scholarly journals Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes

Brain ◽  
2019 ◽  
Vol 142 (11) ◽  
pp. 3565-3579 ◽  
Author(s):  
Yaping Chu ◽  
Scott Muller ◽  
Adriana Tavares ◽  
Olivier Barret ◽  
David Alagille ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopamine Transporter ◽  
Lewy Body ◽  
Alpha Synuclein ◽  
Lewy Body Pathology ◽  
Nigrostriatal Degeneration ◽  
Early Parkinson’S Disease

See Dehay and Bezard (doi:10.1093/brain/awz329) for a scientific commentary on this article. Intrastriatal injections of fibrillar α-synuclein in rodents have been shown to induce a Parkinson’s disease-like spreading of Lewy body pathology. Chu et al. inject exogenous α-synuclein pre-formed fibrils into the putamen of non-human primates, and observe spreading of pathology, nigrostriatal degeneration, and dopamine transporter upregulation indicative of early Parkinson’s disease.

scholarly journals A Matrigel-based 3D construct of SH-SY5Y cells models the α-synuclein pathologies of Parkinson's disease

2022 ◽  
Author(s):  
Zhao-Feng Li ◽  
Lei Cui ◽  
Mi-Mi Jin ◽  
Dong-Yan Hu ◽  
Xiao-Gang Hou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Cultured Cells ◽  
Three Dimensional ◽  
Proteinase K ◽  
All Trans Retinoic Acid ◽  
Lewy Body Pathology ◽  
Rotenone Treatment ◽  
2D And 3D

Parkinson's disease (PD) is featured with α-synuclein-based Lewy body pathology, which however was difficult to observe in conventional two-dimensional (2D) cell culture and even in animal models. We herein aimed to develop a three-dimensional (3D) cellular model of PD to recapitulate the α-synuclein pathologies. All-trans-retinoic acid-differentiated human SH-SY5Y cells and Matrigel were optimized for 3D construction. The 3D cultured cells displayed higher tyrosine hydroxylase expression and improved dopaminergic-like phenotypes than 2D cells as suggested by RNA-sequencing analyses. Multiple forms of α-synuclein, including monomer, low and high molecular weight oligomers, were differentially present in the 2D and 3D cells, but mostly remained unchanged upon the MPP+ or rotenone treatment. Phosphorylated α-synuclein was accumulated and detergent-insoluble α-synuclein fraction was observed in the neurotoxin-treated 3D cells. Importantly, Lewy body-like inclusions were captured in the 3D system, including proteinase K-resistant α-synuclein aggregates, ubiquitin aggregation, β-amyloid and β-sheet protein deposition. The study provides a unique and convenient 3D model of PD which recapitulates critical α-synuclein pathologies and should be useful in multiple PD-associated applications.

scholarly journals Alpha-synuclein alters the faecal viromes of rats in a gut-initiated model of Parkinson’s disease

2021 ◽  
Author(s):  
S. R. Stockdale ◽  
L. A. Draper ◽  
S. M. O’Donovan ◽  
W. Barton ◽  
O. O’Sullivan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Lewy Body ◽  
Neurological Disorder ◽  
Alpha Synuclein ◽  
Observational Period ◽  
Β Diversity ◽  
Potential Trigger ◽  
The Brain

AbstractParkinson’s disease (PD) is a chronic neurological disorder associated with the misfolding of alpha-synuclein (α-syn) into Lewy body aggregates within nerve cells that contribute to their neurodegeneration. Recent evidence suggests α-syn aggregation may begin in the gut and travel to the brain along the vagus nerve, with microbes a potential trigger initiating the misfolding of α-syn. However, changes in the gut virome in response to α-syn alterations have not been investigated. In this study, we show longitudinal changes in the faecal virome of rats administered either monomeric or preformed fibrils (PFF) of α-syn directly into their enteric nervous system. Differential changes in rat viromes were observed when comparing monomeric and PFF α-syn. The virome β-diversity changes after α-syn treatment were compounded by the addition of LPS as an adjunct. Changes in the diversity of rat faecal viromes were observed after one month and did not resolve within the study’s five month observational period. Overall, these results suggest that microbiome alterations associated with PD may, partially, be reactive to host α-syn associated changes.

scholarly journals Molecular Neuroimaging of the Dopamine Transporter as a Patient Enrichment Biomarker for Clinical Trials for Early Parkinson's Disease

2019 ◽  
Vol 12 (3) ◽  
pp. 240-246 ◽  
Author(s):  
Klaus Romero ◽  
Daniela Conrado ◽  
Jackson Burton ◽  
Timothy Nicholas ◽  
Vikram Sinha ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Dopamine Transporter ◽  
Early Parkinson’S Disease

Nigrostriatal dopamine transporter availability in early Parkinson's disease

2018 ◽  
Vol 33 (4) ◽  
pp. 592-599 ◽  
Author(s):  
Patrik Fazio ◽  
Per Svenningsson ◽  
Zsolt Cselényi ◽  
Christer Halldin ◽  
Lars Farde ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopamine Transporter ◽  
Nigrostriatal Dopamine ◽  
Early Parkinson’S Disease

scholarly journals Evaluating dopamine transporter imaging as an enrichment biomarker in a phase 2 Parkinson’s disease trial

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
R. Matthew Hutchison ◽  
Karleyton C. Evans ◽  
Tara Fox ◽  
Minhua Yang ◽  
Jerome Barakos ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Clinical Trial ◽  
Parkinson's Disease ◽  
Dopamine Transporter ◽  
Single Photon ◽  
Photon Emission ◽  
Alpha Synuclein ◽  
Emission Computed Tomography ◽  
Phase 2 ◽  
Dat Spect

Abstract Background Dopamine transporter single-photon emission computed tomography (DaT-SPECT) can quantify the functional integrity of the dopaminergic nerve terminals and has been suggested as an imaging modality to verify the clinical diagnosis of Parkinson’s disease (PD). Depending on the stage of progression, approximately 5–15% of participants clinically diagnosed with idiopathic PD have been observed in previous studies to have normal DaT-SPECT patterns. However, the utility of DaT-SPECT in enhancing early PD participant selection in a global, multicenter clinical trial of a potentially disease-modifying therapy is not well understood. Methods The SPARK clinical trial was a phase 2 trial of cinpanemab, a monoclonal antibody against alpha-synuclein, in participants with early PD. DaT-SPECT was performed at screening to select participants with DaT-SPECT patterns consistent with degenerative parkinsonism. Acquisition was harmonised across 82 sites. Images were reconstructed and qualitatively read at a central laboratory by blinded neuroradiologists for inclusion prior to automated quantitative analysis. Results In total, 482 unique participants were screened between January 2018 and May 2019; 3.8% (15/398) of imaged participants were excluded owing to negative DaT-SPECT findings (i.e., scans without evidence of dopaminergic deficit [SWEDD]). Conclusion A smaller proportion of SPARK participants were excluded owing to SWEDD status upon DaT-SPECT screening than has been reported in prior studies. Further research is needed to understand the reasons for the low SWEDD rate in this study and whether these results are generalisable to future studies. If supported, the radiation risks, imaging costs, and operational burden of DaT-SPECT for enrichment may be mitigated by clinical assessment and other study design aspects. Trial registration ClinicalTrials.gov identifier: NCT03318523. Date submitted: October 19, 2017. First Posted: October 24, 2017.

scholarly journals Clinical diagnosis of Lewy body dementia

BJPsych Open ◽  
2020 ◽  
Vol 6 (4) ◽  
Author(s):  
Ajenthan Surendranathan ◽  
Joseph P. M. Kane ◽  
Allison Bentley ◽  
Sally A. H. Barker ◽  
John-Paul Taylor ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Dopamine Transporter ◽  
Lewy Body ◽  
Lewy Bodies ◽  
Lewy Body Dementia ◽  
Final Diagnosis ◽  
Dopamine Transporter Imaging ◽  
The Uk

Background Lewy body dementia, consisting of both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is considerably under-recognised clinically compared with its frequency in autopsy series. Aims This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis may be contributing to these differences. Method We reviewed the medical notes of 74 people with DLB and 72 with non-DLB dementia matched for age, gender and cognitive performance, together with 38 people with PDD and 35 with Parkinson's disease, matched for age and gender, from two geographically distinct UK regions. Results The cases of individuals with DLB took longer to reach a final diagnosis (1.2 v. 0.6 years, P = 0.017), underwent more scans (1.7 v. 1.2, P = 0.002) and had more alternative prior diagnoses (0.8 v. 0.4, P = 0.002), than the cases of those with non-DLB dementia. Individuals diagnosed in one region of the UK had significantly more core features (2.1 v. 1.5, P = 0.007) than those in the other region, and were less likely to have dopamine transporter imaging (P < 0.001). For patients with PDD, more than 1.4 years prior to receiving a dementia diagnosis: 46% (12 of 26) had documented impaired activities of daily living because of cognitive impairment, 57% (16 of 28) had cognitive impairment in multiple domains, with 38% (6 of 16) having both, and 39% (9 of 23) already receiving anti-dementia drugs. Conclusions Our results show the pathway to diagnosis of DLB is longer and more complex than for non-DLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. For PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.

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