard deviation, median [interquartile range], or n (%).

ADL, activities of daily living; MS, motor symptom; PDQ-39, Parkinson's Disease Questionnaire-39; QoL, quality of life.

a P values were obtained by Kruskal-Wallis test.

b Pairwise comparisons were conducted on the medians with Dunn's tests with Bonferroni correction if the Kruskal-Wallis test p-value was <0.05. Chi-square test was conducted on sex.

c Levodopa-induced reduction of MS was calculated as [1 - (UPDRSIII en Best ON/UPDRS-III en OFF**)] x 100, where ** = MDS UPDRS-III score after taking DOPA (BEST ON)/MDS UPDRS-III score before taking DOPA (OFF).

initial lesions.

We also detected Cluster 2, whose features appeared to be intermediate relative to Clusters 1 and 3. This group was characterized by the absence of cognitive impairment on MoCA and modest cognitive impairment on MDS-UPDRS-I.1 (this small difference may reflect the greater subjectivity of the MDS-UPDRS), and less psychiatric expression than in Cluster 3. It has similar dysautonomia compared to Cluster 3, but particularly prominent sleep disorders.

Clusters 2 and 3 mainly differ in terms of non-motor impairment: both had similar motor impairment, apart from freezing, and equivalent ADL problems but the NMS were more severe in Cluster 3. This explains why QoL was lower in Cluster 3: it has been shown that NMS have a more deleterious impact on QoL than MS [40]. However, Cluster 2 cannot be explained simply as an intermediate group between Clusters 1 and 3 (i.e. it represents the middle stage of progressive worsening of the anatomopathological spread of PD): if that was the case, Cluster 3 would have at least as marked or even more marked sleep impairment as Cluster 2. Thus, Cluster 2 also appears to reflect a particular pathophysiology.

It will be of interest to determine how the MS and NMS of these three endophenotypes have progressed five years after STN-DBS.

## 4.1. Study strengths and limitations

The strengths of our study include the fact that the population was carefully selected due to the precise selection criteria for STN-DBS in PD. Moreover, due to cross-national collaboration, this is one of the largest cohort studies on NMS subtypes. It is also the largest cohort of STN-DBS candidates.

However, the study also has some limitations. First, the large population of our study meant that there were inevitably missing data (on average 8.5 %/variable), which had to be imputed for the PCA/HCA analyses. Nonetheless, the imputed and unimputed data were similar (data not shown) and imputation is a common strategy in studies of this nature. Second, most NMS variables were only evaluated with the MDS-UPDRS scale, which involves subjective measurements. However, specific questionnaires were also used for cognition, depression, anxiety, and apathy, and agreement with the corresponding MDS-UPDRS-I sub-scores was mostly observed. We are also currently conducting further studies on more objectively measured NMS in the PREDISTIM cohort. Finally, our study was focused on patients with severe motor complications related to L-dopa who had the indications for STN-DBS. This explains why clusters with severe NMS were less prevalent.
# 5. Conclusion

This cluster analysis of patients with advanced PD showed three distinct NMS phenotypes, namely, a mainly-motor group, a mainly non-motor group with severe cognitive and psychiatric dysfunction and more freezing, and a group with an intermediate NMS burden but prominent sleep disturbances. These three subtypes may reflect underlying pathophysiological phenotypes. The subtypes require validation in independent cohorts but may be useful for stratifying patients for management (pharmacological, dee brain stimulation, and non-pharmacological treatments) and for inclusion and assessment in clinical trials. The influence of NMS subtype on patient outcome 5 years after STN-DBS will be studied in the future.

## CRediT authorship contribution statement

**Hélène Ducrocq:** Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Conceptualization, Salomé Puisieux: Writing – review & editing, Supervision, Conceptualization. **Lucie Hopes:** Writing – review & editing, Methodology, Conceptualization. **Solène Frismand:** Writing – review & editing, Conceptualization. **Sophie Colnat-Coulbois:** Writing – review & editing. **Maeva Kyheng:** Writing – review & editing. **Anne Sophie Rolland:** Writing – review & editing. **Caroline Moreau:** Writing – review & editing. **Caroline Giordana:** Writing – review & editing. **Teodor Danaila:** Writing – review & editing. **David Maltête:** Writing – review & editing. **Margherita Fabbri:** Writing – review & editing. **Isabelle Benatru:** Writing – review & editing. **Ana Marques:** Writing – review & editing. **Ouhaid Lagha Boukbiza:** Writing – review & editing. **Cecile Hubsch-Bonneaud:** Writing – review & editing. **Tiphaine Rouaud:** Writing – review & editing. **Alexandre Eusebio:** Writing – review & editing. **Sophie Drapier:** Writing – review & editing. **Elodie Hainque:** Writing – review & editing. **Melissa Tir:** Writing – review & editing. **Béchir Jarraya:** Writing – review & editing. **Jean-Christophe Corvol:** Writing – review & editing. **David Devos:** Writing – original draft, Supervision, Methodology, Investigation, Conceptualization.

## Ethical compliance statement

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The study was approved by the local ethics committee of the Lille University Hospital (Personal Protection Committee Nord-Ouest IV No. 13/23, delivered on April 09, 2013). The study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all study participants.

## Funding sources

The study was funded by the France Parkinson Charity, French Ministry of Health (PHRC national 2012), Lille University Hospital, and the Fédération de la Recherche Clinique du CHU de Lille.

## Declaration of competing interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Acknowledgements

We thank Dr. Yinka Zevering of SciMeditor Medical Writing and Editing Services for assistance with the manuscript. We are grateful to all participants and their families for their cooperation.

# Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.parkreldis.2025.107945.

## Data availability

The data are available on reasonable request from the corresponding authors.

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