| 1. |
- Iancu, Ruxandra, et al.
(författare)
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Behavioral characterization of a unilateral 6-OHDA-lesion model of Parkinson's disease in mice.
- 2005
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 162:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Several toxin-induced animals models simulate the motor deficits occurring in PD. Among them, the unilateral 6-hydroxydopamine (6-OHDA) model is frequently used in rats and has the advantage of presenting side-biased motor impairments. However, the behavioral consequences of a unilateral 6-OHDA-lesion have, so far, not been described in detail in mice. The aim of this study was to characterize mice with unilateral 6-OHDA-lesions placed in the median forebrain bundle using several motor behavioral tests in order to identify the most suitable predictor of nigral cell loss. Mice underwent various drug-induced (amphetamine- and apomorphine-induced rotation) and spontaneous motor tests (cylinder, rotarod, elevated body swing, and stride length test). The amphetamine-induced rotation test, the cylinder and the rotarod test were most sensitive and reliable in detecting loss of tyrosine hydroxylase-immunoreactive cells in the substantia nigra. This study demonstrates that substantial and stable unilateral 6-OHDA-induced lesions can be established in mice, and that these lesions can be functionally assessed using several different side-bias-based behavioral tests. This mouse model offers the opportunity to use transgenic mouse strains and study the interactions between genes of interest and toxins in relation to Parkinson's disease etiology in the future.
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| 2. |
- Anisimov, Sergey V., et al.
(författare)
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Transplantation of mesenchymal stem cells : A future therapy for Parkinson's disease?
- 2014
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Ingår i: Future Neurology. - : Future Medicine Ltd. - 1479-6708 .- 1748-6971. ; 9:4, s. 475-486
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Forskningsöversikt (refereegranskat)abstract
- Parkinson's disease (PD) is a common, progressive neurodegenerative disorder associated with a loss of dopaminergic cells in the substantia nigra pars compacta and a lack of dopamine in the striatum. To halt or reverse this disease, neurorestorative approaches or neuroprotective treatments are urgently needed. Recently, the first clinical trials transplanting mesenchymal stem cells (MSCs) have been performed in PD. MSCs are adult stem cells abundant in several tissues, such as the umbilical cord, the bone marrow, the adipose tissue and other tissues. These cells are multipotent, and able to synthesize and secrete a wide spectrum of biologically active factors. MSCs of various origins have been explored as possible substrates for cell therapy in PD animal models. In this review, we summarize MSC-based experimental transplantation studies in PD, and discuss biological mechanisms that may explain the effects of MSC seen in PD models. Furthermore, we critically evaluate the recent clinical transplantation trials using MSCs in patients with PD.
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| 3. |
- Augestad, Ingrid Lovise, et al.
(författare)
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Normalisation of glucose metabolism by exendin-4 in the chronic phase after stroke promotes functional recovery in male diabetic mice
- 2022
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 179:4, s. 677-694
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Glucagon-like peptide-1 (GLP-1) receptor activation decreases stroke risk in people with Type 2 diabetes (T2D), while animal studies have shown the efficacy of this strategy to counteract stroke-induced acute brain damage. However, whether GLP-1 receptor activation also improves recovery in the chronic phase after stroke is unknown. We investigated whether post-acute, chronic administration of the GLP-1 receptor agonist, exendin-4, improves post-stroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice. Experimental Approach: We induced stroke via transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (8 months of high-fat diet) and age-matched controls. Exendin-4 was administered for 8 weeks from Day 3 post-tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests. Insulin sensitivity and glycaemia were evaluated at 4 and 8 weeks post-tMCAO. Neuronal survival, stroke-induced neurogenesis, neuroinflammation, atrophy of GABAergic parvalbumin+ interneurons, post-stroke vascular remodelling and fibrotic scar formation were investigated by immunohistochemistry. Key Results: Exendin-4 normalised T2D-induced impairment of forepaw grip strength recovery in correlation with normalised glycaemia and insulin sensitivity. Moreover, exendin-4 counteracted T2D-induced atrophy of parvalbumin+ interneurons and decreased microglia activation. Finally, exendin-4 normalised density and pericyte coverage of micro-vessels and restored fibrotic scar formation in T2D mice. In non-T2D mice, the exendin-4-mediated recovery was minor. Conclusion and Implications: Chronic GLP-1 receptor activation mediates post-stroke functional recovery in T2D mice by normalising glucose metabolism and improving neuroplasticity and vascular remodelling in the recovery phase. The results warrant clinical trial of GLP-1 receptor agonists for rehabilitation after stroke in T2D.
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| 4. |
- Barker, Roger A., et al.
(författare)
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Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease
- 2019
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 25, s. 1045-1053
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Tidskriftsartikel (refereegranskat)abstract
- Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.
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| 5. |
- Bexell, Daniel, et al.
(författare)
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Rat Multipotent Mesenchymal Stromal Cells Lack Long-Distance Tropism to 3 Different Rat Glioma Models
- 2012
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Ingår i: Neurosurgery. - 0148-396X. ; 70:3, s. 731-739
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Viral gene therapy of malignant brain tumors has been restricted by the limited vector distribution within the tumors. Multipotent mesenchymal stromal cells (MSCs) and other precursor cells have shown tropism for gliomas, and these cells are currently being explored as potential vehicles for gene delivery in glioma gene therapy. OBJECTIVE: To investigate MSC migration in detail after intratumoral and extratumoral implantation through syngeneic and orthotopic glioma models. METHODS: Adult rat bone marrow-derived MSCs were transduced to express enhanced green fluorescent protein and implanted either directly into or at a distance from rat gliomas. RESULTS: We found no evidence of long-distance MSC migration through the intact striatum toward syngeneic D74(RG2), N32, and N29 gliomas in the ipsilateral hemisphere or across the corpus callosum to gliomas located in the contralateral hemisphere. After intratumoral injection, MSCs migrated extensively, specifically within N32 gliomas. The MSCs did not proliferate within tumors, suggesting a low risk of malignant transformation of in vivo grafted cell vectors. Using a model for surgical glioma resection, we found that intratumorally grafted MSCs migrate efficiently within glioma remnants after partial surgical resection. CONCLUSION: The findings point to limitations for the use of MSCs as vectors in glioma gene therapy, although intratumoral MSC implantation provides a dense and tumor-specific vector distribution.
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| 6. |
- Boix, Jordi, et al.
(författare)
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A partial lesion model of Parkinson's disease in mice - Characterization of a 6-OHDA-induced medial forebrain bundle lesion.
- 2015
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 284:Feb 16, s. 196-206
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Tidskriftsartikel (refereegranskat)abstract
- The most frequently used animal models for Parkinson's disease (PD) utilize unilateral injection of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB), which results in total denervation of the dopaminergic nigrostriatal pathway. However, neuroprotective interventions in PD require models resembling earlier stages of PD, where some dopaminergic cells and fibres remain. The aim of the present study was therefore to establish a MFB partial lesion model in mice. We tested four different 6-OHDA doses, and our results show a dose-dependent loss of nigral dopaminergic cells and striatal fibres that correlated with behavioural impairment in several behavioural tests. Specifically, doses of 0.7μg and 1μg of 6-OHDA induced a partial denervation of the nigrostriatal pathway, associated with a mild but quantifiable behavioural impairment. We identified the amphetamine-induced rotation, stepping, corridor and cylinder test to be sensitive enough to select partial lesion animals. Based on our data, we proposed a range of cut-off values for these different behavioural tests to select partial lesion mice. Using a statistical prediction model we identified two behavioural tests (the stepping test and amphetamine-induced rotation test) that with a high sensitivity and specificity predict the extent of nigral dopaminergic cell loss and select mice with a partial nigrostriatal lesion prior to further interventions. This model can serve as an important tool to study neuroprotective therapies for PD in mouse models, especially when the treatment targets the substantia nigra and/or striatum.
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| 7. |
- Brederlau, Anke, 1968, et al.
(författare)
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Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson's disease: effect of in vitro differentiation on graft survival and teratoma formation.
- 2006
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Ingår i: Stem cells (Dayton, Ohio). - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 24:6, s. 1433-40
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Tidskriftsartikel (refereegranskat)abstract
- Human embryonic stem cells (hESCs) have been proposed as a source of dopamine (DA) neurons for transplantation in Parkinson's disease (PD). We have investigated the effect of in vitro predifferentiation on in vivo survival and differentiation of hESCs implanted into the 6-OHDA (6-hydroxydopamine)-lesion rat model of PD. The hESCs were cocultured with PA6 cells for 16, 20, or 23 days, leading to the in vitro differentiation into DA neurons. Grafted hESC-derived cells survived well and expressed neuronal markers. However, very few exhibited a DA neuron phenotype. Reversal of lesion-induced motor deficits was not observed. Rats grafted with hESCs predifferentiated in vitro for 16 days developed severe teratomas, whereas most rats grafted with hESCs predifferentiated for 20 and 23 days remained healthy until the end of the experiment. This indicates that prolonged in vitro differentiation of hESCs is essential for preventing formation of teratomas.
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| 8. |
- Buizza, Carolina, et al.
(författare)
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The Transcriptional Landscape of Pericytes in Acute Ischemic Stroke
- 2023
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Ingår i: Translational Stroke Research. - 1868-4483.
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Tidskriftsartikel (refereegranskat)abstract
- The current treatment options for ischemic stroke aim to achieve reperfusion but are time critical. Novel therapeutic approaches that can be given beyond the limited time window of 3–4.5 h are still an unmet need to be addressed to improve stroke outcomes. The lack of oxygen and glucose in the area of ischemic injury initiates a pathological cascade leading to blood-brain barrier (BBB) breakdown, inflammation, and neuronal cell death, a process that may be intercepted to limit stroke progression. Pericytes located at the blood/brain interface are one of the first responders to hypoxia in stroke and therefore a potential target cell for early stroke interventions. Using single-cell RNA sequencing in a mouse model of permanent middle cerebral artery occlusion, we investigated the temporal differences in transcriptomic signatures in pericytes at 1, 12, and 24 h after stroke. Our results reveal a stroke-specific subcluster of pericytes that is present at 12 and 24 h and characterized by the upregulation of genes mainly related to cytokine signaling and immune response. This study identifies temporal transcriptional changes in the acute phase of ischemic stroke that reflect the early response of pericytes to the ischemic insult and its secondary consequences and may constitute potential future therapeutic targets.
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| 9. |
- Carlsson, Robert, et al.
(författare)
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Molecular Regulation of the Response of Brain Pericytes to Hypoxia
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 24:6
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Forskningsöversikt (refereegranskat)abstract
- The brain needs sufficient oxygen in order to function normally. This is achieved by a large vascular capillary network ensuring that oxygen supply meets the changing demand of the brain tissue, especially in situations of hypoxia. Brain capillaries are formed by endothelial cells and perivascular pericytes, whereby pericytes in the brain have a particularly high 1:1 ratio to endothelial cells. Pericytes not only have a key location at the blood/brain interface, they also have multiple functions, for example, they maintain blood–brain barrier integrity, play an important role in angiogenesis and have large secretory abilities. This review is specifically focused on both the cellular and the molecular responses of brain pericytes to hypoxia. We discuss the immediate early molecular responses in pericytes, highlighting four transcription factors involved in regulating the majority of transcripts that change between hypoxic and normoxic pericytes and their potential functions. Whilst many hypoxic responses are controlled by hypoxia-inducible factors (HIF), we specifically focus on the role and functional implications of the regulator of G-protein signaling 5 (RGS5) in pericytes, a hypoxia-sensing protein that is regulated independently of HIF. Finally, we describe potential molecular targets of RGS5 in pericytes. These molecular events together contribute to the pericyte response to hypoxia, regulating survival, metabolism, inflammation and induction of angiogenesis.
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| 10. |
- Carlsson, Robert, et al.
(författare)
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STAT3 precedes HIF1α transcriptional responses to oxygen and oxygen and glucose deprivation in human brain pericytes
- 2018
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- Brain pericytes are important to maintain vascular integrity of the neurovascular unit under both physiological and ischemic conditions. Ischemic stroke is known to induce an inflammatory and hypoxic response due to the lack of oxygen and glucose in the brain tissue. How this early response to ischemia is molecularly regulated in pericytes is largely unknown and may be of importance for future therapeutic targets. Here we evaluate the transcriptional responses in in vitro cultured human brain pericytes after oxygen and/or glucose deprivation. Hypoxia has been widely known to stabilise the transcription factor hypoxia inducible factor 1-alpha (HIF1α) and mediate the induction of hypoxic transcriptional programs after ischemia. However, we find that the transcription factors Jun Proto-Oncogene (c-JUN), Nuclear Factor Of Kappa Light Polypeptide Gene Enhancer In B-Cells (NFκB) and signal transducer and activator of transcription 3 (STAT3) bind genes regulated after 2hours (hs) of omitted glucose and oxygen before HIF1α. Potent HIF1α responses require 6hs of hypoxia to substantiate transcriptional regulation comparable to either c-JUN or STAT3. Phosphorylated STAT3 protein is at its highest after 5 min of oxygen and glucose (OGD) deprivation, whereas maximum HIF1α stabilisation requires 120 min. We show that STAT3 regulates angiogenic and metabolic pathways before HIF1α, suggesting that HIF1α is not the initiating trans-acting factor in the response of pericytes to ischemia.
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| 11. |
- Ehinger, Johannes K., et al.
(författare)
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Mitochondrial function in peripheral blood cells across the human lifespan
- 2024
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Ingår i: npj Aging. - 2731-6068. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial dysfunction is considered a hallmark of aging. Up to now, a gradual decline of mitochondrial respiration with advancing age has mainly been demonstrated in human muscle tissue. A handful of studies have examined age-related mitochondrial dysfunction in human blood cells, and only with small sample sizes and mainly in platelets. In this study, we analyzed mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) and platelets from 308 individuals across the human lifespan (0–86 years). In regression analyses, with adjustment for false discovery rate (FDR), we found age-related changes in respiratory measurements to be either small or absent. The main significant changes were an age-related relative decline in complex I-linked respiration and a corresponding rise of complex II-linked respiration in PBMCs. These results add to the understanding of mitochondrial dysfunction in aging and to its possible role in immune cell and platelet senescence.
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| 12. |
- Ehinger, Johannes, et al.
(författare)
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Mitochondrial dysfunction in blood cells from amyotrophic lateral sclerosis patients.
- 2015
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Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 1432-1459 .- 0340-5354. ; 262:6, s. 1493-1503
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial dysfunction is implicated in amyotrophic lateral sclerosis, where the progressive degeneration of motor neurons results in muscle atrophy, paralysis and death. Abnormalities in both central nervous system and muscle mitochondria have previously been demonstrated in patient samples, indicating systemic disease. In this case-control study, venous blood samples were acquired from 24 amyotrophic lateral sclerosis patients and 21 age-matched controls. Platelets and peripheral blood mononuclear cells were isolated and mitochondrial oxygen consumption measured in intact and permeabilized cells with additions of mitochondrial substrates, inhibitors and titration of an uncoupler. Respiratory values were normalized to cell count and for two markers of cellular mitochondrial content, citrate synthase activity and mitochondrial DNA, respectively. Mitochondrial function was correlated with clinical staging of disease severity. Complex IV (cytochrome c-oxidase)-activity normalized to mitochondrial content was decreased in platelets from amyotrophic lateral sclerosis patients both when normalized to citrate synthase activity and mitochondrial DNA copy number. In mononuclear cells, complex IV-activity was decreased when normalized to citrate synthase activity. Mitochondrial content was increased in amyotrophic lateral sclerosis patient platelets. In mononuclear cells, complex I activity declined and mitochondrial content increased progressively with advancing disease stage. The findings are, however, based on small subsets of patients and need to be confirmed. We conclude that when normalized to mitochondria-specific content, complex IV-activity is reduced in blood cells from amyotrophic lateral sclerosis patients and that there is an apparent compensatory increase in cellular mitochondrial content. This supports systemic involvement in amyotrophic lateral sclerosis and suggests further study of mitochondrial function in blood cells as a future biomarker for the disease.
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| 13. |
- EHINGER, JOHANNES, et al.
(författare)
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Mitochondrial Respiratory Function in Peripheral Blood Cells from Huntington's Disease Patients
- 2016
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Ingår i: Movement Disorders Clinical Practice. - : Wiley. - 2330-1619. ; 3:5, s. 472-482
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPatients with Huntington's disease display symptoms from both the central nervous system and peripheral tissues. Mitochondrial dysfunction has been implicated as part of the pathogenesis of the disease and has been reported in brain tissue and extracerebral tissues, such as muscle and blood cells, but the results are inconsistent. Therefore, the authors performed a refined evaluation of mitochondrial function in 2 types of peripheral blood cells from 14 patients with Huntington's disease and 21 control subjects. Several hypotheses were predefined, including impaired mitochondrial complex II function (primary), complex I function (secondary), and maximum oxidative phosphorylation capacity (secondary) in patient cells.MethodsHigh-resolution respirometry was applied to viable platelets and mononuclear cells. Data were normalized to cell counts, citrate synthase activity, and mitochondrial DNA copy numbers.ResultsNormalized to citrate synthase activity, platelets from patients with Huntington's disease displayed respiratory dysfunction linked to complex I, complex II, and lower maximum oxidative phosphorylation capacity. No difference was seen in mononuclear cells or when platelet data were normalized to cell counts or mitochondrial DNA. The ratio of complex I respiration through maximum oxidative phosphorylation was significantly decreased in patients compared with controls. The corresponding ratio for complex II was unaffected.ConclusionsThe data indicate decreased function of mitochondrial complex I in peripheral blood cells from patients with Huntington's disease, although this could not be uniformly confirmed. The results do not confirm a systemic complex II dysfunction and do not currently support the use of mitochondrial function in blood cells as a biomarker for the disease.
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| 14. |
- Elabi, Osama F., et al.
(författare)
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DPP-4 Inhibitor and Sulfonylurea Differentially Reverse Type 2 Diabetes-Induced Blood-Brain Barrier Leakage and Normalize Capillary Pericyte Coverage
- 2023
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 72:3, s. 405-414
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Tidskriftsartikel (refereegranskat)abstract
- Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). Although accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride, which restore T2D-induced brain vascular pathology. Microvascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months before sacrifice. We demonstrate that T2D caused leakage of the blood–brain barrier (BBB), induced angiogenesis, and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalized T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial activation, increased microglial–vascular interaction, and increased collagen IV density. This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage, which may contribute to antidiabetic neurorestorative effects.
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| 15. |
- Elabi, Osama F., et al.
(författare)
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High-fat diet-induced diabetes leads to vascular alterations, pericyte reduction, and perivascular depletion of microglia in a 6-OHDA toxin model of Parkinson disease
- 2021
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Diabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson’s disease (PD). Although several hypotheses suggest a number of different mechanisms underlying the aggravation of PD caused by diabetes, less attention has been paid to the fact that diabetes and PD share pathological microvascular alterations in the brain. The characteristics of the interaction of diabetes in combination with PD at the vascular interface are currently not known. Methods: We combined a high-fat diet (HFD) model of diabetes mellitus type 2 (DMT2) with the 6-OHDA lesion model of PD in male mice. We analyzed the association between insulin resistance and the achieved degree of dopaminergic nigrostriatal pathology. We further assessed the impact of the interaction of the two pathologies on motor deficits using a battery of behavioral tests and on microglial activation using immunohistochemistry. Vascular pathology was investigated histologically by analyzing vessel density and branching points, pericyte density, blood–brain barrier leakage, and the interaction between microvessels and microglia in the striatum. Results: Different degrees of PD lesion were obtained resulting in moderate and severe dopaminergic cell loss. Even though the HFD paradigm did not affect the degree of nigrostriatal lesion in the acute toxin-induced PD model used, we observed a partial aggravation of the motor performance of parkinsonian mice by the diet. Importantly, the combination of a moderate PD pathology and HFD resulted in a significant pericyte depletion, an absence of an angiogenic response, and a significant reduction in microglia/vascular interaction pointing to an aggravation of vascular pathology. Conclusion: This study provides the first evidence for an interaction of DMT2 and PD at the brain microvasculature involving changes in the interaction of microglia with microvessels. These pathological changes may contribute to the pathological mechanisms underlying the accelerated progression of PD when associated with diabetes.
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| 16. |
- Elabi, Osama, et al.
(författare)
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Human α-synuclein overexpression in a mouse model of Parkinson’s disease leads to vascular pathology, blood brain barrier leakage and pericyte activation
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The pathological hallmark of Parkinson’s disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (α-syn). Although PD is associated with these distinct histological changes, other pathological features such as microvascular alterations have been linked to neurodegeneration. These changes need to be investigated as they create a hostile brain microenvironment and may contribute to the development and progression of the disease. We use a human α-syn overexpression mouse model that recapitulates some of the pathological features of PD in terms of progressive aggregation of human α-syn, impaired striatal dopamine fiber density, and an age-dependent motor deficit consistent with an impaired dopamine release. We demonstrate for the first time in this model a compromised blood–brain barrier integrity and dynamic changes in vessel morphology from angiogenesis at earlier stages to vascular regression at later stages. The vascular alterations are accompanied by a pathological activation of pericytes already at an early stage without changing overall pericyte density. Our data support and further extend the occurrence of vascular pathology as an important pathophysiological aspect in PD. The model used provides a powerful tool to investigate disease-modifying factors in PD in a temporal sequence that might guide the development of new treatments.
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| 17. |
- Enström, Andreas, et al.
(författare)
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RGS5 : a novel role as a hypoxia-responsive protein that suppresses chemokinetic and chemotactic migration in brain pericytes
- 2022
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Ingår i: Biology Open. - : The Company of Biologists. - 2046-6390. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- Adaptive biological mechanisms to hypoxia are crucial to maintain oxygen homeostasis, especially in the brain. Pericytes, cells uniquely positioned at the blood-brain interface, respond fast to hypoxia by expressing regulator of G-protein signalling 5 (RGS5), a negative regulator of G-protein-coupled receptors. RGS5 expression in pericytes is observed in pathological hypoxic environments (e.g. tumours and ischaemic stroke) and associated with perivascular depletion of pericytes and vessel leakage. However, the regulation of RGS5 expression and its functional role in pericytes are not known. We demonstrate that RGS5 acts as a hypoxia-responsive protein in human brain pericytes that is regulated independent of hypoxia inducible factor-1α (HIF-1α), rapidly stabilized under hypoxia, but degraded under normoxic conditions. We show that RGS5 expression desensitizes pericytes to signalling of platelet-derived growth factor-BB (PDGFBB) and sphingosine 1-phosphate (S1P), and blocks chemokinesis or chemotaxis induced by these factors. Our data imply a role for RGS5 in antagonizing pericyte recruitment and retention to blood vessels during hypoxia and support RGS5 as a target in counteracting vessel leakage under pathological hypoxic conditions. This article has an associated First Person interview with the first author of the paper.
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| 18. |
- Gaceb, Abderahim, et al.
(författare)
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An In Vitro Partial Lesion Model of Differentiated Human Mesencephalic Neurons : Effect of Pericyte Secretome on Phenotypic Markers
- 2020
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Ingår i: Journal of Molecular Neuroscience. - : Springer Science and Business Media LLC. - 0895-8696 .- 1559-1166. ; 70:11, s. 1914-1925
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson’s disease (PD) is characterised by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta. Post-mortem data suggests that the loss of DA markers may long precede the cell death, leaving a window to rescue the DA phenotype. Screening for potential neuroprotective or restorative therapies, however, requires that partial lesions of DA neurons can be modelled in vitro. In order to establish a partial lesion model of DA neurons in vitro, we evaluated the effects of different exposure times to 1-methyl-4-phenylpyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) on the cell survival and DA marker expression using DA neurons derived from the Lund human mesencephalic (LUHMES) cell line. We show that 24-h incubation with 50 μM of MPP+ or 6-h incubation with 100 μM of 6-OHDA leads to a significant decrease in the protein expression of DA markers without affecting overall cell death, consistent with a mild DA lesion. Using conditioned medium of human brain–derived pericytes stimulated with platelet-derived growth factor BB (PDGF-BB), we demonstrate a significant upregulation of DA markers. In conclusion, we provide an experimental model of an in vitro DA neuron partial lesion suitable to study different molecules and their potential neuroprotective or neurorestorative effects on the DA phenotype. We provide evidence that the secretome of brain pericytes stimulated via PDGF-BB/PDGFRβ affects DA marker expression and may represent one possible mechanism contributing to the neurorestoration previously observed in PD by this growth factor.
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| 19. |
- Gaceb, Abderahim, et al.
(författare)
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Pericyte Microvesicles as Plasma Biomarkers Reflecting Brain Microvascular Signaling in Patients with Acute Ischemic Stroke
- 2024
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Ingår i: Stroke. - 0039-2499. ; 55:3, s. 558-568
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Blood-based biomarkers have the potential to reflect cerebrovascular signaling after microvascular injury; yet, the detection of cell-specific signaling has proven challenging. Microvesicles retain parental cell surface antigens allowing detection of cell-specific signaling encoded in their cargo. In ischemic stroke, the progression of pathology involves changes in microvascular signaling whereby brain pericytes, perivascular cells wrapping the microcapillaries, are one of the early responders to the ischemic insult. Intercepting the pericyte signaling response peripherally by isolating pericyte-derived microvesicles may provide not only diagnostic information on microvascular injury but also enable monitoring of important pathophysiological mechanisms. METHODS: Plasma samples were collected from patients with acute ischemic stroke (n=39) at 3 time points after stroke onset: 0 to 6 hours, 12 to 24 hours, and 2 to 6 days, and compared with controls (n=39). Pericyte-derived microvesicles were isolated based on cluster of differentiation 140b expression and quantified by flow cytometry. The protein content was evaluated using a proximity extension assay, and vascular signaling pathways were examined using molecular signature hallmarks and gene ontology. RESULTS: In this case-control study, patients with acute ischemic stroke showed significantly increased numbers of pericyte-derived microvesicles (median, stroke versus controls) at 12 to 24 hours (1554 versus 660 microvesicles/μL; P=0.0041) and 2 to 6 days after stroke (1346 versus 660 microvesicles/μL; P=0.0237). Their proteome revealed anti-inflammatory properties mediated via downregulation of Kirsten rat sarcoma virus and IL (interleukin)-6/JAK/STAT3 signaling at 0 to 6 hours, but proangiogenic as well as proinflammatory signals at 12 to 24 hours. Between 2 and 6 days, proteins were mainly associated with vascular remodeling as indicated by activation of Hedgehog signaling in addition to proangiogenic signals. CONCLUSIONS: We demonstrate that the plasma of patients with acute ischemic stroke reflects (1) an early and time-dependent increase of pericyte-derived microvesicles and (2) changes in the protein cargo of microvesicles over time indicating cell signaling specifically related to inflammation and vascular remodeling.
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| 20. |
- Gaceb, Abderahim, et al.
(författare)
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Pericyte secretome
- 2018
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Ingår i: Pericyte Biology - Novel Concepts. - Cham : Springer International Publishing. - 2214-8019 .- 0065-2598. ; 1109, s. 139-163
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Bokkapitel (refereegranskat)abstract
- The role of pericytes seems to extend beyond their known function in angiogenesis, fibrosis and wound healing, blood-brain barrier maintenance, and blood flow regulation. More and more data are currently accumulating indicating that pericytes, uniquely positioned at the interface between blood and parenchyma, secrete a large plethora of different molecules in response to microenvironmental changes. Their secretome is tissue-specific and stimulus-specific and includes pro- and anti-inflammatory factors, growth factors, and extracellular matrix as well as microvesicles suggesting the important role of pericytes in the regulation of immune response and immune evasion of tumors. However, the angiogenic and trophic secretome of pericytes indicates that their secretome plays a role in physiological homeostasis but possibly also in disease progression or could be exploited for regenerative processes in the future. This book chapter summarizes the current data on the secretory properties of pericytes from different tissues in response to certain pathological stimuli such as inflammatory stimuli, hypoxia, high glucose, and others and thereby aims to provide insights into the possible role of pericytes in these conditions.
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| 21. |
- Gaceb, Abderahim, et al.
(författare)
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Pericytes secrete pro-regenerative molecules in response to platelet-derived growth factor-BB
- 2018
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - 1559-7016. ; 38:1, s. 45-57
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Tidskriftsartikel (refereegranskat)abstract
- Brain pericytes not only maintain the anatomical, biochemical and immune blood-brain barrier, but display features of mesenchymal stem cells (MSCs) in vitro. MSCs have pro-regenerative properties attributed to their secretome. However, whether also brain pericytes possess such pro-regenerative capacities is largely unknown. Here we characterize the secretome and microvesicle (MV) release of human brain pericytes mediated by platelet-derived growth factor-BB (PDGF-BB)/PDGF receptor beta (PDGFRβ) signalling. Upon PDGF-BB, pericytes release not only a plethora of growth factors and a panel of cytokines, but also MVs containing BDNF, FGFb, βNGF, VEGF and PLGF, a response that is specific for PDGFRβ signalling and activation of the ERK 1/2 pathway. In contrast, lipopolysaccharide (LPS), an activator of the innate immune system, stimulates the secretion of much higher amounts of mainly inflammatory cytokines and activates the NFκB pathway. Pericytes change their morphology and undergo opposite changes in surface marker expression, respectively. Our findings provide evidence that the secretome of human brain pericytes varies greatly depending on the exogenous stimulus. The differential secretory functions of pericytes may play an important role in either regulating neuroinflammation or contributing to neurorestoration and identify a possible new target cell for neuroregeneration.
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| 22. |
- Gaceb, Abderahim, et al.
(författare)
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The pericyte secretome : Potential impact on regeneration
- 2018
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Ingår i: Biochimie. - : Elsevier BV. - 0300-9084. ; 155, s. 16-25
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Tidskriftsartikel (refereegranskat)abstract
- Personalized and regenerative medicine is an emerging therapeutic strategy that is based on cell biology and biomedical engineering used to develop biological substitutes to maintain normal function or restore damaged tissues and organs. The secretory capacities of different cell types are now explored as such possible therapeutic regenerative agents in a variety of diseases. A secretome can comprise chemokines, cytokines, growth factors, but also extracellular matrix components, microvesicles and exosomes as well as genetic material and may differ depending on the tissue and the stimulus applied to the cell. With regard to clinical applications, the secretome of mesenchymal stem cells (MSC) is currently the most widely explored. However, other cell types such as pericytes may have similar properties as MSC and the potential therapeutic possibilities of these cells are only just beginning to emerge. In this review, we will summarize the currently available data describing the secretome of pericytes and its potential implications for tissue regeneration, whereby we especially focus on brain pericytes as potential new target cell for neuroregeneration and brain repair.
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| 23. |
- Hansen, Christian, et al.
(författare)
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alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells
- 2011
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 121:2, s. 715-725
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Tidskriftsartikel (refereegranskat)abstract
- Post-mortem analyses of brains from patients with Parkinson disease who received fetal mesencephalic transplants show that alpha-synuclein-containing (alpha-syn-containing) Lewy bodies gradually appear in grafted neurons. Here, we explored whether intercellular transfer of alpha-syn from host to graft, followed by seeding of alpha-syn aggregation in recipient neurons, can contribute to this phenomenon. We assessed alpha-syn cell-to-cell transfer using microscopy, flow cytometry, and high-content screening in several coculture model systems. Coculturing cells engineered to express either GFP- or DsRed-tagged alpha-syn resulted in a gradual increase in double-labeled cells. Importantly, alpha-syn-GFP derived from 1 neuroblastoma cell line localized to red fluorescent aggregates in other cells expressing DsRed-alpha-syn, suggesting a seeding effect of transmitted alpha-syn. Extracellular alpha-syn was taken up by cells through endocytosis and interacted with intracellular alpha-syn. Next, following intracortical injection of recombinant alpha-syn in rats, we found neuronal uptake was attenuated by coinjection of an endocytosis inhibitor. Finally, we demonstrated in vivo transfer of alpha-syn between host cells and grafted dopaminergic neurons in mice overexpressing human alpha-syn. In summary, intercellularly transferred alpha-syn interacts with cytoplasmic alpha-syn and can propagate alpha-syn pathology. These results suggest that alpha-syn propagation is a key element in the progression of Parkinson disease pathology.
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| 24. |
- Huttunen, Henri J., et al.
(författare)
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Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized, Double-Blind, Multicenter Phase 1 Trial
- 2023
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Ingår i: Movement Disorders. - : John Wiley & Sons. - 0885-3185 .- 1531-8257. ; 38:7, s. 1209-1222
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). Objective: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. Methods: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone-anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo-controlled, double-blind, 6-month main study followed by an active-treatment 6-month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18F]FE-PE2I. Results: Drug-related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. Conclusions: Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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| 25. |
- Janz, Carin, et al.
(författare)
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Non-Motor Symptom Management : Insights into Adherence to Treatment Guidelines in Parkinson’s Disease Patients
- 2024
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Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 14:2, s. 297-312
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Tidskriftsartikel (refereegranskat)abstract
- Background:Non-motor symptoms (NMS) reduce quality of life in Parkinson’s disease (PD) patients, who experience three times more NMS than individuals without PD. While there are international and national NMS treatment guidelines, their implication in clinical practice remains unclear.Objective:This study aimed to investigate the adherence to pharmacological NMS treatment guidelines in patients with mild to moderately severe PD.Methods:220 PD patients with ≥1 NMS based on the Non-Motor Symptom Questionnaire and a Hoehn and Yahr stage ≤4 were randomly selected from the Swedish Parkinson registry and screened for inclusion. NMS were evaluated using the International Parkinson and Movement Disorder Society–Non-Motor Rating Scale (MDS-NMS), Parkinson’s Disease Sleep Scale 2, Epworth Sleepiness Scale, and Hospital Anxiety and Depression Scale. Treatment was compared with Swedish national guidelines and international guidelines from the MDS Evidence-Based Medicine Committee.Results:Among 165 included patients, the median number of NMS was 14, and in median 7 symptoms were estimated to require treatment. The most common NMS requiring treatment were pain (69%) and urinary problems (56%). Treatment of depression and constipation demonstrated the highest adherence to guidelines (79% and 77%), while dysphagia and excessive daytime sleepiness exhibited the lowest adherence (0% and 4%). On average, only 32% of NMS were treated in accordance with guidelines.Conclusions:Adherence to pharmacological guidelines for NMS in patients with mild to severe PD was low. This study highlights the need for improved evaluation and treatment of NMS to enhance symptom management and quality of life among PD patients.
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| 26. |
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| 27. |
- Kirkeby, Agnete, et al.
(författare)
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Preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson's disease, STEM-PD
- 2023
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Ingår i: Cell Stem Cell. - 1934-5909. ; 30:10, s. 1299-1314
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Tidskriftsartikel (refereegranskat)abstract
- Cell replacement therapies for Parkinson's disease (PD) based on transplantation of pluripotent stem cell-derived dopaminergic neurons are now entering clinical trials. Here, we present quality, safety, and efficacy data supporting the first-in-human STEM-PD phase I/IIa clinical trial along with the trial design. The STEM-PD product was manufactured under GMP and quality tested in vitro and in vivo to meet regulatory requirements. Importantly, no adverse effects were observed upon testing of the product in a 39-week rat GLP safety study for toxicity, tumorigenicity, and biodistribution, and a non-GLP efficacy study confirmed that the transplanted cells mediated full functional recovery in a pre-clinical rat model of PD. We further observed highly comparable efficacy results between two different GMP batches, verifying that the product can be serially manufactured. A fully in vivo-tested batch of STEM-PD is now being used in a clinical trial of 8 patients with moderate PD, initiated in 2022.
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| 28. |
- Li, Weihua, et al.
(författare)
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11C-PE2I and 18F-Dopa PET for assessing progression rate in Parkinson's : A longitudinal study
- 2018
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 33:1, s. 117-127
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Tidskriftsartikel (refereegranskat)abstract
- 18F-dopa PET measuring aromatic l-amino acid decarboxylase activity is regarded as the gold standard for evaluating dopaminergic function in Parkinson's disease. Radioligands for dopamine transporters are also used in clinical trials and for confirming PD diagnosis. Currently, it is not clear which imaging marker is more reliable for assessing clinical severity and rate of progression. The objective of this study was to directly compare 18F-dopa with the highly selective dopamine transporter radioligand 11C-PE2I for the assessment of motor severity and rate of progression in PD. Thirty-three mild-moderate PD patients underwent 18F-dopa and 11C-PE2I PET at baseline. Twenty-three were followed up for 18.8 ± 3.4 months. Standard multiple regression at baseline indicated that 11C-PE2I BPND predicted UPDRS-III and bradykinesia-rigidity scores (P < 0.05), whereas 18F-dopa Ki did not make significant unique explanatory contributions. Voxel-wise analysis showed negative correlations between 11C-PE2I BPND and motor severity across the whole striatum bilaterally. 18F-Dopa Ki clusters were restricted to the most affected putamen and caudate. Longitudinally, negative correlations were found between striatal (increment)11C-PE2I BPND, (increment)UPDRS-III, and (increment)bradykinesia-rigidity, whereas no significant associations were found for (increment)18F-dopa Ki. One cluster in the most affected putamen was identified in the longitudinal voxel-wise analysis showing a negative relationship between (increment)11C-PE2I BPND and (increment)bradykinesia-rigidity. Striatal 11C-PE2I appears to show greater sensitivity for detecting differences in motor severity than 18F-dopa. Furthermore, dopamine transporter decline is closely associated with motor progression over time, whereas no such relationship was found with aromatic l-amino acid decarboxylase. 11C-PE2I may be more effective for evaluating the efficacy of neuroprotective treatments in PD.
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| 29. |
- Li, Weihua, et al.
(författare)
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Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson's disease
- 2020
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 28
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Tidskriftsartikel (refereegranskat)abstract
- Background: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson's disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time. Objectives: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. Methods: We assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using 11C-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 ± 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. 11C-PE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity. Results: At baseline, PD patients with greater dopaminergic deficits, as measured with 11C-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen. Conclusions: Our findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression.
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| 30. |
- Loane, Clare, et al.
(författare)
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Aberrant nigral diffusion in Parkinson's disease : A longitudinal diffusion tensor imaging study
- 2016
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 31:7, s. 6-1020
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Measuring microstructure alterations with diffusion tensor imaging in PD is potentially a valuable tool to use as a biomarker for early diagnosis and to track disease progression. Previous studies have reported a specific decrease of nigral fractional anisotropy in PD. However, to date the effect of disease progression on nigral or striatal diffusion indices has not been fully explored.METHODS: We have conducted a cross-sectional and longitudinal diffusion tensor imaging study in 18 early stage, treated PD patients and 14 age-matched controls. PD patients were scanned on 2 occasions OFF medication, 19.3 months apart (standard deviation = 3.1 months). Longitudinal change of regional nigral and striatal measures of fractional anisotropy and mean diffusivity were calculated using a region-of-interest approach.RESULTS: Region-of-interest analysis demonstrated that at baseline, PD patients and controls did not differ in regard to diffusion indices in any region assessed. A significant difference of nigral fractional anisotropy and mean diffusivity between controls and PD patients at follow-up was detected and confirmed with longitudinal analysis within PD patients. Alterations in striatal regions were not detected in either group or over time.CONCLUSION: Our findings indicate that nigral diffusion measure may be a valuable measure of disease progression. In the future, larger longitudinal studies will confirm whether diffusion indices may serve as sensitive and clinically meaningful measures of disease progression in PD. © 2016 International Parkinson and Movement Disorder Society.
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| 31. |
- Lodder, Paul, et al.
(författare)
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Type D Personality as a Risk Factor for Adverse Outcome in Patients With Cardiovascular Disease : An Individual Patient-Data Meta-analysis
- 2023
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Ingår i: Psychosomatic Medicine. - : Lippincott Williams & Wilkins. - 0033-3174 .- 1534-7796. ; 85:2, s. 188-202
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveType D personality, a joint tendency toward negative affectivity and social inhibition, has been linked to adverse events in patients with heart disease, although with inconsistent findings. Here, we apply an individual patient-data meta-analysis to data from 19 prospective cohort studies (N = 11,151) to investigate the prediction of adverse outcomes by type D personality in patients with acquired cardiovascular disease.MethodFor each outcome (all-cause mortality, cardiac mortality, myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, major adverse cardiac event, any adverse event), we estimated type D's prognostic influence and the moderation by age, sex, and disease type.ResultsIn patients with cardiovascular disease, evidence for a type D effect in terms of the Bayes factor (BF) was strong for major adverse cardiac event (BF = 42.5; odds ratio [OR] = 1.14) and any adverse event (BF = 129.4; OR = 1.15). Evidence for the null hypothesis was found for all-cause mortality (BF = 45.9; OR = 1.03), cardiac mortality (BF = 23.7; OR = 0.99), and myocardial infarction (BF = 16.9; OR = 1.12), suggesting that type D had no effect on these outcomes. This evidence was similar in the subset of patients with coronary artery disease (CAD), but inconclusive for patients with heart failure (HF). Positive effects were found for negative affectivity on cardiac and all-cause mortality, with the latter being more pronounced in male than female patients.ConclusionAcross 19 prospective cohort studies, type D predicts adverse events in patients with CAD, whereas evidence in patients with HF was inconclusive. In both patients with CAD and HF, we found evidence for a null effect of type D on cardiac and all-cause mortality.
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| 32. |
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| 33. |
- Mehmeti-Ajradini, Meliha, et al.
(författare)
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Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer
- 2020
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Ingår i: Life Science Alliance. - 2575-1077. ; 3:11
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Tidskriftsartikel (refereegranskat)abstract
- Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients cotransplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.
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| 34. |
- Mehmeti-Ajradini, Meliha, et al.
(författare)
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Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer
- 2020
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Ingår i: Life Science Alliance. - : LIFE SCIENCE ALLIANCE LLC. - 2575-1077. ; 3:11
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Tidskriftsartikel (refereegranskat)abstract
- Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.
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| 35. |
- Ogneva, Olga, et al.
(författare)
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Particulate organic matter in the Lena River and its delta : from thepermafrost catchment to the Arctic Ocean
- 2023
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Ingår i: Biogeosciences. - 1726-4170 .- 1726-4189. ; 20:7, s. 1423-1441
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Tidskriftsartikel (refereegranskat)abstract
- Rapid Arctic warming accelerates permafrost thaw, causing an additional release of terrestrial organic matter (OM) into rivers and, ultimately, after transport via deltas and estuaries, to the Arctic Ocean nearshore. The majority of our understanding of nearshore OM dynamics and fate has been developed from freshwater rivers despite the likely impact of highly dynamic estuarine and deltaic environments on the transformation, storage, and age of OM delivered to coastal waters. Here, we studied particulate organic carbon (POC) dynamics in the Lena River delta and compared them with POC dynamics in the Lena River main stem along a similar to 1600 km long transect from Yakutsk, downstream to the delta. We measured POC, total suspended matter (TSM), and carbon isotopes (delta C-13 and Delta C-14) in POC to compare riverine and deltaic OM composition and changes in OM source and fate during transport offshore. We found that TSM and POC concentrations decreased by 70% during transit from the main stem to the delta and Arctic Ocean. We found deltaic POC to be strongly depleted in C-13 relative to fluvial POC. Dual-carbon (Delta C-14 and delta C-13) isotope mixing model analyses indicated a significant phytoplankton contribution to deltaic POC (similar to 68 +/- 6 %) and suggested an additional input of permafrost-derived OM into deltaic waters (similar to 18 +/- 4% of deltaic POC originates from Pleistocene deposits vs. similar to 5 +/- 4% in the river main stem). Despite the lower concentration of POC in the delta than in the main stem (0.41 +/- 0.10 vs. 0.79 +/- 0.30 mg L-1, respectively), the amount of POC derived from Yedoma deposits in deltaic waters was almost twice as large as the amount of POC of Yedoma origin in the main stem (0.07 +/- 0.02 and 0.04 +/- 0.02 mg L-1, respectively). We assert that estuarine and deltaic processes require consideration in order to correctly understand OM dynamics throughout Arctic nearshore coastal zones and how these processes may evolve under future climate-driven change.
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| 36. |
- Ozen, Ilknur, et al.
(författare)
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Brain pericytes acquire a microglial phenotype after stroke.
- 2014
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 128:3, s. 381-396
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Tidskriftsartikel (refereegranskat)abstract
- Pericytes are located on the abluminal side of endothelial cells lining the microvasculature in all organs. They have been identified as multipotent progenitor cells in several tissues of the body including the human brain. New evidence suggests that pericytes contribute to tissue repair, but their role in the injured brain is largely unknown. Here, we investigate the role of pericytes in ischemic stroke. Using a pericyte-reporter mouse model, we provide unique evidence that regulator of G-protein signaling 5 expressing cells are activated pericytes that leave the blood vessel wall, proliferate and give rise to microglial cells after ischemic brain injury. Consistently, we show that activated pericytes express microglial markers in human stroke brain tissue. We demonstrate that human brain-derived pericytes adopt a microglial phenotype and upregulate mRNA specific for activated microglial cells under hypoxic conditions in vitro. Our study indicates that the vasculature is a novel source of inflammatory cells with a microglial phenotype in brain ischemia and hence identifies pericytes as an important new target for the development of future stroke therapies.
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| 37. |
- Ozen, Ilknur, et al.
(författare)
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Perivascular mesenchymal stem cells in the adult human brain: a future target for neuroregeneration?
- 2012
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Ingår i: Clinical and Translational Medicine. - : Wiley. - 2001-1326. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Perivascular adult stem cells have been isolated from several tissues, including the adult human brain. They have unique signatures resembling both pericytes and mesenchymal stem cells. Understanding the nature of these cells in their specific vascular niches is important to determine their clinical potential as a new adult stem cell source. Indeed, they have promising features in vitro in terms of multipotency, immunomodulation and secretion of growth factors and cytokines. However, their in vivo function is less known as yet. Recent emerging data show a crucial role of perivascular mesenchymal stem cells in tissue homeostasis and repair. Furthermore, these cells may play an important role in adult stem cell niche regulation and in neurodegeneration. Here we review the recent literature on perivascular mesenchymal stem cells, discuss their different in vitro functions and highlight especially the specific properties of brain-derived perivascular mesenchymal stem cells. We summarize current evidence that suggests an important in vivo function of these cells in terms of their regenerative potential that may indicate a new target cell for endogenous tissue regeneration and repair.
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| 38. |
- Padel, Thomas, et al.
(författare)
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Brain pericyte activation occurs early in Huntington's disease
- 2018
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 305, s. 139-150
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Tidskriftsartikel (refereegranskat)abstract
- Microvascular changes have recently been described for several neurodegenerative disorders, including Huntington's disease (HD). HD is characterized by a progressive neuronal cell loss due to a mutation in the Huntingtin gene. However, the temporal and spatial microvascular alterations in HD remain unclear. Also, knowledge on the implication of pericytes in HD pathology is still sparse and existing findings are contradictory. Here we examine alterations in brain pericytes in the R6/2 mouse model of HD and in human post mortem HD brain sections. To specifically track activated pericytes, we crossbred R6/2 mice with transgenic mice expressing the Green fluorescent protein gene under the Regulator of G-protein signaling 5 (Rgs5) promoter. We demonstrate an increase in activated pericytes in the R6/2 brain and in post mortem HD brain tissue. Importantly, pericyte changes are already detected before striatal neuronal cell loss, weight loss or behavioural deficits occur in R6/2 mice. This is associated with vascular alterations, whereby striatal changes precede cortical changes. Our findings suggest that pericyte activation may be one of the initial steps contributing to the observed vascular modifications in HD. Thus, pericytes may constitute an important target to address early microvascular changes contributing to disease progression in HD.
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| 39. |
- Padel, Thomas, et al.
(författare)
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Platelet-derived growth factor-BB has neurorestorative effects and modulates the pericyte response in a partial 6-hydroxydopamine lesion mouse model of Parkinson's disease
- 2016
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 94, s. 95-105
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) is a neurodegenerative disease where the degeneration of the nigrostriatal pathway leads to specific motor deficits. There is an unmet medical need for regenerative treatments that stop or reverse disease progression. Several growth factors have been investigated in clinical trials to restore the dopaminergic nigrostriatal pathway damaged in PD. Platelet-derived growth factor-BB (PDGF-BB), a molecule that recruits pericytes to stabilize microvessels, was recently investigated in a phase-1 clinical trial, showing a dose-dependent increase in dopamine transporter binding in the putamen of PD patients. Interestingly, evidence is accumulating that PD is paralleled by microvascular changes, however, whether PDGF-BB modifies pericytes in PD is not known. Using a pericyte reporter mouse strain, we investigate the functional and restorative effect of PDGF-BB in a partial 6-hydroxydopamine medial forebrain bundle lesion mouse model of PD, and whether this restorative effect is accompanied by changes in pericyte features. We demonstrate that a 2-week treatment with PDGF-BB leads to behavioural recovery using several behavioural tests, and partially restores the nigrostriatal pathway. Interestingly, we find that pericytes are activated in the striatum of PD lesioned mice and that these changes are reversed by PDGF-BB treatment. The modulation of brain pericytes may contribute to the PDGF-BB-induced neurorestorative effects, PDGF-BB allowing for vascular stabilization in PD. Pericytes might be a new cell target of interest for future regenerative therapies.
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| 40. |
- Parmar, Malin, et al.
(författare)
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Cell therapies for Parkinson's disease
- 2014
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Ingår i: Advances in Clinical Neuroscience and Rehabilitation. ; 14:3, s. 26-28
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Tidskriftsartikel (refereegranskat)
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| 41. |
- Paul, Gesine, et al.
(författare)
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Microvascular Changes in Parkinson’s Disease- Focus on the Neurovascular Unit
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14
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Forskningsöversikt (refereegranskat)abstract
- Vascular alterations emerge as a common denominator for several neurodegenerative diseases. In Parkinson’s disease (PD), a number of observations have been made suggesting that the occurrence of vascular pathology is an important pathophysiological aspect of the disease. Specifically, pathological activation of pericytes, blood-brain barrier (BBB) disruption, pathological angiogenesis and vascular regression have been reported. This review summarizes the current evidence for the different vascular alterations in patients with PD and in animal models of PD. We suggest a possible sequence of vascular pathology in PD ranging from early pericyte activation and BBB leakage to an attempt for compensatory angiogenesis and finally vascular rarefication. We highlight different pathogenetic mechanisms that play a role in these vascular alterations including perivascular inflammation and concomitant metabolic disease. Awareness of the contribution of vascular events to the pathogenesis of PD may allow the identification of targets to modulate those mechanisms. In particular the BBB has for decades only been viewed as an obstacle for drug delivery, however, preservation of its integrity and/or modulation of the signaling at this interface between the blood and the brain may prove to be a new avenue to take in order to develop disease-modifying strategies for neurodegenerative disorders.
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| 42. |
- Paul, Gesine, et al.
(författare)
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Trophic factors for Parkinson's disease : Where are we and where do we go from here?
- 2019
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 49:4, s. 440-452
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Tidskriftsartikel (refereegranskat)abstract
- Perhaps the most important unmet clinical need in Parkinson's disease (PD) is the development of a therapy that can slow or halt disease progression. Extensive preclinical research has provided evidence for the neurorestorative properties of several growth factors, yet only a few have been evaluated in clinical studies. Attempts to achieve neuroprotection by addressing cell-autonomous mechanisms and targeting dopaminergic neurons have been disappointing. Four different trophic factors have so far entered clinical trials in PD: glial cell line-derived growth factor, its close structural and functional analog neurturin, platelet-derived growth factor and cerebral dopaminergic neurotrophic factor. This article reviews the pre-clinical evidence for the neuroprotective and neurorestorative actions of these growth factors and discusses limitations of preclinical models, which may hamper successful translation to the clinic. We summarize the previous and ongoing clinical trials using growth factors in PD and emphasize the caveats in clinical trial design that may prevent the further development and registration of potentially neuroprotective and neurorestorative treatments for individuals suffering from PD.
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- Paul-Visse, Gesine, et al.
(författare)
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Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients
- 2015
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:3, s. 1339-1346
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 mu g rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD.
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- Paul-Visse, Gesine, et al.
(författare)
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Stem cells: hype or hope?
- 2002
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Ingår i: Drug Discovery Today. - 1878-5832. ; 7:5, s. 295-302
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Forskningsöversikt (refereegranskat)abstract
- Stem cells undergo self-renewal and differentiate into multiple lineages of mature cells. The identification of stem cells in diverse adult tissues and the findings that human embryonic stem cells can be proliferated and differentiated has kindled the imagination of both scientists and the public regarding future stem cell technology. These cells could constitute an unlimited supply of diverse cell types that can be used for cell transplantation or drug discovery. The new options raise several fundamental ethical issues. This review gives an overview of the scientific basis underlying the hope generated by stem cell research and discusses current ethical and funding regulations.
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- Paul-Visse, Gesine, et al.
(författare)
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The adult human brain harbors multipotent perivascular mesenchymal stem cells.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- Blood vessels and adjacent cells form perivascular stem cell niches in adult tissues. In this perivascular niche, a stem cell with mesenchymal characteristics was recently identified in some adult somatic tissues. These cells are pericytes that line the microvasculature, express mesenchymal markers and differentiate into mesodermal lineages but might even have the capacity to generate tissue-specific cell types. Here, we isolated, purified and characterized a previously unrecognized progenitor population from two different regions in the adult human brain, the ventricular wall and the neocortex. We show that these cells co-express markers for mesenchymal stem cells and pericytes in vivo and in vitro, but do not express glial, neuronal progenitor, hematopoietic, endothelial or microglial markers in their native state. Furthermore, we demonstrate at a clonal level that these progenitors have true multilineage potential towards both, the mesodermal and neuroectodermal phenotype. They can be epigenetically induced in vitro into adipocytes, chondroblasts and osteoblasts but also into glial cells and immature neurons. This progenitor population exhibits long-term proliferation, karyotype stability and retention of phenotype and multipotency following extensive propagation. Thus, we provide evidence that the vascular niche in the adult human brain harbors a novel progenitor with multilineage capacity that appears to represent mesenchymal stem cells and is different from any previously described human neural stem cell. Future studies will elucidate whether these cells may play a role for disease or may represent a reservoir that can be exploited in efforts to repair the diseased human brain.
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