Journal of Clinical Neuroscience xxx (2014) xxx–xxx

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Clinical Study

Sex differences in Parkinson’s disease Michal Lubomski a, R. Louise Rushworth a, Will Lee b,c, Kelly L. Bertram b,c, David R. Williams b,c,⇑ a

The University of Notre Dame Australia, School of Medicine, Sydney, NSW, Australia Van Cleef Roet Centre for Nervous Diseases, Monash University, Melbourne, VIC, Australia c Neuroscience Department, Level 4 Centre block, Alfred Hospital, 55 Commercial Road, Melbourne, VIC 3004, Australia b

a r t i c l e

i n f o

Article history: Received 24 August 2013 Accepted 15 December 2013 Available online xxxx Keywords: Disease characteristics Epidemiology Gender differences Parkinson disease Quality of life Sex differences

a b s t r a c t Sex-related differences in Parkinson’s disease (PD) have been recognised, but remain poorly understood. We aimed to further clarify real-life differences in disease experience according to sex, by evaluating quality of life (QoL), demographic and clinical characteristics of PD patients. A cross-sectional survey was conducted on 210 PD patients (129 men, 81 women) attending specialist neurological clinics across three centres. Outcome measures included the motor examination of the Unified Parkinson’s Disease Rating Scale (UPDRS-III) and QoL as measured by the 39-item Parkinson’s Disease Questionnaire (PDQ-39). A male to female ratio of 1.6:1 was observed. Men reported a greater disease burden than women as noted by higher UPDRS-III scores (27 ± 13 versus 23 ± 13, p = 0.032), daily levodopa equivalent doses (898.1 ± 481.3 mg versus 750.7 ± 427.2 mg, p = 0.037) and caregiver reliance (44% versus 29.5%, p = 0.039). The UPDRS-III score was significantly associated with sex after controlling for age and disease duration, with men more severely affected (b = 0.165, r2 = 0.101, p = 0.028). The PDQ-39 showed men reported lower QoL in activities of daily living (ADL), cognition and communication sub-scales (p < 0.05). An association was identified in men between PDQ-39 ADL and cognition sub-scales (r = 0.660, p < 0.001). Men with an appointed caregiver had a higher PDQ-39 Summary Index (t = 3.222, degrees of freedom = 122, p = 0.002). PD was found to have greater overall impact on the health and well-being of male patients in sub-specialty clinical practice. Our study further supports the need for increased sex-delineated clinical assessment and consideration of potential differences required in the management of PD. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction Parkinson’s disease (PD) is a common neurological disorder characterised by the degeneration of several different neuronal populations important for movement, autonomic function and cognition, and is believed to result from an interplay between genetic variations and environmental exposures [1]. Both the prevalence and incidence of PD are significantly higher in men compared to women [1–3] with a male to female ratio of close to 1.6:1 [4,5]. Epidemiological studies suggest symptom onset may be later in women [2]. This difference may be due to the neuroprotective effects of oestrogen [6–11]. Sex-related differences have also been observed in the effect size of PD risk factors [12], medication use [2], levodopa bioavailability [5], type of motor symptoms [4,13– 15], neuropsychiatric and cognitive changes [2,15], development ⇑ Corresponding author at: Neuroscience Department, Level 4 Centre block, Alfred Hospital, 55 Commercial Road, Melbourne, VIC 3004, Australia. Tel.: +61 3 9076 2058; fax: +61 3 8679 3341. E-mail address: [email protected] (D.R. Williams).

of hallucinations [16], caregiver utilisation and reliance [2,17,18] as well as quality of life (QoL) [2,5]. Given these observations, sex differences relating to PD are likely to be important in defining management strategies [2]. The objective of this study was to evaluate sex-related differences in the presentation and QoL in a sample of patients with PD attending sub-specialty clinics.

2. Methods 2.1. Study settings and subjects Eligible patients were recruited from public and private movement disorder clinics at three hospitals across regional and metropolitan areas in Victoria, Australia. Patients were included if they had a clinical diagnosis of idiopathic PD and were managed by a specialist neurologist. Exclusions included a requirement for an interpreting service and significant cognitive impairment demonstrated by incapacity to provide consent. Ethics approval was

http://dx.doi.org/10.1016/j.jocn.2013.12.016 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Lubomski M et al. Sex differences in Parkinson’s disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2013.12.016

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M. Lubomski et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx

received from the Alfred Hospital, Ballarat Health Services and the University of Notre Dame Australia Human Research Ethics Committees. Written consent was obtained from all participants, as previously reported [19]. 2.2. Data collection Patients attending the clinics between February and October 2011 were recruited to complete a self-administered questionnaire. Information regarding socio-demographic factors and clinical management was collected. Patients also completed the 39-item Parkinson’s Disease Questionnaire (PDQ-39), a validated measure of QoL in PD that includes eight disease-specific scales of subjective health status: mobility, activities of daily living (ADL), emotions, social stigma, social support, cognition, communication, and bodily discomfort. Each scale is scored from 0 (least affected) to 100 (most affected) [20,21]. A license for use of the PDQ-39 was obtained from ISIS Innovation Ltd., Oxford, UK. The Unified Parkinson’s Disease Rating Scale motor examination (UPDRS-III) scores were provided by the examining neurologists as an objective measure of the patient’s prevailing motor function during clinic consultations [22]. Medications were compared following standard methods for calculating daily levodopa equivalent dose (LED) [23]. 2.3. Statistical analysis The 39-item Parkinson’s Disease Questionnaire Summary Index (PDQ-39 SI) was calculated from the eight health status dimensions of the PDQ-39. Two sample, independent t-tests were used to analyse differences between the groups for continuous variables. Chi-squared tests were used to compare differences between categorical variables. A 5% level of significance was used. Pearson correlation coefficients were calculated to assess the relationship between two continuous variables. Linear regression models were constructed to evaluate the effect of sex on UPDRS-III scores and LED after controlling for age and disease duration. Features of patients with disease duration greater than 5 years (later disease) were also investigated between the sexes using this method. Further sub-group linear regression models were developed to examine predictors of QoL (PDQ-39 SI and sub-scales). Data analysis was performed using the Statistical Package for the Social Sciences version 19 (SPSS Inc., Chicago, IL, USA). 3. Results 3.1. Demographic characteristics A total of 240 patients with PD were eligible to participate in the study and 210 (88%) responded to the survey (Table 1). Of the total study sample, 46% of the patients were seen at regional clinics. There was no significant difference in the survey response rate between patients attending regional and metropolitan clinics. Of all patients, 61.4% were men, corresponding to a male to female ratio of 1.6:1. The mean age of the study population was 69.1 years (range 32–89, standard deviation [SD] 10.8). The mean age of symptom onset was 60.6 years (SD 12.1) and mean duration of disease was 7.3 years (SD 5.7). A significantly higher proportion of women (43.8% versus 23.6%, p = 0.003) were single or widowed. Education level differed significantly, with 19.8% of men completing tertiary studies compared to 8.9% of women (p = 0.030, Table 1). Most (82.2%) respondents were retired with no difference between the sexes. 3.2. Clinical characteristics Male patients had significantly higher levels of motor impairment than female patients as assessed by the UPDRS-III scores

(27 ± 13 versus 23 ± 13, p = 0.032). In addition, women reported a significantly lower mean daily LED than men (750.7 ± 427.2 mg versus 898.1 ± 481.3 mg, p = 0.037, Table 1). Linear regression models were developed to assess the effect of sex on the UPDRS-III score and daily LED. After controlling for age and disease duration, male patients demonstrated significantly higher UPDRS-III scores (b = 0.165, r2 = 0.101, p = 0.028). Similarly, levodopa requirement in men was significantly higher after controlling for age, disease duration and severity (b = 0.152, r2 = 0.160, p = 0.049). Among patients with ‘‘later disease’’, linear regression modelling demonstrated that men were significantly more likely than women to have higher UPDRS-III scores (b = 0.168, r2 = 0.111, p = 0.023). A greater proportion of men than women reported ever requiring assistance from a carer (44% versus 29.5%, v2 = 4.276, degrees of freedom [df] = 1, p = 0.039). Men were also more likely to report increased caregiver reliance in ‘‘later disease’’ (69% versus 31%, v2 = 3.382, df = 1, p = 0.049). 3.3. QoL Of the individual PDQ-39 scales, men reported significantly lower QoL in ADL, cognition and communication (all p < 0.05, Table 2). In the total cohort, positive correlations were found between the PDQ-39 SI and UPDRS-III scores (r = 0.344, p < 0.001), and the PDQ-39 SI and daily LED (r = 0.323, p < 0.001). There was also a significant positive correlation between PDQ-39 ADL and cognition sub-scales in men only (r = 0.660, p < 0.001). However, there was no difference between the sexes on linear regression modelling of each of these variables after controlling for age. Using linear regression models of patients with ‘‘later disease’’, men were significantly more likely to report decreased subjective cognitive function (b = 0.139, r2 = 0.084, p = 0.042) and increased difficulties with communication (b = 0.133, r2 = 0.150, p = 0.043) than women. A similar trend was observed for the ADL sub-scale, with men with ‘‘later disease’’ reporting significantly worse scores than women (b = 0.143, r2 = 0.167, p = 0.027). Significant associations were also identified between the PDQ-39 informed QoL and caregiver assistance in men only. Implicated categories included mobility (57 ± 30 versus 34 ± 31, t = 4.284, df = 122, p < 0.001), ADL (51 ± 26 versus 34 ± 30, t = 3.205, df = 121, p = 0.002), cognition (42 ± 24 versus 33 ± 22, t = 2.110, df = 119, p = 0.037) and bodily discomfort (43 ± 25 versus 34 ± 25, t = 2.019, df = 123, p = 0.046) as well as the PDQ-39 SI (38 ± 18 versus 27 ± 18, t = 3.222, df = 122, p = 0.002). Men who had an appointed carer reported an overall lower QoL. 4. Discussion We have identified clinically important sex-specific differences across a number of demographic and clinical characteristics in patients with PD. In our cohort, men demonstrated higher UPDRS-III scores and required significantly higher daily LED even after controlling for age and disease duration. Greater motor impairment in men was reflected in the increased need for assistance from caregivers, despite having comparable disease duration and age of symptom onset as women. Furthermore, important and significant sex-related differences in QoL were evident in men who reported greater difficulties with ADL, cognition and communication. These differences have important management implications and also allude to notable differences in disease experience and QoL perception between the sexes. Our cohort had a male to female ratio of 1.6:1, consistent with PD epidemiology [4]. We identified comparable marital demographics but a lower rate of tertiary study completion in our cohort compared to other studies [4]. The mean disease duration in our

Please cite this article in press as: Lubomski M et al. Sex differences in Parkinson’s disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2013.12.016

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M. Lubomski et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx Table 1 Clinical and demographic characteristics of 210 Victorian Parkinson’s disease patients, subdivided by sex

Number of patients, n (%) Patient age, years Age at onset, years Age at diagnosis, years Time to diagnosis, Disease duration, years Years treated for PD Marital status, n (%) Married/De facto Single/Widowed Occupation, n (%) Professional Labourer/Farmer Other Education level, n (%) High school TAFE/Diploma Tertiary Appointed caregiver, n (%) Daily LED, mg Total UPDRS

Total PD patients

Men

Women

210 (100) 69.1 (10.8) 60.6 (12.1) 62.1 (11.9) 1.4 (2.4) 7.3 (5.7) 7.1 (5.6)

129 (61.4) 70.1 (10.4) 61.8 (11.9) 63.1 (11.8) 1.2 (2.1) 7.4 (5.7) 7.2 (5.6)

81 (38.6) 67.6 (11.3) 58.9 (12.2) 60.6 (11.9) 1.7 (2.8) 7.0 (5.8) 6.9 (5.7)

142 (68.6) 65 (31.4)

97 (76.4) 30 (23.6)

45 (56.2) 35 (43.8)

33 (18.1) 29 (15.9) 120 (66.0)

21 (18.6) 27 (23.9) 65 (57.5)

12 (17.4) 2 (2.9) 55 (79.7)

144 (72.0) 25 (12.5) 31 (15.5) 78 (38.4) 842.3 (465.8) 25.5 (13.2)

79 (65.3) 18 (14.9) 24 (19.8) 55 (44.0) 898.1 (481.3) 27.1 (13.2)

65 (82.3) 7 (8.9) 7 (8.9) 23 (29.5) 750.7 (427.2) 22.6 (12.8)

Test statistic (df)

p value

t = 1.595 (208)a t = 1.708 (206)a t = 1.458 (207)a t = 1.551 (208)a t = 0.651 (206)a t = 0.572 (206)a v2 = 9.231 (1)b

0.112 0.089 0.146 0.122 0.618 0.724 0.003

v2 = 15.082 (2)b

0.001

v2 = 7.013 (2)b

0.030

v2 = 4.276 (1)b

0.039 0.037 0.032

t = 2.105 (183)a t = 2.163 (168)a

Data are presented as mean (standard deviation) unless otherwise stated. Significant p values are in bold. df = degrees of freedom, LED = levodopa equivalent dose, PD = Parkinson’s disease, TAFE = technical and further education, UPDRS = Unified Parkinson’s Disease Rating Scale. a Independent sample t-test. b Pearson’s chi-squared test.

Table 2 Analysis of PDQ-39 responses by sex

Mobility ADL Emotional well-being Stigma Social support Cognition Communication Bodily discomfort PDQ-39 Summary Index

Total PD patients

Men (n = 129)

Women (n = 81)

Test statistica (df)

p value

42 38 31 21 15 35 28 40 32

44 42 29 22 14 38 31 38 32

39 33 34 21 17 31 24 43 30

t = 1.068 (206) t = 2.132 (205) t = 1.550 (204) t = 0.278 (203) t = 0.965 (201) t = 2.030 (202) t = 1.973 (202) t = 1.427 (206) t = 0.906 (206)

0.287 0.034 0.123 0.782 0.336 0.044 0.049 0.155 0.366

(31) (30) (23) (23) (22) (23) (24) (26) (19)

(32) (29) (23) (23) (20) (24) (25) (25) (19)

(30) (30) (22) (23) (25) (21) (22) (26) (19)

Data are presented as mean (standard deviation). Significant p values are in bold. ADL = Activities of Daily Living, df = degrees of freedom, PD = Parkinson’s disease, PDQ-39 = 39-item Parkinson’s Disease Questionnaire. a Independent sample t-test.

study population was 7.3 ± 5.7 years. This is notably longer than other accounts investigating PD sex differences (4.6 ± 4.6 years) despite comparable mean population age [15]. This may be a reflection of our cohort having earlier access to specialist care. Compared to other reports with patients of similar disease duration, the mean UPDRS-III score of our study population was similar [15,24]. Interestingly, women had significantly lower UPDRS-III scores than men, despite comparable disease duration. This trend persisted in patients with disease duration greater than 5 years, consistent with published literature [15]. We found that the average daily LED of women was 147.4 mg (SD 54.1 mg) lower than that for men. These trends in UPDRS-III scores and LED persisted even after controlling for age, disease duration and severity. This observation may be due to the tendency for earlier presentation in women, with consequently milder clinical features. Alternatively, this difference may be due to better levodopa bioavailability in women [3,5,14], or a lower dose producing similar clinical efficacy due to weight and body size differences which may result in similar mg/kg dose when adjusted for body weight. Despite the similarity in UPDRS-III [15,24], our patient cohort had on average higher LED than other reported groups of comparable disease duration [4,14,22].

Previous studies have found lower QoL in women with PD compared to men, using the PDQ-39 and other validated QoL assessment tools [2,5,25]. We found that the sex differences in QoL were most significant for patients who had PD for more than 5 years (‘‘later disease’’). Our cohort showed that men with an appointed caregiver reported lower QoL as depicted by the PDQ39 SI. Further subclass analysis of the PDQ-39 suggested men with an appointed caregiver were most concerned by reduced mobility, restricted ability to carry out ADL and physical discomfort. Our analysis of caregiver assistance revealed that women were more likely to believe they did not require support from an appointed caregiver compared to men. It has been shown that having a caregiver can prevent hospitalisations and delay nursing home admission [18]. Therefore, our findings suggest that women with PD may be disadvantaged in this regard, particularly those with ‘‘later disease’’ who would benefit from such assistance. Management strategies should aim to equip caregivers with the skills necessary to handle these issues on a day-to-day basis. We showed in a previous study that patients with PD residing in urban areas reported poorer QoL compared to patients from regional Victoria [19]. No other significant QoL scale differences were identified between sexes in either locality than those identified

Please cite this article in press as: Lubomski M et al. Sex differences in Parkinson’s disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2013.12.016

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collectively. Despite better access to medical care and allied health services in urban areas, the QoL in male patients remained inferior to their female counterparts. In the present study, difficulties with subjective cognition were more severe in men than women. When controlled for disease duration, this sex difference existed only for those with a disease duration greater than 5 years. These findings are consistent with previous studies [4,14,24]. Miller et al. suggested that greater cognitive deficits in male patients may contribute to increased difficulties with ADL perceived by men [26]. This trend was also observed in our study, with men reporting reduced QoL on PDQ-39 for both ADL and cognition subscales. In addition, these two subscales demonstrated strong correlation. Differences in oestrogenic effects on dopamine signalling have been postulated as a potential link between men’s and women’s cognitive and clinical characteristics [26]. While our data do not address certain potential confounding factors including psychiatric comorbidities and effects of hormone replacement therapy in women, several important sex-related differences in PD were identified. The findings of this study should be interpreted in light of its limitations including the self-reporting nature of the data and potential selection bias of the study population being drawn from specialist PD clinics. The greater disease burden demonstrated by men in this study may be a reflection of recruitment bias inherent in this cross-sectional survey design, whereby older patients with greater motor disability may have been over-represented among the clinic attendees.

5. Conclusion Our study demonstrated distinct PD sex-related differences in clinical characteristics, including the UPDRS-III and daily LED as well as QoL. Women’s lack of caregiver support and men’s higher disease burden as represented by the UPDRS-III, increased caregiver reliance and diminished reported QoL highlight the different needs male and female patients have. Further research and recognition by clinicians of the importance of sex and its effects are vital in offering sex-specific strategies in the management of PD.

Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Acknowledgements We acknowledge the support of nursing, allied health and secretarial staff across the Melbourne and Ballarat neurology clinics, in particular the Alfred Hospital Movement Disorder Clinic for recruiting patients throughout the study.

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Sex differences in Parkinson's disease.

Sex-related differences in Parkinson's disease (PD) have been recognised, but remain poorly understood. We aimed to further clarify real-life differen...
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