Journal of Parkinson's Disease - Volume 11, issue 3

Authors: Renko, Juho-Matti | Mahato, Arun Kumar | Visnapuu, Tanel | Valkonen, Konsta | Karelson, Mati | Voutilainen, Merja H. | Saarma, Mart | Tuominen, Raimo K. | Sidorova, Yulia A.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the …transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo . Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP+ -induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and seemed to protect dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying, therapy for PD. Show more

Keywords: BT44, RET agonist, glial cell line-derived neurotrophic factor, receptor tyrosine kinase RET, AKT pathway, MAPK pathway, rat 6-hydroxydopamine (6-OHDA) model, neuroprotection, Parkinson’s disease

DOI: 10.3233/JPD-202400

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1023-1046, 2021

Authors: Suzuki, Keisuke | Numao, Ayaka | Komagamine, Tomoko | Haruyama, Yasuo | Kawasaki, Akiko | Funakoshi, Kei | Fujita, Hiroaki | Suzuki, Shiho | Okamura, Madoka | Shiina, Tomohiko | Hirata, Koichi

Article Type: Research Article

Abstract: Background: The coronavirus disease 2019 (COVID-19) pandemic has negatively affected the mental health of the general population. Objective: We investigated the determinants of quality of life (QOL) in Parkinson’s disease (PD) patients during the COVID-19 pandemic. Methods: Impacts of lifestyle changes due to the COVID-19 pandemic on 100 patients with PD and their caregivers/spouses were assessed. The Hospital Anxiety and Depression Scale was used to assess anxiety and depression. The physical component summary (PCS) and mental component summary (MCS) scores of the short form (SF)-8 were used to evaluate health-related QOL. Results: Regarding health-related …QOL, physical function, role physical, general health, vitality and the PCS score were significantly worse in PD patients than in caregivers. Worsening of PD-related symptoms, increased stress, and decreased physical activity were observed in 29.0%, 37.0% and 44.0% of PD patients, respectively. Sixteen patients (16.0%) experienced problems with hospital access, but none reported medication shortages. Strong concerns about COVID-19 were reported by 47.0% of caregivers and 50.0% of PD patients. In PD patients, increased gait disturbance and rigidity, disease severity, smoking, the levodopa equivalent dose and decreased body weight predicted a worse PCS score; anxiety, depression, female sex, stress and long disease duration predicted a worse MCS score. In caregivers, age and smoking contributed to a worse PCS score; depression, stress and worsening patient mood contributed to a worse MCS score. Conclusion: We report the negative impacts of the COVID-19 pandemic on health-related QOL and its determinants in PD patients and their caregivers. Show more

Keywords: Caregivers, COVID-19, Parkinson’s disease, quality of life, SARS-CoV-2

DOI: 10.3233/JPD-212560

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1047-1056, 2021

Authors: Phanhdone, Tiffany | Drummond, Patrick | Meisel, Talia | Friede, Naomi | Di Rocco, Alessandro | Chodosh, Joshua | Fleisher, Jori

Article Type: Research Article

Abstract: Background: Patients with Parkinson’s disease (PD) are at higher risk of vaccine-preventable respiratory infections. However, advanced, homebound individuals may have less access to vaccinations. In light of COVID-19, understanding barriers to vaccination in PD may inform strategies to increase vaccine uptake. Objective: To identify influenza and pneumococcal vaccination rates, including barriers and facilitators to vaccination, among homebound and ambulatory individuals with PD and related disorders. Methods: Cross-sectional US-based study among individuals with PD, aged > 65 years, stratified as homebound or ambulatory. Participants completed semi-structured interviews on vaccination rates and barriers, and healthcare utilization. Results: Among …143 participants, 9.8% had missed all influenza vaccinations in the past 5 years, and 32.2% lacked any pneumococcal vaccination, with no between-group differences. Homebound participants (n  = 41) reported difficulty traveling to clinic (p  < 0.01) as a vaccination barrier, and despite similar outpatient visit frequencies, had more frequent emergency department visits (31.7% vs. 9.8%, p  < 0.01) and hospitalizations (14.6% vs. 2.9%, p  = 0.03). Vaccine hesitancy was reported in 35% of participants, vaccine refusal in 19%, and 13.3% reported unvaccinated household members, with no between-group differences. Nearly 13% thought providers recommended against vaccines for PD patients, and 31.5% were unsure of vaccine recommendations in PD. Conclusion: Among a sample of homebound and ambulatory people with PD, many lack age-appropriate immunizations despite ample healthcare utilization. Many participants were unsure whether healthcare providers recommend vaccinations for people with PD. In light of COVID-19, neurologist reinforcement that vaccinations are indicated, safe, and recommended may be beneficial. Show more

Keywords: Vaccine hesitancy, vaccination, Parkinson’s disease, COVID-19, influenza, pneumonia, health services, homebound

DOI: 10.3233/JPD-202497

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1057-1065, 2021

Authors: Templeton, John Michael | Poellabauer, Christian | Schneider, Sandra

Article Type: Research Article

Abstract: Background: Due to the COVID-19 pandemic, beneficial physical intervention classes for individuals with Parkinson’s disease (PD) were cancelled. Objective: To understand effects of the COVID-19 stay-at-home mandate and the inability to participate in recommended and structured physical interventions as a consequence of these mandates, specifically designed mobile assessments were used that collected both self-reporting information and objective task-based metrics of neurocognitive functions to assess symptom changes for individuals with PD. Methods: Self-reporting questionnaires focusing on overall quality of life (e.g., when individuals typically feel at their best, changes in activity levels, and symptom progression) were given …to all individuals (n  = 28). In addition, mobile-based neurocognitive assessments were administered to a subset of the population (n  = 8) to quantitatively assess changes due to COVID-19 restrictions. Results: The highest self-reported factors in which individuals denoted feeling their best were after exercise (67.86%) and being in a comfortable and supportive environment (60.71%). Objective measures found overall duration of physical activity during the stay-at-home mandate decreased significantly (p  = 0.022). With the lack of overall activity, 82.14%of individuals self-reported having at least one symptom that worsened moderately or higher. Further testing, using mobile-based assessments, showed average completion times of functional tasks increased, taking about 2.1 times longer, while accuracy metrics showed overall degradation. Conclusion: Although the COVID-19 stay-at-home mandate was intended to help protect individuals at high risk from coming into contact with the virus, it also prevented individuals from receiving recommended supervised exercise interventions resulting in significant negative effects in social well-being and across motor and speech neurocognitive tasks for individuals with PD. Show more

Keywords: COVID-19, Parkinson’s disease, physical interventions, neurocognitive assessment, quality of life

DOI: 10.3233/JPD-212553

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1067-1077, 2021

Authors: Poewe, Werner | Volc, Dieter | Seppi, Klaus | Medori, Rossella | Lührs, Petra | Kutzelnigg, Alexandra | Djamshidian, Atbin | Thun-Hohenstein, Caroline | Meissner, Wassilios G. | Rascol, Olivier | Schneeberger, Achim | Staffler, Günther | on behalf of the AFF011 investigators | AFF011 study investigators: | Poewe, Werner | Seppi, Klaus | Djamshidian, Atbin | deMarzi, Roberto | Heim, Beatrice | Mangesius, Stephanie | Stolz, Raphaela | Wachowicz, Katarzyna | Volc, Dieter | Thun-Hohenstein, Caroline | Riha, Constanze | Schneeberger, Achim | Bürger, Vera | Galabova, Gergana

Article Type: Research Article

Abstract: Background: Immunotherapies targeting α-synuclein aim to limit its extracellular spread in the brain and prevent progression of pathology in Parkinson’s disease (PD). PD03A is a specific active immunotherapy (SAIT) involving immunization with a short peptide formulation. Objective: This phase 1 study characterized the safety and tolerability of PD03A in patients with early PD. A key secondary objective was to evaluate immunological activity following immunization. Methods: This was a phase 1 study of two different doses of PD03A versus placebo in PD patients. Patients were randomized (1:1:1) to receive four priming plus one booster vaccination of PD03A …15μg, PD03A 75μg or placebo and were followed for 52 weeks. Results: Overall, 36 patients were randomized, of which 35 received five immunizations and completed the study. All patients experienced at least one adverse event. Transient local injection site reactions affected all but two patients; otherwise most AEs were considered unrelated to study treatment. A substantial IgG antibody response against PD03 was observed with a maximum titer achieved at Week-12. Differences in titers between both active groups versus placebo were statistically significant from the second immunization at Week-8 until Week-52. Conclusion: The safety profile and positive antibody response of PD03A supports the further development of active immunotherapeutic approaches for the treatment of PD. Show more

Keywords: Parkinson’s disease, α-synuclein, immunization, active immunotherapy

DOI: 10.3233/JPD-212594

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1079-1089, 2021

Authors: Boutros, Sydney Weber | Raber, Jacob | Unni, Vivek K.

Article Type: Research Article

Abstract: Background: Alpha-synuclein (αsyn) characterizes neurodegenerative diseases known as synucleinopathies. The phosphorylated form (psyn) is the primary component of protein aggregates known as Lewy bodies (LBs), which are the hallmark of diseases such as Parkinson’s disease (PD). Synucleinopathies might spread in a prion-like fashion, leading to a progressive emergence of symptoms over time. αsyn pre-formed fibrils (PFFs) induce LB-like pathology in wild-type (WT) mice, but questions remain about their progressive spread and their associated effects on behavioral performance. Objective: To characterize the behavioral, cognitive, and pathological long-term effects of LB-like pathology induced after bilateral motor cortex PFF injection in …WT mice and to assess the ability of mouse αsyn-targeted antisense oligonucleotides (ASOs) to ameliorate those effects. Methods: We induced LB-like pathology in the motor cortex and connected brain regions of male WT mice using PFFs. Three months post-PFF injection (mpi), we assessed behavioral and cognitive performance. We then delivered a targeted ASO via the ventricle and assessed behavioral and cognitive performance 5 weeks later, followed by pathological analysis. Results: At 3 and 6 mpi, PFF-injected mice showed mild, progressive behavioral deficits. The ASO reduced total αsyn and psyn protein levels, and LB-like pathology, but was also associated with some deleterious off-target effects not involving lowering of αsyn, such as a decline in body weight and impairments in motor function. Conclusions: These results increase understanding of the progressive nature of the PFF model and support the therapeutic potential of ASOs, though more investigation into effects of ASO-mediated reduction in αsyn on brain function is needed. Show more

Keywords: Alpha-synuclein, antisense oligonucleotides, preformed fibril, synucleinopathies, lewy body, learning, memory

DOI: 10.3233/JPD-212566

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1091-1115, 2021

Authors: Ma, Ling-Zhi | Zhang, Can | Wang, Han | Ma, Ya-Hui | Shen, Xue-Ning | Wang, Jian | Tan, Lan | Dong, Qiang | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Neurofilament light (NfL) can reflect the extent of neuron/axon damage, thus providing an opportunity to examine the severity and progression of the diseases with such damage. Objective: Whether serum NfL can be used as an indicator to monitor the cognitive progress of de novo Parkinson’s disease (PD) remains unclear. Methods: In this research, 144 healthy controls and 301 de novo PD patients from Parkinson’s Progression Markers Initiative (PPMI) were recruited. Linear mixed effects models were used to examine the associations of baseline/longitudinal serum NfL with cognitive decline. Cox regression was used to detect cognitive progression …in PD participants. Results: We found PD patients had higher serum NfL than controls at baseline (p  = 0.031), and NfL increase was faster in PD group (p  < 0.001). Both baseline serum NfL and its rate of change predicted measurable cognitive decline in early PD (MoCA, β= –0.014, p  < 0.001; β= –0.002, p  < 0.001, respectively). Additionally, we observed that NfL levels were also able to predict progression in different diagnostic groups and Amyloid- PD and Amyloid+PD groups. After an average follow-up of 6.37±1.84 years, the baseline NfL of the third tertile of high concentrations was associated with a future high risk of PD dementia (adjusted HR 6.33, 95% CI 2.62–15.29, p  < 0.001). Conclusion: In conclusion, our results indicated that the serum NfL concentration could function as an easily accessible biomarker to monitor the severity and progression of cognitive decline in PD. Show more

Keywords: Parkinson’s disease, neurofilament light, Parkinson’s progression markers initiative, cognition, tau

DOI: 10.3233/JPD-212535

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1117-1127, 2021

Authors: Chen, Szu-Ju | Chi, Yu-Chiao | Ho, Chang-Han | Yang, Wei-Shiung | Lin, Chin-Hsien

Article Type: Research Article

Abstract: Background: Lipopolysaccharide-binding protein (LBP) presents bacterial endotoxin, lipopolysaccharides, to cellular surface pattern receptors for immune responses in the gut-brain axis of Parkinson’s disease (PD). Objective: We investigated whether plasma LBP levels were associated with PD severity and progression. Methods: This study included 397 participants (248 PD patients and 149 controls). We measured participants’ plasma levels of LBP and pro-inflammatory cytokines, including TNF-α , IL-6, andIL-17A. PD patients underwent motor and cognition evaluations at baseline and at a mean follow-up interval of 4.7±2.3 years. We assessed the progression of motor and cognition symptoms based on changes in …the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III motor score and Mini-Mental State Examination (MMSE) score, respectively. Results: Plasma LBP levels were lower in PD patients than controls (9.08±2.91 vs. 10.10±3.00μ g/ml, p  < 0.01). A multiple logistic regression model with adjustment for age, sex, and plasma cytokine levels revealed that reduced plasma LBP levels were associated with increased PD risk (odds ratio 0.816, [95% CI 0.717–0.929], p  = 0.002). Among PD patients, LBP levels were correlated with MDS-UPDRS part III motor score after adjustment for confounders (coefficient = 0.636, p  = 0.017), but not with MMSE score. Adjusted Cox regression analysis showed that higher plasma LBP levels associated with faster motor progression (adjusted hazard ratio 1.084 [95% CI 1.011–1.163], p  = 0.024) during follow-up. Conclusion: Our results demonstrated that plasma LBP levels reflect risk, motor symptom severity and progression in patients with PD. Show more

Keywords: Parkinson’s disease, lipopolysaccharide-binding protein (LBP), lipopolysaccharide, endotoxin, neuroinflammation, gut-brain axis

DOI: 10.3233/JPD-212574

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1129-1139, 2021

Authors: Avisar, Hila | Guardia-Laguarta, Cristina | Area-Gomez, Estela | Surface, Matthew | Chan, Amanda K. | Alcalay, Roy N. | Lerner, Boaz

Article Type: Research Article

Abstract: Background: The role of the lipidome as a biomarker for Parkinson’s disease (PD) is a relatively new field that currently only focuses on PD diagnosis. Objective: To identify a relevant lipidome signature for PD severity markers. Methods: Disease severity of 149 PD patients was assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Montreal Cognitive Assessment (MoCA). The lipid composition of whole blood samples was analyzed, consisting of 517 lipid species from 37 classes; these included all major classes of glycerophospholipids, sphingolipids, glycerolipids, and sterols. To handle the high number of lipids, the selection …of lipid species and classes was consolidated via analysis of interrelations between lipidomics and disease severity prediction using the random forest machine-learning algorithm aided by conventional statistical methods. Results: Specific lipid classes dihydrosphingomyelin (dhSM), plasmalogen phosphatidylethanolamine (PEp), glucosylceramide (GlcCer), dihydro globotriaosylceramide (dhGB3), and to a lesser degree dihydro GM3 ganglioside (dhGM3), as well as species dhSM(20:0), PEp(38:6), PEp(42:7), GlcCer(16:0), GlcCer(24:1), dhGM3(22:0), dhGM3(16:0), and dhGB3(16:0) contribute to PD severity prediction of UPDRS III score. These, together with age, age at onset, and disease duration, also contribute to prediction of UPDRS total score. We demonstrate that certain lipid classes and species interrelate differently with the degree of severity of motor symptoms between men and women, and that predicting intermediate disease stages is more accurate than predicting less or more severe stages. Conclusion: Using machine-learning algorithms and methodologies, we identified lipid signatures that enable prediction of motor severity in PD. Future studies should focus on identifying the biological mechanisms linking GlcCer, dhGB3, dhSM, and PEp with PD severity. Show more

Keywords: Parkinson’s disease (PD), PD severity, lipidomics, lipidome, UPDRS, machine learning

DOI: 10.3233/JPD-202476

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1141-1155, 2021

Authors: Hughes, Laura P. | Pereira, Marilia M.M. | Hammond, Deborah A. | Kwok, John B. | Halliday, Glenda M. | Lewis, Simon J.G. | Dzamko, Nicolas

Article Type: Research Article

Abstract: Background: Reduced activity of lysosomal glucocerebrosidase is found in brain tissue from Parkinson’s disease patients. Glucocerebrosidase is also highly expressed in peripheral blood monocytes where its activity is decreased in Parkinson’s disease patients, even in the absence of GBA mutation. Objective: To measure glucocerebrosidase activity in cryopreserved peripheral blood monocytes from 30 Parkinson’s disease patients and 30 matched controls and identify any clinical correlation with disease severity. Methods: Flow cytometry was used to measure lysosomal glucocerebrosidase activity in total, classical, intermediate, and non-classical monocytes. All participants underwent neurological examination and motor severity was assessed by …the Movement Disorders Society Unified Parkinson’s Disease Rating Scale. Results: Glucocerebrosidase activity was significantly reduced in the total and classical monocyte populations from the Parkinson’s disease patients compared to controls. GCase activity in classical monocytes was inversely correlated to motor symptom severity. Conclusion: Significant differences in monocyte glucocerebrosidase activity can be detected in Parkinson’s disease patients using cryopreserved mononuclear cells and monocyte GCase activity correlated with motor features of disease. Being able to use cryopreserved cells will facilitate the larger multi-site trials needed to validate monocyte GCase activity as a Parkinson’s disease biomarker. Show more

Keywords: Parkinson’s disease, glucocerebrosidase, monocyte, inflammation, toll-like receptor

DOI: 10.3233/JPD-202508

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1157-1165, 2021