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Orädd, Greger
Publications (10 of 54) Show all publications
Andersson, G., Orädd, G., Sultan, F. & Novikov, L. N. (2018). In vivo Diffusion Tensor Imaging, Diffusion Kurtosis Imaging, and Tractography of a Sciatic Nerve Injury Model in Rat at 9.4T. Scientific Reports, 8, Article ID 12911.
Open this publication in new window or tab >>In vivo Diffusion Tensor Imaging, Diffusion Kurtosis Imaging, and Tractography of a Sciatic Nerve Injury Model in Rat at 9.4T
2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12911Article in journal (Refereed) Published
Abstract [en]

Peripheral nerve injuries result in severe loss of sensory and motor functions in the afflicted limb. There is a lack of standardised models to non-invasively study degeneration, regeneration, and normalisation of neuronal microstructure in peripheral nerves. This study aimed to develop a non-invasive evaluation of peripheral nerve injuries, using diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and tractography on a rat model of sciatic nerve injury. 10 female Sprague Dawley rats were exposed to sciatic nerve neurotmesis and studied using a 9.4 T magnet, by performing DTI and DKI of the sciatic nerve before and 4 weeks after injury. The distal nerve stump showed a decrease in fractional anisotropy (FA), mean kurtosis (MK), axonal water fraction (AWF), and radial and axonal kurtosis (RK, AK) after injury. The proximal stump showed a significant decrease in axial diffusivity (AD) and increase of MK and AK as compared with the uninjured nerve. Both mean diffusivity (MD) and radial diffusivity (RD) increased in the distal stump after injury. Tractography visualised the sciatic nerve and the site of injury, as well as local variations of the diffusion parameters following injury. In summary, the described method detects changes both proximal and distal to the nerve injury.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-151785 (URN)10.1038/s41598-018-30961-1 (DOI)000442870300089 ()30150697 (PubMedID)
Funder
Swedish Research Council, 2014-2306
Available from: 2018-09-14 Created: 2018-09-14 Last updated: 2018-09-14Bibliographically approved
Olmedo-Díaz, S., Estévez-Silva, H., Orädd, G., af Bjérken, S., Marcellino, D. & Virel, A. (2017). An altered blood–brain barrier contributes to brain iron accumulation and neuroinflammation in the 6-OHDA rat model of Parkinson's disease. Neuroscience, 362, 141-151
Open this publication in new window or tab >>An altered blood–brain barrier contributes to brain iron accumulation and neuroinflammation in the 6-OHDA rat model of Parkinson's disease
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2017 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 362, p. 141-151Article in journal (Refereed) Published
Abstract [en]

Brain iron accumulation is a common feature shared by several neurodegenerative disorders including Parkinson's disease. However, what produces this accumulation of iron is still unknown. In this study, the 6-hydroxydopamine (6-OHDA) hemi-parkinsonian rat model was used to investigate abnormal iron accumulation in substantia nigra. We investigated three possible causes of iron accumulation; a compromised blood-brain barrier (BBB), abnormal expression of ferritin, and neuroinflammation. We identified alterations in the BBB subsequent to the injection of 6-OHDA using gadolinium-enhanced magnetic resonance imaging (MRI). Moreover, detection of extravasated IgG suggested that peripheral components are able to enter the brain through a leaky BBB. Presence of iron following dopamine cell degeneration was studied by MRI, which revealed hypointense signals in the substantia nigra. The presence of iron deposits was further validated in histological evaluations. Furthermore, iron inclusions were closely associated with active microglia and with increased levels of L-ferritin indicating a putative role for microglia and L-ferritin in brain iron accumulation and dopamine neurodegeneration.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
brain-iron, 6-OHDA, MRI, blood-brain barrier, microglia
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-142910 (URN)10.1016/j.neuroscience.2017.08.023 (DOI)000412382100013 ()28842186 (PubMedID)
Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2018-06-09Bibliographically approved
Gorbach, T., Pudas, S., Lundquist, A., Orädd, G., Josefsson, M., Salami, A., . . . Nyberg, L. (2017). Longitudinal association between hippocampus atrophy and episodic-memory decline. Neurobiology of Aging, 51, 167-176
Open this publication in new window or tab >>Longitudinal association between hippocampus atrophy and episodic-memory decline
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2017 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 51, p. 167-176Article in journal (Refereed) Published
Abstract [en]

There is marked variability in both onset and rate of episodic-memory decline in aging. Structural magnetic resonance imaging studies have revealed that the extent of age-related brain changes varies markedly across individuals. Past studies of whether regional atrophy accounts for episodic-memory decline in aging have yielded inconclusive findings. Here we related 15-year changes in episodic memory to 4-year changes in cortical and subcortical gray matter volume and in white-matter connectivity and lesions. In addition, changes in word fluency, fluid IQ (Block Design), and processing speed were estimated and related to structural brain changes. Significant negative change over time was observed for all cognitive and brain measures. A robust brain-cognition change-change association was observed for episodic-memory decline and atrophy in the hippocampus. This association was significant for older (65-80 years) but not middle-aged (55-60 years) participants and not sensitive to the assumption of ignorable attrition. Thus, these longitudinal findings highlight medial-temporal lobe system integrity as particularly crucial for maintaining episodic-memory functioning in older age. 

Keywords
Aging, cognitive decline, episodic memory, hippocampus, longitudinal changes, non-ignorable attrition
National Category
Probability Theory and Statistics Neurosciences
Identifiers
urn:nbn:se:umu:diva-128725 (URN)10.1016/j.neurobiolaging.2016.12.002 (DOI)000397168600018 ()28089351 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelse
Available from: 2016-12-15 Created: 2016-12-13 Last updated: 2019-01-25Bibliographically approved
Karalija, A., Novikova, L. N., Orädd, G., Wiberg, M. & Novikov, L. N. (2016). Differentiation of pre- and postganglionic nerve injury using MRI of the spinal cord. PLoS ONE, 11(12), Article ID e0168807.
Open this publication in new window or tab >>Differentiation of pre- and postganglionic nerve injury using MRI of the spinal cord
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0168807Article in journal (Refereed) Published
Abstract [en]

Brachial plexus injury (BPI) is a devastating type of nerve injury, potentially causing loss of motor and sensory function. Principally, BPI is either categorized as preganglionic or post- ganglionic, with the early establishment of injury level being crucial for choosing the correct treatment strategy. Despite diagnostic advances, the need for a reliable, non-invasive method for establishing the injury level remains. We studied the usefulness of in vivo mag- netic resonance imaging (MRI) of the spinal cord for determination of injury level. The find- ings were related to neuronal and glial changes. Rats underwent unilateral L4 & L5 ventral roots avulsion or sciatic nerve axotomy. The injuries served as models for pre- and postgan- glionic BPI, respectively. MRI of the L4/L5 spinal cord segments 4 weeks after avulsion showed ventral horn (VH) shrinkage on the injured side compared to the uninjured side. Axotomy induced no change in the VH size on MRI. Following avulsion, histological sections of L4/L5 revealed shrinkage in the VH grey matter area occupied by NeuN-positive neurons, loss of microtubular-associated protein-2 positive dendritic branches (MAP2), pan-neurofila- ment positive axons (PanNF), synaptophysin-positive synapses (SYN) and increase in immunoreactivity for the microglial OX42 and astroglial GFAP markers. Axotomy induced no changes in NeuN-reactivity, modest decrease of MAP2 immunoreactivity, no changes in SYN and PanNF labelling, and a modest increase in OX42 and SYN labeling. Histological and radiological findings were congruent when assessing changes after axotomy, while MRI somewhat underestimated the shrinkage. This study indicates a potential diagnostic value of structural spinal cord MRI following BPI. 

Keywords
Neural injury, Surgery, MRI, Rat, Axonal injury, Brachial plexus injury
National Category
Neurosciences
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-127437 (URN)10.1371/journal.pone.0168807 (DOI)000391229300032 ()
Available from: 2016-11-11 Created: 2016-11-11 Last updated: 2018-06-09Bibliographically approved
Virel, A., Rehnmark, A., Orädd, G., Olmedo-Diaz, S., Faergemann, E. & Strömberg, I. (2015). Magnetic resonance imaging as a tool to image neuroinflammation in a rat model of Parkinson's disease: phagocyte influx to the brain is promoted by bilberry-enriched diet. European Journal of Neuroscience, 42(10), 2761-2771
Open this publication in new window or tab >>Magnetic resonance imaging as a tool to image neuroinflammation in a rat model of Parkinson's disease: phagocyte influx to the brain is promoted by bilberry-enriched diet
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2015 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 42, no 10, p. 2761-2771Article in journal (Refereed) Published
Abstract [en]

Neuroinflammation is a chronic event in neurodegenerative disorders. In the rat model of Parkinson's disease, including a striatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA), antioxidant treatment affects the inflammatory process. Despite a heavy accumulation of microglia early after the injury, dopamine nerve fibre regeneration occurs. It remains unclear why this heavy accumulation of microglia is found early after the lesion in antioxidant-treated animals, or even more, what is the origin of these microglia. In this study magnetic resonance imaging (MRI) was used to elucidate whether the inflammatory response was generated from the blood or from activated brain microglia. Superparamagnetic iron oxide (SPIO) nanoparticles were injected intravenously prior to a striatal 6-OHDA injection to tag phagocytes in the blood. Rats were fed either with bilberry-enriched or control diet. T2*-weighted MRI scans were performed 1 week after the lesion, and hypointense areas were calculated from T2*-weighted images, to monitor the presence of SPIO particles. The results revealed that feeding the animals with bilberries significantly promoted accumulation of blood-derived immune cells. Gadolinium-enhanced MRI demonstrated no difference in leakage of the blood-brain barrier independent of diets. To conclude, bilberry-enriched diet promotes an influx of periphery-derived immune cells to the brain early after injury.

Keywords
6-OHDA, blood-brain barrier, microglia, superparamagnetic iron oxide nanoparticles
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-116111 (URN)10.1111/ejn.13044 (DOI)000368242200002 ()26273789 (PubMedID)
Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2018-06-07Bibliographically approved
Chermenina, M., Schouten, P., Nevalainen, N., Johansson, F., Orädd, G. & Strömberg, I. (2014). GDNF is important for striatal organization and maintenance of dopamine neurons grown in the presence of the striatum. Neuroscience, 270, 1-11
Open this publication in new window or tab >>GDNF is important for striatal organization and maintenance of dopamine neurons grown in the presence of the striatum
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2014 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 270, p. 1-11Article in journal (Refereed) Published
Abstract [en]

Glial cell-derived neurotrophic factor (GDNF) exerts neuroprotective and neurorestorative effects on neurons and GDNF plays a significant role in maintenance of the dopamine neurons utilizing grafting to create a nigrostriatal microcircuit of Gdnf knockout (Gdnf(-/-)) tissue. To further evaluate the role of GDNF on organization of the nigrostriatal system, single or double grafts of ventral mesencephalon (VM) and lateral ganglionic eminence (LGE) with mismatches in Gdnf genotypes were performed. The survival of single grafts was monitored utilizing magnetic resonance imaging (MRI) and cell survival and graft organization were evaluated with immunohistochemistry. The results revealed that the size of VM single grafts did not change over time independent of genotype, while the size of the LGE transplants was significantly reduced already at 2weeks postgrafting when lacking GDNF. Lack of GDNF did not significantly affect the survival of tyrosine hydroxylase (TH)-positive neurons in single VM grafts. However, the survival of TH-positive neurons was significantly reduced in VM derived from Gdnf(+/+) when co-grafted with LGE from the Gdnf(-/-) tissue. In contrast, lack of GDNF in the VM portion of co-grafts had no effect on the survival of TH-positive neurons when co-grafted with LGE from Gdnf(+/+) mice. The TH-positive innervation of co-grafts was sparse when the striatal co-grafts were derived from the Gdnf(-/-) tissue while dense and patchy when innervating LGE producing GDNF. The TH-positive innervation overlapped with the organization of dopamine and cyclic AMP-regulated phosphoprotein-relative molecular mass 32,000 (DARPP-32)-positive neurons, that was disorganized in LGE lacking GDNF production. In conclusion, GDNF is important for a proper striatal organization and for survival of TH-positive neurons in the presence of the striatal tissue.

Keywords
GDNF, GDNF knockout, dopamine, substantia nigra, striatum, DARPP-32
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-88075 (URN)10.1016/j.neuroscience.2014.04.008 (DOI)000336624000001 ()24726488 (PubMedID)
Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2018-06-08Bibliographically approved
Virel, A., Faergemann, E., Orädd, G. & Strömberg, I. (2014). Magnetic Resonance Imaging (MRI) to Study Striatal Iron Accumulation in a Rat Model of Parkinson's Disease. PLoS ONE, 9(11), e112941
Open this publication in new window or tab >>Magnetic Resonance Imaging (MRI) to Study Striatal Iron Accumulation in a Rat Model of Parkinson's Disease
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112941-Article in journal (Refereed) Published
Abstract [en]

Abnormal accumulation of iron is observed in neurodegenerative disorders. In Parkinson's disease, an excess of iron has been demonstrated in different structures of the basal ganglia and is suggested to be involved in the pathogenesis of the disease. Using the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease, the edematous effect of 6-OHDA and its relation with striatal iron accumulation was examined utilizing in vivo magnetic resonance imaging (MRI). The results revealed that in comparison with control animals, injection of 6-OHDA into the rat striatum provoked an edematous process, visible in T2-weighted images that was accompanied by an accumulation of iron clearly detectable in T2*-weighted images. Furthermore, Prussian blue staining to detect iron in sectioned brains confirmed the existence of accumulated iron in the areas of T2* hypointensities. The presence of ED1-positive microglia in the lesioned striatum overlapped with this accumulation of iron, indicating areas of toxicity and loss of dopamine nerve fibers. Correlation analyses demonstrated a direct relation between the hyperintensities caused by the edema and the hypointensities caused by the accumulation of iron.

National Category
Radiology, Nuclear Medicine and Medical Imaging Neurosciences
Identifiers
urn:nbn:se:umu:diva-98441 (URN)10.1371/journal.pone.0112941 (DOI)000345558500115 ()25398088 (PubMedID)2-s2.0-84911902551 (Scopus ID)
Available from: 2015-02-04 Created: 2015-01-22 Last updated: 2018-06-07Bibliographically approved
Hohsfield, L. A., Daschil, N., Orädd, G., Strömberg, I. & Humpel, C. (2014). Vascular pathology of 20-month-old hypercholesterolemia mice in comparison to triple-transgenic and APPSwDI Alzheimer's disease mouse models. Molecular and cellular neuroscience, 63, 83-95
Open this publication in new window or tab >>Vascular pathology of 20-month-old hypercholesterolemia mice in comparison to triple-transgenic and APPSwDI Alzheimer's disease mouse models
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2014 (English)In: Molecular and cellular neuroscience, ISSN 1044-7431, Vol. 63, p. 83-95Article in journal (Refereed) Published
Abstract [en]

Several studies have shown that elevated plasma cholesterol levels (i.e. hypercholesterolemia) serve as a risk factor for late-onset Alzheimer's disease (AD). However, it remains unclear how hypercholesterolemia may contribute to the onset and progression of AD pathology. In order to determine the role of hypercholesterolemia at various stages of AD, we evaluated the effects of high cholesterol diet (5% cholesterol) in wild-type (WT; C57BL6) and triple-transgenic AD (3xTg-AD: Psen1, APPSwe, tauB301L) mice at 7, 14, and 20 months. The transgenic APP-Swedish/Dutch/Iowa AD mouse model (APPSwDI) was used as a control since these animals are more pathologically-accelerated and are known to exhibit extensive plaque deposition and cerebral amyloid angiopathy. Here, we describe the effects of high cholesterol diet on: (1) cognitive function and stress, (2) AD-associated pathologies, (3) neuroinflammation, (4) blood-brain barrier disruption and ventricle size, and (5) vascular dysfunction. Our data show that high dietary cholesterol increases weight, slightly impairs cognitive function, promotes glial cell activation and complement-related pathways, enhances the infiltration of blood-derived proteins and alters vascular integrity, however, it does not induce AD-related pathologies. While normal-fed 3xTg-AD mice display a typical AD-like pathology in addition to severe cognitive impairment and neuroinflammation at 20 months of age, vascular alterations are less pronounced. No microbleedings were seen by MRI, however, the ventricle size was enlarged. Triple-transgenic AD mice, on the other hand, fed a high cholesterol diet do not survive past 14 months of age. Our data indicates that cholesterol does not markedly potentiate AD-related pathology, nor does it cause significant impairments in cognition. However, it appears that high cholesterol diet markedly increases stress-related plasma corticosterone levels as well as some vessel pathologies. Together, our findings represent the first demonstration of prolonged high cholesterol diet and the examination of its effects at various stages of cerebrovascular- and AD-related disease.

Place, publisher, year, edition, pages
Academic Press, 2014
Keywords
Alzheimer's disease, hypercholesterolemia, cholesterol, β-amyloid, tau, neuroinflammation, scular pathology, learning, memory, MRI
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-97896 (URN)10.1016/j.mcn.2014.10.006 (DOI)000346227200009 ()
Available from: 2015-01-12 Created: 2015-01-08 Last updated: 2018-06-07Bibliographically approved
Strömberg, I., Rehnmark, A., Orädd, G. & Virel, A. (2013). Neuroinflammation Using MRI: Phagocytes From Blood to Brain With the Help of Bilberries. Cell Transplantation, 22(5), 917-917
Open this publication in new window or tab >>Neuroinflammation Using MRI: Phagocytes From Blood to Brain With the Help of Bilberries
2013 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 22, no 5, p. 917-917Article in journal, Meeting abstract (Other academic) Published
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-73089 (URN)000318585300084 ()
Available from: 2013-06-17 Created: 2013-06-17 Last updated: 2018-06-08Bibliographically approved
Orädd, G., Schmidtchen, A. & Malmsten, M. (2011). Effects of peptide hydrophobicity on its incorporation in phospholipid membranes - an NMR and ellipsometry study. Biochimica et Biophysica Acta, 1808(1), 244-252
Open this publication in new window or tab >>Effects of peptide hydrophobicity on its incorporation in phospholipid membranes - an NMR and ellipsometry study
2011 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1808, no 1, p. 244-252Article in journal (Refereed) Published
Abstract [en]

Effects of peptide hydrophobicity on lipid membrane binding, incorporation, and defect formation was investigated for variants of the complement-derived antimicrobial peptide CNY21 (CNYITELRRQHARASHLGLAR), in anionic 1-palmitoyl-2-oleoylphosphatidylethanolamine (POPE)/1-palmitoyl-2-oleoylphosphatidylglycerol (POPG) and zwitterionic 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) membranes. Using a method combination of, e.g., ellipsometry, CD, and fluorescence spectroscopy, it was shown that peptide adsorption, as well as peptide-induced liposome leakage and bactericidal potency against Escherichia coli and Pseudomonas aeruginosa, was promoted by increasing the hydrophobicity of CNY21 through either substituting the two histidines (H) in CNY21 with more hydrophobic leucine (L) residues, or end-tagging with tritryptophan (WWW). Fluorescence spectroscopy revealed that both CNY21WWW and the WWW tripeptide localized to the polar headgroup region of these phospholipid membranes. Deuterium NMR experiments on macroscopically oriented membranes containing fully (palmitoyl) deuterated POPC (POPC-d(31)) demonstrated that both CNY21L and CNY21WWW induced disordering of the lipid membrane. In contrast, for cholesterol-supplemented POPC-d(31) bilayers, peptide-induced disordering was less pronounced in the case of CNY21L, indicating that the peptide is unable to partition to the interior of the lipid membrane in the presence of cholesterol. CNY21WWW, on the other hand, retained its membrane-disordering effect also for cholesterol-supplemented POPC-d(31). These findings were supported by pulsed field gradient NMR experiments where the lateral lipid diffusion was determined in the absence and presence of peptides. Overall, the results provide some mechanistic understanding to previously observed effects of peptide hydrophobization through point mutations and end-tagging, particularly so for complement-based antimicrobial peptides.

Keywords
AMP, antimicrobial peptide, ellipsometry, liposome, membrane, NMR
Identifiers
urn:nbn:se:umu:diva-38791 (URN)10.1016/j.bbamem.2010.08.015 (DOI)20801096 (PubMedID)
Available from: 2011-01-03 Created: 2010-12-30 Last updated: 2018-06-08Bibliographically approved
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