Introduction

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. Traditionally characterised by the motor symptoms of bradykinesia, rigidity and tremor,1 there is increasing recognition of additional and highly variable motor and non-motor symptoms affecting the quality of life (QoL).2 The prevalence of PD is predicted to double by 2040 and the increasing symptom burden with disease progression foreshadows the wider societal impact.3 A thorough understanding of its pathomechanisms, its course and most importantly, its impact on the lives of persons with PD (PwPD) and their highly involved caregivers is therefore of the utmost importance.

Degeneration of dopaminergic cells in the substantia nigra is a pathophysiological pillar of PD.4 5 However, aberrant interactions beyond the dopaminergic system and even at the peripheral nervous system also condition symptoms of those affected.6–8 Considerable efforts are being made to identify biomarkers to stratify PD subtypes9–11 but also to predict disease progression.12 Preventing alpha-synuclein deposition6 may alleviate symptoms and, more importantly, also modulate the disease’s course13—a goal that has not yet been achieved.14 15 Otherwise, these recent trials have fuelled debate about whether the focus on alleviating motor symptoms may not reflect the multifaceted nature of PD.6

At advanced stages of the disease, PwPD may experience physical, psychological and cognitive disability, which increases their need for ongoing support. This regularly has a negative impact on their emotional well-being16 and social functioning.17 Loss of autonomy in daily activities, and mobility further contribute to the burden experienced by patients, often relying heavily on caregiver support. This high dependence on caregivers causes distress not only in patients but also in caregivers themselves.18 19 A striking conflict can be observed, with overburdened relatives20 21 trying to maintain care in the home environment for as long as possible.22 Due to the social, psychological, cognitive and physical limitations experienced by PwPD, caregivers may become patients themselves19 23 although there may be protective personality traits such as resiliency. Even though patients and caregivers can be regarded as a ‘unit of care’ overburdened caregivers are often neglected in medical consultations, despite the fact that loss of their own QoL often has a negative impact on patient care24 and is recognised as an independent risk factor for mortality.25 To achieve a comprehensive understanding of patient and caregiver QoL, it is essential to consider the bio-psycho-social aspects of the illness. This approach not only helps to identify disease biomarkers but also enables tailored care, leading to improved patient safety and QoL.26 27 In the future, when exploring disease-modifying treatments, it will be crucial to use appropriate outcome measures that provide a realistic and comprehensive assessment of disease burden beyond motor improvement.28

The discussion on how to measure QoL in PD is gaining momentum. The current WHO definition of QoL as ‘an individual’s perception of his or her position in life in the context of the culture and value systems in which he or she lives and in relation to his or her goals, expectations, norms and concerns’29 exposes fundamental shortcomings of current QoL questionnaires, although they have been used in seminal work to determine therapeutic success in PD.28 A major criticism is that these questionnaires focus on disease-related limitations but are missing possibly beneficial circumstances.30 31 As the existing literature has shown that QoL depends on factors beyond the mere absence of disease symptoms,32 broader measures of QoL in PD have been proposed.

Here, we present the protocol for a longitudinal cohort study over the next two decades. For this long-term study, we aim to closely follow 1000 PwPD and their caregivers, including thorough examinations, collection of various biosamples and questionnaire data over time. In addition to identifying biomarkers that may help elucidate the heterogeneity of the disease, our study is unique in its emphasis on a holistic assessment of QoL (hQoL) which goes beyond common QoL questionnaires by investigating the causality and consequences of subjectively assessed patient and caregiver QoL. The ‘Challenges And Potentials’ (CHAPO) model serves as the basis for this, providing an integrative framework for analysing QoL at three levels: descriptive, evaluative and normative (figure 1). The descriptive level encompasses the examination of life situations and living conditions. The evaluative level focuses on the subjective assessment of QoL. Finally, the normative level explores the standards and norms prevalent in society (figure 1). The assessment of QoL considers the alignment of external factors, such as societal values, with individual values, as well as the harmony between external factors, such as ecological conditions and internal factors, such as personal competencies. Individuals evaluate their own QoL by considering their unique resources, values, and the role and appreciation of later life within society. By adopting the CHAPO model, this study aims to encompass both an objective view of QoL and subjective well-being. The collected data is expected to serve as a foundation point for refining a patient- and family-centred approach to care in PD.

Figure 1

The Challenges And Potentials framework adapted from Wagner et al.37

MethodsStudy design

This prospective observational cohort study was approved by the local ethics committee of the University Hospital of Marburg (study number: 209/19). The statistical rationale is to explore a holistic understanding of QoL, as its characteristics are important anchors for PwPD in their disease-related process of resource loss.33 Given the exploratory nature of this study, with its in-depth phenotyping approach involving the measurement of many psychometric and biological variables, and the high variability to be expected due to a deliberately liberal set of inclusion criteria, we chose a sample size large enough to allow the exploration of multivariate models with many influencing factors. Therefore, we aim to include 1000 PwPD with at least probable idiopathic PD (iPD) according to modern diagnostic criteria at the time of enrolment (https://www.invo.org.uk/wp-content/uploads/2019/04/Copro_Guidance_Feb19.pdf).

Study population

PwPD aged 30–100 years with a clinical diagnosis of at least probable iPD (https://www.invo.org.uk/wp-content/uploads/2019/04/Copro_Guidance_Feb19.pdf) according to two movement disorders specialists may be included. There should be no clinical signs for ‘atypical Parkinsonian syndromes’ at inclusion, whereas later diagnosis of multisystem atrophy,34 progressive supranuclear palsy,35 frontotemporal lobar degeneration or corticobasal syndrome does not imply study exclusion. Patients at Hoehn and Yahr stage 5 will not be included, otherwise, there are no restrictions regarding disease duration, severity of motor or non-motor symptoms, or residential status of PwPD. Further inclusion criteria are the ability to speak and write German and the willingness to comply with the protocol. Exclusion criteria are limited to participants under guardianship or who may not be able to give informed consent prior to enrolment, people with secondary Parkinsonian symptoms (eg, due to antidopaminergic medication or structural brain lesions indicating a Parkinsonian association), severe concomitant neurological conditions or life-limiting diseases such as terminal cancer or patients with chronic renal failure requiring dialysis. In addition to all patients, one caregiver per patient who is identified as such by the patient himself will also be offered the opportunity to participate in this study. Participants will be enrolled over the course of 20 years or until the recruitment target of 1000 participants and associated caregivers has been reached. All patients and caregivers will provide written informed consent prior to participation.

All participants should understand the nature of the study, the potential risks and benefits, and the options available to them. They will be informed of their right to withdraw from the study at any time without any consequences. Informed consent will be obtained through a process of open communication and dialogue between the participant and the researcher. It will be ensured that information is provided in a clear and understandable way, taking into account the participant’s cognitive and communication abilities. Over a follow-up period of 20 years, all enrolled subjects will undergo up to 40 comprehensive assessments (see the Study procedures section and figure 2).

Figure 2

Course of the study for each participant. Examinations are carried out every 6 months, but for ease of reading, the presentation is simplified at this point. QoL, quality of life.

Recruitment and enrolment

The majority of participants will be recruited from the University Hospital Marburg (UHM), where there are around 2000 contacts with PwPD each year. However, in order to represent the true diversity of this population, patients within a reasonable distance from the centre will be able to participate. To this end, anyone interested in the study can contact the study centre directly and, after checking the inclusion and exclusion criteria, be included in the study. In addition, participation in the study will be promoted through the local network of PwPD and caregivers, the Parkinson Network Alliance Marburg (PANAMA) network (see www.panama-marburg.com), as well as through regional PD self-help groups, by making their members aware of the HessenKohorte2042.

Study procedures and assessments

The study spans a 20-year period starting 1 August 2024 and ending on 31 July 2044. It thus provides for a maximum of 40 data collection time points: a baseline visit and 39 consecutive semiannual follow-ups (figure 2) scheduled with a tolerance of ±100 days.

The in-person visits will take place at the UHM. After ensuring that all necessary criteria for inclusion (baseline) or proceeding (follow-ups) are met, questionnaires will be administered at every visit and at the annual visits of patients also biospecimens will be collected and an MRI will be performed.

Questionnaires

A comprehensive list of questionnaires and tests applied can be found in table 1.

Table 1

Psychometric assessments of patients and caregivers as scheduled in the study visits52–64

The backbone of the study will be the examination of QoL. Recent debates suggest that established measurement tools do not capture QoL with a holistic view but focus on the health-related experience of QoL.28 36 Furthermore, it is unclear which factors influence QoL in PD beyond mere symptom burden and how QoL evolves over the course of the disease. The HessenKohorte2042 offers a unique opportunity to capture changes in QoL in a large study population and to gain a comprehensive understanding of this important concept. The study therefore has two aims: (1) to develop and validate an instrument (HQ-PD) to measure hQoL in PwPD and (2) to monitor hQoL and the factors associated with it in PwPD longitudinally.

In order to accomplish the initial objective, a scholarly approach will be employed to develop an instrument that is grounded in evidence, centred around the patient and encourages participation. This instrument draws inspiration from the German NRW80+ study.37 The development process will commence in the first year of the cohort and subsequent validation will be carried out with the cohort from the second year onwards. The NRW80+ study serves as a valuable reference, as it was the first study in Germany to investigate the QoL of older individuals, using the ‘CHAPO’ model37 (figure 2).

To this end, participants will be interviewed about their personal experience of QoL and actively involved in the development process of an instrument to holistically assess QoL in PwPD according to the INVOLVE-guideline (https://www.invo.org.uk/wp-content/uploads/2019/04/Copro_Guidance_Feb19.pdf).

Another pivotal aspect in the HessenKohorte2042 is the analysis of specimens which will be interpreted with respect to disease progression and changes in hQoL. Therefore, samples of blood, urine, saliva and stool, along with hair samples will be collected for metabolomic profiles of every PwPD. Furthermore, MRI scans will also be acquired annually at the UHM 3T scanner (see the MRI scans section). The semiannual follow-ups will be conducted with self-administered questionnaires via an online survey module. For those participants without access to electronic devices, questionnaires will either be distributed on a tablet during the visits or a paper-based version will be made available. In the annual visits, the physician will verify the cognitive state of the participants including the ability to give informed consent for the scheduled examinations. If this cannot be verified, informed consent is sought to be obtained from a legal representative who may or may not be included in the study as a caregiver. Patients are informed about this procedure at the point of inclusion in the study. Data of patients whose proxies do not consent to further follow-up, however, will remain in the database unless they specifically request their deletion. Caregivers will be systematically examined every 6 months to assess multidimensional stress, resilience, symptom perception, positive psychology, quality of care and digital health competence by the self-administered response to questionnaires. See table 1 for a complete schedule of the psychometric assessments in patients and caregivers and the study protocol for a detailed description.

Biosample collection

Trained study nurses will collect the biospecimens and the Comprehensive Biobank Marburg (CBBMR) will perform further pre-analytical procedures and sample storage according to standardised and quality-controlled protocols.

Whole blood samples will be taken for blood count and genetic analyses and CBC will be performed immediately after blood collection. Furthermore, 5 mL blood will be stored for later DNA extraction. For peripheral blood mononuclear cell collection, citrate vials will be processed. For later transcriptomics, a PAXgene (Becton-Dickinson, Heidelberg, Germany) sample will be collected and stored.

Two saliva samples will be collected by using Sarstedt Salivette (Sarstedt, Nümbrecht, Germany) and the Saliva Gene Collector system (Invitak, Berlin, Germany). One is used for metabolomics analyses for PwPD while the other will be used for DNA extraction.

Hair samples have been identified as a useful biospecimen for metabolomic analysis,38 as it appears to be a particularly robust source of stable longitudinal metabolite information, especially due to its lower influence on daily activities and dietary variations. Therefore, we plan to analyse hair metabolomics over time during the course of the study. Furthermore, we will measure levels of cortisol as a biomarker of stress. Data samples will be collected according to a specific protocol which is provided online (https://drks.de/search/de/trial/DRKS00023598) and specifies for example, the collection site, technique and processing.

Urine samples (40 mL of midstream urine) will be collected for biomarker analysis. Pellets will be re-suspended in DNA/RNA Zymo research shields (Biozol, München, Germany) for nucleic acid analysis.

Patients are provided with a stool tool kit for stool sampling. It contains two sampling systems, the OMNIgeneGUT collection kit (DNAgenotek, Ottawa, Canada) and the FTAWhatman card (Merck, Darmstadt, Germany) for later microbiome analysis.

All pseudonymised biospecimens will be stored at the CBBMR, which provides a sample tracking system, sample processing system operating procedures and standardised sample storage conditions.

MRI scans

MRI scans will be scheduled annually over the course of the study on a 3 Tesla MR scanner (Magnetom TrioTim Syngo, Siemens, Erlangen) at the Department for Psychiatry and Psychotherapy of the University Hospital of Marburg, Germany. The MRI protocol includes sequences for structural (T1- and T2-weighted) imaging, diffusion-weighted imaging, resting-state functional MRI with T2*-weighting and neuromelanin-sensitive MRI. MRI will only be offered to those who do not present with contraindications, that is, implanted electrical devices (eg, pacemakers, drug pumps, etc), metal parts in or attached to their body which are not conform with performing an MRI (eg, screws after fractures, intrauterine device) and pregnancy.

Subject retention strategies and quality management

A telephone information service and email contact service will be proactively set up to answer questions about the conduct of the study. As a retention strategy, a subsection of the PANAMA website (www.parkinson-marburg.com) will provide regular recruitment updates. All sub-investigators will be trained and certified to GCP standards, and monthly study team meetings will ensure rigorous control of data entry and removal of drop-outs from the database. In addition, annual interim analyses will be performed to ensure data quality through frequent monitoring and to identify potential systematic and random deviations.

Patient and public involvement

The primary outcome of the study, as well as the proposed model for measuring QoL, were derived from interviews conducted with elderly participants. To identify any potential flaws and drawbacks, a pilot study was conducted with 30 patients using the questionnaire that will be used at the beginning of this study. As previously mentioned, the objective of this study is to validate significant aspects of QoL and make them accessible to individuals with Parkinson’s disease (PwPD). For the dissemination of results, refer to the subsequent sections.

Data processing and statistical analyses

A wide range of psychometric and biological measures will be collected in this study. Questionnaire data will be analysed for main and subscale scores according to the reference manuals. MRI data will be pre-processed using standard pipelines and various structural and functional measures, for example, volumetric values and connectivity, will be obtained. Extracts from blood plasma samples will be measured by gas chromatography coupled to mass spectrometry.39 In addition, scalp hair and saliva samples will be analysed for cortisol concentration by luminescence immunoassay. Finally, 16S rRNA gene sequences will be used for metabolomic profiling of stool and urine samples.40

For the analysis of all these measures, appropriate parametric or non-parametric methods will be used, depending on the level of measurement and the empirical distribution of the data. Linear and, where appropriate, non-linear regression methods will be the main approach for modelling changes in the dependent measures over time. In particular, we will assess the validity of our newly developed hQoL tool by using correlation analyses in a multiscale validation approach. Moderator and mediator analyses will furthermore be used to identify psychometric and biological factors influencing hQoL and motor and non-motor symptoms in PwPD. Multivariate methods such as path analysis, dimensionality reduction, feature generation and selection, and machine learning models for classification and regression will be applied and tested on the psychometric, imaging and metabolomics datasets to derive explanatory models and surrogate biomarker signatures for hQoL.

Ethics and disseminationPatient safety considerations

Participation in this study may involve physical, psychological and time challenges and risks for participants and their caregivers. The physical risks that may occur are minor and mostly related to the collection of biospecimens. For example, there are risks associated with taking blood samples, such as bleeding and infection, or risks associated with MRI scans, such as the occurrence of tinnitus or tissue heating due to the presence of metal artefacts in the body. The psychological risks of taking part in this study are mainly due to exposure to the disease and the long time frame of the study. Although participation in the study only requires a biannual examination and answering of questions, there is also a potential time commitment. Providing adequate and transparent information about these risks is a high priority to ensure that participants are able to give informed consent at all times.

Data safety considerations

The safety of patient and caregiver data will be protected by following a formal data protection protocol which includes a risk analysis as well as a role concept that restricts data access according to different responsibilities within the study (see the Data management and protection of subject privacy section).

Dissemination

The results of this study will be disseminated through peer-reviewed open access publications and presented at relevant scientific conferences. In addition, all participants will be invited to an annual meeting to provide general and new information about the HessenKohorte2042. It is expected that this study and subsequent findings will generate widespread media interest and thus media recognition for the general public. Furthermore, the key element of all communication and dissemination activities to the interested public regarding all activities within the scope of this study will be accessible via the project’s own website. Here, PwPD and their caregivers can also access information and follow the latest developments at any time.

Data management and protection of subject privacy

The survey data and associated biomaterials will be stored in pseudonymised form on a departmental server. Once a participant has been enrolled, his or her personally identifiable information will be stored separately in a key list to which only the principal investigator has access. Each participant will be assigned a unique pseudonym (ID) and, in the case of online access, a unique password. The ID and password will be given to the participant and will also be stored electronically in an electronic data capture and management system.

The according server is located at the UHM with appropriate access restrictions to ensure that only authorised study staff members have access to the data. In the case of direct electronic data collection, that is, without prior collection on paper and subsequent transfer to an electronic representation, individual access codes allow participants to log in to the electronic data collection and management system to complete the relevant questionnaires. In order to control and ensure that participants complete the intended questionnaires and do so only once, an automatic allocation will be used for each required questionnaire. This mechanism is triggered during the initial submission of the participant’s credentials and can be retriggered by the study staff as required during the course of the study. All assessment and biomarker data beyond the biannual questionnaires will also be stored under the assigned pseudonym. The completeness and content of the data will be checked by the study personnel and, in case of irregularities, by the entire study team. In addition, the data will be subject to an annual interim analysis.

Backups will be stored locally at a separate location. Data collection from biospecimens will be carried out according to written standardised operating procedures, which are closely based on those already published in other biospecimen studies.39 41–43 Data will be retained for 10 years after the end of the study, unless participants withdraw their consent for further use.

Discussion

Here we propose a cohort study of a large group of patients in a representative region of Germany which uses neurobiological, psychometrical and biosample data to assess pathomechanisms related to PD and especially how hQoL evolves over time in those affected by the disease, patients and caregivers alike.

Cohort studies, with their longitudinal design, provide an excellent means of studying the progression of a disease and understanding its natural history and associated variables. In PD, the extensive burden on the patient-caregiver-dyad has been convincingly demonstrated by predominantly cross-sectional study designs.16 18 Previous studies with long-term follow-up have been instrumental in understanding the progression of motor and non-motor symptoms in PwPD.44–46 However, understanding how well-being in PD evolves over time and what factors contribute to change or stability remains relatively unexplored. In this context, the HessenKohorte2042 provides a unique opportunity to explore the complex dynamics of holistic QoL in PwPD and their caregivers. Through this structured and interconnected network, we have the opportunity to follow a large number of participants longitudinally, to better understand the complexity of their experiences and to shed light on the determinants of a key aspect of health, QoL, over the course of a neurodegenerative disease.

Perceptions of QoL are central to the experience of PD across the care continuum, but there are important challenges in trying to grasp this construct. It is clear that disease-specific scales have greater sensitivity to detect change over time,47 but there is increasing evidence that PwPD do not perceive QoL solely in direct relation to the physical experience of the disease.28 Failure to recognise this may not only lead to inaccurate conclusions about the well-being of PwPD, but may also overlook important factors influencing QoL. We will therefore exploit the potential of the Hessenkohorte2042 to promote a holistic understanding of QoL in PwPD by establishing a rigorous measurement tool (HQ-PD), but also by exploring associated bio-psycho-social variables, including a wealth of known and potential markers of disease progression. In particular, we are using MRI scans to identify imaging morphological correlates (eg, to examine the progression of regional brain atrophy) and we are investigating the associations of biospecimen analyses (eg, to assess changes in metabolite levels) with hQoL and disease progression. Together with clinical and survey data, this will allow the dynamic capture of a variety of phenotypes in a real population of PwPD. We envisage that our results will be used to monitor disease progression and allow early detection of changes in well-being and/or disease manifestation. With this approach, the relationship between hQoL and motor and non-motor symptoms and the holistic effects of treatment strategies can be sufficiently objectified.24 48 49

Such benchmarking is unprecedented compared with other large cohort studies50 51 in that a bio-psycho-social concept of the disease and its impact on QoL can be studied over the long term. Through extensive scientific monitoring of PwPD, we expect to identify factors that correlate with the self-reported holistic well-being of patients and their caregivers. These results may not only provide a more thorough understanding of a common but complex disease, but will also inform clinicians and policy makers about patient-relevant outcomes which can ultimately be used to optimise therapeutic approaches and care structures tailored to the needs of the dyad.