| 1. |
- Barrueta Tenhunen, Annelie, et al.
(författare)
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Does the antisecretory peptide AF-16 reduce lung oedema in experimental ARDS?
- 2019
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 124:4, s. 246-253
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Tidskriftsartikel (refereegranskat)abstract
- Background: Acute respiratory distress syndrome (ARDS) is an acute inflammatory condition with pulmonary capillary leakage and lung oedema formation. There is currently no pharmacologic treatment for the condition. The antisecretory peptide AF-16 reduces oedema in experimental traumatic brain injury. In this study, we tested AF-16 in an experimental porcine model of ARDS. Methods: Under surgical anaesthesia 12 piglets were subjected to lung lavage followed by 2 hours of injurious ventilation. Every hour for 4 hours, measurements of extravascular lung water (EVLW), mechanics of the respiratory system, and hemodynamics were obtained. Results: There was a statistically significant (p = 0.006, two-way ANOVA) reduction of EVLW in the AF-16 group compared with controls. However, this was not mirrored in any improvement in the wet-to-dry ratio of lung tissue samples, histology, inflammatory markers, lung mechanics, or gas exchange. Conclusions: This pilot study suggests that AF-16 might improve oedema resolution as indicated by a reduction in EVLW in experimental ARDS.
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| 2. |
- Clausen, Fredrik, et al.
(författare)
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Intranasal Administration of the Antisecretory Peptide AF-16 Reduces Edema and Improves Cognitive Function Following Diffuse Traumatic Brain Injury in the Rat
- 2017
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- A synthetic peptide with antisecretory activity, antisecretory factor (AF)-16, improves injury-related deficits in water and ion transport and decreases intracranial pressure after experimental cold lesion injury and encephalitis although its role in traumatic brain injury (TBI) is unknown. AF-16 or an inactive reference peptide was administrated intranasally 30 min following midline fluid percussion injury (mFPI; n = 52), a model of diffuse mild-moderate TBI in rats. Sham-injured (n = 14) or naive (n = 24) animals were used as controls. The rats survived for either 48 h or 15 days post-injury. At 48 h, the animals were tested in the Morris water maze (MWM) for memory function and their brains analyzed for cerebral edema. Here, mFPI-induced brain edema compared to sham or naive controls that was significantly reduced by AF-16 treatment (p < 0.05) although MWM performance was not altered. In the 15-day survival groups, the MWM learning and memory abilities as well as histological changes were analyzed. AF-16-treated brain-injured animals shortened both MWM latency and swim path in the learning trials (p < 0.05) and improved probe trial performance compared to brain-injured controls treated with the inactive reference peptide. A modest decrease by AF-16 on TBI-induced changes in hippocampal glial acidic fibrillary protein (GFAP) staining (p = 0.11) was observed. AF-16 treatment did not alter any other immunohistochemical analyses (degenerating neurons, beta-amyloid precursor protein (beta-APP), and Olig2). In conclusion, intranasal AF-16-attenuated brain edema and enhanced visuospatial learning and memory following diffuse TBI in the rat. Intranasal administration early post-injury of a promising neuroprotective substance offers a novel treatment approach for TBI.
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| 3. |
- Eide, P. K., et al.
(författare)
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Astrogliosis and impaired aquaporin-4 and dystrophin systems in idiopathic normal pressure hydrocephalus
- 2018
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846. ; 44:5, s. 474-490
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Idiopathic normal pressure hydrocephalus (iNPH) is one subtype of dementia that may improve following drainage of cerebrospinal fluid (CSF). This prospective observational study explored whether expression of the water channel aquaporin-4 (AQP4) and the anchoring molecule dystrophin 71 (Dp71) are altered at astrocytic perivascular endfeet and in adjacent neuropil of iNPH patient. Observations were related to measurements of pulsatile and static intracranial pressure (ICP). Methods: The study included iNPH patients undergoing overnight monitoring of the pulsatile/static ICP in whom a biopsy was taken from the frontal cerebral cortex during placement of the ICP sensor. Reference (Ref) biopsies were sampled from 13 patients who underwent brain surgery for epilepsy, tumours or cerebral aneurysms. The brain tissue specimens were examined by light microscopy, immunohistochemistry, densitometry and morphometry. Results: iNPH patients responding to surgery (n = 44) had elevated pulsatile ICP, indicative of impaired intracranial compliance. As compared to the Ref patients, the cortical biopsies of iNPH patients revealed prominent astrogliosis and reduced expression of AQP4 and Dp71 immunoreactivities in the astrocytic perivascular endfeet and in parts of the adjacent neuropil. There was a significant correlation between degree of astrogliosis and reduction of AQP4 and Dp71 at astrocytic perivascular endfeet. Conclusions: Idiopathic normal pressure hydrocephalus patients responding to CSF diversion present with abnormal pulsatile ICP, indicative of impaired intracranial compliance. A main histopathological finding was astrogliosis and reduction of AQP4 and of Dp71 in astrocytic perivascular endfeet. We propose that the altered AQP4 and Dp71 complex contributes to the subischaemia prevalent in the brain tissue of iNPH.
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| 4. |
- Eide, P. K., et al.
(författare)
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Cortical astrogliosis and increased perivascular aquaporin-4 in idiopathic intracranial hypertension
- 2016
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993. ; 1644, s. 161-175
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Tidskriftsartikel (refereegranskat)abstract
- The syndrome idiopathic intracranial hypertension (IIH) includes symptoms and signs of raised intracranial pressure (ICP) and impaired vision, usually in overweight persons. The pathogenesis is unknown. In the present prospective observational study, we characterized the histopathological changes in biopsies from the frontal brain cortical parenchyma obtained from 18 IIH patients. Reference specimens were sampled from 13 patients who underwent brain surgery for epilepsy, tumors or acute vascular diseases. Overnight ICP monitoring revealed abnormal intracranial pressure wave amplitudes in 14/18 IIH patients, who underwent shunt surgery and all responded favorably. A remarkable histopathological observation in IIH patients was patchy astrogliosis defined as clusters of hypertrophic astrocytes enclosing a nest of nerve cells. Distinct astrocyte domains (i.e. no overlap between astrocyte processes) were lacking in most IIH biopsy specimens, in contrast to their prevalence in reference specimens. Evidence of astrogliosis in IIH was accompanied with significantly increased aguaporin-4 (AQP4) immunoreactivity over perivascular astrocytic endfeet, compared to the reference specimens, measured with densitometry. Scattered CD68 immunoreactive cells (activated microglia and macrophages) were recognized, indicative of some inflammation. No apoptotic cells were demonstrable. We conclude that the patchy astrogliosis is a major finding in patients with IIH. We propose that the astrogliosis impairs intracranial pressure-volume reserve capacity, i.e. intracranial compliance, and contributes to the IIH by restricting the outflow of fluid from the cranium. The increased perivascular AQP4 in IIH may represent a compensatory mechanism to enhance brain fluid drainage.
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| 5. |
- Eidsvaag, V. A., et al.
(författare)
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Brain Capillary Ultrastructure in Idiopathic Normal Pressure Hydrocephalus: Relationship With Static and Pulsatile Intracranial Pressure
- 2017
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Ingår i: Journal of Neuropathology and Experimental Neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 76:12, s. 1034-1045
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease of unknown cause. We investigated the morphology of capillaries in frontal cortex biopsies from iNPH patients and related the observations to overnight intracranial pressure (ICP) scores. A biopsy (0.9x10 mm) was taken from where the ICP sensor subsequently was inserted. Brain capillaries were investigated by electron microscopy of biopsies from 27 iNPH patients and 10 reference subjects, i.e. patients (not healthy individuals) without cerebrospinal fluid circulation disturbances, in whom normal brain tissue was removed as part of necessary neurosurgical treatment. Degenerating and degenerated pericyte processes were identified in 23/27 (85%) iNPH and 6/10 (60%) of reference specimens. Extensive disintegration of pericyte processes were recognized in 11/27 (41%) iNPH and 1/10 (10%) reference specimens. There were no differences in basement membrane (BM) thickness or pericyte coverage between iNPH and reference subjects. The pulsatile or static ICP scores did neither correlate with the BM thickness nor with pericyte coverage. We found increased prevalence of degenerating pericytes in iNPH while the BM thickness and pericyte coverage did not differ from the reference individuals. Observations in iNPH may to some extent be age-related since the iNPH patients were significantly older than the reference individuals.
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| 6. |
- Eidsvaag, V. A., et al.
(författare)
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Cerebral microvascular abnormalities in patients with idiopathic intracranial hypertension
- 2018
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993. ; 1686, s. 72-82
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Idiopathic intracranial hypertension (IIH) is characterized by symptoms indicative of increased intracranial pressure (ICP), such as headache and visual impairment. We have previously reported that brain biopsies from IIH patients show patchy astrogliosis and increased expression of the water channel aquaporin-4 (AQP4) at perivascular astrocytic endfeet. Methods: The present study was undertaken to investigate for ultrastructural changes of the cerebral capillaries in individuals with IIH. We examined by electron microscopy (EM) biopsies from the cortical parenchyma of 10 IIH patients and 8 reference subjects (patients, not healthy individuals), in whom tissue was retrieved from other elective and necessary brain surgeries (epilepsy, tumors or vascular diseases). IIH patients were diagnosed on the basis of typical clinical symptoms and abnormal intracranial pressure wave amplitudes during overnight ICP monitoring. Results: All 10 IIH patients underwent shunt surgery followed by favorable clinical outcome. EM revealed abnormal pericyte processes in IIH. The basement membrane (BM) showed more frequently evidence of degeneration in IIH, but neither the BM dimensions nor the pericyte coverage differed between IIH and reference tissue. The BM thickness increased significantly with increasing age. Reference individuals were older than IIH cases; observations may to some extent be age-related. Conclusion: The present study disclosed marked changes of the cerebral cortical capillaries in IIH patients, suggesting that microvascular alterations are involved in the evolvement of IIH. © 2018 Elsevier B.V.
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| 7. |
- Eidsvaag, V. A., et al.
(författare)
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Human and mouse cortical astrocytes differ in aquaporin-4 polarization toward microvessels
- 2017
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Ingår i: Glia. - : Wiley. - 0894-1491. ; 65:6, s. 964-973
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Tidskriftsartikel (refereegranskat)abstract
- Aquaporin-4 (AQP4), the predominant water channel in the brain, is expressed in astrocytes and ependymal cells. In rodents AQP4 is highly polarized to perivascular astrocytic endfeet and loss of AQP4 polarization is associated with disease. The present study was undertaken to compare the expression pattern of AQP4 in human and mouse cortical astrocytes. Cortical tissue specimens were sampled from 11 individuals undergoing neurosurgery wherein brain tissue was removed as part of the procedure, and compared with cortical tissue from 5 adult wild-type mice processed similarly. The tissue samples were immersion-fixed and prepared for AQP4 immunogold electron microscopy, allowing quantitative assessment of AQP4's subcellular distribution. In mouse we found that AQP4 water channels were prominently clustered around vessels, being 5 to 10-fold more abundant in astrocytic endfoot membranes facing the capillary endothelium than in parenchymal astrocytic membranes. In contrast, AQP4 was markedly less polarized in human astrocytes, being only two to three-fold enriched in astrocytic endfoot membranes adjacent to capillaries. The lower degree of AQP4 polarization in human subjects (1/3 of that in mice) was mainly due to higher AQP4 expression in parenchymal astrocytic membranes. We conclude that there are hitherto unrecognized species differences in AQP4 polarization toward microvessels in the cerebral cortex.
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| 8. |
- Hasan-Olive, M. M., et al.
(författare)
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Blood-Brain Barrier Dysfunction in Idiopathic Intracranial Hypertension
- 2019
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Ingår i: Journal of Neuropathology and Experimental Neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 78:9, s. 808-818
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic intracranial hypertension (IIH) is traditionally considered benign and characterized by symptoms related to increased intracranial pressure, including headache and impaired vision. We have previously demonstrated that brains of IIH patients exhibit patchy astrogliosis, increased perivascular expression of the water channel aquaporin-4 (AQP4) as well as degenerating pericyte processes and capillary basement membranes. Given the established association between pericyte degeneration and blood-brain barrier (BBB) dysfunction, we investigated blood protein leakage by light microscopic immunohistochemistry. We also assessed perivascular AQP4 expression by immunogold transmission electron microscopy. The study included 14 IIH patients and 14 reference (REF) subjects undergoing neurosurgery for epilepsy, aneurysm, or tumor. Evidence of BBB dysfunction, measured as area extravasated fibrinogen/fibrin, was significantly more pronounced in IIH than REF individuals. The extent of extravasated fibrinogen was positively correlated with increasing degree of astrogliosis and vascular AQP4 immunoreactivity, determined by light microscopy. Immunogold transmission electron microscopy revealed no overall changes in AQP4 expression at astrocytic vascular endfeet in IIH (n = 8) compared to REF (n = 11) individuals. Our results provide evidence of BBB leakage in IIH, signifying that IIH is a more serious neurodegenerative disease than previously considered.
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| 9. |
- Hasan-Olive, M. M., et al.
(författare)
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Loss of perivascular aquaporin-4 in idiopathic normal pressure hydrocephalus
- 2019
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Ingår i: Glia. - : Wiley. - 0894-1491. ; 67:1, s. 91-100
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic normal pressure hydrocephalus (iNPH) is a subtype of dementia that may be successfully treated with cerebrospinal fluid (CSF) diversion. Recently, magnetic resonance imaging (MRI) using a MRI contrast agent as a CSF tracer revealed impaired clearance of the CSF tracer from various brain regions such as the entorhinal cortex of iNPH patients. Hampered clearance of waste solutes, for example, soluble amyloid-beta, may underlie neurodegeneration and dementia in iNPH. The goal of the present study was to explore whether iNPH is associated with altered subcellular distribution of aquaporin-4 (AQP4) water channels, which is reported to facilitate CSF circulation and paravascular glymphatic drainage of metabolites from the brain parenchyma. Cortical brain biopsies of 30 iNPH patients and 12 reference individuals were subjected to AQP4 immunogold cytochemistry. Electron microscopy revealed significantly reduced density of AQP4 water channels in astrocytic endfoot membranes along cortical microvessels in patients with iNPH versus reference subjects. There was a significant positive correlation between density of AQP4 toward endothelial cells (perivascular) and toward parenchyma, but the reduced density of AQP4 toward parenchyma was not significant in iNPH. We conclude that perivascular AQP4 expression is attenuated in iNPH, potentially contributing to impaired glymphatic circulation, and waste clearance, and subsequent neurodegeneration. Hence, restoring normal perivascular AQP4 distribution may emerge as a novel treatment strategy for iNPH.
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| 10. |
- Hasan-Olive, M. M., et al.
(författare)
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Pathological mitochondria in neurons and perivascular astrocytic endfeet of idiopathic normal pressure hydrocephalus patients
- 2019
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Ingår i: Fluids and Barriers of the Cns. - : Springer Science and Business Media LLC. - 2045-8118. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background A growing body of evidence suggests that the accumulation of amyloid-beta and tau (HP tau) in the brain of patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) is associated with delayed extravascular clearance of metabolic waste. Whether also clearance of intracellular debris is affected in these patients needs to be examined. Hypothetically, defective extra- and intra-cellular clearance of metabolites may be instrumental in the neurodegeneration and dementia characterizing iNPH. This study explores whether iNPH is associated with altered mitochondria phenotype in neurons and astrocytes. Methods Cortical brain biopsies of 9 reference (REF) individuals and 30 iNPH patients were analyzed for subcellular distribution and morphology of mitochondria using transmission electron microscopy. In neuronal soma of REF and iNPH patients, we identified normal, pathological and clustered mitochondria, mitochondria-endoplasmic reticulum contact sites and autophagic vacuoles. We also differentiated normal and pathological mitochondria in pre- and post-synaptic nerve terminals, as well as in astrocytic endfoot processes towards vessels. Results We found a high prevalence of pathological mitochondria in neuronal soma and pre- and post-synaptic terminals, as well as increased mitochondrial clustering, and altered number of mitochondria-endoplasmic reticulum contact sites in iNPH. Non-fused autophagic vacuoles were more abundant in neuronal soma of iNPH patients, suggestive of cellular clearance failure. Moreover, the length of postsynaptic densities was reduced in iNPH, potentially related to reduced synaptic activity. In astrocytic endfoot processes, we also found increased number, area and area fraction of pathological mitochondria in iNPH patients. The proportion of pathological mitochondria correlated significantly with increasing degree of astrogliosis and reduced perivascular expression of aquaporin-4 (AQP4), assessed by light microscopy immunohistochemistry. Conclusion Our results provide evidence of mitochondrial pathology and signs of impaired cellular clearance in iNPH patients. The results indicate that iNPH is a neurodegenerative disease with close similarity to Alzheimer's disease.
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