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| 2. |
- Parmar, Malin, et al.
(författare)
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In vivo conversion of dopamine neurons in mouse models of Parkinson's disease - a future approach for regenerative therapy?
- 2021
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Ingår i: Current Opinion in Genetics & Development. - : Elsevier BV. - 1879-0380 .- 0959-437X. ; 70, s. 76-82
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Forskningsöversikt (refereegranskat)abstract
- Recent advances in cell reprogramming have made it possible to form new therapeutic cells within the body itself via a process called direct conversion or lineage reprogramming. A series of studies have shown that it is possible to reprogram resident glia into new neurons within the brain parenchyma. These studies opened up for the targeted attempts to achieve functional brain repair using in vivo conversion. Because of the relatively focal degeneration, Parkinson's Disease (PD) is an attractive target for both transplantation-based and in vivo conversion-based reparative approaches. Fetal cell transplants have provided proof-of-concept and stem cell-based therapies for PD are now on the verge of entering clinical trials. In the future, in vivo conversion may be an alternative to transplantation-based therapies.
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| 3. |
- Adler, Andrew, et al.
(författare)
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Transsynaptic tracing and its emerging use to assess graftreconstructed neural circuits
- 2020
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 38:6, s. 716-726
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Tidskriftsartikel (refereegranskat)abstract
- Fetal neural progenitor grafts have been evaluated in preclinical animal models of spinal cord injury and Parkinson’s disease for decades, but the initial reliance on primary tissue as a cell source limited the scale of their clinical translatability. With the development of robust methods to differentiate human pluripotent stem cells to specific neural subtypes, cell replacement therapy holds renewed promise to treat a variety of neurodegenerative diseases and injuries at scale. As these cell sources are evaluated in preclinical models, new transsynaptic tracing methods are making it possible to study the connectivity between host and graft neurons with greater speed and detail than was previously possible. To date, these studies have revealed that widespread, long-lasting, and anatomically-appropriate synaptic contacts are established between host and graft neurons, as well as new aspects of host-graft connectivity which may be relevant to clinical cell replacement therapy. It is not yet clear, however, whether the synaptic connectivity between graft and host neurons is as celltype specific as it is in the endogenous nervous system, or whether that connectivity is responsible for the functional efficacy of cell replacement therapy. Here, we review evidence suggesting that the new contacts established between host and graft neuronsmay indeed be cell-type specific, and how transsynaptic tracing can be used inthe future to further elucidate the mechanisms of graft-mediated functional recovery in spinal cord injury and Parkinson’s disease.
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| 4. |
- Baranowska, Julia, et al.
(författare)
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Associations between medical therapy after surgical aortic valve replacement for aortic stenosis and long-term mortality: a report from the SWEDEHEART registry.
- 2022
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Ingår i: European heart journal. Cardiovascular pharmacotherapy. - : Oxford University Press (OUP). - 2055-6837 .- 2055-6845. ; 8:8, s. 837-846
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Tidskriftsartikel (refereegranskat)abstract
- The association between use of statins, renin-angiotensin system (RAS) inhibitors and/or β-blockers and long-term mortality in patients with aortic stenosis who underwent surgical aortic valve replacement (SAVR) is unknown.All patients with aortic stenosis who underwent isolated first time SAVR in Sweden from 2006 to 2017 and survived six months after discharge were included. Individual patient data from four mandatory nationwide registries were merged. Cox proportional hazards models, with time-updated data on medication status and adjusted for age, sex, comorbidities, type of prosthesis, and year of surgery, were used to investigate associations between dispensed statins, RAS inhibitors, and β-blockers, and all-cause mortality. In total, 9553 patients were included, and median follow-up time was 4.9 years (range 0-11); 1738 patients (18.2%) died during follow-up. Statins were dispensed to 49.1% and 49.0% of the patients within six months of discharge from hospital and after ten years, respectively. Corresponding figures were 51.4% and 53.9% for RAS inhibitors, and 79.3% and 60.7% for β-blockers. Ongoing treatment was associated with lower mortality risk for statins [adjusted hazard ratio (aHR) 0.67 (95% confidence interval 0.60-0.74), p<0.001] and RAS inhibitors [aHR 0.84 (0.76-0.93), p<0.001] but not for β-blockers [aHR 1.17 (1.05-1.30), p=0.004]. The associations were robust in subgroups based on age, sex, and comorbidities (p for interactions>0.05).The results of this large population-based real-world study support the use of statins and RAS inhibitors for patients who underwent SAVR due to aortic stenosis.
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| 5. |
- Barker, Roger A, et al.
(författare)
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Animal Models of Parkinson's Disease : Are They Useful or Not?
- 2020
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Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 10:4, s. 1335-1342
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Forskningsöversikt (refereegranskat)abstract
- The use of animal models in Parkinson's disease research has been controversial in terms of how well they relate to the clinical condition and thus their utility for translating therapies from the lab to the clinic. In this article, two researchers debate this issue with Roger Barker taking the view that such models are not useful and may even be misleading, while Anders Björklund defends their use and highlights their value in better understanding and treating this condition.
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| 6. |
- Barker, Roger A., et al.
(författare)
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GDNF and Parkinson's Disease : Where Next? A Summary from a Recent Workshop
- 2020
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Ingår i: Journal of Parkinson's Disease. - 1877-7171. ; 10:3, s. 875-891
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Tidskriftsartikel (refereegranskat)abstract
- The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design.
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| 7. |
- Barker, Roger A., et al.
(författare)
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Restorative cell and gene therapies for Parkinson's disease
- 2023
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Ingår i: Precision Medicine in Neurodegenerative Disorders, Part II. - 0072-9752 .- 2212-4152. - 9780323855556 ; 193, s. 211-226
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Bokkapitel (refereegranskat)abstract
- One of the core pathological features of Parkinson's disease (PD) is the loss of the dopaminergic nigrostriatal pathway which lies at the heart of many of the motor features of this condition as well as some of the cognitive problems. The importance of this pathological event is evident through the clinical benefits that are seen when patients with PD are treated with dopaminergic agents, at least in early-stage disease. However, these agents create problems of their own through stimulation of more intact dopaminergic networks within the central nervous system causing major neuropsychiatric problems including dopamine dysregulation. In addition, over time the nonphysiological stimulation of striatal dopamine receptors by L-dopa containing drugs leads to the genesis of L-dopa-induced dyskinesias that can become very disabling in many cases. As such, there has been much interest in trying to better reconstitute the dopaminergic nigrostriatal pathway using either factors to regrow it, cells to replace it, or gene therapies to restore dopamine transmission in the striatum. In this chapter, we lay out the rationale, history and current status of these different therapies as well as highlighting where the field is heading and what new interventions might come to clinic in the coming years.
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| 8. |
- Barker, Roger A, et al.
(författare)
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Stem Derived Dopamine Neurons : Will They Replace DBS as the Leading Neurosurgical Treatment for Parkinson's Disease?
- 2021
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Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 11:3, s. 909-917
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Tidskriftsartikel (refereegranskat)abstract
- The use of stem cell derived dopamine neurons for treating patients with Parkinson's disease has now evolved to the first in human clinical trials. In this debate, we argue that assuming these trials give positive outcomes that this therapy will supercede DBS as the neurosurgical treatment of choice for PD patients in the future given it is a one-off therapy that repairs a critical pathway in the parkinsonian brain.
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| 9. |
- Björklund, Anders, et al.
(författare)
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A Combined α-Synuclein/Fibril (SynFib) Model of Parkinson-Like Synucleinopathy Targeting the Nigrostriatal Dopamine System
- 2022
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Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 12:8, s. 2307-2320
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Forskningsöversikt (refereegranskat)abstract
- Injections of pre-formed α-synuclein fibrils (PFFs) or overexpression of α-synuclein using AAV vectors are commonly used as models of Parkinson-like synucleinopathy in rats and mice. In the modified method reviewed here, the "SynFib" model, the PFFs and the AAV vector are administered together unilaterally into the substantia nigra. This approach combines the key features of these two models, i.e., the generation of toxic α-synuclein aggregates and Lewy body-like inclusions, in combination with the increased vulnerability caused by increased cellular levels of α-synuclein. The combined AAV/PFF delivery offers several advantages over the standard PFF model due to the enhanced and accelerated α-synuclein pathology and microglial response induced by the PFF seeds in the presence of an elevated α-synuclein level. Injection of the AAV/PFF mixture into the substantia nigra makes it possible to target a larger proportion of the nigral dopamine neurons and obtain a level of dopamine cell loss (>60%) needed to induce significant impairments in drug-induced and spontaneous motor tests. The SynFib model shares attractive features of the standard 6-OHDA lesion model: a single unilateral stereotaxic intervention; pathology and cell loss developing over a short time span; and the possibility to monitor the degenerative changes using tests of motor behavior.
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