Journal of Parkinson's Disease - Volume 11, issue 1

Authors: Rutten, Sonja | van den Heuvel, Odile A. | de Kruif, Anja (J.) T.C.M. | Schoonmade, Linda J. | Schumacher, Eva I.M. | Vermunt, Kees | Hagen, Rob | van Wegen, Erwin E.H. | Rutten, Koen

Article Type: Review Article

Abstract: Background: A better understanding of the subjective experience of living with Parkinson’s disease (PD) and the factors that influence this experience can be used to improve wellbeing of people with PD (PwP). Objective: To gain more insight in the subjective experience of PD from the PwP’s perspective, and the factors that contribute to this experience. Methods: In this qualitative review, we performed a systematic search of qualitative studies discussing the subjective experience of PD and extracted reported themes (first order themes). Using a meta-ethnographic approach, we categorized the first order themes into second order themes, and …created a third order construct: a holistic model of the subjective experience of living with PD. Results: We included 20 studies with a total sample of 279 PwP. Data-extraction yielded 227 first order themes, which were categorized into the second order themes: 1) Awareness, 2) Disruption, 3) Adjustment, 4) The external environment, and 5) The changing self. With these themes, we developed the “model of dialectic change” which conceptualizes life with PD as a transformative journey, wherein PwP employ strategies to stabilize their changeable relationship with their external environment, while simultaneously redefining their self-concept. Conclusion: Our findings indicate that not only the symptoms of PD, but also the manner in which these cause disruptions in the PwP’s interaction with their personal environment and self-concept, determine the subjective experience of PD and quality of life. Some PwP experience problems with adjusting, resulting in psychological distress. This calls for a holistic, multidisciplinary and participatory approach of PD. Show more

Keywords: Qualitative research, review, meta-ethnography, Parkinson’s disease, lived experience, subjective experience

DOI: 10.3233/JPD-202299

Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 139-151, 2021

Authors: Cirstea, Mihai S. | Sundvick, Kristen | Golz, Ella | Yu, Adam C. | Boutin, Rozlyn C.T. | Kliger, Daniel | Finlay, Brett B. | Appel-Cresswell, Silke

Article Type: Short Communication

Abstract: The gut microbiome has been increasingly implicated in Parkinson’s disease (PD); however, most existing studies employ bacterial-specific sequencing, and have not investigated non-bacterial microbiome constituents. Here, we use fungal-specific internal transcribed spacer (ITS)-2 amplicon sequencing in a cross-sectional PD cohort to investigate associations between the fungal gut microbiome and PD. Fungal load among participants was extremely low, and genera identified were almost exclusively of proposed dietary or environmental origin. We observed significantly lower fungal DNA relative to bacterial DNA among PD patients. No fungi differed in abundance between patients and controls, nor were any associated with motor, cognitive, or gastrointestinal …features among patients. Show more

Keywords: Fungal microbiome, gut microbiome, gut-brain axis, mycobiome, Parkinson’s disease

DOI: 10.3233/JPD-202237

Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 153-158, 2021

Authors: Cilia, Roberto | Piatti, Marco | Cereda, Emanuele | Bolliri, Carlotta | Caronni, Serena | Ferri, Valentina | Cassani, Erica | Bonvegna, Salvatore | Ferrarese, Carlo | Zecchinelli, Anna L. | Barichella, Michela | Pezzoli, Gianni

Article Type: Research Article

Abstract: Background: Although abnormalities in gut microbiota are hypothesized to influence the pathogenesis and clinical phenotype of Parkinson’s disease (PD), prospective studies on de novo patients are lacking. Objective: To preliminarily investigate whether gut microbiota in early untreated PD may predict motor and non-motor features progression over a 3-year period. Methods: 16S ribosomal RNA gene amplicons were sequenced on fecal samples of 39 de novo PD patients. Multiple confounders were taken into account, including dietary habits. Motor and non-motor symptoms were assessed using validated scales at baseline and followed-up yearly for 3 years. At last …follow-up, a detailed neuropsychological assessment was additionally performed. A general linear model for repeated measurements— adjusted by dopaminergic therapy at follow-up— was used to investigate the relationship between bacterial taxa abundance at baseline (stratified by the median of distribution at baseline) and outcome variables. Results: Twenty-five patients were included (11 refused, 2 lost at follow-up, 1 died). Lower abundance of Roseburia (Firmicutes phylum) at baseline was associated with worse evolution of motor, non-motor and cognitive functions at 3-year follow-up. Similarly, lower abundance of Ruminococcaceae and Actinobacteria at baseline was associated with faster worsening of global cognitive functions. At follow-up, frontal lobe functions were the features most robustly associated with baseline microbial abnormalities. Conclusion: In the present exploratory study on de novo PD, we found an association between abnormal distribution of specific bacterial taxa and the progression of motor and non-motor features over a 3-year period. This proof-of-principle study supports the design of a larger observational study aiming to determine whether these differences survive multiple-comparison correction and define microbiota-specific subgroups suitable for therapeutic targeting. Show more

Keywords: Parkinson’s disease, de novo, gut microbiota, prospective study, prognosis

DOI: 10.3233/JPD-202297

Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 159-170, 2021

Authors: Cossais, François | Schaeffer, Eva | Heinzel, Sebastian | Zimmermann, Jessica | Niesler, Beate | Röth, Ralph | Rappold, Gudrun | Scharf, Amelie | Zorenkov, Dmitri | Lange, Christina | Barrenschee, Martina | Margraf, Nils G. | Ellrichmann, Mark | Berg, Daniela | Böttner, Martina | Wedel, Thilo

Article Type: Short Communication

Abstract: Still little is known about the nature of the gastrointestinal pathological alterations occurring in Parkinson’s disease (PD). Here, we used multiplexed mRNA profiling to measure the expression of a panel of 770 genes related to neuropathological processes in deep submucosal rectal biopsies of PD patients and healthy controls. Altered enteric neuropathological traits based on the expression of 22 genes related to neuroglial and mitochondrial functions, vesicle trafficking and inflammation was observed in 9 out of 12 PD patients in comparison to healthy controls. These results provide new evidences that intestinal neuropathological alterations may occur in a large proportion of PD …patients. Show more

Keywords: Parkinson’s disease, gut-brain-axis, neuropathology, inflammation, cyclooxygenase 2, adaptor protein complex 2, toll-like receptor, nuclear receptor NR4A2, neuro-oncological ventral antigen 1, phospholipase A2 group IIA

DOI: 10.3233/JPD-202258

Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 171-176, 2021

Authors: Olanow, C. Warren | Espay, Alberto J. | Stocchi, Fabrizio | Ellenbogen, Aaron L. | Leinonen, Mika | Adar, Liat | Case, Ryan J. | Orenbach, Shir Fuchs | Yardeni, Tami | Oren, Sheila | Poewe, Werner | for the 006 study group

Article Type: Research Article

Abstract: Background: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson’s disease (PD) experiencing motor fluctuations Objective: Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD. Methods: This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour ‘waking-day’ infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). Supplemental oral doses of levodopa were permitted for patients in both …groups if required. In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours). Results: A total of 38 patients were randomized and 33 (87%) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[– 3.3, – 0.7] hours (p  = 0.003). ON time with no/mild dyskinesia (no troublesome dyskinesia) was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p  < 0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[– 1.8, – 0.5] hours (p ≤0.001). Reduction in OFF time was larger in the 24-hour group (– 2.8[– 4.6, – 0.9] hours; p  = 0.004) than in the 14-hour group (– 1.3[– 3.1, 0.5] hours; p  = 0.16). Complete resolution of OFF time was observed in 42% (n  = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event. Conclusion: This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy. Show more

Keywords: Motor fluctuations, ND0612, Parkinson’s disease, subcutaneous levodopa infusion

DOI: 10.3233/JPD-202285

Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 177-186, 2021

Authors: Abbruzzese, Giovanni | Kulisevsky, Jaime | Bergmans, Bruno | Gomez-Esteban, Juan C. | Kägi, Georg | Raw, Jason | Stefani, Alessandro | Warnecke, Tobias | Jost, Wolfgang H. | the SYNAPSES Study Investigators Group

Article Type: Research Article

Abstract: Background: Safinamide modulates both dopaminergic and glutamatergic systems with positive effects on motor and non-motor symptoms of Parkinson’s disease (PD). The drug utilization study SYNAPSES was designed to investigate the use of safinamide in routine clinical practice, as recommended by the European Medicines Agency. Objective: To describe the occurrence of adverse events in PD patients treated with safinamide in real-life conditions. Methods: The SYNAPSES trial is an observational, European, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months with analyses performed in the overall population and in patients aged >75 years, with relevant comorbidities …and with psychiatric conditions. Results: Of the 1610 patients included, 82.4% were evaluable after 12 months with 25.1% of patients >75 years, 70.8% with relevant comorbidities and 42.4% with psychiatric conditions. During observation 45.8% patients experienced adverse events, 27.7% patients had adverse drug reactions and 9.2% patients had serious adverse events. The adverse events were those already described in the patients’ information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroup of patients. Clinically significant improvements were seen in the UPDRS motor score and in the UPDRS total score in ≥40% of patients, according to the criteria developed by Shulman et al. Conclusion: The SYNAPSES study confirms the good safety profile of safinamide even in special groups of patients. Motor complications and motor scores improved with clinically significant results in the UPDRS scale maintained in the long-term. Show more

Keywords: Parkinson’s disease, safinamide, MAO-B inhibitor, real-life evaluation

DOI: 10.3233/JPD-202224

Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 187-198, 2021

Authors: Lai, Yijie | Song, Yunhai | Huang, Peng | Wang, Tao | Wang, Linbin | Pan, Yixin | Sun, Qingfang | Sun, Bomin | Zhang, Chencheng | Li, Dianyou

Article Type: Research Article

Abstract: Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) has been reported to be effective for camptocormia in Parkinson’s disease (PD). However, the association between clinical effectiveness and the stimulated volumes or structural connectivity remains unexplored. Objective: To investigate the effectiveness of STN-DBS for treating camptocormia in PD and its association with volumes of tissue activated (VTA) and structural connectivity. Methods: We reviewed video recordings of patients who had undergone STN-DBS. The total and upper camptocormia (TCC and UCC) angles were measured to quantify changes in camptocormia. The Movement Disorders Society Unified Parkinson’s Disease Rating Scale …III (MDS-UPDRS III) was used to assess motor symptoms. Pre- and postoperative brain images were collected for modeling volume of VTA and structural connectivity using Lead-DBS software. Results: Participants included 36 patients with PD (8 with TCC-camptocormia and 2 with UCC-camptocormia) treated with bilateral STN-DBS. After surgery, patients showed a significant improvement in postural alignment at follow-up (mean follow-up duration: 6.0±2.2 months). In the entire sample, higher structural connectivity to the right supplementary motor area (SMA) and right lateral premotor cortex along the dorsal plane (PMd) was associated with larger postsurgical improvements in axial signs and TCC angles after stimulation was turned on. In patients diagnosed with camptocormia, larger improvement in camptocormia angles after STN-DBS was associated with a larger VTA overlap with STN (R  = 0.75, p  = 0.032). Conclusion: This study suggests that both VTA overlap with STN and structural connectivity to cortical motor regions are associated with the effectiveness of STN-DBS for managing camptocormia in PD. Show more

Keywords: Deep brain stimulation, Parkinson’s disease, camptocormia, subthalamic nucleus, volume of tissue activated, structural connectivity

DOI: 10.3233/JPD-202259

Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 199-210, 2021

Authors: Kim, Ji Hee | Lee, Heui Seung | Ahn, Jun Hyong | Oh, Jae Keun | Chang, In Bok | Song, Joon Ho | Wee, Jee Hye | Min, Chan Yang | Yoo, Dae Myoung | Choi, Hyo Geun

Article Type: Research Article

Abstract: Background: Although the dopaminergic system is interconnected with the hypothalamic-pituitary-thyroid axis, few studies have explained the causal relationship between thyroid disease and Parkinson’s disease (PD). Objective: The goal of this study was to investigate the association between thyroid diseases and PD in Korean residents. Methods: The Korean National Health Insurance Service-National Sample Cohort, which includes individuals aged ≥40 years, was assessed from 2002 to 2015. A total of 5,586 PD patients were matched by age, sex, income, and the region of residence with 22,344 control participants at a ratio of 1:4. In the PD and control …groups, previous histories of levothyroxine treatment, goiter, hypothyroidism, thyroiditis, and hyperthyroidism were investigated. Results: The rates of levothyroxine treatment for more than 3 months, hypothyroidism, and hyperthyroidism were higher in the PD group than the control group (3.2%, 3.8%, and 2.8% vs. 2.5%, 2.9%, and 1.9%, respectively, p  < 0.05). The adjusted odds ratios (ORs) in model 2, which was adjusted for all potential confounders, for hypothyroidism and hyperthyroidism in the PD group were 1.25 (95% confidence interval (CI) 1.01–1.55, p  = 0.044) and 1.37 (95% CI 1.13–1.67, p  = 0.002), respectively. In subgroup analyses, the association between hypothyroidism and PD was maintained in men older than 70 years and the association between hyperthyroidism and PD was maintained in women younger than 70 years. Conclusion: Both hyperthyroidism and hypothyroidism were associated with higher risk of PD, particularly for women younger than 70 years and men older than 70 years, respectively. Show more

Keywords: Hyperthyroidism, hypothyroidism, neurodegenerative disorder, Parkinson’s disease, pathophysiology, thyroid disease, thyroid dysfunction

DOI: 10.3233/JPD-202265

Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 211-220, 2021

Authors: Niimi, Yoshiki | Mizutani, Yasuaki | Akiyama, Hisako | Watanabe, Hirohisa | Shiroki, Ryoichi | Hirabayashi, Yoshio | Hoshinaga, Kiyotaka | Mutoh, Tatsuro

Article Type: Research Article

Abstract: Background: As mutations in glucocerebrosidase 1 (GBA1 ) are a major risk factor for Parkinson’s disease (PD), decreased GBA1 activity might play an important role in the pathogenesis of the disease. However, there are currently no reports on glucosylceramide levels in the cerebrospinal fluid (CSF) in PD. Objective: We investigated whether glucosylceramide accumulation and abnormal immune status in the brain are associated with PD. Methods: We measured glucosylceramide by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) as well as levels of the active fragment of complement C5, C5a, in the CSF of 33 PD, 15 amyotrophic lateral …sclerosis (ALS) and 22 neurologically normal control (NNC) subjects. Serum C5a levels in all PD and ALS cases and in a limited number of NNC subjects (n  = 8) were also measured. Results: C5a levels in CSF were significantly downregulated in PD compared with NNC. Moreover, CSF C5a/serum C5a ratio showed pronounced perturbations in PD and ALS patients. LC-ESI-MS/MS revealed a statistically significant accumulation of a specific subspecies of glucosylceramide (d18 : 1/C23 : 0 acyl chain fatty acid) in ALS, but not in PD. Interestingly, CSF glucosylceramide (d18 : 1/C23 : 0) exhibited a significant correlation with CSF C5a levels in PD, but not ALS. No correlation was observed between C5a levels or glucosylceramide subspecies content and disease duration, levodopa equivalent daily dose or Hoehn & Yahr staging in PD. Conclusion: Our findings demonstrate complement dysregulation without glucosylceramide accumulation in PD CSF. Furthermore, we found an association between a specific glucosylceramide subspecies and immune status in PD. Show more

Keywords: Parkinson’s disease, complement, mass spectrometry, innate immunity, glycosphingolipids

DOI: 10.3233/JPD-202310

Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 221-232, 2021

Authors: Tong, Qiang | Chen, Liam

Article Type: Short Communication

Abstract: Orthostatic hypotension (OH) is a common non-motor symptom in Parkinson’s disease (PD) and is linked with increased mortality risk among the elderly. Although the locus coeruleus (LC) is the major source of noradrenaline (NA) modulation in the brain, its role in the pathogenesis of OH in PD remains largely elusive. Here we examined 44 well characterized postmortem brains of PD patients and available clinical data to explore the relationship between OH and LC pathology in PD. Our results failed to indicate that the LC pathology as well as the substantia nigra pathology were robustly associated with the presence of OH …in PD patients, suggesting targeting LC norepinephrinergic system alone may not be sufficient to treat OH in PD. Show more

Keywords: Parkinson’s disease, locus coeruleus, substantia nigra, orthostatic hypotension, norepinephrinergic

DOI: 10.3233/JPD-202325

Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 233-237, 2021