Journal of Parkinson's Disease - Volume Pre-press, issue Pre-press

Authors: Weber Boutros, Sydney | 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. Pre-press, no. Pre-press, pp. 1-24, 2021

Authors: Lawson, Rachael A. | Williams-Gray, Caroline H. | Camacho, Marta | Duncan, Gordon W. | Khoo, Tien K. | Breen, David P. | Barker, Roger A. | Rochester, Lynn | Burn, David J. | Yarnall, Alison J. | on behalf of the ICICLE-PD study group

Article Type: Research Article

Abstract: Background: Cognitive impairment is common in Parkinson’s disease (PD), with 80% cumulatively developing dementia (PDD). Objective: We sought to identify tests that are sensitive to change over time above normal ageing so as to refine the neuropsychological tests predictive of PDD. Methods: Participants with newly diagnosed PD (n  = 211) and age-matched controls (n  = 99) completed a range of clinical and neuropsychological tests as part of the ICICLE-PD study at 18-month intervals over 72 months. Impairments on tests were determined using control means (<1-2SD) and median scores. Mild cognitive impairment (PD-MCI) was classified using 1-2SD below normative …values. Linear mixed effects modelling assessed cognitive decline, while Cox regression identified baseline predictors of PDD. Results: At 72 months, 46 (cumulative probability 33.9%) participants had developed PDD; these participants declined at a faster rate in tests of global cognition, verbal fluency, memory and attention (p  <  0.05) compared to those who remained dementia-free. Impaired baseline global cognition, visual memory and attention using median cut-offs were the best predictors of early PDD (area under the curve [AUC] = 0.88, p  <  0.001) compared to control-generated cut-offs (AUC = 0.76–0.84, p  <  0.001) and PD-MCI (AUC] = 0.64–0.81, p  <  0.001). Impaired global cognition and semantic fluency were the most useful brief tests employable in a clinical setting (AUC = 0.79, p  <  0.001). Conclusion: Verbal fluency, attention and memory were sensitive to change in early PDD and may be suitable tests to measure therapeutic response in future interventions. Impaired global cognition, attention and visual memory were the most accurate predictors for developing a PDD. Future studies could consider adopting these tests for patient clinical trial stratification. Show more

Keywords: Parkinson’s disease, neurocognitive disorders, cognitive dysfunction, neuropsychological tests

DOI: 10.3233/JPD-212581

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Kim, Seung Woo | Chung, Seok Jong | Lee, Sangwon | Oh, KyeongTaek | Yoo, Sun Kook | Lee, Phil Hyu | Kim, Seung Min | Young Shin, Ha | Yun, Mijin

Article Type: Research Article

Abstract: Background: Sudomotor dysfunction is common in patients with multiple system atrophy (MSA). Postganglionic sudomotor dysfunction in MSA, which can be assessed using quantitative sudomotor axon reflex testing (QSART), results from the degeneration of preganglionic sympathetic neurons and direct loss of postganglionic fibers. Objective: We investigate whether abnormal QSART responses in patients with MSA are associated with disease severity. Methods: In this retrospective study, patients with probable MSA who underwent both 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT) and autonomic function tests were included. Autonomic function test results were integrated divided into three sub-scores, including sudomotor, …cardiovagal, and adrenergic sub-scores. The sudomotor sub-score represented postganglionic sudomotor function. Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, Part II, and sum of Part I and II scores (Part I + II) to reflect disease severity and 18 F-FDG-PET/CT results were collected. Results: Of 74 patients with MSA, 62.2%demonstrated abnormal QSART results. The UMSARS Part I + II score was significantly higher in the abnormal QSART group than in the normal QSART group (p  = 0.037). In the regression analysis, both UMSARS Part I (β= 1.185, p  = 0.013) and Part II (β= 1.266, p  = 0.021) scores were significantly associated with the sudomotor sub-score. On 18 F-FDG-PET/CT, the abnormal QSART group exhibited more severely decreased metabolic activity in the cerebellum and basal ganglia in patients with MSA-P and MSA-C, respectively. The sudomotor sub-score was significantly associated with regional metabolism in these areas. Conclusion: Patients with MSA and postganglionic sudomotor dysfunction may have worse disease severity and greater neuropathological burden than those without. Show more

Keywords: Multiple system atrophy, sudomotor dysfunction, autonomic dysfunction, brain metabolism.

DOI: 10.3233/JPD-202524

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Yoo, Sang-Won | Ha, Seunggyun | Yoon, Hyukjin | Yoo, Ji-Yeon | Lee, Kwang-Soo | Kim, Joong-Seok

Article Type: Research Article

Abstract: Background: Orthostatic hypotension (OH) may antedate Parkinson’s disease (PD) or be found in early stages of the disease. OH may induce a PD brain to chronic hypotensive insults. 18 F-Florbetaben (18 F-FBB) tracer has a high first-pass influx rate and can be used with positron emission tomography (PET) as a surrogate marker for early- and late-phase evaluation of cerebral perfusion and cerebral amyloidosis, respectively. Objective: In this study, we evaluated whether 18 F-FBB uptake in the early- and late-phases of PD was related to OH. This study manipulated the imaging modality to illustrate the physiology of cerebral flow …with OH in PD (PD + OH). Methods: A group of 73 early-stage PD patients was evaluated with a head-up tilt-test and 18 F-FBB PET imaging. The cognitive status was assessed by a comprehensive battery of neuropsychological tests. PET images were normalized, and both early- and late-phase standardized uptake value ratios (SUVRs) of pre-specified regions were obtained. The associations between regional SUVRs and OH and cognitive status were analyzed. Results: Twenty (27.4%) participants had OH. Thirteen (17.8%) patients were interpreted as having amyloid pathology based on regional 18 F-FBB uptake. Early-phase SUVRs were higher in specific brain regions of PD + OH patients those without OH. However, late-phase SUVRs did not differ between the groups. The early-phase SUVRs were not influenced by amyloid burden or by interaction between amyloid and orthostatic hypotension. Cognitive functions were not disparate when PD + OH patients were contrasted with non-OH patients in this study. Conclusion: Cerebral blood flow was elevated in patients with early PD + OH. This finding suggests augmented cerebral perfusion in PD + OH might be a compensatory regulation in response to chronic OH. Show more

Keywords: Parkinson’s disease, orthostatic hypotension, cerebral perfusion, cerebral autoregulation, 18F-Florbetaben (FBB), positron emission tomography

DOI: 10.3233/JPD-212596

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Tolosa, Eduardo | Ebersbach, Georg | Ferreira, Joaquim J. | Rascol, Olivier | Antonini, Angelo | Foltynie, Thomas | Gibson, Rachel | Magalhaes, Diogo | Francisco Rocha, J. | Lees, Andrew

Article Type: Research Article

Abstract: Background: A greater understanding of the everyday experiences of people with Parkinson’s disease (PD) and their carers may help improve clinical practice. Objective: The Parkinson’s Real-world Impact assesSMent (PRISM) study evaluated medication use, health-related quality of life (HRQoL) and the use of healthcare resources by people with PD and their carers. Methods: PRISM is an observational cross-sectional study, in which people with PD and their carers completed an online survey using structured questionnaires, including the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39), Non-Motor Symptoms Questionnaire (NMSQuest) and Zarit Burden Interview (ZBI). Results: Data were …collected from 861 people with PD (mean age, 65.0 years; mean disease duration, 7.7 years) and 256 carers from six European countries. People with PD reported a large number of different co-morbidities, non-motor symptoms (mean NMSQuest score, 12.8), and impaired HRQoL (median PDQ-39 summary score, 29.1). Forty-five percent of people with PD reported at least one impulse control behaviour. Treatment patterns varied considerably between different European countries. Levodopa was taken in the last 12 months by 85.9% of participants, and as monotherapy by 21.8% . Carers, who were mostly female (64.8%) and the partner/spouse of the person with PD (82.1%), reported mild to moderate burden (mean ZBI total score, 26.6). Conclusions: The PRISM study sheds light on the lives of people with PD and those who care for them, re-emphasising the many challenges they face in everyday life. The study also provides insights into the current treatment of PD in Europe. Show more

Keywords: Caregivers, catechol o-methyltransferase inhibitors, comorbidity, dopamine agonists, Europe, levodopa, observational study, Parkinson’s disease, quality of life, surveys and questionnaires

DOI: 10.3233/JPD-212611

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Sackner-Bernstein, Jonathan

Article Type: Research Article

Abstract: Background: The hallmark of Parkinson’s disease is depletion of dopamine in the basal ganglia. Models of Parkinson’s disease include dopamine as a contributor to disease progression. However, intraneuronal levels of dopamine have not been reported. Objective: Meta-analytic methods were utilized to determine intracellular dopamine levels in Parkinson’s disease. Methods: A systematic review of the literature and frequentist meta-analyses were performed. Dopamine levels were scaled for cell and axon numbers as well as VMAT2 protein levels. Results: Reduced tissue dopamine, dopaminergic cell bodies and VMAT2 protein were confirmed. The ratio of Parkinson’s to normal brain …intracellular dopamine scaled for either cell or axon number, each with VMAT2 level in the caudate ranged from 1.49 to 1.87 (p  = 0.51 and p  = 0.12, respectively) and in the putamen from 0.75 to 4.61 (p  = 0.40 and 0.001, respectively). Conclusion: Free, intracellular dopamine levels are not reduced in Parkinson’s disease compared to normals to a similar degree as are total tissue concentrations, supporting the relevance of modulating VMAT2, neuromelanin and/or dopamine synthesis as rational neuroprotective strategies. Show more

Keywords: Parkinson’s disease, dopamine, dopaminergic neurons, cytosolic dopamine, intracellular dopamine, dopamine toxicity, dopamine oxidation

DOI: 10.3233/JPD-212715

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

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 could have protected 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. Pre-press, no. Pre-press, pp. 1-24, 2021

Authors: Morizane, Asuka | Takahashi, Jun

Article Type: Review Article

Abstract: Stem cell-based therapies for Parkinson’s disease are now being applied clinically. Notably, studies have shown that controlling the graft-induced immune response improves the results. In this mini-review, we concisely summarize current approaches used for this control. We focus on four modes of stem cell-based therapies: autologous transplantation, allogeneic transplantation with human leukocyte antigen-matching and allogeneic transplantation without, and finally the application of “universal” pluripotent stem cells. We also discuss immuno-suppressive treatments and the monitoring of immune reactions in the brain.

Keywords: Parkinson’s disease, immune response, human leukocyte antigen, autologous, allogeneic

DOI: 10.3233/JPD-212608

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Sieurin, Johanna | Zhan, Yiqiang | Pedersen, Nancy L. | Wirdefeldt, Karin

Article Type: Research Article

Abstract: Background: The relationship among neuroticism, smoking, and Parkinson’s disease (PD) is less examined. Objective: To examine the causal associations between neuroticism, smoking initiation, and the risk of PD. Methods: We performed a two-sample Mendelian randomization (MR) design in a network framework. Summary statistics from meta-analyses of genome-wide association studies (GWAS) were based on large cohorts of European ancestry. Study participants were from various cohort studies for neuroticism and smoking initiation, and case-control studies or cohort studies of PD from previously published GWAS meta-analyses. Patients with PD were ascertained from either clinical visit or self-reported. …Results: The two-sample MR analysis showed no evidence for a causal association between neuroticism and PD risk (odds ratio [OR] 0.86, 95%confidence intervals [CIs] 0.67 to 1.12). While we did not find a significant association between neuroticism and PD, one SNP, rs58879558 (located in MAPT region), was associated with both neuroticism and PD. We found a significant association of neuroticism on smoking initiation (OR: 1.10, 95%CI: 1.05 to 1.14). Further, our results provided evidence for a protective effect of smoking initiation on the risk of PD (OR: 0.75, 95%CI: 0.62 to 0.91). Conclusion: These findings do not support a causal association of neuroticism on PD risk. However, they provide evidence for a causal relationship between neuroticism and smoking initiation and a strong causal effect of smoking initiation on a reduced risk of PD. Show more

Keywords: Neuroticism, smoking, Parkinson’s disease, mendelian randomization.

DOI: 10.3233/JPD-202522

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Wang, Keran | Luo, Zhehui | Li, Chenxi | Huang, Xuemei | Shiroma, Eric J. | Simonsick, Eleanor M. | Chen, Honglei

Article Type: Research Article

Abstract: Background: Literature shows an inverse association of circulating cholesterol level with the risk of Parkinson’s disease (PD); this finding has important ramifications, but its interpretation has been debated. Objective: To longitudinally examine how blood total cholesterol changes during the development of PD. Methods: In the Health, Aging and Body Composition study (n  = 3,075, 73.6±2.9 years), blood total cholesterol was measured at clinic visit years 1, 2, 4, 6, 8, 10, and 11. We first examined baseline cholesterol in relation to PD risk, adjusting for potential confounders and competing risk of death. Then, by contrasting the observed …with expected cholesterol levels, we examined the trajectory of changes in total cholesterol before and after disease diagnosis. Results: Compared to the lowest tertile of baseline total cholesterol, the cumulative incident ratio of PD and 95%confidence interval was 0.41 (0.20, 0.86) for the second tertile, and 0.69 (0.35, 1.35) for the third tertile. In the analysis that examined change of total cholesterol level before and after PD diagnosis, we found that its level began to decrease in the prodromal stage of PD and became statistically lower than the expected values∼4 years before disease diagnosis (observed-expected difference, –6.68 mg/dL (95%confidence interval: –13.14, –0.22)). The decreasing trend persisted thereafter; by year-6 post-diagnosis, the difference increased to –13.59 mg/dL (95%confidence interval: –22.12, –5.06), although the linear trend did not reach statistical significance (p  = 0.10). Conclusion: Circulating total cholesterol began to decrease in the prodromal stage of PD, which may in part explain its reported inverse association with PD. Show more

Keywords: Parkinson’s disease, cholesterol, longitudinal studies, prodromal symptoms

DOI: 10.3233/JPD-212670

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021