Impact of sexual functioning on health-related quality of life in Parkinson's disease patients: results of a European survey

MESTRADO

EVIDÊNCIA E DECISÃO EM SAÚDE

Impact of sexual functioning on health-related quality of life in Parkinson’s disease patients:

results of a European survey Olga Daniela Silva Marinho

M

FACULDADE DE MEDICINA

MESTRADO

EVIDÊNCIA E DECISÃO EM SAÚDE

Impact of sexual functioning on health-related quality of life in Parkinson’s disease patients:

results of a European survey Olga Daniela Silva Marinho

M

ADVISOR PROF. DR. CLAUDIA CAMILA DIAS

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Acknowledgements

I am extremely thankful to my advisor Prof. Dr. Cláudia Camila Dias and to Prof.

Matilde Soares for their invaluable patience and feedback. I also could not have undertaken this journey without Dr. João Massano and Prof. Dr. George Ebersbach, who generously provided knowledge and expertise. An additional thanks goes to the collaboration of Dr. Thomas Kinateder and Dr. Laura Hatzler for their contribution. Additionally, this endeavour would not have been possible without the generous support from Bial pharmaceuticals, who provided the database used in my research.

I am also grateful to my classmates for all the so important scientific discussions, all the sharing and moral support. Thanks should also go to my work colleagues that always supported, impacted and inspired me to conclude this work.

Lastly, I would be remiss in not mentioning my family, especially my husband and my parents. Their belief in me has kept my spirits and motivation high during this process.

Resumo

Introdução: A doença de Parkinson (PD) é uma doença neurodegenerativa clinicamente caracterizada por sintomas motores mas também por manifestações não motoras. A disfunção sexual é um sintoma não motor presente em muitas destas pessoas e que pode impactar significativamente a sua qualidade de vida relacionada com a saúde (HR-QoL) bem como as suas relações interpessoais.

Não obstante, até agora, a investigação científica nesta área é escassa. O objetivo principal deste trabalho é explorar a possível associação entre a função sexual e a HR-QoL em pessoas com PD.

Métodos: Este estudo em pessoas com PD explorou dados de mundo real recolhidos no âmbito do estudo PRISM: um estudo observacional, transversal, realizado em cinco países europeus (Portugal, Espanha, Itália, Reino Unido e Alemanha). O objetivo principal da análise realizada foi investigar a associação entre a função sexual e a HR-QoL através da aplicação dos questionários: Sexual Problems Measures Survey (MOS-SFS), as questões 18 e 19 do Non-motor Symptom Scale Questionnaire e a pergunta sobre sexualidade do Questionnaire for Impulsive- Compulsive Disorder in Parkinson's Disease e HR-QoL avaliada utilizando o Parkinson's Disease Questionaire-39 (PDQ-39). O método estatístico de regressão linear foi aplicado para determinar a relação entre a pontuação total das referidas escalas. Secundariamente neste estudo, o perfil dos doentes que decidiram não responder ao MOS-SFS foi investigado e descrito utilizando estatística descritiva.

Serão considerados os dados de todos os indivíduos que completaram a PDQ- 39.

Resultados: Foi observada uma associação significativa entre a função sexual e a HR-QoL: os doentes que apresentaram pior função sexual reportaram uma HR-QoL significativamente pior independentemente da escala utilizada para avaliação da sexualidade. Secundáriamente, foi ainda identificado o perfi de doentes que não respondeu à MOS-SFS: mulheres, doentes mais velhos, de França, Portugal, Espanha e Itália e com menor nível de escolaridade.

Conclusão: Este estudo fornece informação adicional relevante sobre a associação entre função sexual e HR-QoL de pessoas com PD. Foi também identificando um perfil de doentes que pode sentir maior inibição em abordar

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aspetos relacionados com a sua função sexual. Os resultados obtidos reinforçam a importância de abordar estas questões durante a consulta médica contribuindo para uma melhor prática clínica que se poderá traduzir em melhores resultados nestes pessoas.

Abstract

Background: Parkinson’s disease (PD) is a neurodegenerative disease clinically characterized by motor symptoms plus increasingly recognized non-motor manifestations. Sexual dysfunction is a major non-motor feature of PD that may affect the health-related quality of life (HR-QoL) of many people and their interpersonal relationships. However, few studies have addressed this distressing condition. The aim of this study is to explore the association between sexual function and HR-QoL in PD patients.

Methods/study design: This is an exploratory study that analysed real-world data about sexual function and HR-QoL in people with PD collected in the PRISM study: an observational, cross-sectional study, conducted in five European countries (Portugal, Spain, Italy, United Kingdom and Germany). The main endpoint of this work was to investigate the association between sexual function (assessed using the Medical Outcomes Study Sexual Functioning Scale (MOS-SFS), the questions 18 and 19 of the Non-motor Symptom Scale Questionnaire and the question about sexuality of the Questionnaire for Impulsive-Compulsive Disorder in Parkinson’s Disease) and HR-QoL assessed using the Parkinson’s Disease Questionaire-39 (PDQ-39). Linear regression was applied to determine the relationship between the total score of the scales of sexual function and HR-QoL. Secondarily, in this study, the profile of the patients that decided do not respond to the MOS-SFS was investigated and described using descriptive statistics. Data from all the people with PD that completed the PDQ-39 was considered.

Results: It was observed a significant association between sexual function and HR-QoL: subjects presenting worst sexual function reported a significantly worst HR-QoL independently of the scale used in the evaluation of the sexual function.

Secondarly, the group of patients that didn’t answer to the questions about sexuality in the MOS-SFS was also identified: women, older patients, from France, Portugal, Spain and Italy and with a lower level of educational degree.

Conclusion: This study provides additional relevant information to the clinical community about the impact of the sexual functioning on the HR-QoL of people with PD. Additionally, a profile of patients that may need caution in the

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evaluation of this symptoms was highlighted. The observed association between sexual function and HR-QoL underlines the importance of addressing this issue during medical consultation. This may contribute to a better clinical practice allowing improved outcomes in these patients.

Table of Contents

Acknowledgements ... II Resumo...III Abstract ...V Abbreviations ... VIII Index of Tables ... IX Thesis outline ... X Scientific outcomes ... XII

Introduction / Motivation ... 1

Research question and aims ... 2

State of the art ... 3

Material and Methods ... 8

Results ... 13

Discussion ... 33

Conclusions ... 40

Future work ... 41

References ... 43

Attachments ... 46

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Abbreviations

ADL BOD CI COG COM EMO HR-QoL IBM SPSS MOB MOS-SFS

Activities of Daily Living domain Bodily Discomfort domain Confidence Interval Cognition domain Communication domain Emotional Well-Being domain Health Related Quality of Life

IBM Statistical Package for the Social Sciences Mobility domain

Medical Outcomes Study Sexual Functioning Scale

NMSQuest Non-motor Symptom Scale Questionnaire

PD Parkinson’s Disease

PDQ-39 Parkinson’s Disease Questionnaire-39 items

QUIP Questionnaire for Impulsive-Compulsive Disorder in

Parkinson’s Disease SD

SOC STI

Standard Deviation Social Support domain Stigma domain

Index of Tables

Table 1 Demographic characteristics of the patients included (patients that answered PDQ-39) ... 14 Table 2 - Univariate analysis ... 15 Table 3 - Association between the MOS-SFS total score and the PDQ-39 total score ... 16 Table 4 - Association between the MOS-SFS total score and the PDQ-39 individual domains score ... 18 Table 5 - Association between sexual function evaluated in the QUIP and the PDQ-39 total score ... 20 Table 6 – Association between sexual function evaluated in the QUIP and the PDQ-39 individual domains score ... 22 Table 7 – Association between Question 18 of NMSQuest and the PDQ-39 total score ... 24 Table 8 – Association between Question 19 of NMSQuest and the PDQ-39 total score ... 24 Table 9 – Association between answer to the Question 18 of NMSQuest and the PDQ-39 individual domains score ... 26 Table 10 – Association between answer to the Question 18 of NMSQuest and the PDQ-39 individual domains score ... 29 Table 11 – Characterisation of the population that did not answer to the MOS- SFS ... 32

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Thesis outline

1. Introduction / Motivation

In this section, it is presented a brief overview of Parkinson’s Disease and a contextualization of the non-motor symptoms (namely sexual dysfunction) in people suffering from this disease. Additionally, an explanation regarding the relevance of the present work can be found.

2. Research question and aims

The research question, as well as the primary and secondary endpoints are presented in this section.

3. State of the art

This section is subdivided into topics giving the context to the work developed. It starts presenting Parkinson’s Disease main symptoms and diagnosis criteria. After, a special focus on the impact of the disease on sexual function and its importance for the HR-QoL of patients are addressed. Since the information collected using some scales will be analysed in this work, a brief explanation of each of the used scales can be also found in this section. Finally, a comment about the already existing studies on this field and the relevance of this work is presented.

4. Material and Methods

This section is subdivided in different sub-sections. It starts describing the type of research study followed by the description of the patients recruiting methods and the presentation of the eligibility criteria. After, sample size and data collection methods are presented. Finally, the analysed variables in the primary and secondary aims are described.

5. Results

This section presents the detailed results obtained after applying the statistical methods to achieve the proposed aims.

6. Discussion

In the discussion section, a reflection on the results is made, as well as a contextualization of them considering previous work. Additionally, the limitations of the present study are explored here.

7. Conclusions and recommendations

This section summarizes the main results found in this work presenting the answer to the research question.

8. Future work

Additional relevant work on the analysed topic is suggested in this section.

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Scientific outcomes

The expected main outcomes of this study will be the:

• publication of an original manuscript in a peer-reviewed international journal in the Neurology field, and

• presentation of this work in the European Congress of Neurology 2023.

During the period of the current work, I also had the opportunity to collaborate in a sub-analysis related to the subject of this work that was published in an international peer-reviewed journal: Kinateder T, Marinho D, Gruber D, Hatzler L, Ebersbach G, Gandor F. Sexual Dysfunctions in Parkinson's Disease and Their Influence on Partnership-Data of the PRISM Study. Brain Sci. 2022 25;12(2):159.

Additionally, I also collaborated in the development of some abstracts related to opicapone (a medicine used in patients with PD) accepted and presented in the European Congress of Neurology 2021:

• W. Jost, H. Reichmann, A. Lees, D. Marinho, D. Magalhães, J. Rocha, P. Soares-da-silva. Influence of onset of motor fluctuations in the Opicapone effectiveness in Parkinson’s: real-world OPTIPARK study.

2021 European Journal of Neurology, 28 (Suppl. 1), 335–430. EPR-260

• W. Jost, H. Reichmann, A. Lees, D. Marinho, D. Magalhães, J. Rocha, P. Soares-da-silva. Effectiveness of Opicapone in Parkinson’s according to baseline use of entacapone: the real-world OPTIPARK study. 2021 European Journal of Neurology, 28 (Suppl. 1), 335–430. EPR-261

• T. Warnecke, H. Reichmann, A. Lees, D. Marinho, D. Magalhães, J.F.

Rocha, P. Soares-da-silva. Influence of disease duration in the Opicapone effectiveness in Parkinson’s patients: real-world OPTIPARK study. 2021 European Journal of Neurology, 28 (Suppl. 1), 753–921. EPO-746

• W. Jost, H. Reichmann, A. Lees, D. Marinho, D. Magalhães, J. Rocha, P. Soares-da-silva. Effectiveness of Opicapone in Parkinson’s according to baseline use of dopamine agonists: the real-world OPTIPARK study.

2021 European Journal of Neurology, 28 (Suppl. 1), 753–921. EPO-747

1. Introduction / Motivation

Parkinson’s disease (PD) is a neurodegenerative disease being considered the most common neurodegenerative movement disorder, with an estimated prevalence and incidence, in Europe, of approximately 108–257/100 000 people and 11–19/100 000 people per year, respectively.¹ This is a heterogeneous disorder that encompasses both motor and non-motor symptoms.¹ In fact, although PD is historically defined as a movement disorder, non motor symptoms are an important aspect of the clinical picture.¹ The spectrum of these symptoms is broad and includes sexual dysfunction.¹ This is a major and common non motor feature of PD that may affect the quality of life of many patients, men and women, and their interpersonal relationships.^2,3 Data from epidemiological studies show that the decrease in libido or lack of desire for sexual activity in women with PD ranges from 46.9 to 84% and in men with PD between 27% and 83%.³ However, from the clinicians’ perspective, examination of a patient’s sexual life is often neglected during the clinical interview.^4,5 Likewise, for many people talking about intimate relations is considered uncomfortable.⁶ Notwithstanding, studies addressing this distressing aspect of autonomic function in PD are sparse ² and the most commonly used tools to evaluate non motor symptoms and health-related quality of life (HR-QoL) in people with PD contain either a few or no items related to sexual function.^4,7 By further analysing data from a subset of patients from the PRISM study (Parkinson’s Real-world Impact assesSMent study)⁸, the present work aims to evaluate the association between sexual function and the HR-QoL of people with PD. Since the questions related to sexual functioning were considered more sensitive and the completion of the questionnaire used to adress sexual functioning was optional in the PRISM survey (see Annex 1), secondarily on this study we also explored the profile of patients that tend to be less responsive to these questions. We consider that the analysis and interpretation of data collected from real-world experiences of people with PD can contribute to improving the clinical practice and thus optimising the HR-QoL of people with PD and their caregivers.

Research question and aims 2

2. Research question and aims

This thesis research question was:

In patients with Parkinson’s Disease, is there any association between sexual function and health-related quality of life?

P – Patients with Parkinson’s Disease I - impaired sexual functioning C - unimpaired sexual functioning

O - health-related quality of life assessed using the Parkinson’s Disease Questionaire-39

Primary aim:

To investigate if there is an association between the patients’ sexual function (assessed using the Sexual Problems Measures Survey, the questions 18 and 19 of the Non-Motor Symptoms Questionnaire and the question addressing sexual function presented in the Questionnaire for Impulsive-Compulsive Disorder in Parkinson’s Disease) and HR-QoL (assessed using the Parkinson’s Disease Questionaire-39)

Secondary aim:

To characterise the profile of the patients that decided not to answer the Sexual Problems Measures Survey: age, gender, country, number of comorbidities, educational level, disease duration and HR-QoL (assessed using the Parkinson’s Disease Questionaire-39)

3. State of the art

Parkinson’s Disease

PD is a condition involving the prominent death of dopaminergic neurons in the substantia nigra pars compacta (located in the basal ganglia in the central nervous system).⁹ Dopamine is one of the neurotransmitters most widely implicated in motor control and its resultant deficiency plays an important role in the pathophysiology of PD.⁹ Dopamine deficiency within the basal ganglia leads to a neurodegenerative movement disorder characterized by classic parkinsonian motor symptoms – PD. Other neurotransmitters can also contribute to the disease like acetylcholine and glutamate. In PD, excitatory acetylcholine activity is not counteracted by inhibitory dopamine activity, so movement is disrupted.¹⁰ In the same way, the increased glutamatergic activity in various regions of the brain may contribute to movement disorders, like PD.¹¹

There is a well-described clinical and pathological phenotype of PD.^9,12 PD is clinically characterized by changes in motor function, namely bradykinesia, resting tremor and/or rigidity, and postural instability, plus increasingly recognized non-motor manifestations.^{9, 12}

The clinical criterium for PD is the development of bradykinesia: slowness of initiation of voluntary movement with a progressive reduction in the speed and amplitude of repetitive actions.¹² Tremor, which is often present as the initial symptom is the most well-known feature. It is usually unilateral, and it is classically described as ‘pill-rolling’ (pronation/supination). Tremor is present in most patients but not in all of them.¹² Rigidity is an increase in muscle tone or amplified resistance to a passive range of motion.¹² A fourth clinical feature that usually occurs later in the course of PD is postural instability, which is a notable

State of the art 4 decline in or loss of the ability to maintain an upright posture, leading to impaired balance.¹²

Although the main clinical focus in PD for many years has been on motor symptoms, there is increasing emphasis on the importance of non motor symptoms. The presence of non motor symptoms contributes toward a definitive diagnosis of PD and they are indicative of the pre-motor or prodromal phase of the disease.² A “prodrome” is an early sign or symptom that suggests the onset of a disease before more diagnostically specific signs and symptoms develop.

Studies have identified several prodromal markers that potentially predict the conversion from a healthy brain to clinical PD.¹³ The non motor symptoms are also a significant cause of disability and poor HR-QoL for patients with PD.² These symptoms encompass sensory abnormalities, behavioral changes, sleep disturbances, autonomic dysfunction, and some more difficult to categorize symptoms such as fatigue. Autonomic dysfunction includes many symptoms, being sexual dysfunction one of them. Sexual dysfunction is common in both men and women with PD, but studies addressing this distressing aspect of autonomic function in PD are sparse.²

Risk factors for Parkinson’s disease

Although PD is primarily a disease of elderly people, it can develop in individuals aged <50 years¹⁴ being early onset defined as PD occurring in individuals under 40 years of age.⁹ There is an incidence ratio men/women of 3:2⁹, with delayed onset in women possibly due to the potential neuroprotective effects of estrogen on the nigrostriatal dopaminergic system.¹⁵ Women with PD report less sexual desire, but men with PD showed more sexual dysfunction and dissatisfaction with their sex life compared to women.³

The variable prevalence of PD throughout the world suggests that environmental, genetic factors and ethnic differences play a role in the disease pathogenesis.⁹ Environmental risk factors for PD include pesticide and solvent exposure, prior head injury, rural living, β-blocker use, agricultural occupation, and drinking well water.⁹ The role of genetics in PD is illustrated by an increased risk of the disease in individuals with a family history of PD or tremor. Advances in genetic studies during the past decade have led to the identification of dozens of potential gene loci involved in the development of PD.⁹

Sexual dysfunction in Parkinson’s Disease

Sexual health is a fundamental aspect that contributes to an individual’s quality of life and is a right of every person to have individual control over sexual and reproductive behaviour with adequate information and treatment.^3,16

The neuroanatomic and physiologic aspects are essential for controlling sexual behaviours. For correct sexual functioning, the roles of the autonomous, sensory and motor systems must be interconnected, with an intrinsic interdependence between the neurological, vascular, and endocrine systems.³ Indeed it is described that chronic diseases have an impact on sexual functioning.¹⁷

In general, sexual dysfunction can affect people with PD in two different and opposite ways: decrease or increase in sexual behaviors.³ On one side, hypothalamic dysfunction is mostly responsible for the sexual dysfunction (decrease in libido and erection) in PD, via altered dopamine-oxytocin pathways, which normally promote libido and erection.¹⁸ On another side, other factors like the use of dopamine agonists (a class of drugs frequently prescribed in the treatment of PD) may be associated with an enhanced sexual response leading to compulsive sexual behaviour (an impulse control disorder).³

State of the art 6 When evaluating sexual disfunction in PD it is also important to consider some variables due to their possible influence such as age, personal relationships, disease stage, sleep disorders, drug therapy and some psychiatric disorders namely depression and anxiety. Epidemiological studies have shown that the most important factor in the development of sexual dysfunction is aging.

Depressive symptoms and their pharmacologic treatment are factors that should be taken into account when assessing sexual function in PD as potential etiologic variables.¹⁹ Depression and anxiety are disorders that affect both each other and sexual functions. They have been shown to be related to sexual disfunction in the general population but even more in people with PD.²⁰ A considered level of frustration and treatment-seeking is reported from people presenting sexual compulsion, as well as those who suffer from erectile dysfunction, limited performance sexual, and inability to achieve orgasm.

Considering this, although motor manifestations have more attention from physicians and patients and are the basis for the diagnosis of PD, non motor symptoms (like sexual dysfunction) deserve to be highlighted as much as motor problems because of their strong presence and discomfort in patients, causing impairment in HR-QoL.³

Scales to measure sexual dysfunction and quality of life

The most commonly used tools to evaluate non-motor symptoms, as well as HR- QoL, in PD, contain either a few or no items related to sexual function.¹⁸ The Parkinson’s Disease Questionnaire (PDQ-39) is a PD-specific questionnaire that assesses general health status and informs on quality of life (see Annex 1). It comprises 39 items and 8 scales addressing different dimensions of PD (Mobility, Activities of daily living, Emotional well-being, Stigma, Social support, Cognition, Communication and Bodily discomfort). The questions relate to how

the patient has functioned or been feeling during the last month and include questions about daily activities and mental health. It is proven by validation and feasibility studies and it is available in several language versions.²¹

Sexual function can be measured by the Medical Outcomes Study Sexual Functioning Scale (MOS-SFS) (see Annex 2). This scale covers Section 7 of the Medical Outcomes Study survey, which focuses on relationships with family.

This survey covers three aspects regardless of the sex of the patients and includes one specific question for males and another specific question for females. This questionnaire was not designed specifically for PD patients.²²

Relevant topics about sexual function can be also found in the Non-motor Symptom Questionnaire (NMS-Quest)²³ and in the Questionnaire for Impulsive- Compulsive Disorder in Parkinson's Disease-Rating Scale (QUIP).²⁴

The NMSQuest (see Annex 3) is a patient-based screening tool designed to draw attention to the presence of non motor symptoms (including sexual function) in patients for further investigation or treatment. It was not designed to assess the severity of symptoms or measure the effect of treatment.²³

The QUIP (see Annex 4) is a global screening instrument developed and validated to assess impulsive compulsive disorders and related diseases. Patients are asked whether they, or others close to them, thought that they had problems related to gambling, hypersexuality, buying too much, eating too much, taking too much PD medication, or spending too much time on hobbies (‘hobbyism’).²⁴

Materials and Methods 8

4. Material and Methods

Type of study

This is a cross-sectional study that explores data about sexual function and HR- QoL in PD patients collected in the PRISM study⁷: a European study that included a survey designed by an international scientific committee in collaboration with The Cure Parkinson’s Trust (a United Kingdom-based research-driven charity) to evaluate medication use, HR-QoL and the use of healthcare resources by people with PD and their caregivers (see Annex 5).

Selection of participants

This study involves data from PD patients collected in the PRISM study⁷. In the PRISM study, people with PD and their caregivers were recruited with the help of PD advocacy groups in 5 European countries: Portugal, Spain, Italy, the United Kingdom and Germany. Such advocacy groups maintain online networks of people with PD, through regular newsletters, online forums and social media.

In each country, recruitment was made using email and social media campaigns.

Additionally, in Portugal, Spain and the United Kingdom leaflets were provided at patient advocacy group events, and specialist PD clinics in Spain were also used to make the survey available.

In the PRISM study, participation in the online survey was voluntary and it was not possible to actively screen for a patient sample that was considered representative of the whole PD population. A convenience sampling method was used. No other eligibility criteria were applied.

All participants were informed before entering the survey that all information would be treated confidentially and stored securely, as required by General Data

Protection Regulation. Healthcare professionals had no direct role in recruitment.

For the primary aim patients with missing answers to the PDQ-39 were not included, as a total score could not be calculated for these patients. For the secondary aim, all the patients were included.

Sample size

PRISM study was an exploratory analysis and target sample recruitment was not based on achieving a given level of statistical power. Recruitment efforts were made to reach the maximum number of people with PD in each of the included countries, with a target of 100 responses per country. In the present work, the sample size calculation was not done because this is a sub-analysis of data from a larger study.

Data collection methods

Data that was considered in this sub-analysis were collected using an online questionnaire. The questionnaire comprised two main sections: the first was completed from the perspective of the people with PD, either by themselves or with the help of their caregivers, and the second was completed by the primary caregiver. Data were collected between 11 April 2019 and 31 July 2019.

For people with PD, socio-demographic data and information on co-morbidities, impact of the disease on HR-QoL, family relationships, sexual relationships and impulse control behaviour were obtained using structured questionnaires.

For the purpose of this analysis, we considered the collected data regarding HR- QoL (assessed using the PDQ-39), sexual functioning (assessed using the MOS- SFS, questions 18 and 19 of NMSQuest and the QUIP question about sexuality)

Materials and Methods 10 and socio-demographic data. Information about demographics was collected without specific tools/questionnaires.

Variables

Primary aim:

• Parkinson’s Disease Quality of Life Questionnaire (PDQ-39) total score and individual domains total score

o PDQ-39 is comprised of 39 questions that are divided in 8 domains. For each of these questions patients should select one of the following options: Never, Occasionally, Sometimes, Often or Always. For this study, it was also calculated the total score of each patient in the PDQ-39. The total score was the mean of the sum of all the domain scores. For the domain scores calculation, it was assumed a score for each question considering the answer selected by the patient:

Never=0 points; Occasionally=25; Sometimes=50;

Often=75; Always=100. A higher score in the PDQ-39 total score may indicate worse HR-QoL.

• Medical Outcomes Study Sexual Functioning Scale (MOS-SFS) total score

o MOS-SF is comprised of 5 questions: 3 of these questions should be answered by female and male patients and 2 of the questions are gender specific (one for male patients and another for female patients). For each of these questions, patients should select one of the following options: Not a problem, Little of a problem, Somewhat a problem or Very much a problem. The total score was the mean of the sum of all the

individual question scores. The score of each question was calculated considering the answer selected by the patient:

Not a problem=0; Little a problem=33.3; Somewhat a problem=66.6; Very much a problem=100

• Non-Motor Symptoms Questionnaire (NMSQuest) – question 18 (Feeling less interested in sex or more interested in sex) and question 19 (Finding it difficult to have sex when you try)

• Questionnaire for Impulsive-Compulsive Disorder in Parkinson’s Disease (QUIP) – question about sexual behaviour

Secondary aim:

o Demographic characteristics: gender, age, number of comorbidities, educational degree, country, time since diagnosis and HR-QoL (using PDQ-39 total score)

Statistical analysis

Categorical variables were described as absolute frequencies (n) and relative frequencies (%). Median and percentiles were used for non-normal continuous variables or mean and standard deviation for continuous variables with normal distribution.

When testing a hypothesis about continuous variables, nonparametric tests were used as appropriate, taking into account normality assumptions and the number of groups compared. When testing a hypothesis about categorical variables a chi-square test and Fisher’s exact test were used, as appropriate.

Linear regression was applied to determine the relationship between MOS- SFS total score and PDQ-39 total score, adjusted for other patients’

Materials and Methods 12 characteristics with clinical or statistical significance (number of comorbidities, age, gender, and time since diagnosis). Additionally, studies have shown that depression and anxiety are important predictors of poor HR-QoL in PD^25,26. However, these two variables were not included in the model since information about depression and anxiety is already reported in the dependent variable (question 17 and 21 of the PDQ-39). For the modelling, it was applied the ENTER selection method. Coefficient regression (beta) and 95% confidence intervals (95% CI) were presented. An equal method was applied to test the relationship between MOS-SFS and the total score of each PDQ-39 domain.

For the analysis of the association between the answer to the questions 18 and 19 of the NMSQuest and both the PDQ-39 total score and PDQ-39 domains total score the same method was applied, as well as for the association between the QUIP question about sexuality and PDQ-39 total score and PDQ-39 domains total score.

For comparisons, results were considered statistically significant for a p-value

≤ 0.05.

Statistical analyses were performed with IBM SPSS Statistics 27.

5. Results

5.1. Study population characteristics

A total of 861 PD patients were enrolled in the PRISM study. Of these, 859 completed the PDQ-39. The median PDQ-39 summary score was 29.1 and the median MOS-SFS summary score was 25.0. Considering the group of subjects that answered the PDQ-39 questionnaire, there was observed a similar distribution between both genders and the mean age was 65.0. There were collected answers from patients of all the countries in which the study was conducted (Portugal, Spain, the United Kingdom, France, Italy, and Germany).

In addition to PD, the patients included presented a median of 2 comorbidities and a median of 7 years of disease duration. About 60% of patients reported an educational level below a university degree and 40% reported at least 1 year of university frequency. Table 1 summarizes the characteristics of the patients included in the study.

Results 14

Table 1 Demographic characteristics of the patients included (patients that answered PDQ-39) n 859

Missings 2

PDQ-39 total score, Median (P25-P75) 29.1 (18.0-43.9)

PDQ-39 Domains, Median (P25-P75) ADL 25.0 (12.5-50.0) BOD 41.7 (25.7-58.3) COG 31.3 (12.5-50.0) COM 25.0 (8.3-41.7) EMO 33.3 (16.7-54.2) MOB 35.0 (15.0-62.5) SOC 16.7 (0.0-33.3)

STI 18.8 (6.3-37.5)

Gender, n (%)^† Male 433 (50.9)

Female 418 (49.1) Age (years), Mean (SD)^‡ 65.0 (10.2)

Country, n (%) France 63 (7.3)

Germany 92 (10.7) Italy 264 (30.7) Portugal 80 (9.3)

Spain 149 (17.3) United Kingdom 213 (24.7) Number of comorbidities, Median

(P25-P75)^# 2 (1-3) Time (years) since diagnosis, Median

(P25-P75) 7.0 (4.0-12.0)

Educational degree, n (%)^♦ Primary or secondary school / vocational level 1 & 2 / trade apprenticeship

170 (20.2)

Secondary school advanced or

vocational level 3 158 (18.8) Further education or training

college below degree level 171 (20.3) Some university 51 (6.1) Completed university degree 190 (22.6)

Post-graduate degree 102 (12.1)

ADL, activities of daily living domain; BOD, bodily discomfort domain; COG, cognition domain; COM, communication domain; EMO, emotional well-being domain; MOB, mobility domain; SD, Standard Deviation; SOC, social support domain; STI, stigma domain.

†information about the gender of 10 patients was not reported; ‡ information about the age of 6 patients was not reported; # information about the number of comorbidities of 2 patients was not reported; ♦ information about the educational degree of 19 patients was not reported

5.2. Variables considered in the model

In addition to the scales that evaluated sexual function, it was considered important to have into account other relevant variables in our model for their possible impact on the HR-QoL of these patients. The results of the univariate analysis are presented in table 2. Since the number of comorbidities, age and time since diagnosis showed a significant effect on the HR-QoL they were included in the model. Regarding to gender, although a significant difference was not found for this variable, it was also included in the model considering that past studies have been shown gender differences in HR-QoL²⁷ in PD patients and so, this variable was considered clinically relevant.

Table 2 - Univariate analysis Dependent

variable Independent

variables Regression coefficient (beta)

95% CI p-value

PDQ-39 total score

Number of

comorbidities 4.797 3.885; 5.710 <0.001

Gender -1.855 -4.322; 0.611 0.140

Age 0.283 0.164; 0.402 <0.001

Time since

diagnosis 0.776 0.580; 0.971 <0.001

Results 16

5.3. Association between MOS-SFS and PDQ-39

PDQ-39 total score

The results for the association between MOS-SFS total score and PDQ-39 total score are presented in table 3. Considering the presented model we can observe that, holding all the other included variables, an increase in the MOS-SFS total score is associated with an increase in the PDQ-39 total score (regression coefficient (beta)=0.092; CI 95% [0.044-0.140]; p<0.001).

Table 3 - Association between the MOS-SFS total score and the PDQ-39 total score Dependent

variable Independent

variables Regression coefficient (beta)

95% CI p-value

PDQ-39 total score

MOS-SFS total

score 0.092 0.044; 0.140 <0.001

Number of

comorbidities 4.646 3.535; 5.938 <0.001

Gender (male) -3.832 -6.978; -0.669 0.018

Age -0.087 -0.261; 0.087 0.326

Time since

diagnosis 0.728 0.466; 0.990 <0.001

R² = 0.217

PDQ-39 individual domains score

After applying a linear regression, considering the presented model, we can observe that holding all the other included variables, an increase in the MOS-SFS total score is associated to a significant increase in the PDQ-39 total score domain activities of daily living (beta=0.111; CI 95% [0.042-0.180]; p<0.001), emotional well-being (beta=0.095; CI 95% [0.028-0.162]; p=0.006), stigma (beta=0.072; CI 95% [0.004-0.140]; p=0.037), social support (beta=0.099; CI 95% [0.046-0.167]; p=0.002), cognition (beta=0.115; CI 95% [0.067-0.189];

p<0.001), communication (beta=0.118 ; CI 95% [0.061-0.190]; p<0.001) and body discomfort (beta=0.091; CI 95% [0.034-0.17]; p=0.012). MOS-SFS did not achieve a significant relation with the domain mobility. Other variables that were included in the model were the number of comorbidities, age, gender, and time since diagnosis. The results can be found in table 4.

Results 18

Table 4 - Association between the MOS-SFS total score and the PDQ-39 individual domains score Dependent

variable Independent variables Regression coefficient (beta)

95% CI p-value

Activities of daily

living MOS-SFS total score 0.111 0.042; 0.180 <0.001

Number of

comorbidities 5.480 3.619; 7.341 <0.001

Gender (male) 3.386 -1.156; 7.928 8.287

Age 0.015 -0.235; 0.266 0.343

Time since diagnosis 1.126 0.749; 1.503 <0.001 R²=0.198

Emotional well-

being MOS-SFS total score 0.095 0.028; 0.162 0.006

Number of

comorbidities 6.260 4.454; 8.065 <0.001

Gender (male) -9.479 -13.886; -5.071 <0.001

Age -0.167 -0.410; 0.076 0.178

Time since diagnosis 0.402 0.037; 0.768 0.031

R²=0.175

Stigma MOS-SFS total score 0.072 0.004; 0.140 0.037

Number of

comorbidities 2.361 0.491; 4.142 0.013

Gender (male) -2.266 -6.722; 2.189 0.318

Age -0.245 -0.491; 0.001 0.052

Time since diagnosis 0.169 -0.200; 0.539 0.369

R²=0.039

Social support MOS-SFS total score 0.099 0.046; 0.167 0.002

Number of

comorbidities 2.844 0.976; 4.302 <0.001

Gender (male) -7.740 -11.836; -3.749 <0.001

Age -0.396 -0.58; -0.123 <0.001

Time since diagnosis 0.124 -0.609; 0.858 0.007

R²=0.119

Cognition MOS-SFS total score 0.115 0.067; 0.189 <0.001 Number of

comorbidities 5.707 3.968; 7.330 <0.001

Gender (male) 0.325 -4.053; 4.124 0.876

Age 0.048 -0.149; 0.291 0.679

Time since diagnosis 0.713 -0.771; 0.713 <0.001 R²=0.189

Communication MOS-SFS total score 0.118 0.061; 0.190 <0.001

Number of

comorbidities 3.747 1.740; 5.288 <0.001

Gender (male) 3.538 -0.742; 7.884 0.106

Age -0.205 -0.395; 0.069 0.090

Time since diagnosis 0.914 -0.692; 0.873 <0.001 R²=0.147

Body discomfort MOS-SFS total score 0.091 0.034, 0.171 0.012

Number of

comorbidities 4.035 2.158; 5.941 <0.001

Gender (male) -11.859 -16.670; -7.470 <0.001

Age -0.181 -0.394; 0.101 0.169

Time since diagnosis 0.544 -0.926; 0.743 0.006

R²=0.130

Mobility MOS-SFS total score 0.035 -0.017; 0.139 0.362

Number of

comorbidities 6.778 4.245; 8.537 <0.001

Gender (male) -6.490 -11.342; -0.906 0.011

Age 0.435 0.268; 0.829 0.002

Time since diagnosis 1.495 -2.093; -0.200 <0.001 R²=0.258

Results 20

5.3. Association between the question about sexuality (compulsive urges) of the QUIP and PDQ-39

PDQ-39 total score

Considering the presented model we can observe that, holding all the other included variables, patients that reported compulsive urges in the QUIP showed a significant increase in the PDQ-39 total score (beta=5.048; CI 95% [2.464- 11.234]; p<0.023). Table 5 presents the main results found for this association.

Table 5 - Association between sexual function evaluated in the QUIP and the PDQ-39 total score

Dependent variable Independent

variables Regression

coefficient (beta)

95% CI p-value

PDQ-39 total score

QUIP - sexual

compulsive urges 5.048 2.464; 11.234 0.023

Number of

comorbidities 4.781 3.440; 5.708 <0.001

Gender (male) -2.516 -5.199; 0.510 0.076

Age 0.155 0.086; 0.375 0.038

Time since diagnosis 0.789 -0.938; 0.079 <0.001 R² = 0.220

PDQ-39 individual domains score

In the analysis of the association between the answers about having a compulsive sexual behaviour (evaluated in the QUIP) and the PDQ-39 domains total score it was observed that considering the presented model, holding all the other included variables, patients that reported compulsive urges in the QUIP showed a significant increase in the PDQ-39 total score for the domain emotional well- being (beta=8.257; CI 95% [2.264- 14.251]; p=0.007), social support (beta=7.940; CI 95% [2.529-13.351]; p=0.004) and cognition (beta=8.161; CI 95% [2.666-13.655]; p=0.004). The domains that did not achieve a significant difference for this association were the activities of daily living, stigma, communication, body discomfort and mobility. The results can be found in table 6.

Results 22

Table 6 – Association between sexual function evaluated in the QUIP and the PDQ-39 individual domains score

Dependent variable Independent variables Regression coefficient (beta)

CI 95% p-value

Activities of daily

living QUIP – compulsive

sexual behaviour 0.999 -2.107; 10.913 0.757

Number of comorbidities 5.764 3.389; 6.757 <0.001

Gender (male) 5.254 1.021; 9.497 0.039

Age 0.495 0.426; 0.854 <0.001

Time since diagnosis 1.380 -1.559; -0.049 <0.001 R²=0.259

Emotional well-being QUIP – compulsive

sexual behaviour 8.257 2.264; 14.251 0.007

Number of comorbidities 6.096 4.565; 7.627 <0.001 Gender (male) -7.552 -11.368; -3.736 <0.001

Age 0.038 -0.162; 0.238 0.238

Time since diagnosis 0.298 -0.009; 0.605 0.057 R²=0.142

Stigma QUIP – compulsive

sexual behaviour 0.907 -4.916; 6.729 0.760

Number of comorbidities 1.915 0.428; 3.402 0.012

Gender (male) -1.966 -5.673; 1.742 0.298

Age -0.073 -0.267; 0.122 0.463

Time since diagnosis 0.318 0.020; 0.617 0.037 R²=0.021

Social support QUIP – compulsive

sexual behaviour 7.940 2.529; 13.351 0.004

Number of comorbidities 3.231 1.8491; 4.613 <0.001 Gender (male) -6.696 -10.142; -3.250 <0.001

Age -0.340 -0.521; -0.159 <0.001

Time since diagnosis 0.526 0.249; 0.804 <0.001 R²=0.103

Cognition QUIP – compulsive

sexual behaviour 8.161 2.666; 13.655 0.004

Number of comorbidities 6.051 4.648; 7.455 <0.001

Gender (male) 2.745 -0.754; 6.244 0.124

Age 0.263 0.080; 0.447 0.005

Time since diagnosis 0.745 0.463; 1.026 <0.001 R²=0.214

Communication QUIP – compulsive

sexual behaviour 4.400 1.244; 13.044 0.145

Number of comorbidities 4.399 2.591; 5.643 <0.001

Gender (male) 3.807 0.416; 8.099 0.048

Age 0.056 -0.041; 0.348 0.577

Time since diagnosis 0.993 -1.076; 0.293 <0.001 R²=0.148

Body discomfort QUIP – compulsive

sexual behaviour 5.695 -0.291; 11.680 0.062

Number of comorbidities 4.175 2.646; 5.704 <0.001 Gender (male) -9.976 -13.788; -6.164 <0.001

Age 0.066 -0.134; 0.266 0.514

Time since diagnosis 0.548 0.241; 0.855 <0.001 R²=0.118

Mobility QUIP – compulsive

sexual behaviour 4.024 -2.654; 10.703 0.237

Number of comorbidities 6.617 4.912; 8.323 <0.001

Gender (male) -4.745 -8.998; -0.492 0.029

Age 0.733 0.509; 0.956 <0.001

Time since diagnosis 1.505 1.162; 1.847 <0.001 R²=0.302

Results 24

5.4. Association between questions 18 and 19 of NMSQuest and PDQ-39

PDQ-39 total score

The results for the association between questions 18 (Feeling less interested in sex or more interested in sex) and 19 (Finding it difficult to have sex when you try) of NMSQuest and PDQ-39 total score are presented in table 7 and 8 respectively. Considering the presented model, we can observe that, holding all the other included variables, patients that answered “yes” in the question 18 (beta=7.669; CI 95%

[4.992; 10.346]; p<0.001) and 19 (beta=4.542; CI 95% [1.604; 7.480]; p<0.003) showed a significant increase in the PDQ-39 total score.

Table 7 – Association between Question 18 of NMSQuest and the PDQ-39 total score Dependent variable Independent variables Regression

coefficient (beta)

95% CI p-value

PDQ-39 total score

Question 18 NMSQuest (Yes) 7.669 4.992; 10.346 <0.001

Number of comorbidities 4.354 3.264; 5.444 <0.001

Gender (male) -2.906 -5.564; -0.248 0.032

Age 0.196 0.052; 0.332 0.007

Time since diagnosis 0.717 0.502; 0.932 <0.001

R² = 0.247

Table 8 – Association between Question 19 of NMSQuest and the PDQ-39 total score Dependent variable Independent variables Regression

coefficient (beta)

95% CI p-value

PDQ-39 total score

Question 19 NMSQuest (Yes) 4.542 1.604; 7.480 0.003

Number of comorbidities 4.378 3.248; 5.508 <0.001

Gender (male) -3.296 -6.160; -0.431 0.024

Age 0.155 0.012; 0.299 0.034

Time since diagnosis 0.757 0.538; 0.976 <0.001

PDQ-39 individual domains score

Question 18: Feeling less interested in sex or more interested in sex In the analysis of the association between the answers to question 18 of NMSQuest and the PDQ-39 domains total score it was observed that, considering the presented model, holding all the other included variables, patients that answered “yes” in the question 18 showed a significant increase in all the PDQ-39 domains total score: activities of daily living (beta=6.673; CI 95%

[2.760; 10.586]; p<0.001), emotional well-being (beta=10.830; CI 95% [7.153;

14.508]; p<0.001), stigma (beta=8.493; CI 95% [4.912; 12.074]; p<0.001), social support (beta=6.360; CI 95% [3.004; 9.716]; p<0.001), cognition (beta=9.605;

CI 95% [6.210; 13.001]; p<0.001), communication (beta=8.604; CI 95% [4.987;

12.222]; p<0.001), body discomfort (beta=5.260; CI 95% [1.551; 8.969];

p=0.006) and mobility (beta=5.524; CI 95% [1.320; 9.728]; p<0.001). The results can be found in table 9.

Results 26

Table 9 – Association between answer to the Question 18 of NMSQuest and the PDQ-39 individual domains score

Dependent variable Independent variables Regression coefficient (beta)

CI 95% p-value

Activities of daily

living Question 18 NMSQuest

(yes) 6.673 2.760; 10.586 <0.001

Number of comorbidities 5.549 3.956; 7.143 <0.001

Gender (male) 3.269 -0.616; 7.154 0.099

Age 0.529 0.325; 0.734 <0.001

Time since diagnosis 1.294 0.980; 1.608 <0.001 R²=0.272

Emotional well-being Question 18 NMSQuest

(yes) 10.830 7.153; 14.508 <0.001

Number of comorbidities 5.422 3.924; 6.920 <0.001

Gender (male) -7.861 -11.512; -

4.210 <0.001

Age 0.093 -0.099; 0.285 0.343

Time since diagnosis 0.222 -0.073; 0.517 0.140

R²=0.172

Stigma Question 18 NMSQuest

(yes) 8.493 4.912; 12.074 <0.001

Number of comorbidities 1.414 -0.045; 2.872 0.057

Gender (male) -3.225 -6.780; 0.330 0.075

Age -0.027 -0.214; 0.160 0.776

Time since diagnosis 0.199 -0.088; 0.486 0.174

R²=0.055

Social support Question 18 NMSQuest

(yes) 6.360 3.004; 9.716 <0.001

Number of comorbidities 2.826 1.459; 4.193 <0.001

Gender (male) -6.121 -9.453; -2.789 <0.001

Age -0.294 -0.469; -0.118 0.001

Time since diagnosis 0.457 0.188; 0.726 <0.001 R²=0.100

Cognition Question 18 NMSQuest

(yes) 9.605 6.210; 13.001 <0.001

Number of comorbidities 5.462 4.079; 6.845 <0.001

Gender (male) 2.789 -0.583; 6.160 0.105

Age 0.307 0.130; 0.485 <0.001

Time since diagnosis 0.665 0.393; 0.938 <0.001 R²=0.237

Communication Question 18 NMSQuest

(yes) 8.604 4.987; 12.222 <0.001

Number of comorbidities 4.050 2.577; 5.524 <0.001

Gender (male) 3.236 -0.355; 6.828 0.077

Age 0.084 -0.106; 0.273 0.386

Time since diagnosis 0.928 0.637; 1.218 <0.001 R²=0.178

Body discomfort Question 18 NMSQuest

(yes) 5.260 1.551; 8.969 0.006

Number of comorbidities 3.810 2.299; 5.321 <0.001

Gender (male) -10.317 -13.999; -

6.634 <0.001

Age 0.076 -0.118; 0.270 0.441

Time since diagnosis 0.498 0.201; 0.796 0.001

R²=0.121

Mobility Question 18 NMSQuest

(yes) 5.524 1.320; 9.728 <0.001

Number of comorbidities 6.296 4.584; 8.009 <0.001

Gender (male) -5.018 -9.192; -0.845 0.050

Age 0.770 0.551; 0.990 <0.001

Time since diagnosis 1.472 1.134; 1.809 0.112

R²=0.302

Results 28

Question 19: Finding it difficult to have sex when you try

In the analysis of the association between the answers to question 19 of NMSQuest and the PDQ-39 domains total score it was observed that, considering the presented model, holding all the other included variables, patients that answered “yes” in the question 19 showed a significant increase in the PDQ-39 total score for the domain activities of daily living (beta=4.779; CI 95% [0.545; 9.013]; p=0.027), emotional well-being (beta=4.075; CI 95% [0.020;

8.130]; p=0.049), stigma (beta=3.968; CI 95% [0.062; 7.874]; p=0.046), social support (beta=6.109; CI 95% [2.490; 9.729]; p<0.001) and cognition (beta=6.661; CI 95% [2.950; 10.372]; p<0.001). The results can be found in table 10.

Table 10 – Association between answer to the Question 18 of NMSQuest and the PDQ-39 individual domains score

Dependent

variable Independent variables Regression coefficient (beta)

CI 95% p-value

Activities of

daily living Question 19 NMSQuest

(yes) 4.779 0.545; 9.013 0.027

Number of

comorbidities 5.487 3.859; 7.116 <0.001

Gender (male) 2.606 -1.521; 6.734 0.215

Age 0.501 0.294; 0.708 <0.001

Time since diagnosis 1.320 1.004; 1.635 <0.001

R²=0.264 Emotional well-

being Question 19 NMSQuest

(yes) 4.075 0.020; 8.130 0.049

Number of

comorbidities 5.586 4.027; 7.145 <0.001

Gender (male) -7.574 -11.527; -3.621 <0.001

Age 0.053 -0.145; 0.251 0.598

Time since diagnosis 0.303 0.000; 0.605 0.050

R²=0.128

Stigma Question 19 NMSQuest

(yes) 3.968 0.062; 7.874 0.046

Number of

comorbidities 1.462 -0.040; 2.964 0.056

Gender (male) -3.286 -7.093; 0.522 0.091

Age -0.054 -0.245; 0.137 0.580

Time since diagnosis 0.253 -0.038; 0.545 0.088

R²=0.024

Social support Question 19 NMSQuest

(yes) 6.109 2.490; 9.729 <0.001

Number of

comorbidities 2.646 1.254; 4.038 <0.001

Gender (male) -7.291 -10.820; -3.762 <0.001

Age -0.323 -0.500; -0.146 <0.001

Time since diagnosis 0.470 0.200; 0.740 <0.001

R²=0.094