| 51. |
- Mattsson, Niklas, 1979, et al.
(författare)
-
Cerebrospinal Fluid Microglial Markers in Alzheimer's Disease: Elevated Chitotriosidase Activity but Lack of Diagnostic Utility
- 2011
-
Ingår i: NeuroMolecular Medicine. - : Springer Science and Business Media LLC. - 1535-1084 .- 1559-1174. ; 13:2, s. 151-159
-
Tidskriftsartikel (refereegranskat)abstract
- Activated microglial cells, which are the resident macrophages of the central nervous system, surround amyloid beta-plaques in Alzheimer's disease (AD) brains. Inflammation including microglial activation may contribute in AD pathogenesis, and biomarkers for this process may thus be of value to study AD pathogenesis and might facilitate development of therapies targeting these cells. We therefore examined cerebrospinal fluid (CSF) biomarkers in patients with AD, other dementias, mild cognitive impairment and in healthy controls. Samples were analyzed for markers with known association to macrophage activity, including chitotriosidase, YKL-40 (CHI3L1, HC gp-39) and chemokine CC motif ligand 2 (CCL2, MCP1). Patients with AD had higher chitotriosidase activity than controls and patients with stable mild cognitive impairment, consistent with the presence of activated microglial cells in AD brains, but with large overlaps between groups. CCL2 and YKL-40 concentrations did not differ among groups. Microglial markers are unlikely to be useful for AD diagnosis, but might be useful for identification of distinct subgroups of patients, and for the development and implementation of drugs targeting microglial pathology.
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| 52. |
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| 53. |
- Mattsson, Niklas, 1979, et al.
(författare)
-
Growth factors in Parkinson's disease.
- 2011
-
Ingår i: Biomarkers in medicine. - 1752-0363. ; 5:2, s. 201-2
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 54. |
- Mattsson, Niklas, 1979, et al.
(författare)
-
It is all about clearance.
- 2011
-
Ingår i: Biomarkers in medicine. - 1752-0363. ; 5:2
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 55. |
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| 56. |
- Mellergård, Johan, et al.
(författare)
-
Association between Change in Normal Appearing White Matter Metabolites and Intrathecal Inflammation in Natalizumab-Treated Multiple Sclerosis
- 2012
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:9
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple sclerosis (MS) is associated not only with focal inflammatory lesions but also diffuse pathology in the central nervous system (CNS). Since there is no firm association between the amount of focal inflammatory lesions and disease severity, diffuse pathology in normal appearing white matter (NAWM) may be crucial for disease progression. Immunomodulating treatments for MS reduce the number of focal lesions, but possible effects on diffuse white matter pathology are less studied. Furthermore, it is not known whether intrathecal levels of inflammatory or neurodegenerative markers are associated with development of pathology in NAWM. Methods: Quantitative proton magnetic resonance spectroscopy (H-1-MRS) was used to investigate NAWM in 27 patients with relapsing MS before and after one year of treatment with natalizumab as well as NAWM in 20 healthy controls at baseline. Changes in H-1-MRS metabolite concentrations during treatment were also correlated with a panel of intrathecal markers of inflammation and neurodegeneration in 24 of these 27 patients. Results: The group levels of H-1-MRS metabolite concentrations were unchanged pre-to posttreatment, but a pattern of high magnitude correlation coefficients (r = 0.43-0.67, p<0.0005-0.03) were found between changes in individual metabolite concentrations (total creatine and total choline) and levels of pro-inflammatory markers (IL-1 beta and CXCL8). Conclusions: Despite a clinical improvement and a global decrease in levels of inflammatory markers in cerebrospinal fluid during treatment, high levels of pro-inflammatory CXCL8 and IL-1 beta were associated with an increase in H-1-MRS metabolites indicative of continued gliosis development and membrane turnover in NAWM.
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| 57. |
- Mellergård, Johan, et al.
(författare)
-
Cerebrospinal fluid levels of neurofilament and tau correlate with brain atrophy in natalizumab-treated multiple sclerosis
- 2017
-
Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 24:1, s. 112-121
-
Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Brain atrophy is related to clinical deterioration in multiple sclerosis (MS) but its association with intrathecal markers of inflammation or neurodegeneration is unclear. Our aim was to investigate whether cerebrospinal fluid (CSF) markers of inflammation or neurodegeneration are associated with brain volume change in natalizumab-treated MS and whether this change is reflected in non-lesional white matter metabolites. Methods: About 25 patients with natalizumab-treated MS were followed for 3 years with assessment of percentage brain volume change (PBVC) and absolute quantification of metabolites with proton magnetic resonance spectroscopy (1 H MRS). Analyses of inflammatory [interleukin 1 beta (IL-1 beta), IL-6, C-X-C motif chemokine 8 (CXCL8), CXCL10, CXCL11, C-C motif chemokine 22] and neurodegenerative [neurofilament light protein (NFL), glial fibrillary acidic protein, myelin basic protein, tau proteins] markers were done at baseline and 1-year follow-up. Results: The mean decline in PBVC was 3% at the 3-year follow-up, although mean H-1 MRS metabolite levels in non-lesional white matter were unchanged. CSF levels of NFL and tau at baseline correlated negatively with PBVC over 3 years (r = -0.564, P = 0.012, and r = -0.592, P = 0.010, respectively). Conclusions: A significant 3-year whole-brain atrophy was not reflected in mean metabolite change of non-lesional white matter. In addition, our results suggest that CSF levels of NFL and tau correlate with brain atrophy development and may be used for evaluating treatment response in inflammatory active MS.
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| 58. |
- Nguy, Lisa, 1985, et al.
(författare)
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Adenine-induced chronic renal failure in rats decreases aortic relaxation rate and alters expression of proteins involved in vascular smooth muscle calcium handling
- 2016
-
Ingår i: Acta Physiologica. - : Wiley. - 1748-1716 .- 1748-1708. ; 218:4, s. 250-264
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: Rats with adenine-induced chronic renal failure (A-CRF) develop a reduced rate of relaxation of the thoracic aorta. The aim of this study was to elucidate the mechanisms underlying this abnormality. Methods: Male Sprague Dawley rats received either chow containing adenine or were pair-fed with normal chow (controls). After 8–14 weeks, arterial function was analysed ex vivo using wire myography and the expression of proteins involved in vascular smooth muscle excitation–contraction coupling in the thoracic aorta was analysed. Results: The rate of relaxation following washout of KCl was reduced in A-CRF rats vs. controls in the thoracic aorta (P
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| 59. |
- Olofsson, Louise, 1977, et al.
(författare)
-
Preliminary report: Zn-alpha2-glycoprotein genotype and serum levels are associated with serum lipids.
- 2010
-
Ingår i: Metabolism. - : Elsevier BV. - 1532-8600 .- 0026-0495. ; 59:9, s. 1316-1318
-
Tidskriftsartikel (refereegranskat)abstract
- Zn-alpha2-glycoprotein (ZAG) is a serum protein implicated in cancer cachexia and lipolysis. Our aim was to investigate serum levels of ZAG and polymorphisms in the ZAG gene in relation to serum lipids in man. Serum levels of ZAG correlated with serum levels of cholesterol (P = .00088) in healthy subjects and during weight loss (P = .059). The ZAG genotype was associated with total cholesterol (P = .014) and low-density lipoprotein cholesterol (P = .026) in healthy subjects, and the associations were replicated in an additional cohort (P = .0017 and P = .060, respectively). Our data indicate that ZAG plays a role in lipid metabolism.
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| 60. |
- Olsson, Bob, 1969, et al.
(författare)
-
Apolipoprotein C-I genotype and serum levels of triglycerides, C-reactive protein and coronary heart disease
- 2010
-
Ingår i: Metabolism. - : Elsevier BV. - 0026-0495. ; 59:12, s. 1736-1741
-
Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein C-I (apoCI) is implicated in lipid metabolism and inflammatory response, both important risk factors for human heart disease. However, most findings come from in vitro or animal studies, whereas data on human apoCI are sparse. To elucidate the role of apoCI in human disease, we analyzed a functional polymorphism in the promoter region of the apoCI gene in relation to blood lipids, C-reactive protein (CRP), coronary artery disease (CAD), and myocardial infarction (MI). Rs11568822 is a 4-base pair insertion/deletion (Ins/Del) polymorphism, and the Ins allele leads to a higher transcription in vitro compared with the Del allele. This polymorphism was analyzed in the Intergene study, a case-control study for CAD (N = 1236), and the Stockholm Heart Epidemiology Program, a case-control study for MI (N = 2774). Subjects homozygous for the Ins genotype had significantly higher serum levels of triglycerides (P = .01 and P = .006) and lower serum levels of CRP (P = .02 and P < .0001) compared with all other subjects in both studies. Similar results were obtained when analyzing only the controls of both studies (P = .002 and P = .0002, triglycerides; P = .002 and P < .0001, CRP). However, apoCI was not associated with CAD or MI. In conclusion, our data show that apoCI genotype is associated with serum levels of triglycerides and CRP, confirming the role of apoCI in lipid metabolism and suggesting that it also influences inflammation.
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| 61. |
- Olsson, Bob, 1969, et al.
(författare)
-
Biomarker-based dissection of neurodegenerative diseases.
- 2011
-
Ingår i: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 95:4, s. 520-534
-
Forskningsöversikt (refereegranskat)abstract
- The diagnosis of neurodegenerative diseases within neurology and psychiatry are hampered by the difficulty in getting biopsies and thereby validating the diagnosis by pathological findings. Biomarkers for other types of disease have been readily adopted into the clinical practice where for instance troponins are standard tests when myocardial infarction is suspected. However, the use of biomarkers for neurodegeneration has not been fully incorporated into the clinical routine. With the development of cerebrospinal fluid (CSF) biomarkers that reflect pathological events within the central nervous system (CNS), important clinical diagnostic tools are becoming available. This review summarizes the most promising biomarker candidates that may be used to monitor different types of neurodegeneration and protein inclusions, as well as different types of metabolic changes, in living patients in relation to the clinical phenotype and disease progression over time. Our aim is to provide the reader with an updated lexicon on currently available biomarker candidates, how far they have come in development and how well they reflect pathogenic processes in different neurodegenerative diseases. Biomarkers for specific pathogenetic processes would also be valuable tools both to study disease pathogenesis directly in patients and to identify and monitor the effect of novel treatment strategies.
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| 62. |
- Olsson, Bob, 1969, et al.
(författare)
-
Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet
- 2005
-
Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:2, s. 920-30
-
Tidskriftsartikel (refereegranskat)abstract
- It is known that bovine GH (bGH) transgenic mice have increased body mass, insulin resistance, and altered lipoprotein metabolism when fed a normal diet (ND). In this study, the effects of 8 wk of high-fat diet (HFD) were investigated in 6-month-old male bGH mice. Although littermate controls had unchanged energy intake, energy intake was higher in the bGH mice on a HFD than on a low-fat diet. Nevertheless, the bGH mice were resistant to diet-induced weight gain, and only in the bGH mice did the HFD result in increased energy expenditure. Glucose oxidation was higher in the bGH mice compared with littermate controls on both a HFD and ND. In addition, the bGH mice had 0.5 C higher body temperature throughout the day and increased hepatic uncoupling protein 2 expression; changes that were unaffected by the HFD. On a HFD, the effect of bGH overexpression on serum triglycerides and apolipoprotein B was opposite to that on a ND, resulting in higher serum concentrations of triglycerides and apolipoprotein B compared with littermate controls. Increased serum triglycerides were explained by decreased triglyceride clearance. The HFD led to diabetes only in the bGH mice. In conclusion, bGH transgenic mice were resistant to diet-induced obesity despite hyperphagia, possibly due to increased energy expenditure. On a HFD, bGH mice became dyslipidemic and diabetic and thereby more accurately reflect the metabolic situation in acromegalic patients.
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| 63. |
- Olsson, Bob, 1969, et al.
(författare)
-
Cerebrospinal Fluid Levels of Heart Fatty Acid Binding Protein are Elevated Prodromally in Alzheimer's Disease and Vascular Dementia
- 2013
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 34:3, s. 673-679
-
Tidskriftsartikel (refereegranskat)abstract
- Heart fatty acid binding protein (HFABP) is expressed in the brain and is elevated in cerebrospinal fluid (CSF) from patients with several forms of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease with dementia, Lewy body dementia, vascular dementia (VaD), and Creutzfeldt-Jakob disease. However, whether HFABP in CSF is a stable biomarker or if it can help predict conversion from mild cognitive impairment (MCI) to AD or VaD has not been well studied. To address the role of HFABP in neurodegeneration, we analyzed CSF levels of HFABP in 96 AD patients and 65 controls and also in 170 patients with MCI with an average follow up time of 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six month interval in between. HFABP levels in CSF were very stable over the six month period (r = 0.93, p < 0.001). Furthermore, the CSF levels of HFABP were significantly elevated in AD compared with controls after adjustments for age and gender (p < 0.001). They were also elevated in the patients with MCI that subsequently converted to AD or VaD compared with those that remained stable (p < 0.001 and p < 0.05, respectively). However, ROC curve analysis showed that HFABP had lesser predictive value in determining conversion from MCI to AD and VaD than A beta(42), t-tau, and p-tau. In conclusion, HFABP seems to be a stable CSF biomarker that reflects neuronal cell death in several neurodegenerative disorders, including early stages of AD and VaD.
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| 64. |
- Olsson, Bob, 1969, et al.
(författare)
-
Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura.
- 2005
-
Ingår i: Thrombosis and haemostasis. - 0340-6245. ; 93:1, s. 139-44
-
Tidskriftsartikel (refereegranskat)abstract
- Idiopathic thrombocytopenic purpura (ITP) is an organ specific autoimmune disorder in which T-lymphocyte abnormalities have pathogenetic importance. In a DNA microarray screen of CD3+ T-lymphocytes from ITP patients and healthy controls we found an altered expression of genes associated with apoptosis, e.g. A20, caspase-8 and Bax. This together with our previous findings of increased gene expression of Fas, interferon-g and IL-2 receptor beta (IL2RB) indicated an altered activation induced cell death (AICD) of T-cells in ITP. Using a proliferation assay we found that CD3+ lymphocytes from ITP patients were significantly more resistant to dexamethasone induced suppression compared to normal lymphocytes. We also found that cultured CD3+ lymphocytes from ITP patients in remission were more susceptible to apoptosis both in the presence and absence of dexamethasone compared to cells from patient with active ITP and healthy controls, as indicated by increased staining of AnnexinV binding. Our findings suggest that apoptotic resistance of activated T-lymphocytes in patients with active ITP may lead to defective clearance of autoreactive T-lymphocytes through AICD, which might cause a continued immune destruction of platelets. Conversely, a loss of resistance to AICD in ITP patients in remission might be an important mechanism for the achievement of remission.
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| 65. |
- Olsson, Bob, 1969, et al.
(författare)
-
Extreme Stability of Chitotriosidase in Cerebrospinal Fluid makes it a Suitable Marker for Microglial Activation in Clinical Trials
- 2012
-
Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 32:2, s. 273-276
-
Tidskriftsartikel (refereegranskat)abstract
- Microglia is thought to be important in Alzheimer's disease. Therefore, our aim was to investigate the usefulness of the microglial marker chitotriosidase in clinical trials. Chitotriosidase was analyzed in cerebrospinal fluid from Alzheimer's disease patients on acetylcholine esterase inhibitors (AChEI) and in cerebrospinal fluid from multiple sclerosis patients before and after natalizumab treatment. Chitotriosidase activity was extremely stable during treatment with the non-inflammatory drug AChEI. However, the immunomodulatory treatment with natalizumab led to lower chitotriosidase activity. Thus, chitotriosidase may be useful in clinical trials where microglia is targeted or as a safety biomarker in other trials where the brain is a bystander organ.
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| 66. |
- Olsson, Bob, 1969, et al.
(författare)
-
Imatinib treatment and Aβ42 in humans.
- 2014
-
Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 10:5, supplement
-
Tidskriftsartikel (refereegranskat)abstract
- The first-line treatment in chronic myeloid leukemia (CML), imatinib, has been shown to decrease the production of amyloid-β (Aβ) invitro and in animal studies. However, whether imatinib has this effect in humans is not known.
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| 67. |
- Olsson, Bob, 1969, et al.
(författare)
-
Increased number of B-cells in the red pulp of the spleen in ITP
- 2012
-
Ingår i: Annals of Hematology. - : Springer Science and Business Media LLC. - 1432-0584 .- 0939-5555. ; 91:2, s. 271-277
-
Tidskriftsartikel (refereegranskat)abstract
- Platelets are targeted by autoantibodies and destroyed in the reticuloendothelial system in the spleen, liver and bone marrow in patients with immune thrombocytopenia (ITP). Other mechanisms such as destruction by cytotoxic T-cells and defective production of platelets in the bone marrow also exist. Splenectomy normalizes the platelet count in 70% of ITP patients, however, precious little is known about the spleen in this disease. Our aim was therefore to investigate the splenic morphology and especially the number and localization of splenic leukocytes in patients with ITP and controls and to evaluate factors predicting outcome of splenectomy. Spleen sections from 29 ITP patients and 11 individuals splenectomized due to trauma were analyzed by immunohistochemistry. All except one of the ITP patients had a normalized platelet count 12months after splenectomy and the platelet count was inversely correlated with age. ITP patients had an increased number of B-cells in the red pulp. The number of white pulp B-cells and number of T-cells in both compartments was unchanged. In conclusion, B-cells are increased in the red pulp of the spleen and together with cytotoxic T-cells, helper T-cells and macrophages line the sinusoids enabling the immunological attack on platelets in ITP.
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| 68. |
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| 69. |
- Olsson, Bob, 1969, et al.
(författare)
-
Microglial markers are elevated in the prodromal phase of Alzheimer's disease and vascular dementia.
- 2013
-
Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908 .- 1387-2877. ; 33:1, s. 45-53
-
Tidskriftsartikel (refereegranskat)abstract
- Microglia manage immunosurveillance and mediate inflammation, both suggested to be important in Alzheimer's disease (AD). The aim of this study was to investigate if microglial markers could differentiate, firstly between AD and controls, and secondly between stable mild cognitive impairment (MCI) and those progressing to AD and vascular dementia (VaD). Furthermore, we investigated if these markers were sufficiently stable to be used in clinical trials. We quantified YKL-40 and sCD14 in cerebrospinal fluid (CSF) from 96 AD patients, 65 healthy controls, and 170 patients with MCI from baseline and over 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six-month interval in between. YKL-40, but not sCD14, was significantly elevated in AD compared with healthy controls (p = 0.003). Furthermore, YKL-40 and sCD14 were increased in MCI patients who converted to VaD (p = 0.029 and p = 0.008), but not to AD according to NINCDS-ADRDA. However, when stratified according to CSF levels of tau and Aβ42, YKL-40 was elevated in those with an AD-indicative profile compared with stable MCI with a normal profile (p = 0.037). In addition, YKL-40 and sCD14 were very stable in AD patients with good correlation between time-points (r = 0.94, p = 3.4 × 10-25; r = 0.77, p = 2.0 × 10-11) and the cortical damage marker T-tau. Thus, microglial markers are stable and may be used as safety markers for monitoring CNS inflammation and microglia activation in clinical trials. Moreover, YKL-40 differentiates between AD and controls and between stable MCI to AD and those that convert to AD and VaD.
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| 70. |
- Olsson, Bob, 1969, et al.
(författare)
-
NFL is a marker of treatment response in children with SMA treated with nusinersen
- 2019
-
Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 266:9, s. 2129-2136
-
Tidskriftsartikel (refereegranskat)abstract
- Background Recently, the anti-sense oligonucleotide drug nusinersen was approved for spinal muscular atrophy (SMA) and our aim was to find a response marker for this treatment. Methods Twelve children with SMA type 1 and two copies of the SMN2 gene were included in a consecutive single-center study. The children were sampled for CSF at baseline and every time nusinersen was given intrathecally. The neuronal biomarkers NFL and tau and the glial biomarker GFAP were measured. Motor function was assessed using CHOP INTEND. Eleven similarly aged children, who were investigated to rule out neurological or infectious disease, were used as controls. Results Baseline levels of NFL (4598 +/- 981 vs 148 +/- 39, P = 0.001), tau (939 +/- 159 vs 404 +/- 86, P = 0.02), and GFAP (236 +/- 44 vs 108 +/- 26, P = 0.02) were significantly higher in SMA children than controls. Motor function improved by nusinersen treatment in median 13 points corresponding to 5.4 points per month of treatment (P = 0.001). NFL levels typically normalized ( < 380 pg/ml) between the fourth and fifth doses [- 879.5 pg/mL/dose, 95% CI (- 1243.4, - 415.6), P = 0.0001], tau levels decreased [- 112.6 pg/mL/dose, 95% CI (- 206-7, - 18.6), P = 0.01], and minor decreases in GFAP were observed [- 16.9 pg/mL/dose, 95% CI (- 22.8, - 11.2), P = 0.02] by nusinersen treatment. Improvement in motor function correlated with reduced concentrations of NFL (rho = - 0.64, P = 0.03) and tau (rho = - 0.85, P = 0.0008) but not GFAP. Conclusions Nusinersen normalized the axonal damage marker NFL and correlated with motor improvement in children with SMA. NFL may, therefore, be a novel biomarker to monitor treatment response early in the disease course.
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| 71. |
- Olsson, Bob, 1969, et al.
(författare)
-
Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1.
- 2008
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 112:4, s. 1078-84
-
Tidskriftsartikel (refereegranskat)abstract
- In idiopathic thrombocytopenic purpura (ITP), platelets are destroyed in the spleen, liver, and bone marrow (BM) by autoantibodies and cytotoxic T cells. In a DNA microarray screen of peripheral blood T cells, we found that VLA-4, CX3CR1, and CXCR4, involved in T-cell homing, had increased expression in ITP patients compared with controls. However, we only found increased protein expression of VLA-4 on T cells from peripheral blood by flow cytometry. To address a possible recruitment of T cells into the organs involved in platelet destruction, we analyzed T cells in BM. In BM, T-cell surface expression of VLA-4 and CX3CR1 was increased in ITP patients compared with controls. Furthermore, the number of CD3(+) T cells in BM, but not in blood, was increased in ITP patients compared with controls. This finding was confirmed by immunohistochemistry of BM biopsies. The number of regulatory T cells (CD4(+)/CD25(bright)) was decreased in the BM of ITP patients, whereas Fas expression was increased. In conclusion, ITP is associated with accumulation and activation of T cells in the BM. Recruitment of T cells into the target organ (eg, BM) is plausible and may be facilitated through increased VLA-4 and CX3CR1 expression. These molecules might serve as new treatment targets in ITP.
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| 72. |
- Olsson, Bob, 1969, et al.
(författare)
-
T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.
- 2003
-
Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 9:9, s. 1123-4
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Tidskriftsartikel (refereegranskat)abstract
- Chronic idiopathic thrombocytopenic purpura (ITP) is a bleeding disorder that is characterized by increased platelet destruction and is believed to be autoantibody mediated. In this study, CD3+ T cells from ITP patients had increased expression of genes involved in cell-mediated cytotoxicity. In addition, cytotoxic cell-mediated lysis of autologous platelets was shown in active ITP. Our data suggest that T-cell-mediated cytotoxicity is an alternative mechanism for platelet destruction in ITP.
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| 73. |
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| 74. |
- Olsson, Bob, 1969, et al.
(författare)
-
The glial marker YKL-40 is decreased in synucleinopathies.
- 2013
-
Ingår i: Movement disorders : official journal of the Movement Disorder Society. - : Wiley. - 1531-8257. ; 28:14, s. 1882-1885
-
Tidskriftsartikel (refereegranskat)abstract
- Microglia are resident immunosurveillant cells in the central nervous system, and astrocytes are important for blood flow, plasticity, and neurotransmitter regulation. The aim of this study was to investigate whether astrocyte and microglial activation, estimated through markers in cerebrospinal fluid and serum, differed between synucleinopathies, tauopathies, and controls.
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| 75. |
- Olsson, Bob, 1969
(författare)
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The role of GH in the regulation of energy homeostasis, lipid metabolism and cardiovascular function in transgenic mice
- 2001
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was, using two transgenic models, to investigate some metabolic diseases associated with acromegaly e.g. hypertension and alterations in lipid and lipoprotein metabolism. We also studied the positive effect of Growth Hormone (GH), and possible molecular causes, on body composition and energy homeostasis using these GH transgenic models.We have used two different GH transgenic mouse models, one model overexpressing GH generally, controlled by the metallothionine promoter (Mt-bGH), and one model where the GH overexpression is restricted to the CNS, using the glial fibrillary acidic protein promoter (GFAP-bGH).Using telemetric technique, we have found that Mt-bGH transgenic mice have a salt-insensitive hypertension. Furthermore, the Mt-bGH transgenic mice have altered lipoprotein profiles and serum lipids, hyperinsulinemia and hyperglycaemia. Moreover, the hepatic gene expression profiles analysed by micro-array, revealed decreased gene expression of PPARa and SREBP-1 together with decreased expression of genes involved in fatty acid activation, b-oxidation, ketone body formation, lipogenesis, cholesterol metabolism, gluconeogenesis and amino acid catabolism. When analysed by indirect calorimetry, the Mt-bGH transgenic mice also had an increased resting metabolic rate on a normal diet that was enhanced by a Western diet, increased body temperature and increased hepatic gene expression of UCP2. Furthermore, the Mt-bGH transgenic mice had an increased respiratory exchange rate and food intake on both diets but still a lean body composition.The GFAP-bGH mice had an increased food intake resulting in massive obesity along with an increased expression of AGRP and NPY. These mice also had alterations in lipid and lipoprotein metabolism, hyperinsulinemia and pancreatic islet hypertrophy but normal blood glucose levels.GH stimulates food intake by increasing the hypothalamic gene expression of AGRP and NPY. This results in obesity in the GFAP-bGH transgenic mice but the high circulating levels of GH in the Mt-bGH mice, resulting in elevated RMR, body temperature, and T3 levels prevent obesity and result in a lean body composition. We have also found several risk factors for cardiovascular disease in these two GH transgenic models, such as high LDL cholesterol, insulin resistance, hypertension and indications of a decreased reverse cholesterol transport. These models may be useful tools in understanding the underlying mechanisms for cardiovascular disease in patients with acromegaly.
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| 76. |
- Olsson, Bob, 1969, et al.
(författare)
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The use of cerebrospinal fluid biomarkers to measure change in neurodegeneration in Alzheimer's disease clinical trials
- 2017
-
Ingår i: Expert Review of Neurotherapeutics. - : Informa UK Limited. - 1473-7175 .- 1744-8360. ; 17:8, s. 767-775
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: All recent phase 3 trials of potentially disease-modifying therapies for Alzheimer's disease (AD) have so far failed. Potential reasons include enrolling subjects whose disease is too advanced or who do not have AD pathology, or simply incorrect drug targets. The goal of disease-modifying AD trials is to halt the progress of neuronal damage and death and this can be assessed in vivo using cerebrospinal fluid (CSF) biomarkers.Areas covered: The authors conducted a literature search of the use of CSF biomarkers in disease-modifying AD clinical trials using PubMed. The authors show that CSF biomarkers have only sparsely been used as outcome measures, and where they have, only in small subsets of patients. No clinical trials have yet showed any substantial effects on CSF biomarkers of neurodegeneration.Expert commentary: In future trials, the authors advocate that CSF biomarkers be used more extensively to optimize the chance of detecting positive drug effects. This includes the identification of potential AD patients - already in the early prodromal stage - for inclusion, for stratification, as readout i.e. proximity markers for changes in axonal/neurodegeneration between treatment and placebo groups - this also enables proof of principle verification in the discovery/dose finding phase, and for monitoring of side effects.
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| 77. |
- Palsdottir, Vilborg, 1979, et al.
(författare)
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Long-term effects of perinatal essential fatty acid deficiency on anxiety-related behavior in mice.
- 2012
-
Ingår i: Behavioral neuroscience. - : American Psychological Association (APA). - 1939-0084 .- 0735-7044. ; 126:2, s. 361-9
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Tidskriftsartikel (refereegranskat)abstract
- Dietary essential fatty acids have been shown to regulate behavioral and cognitive functions in rodents. However, the long-term effect on behavior, besides memory and learning, of essential fatty acid deficiency (EFAD), i.e., lack of n-3 and n-6 fatty acids, during the perinatal period has not been investigated. Therefore, pregnant C57Bl/6 mice were given either an EFAD or an isoenergetic control diet from gestational day 16 and throughout lactation. The female offspring were given standard chow from 3 weeks of age, and at 12 to 14 weeks of age, open-field, object recognition, light-dark transition, elevated plus maze, and social interaction tests were performed. The brain glycerophospholipid fatty acid composition was investigated in 3-week-old and adult offspring by gas chromatography. The differences observed in behavior were indicative of lower anxiety in the EFAD mice compared to controls illustrated by more time spent in the open arms of the elevated plus maze (+ 41%, p < .05) and in the light compartment in the light-dark transition test (+ 63%, p < .05). The proportion of total n-3 fatty acids, especially 22:6n-3 in the brain, was lower with a compensatory increase in the proportion of total n-6 fatty acids, foremost 22:5n-6, in the EFAD mice compared to controls at 3 weeks of age. In the adult brains the fatty acid composition was normalized. In conclusion, our data show that EFAD during the perinatal period results in short-term alterations of fatty acid composition in brain and decreased anxiety in adult life.
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| 78. |
- Palsdottir, Vilborg, 1979, et al.
(författare)
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Postnatal essential fatty acid deficiency in mice affects lipoproteins, hepatic lipids, fatty acids and mRNA expression
- 2011
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Ingår i: Prostaglandins, Leukotrienes and Essential Fatty Acids. - : Elsevier BV. - 1532-2823 .- 0952-3278. ; 85:3-4, s. 179-88
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Tidskriftsartikel (refereegranskat)abstract
- We have previously reported that essential fatty acid deficiency (EFAD) during suckling in mice resulted in an adult lean phenotype and a resistance to diet-induced obesity. We now hypothesized that postnatal EFAD would cause long-term effects on lipid metabolism. C57BL/6 mice were fed an EFAD or a control diet from the 16th day of gestation and throughout lactation. The pups were weaned to standard diet (STD) and at 15 weeks of age given either high fat diet (HFD) or STD. Lipoprotein profiles, hepatic lipids, fatty acids and mRNA expression were analyzed in 3-week-old and 25-week-old offspring. At weaning, the EFAD pups had higher cholesterol levels in both plasma and liver and 6-fold higher concentrations of hepatic cholesterol esters than control pups. Adult EFAD offspring had higher levels of hepatic cholesterol and linoleic acid, but lower levels of dihomo-γ-linolenic acid and Pparg mRNA expression in the liver. In addition, HFD fed EFAD offspring had lower plasma total cholesterol, lower hepatic triglycerides and lower liver weight compared to controls fed HFD. In conclusion, early postnatal EFAD resulted in short-term alterations with increased hepatic cholesterol accumulation and long-term protection against diet-induced liver steatosis and hypercholesterolemia.
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| 79. |
- Portelius, Erik, 1977, et al.
(författare)
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Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology.
- 2018
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 136:3, s. 363-376
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Tidskriftsartikel (refereegranskat)abstract
- Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer's disease dementia (ADD),and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson's disease (p<0.0001), frontotemporal dementia (p<0.0001), and amyotrophic lateral sclerosis (p=0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score, p=0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p=0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p=0.0006 and p<0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.
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| 80. |
- Sjögren, Klara, 1970, et al.
(författare)
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Disproportional skeletal growth and markedly decreased bone mineral content in growth hormone receptor -/- mice.
- 2000
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 267:2, s. 603-8
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Tidskriftsartikel (refereegranskat)abstract
- Growth hormone (GH) is important for skeletal growth as well as for a normal bone metabolism in adults. The skeletal growth and adult bone metabolism was studied in mice with an inactivated growth hormone receptor (GHR) gene. The lengths of femur, tibia, and crown-rump were, as expected, decreased in GHR-/- mice. Unexpectedly, GHR-/- mice displayed disproportional skeletal growth reflected by decreased femur/crown-rump and femur/tibia ratios. GHR-/- mice demonstrated decreased width of the growth plates in the long bones and disturbed ossification of the proximal tibial epiphysis. Furthermore, the area bone mineral density (BMD) as well as the bone mineral content (BMC)/body weight were markedly decreased in GHR-/- mice. The decrease in BMC in GHR-/- mice was not due to decreased trabecular volumetric BMD but to a decreased cross-sectional cortical bone area In conclusion, GHR-/- mice demonstrate disproportional skeletal growth and markedly decreased bone mineral content.
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| 81. |
- Wei, Yuan, 1978, et al.
(författare)
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Not all imatinib resistance in CML are BCR-ABL kinase domain mutations.
- 2006
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Ingår i: Annals of hematology. - : Springer Science and Business Media LLC. - 0939-5555 .- 1432-0584. ; 85:12, s. 841-7
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Tidskriftsartikel (refereegranskat)abstract
- Point mutations within the ABL kinase domain of the BCR-ABL gene are associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML). To obtain more information about the association between BCR-ABL mutations and type of imatinib resistance, we studied 30 early chronic phase (CP) CML patients, commencing imatinib therapy, using a conventional sequencing technique. Seven patients treated in late CP and three patients treated in the accelerated phase were included for comparison. Blood samples were collected before and every third month during imatinib therapy. Mutations were not seen in any blood sample collected before start of therapy. During imatinib treatment, 2 of the 30 early CP patients acquired point mutations and both of them had other signs of imatinib resistance. None of the five early CP patients with a complete hematologic response (HR), but no cytogenetic response at 12 months, displayed any missense mutation. Likewise, none of 12 early CP patients with detectable BCR-ABL transcripts but in complete hematologic and cytogenetic remission at 12 months displayed any mutation. We conclude that screening early CP patients for BCR-ABL mutations before start of imatinib therapy is not cost-effective. BCR-ABL kinase domain mutations do not appear to explain cytogenetic or molecular (detectable BCR-ABL transcripts by polymerase chain reaction) disease persistence in patients otherwise in stable disease. However, in patients with signs of expanding disease burden, a search for BCR-ABL mutations is warranted.
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| 82. |
- Wernstedt, Ingrid, 1978, et al.
(författare)
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Increased levels of acylation-stimulating protein in interleukin-6-deficient (IL-6(-/-)) mice
- 2006
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 147:6, s. 2690-5
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Tidskriftsartikel (refereegranskat)abstract
- IL-6-deficient (IL-6(-/-)) mice develop obesity at 6-7 months of age. To elucidate the mechanisms of this mature-onset obesity, global gene expression profiles of 3-month-old preobese IL-6(-/-) were compared with those of IL-6(+/+) mice using DNA arrays. Genes that were up-regulated in IL-6(-/-) mice included the factors transthyretin and properdin in white adipose tissue and adipsin in muscle. These factors have been shown to influence the formation of acylation-stimulating protein (ASP), a cleavage product of complement C3. ASP stimulates the synthesis of triacylglycerol in adipocytes, and ASP-deficient mice are resistant to diet-induced obesity. In line with the increases in transthyretin, properdin, and adipsin, ASP levels in serum were increased by 31-54% in IL-6(-/-) compared with IL-6(+/+) mice. Furthermore, IL-6 replacement treatment in IL-6(-/-) mice decreased ASP levels significantly by 25-60%. In conclusion, ASP levels are increased in preobese IL-6(-/-) mice. This increase may result in increased triacylglycerol formation and uptake in IL-6(-/-) adipocytes and thereby contribute to the development of obesity in IL-6(-/-) mice.
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| 83. |
- Zetterberg, Henrik, 1973, et al.
(författare)
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Use of theragnostic markers to select drugs for phase II/III trials for Alzheimer disease.
- 2010
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Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 2:6
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Forskningsöversikt (refereegranskat)abstract
- ABSTRACT: In a slowly progressive disorder like Alzheimer disease, evaluation of the clinical effect of novel drug candidates requires large numbers of patients and extended treatment periods. Current cell- and animal-based disease models of Alzheimer disease are poor at predicting a positive treatment response in patients. To help bridge the gap between disease models and large and costly clinical trials with high failure rates, biomarkers for the intended biochemical drug effect may be of value. Such biomarkers may be called 'theragnostic'. Here, we review the literature addressing the prospective value of these biomarkers.
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