Introduction

Parkinson’s disease (PD) is a common and intricate neurodegenerative disorder characterized by a wide range of motor and non-motor symptoms (NMS). Increasing evidence has demonstrated that PD is heterogeneous in its clinical manifestations, pathology and rate of progression, which suggests that it may be divisible into subtypes1 instead of being a pure entity. In recent decades, subtype classification of PD has been a clinical research priority.2 Among all kinds of subtype classifications, one of the earliest and classic classifications assigned PD patients into tremor-dominant (TD) and postural instability and gait difficulty dominant (PIGD) subtypes based on the ratio of their mean tremor score and mean PIGD score, assessed by Unified Parkinson’s Disease Rating Scale (UPDRS).3 However, the TD-PD and PIGD-PD subtypes only considered the motor symptoms of PD patients, with NMS being ignored. More recently, a new clinical PD classification has been proposed by data-driven clustering techniques, which allow patients to be assigned to a specific subtype considering both motor and non-motor symptoms, without any a priori hypothesis.4 Nonetheless, the validated methods used to evaluate NMS in this study were large practical obstacles to completing the same subtype classification in another cohort. Fereshtehnejad et al. categorized PD patients into three subtypes: mild motor-predominant (PD-MMP), intermediate (PD-IM) and diffuse malignant (PD-DM) subtypes, based on the results of scales and questionnaires used to evaluate motor function, cognition, rapid-eye-movement (REM)-sleep behaviour disorder (RBD) and dysautonomia.5 Longitudinal assessment has validated the feasibility and accuracy of the subtype classification and demonstrated that the DM subtype not only demonstrated the most severe motor deficits and NMS at baseline but also progressed fastest and had a substantially worse prognosis.6

Quality of life (QoL) is a vital outcome indicator for disease management among PD patients, as it not only makes necessary complements to clinical evaluation but also supplies information about disease status and the effects of therapy. One of the most important objectives of the treatment and care in PD is the maintenance or improvement of QoL since it is currently incurable.7 A large number of studies suggest that both motor dysfunction and NMS have negative effects on QoL in PD.8 To date, no study has investigated QoL and its determinants among the novel clinical subtypes of PD proposed by Fereshtehnejad et al.5 To accomplish more precise pharmacological and nonpharmacological interventions to improve or maintain QoL, physician should explore the clinical characteristics and differences of QoL based on subtypes in more detail. In addition, research on the novel clinical subtypes of PD is in its infancy, and its feasibility needs to be confirmed in different cohorts. Therefore, we explored the feasibility of the classification of the novel clinical subtypes in Chinese PD patients and then investigated the possible different determinants of QoL among PD-MMP, PD-IM and PD-DM patients in the current study.

Materials and Methods Patients

All patients in this study were successively enrolled at Huashan Hospital, Fudan University from March 2011 to February 2019. The diagnosis of PD was made by two neurologists specializing in movement disorders based on the UK Brain Bank criteria.9 Recruitment criteria included age ≥ 30, disease duration ≤ 48 months, and Hoehn and Yahr (H&Y) staging I–II.

Standard protocol approvals, registrations, and patient consents

The study was approved by the Human Studies Institutional Review Board, Huashan Hospital, Fudan University. Written informed consent in conformity to the Declaration of Helsinki were acquired from all participated patients in this study.

Clinical assessments and neuropsychological tests

All the clinical assessments and neuropsychological tests were completed by two clinicians specializing in movement disorders. Movement dysfunction was assessed by H&Y staging and the Unified Parkinson’s Disease Rating Scale-part III (UPDRS-III) during the off-medication state, which was defined as the withdrawal of anti-PD medications for at least 12 h. NMS were determined by Non-Motor Symptom Questionnaire (NMSQ).10 In addition, some other specific scales and questionnaires were used to assess the corresponding NMS, including the Geriatric Depression Rating Scale (GDS) for depression,11 the REM-sleep Behaviour Disorder Screening Questionnaire (RBDSQ) for RBD,12 the Epworth Sleepiness Scale (ESS) for excessive daytime sleepiness (EDS)13 and the Sniffin’ Sticks Screening Test 12 (SSST-12) for olfaction dysfunction.14 The levodopa equivalent dose (LED) was calculated as a previous study suggested.15

QoL was recorded by the 39-item Parkinson's Disease Questionnaire (PDQ-39) which comprises 39 items that were separated into eight subdomains: mobility, activity of daily living, emotional well-being, stigma, social support cognition, communication, and bodily discomfort.16 Each item on the PDQ-39 is recorded on a 5-point Likert scale. In the current study, the PDQ-39 summary index (PDQ-39 SI) was standardized from the original PDQ-39 scores by dividing the scored points by the maximum possible points and then multiplying by 100. Hence, a range of 0 to 100 for the PDQ-39 SI was defined, with higher scores meaning worse QoL.

All participants were in the ON condition during cognitive assessment to minimize the confounding impact of motor symptoms. Global cognitive abilities were assessed by the Mini Mental State Examination (MMSE).17 Other neuropsychological tests included attention and working memory [Symbol Digit Modalities Test (SDMT)]18 and [Trail Making Test A (TMT-A)],19 executive function [Stroop Color-Word Test (CWT)]20 and [Trail Making Test B (TMT-B)],19 language [Boston Naming Test (BNT)]21 and [Animal Fluency Test (AFT)],22 memory[Auditory Verbal Learning Test (AVLT)]23 and [delayed recall of the Rey-Osterrieth Complex Figure Test (CFT-delay)],24 visuospatial function[Clock Drawing Test (CDT)]25 and [copy task of the Rey-Osterrieth Complex Figure test (CFT)].24

Clinical definition of the three subtypes

Subtypes classification proposed by Fereshtehnejad et al.5 were adapted in the current study. Notably, we employed scores on the autonomic dysfunction-related items in the NMSQ,10 including items 1, 4–9, 18–20 and 28, defined as autonomic dysfunction-related items in the NMSQ (NMSQ-AD) score, to evaluate dysautonomia. In addition, we adopted a composite cognitive z score, subtracting the mean test score of the control sample from the individual raw scores and then dividing the difference by the standard deviation (SD) of the score of the control sample, to evaluate the cognitive function of PD patients. Calculations for the z score of each neuropsychological test were z-score = (crude scorepatient − meanhealthy control)/SDhealthy control. The mean score and SD of the neuropsychological tests from an age- and sex-matched healthy control cohort consisting of 100 subjects are shown in Table S1. Four critical clinical features, including motor (UPDRS-III score), cognition (composite cognitive z score), RBD (RBDSQ score), and dysautonomia (NMSQ-AD score), were used to classify patients into subtypes.5 The corresponding 75th percentile was calculated for each critical clinical feature, and patients were classified into three subtypes according to the following criteria: (1) PD-MMP subtype: both motor and all NMS scores were less than 75th percentile; (2) PD-DM subtype: either (ⅰ) motor score >75th percentile and at least 1 NMS score >75th percentile; or (ⅱ) all three NMS scores >75th percentile; (3) PD-IM subtype: those not meeting criteria for PD-MMP or PD-DM subtypes. The corresponding values for the 25th, 50th and 75th percentiles of the main clinical features used for subtype classification are shown in Table S2.

Statistical analysis

Continuous variables were showed in the form of mean ± standard deviation (SD) or median (25%, 75%) and categorical variables were showed in the form of frequencies (%). The continuous variables were compared among the three subtypes by Kruskal–Wallis test followed by a Dunn–Bonferroni test for post hoc comparisons. The chi-squared test was used for the comparisons of categorical variables among the three subtypes. Univariate linear analyses between the clinical variables, including sex, age, education, disease duration, H&Y, UPDRS-III score, NMSQ, RBDSQ, ESS, GDS score, SSST-12, MMSE, and PDQ-39 were performed for each of the three subtypes. The multiple linear stepwise regression analysis with all variables with p < 0.2 in the univariate models included was conducted in the three subtypes,26 respectively, to identify the main determinants of QoL in PD-MMP, PD-IM and PD-DM patients. A partial R2 value contributed by each variable was calculated for this multivariate model. The total R2 value was used to represent the proportion of total variability explained by the independent variables. The variance inflation factor (VIF) was used to evaluate the multicollinearity among independent variables in the multiple linear stepwise regression analysis. The statistically significant differences were defined as two-tailed p < 0.05. Data analysis was performed using SPSS (version 22.0).

Data availability statement

The data supporting all the findings of the study are available on request from the corresponding author (wangjian_hs@fudan.edu.cn; tangyilin@fudan.edu.cn).

Results Demographic and clinical characteristics of the three subtypes

A total of 298 patients (180 males, 118 females), with a mean (SD) age of 52.17 (11.44) years and a mean (SD) disease duration of 22.95 (10.28) months, were recruited for the study. Based on the subtype classification criteria proposed by Fereshtehnejad et al.,5 129 (43.28%) patients were assigned to the PD-MMP subtype, 121 patients (40.60%) were assigned to the PD-IM subtype, and 48 (16.11%) patients were assigned to the PD-DM subtype. The demographic and clinical features of the three subtypes are demonstrated in Tables 1 and 2. No differences in sex, disease duration or LED among the three subtypes were observed. PD-MMP and PD-IM patients were significantly younger at diagnosis than PD-DM patients. Tables 1 and 2 details post hoc pairwise comparisons of the three subtypes. In summary, the PD-MMP patients had the lowest H&Y stage, UPDRS-III score, NMSQ score, RBDSQ score, SSST-12 score and the least impaired cognitive scores (all neuropsychological tests except CDT). On the other side of the spectrum, the PD-DM patients had the highest H&Y stage, UPDRS-III score, GDS score, and the worst performance on neuropsychological tests, including the MMSE, SDMT, TMT-A, CWT-C and TMT-B.

Table 1. Demographic and clinical characteristics of the three subtypes. Characteristic

Phenotype I Mild

Motor-predominant

(n = 129)

Phenotype II

Intermediate

(n = 121)

Phenotype III

Diffuse malignant

(n = 48)

p value* Significant adjusted pairwise comparisons Sex (M/F) 74/55 73/48 33/15 0.3874# NA Age at diagnosis(y) 48.48 ± 10.77 52.09 ± 11.56 58.24 ± 9.98 <0.0001 I versus III, II versus III Education (y) 12.68 ± 3.38 10.40 ± 3.81 9.62 ± 3.85 <0.0001 I versus II, I versus III Disease duration (M) 22.09 ± 10.18 22.64 ± 10.40 26.00 ± 9.86 0.0727 None LED (mg/day) 300.00 (168.80, 400.00) 325.60 (200.00, 450.00) 325.00 (200.00, 425.00) 0.0833 None Motor symptoms and signs H&Y 1 (1, 2) 2 (1, 2) 2 (2, 2) <0.0001 All comparisons UPDRS-III score 18.05 ± 6.60 22.79 ± 9.51 34.77 ± 8.96 <0.0001 All comparisons Non-motor symptoms and signs ESS 4.35 ± 3.66 5.94 ± 4.59 5.23 ± 3.22 0.0090 I versus II NMSQ 6.22 ± 3.90 10.83 ± 6.20 11.11 ± 5.24 <0.0001 I versus II, I versus III NMSQ-AD score 2.39 ± 1.44 4.42 ± 2.60 4.66 ± 2.57 <0.0001 I versus II, I versus III GDS score 8.31 ± 5.58 9.86 ± 6.85 12.64 ± 6.57 0.0008 I versus III, II versus III RBDSQ 2.03 ± 1.07 4.03 ± 2.70 4.83 ± 3.05 <0.0001 I versus II, I versus III SSST-12 score 5.97 ± 2.32 5.20 ± 2.41 4.36 ± 2.50 0.0006 I versus II, I versus III ESS, Epworth Sleepiness Score; GDS, Geriatric Depression Rating Scale; H&Y, Hoehn and Yahr; LED, levodopa-equivalent daily dose; NMSQ, Nonmotor Symptoms Questionnaire; NMSQ-AD, autonomic dysfunction related items in Nonmotor Symptoms Questionnaire; RBDSQ, Rapid-Eye-Movement Sleep Behavior Disorder Screening Questionnaire; SSST-12, Sniffin’ Sticks screening 12 test; UPDRS-III, Unified Parkinson’s Disease Rating Scale part III. The data of H&Y and LED are presented as median (25%, 75%), and the other continuous data are presented as mean ± SD. The continuous variables were compared among the three subtypes by Kruskal–Wallis test followed by a Dunn–Bonferroni test for post hoc comparisons. * Comparison among the three subtypes. # The categorical variables were compared among the three groups by the chi-squared test. Table 2. Neuropsychological tests of the three subtypes. Characteristic

Phenotype I Mild

motor-predominant

(n = 129)

Phenotype II

Intermediate

(n = 121)

Phenotype III

Diffuse malignant

(n = 48)

p value* Significant adjusted pairwise comparisons MMSE 28.74 ± 1.29 27.47 ± 2.49 26.42 ± 2.85 <0.0001 All comparisons SDMT 47.67 ± 12.16 39.88 ± 14.15 28.73 ± 12.94 <0.0001 All comparisons TMT-A (s) 48.70 ± 16.06 64.45 ± 31.41 82.69 ± 39.13 <0.0001 All comparisons CWT-C time (s) 66.94 ± 16.17 79.78 ± 21.25 89.80 ± 22.50 <0.0001 All comparisons CWT-C right 47.78 ± 2.64 45.87 ± 4.92 42.23 ± 8.31 <0.0001 All comparisons TMT-B (s) 119.30 ± 39.72 152.00 ± 57.49 184.90 ± 66.69 <0.0001 All comparisons BNT 24.59 ± 3.44 22.21 ± 4.36 21.70 ± 4.90 <0.0001 I versus II, I versus III AFT 18.46 ± 4.57 15.62 ± 4.97 15.89 ± 3.96 <0.0001 I versus II, I versus III AVLT-delay recall 6.34 ± 5.36 4.28 ± 2.28 3.33 ± 2.01 <0.0001 I versus II, I versus III AVLT-T 30.57 ± 9.47 24.11 ± 8.45 20.02 ± 7.71 <0.0001 I versus II, I versus III CFT-delay recall 17.52 ± 7.19 14.08 ± 7.44 11.05 ± 6.23 <0.0001 I versus II, I versus III CFT 33.99 ± 2.09 31.82 ± 8.56 29.02 ± 8.75 <0.0001 I versus II, I versus III CDT 20.66 ± 6.02 19.63 ± 6.55 19.80 ± 5.33 0.3113 None AFT, Animal Fluency Test; AVLT, Auditory Verbal Learning Test; BNT, Boston Naming Test; CDT, Clock Drawing Test; CFT, the Rey-Osterrieth Complex Figure Test; CWT, Stroop Color-Word Test; MMSE, Mini Mental State Examination; SDMT, Symbol Digit Modality Test; TMT, Trail Making Test. The results of neuropsychological tests are presented as mean ± SD. The continuous variables were compared among the three subtypes by Kruskal–Wallis test followed by a Dunn–Bonferroni test for post hoc comparisons. * Comparison among the three subtypes. QoL in PD subtypes

QoL, which was evaluated using the PDQ-39, is shown in Table 3 for all three subtypes. PD-DM and PD-IM patients demonstrated higher scores on the PDQ-39 SI, indicating worse quality of life than PD-MMP patients. The most affected subdomains of the PDQ-39 were bodily discomfort (17.69 ± 18.07), stigma (17.67 ± 21.09) and emotional well-beings (17.21 ± 15.21) in PD-MMP patients, while the most affected subdomains were bodily discomfort (26.12 ± 21.29), cognition (23.84 ± 17.99) and stigma (22.06 ± 22.19) in PM-IM patients and bodily discomfort (28.13 ± 20.60), cognition (27.60 ± 19.12) and emotional well-beings (23.87 ± 18.07) in PD-DM patients.

Table 3. Quality of life assessment in the three subtypes.

Phenotype I Mild

motor-predominant

(n = 129)

Phenotype II

Intermediate

(n = 121)

Phenotype III

Diffuse malignant

(n = 48)

p value* Significant adjusted pairwise comparisons PDQ-39 SI 11.79 ± 8.11 16.21 ± 11.49 20.21 ± 13.20 <0.0001 I versus II, I versus III Mobility SI 9.61 ± 12.12 12.65 ± 14.18 18.85 ± 15.78 <0.0001 I versus III, II versus III Activity of daily living SI 8.74 ± 12.15 10.78 ± 12.30 16.84 ± 18.67 0.0121 I versus III Emotional well-beings SI 17.21 ± 15.21 19.68 ± 18.02 23.87 ± 18.07 0.0686 None Stigma SI 17.67 ± 21.09 22.06 ± 22.19 22.40 ± 24.01 0.1367 None Social support SI 3.77 ± 7.95 10.01 ± 18.11 8.16 ± 11.34 0.0060 I versus II, I versus III Cognitions SI 13.78 ± 13.08 23.84 ± 17.99 27.60 ± 19.12 <0.0001 I versus II, I versus III Communication SI 5.81 ± 10.87 10.29 ± 15.33 15.45 ± 21.12 0.0007 I versus II, I versus III Bodily discomfort SI 17.69 ± 18.07 26.12 ± 21.29 28.13 ± 20.60 0.0005 I versus II, I versus III PDQ-39, 39-item Parkinson’s disease questionnaire; SI, summary index * Comparison among the three subtypes. Determinants of QoL in PD subtypes

To find out the determinants of QoL in the three subtypes, we firstly performed univariate linear analyses between the clinical variables, including sex, age, education, disease duration, H&Y, UPDRS-III score, NMSQ, RBDSQ, ESS, GDS score, SSST-12 and MMSE, and PDQ-39 in the three subtypes, respectively, and the results are shown in Table 4. Next, we conducted the multiple linear stepwise regression analysis with all variables with p < 0.2 in the univariate models to reveal the determinants of QoL in the three subtypes (Table 5). All VIFs of the variables included in the multiple linear stepwise regression of the three subtypes were less than 10 (Table S3), which indicated that multicollinearity didn’t exist between one independent variable and the other independent variables. In PD-MMP patients, the most important determinants of QoL were GDS score (R2 = 0.336, β = 0.682, p = 0.000), NMSQ (R2 = 0.059, β = 0.703, p = 0.007), UPDRS-III score (R2 = 0.041, β = 0.369, p = 0.004) and ESS (R2 = 0.033, β = 0.606, p = 0.009). In PD-IM patients, the most important determinants of QoL were GDS score (R2 = 0.494, β = 1.696, p = 0.000), followed by ESS (R2 = 0.024, β = 0.689, p = 0.011) and SSST-12 (R2 = 0.022, β = −1.162, p = 0.021). In PD-DM patients, the most vital determinants of QoL were GDS score (R2 = 0.429, β = 1.737, p = 0.000), followed by MMSE (R2 = 0.098, β = −2.437, p = 0.006).

Table 4. The results of univariate linear analyses of clinical characteristics and PDQ-39 in the three subtypes. Variables PDQ-39 PD-MMP PD-IM PD-DM β p value β p value β p value Sex1 −0.351 0.880 −0.718 0.832 −1.824 0.779 Age (y) −0.029 0.785 −0.201 0.179* −0.505 0.100* Education (y) 0.014 0.967 −0.950 0.029* −1.704 0.037* Disease duration (y) 0.194 0.086* 0.023 0.886 0.388 0.207 LED (mg/day) −0.008 0.356 −0.007 0.347 −0.005 0.792 H&Y 1.039 0.655 2.227 0.508 11.981 0.205 UPDRS−III score 0.655 0.000* 0.089 0.624 −0.071 0.834 NMSQ 1.855 0.000* 0.780 0.003* 1.951 0.000* RBDSQ −0.077 0.939 −0.052 0.933 0.163 0.873 ESS