Journal of Parkinson's Disease - Volume 14, issue 4

Authors: LeWitt, Peter A.

Article Type: Editorial

DOI: 10.3233/JPD-249004

Citation: Journal of Parkinson's Disease, vol. 14, no. 4, pp. 637-637, 2024

Authors: LeWitt, Peter A.

Article Type: Editorial

DOI: 10.3233/JPD-230301

Citation: Journal of Parkinson's Disease, vol. 14, no. 4, pp. 639-642, 2024

Authors: Gionco, John T. | Bernstein, Alison I.

Article Type: Review Article

Abstract: Environmental risk factors and gene-environment interactions play a critical role in Parkinson’s disease (PD). However, the relatively large contribution of environmental risk factors in the overwhelming majority of PD cases has been widely neglected in the field. A “PD prevention agenda” proposed in this journal laid out a set of research priorities focused on preventing PD through modification of environmental risk factors. This agenda includes a call for preclinical studies to employ new high-throughput methods for analyzing transcriptomics and epigenomics to provide a deeper understanding of the effects of exposures linked to PD. Here, we focus on epitranscriptomics as a …novel area of research with the potential to add to our understanding of the interplay between genes and environmental exposures in PD. Both epigenetics and epitranscriptomics have been recognized as potential mediators of the complex relationship between genes, environment, and disease. Multiple studies have identified epigenetic alterations, such as DNA methylation, associated with PD and PD-related exposures in human studies and preclinical models. In addition, recent technological advancements have made it possible to study epitranscriptomic RNA modifications, such as RNA N6 -methyladenosine (m6 A), and a handful of recent studies have begun to explore epitranscriptomics in PD-relevant exposure models. Continued exploration of epitranscriptomic mechanisms in environmentally relevant PD models offers the opportunity to identify biomarkers, pre-degenerative changes that precede symptom onset, and potential mitigation strategies for disease prevention and treatment. Show more

Keywords: Parkinson’s disease, epigenomics, epigenetics, RNA methylation, toxicology, DNA methylation

DOI: 10.3233/JPD-230457

Citation: Journal of Parkinson's Disease, vol. 14, no. 4, pp. 643-656, 2024

Authors: Wyse, Richard K. | Isaacs, Tom | Barker, Roger A. | Cookson, Mark R. | Dawson, Ted M. | Devos, David | Dexter, David T. | Duffen, Joy | Federoff, Howard | Fiske, Brian | Foltynie, Thomas | Fox, Susan | Greenamyre, J. Timothy | Kieburtz, Karl | Kordower, Jeffrey H. | Krainc, Dimitri | Matthews, Helen | Moore, Darren J. | Mursaleen, Leah | Schwarzschild, Michael A. | Stott, Simon R.W. | Sulzer, David | Svenningsson, Per | Tanner, Caroline M. | Carroll, Camille | Simon, David K. | Brundin, Patrik

Article Type: Review Article

Abstract: In 2011, the UK medical research charity Cure Parkinson’s set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson’s disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT …committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD. Show more

Keywords: Clinical trials, Parkinson’s disease, disease modification, neuroprotection, drug repurposing

DOI: 10.3233/JPD-230363

Citation: Journal of Parkinson's Disease, vol. 14, no. 4, pp. 657-666, 2024

Authors: Schaeffer, Eva | Kluge, Annika | Schulte, Claudia | Deuschle, Christian | Bunk, Josina | Welzel, Julius | Maetzler, Walter | Berg, Daniela

Article Type: Research Article

Abstract: Background: Misfolded α-synuclein can be detected in blood samples of Parkinson’s disease (PD) patients by a seed amplification assay (SAA), but the association with disease duration is not clear, yet. Objective: In the present study we aimed to elucidate whether seeding activity of misfolded α-synuclein derived from neuronal exosomes in blood is associated with PD diagnosis and disease duration. Methods: Cross-sectional samples of PD patients were analyzed and compared to samples of age- and gender-matched healthy controls using a blood-based SAA. Presence of α-synuclein seeding activity and differences in seeding parameters, including fluorescence response (in arbitrary …units) at the end of the amplification assay (F60 ) were analyzed. Additionally, available PD samples collected longitudinally over 5–9 years were included. Results: In the cross-sectional dataset, 79 of 80 PD patients (mean age 69 years, SD = 8; 56% male) and none of the healthy controls (n  = 20, mean age 70 years, SD = 10; 55% male) showed seeding activity (sensitivity 98.8%). When comparing subgroups divided by disease duration, longer disease duration was associated with lower α-synuclein seeding activity (F60 : p  < 0.001). In the longitudinal analysis 10/11 patients showed a gradual decrease of α-synuclein seeding activity over time. Conclusions: This study confirms the high sensitivity of the blood-based α-synuclein SAA applied here. The negative association of α-synuclein seeding activity in blood with disease duration makes this parameter potentially interesting as biomarker for future studies on the pathophysiology of disease progression in PD, and for biologically oriented trials in this field. Show more

Keywords: Parkinson’s disease, alpha-synuclein, biomarker

DOI: 10.3233/JPD-230390

Citation: Journal of Parkinson's Disease, vol. 14, no. 4, pp. 667-679, 2024

Authors: Erdmann, Leonie | Santos, Patrícia I. | Rieper, Petra | Klafki, Hans W. | Beutner, Dirk | Wiltfang, Jens | Outeiro, Tiago F. | Setz, Cristian

Article Type: Research Article

Abstract: Background: Alpha-synuclein (aSyn) is a key player in neurodegenerative diseases such as Parkinson’s disease (PD), dementia with Lewy bodies, or multiple system atrophy. aSyn is expressed throughout the brain, and can also be detected in various peripheral tissues. In fact, initial symptoms of PD are non-motoric and include autonomic dysfunction, suggesting that the periphery might play an important role in early development of the disease. aSyn is expressed at relatively low levels in non-central tissues, which brings challenges for its detection and quantification in different tissues. Objective: Our goal was to assess the sensitivity of aSyn detection in …central and peripheral mouse tissues through capillary electrophoresis (CE) immunoblot, considering the traditional SDS-PAGE immunoblot as the current standard. Methods: Tissues from central and non-central origin from wild type mice were extracted, and included midbrain, inner ear, and esophagus/stomach. aSyn detection was assessed through immunoblotting using Simple Western size-based CE and SDS-PAGE. Results: CE immunoblots show a consistent detection of aSyn in central and peripheral tissues. Through SDS-PAGE, immunoblots revealed a reliable signal corresponding to aSyn, particularly following membrane fixation. Conclusion: Our results suggest a reliable detection of aSyn in central and peripheral tissues using the CE Simple Western immunoblot system. These observations can serve as preliminary datasets when aiming to formally compare CE with SDS-PAGE, as well as for further characterization of aSyn using this technique. Show more

Keywords: Alpha-synuclein, biomarkers, capillary electrophoresis, immunoblot, Parkinson’s disease

DOI: 10.3233/JPD-230379

Citation: Journal of Parkinson's Disease, vol. 14, no. 4, pp. 681-692, 2024

Authors: Fredlund, Filip | Jimenez-Ferrer, Itzia | Grabert, Kathleen | Belfiori, Lautaro Francisco | Luk, Kelvin | Swanberg, Maria

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is characterized by alpha-synuclein (α -Syn) pathology, neurodegeneration and neuroinflammation. Human leukocyte antigen (HLA ) variants associated with PD and α -Syn specific CD4+ T lymphocytes in PD patients highlight the importance of antigen presentation in PD etiology. The class II transactivator (CIITA) regulates major histocompatibility complex class II (MHCII) expression. Reduced Ciita levels significantly increase α -Syn pathology, nigrostriatal neurodegeneration and behavioral deficits in α -Syn-induced rat PD models. Objective: Characterize immune profiles associated with enhanced PD-like pathology observed in rats expressing lower Ciita levels (DA.VRA4) compared to the background strain …(DA). Methods: To model PD, we combined rAAV-mediated α -Syn overexpression in the substantia nigra with striatal injection of α -Syn preformed fibrils. Immune profiles in brain and blood were analyzed by flow cytometry and multiplexed ELISA in naïve rats, 4- and 8 weeks post rAAV injection. Results: Flow cytometry showed Ciita -dependent regulation of MHCII on microglia, brain macrophages and circulating myeloid cells. The MHCII-dependent microglial response was highest at 4 weeks post rAAV injection, whereas the MHCII levels in circulating myeloid cells was highest at 8 weeks. There was no major infiltration of macrophages or T lymphocytes into the CNS in response to α -Syn and only subtle Ciita - and/or α -Syn-dependent changes in the T lymphocyte compartment. Lower Ciita levels were consistently associated with higher TNF levels in serum. Conclusions: Ciita regulates susceptibility to PD-like pathology through minor but detectable changes in resident and peripheral immune cells and TNF levels, indicating that mild immunomodulatory therapies could have therapeutic effects in PD. Show more

Keywords: Parkinson’s disease, MHC class II transactivator protein, MHC class II genes, alpha-synuclein, tumor necrosis factor, neuroinflammation

DOI: 10.3233/JPD-240062

Citation: Journal of Parkinson's Disease, vol. 14, no. 4, pp. 693-711, 2024

Authors: Welton, Thomas | Teo, Thomas Wei Jun | Chan, Ling Ling | Tan, Eng-King | Tan, Louis Chew Seng

Article Type: Research Article

Abstract: Background: A genome-wide association study (GWAS) variant associated with Parkinson’s disease (PD) risk in Asians, rs9638616, was recently reported, and maps to WBSCR17/GALNT17, which is involved in synaptic transmission and neurite development. Objective: To test the association of the rs9638616 T allele with imaging-derived measures of brain microstructure and function. Methods: We analyzed 3-Tesla MRI and genotyping data from 116 early PD patients (aged 66.8±9.0 years; 39% female; disease duration 1.25±0.71 years) and 57 controls (aged 68.7±7.4 years; 54% female), of Chinese ethnicity. We performed voxelwise analyses for imaging-genetic association of rs9638616 T allele with white …matter tract fractional anisotropy (FA), grey matter volume and resting-state network functional connectivity. Results: The rs9638616 T allele was associated with widespread lower white matter FA (t = –1.75, p  = 0.042) and lower functional connectivity of the supplementary motor area (SMA) (t = –5.05, p  = 0.001), in both PD and control groups. Interaction analysis comparing the association of rs9638616 and FA between PD and controls was non-significant. These imaging-derived phenotypes mediated the association of rs9638616 to digit span (indirect effect: β= –0.21 [–0.42,–0.05], p  = 0.031) and motor severity (indirect effect: β= 0.15 [0.04,0.26], p  = 0.045). Conclusions: We have shown that a novel GWAS variant which is biologically linked to synaptic transmission is associated with white matter tract and functional connectivity dysfunction in the SMA, supported by changes in clinical motor scores. This provides pathophysiologic clues linking rs9638616 to PD risk and might contribute to future risk stratification models. Show more

Keywords: Imaging-genetics, Parkinsonism, magnetic resonance imaging, mediation analysis, Asian ethnicity, susceptibility

DOI: 10.3233/JPD-230455

Citation: Journal of Parkinson's Disease, vol. 14, no. 4, pp. 713-724, 2024

Authors: Bruno, Michiko Kimura | Matsunaga, Masako | Krening, Emma | Gao, Fay | Chen, John J. | Seto, Todd | Ross, G. Webster

Article Type: Research Article

Abstract: Background: Little is known about the epidemiology of Parkinson’s disease (PD) patients in Native Hawaiian Or Other Pacific Islander (NHPI) and Asian American (AA) subgroups. Objective: To determine if the prevalence of hospitalized PD patients is different across age groups and racial/ethnic subgroups in Hawaii. Methods: We conducted a retrospective analysis of Hawaii statewide registry (2016–2020) hospitalization data for patients who were 50 years or older. PD patients were identified using an ICD 10 code: Parkinson’s Disease (G20) as their primary/secondary hospitalization discharge diagnosis code. Demographic and clinical characteristics among racial/ethnic subgroups (White, Japanese, Filipino, Chinese, …NHPI, or Other) were compared. Results: Of 146,844 total hospitalized patients (n  = 429,879 records), 1.6% (n  = 2,401) had a PD diagnosis. The prevalence of hospitalized PD patients was 2.3% among Japanese and Chinese, followed by 1.7% for Whites, 1.2% for Filipinos and was lowest for NHPI with 0.9% (p  < 0.001). As patient’s age increased, the prevalence of hospitalized PD patients increased, with 80–84 years old for the highest age range (3.4%). The prevalence of hospitalized PD patients at 80–84 years old varied across the race/ethnic subgroups (Chinese 4.3%, Japanese 4.0%, Whites 3.7%, Filipinos 2.5%, NHPI 2.3%). Conclusions: The prevalence of hospitalized PD patients among all case hospitalizations were lower for NHPI and Filipino compared to that of Japanese, Chinese, and Whites. As patients’ age increased, the prevalence of hospitalized patients with PD increased, but less so in NHPI and Filipino groups. Further research is warranted to understand the reason for these observed differences among racial/ethnic subgroups. Show more

Keywords: Parkinson’s disease, hospitalization, Native Hawaiian or Other Pacific Islander, Asian, prevalence

DOI: 10.3233/JPD-230341

Citation: Journal of Parkinson's Disease, vol. 14, no. 4, pp. 725-735, 2024

Authors: Brown, Ethan G. | Goldman, Samuel M. | Coffey, Christopher S. | Siderowf, Andrew | Simuni, Tanya | Meng, Cheryl | Brumm, Michael C. | Caspell-Garcia, Chelsea | Marek, Kenneth | Tanner, Caroline M.

Article Type: Research Article

Abstract: Background: The penetrance of common genetic risk variants for Parkinson’s disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well understood. Objective: To determine the relationship between occupational pesticide exposure and PD in people with LRRK2 and GBA risk variants. Methods: Participants of the Parkinson’s Progression Markers Initiative (PPMI) with a LRRK2-G2019 S or GBA risk variant provided information about occupational pesticide exposure. We compared exposure in carriers with and without PD. Among carriers with PD, we used Cox proportional hazard models to compare time-to impairment in …balance, cognition, and activities of daily living (ADLs) between participants with and without prior occupational pesticide exposure. Results: 378 participants with a risk variant provided exposure information; 176 with LRRK2-G2019 S (54 with and 122 without PD) and 202 with GBA variants (47 with and 155 without PD). Twenty-six participants reported pesticide exposure. People with a GBA variant and occupational pesticide exposure had much higher odds of PD (aOR: 5.4, 95% CI 1.7–18.5, p  < 0.01). People with a LRRK2 variant and a history of occupational pesticide exposure had non-significantly elevated odds of PD (aOR 1.3, 95% CI 0.4–4.6, p  = 0.7). Among those with PD, pesticide exposure was associated with a higher risk of balance problems and cognitive impairment in LRRK2-PD and functional impairment in GBA-PD, although associations were not statistically significant. Conclusions: Occupational pesticide exposure may increase penetrance of GBA-PD and may be associated with faster symptom progression. Further studies in larger cohorts are necessary. Show more

Keywords: Parkinson’s disease, environmental exposure, GBA associated Parkinson’s disease, LRRK2 associated Parkinson’s disease, pesticide exposure

DOI: 10.3233/JPD-240015

Citation: Journal of Parkinson's Disease, vol. 14, no. 4, pp. 737-746, 2024