Parkinson's disease (PD) is a debilitating neurodegenerative disorder occurring in 7 million patients worldwide. PD is caused by progressive loss of nigro-striatal dopamine cells, which causes motor symptoms such as slowness of movement and tremor, and non-motor symptoms such as cognitive dysfunction. Converging clinical evidence indicates that PD patients are very sensitive to the effects of psychological stress. There is a high prevalence of stressrelated neuropsychiatric symptoms in PD: 30-40% of patients experience depression and 25-30% have anxiety. Furthermore, stress worsens many motor symptoms, e.g. tremor, freezing of gait, and dyskinesia. In addition to these immediate negative effects, chronic stress may also have detrimental long-term consequences, and specifically by accelerating disease progression, as suggested by animal models. However, this hypothesis remains to be confirmed in humans. Better evidence about the impact of stress on PD would have major treatment consequences: novel stress-reducing interventions may have symptomatic effects, and perhaps also disease-modifying effects. The aim of this study is to test whether a stress-reducing intervention improves clinical symptoms, slows neurodegeneration, and/or enhances neuroplasticity in PD. In a randomized controlled trial, the investigators will compare a stress-reducing mindfulness-based intervention group (MBI; one year) to a treatment as usual (TAU) group on clinical symptoms, cerebral markers of nigro-striatal dysfunction and stressor-reactivity (MRI), and inflammatory markers (serum).

Parkinson's disease (PD) is a common and fast-growing neurological disease, clinically characterized by motor slowing (bradykinesia), stiffness (rigidity) and resting tremor. The pathological hallmark of PD is nigro-striatal dopamine depletion, but the noradrenergic (stress) system is also affected. Indeed, the prevalence of stress-related neuropsychiatric symptoms in PD is high and many PD patients suffer from reduced health-related quality of life. Also, (chronic) stress worsens many motor symptoms and may have detrimental long-term consequences by accelerating disease progression, as suggested by animal models.

There is no cure for PD, and currently no treatments to slow down disease progression. Therefore, the development of new and effective treatments is crucial. Given the large role of stress on PD symptoms, stress reduction might improve motor as well as non-motor symptoms. Intriguingly, recent evidence suggests that mindfulness training, where mindfulness is the trainable capacity to experience the present moment on purpose and without judgment, is an effective way to achieve such stress reduction. In fact, the effects of mindfulness practice have gained much interest as a topic of scientific research and clinical practise recently, where Mindfulness-Based Cognitive Therapy (MBCT) is one of the most commonly applied interventions, shown to be effective for a variety of somatic and psychiatric disorders. Importantly, previous trials investigating the effect of mindfulness-based interventions (MBIs) on clinical symptoms in PD showed positive effects on depression in 6/8 trials, on anxiety in 4/7 trials and on motor symptoms in 2/3 studies. Also, a large online survey on patients' experiences with stress and mindfulness showed that on one hand, patients experienced considerably more stress than controls, and significant stress-related worsening of PD symptoms; on the other, PD mindfulness users reported positive effects of mindfulness on anxiety and depression. In summary, current evidence suggests a positive effect of MBIs on psychological distress in PD, but clinical evidence is inconclusive. Also, to date, there is no research on the (cerebral) mechanisms underlying the (positive) effects of mindfulness in PD. Insight to the cerebral mechanisms of MBIs can pave the way for developing new, mechanism-based interventions, and can help to uncover the nature of the effects of stress on Parkinson's disease. Specifically, a mechanism based approach allows us to disentangle the symptomatic (stress as an amplifying factor on motor dysfunction) as opposed to neurodegenerative (nigro-striatal cell loss) effects of stress.

In this study, the investigators will test the effect of MBCT on the clinical (symptomatic) and neurodegenerative course of PD. If proven to be effective, MBCT can be applied as a new and cost-effective therapy to PD patients. The investigators will perform a randomized controlled trial with MBCT as intervention and a treatment as usual (TAU) control group. The investigators will evaluate whether a MBCT mindfulness course can lead to clinically relevant reductions in psychological distress (measured with the Hamilton Anxiety and Depression Scale) in PD patients with mild to moderate symptoms of psychological distress. Also, the investigators will evaluate the effects of a MBCT mindfulness course on other PD symptoms (e.g. motor dysfunction), cerebral markers of neurodegeneration, and neuroplasticity, and explore whether the intervention lowers systemic inflammatory tone in PD. The total duration of data acquisition per participant will be 12 months, consisting of a baseline measurement (T0), an intervention period of 2 months followed by a post-measurement (T1), and a final measurement (T2) that takes place 12 months after T0.

Inclusion criteria for the RCT:

• A diagnosis of idiopathic PD made by a movement disorders specialist.
• PD disease duration is ≤10 years, defined as time since diagnosis made by a neurologist.
• Mild-moderate symptoms of psychological distress (Hospital Anxiety and Depression Scale score >10 points).
• Subject can read and understand the Dutch language.

Exclusion criteria for the RCT:

• Severe neurological or psychiatric co-morbidity (e.g. psychosis or suicidality).
• Contraindications for MRI (e.g. brain surgery in medical history, claustrophobia, an active implant, epilepsy, pregnancy, and/or metal objects in the upper body that are incompatible with MRI).
• Moderate to severe head tremor (to avoid artifacts caused by extensive head motion during scanning).
• Cognitive dysfunction (clinical diagnosis of dementia, or a score of 20 or lower on the MoCA, which will be measured at T0).
• Previous participation in MBSR or MBCT (>4 sessions).

Inclusion criteria (HC group):

• Participants of the HC group must be able to read and understand the Dutch language.

Exclusion criteria (HC group):

• Severe neurological or psychiatric co-morbidity (e.g. psychosis or suicidality).
• Contraindications for MRI (e.g. brain surgery in medical history, claustrophobia, an active implant, epilepsy, pregnancy, and/or metal objects in the upper body that are incompatible with MRI).
• Cognitive dysfunction (clinical diagnosis of dementia, or a score of 20 or lower on the MoCA, which will be measured at T0).
• Detailed knowledge about the nature of the stress induction paradigm prior to participating in the study.

The involved researchers will not be blinded to the treatment allocation, because this would not be feasible with the current design. Patients receiving MBCT need to be allocated to a specific treatment group, which requires extensive communication between the patient, mindfulness center and researcher. Also, patients receiving the treatment will perform different questionnaires in the course of the study, which makes it impossible for the researcher to be blinded for group allocation. We do not expect any bias on our primary outcome measure (self-report questionnaire). Secondary outcome measures (MRI, blood serum, hair cortisol) are unlikely to be biased by the researcher. UPDRS-III performance will be video recorded to allow blinded ratings by independent researchers after collecting the data (hence blinded outcome assessor). Patients will be informed about their intervention after randomization.