Cognitive Training in Parkinson Study

This study evaluates the efficacy of an eight-week online cognitive training program on objective and subjective cognitive functions in Parkinson's disease. Moreover, we intend to map the effect on brain network function, and if cognitive training can prevent the development of PD-MCI/PD-D after one- and two-year follow-up. In this study, two training groups will be compared (N: 70 vs 70). In a part of the participants MRI will be assessed (N: 40 vs. 40). We expect cognitive training to improve cognitive functions, and to improve the efficiency of brain network function. Moreover, we expect that cognitive training can decrease the risk of PD-MCI/PD-D at one- and two-year follow-up.

BACKGROUND In Parkinson's disease (PD), cognitive dysfunction is frequently reported - approximately 50% of PD patients experience cognitive impairment (Litvan et al., 2011). Of these impairments, executive dysfunction is most frequently reported early in the disease trajectory (Bosboom, Stoffers, \& Wolters, 2004; Muslimovic, Post, Speelman, \& Schmand, 2005), while impairments in other cognitive domains (i.e. attention, episodic memory, visuospatial functions) are also highly prevalent (Bosboom et al., 2004). The majority of PD patients ultimately develops PD dementia (PD-D; Aarsland, Andersen, Larsen, Lolk, \& Kragh-Sorensen, 2003; Hely, Reid, Adena, Halliday, \& Morris, 2008). Moreover, about 10% of the PD patients develops PD-D every year (Aarsland \& Kurz, 2010). Cognitive dysfunctions in PD have a significant negative influence on the quality of life (Klepac, Trkulja, Relja, \& Babic, 2008), while treatment of these dysfunctions is in its infancy.

Cognitive training may provide a new intervention for reducing cognitive complaints and delaying the onset of mild cognitive impairment (MCI) or PD-D. This intervention has been widely studied in other diseases (Cicerone et al., 2011; Olazaran et al., 2010). Moreover, studies have provided evidence not only for behavioral influences, but also for brain connectivity and activity effects of cognitive training (Chapman et al., 2015; Castellanos et al., 2010; Subramaniam et al., 2012; Subramaniam et al., 2014; Belleville et al., 2011; Rosen, Sugiura, Kramer, Whitfield-Gabrieli, \& Gabrieli, 2011). This suggests a restorative effect of cognitive training on disrupted brain networks.

In PD, cognitive dysfunction - mainly executive dysfunction - is associated with disruption of the cortico-striato-thalamo-corticale circuits by depletion of dopamine. Dysfunction of these circuits seems to disrupt several cognitive networks, which leads to cognitive dysfunction (Baggio et al., 2014). Cognitive training could counteract these disruptions by normalising activity and connectivity, and ultimately lead to a reduction of impairment. Since earlier studies in different patient populations have shown that cognitive training has lasting effects (Petrelli et al., 2015), normalising disruptions underlying cognitive impairment could prevent cognitive deterioration and therefore prevent or delay the development of PD-D.

Few studies in PD have focused on cognitive training and its neural correlates. A meta-analysis by Leung et al. (2015) showed positive effects of cognitive training on mainly 'frontal' cognitive functions (i.e. working memory, executive functions, processing speed). In addition, earlier research has described a neuroprotective effect of cognitive training on the development of MCI in PD (odds ratio: 3; Petrelli et al., 2015). Until now, however, studies have been relatively small and mainly without a controlled design - consequently, there is a need for large randomized controlled studies (Hindle, Petrelli, Clare, \& Kalbe, 2013; Leung et al., 2015). Moreover, neural effects of cognitive training are largely unknown in PD. Furthermore, it is important to study the improvement of patients on daily functioning after cognitive training, rather than solely focusing on cognitive tasks and neural measures. Finally, cognitive training has been performed mainly in hospital settings, while PD patients have mobility problems - a training method suitable to perform from home is therefore needed for this population.

OBJECTIVES The study objective is primarily to measure the effect of an online cognitive training in patients with mild cognitive complaints in PD. An online training, specifically altered for PD patients (BrainGymmer) will be compared with an active comparator. In both conditions, participants will train eight weeks, three times a week during 45 minutes.

Primary objective:

- To measure the effect of an online cognitive training (as compared to the active comparator), eight weeks, three times a week, on executive functions in patients with mild cognitive complaints in PD.

Secondary objectives:

* To measure the effect of online cognitive training on daily functioning.
* To measure the endurance of the training effect after six months, one and two years.
* To assess the reduced risk of MCI and PD-D development by cognitive training.
* To assess the effect of cognitive training on brain network efficiency and connectivity.
* To assess the effect of cognitive training on brain network topology and connectivity, and cognition, relative to those of matched healthy control participants.
* To assess the difference in brain network topology and connectivity, and cognition, between Parkinson's disease patients with or without cognitive impairment and healthy control participants.

Eligibility Criteria:
--- Parkinson's disease patients ---

Inclusion Criteria:

* Subjective cognitive complaints, measured by the Parkinson's Disease Cognitive Functional Rating Scale score \> 3 (PD-CFRS). A score above 3 indicates significant cognitive complaints, that are milder than complaints associated with Parkinson's disease dementia. This questionnaire is filled in by the patient.
* Participants' Hoehn \& Yahr stage is lower than 4. Patients are stable on dopaminergic medication at least a month before starting the intervention. During the intervention, patient and neurologist will be asked to keep the dopaminergic medication dosage as stable as possible.
* Participants have access to a computer or tablet, with access to the Internet. If the participant uses a computer, he or she is capable of using a keyboard and computer mouse.
* Participants are willing to sign informed consent.

Exclusion Criteria:

General criteria:

* Indications for a dementia syndrome, measured by the Self-administered Gerocognitive Examination score \< 14 or the Montreal Cognitive Assessment score \< 22.
* Current drug- or alcohol abuse, measured by a score \> 1 on the four CAGE AID-questions (according to the Trimbos guidelines).
* The inability to undergo extensive neuropsychological assessment, or eight weeks of intervention.
* Moderate to severe depressive symptoms, as defined by the Beck Depression Inventory score \> 18.
* An impulse control disorder, including internet addiction, screened by the impulse control disorder criteria interview.
* Psychotic symptoms, screened by the Questionnaire for Psychotic Experiences. Benign hallucinations with insight are not contraindicated.
* Traumatic brain injury, only in case of a contusio cerebri with 1) loss of consciousness for \> 15 minutes and 2) posttraumatic amnesia \> 1 hour.
* A space occupying lesion defined by a radiologist, or significant vascular abnormalities (Fazekas \> 1).

For participation in MRI research:

* Severe claustrophobia
* Metal in the body (for example, deep brain stimulator or pacemaker)
* Pregnancy
* Problems with or shortness of breath during 60 minutes of lying still.

  * Healthy control subjects ---

Inclusion criteria:

- Participants are willing to sign informed consent.

Exclusion criteria:

* Indications for a neurological disease, such as Parkinson's disease, Alzheimer's disease, mild cognitive impairment, multiple sclerosis or Huntington's disease;
* Indications for a dementia syndrome, measured by the Montreal Cognitive Assessment score \< 22.
* Indications for a current stroke or CVA, or in the past.
* Indications for the presence of a psychotic or depressive disorder, measured with a positive screening on the SAPS-PD (benign hallucinations with insight are not contraindicated) and a BDI \> 18 respectively.
* Current drug- or alcohol abuse, measured by a score \> 1 on the four CAGE AID-questions (according to the Trimbos guidelines).
* The inability to undergo extensive neuropsychological assessment, or eight weeks of intervention.
* Traumatic brain injury, only in case of a contusio cerebri with 1) loss of conciousness for \> 15 minutes and 2) posttraumatic amnesia \> 1 hour.
* A space occupying lesion defined by a radiologist, or significant vascular abnormalities (Fazekas \> 1).
* Contra-indications for participation in MRI scanning (see above)