Studies on eye movements in Parkinson's disease

Heterogeneity in Parkinson’s Disease (PD) phenotype and genotype is probably the main reason why, despite the abundance of biomarkers, we still lack a robust method for diagnosis and prognosis, besides clinical evaluation. Subjective changes in vision and objective measures in eye movements have been extensively studied, but the results are mainly used to better understand the pathophysiology of PD and are not integrated into the clinical praxis. The aim of this doctoral project was to examine if eye movements could serve as useful biomarkers for PD diagnosis and prognosis, and investigate their association with motor function, cognition, and medication effect. In addition, we aimed to examine cognition in a group of patients with a rare metabolic disorder and prominent eye-movement difficulties, the Norrbottnian Gaucher Disease 3 (GD3). Saccades, reading, and sustained fixation were examined in PD patients and healthy controls (HC) in the first three studies. Recruitment took place at Karolinska University Hospital Huddinge for the first two studies, and for the third study at Academic Specialist Center in Stockholm. Three different eye trackers were used, a head-mounted and two screen based, and the assessments were performed in a clinical setting. In the first two studies patients were examined in ON and OFF medication status, in order to evaluate the role of levodopa. In study 1, we examined saccadic parameters in 20 HC and 40 PD patients; study 2 involved reading assessments for 13 HC and 19 PD patients; in study 3 we examined sustained fixation in 43 HC and 50 PD patients. Recruitment for study 4 took place at Sunderby Regional Hospital, in Luleå, and we examined 10 patients with the Norrbottnian type of GD3. Cognitive evaluation was done with the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). PD participants had worse saccadic performance, a slower reading speed, and deficient fixation control. Saccadic gain was associated with motor performance, while latency was related to cognition. Levodopa had no effect on saccadic gain, it worsened latency for the horizontal visually guided saccades and ameliorated the latency of antisaccades, but not the error rate or reading performance. We assumed that reading difficulties were attributed to cognitive, rather than oculomotor deficits. Fixation was more easily interrupted in PD compared to HC, and PD participants’ pupils did not dilate to the same extent as HC, in response to the cognitive effort put during sustained fixation. In study 4 we found that patients with the Norrbottnian type of GD3 have an overall worse cognitive performance compared to that of healthy population, scoring worse in memory and attention tests, present however with preserved language and visuospatial skills. The eye-tracking studies led to the conclusion that this method could be integrated into the clinical praxis as part of the clinical evaluation. It is easy to perform and provides reliable results that enable the understanding of motor, cognitive, and behavioral changes in PD. In order to do so, we would need a common protocol of assessment, so that the results would be comparable between different populations. The last study identified RBANS as a useful and easy-to-use tool for the cognitive examination of Norrbottnian GD3 patients

Reduction of spontaneous cortical beta bursts in Parkinson's disease is linked to symptom severity

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Attenuated beta rebound to proprioceptive afferent feedback in Parkinson’s disease

Motor symptoms are defining traits in the diagnosis of Parkinson’s disease (PD). A crucial component in motor function is the integration of afferent proprioceptive sensory feedback. Previous studies have indicated abnormal movement-related cortical oscillatory activity in PD, but the role of the proprioceptive afference on abnormal oscillatory activity in PD has not been elucidated. We examine the cortical oscillations in the mu/beta-band (8–30 Hz) in the processing of proprioceptive stimulation in PD patients, ON/OFF levodopa medication, as compared to that of healthy controls (HC). We used a proprioceptive stimulator that generated precisely controlled passive movements of the index finger and measured the induced cortical oscillatory responses following the proprioceptive stimulation using magnetoencephalography. Both PD patients and HC showed a typical beta-band desynchronization during the passive movement. However, the subsequent beta rebound after the passive movement that was almost absent in PD patients compared to HC. Furthermore, we found no difference in the degree of beta rebound attenuation between patients ON and OFF levodopa medication. The results demonstrate a disease-related deterioration in cortical processing of proprioceptive afference in PD.peerReviewe

A Phase 2a Trial Investigating the Safety and Tolerability of the Novel Cortical Enhancer IRL752 in Parkinson's Disease Dementia

Background: IRL752 is a novel small-molecule compound that acts to regioselectively enhance norepinephrine, dopamine, and acetylcholine neurotransmission in the cerebral cortex. Objective: The primary objective of the trial was to investigate the safety and tolerability of IRL752 in patients with Parkinson's disease and dementia. Methods: Patients with Parkinson's disease and dementia were randomized to IRL752 or placebo treatment (3:1 ratio) for 28 days. The study drug was given as an adjunct treatment to the patients’ regular stable antiparkinsonian medication. Dosing was individually titrated for 14 days after which the dose was kept stable for an additional 14 days. Results: A total of 32 patients were randomized to treatment, and 29 patients completed the 4-week treatment. Adverse events were generally mild and transient and were mostly reported during the dose titration phase. There were 2 serious adverse events, and none of them were related to the experimental treatment. The average dose achieved in the stable dose phase was 600 mg daily, yielding a 2-hour postdose plasma concentration of about 4 μM on day 28. Exploratory assessment of secondary outcomes indicated efficacy for symptoms and signs known to be poorly responsive to levodopa. Conclusions: IRL752 appears to be safe and well tolerated for a 4-week treatment in patients with Parkinson's disease and dementia

Cerebrospinal Fluid Levels of Kininogen‐1 Indicate Early Cognitive Impairment in Parkinson's Disease

International audienceThe aim of this study was to investigate CSF markers associated with cognition in early PD.Cognitive impairment is common in patients with PD. Core markers of Alzheimer's dementia have been related also to PD dementia, but no disease-specific signature to predict PD dementia exists to date