Purpose The purpose of this study was to explore the lived experience of dancing with Parkinson's and Multiple Sclerosis in an inclusive dance group called ReDiscoverMe (RDM). Methods Participatory... Show morePurpose The purpose of this study was to explore the lived experience of dancing with Parkinson's and Multiple Sclerosis in an inclusive dance group called ReDiscoverMe (RDM). Methods Participatory research approaches and interpretative phenomenological analysis were used to make sense of the lived experience captured in interviews and observations. Arthur Frank's conceptual framework on embodied storytelling from his book The Wounded Storyteller was the study's theoretical lens. Themes are both described and represented in images made by an RDM participant. Findings Dancing in a nonjudgmental environment was described by participants as a way to rediscover themselves while continually adapting to living with chronic illness. We interpreted this experience of rediscovery as an active, recursive process involving three "movements": escaping, expanding, and embracing. Through these movements, participants could rise above the self and illness. Conclusions The lived experience of dancing in this group was characterized by transformations of the body, self, and life. Through escaping, expanding, and embracing, participants could more easily embrace the body's contingency, integrate the self and body by becoming dancers, connect with others living with illness, and produce desire through passion. Participants could therefore experience illness as a journey and gain something from the experience. Show less
This thesis is divided into three parts. The first part of this thesis describes the epidemiology of infections with Clostridioides difficile, meticillin-resistant Staphylococcus aureus and... Show moreThis thesis is divided into three parts. The first part of this thesis describes the epidemiology of infections with Clostridioides difficile, meticillin-resistant Staphylococcus aureus and colistin-resistant Enterobacterales. An important treatment strategy for recurrent C. difficile infections is restoring the disturbed gut microbiota by faecal microbiota transplantation (FMT). The second part discusses the risk of transmission of pathogenic and/or multidrug-resistant bacteria via FMT and procedures to prevent this. Apart from recurrent C. difficile infections, several new potential indications of FMT are being explored. In the third part of this thesis, FMT is explored as a potential new treatment strategy for several neurological disorders, with a main focus on Parkinson’s disease. Show less
Hepp, D.H.; Wageningen, T.A. van; Kuiper, K.L.; Dijk, K.D. van; Oosterveld, L.P.; Berendse, H.W.; Berg, W.D.J. van de 2023
An altered immune response has been identified as a pathophysiological factor in Parkinson’s disease (PD). We aimed to identify blood immunity-associated proteins that discriminate PD from controls... Show moreAn altered immune response has been identified as a pathophysiological factor in Parkinson’s disease (PD). We aimed to identify blood immunity-associated proteins that discriminate PD from controls and that are associated with long-term disease severity in PD patients. Immune response-derived proteins in blood plasma were measured using Proximity Extension Technology by OLINK in a cohort of PD patients (N = 66) and age-matched healthy controls (N = 52). In a selection of 30 PD patients, we evaluated changes in protein levels 7–10 years after the baseline and assessed correlations with motor and cognitive assessments. Data from the Parkinson’s Disease Biomarkers Program (PDBP) cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort were used for independent validation. PD patients showed an altered immune response compared to controls based on a panel of four proteins (IL-12B, OPG, CXCL11, and CSF-1). The expression levels of five inflammation-associated proteins (CCL23, CCL25, TNFRSF9, TGF-alpha, and VEGFA) increased over time in PD and were partially associated with more severe motor and cognitive symptoms at follow-up. Increased CCL23 levels were associated with cognitive decline and the APOE4 genotype. Our findings provide further evidence for an altered immune response in PD that is associated with disease severity in PD over a long period of time. Show less
The validation of objective and easy-to-implement biomarkers that can monitor the effects of fast-acting drugs among Parkinson's disease (PD) patients would benefit antiparkinsonian drug... Show moreThe validation of objective and easy-to-implement biomarkers that can monitor the effects of fast-acting drugs among Parkinson's disease (PD) patients would benefit antiparkinsonian drug development. We developed composite biomarkers to detect levodopa/carbidopa effects and to estimate PD symptom severity. For this development, we trained machine learning algorithms to select the optimal combination of finger tapping task features to predict treatment effects and disease severity. Data were collected during a placebo-controlled, crossover study with 20 PD patients. The alternate index and middle finger tapping (IMFT), alternative index finger tapping (IFT), and thumb-index finger tapping (TIFT) tasks and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III were performed during treatment. We trained classification algorithms to select features consisting of the MDS-UPDRS III item scores; the individual IMFT, IFT, and TIFT; and all three tapping tasks collectively to classify treatment effects. Furthermore, we trained regression algorithms to estimate the MDS-UPDRS III total score using the tapping task features individually and collectively. The IFT composite biomarker had the best classification performance (83.50% accuracy, 93.95% precision) and outperformed the MDS-UPDRS III composite biomarker (75.75% accuracy, 73.93% precision). It also achieved the best performance when the MDS-UPDRS III total score was estimated (mean absolute error: 7.87, Pearson's correlation: 0.69). We demonstrated that the IFT composite biomarker outperformed the combined tapping tasks and the MDS-UPDRS III composite biomarkers in detecting treatment effects. This provides evidence for adopting the IFT composite biomarker for detecting antiparkinsonian treatment effect in clinical trials. & COPY; 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Show less
Degenerative diseases of the nervous system, such as Alzheimer's, Parkinson's and ALS, are severe, progressive and ultimately fatal. Most existing drugs for these neurodegenerative diseases only... Show moreDegenerative diseases of the nervous system, such as Alzheimer's, Parkinson's and ALS, are severe, progressive and ultimately fatal. Most existing drugs for these neurodegenerative diseases only temporarily relieve symptoms, increase mobility or relieve pain, but do not slow disease progression.This dissertation describes a method to efficiently carry out the development of new drugs that could inhibit disease progression in neurodegenerative diseases. Namely, by using pharmacodynamic biomarkers. These are signaling substances to measure the magnitude of a drug response.These biomarkers can be used in early clinical-pharmacological studies in healthy volunteers or small groups of patients to select the best drug candidates and their expected therapeutic doses as early as possible in the development stage. This helps to make informed choices to advance a potential new drug into large and expensive phase 2 and 3 (registration) studies, or conversely to discontinue development of a non-potential drug as early as possible. This biomarker method was applied in this dissertation to investigate 2 new drugs that could potentially slow disease progression in Alzheimer's and ALS (a RIPK1 inhibitor) or Parkinson's disease (a LRRK2 inhibitor). The research results from multiple early clinical-pharmacological studies in healthy volunteers and patients described in this thesis form the basis for larger phase 2 and 3 follow-up studies that have now been initiated with ALS patients and Parkinson's disease patients. Both with the goal of confirming whether these agents can indeed slow disease progression, which would represent a major breakthrough in the treatment of these conditions. Show less
Prins, S.; Borghans, L.; Kam, M.L. de; Groeneveld, G.J.; Gerven, J. van 2023
Background The prevalence of neurodegenerative diseases increases significantly with increasing age. Neurodegeneration is the progressive loss of function of neurons that eventually leads to cell... Show moreBackground The prevalence of neurodegenerative diseases increases significantly with increasing age. Neurodegeneration is the progressive loss of function of neurons that eventually leads to cell death, which in turn leads to cognitive disfunction. Cognitive performance can therefore also be considered age dependent. The current study investigated if the NeuroCart can detect age related decline on drug-sensitive CNS-tests in healthy volunteers (HV), and whether there are interactions between the rates of decline and sex. This study also investigated if the NeuroCart was able to differentiate disease profiles of neurodegenerative diseases, compared to age-matched HV and if there is age related decline in patient groups. Methods This retrospective study encompassed 93 studies, performed at CHDR between 2005 and 2020 that included NeuroCart measurements, which resulted in data from 2729 subjects. Five NeuroCart tests were included in this analysis: smooth and saccadic eye movements, body sway, adaptive tracking, VVLT and N-back. Data from 84 healthy male and female volunteer studies, aged 16-90, were included. Nine studies were performed in patients with Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) or vascular dementia (VaD). The data were analyzed with regression analyses on age by group, sex, sex by age, group by sex and group by sex by age. Least square means (LSMs) and 95% confidence intervals (CIs) were calculated for each group at the average age of the group, and at the average age of each of the other groups, and per sex. Results Mean age and standard deviation (SD) for all groups was: HV 36.2 years (19.3), AD 68.3 years (8), PD 62.7 years (8.5), HD 51.4 years (9.8) and VaD 66.9 years (8.1). Performance on all NeuroCart tests decreased significantly each year in HV. Saccadic peak velocity (SPV) was increased in AD compared to age-matched HV (+26.28 degrees/s, p =0.007), while SPV was decreased for PD and HD compared to age-matched HV (PD: -15.87 degrees/s, p=0.038, HD: -22.52 degrees/s, p=0.018). In HD patients SPV decreased faster with age compared to HV. On saccadic peak velocity the slopes between HD vs HV were significantly different, indicating a faster decline in performance on this task for HD patients compared to HV per age year. Smooth pursuit showed an overall significant difference between subject groups (p=0.037. Significantly worse performance was found for AD (-12.87%, p=<0.001), PD (-4.45%, p=<0.001) and VaD (-5.69%, p=0.005) compared to age-matched HV. Body sway significantly increased with age (p=0.021). Postural stability was decreased for both PD and HD compared to age-matched HV (PD: +38.8%, p=<0.001, HD: 154.9%, p=<0.001). The adaptive tracking was significantly decreased with age (p=<0.001). Adaptive tracking performance by AD (-7.54%, p=<0.001), PD (-8.09%, p=<0.001), HD (-5.19%, p=<0.001) and VaD (-5.80%, p=<0.001) was decreased compared to age-matched HV. Adaptive tracking in PD patients vs HV and in PD vs HD patients was significantly different, indicating a faster decline on this task per age year for PD patients compared to HV and HD. The VVLT delayed word recall showed an overall significant effect of subject group (p=0.006. Correct delayed word recall was decreased for AD (-5.83 words, p=<0.001), HD (-3.40 words, p=<0.001) and VaD (-5.51 words, p=<0.001) compared to age-matched HV. Conclusion This study showed that the NeuroCart can detect age-related decreases in performance in HV, which were not affected by sex. The NeuroCart was able to detect significant differences in performance between AD, PD, HD, VaD and age-matched HV. Disease durations were unknown, therefore this cross-sectional study was not able to show age-related decline after disease onset. This article shows the importance of investigating age-related decline on digitalized neurocognitive test batteries. Performance declines with age, which emphasizes the need to correct for age when including HV in clinical trials. Patients with different neurogenerative diseases have distinct performance patterns on the NeuroCart , which this should be considered when performing NeuroCart tasks in patients with AD, PD, HD and VaD. Show less
Background: Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD).Objective: The aim of this study was to evaluate the... Show moreBackground: Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD).Objective: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD.Methods: Two randomized, double-blind, placebo-controlled studies were completed. The phase 1 study (DNLI-C-0001) evaluated single and multiple doses of BIIB122 for up to 28 days in healthy participants. The phase 1b study (DNLI-C-0003) evaluated BIIB122 for 28 days in patients with mild to moderate PD. The primary objectives were to investigate the safety, tolerability, and plasma pharmacokinetics of BIIB122. Pharmacodynamic outcomes included peripheral and central target inhibition and lysosomal pathway engagement biomarkers.Results: A total of 186/184 healthy participants (146/145 BIIB122, 40/39 placebo) and 36/36 patients (26/26 BIIB122, 10/10 placebo) were randomized/treated in the phase 1 and phase 1b studies, respectively. In both studies, BIIB122 was generally well tolerated; no serious adverse events were reported, and the majority of treatment-emergent adverse events were mild. BIIB122 cerebrospinal fluid/unbound plasma concentration ratio was similar to 1 (range, 0.7-1.8). Dose-dependent median reductions from baseline were observed in whole-blood phosphorylated serine 935 LRRK2 (<= 98%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (<= 93%), cerebrospinal fluid total LRRK2 (<= 50%), and urine bis (monoacylglycerol) phosphate (<= 74%).Conclusions: At generally safe and well-tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD. (c) 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Show less
BackgroundIncreased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders. In this study, we aimed to investigate the... Show moreBackgroundIncreased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders. In this study, we aimed to investigate the distribution of neurofilaments in the cerebral cortex of Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) donors, and its association with pathology load and MRI measures of atrophy and diffusivity.MethodsUsing a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI. After autopsy, pathological hallmarks (pSer129-αSyn, p-tau and amyloid-β load) together with neurofilament light-chain (NfL) and phosphorylated-neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in seven cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models.ResultsCompared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. The increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB.ConclusionsTaken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increased pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process. Show less
Parkinson's disease is the second most common neurodegenerative disease in the world. One of its symptoms is the loss of dopaminergic neurons in the substantia nigra pars compacta. A number of... Show moreParkinson's disease is the second most common neurodegenerative disease in the world. One of its symptoms is the loss of dopaminergic neurons in the substantia nigra pars compacta. A number of phenotypes, including the aggregation of misfolded proteins, mitochondrial dysfunction, and neuroinflammatory chemicals released by microglia and activated astrocytes, may all play a role in its pathogenesis.Due to the multisystemic nature of Parkinson's disease, novel tools for developing mechanistic models that simulate its pathogenic processes have been proposed. Furthermore, as the amount of information in biological databases grows and the cost of omics experiments decreases, methods for integrating different types of biological data have become essential for increasing the level of detail in mechanistic models of biological systems.Constraint-based modelling is a valuable tool in bioengineering and biomedicine. It is used to estimate the reaction flux in a metabolic network. The constraints represent essential characteristics of a biological system, including connectivity between metabolites and reactions, thermodynamics, maximum and minimum flux rates, and the steady-state.This thesis presents studies and tools for integrating various types of specific information to genome-scale models used in constraint-based modelling. In addition, is presented the iDopaNeuro default models, genome-scale models of a culture of dopaminergic neurons derived from induced pluripotent stem cells. Show less
Sleep/wake alterations are predominant in neurological and neuropsychiatric disorders involving dopamine dysfunction. Unfortunately, specific, mechanisms-based therapies for these debilitating... Show moreSleep/wake alterations are predominant in neurological and neuropsychiatric disorders involving dopamine dysfunction. Unfortunately, specific, mechanisms-based therapies for these debilitating sleep problems are currently lacking. The pathophysiological mechanisms of sleep/wake alterations within a hypodopaminergic MitoPark mouse model of Parkinson's disease (PD) are investigated. MitoPark mice replicate most PD-related sleep alterations, including sleep fragmentation, hypersomnia, and daytime sleepiness. Surprisingly, these alterations are not accounted for by a dysfunction in the circadian or homeostatic regulatory processes of sleep, nor by acute masking effects of light or darkness. Rather, the sleep phenotype is linked with the impairment of instrumental arousal and sleep modulation by behavioral valence. These alterations correlate with changes in high-theta (8-11.5 Hz) electroencephalogram power density during motivationally-charged wakefulness. These results demonstrate that sleep/wake alterations induced by dopamine dysfunction are mediated by impaired modulation of sleep by motivational valence and provide translational insights into sleep problems associated with disorders linked to dopamine dysfunction. Show less
Liu et al. report that specific mitochondrial haplogroups are associated with the progression of cognitive decline in patients with Parkinson's disease, but not with the progression of motor... Show moreLiu et al. report that specific mitochondrial haplogroups are associated with the progression of cognitive decline in patients with Parkinson's disease, but not with the progression of motor impairment. Mitochondrial haplotypes may thus be useful for stratifying patients according to their risk of cognitive decline. Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U-# had a 41% lower risk of cognitive progression with P = 2.42 x 10(-6) compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 x 10(-5). Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time. Show less
Thijssen, E.; Makai-Boloni, S.; Brummelen, E. van; Heijer, J. den; Yavuz, Y.; Doll, R.J.; Groeneveld, G.J. 2022
Background: Movement Disorder Society-Unified Parkinson's Rating Scale Part III (MDS-UPDRS III) is the gold standard for assessing medication effects in patients with Parkinson's disease (PD).... Show moreBackground: Movement Disorder Society-Unified Parkinson's Rating Scale Part III (MDS-UPDRS III) is the gold standard for assessing medication effects in patients with Parkinson's disease (PD). However, short and rater-independent measurements would be ideal for future trials. Objectives: To assess the ability of 3 different finger tapping tasks to detect levodopa/carbidopa-induced changes over time and to determine their correlation and compare their discriminatory power with MDS-UPDRS III. Methods: This was a randomized, double-blind, crossover study in 20 patients with PD receiving levodopa/carbidopa and placebo capsules after overnight medication withdrawal. Pre- and up to 3.5 hours postdose, MDS-UPDRS III and tapping tasks were performed. Tasks included 2 touchscreen-based alternate finger tapping tasks (index finger versus index-middle finger tapping) and a thumb-index finger task using a goniometer. Results: In the alternate index finger tapping task, levodopa/carbidopa compared with placebo resulted in significantly faster (total taps: 12.5 [95% confidence interval, CI, 6.7-18.2]) and less accurate tapping (total spatial error: 240 mm [95% CI, 123-357 mm]) with improved rhythm (intertap interval standard deviation [SD], -16.3% [95% CI, -29.9% to 0.0%]). In the thumb-index finger task, tapping was significantly faster (mean opening velocity, 151 degree/s [64-237 degree/s]), with a higher mean amplitude (8.4 degrees [3.7-13.0 degrees]) and improved rhythm (intertap interval SD, -46.4% [95% CI, -63.7% to -20.9%]). The speed-related endpoints showed a moderate-to-strong correlation with the MDS-UPDRS III (r = 0.45-0.70). The effect sizes of total taps and spatial error in the alternate index finger tapping task and opening velocity in the thumb-index finger task were comparable with the MDS-UPDRS III. In contrast, the MDS-UPDRS III performed better than the alternate index-middle finger task. Conclusion: The alternate index finger and the thumb-index finger tapping tasks provide short, rater-independent measurements that are sensitive to levodopa/carbidopa effects with a similar effect size as the MDS-UPDRS III. Show less
Heuvel, L. van den; Knippenberg, M.; Post, B.; Meinders, M.J.; Bloem, B.R.; Stiggelbout, A.M. 2022
Background: There is a great need for the development of personalized prediction models (PPMs) that can predict the rate of disease progression for persons with Parkinson's disease (PD), based on... Show moreBackground: There is a great need for the development of personalized prediction models (PPMs) that can predict the rate of disease progression for persons with Parkinson's disease (PD), based on their individual characteristics. In this study, we aimed to clarify the perspective of persons diagnosed with PD on the value of such hypothetical PPMs. Methods: We organized four focus group discussions, each including five persons with PD who were diagnosed within the last 5 years. The sessions focused on what they think of receiving a personalized prediction; what outcomes are important to them; if and how the possibility of influencing the prognosis would change the way they think of personalized predictions; how they deal with the uncertainty from a PPM; and what barriers and facilitators they expect for using a PPM. Results: The wish of persons with PD for receiving personalized prognostic information was highly heterogenous, for various reasons. Most persons with PD would like to receive more personalized prognostic information, mainly to better prepare themselves and their loved ones for the future. The prediction provided should be as personalized as possible, and there should be adequate supervision and coaching by a professional when providing the information. They were particularly interested in receiving prognostic information when their interventions would be available that could subsequently influence the identified prognostic factor and thereby affect the disease course beneficially. Conclusion: Most persons with PD in this study want more insight into their own future by means of prediction models, provided that this is explained and supervized properly by professionals. Patient or Public Contribution: Two patient-researchers were involved in the study design, conduct of the study, interpretation of the data and in preparation of the manuscript. Show less
Yu, H.J.; Thijssen, E.; Brummelen, E. van; Plas, J.L. van der; Radanovic, I.; Moerland, M.; ... ; Dodart, J.C. 2022
Background: alpha-Synuclein (alpha Syn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic... Show moreBackground: alpha-Synuclein (alpha Syn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic alpha Syn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar alpha Syn, making UB-312 a potential immunotherapeutic for synucleopathies. Objective: To investigate the safety, tolerability, and immunogenicity of UB-312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first-in-patient study. Methods: Fifty eligible healthy participants were enrolled in a 44-week, randomized, placebo-controlled, double-blind study. Participants in seven cohorts were randomized to three intramuscular UB-312 or placebo injections at weeks 1, 5, and 13 (doses ranging between 40 and 2000 mu g). Safety and tolerability were assessed by adverse events, clinical laboratory, vital signs, electrocardiograms, and neurological and physical examinations. Immunogenicity was assessed by measuring serum and cerebrospinal fluid (CSF) anti-aSyn antibody concentrations. Results: Twenty-three participants received all three vaccinations of UB-312. Most adverse events were mild, transient, and self-resolving. Common treatment-emergent adverse events included headache, nasopharyngitis, vaccination-site pain, lumbar puncture-site pain, and fatigue. UB-312 induced dose- and time-dependent antibody production. Antibodies were detectable in serum and CSF of all participants receiving the 300/300/300 mu g UB-312 dose regimen. The average CSF/serum ratio was 0.2%. Conclusions: UB-312 was generally safe, well tolerated, and induced anti-aSyn antibodies in serum and CSF of healthy participants. The 100 and 300 mu g doses are selected for further evaluation in participants with PD. (C) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society Show less
Introduction: Apomorphine is used to treat OFF periods in Parkinson's disease (PD) patients. AZ-009 is a novel apomorphine formulation that delivers a thermally-generated aerosol to the deep lung... Show moreIntroduction: Apomorphine is used to treat OFF periods in Parkinson's disease (PD) patients. AZ-009 is a novel apomorphine formulation that delivers a thermally-generated aerosol to the deep lung via inhalation with a single breath.Methods: Part A was a randomized, placebo-controlled, double-blind study investigating the safety and pharmacokinetics of multiple ascending doses of AZ-009. PD patients (n = 24) received placebo or 2, 3 or 4 mg AZ-009 once daily for 5 days, followed by three times daily for 2 days with 2 h between doses. Part B was a double-blind crossover study in 8 PD patients who experience OFF periods. During an OFF state, patients received 4 mg AZ-009 and placebo on two consecutive days in a randomized order. MDS-UPDRS III and ON/OFF state were assessed pre- and post-dose.Results: Three times daily dosing with 2, 3 and 4 mg AZ-009 was relatively well tolerated with no apparent accumulation or changes in safety profile. Mild and transient throat irritation and cough were reported most often. AZ-009 was rapidly absorbed with median T-max between 1 and 2 min. When corrected for placebo response, the maximum effect of 4 mg AZ-009 based on MDS-UPDRS III scores was observed at 10 and 30 min post-dose with mean (SD) reductions of 6.8 (9.4) and 6.1 (9.1) points respectively. Whereas 0% of patients turned ON after placebo, 50% turned ON 10 min after 4 mg AZ-009 treatment.Conclusion: AZ-009 is rapidly systemically absorbed and safe to dose three times daily. AZ-009 could provide a faster-acting and easier to use formulation than currently available therapies. Show less
This thesis focusses on the further unravelling of one of the mechanisms involved in developing Parkinson's disease: the GBA1 gene, encoding the lysosomal enzyme GCase. Several questions are... Show moreThis thesis focusses on the further unravelling of one of the mechanisms involved in developing Parkinson's disease: the GBA1 gene, encoding the lysosomal enzyme GCase. Several questions are addressed: How prevalent are mutations in this gene in the Netherlands and does it affect disease onset (chapter 2 and 5)? What methodological challenges accompany the sequencing of this gene (chapter 3 and 4)? What biomarkers may be used in clinical trials targeting GCase (chapter 6)? And what are the effects of the novel GCase activator LTI-291, when first administered to healthy volunteers (chapter 7) and to GBA-PD patients (chapter 8)? Show less
Heuvel, L. van den; Meinders, M.J.; Post, B.; Bloem, B.R.; Stiggelbout, A.M. 2022
Background: The large variety in symptoms and treatment effects across different persons with Parkinson's disease (PD) warrants a personalized approach, ensuring that the best decision is made for... Show moreBackground: The large variety in symptoms and treatment effects across different persons with Parkinson's disease (PD) warrants a personalized approach, ensuring that the best decision is made for each individual. We aimed to further clarify this process of personalized decision-making, from the perspective of medical professionals. Methods: We audio-taped 52 consultations with PD patients and their neurologist or PD nurse-specialist, in 6 outpatient clinics. We focused coding of the transcripts on which decisions were made and on if and how decisions were personalized. We subsequently interviewed professionals to elaborate on how and why decisions were personalized, and which decisions would benefit most from a more personalized approach. Results: Most decisions were related to medication, referral or lifestyle. Professionals balanced clinical factors, including individual (disease-) characteristics, and non-clinical factors, including patients' preference, for each type of decision. These factors were often not explicitly discussed with the patient. Professionals experienced difficulties in personalizing decisions, mostly because evidence on the impact of characteristics of an individual patient on the outcome of the decision is unavailable. Categories of decisions for which professionals emphasized the importance of a more personalized perspective include choices not only for medication and advanced treatments, but also for referrals, lifestyle and diagnosis. Conclusions: Clinical decision-making is a complex process, influenced by many different factors that differ for each decision and for each individual. In daily practice, it proves difficult to tailor decisions to individual (disease-) characteristics, probably because sufficient evidence on the impact of these individual characteristics on outcomes is lacking. Show less
Background: Inhalation of apomorphine could be a faster-acting and more user-friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD). Objective: The aim... Show moreBackground: Inhalation of apomorphine could be a faster-acting and more user-friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD). Objective: The aim of this study was to compare the safety and pharmacokinetics of inhaled apomorphine (AZ-009) with subcutaneous apomorphine (APO-go PEN) in healthy volunteers (HVs) and to examine the safety, pharmacokinetics, and efficacy of AZ-009 in patients with PD. Methods: In part A of this study, eight HVs received 1 mg AZ-009 and 2 mg subcutaneous apomorphine in a randomized crossover manner. In the subsequent single ascending dose parts in HVs (part B, n = 16) and patients with PD (part C, n = 25), participants were randomized to placebo or AZ-009 up to 4 mg. In patients, after medication withdrawal, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III and on/off states were assessed predose and postdose. Results: AZ-009 was rapidly absorbed with peak plasma concentrations at 2 minutes, as compared to 30 minutes for subcutaneous apomorphine. Adverse events for AZ-009 were comparable to subcutaneous apomorphine, except for mild and transient throat irritation. Adverse events limited AZ-009 dose escalation in HVs to 3 mg. Patients tolerated up to 4 mg. In patients with PD, 2, 3, and 4 mg AZ-009 reduced mean Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score (standard deviation) by 10.7 (13.6), 12.8 (7.9), and 10.3 (3.7) points, respectively, compared to 4.8 (4.9) after placebo at 10 minutes postdose. The percentage of patients achieving full on within 45 minutes postdose increased dose dependently: 0% (placebo), 17% (2 mg), 50% (3 mg), and 83% (4 mg). Conclusions: AZ-009 appears to be a rapid-acting and reasonably well-tolerated formulation for treating off periods. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society Show less
Geerse, D.J.; Coolen, B.; Hilten, J.J. van; Roerdink, M. 2022
External visual cueing is a well-known means to target freezing of gait (FOG) in Parkinson's disease patients. Holocue is a wearable visual cueing application that allows the HoloLens 1 mixed... Show moreExternal visual cueing is a well-known means to target freezing of gait (FOG) in Parkinson's disease patients. Holocue is a wearable visual cueing application that allows the HoloLens 1 mixed-reality headset to present on-demand patient-tailored action-relevant 2D and 3D holographic visual cues in free-living environments. The aim of this study involving 24 Parkinson's disease patients with dopaminergic "ON state " FOG was two-fold. First, to explore unfamiliarity and habituation effects associated with wearing the HoloLens on FOG. Second, to evaluate the potential immediate effect of Holocue on alleviating FOG in the home environment. Three sessions were conducted to examine (1) the effect of wearing the unfamiliar HoloLens on FOG by comparing walking with and without the HoloLens, (2) habituation effects to wearing the HoloLens by comparing FOG while walking with HoloLens over sessions, and (3) the potential immediate effect of Holocue on FOG by comparing walking with HoloLens with and without Holocue. Wearing the HoloLens (without Holocue) did significantly increase the number and duration of FOG episodes, but this unfamiliarity effect disappeared with habituation over sessions. This not only emphasizes the need for sufficient habituation to unfamiliar devices, but also testifies to the need for research designs with appropriate control conditions when examining effects of unfamiliar wearable cueing devices. Holocue had overall no immediate effect on FOG, although objective and subjective benefits were observed for some individuals, most notably those with long and/or many FOG episodes. Our participants raised valuable opportunities to improve Holocue and confirmed our assumptions about current and anticipated future design choices, which supports ongoing Holocue development for and with end users. Show less
