Rodent Models of Cerebral Microinfarct and Microhemorrhage.
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ABSTRACT:
SUBMITTER: Shih AY
PROVIDER: S-EPMC5851653 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
Publications
Rodent Models of Cerebral Microinfarct and Microhemorrhage.
Shih Andy Y AY Hyacinth Hyacinth I HI Hartmann David A DA van Veluw Susanne J SJ
Stroke 20180219 3
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Project description:ObjectiveTo estimate whole-brain microinfarct burden from microinfarct counts in routine postmortem examination.MethodsWe developed a simple mathematical method to estimate the total number of cerebral microinfarcts from counts obtained in the small amount of tissue routinely examined in brain autopsies. We derived estimates of total microinfarct burden from autopsy brain specimens from 648 older participants in 2 community-based clinical-pathologic cohort studies of aging and dementia.ResultsOur results indicate that observing 1 or 2 microinfarcts in 9 routine neuropathologic specimens implies a maximum-likelihood estimate of 552 or 1,104 microinfarcts throughout the brain. Similar estimates were obtained when validating in larger sampled brain volumes.ConclusionsThe substantial whole-brain burden of cerebral microinfarcts suggested by even a few microinfarcts on routine pathologic sampling suggests a potential mechanism by which these lesions could cause neurologic dysfunction in individuals with small-vessel disease. The estimation framework developed here may generalize to clinicopathologic correlations of other imaging-negative micropathologies.
| S-EPMC3662273 | biostudies-literature
Project description:Background and purposeCerebral microinfarcts (CMI) are important contributors to vascular cognitive impairment. Magnetic resonance imaging diffusion-weighted imaging (DWI) hyperintensities have been suggested to represent acute CMI. We aim to describe a mathematical method for estimating total number of CMI based on the presence of incidental DWI lesions.MethodsWe reviewed magnetic resonance imaging scans of subjects with cognitive decline, cognitively normal subjects and previously reported subjects with past intracerebral hemorrhage (ICH). Based on temporal and spatial characteristics of DWI lesions, we estimated the annual rate of CMI needed to explain the observed rate of DWI lesion detection in each group. To confirm our estimates, we performed extensive sampling for CMI in the brain of a deceased subject with past lobar ICH who found to have a DWI lesion during life.ResultsClinically silent DWI lesions were present in 13 of 343 (3.8%) cognitively impaired and 10 of 199 (5%) cognitively intact normal non-ICH patients, both lower than the incidence in the past ICH patients (23 of 178; 12.9%; P<0.0006). The predicted annual incidence of CMI ranges from 16 to 1566 for non-ICH and 50 to 5041 for ICH individuals. Histological sampling revealed a total of 60 lesions in 32 sections. Based on previously reported methods, this density of CMI yields an estimated total brain burden maximum likelihood estimate of 9321 CMIs (95% confidence interval, 7255-11 990).ConclusionsDetecting even a single DWI lesion suggests an annual incidence of hundreds of new CMI. The cumulative effects of these lesions may directly contribute to small-vessel-related vascular cognitive impairment.
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Project description: Not available
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Project description:Microhemorrhages are strongly associated with advanced cerebral amyloid angiopathy (CAA). Although it has been frequently proposed that the deposition of Aβ in the walls of cortical vessels directly causes microhemorrhages, this has not been studied in great detail, mainly because the ruptured vessels are often missed on routine histopathologic examination. Here, we examined histopathological data from studies targeting microhemorrhages with high-resolution ex vivo 7 T MRI in nine cases with moderate-to-severe CAA, and assessed the presence of Aβ in the walls of involved vessels. We also assessed the density of Aβ positive cortical vessels in areas surrounding microhemorrhages compared to control areas. In seven out of 19 microhemorrhages, the presumed involved vessel could be identified on the histopathological section. Only one of these vessels was positive for Aβ at the site of rupture. Moreover, the density of Aβ positive cortical vessels was lower (1.0 per mm2) within a range of 315 µm surrounding the microhemorrhage, compared to control areas (2.0 per mm2; p < 0.05). These findings question the widely held assumption that the deposition of Aβ in the walls of cortical vessels directly causes microhemorrhages.
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Project description:The sphingosine-1-phosphate (S1P) receptor agonist fingolimod (FTY720), that has shown efficacy in advanced multiple sclerosis clinical trials, decreases reperfusion injury in heart, liver, and kidney. We therefore tested the therapeutic effects of fingolimod in several rodent models of focal cerebral ischemia. To assess the translational significance of these findings, we asked whether fingolimod improved long-term behavioral outcomes, whether delayed treatment was still effective, and whether neuroprotection can be obtained in a second species.We used rodent models of middle cerebral artery occlusion and cell-culture models of neurotoxicity and inflammation to examine the therapeutic potential and mechanisms of neuroprotection by fingolimod.In a transient mouse model, fingolimod reduced infarct size, neurological deficit, edema, and the number of dying cells in the core and periinfarct area. Neuroprotection was accompanied by decreased inflammation, as fingolimod-treated mice had fewer activated neutrophils, microglia/macrophages, and intercellular adhesion molecule-1 (ICAM-1)-positive blood vessels. Fingolimod-treated mice showed a smaller infarct and performed better in behavioral tests up to 15 days after ischemia. Reduced infarct was observed in a permanent model even when mice were treated 4 hours after ischemic onset. Fingolimod also decreased infarct size in a rat model of focal ischemia. Fingolimod did not protect primary neurons against glutamate excitotoxicity or hydrogen peroxide, but decreased ICAM-1 expression in brain endothelial cells stimulated by tumor necrosis factor alpha.These findings suggest that anti-inflammatory mechanisms, and possibly vasculoprotection, rather than direct effects on neurons, underlie the beneficial effects of fingolimod after stroke. S1P receptors are a highly promising target in stroke treatment.
| S-EPMC3200194 | biostudies-literature
Project description:Oleic acid (OA) is released from brain phospholipids after cerebral ischaemia; however, its role in ischaemic injury remains unknown. We hypothesised that OA has neuroprotective effects after cerebral ischaemia, which may be exerted through peroxisome proliferator-activated receptor gamma (PPAR-γ) activation, since OA is an endogenous ligand of PPAR-γ. The effects of OA administration were evaluated in rodent models of middle cerebral artery occlusion (MCAO), photothrombosis, and four-vessel occlusion (4-VO). We determined the time window of therapeutic opportunity and examined the ability of the PPAR-γ antagonist GW9662 to reverse OA's protective effects after MCAO. We found that OA administration decreased the MCAO-induced infarct volume and functional deficits, photothrombosis-induced infarct volume, and 4-VO-induced hippocampal neuronal death. Additionally, OA was highly efficacious when administered up to 3 h after MCAO. Pre-treatment with GW9662 abolished the inhibitory effects of OA on the infarct volume and immunoreactivity of key inflammatory mediators in the ischaemic cortex. Our results indicate that OA has neuroprotective effects against transient and permanent focal cerebral ischaemia, as well as global cerebral ischaemia. It may have therapeutic value for the ischaemic stroke treatment with a clinically feasible therapeutic window. The OA-mediated neuroprotection might be attributable to its anti-inflammatory actions through PPAR-γ activation.
| S-EPMC6656890 | biostudies-literature
Project description:The pathophysiology of microhemorrhages in the context of cerebral amyloid angiopathy (CAA) remains poorly understood. Here we used in vivo two-photon microscopy in aged APP/PS1 mice with mild-to-moderate CAA to assess the formation of microhemorrhages and their spatial relationship with vascular Aβ depositions in the surrounding microvascular network. Mice with chronic cranial windows were intravenously injected with fluorescent dextran to visualize the vessels and a fluorescently labeled anti-fibrin antibody to visualize microhemorrhages. Focal vessel irradiations resulted in extravascular fibrin-positive clots at individual rupture sites that remained visible for weeks. Spontaneous extravascular fibrin-positive clots were more often observed in 19-month-old transgenic APP/PS1 mice compared to their wild-type littermate controls (p = 0.039), after heparin administration. In the transgenic mice, these spontaneous leakage sites frequently occurred at arteriolar segments without CAA at bifurcations or vessel bends. These findings suggest that the presence of vascular Aβ per se does not directly predispose vessels to leak, but that complex flow dynamics within CAA-affected vascular networks likely play a role. Our in vivo approach for the detection of individual spontaneous leakage sites may be used in longitudinal studies aimed to assess structural and functional alterations at the single-vessel level leading up to microhemorrhage formation.
| S-EPMC7747164 | biostudies-literature
Project description:Glia account for 90% of human brain cells and have a significant role in brain homeostasis. Thus, specific in vivo imaging markers of glial metabolism are potentially valuable. In the brain, 2-fluoroacetate is selectively taken up by glial cells and becomes metabolically trapped in the tricarboxylic acid cycle. Recent work in rodent brain injury models demonstrated elevated lesion uptake of 2-[(18)F]fluoroacetate ([(18)F]FACE), suggesting possible use for specifically imaging glial metabolism. To assess this hypothesis, we evaluated [(18)F]FACE kinetics in rodent models of cerebral hypoxia-ischemia at 3 and 24 hours post insult. Lesion uptake was significantly higher at 30 minutes post injection (P<0.05). An image-based method for input function estimation using cardiac blood was validated. Analysis of whole blood showed no significant metabolites and plasma activity concentrations of ?50% that of whole blood. Kinetic models describing [(18)F]FACE uptake were developed and quantitatively compared. Elevated [(18)F]FACE uptake was found to be driven primarily by K?/k? rather than k?, but changes in the latter were detectable. The two-tissue irreversible uptake model (2T3k) was found to be necessary and sufficient for modeling [(18)F]FACE uptake. We conclude that kinetic modeling of [(18)F]FACE uptake represents a potentially useful tool for interrogation of glial metabolism.
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Project description:Alzheimer's disease (AD) immunotherapy accomplished by vaccination with beta-amyloid (Abeta) peptide has proved efficacious in AD mouse models. However, "active" Abeta vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) Abeta vaccination approach and evaluated efficacy and monitored for deleterious side effects, including meningoencephalitis and microhemorrhage, in WT mice and a transgenic mouse model of AD. We demonstrate that t.c. immunization of WT mice with aggregated Abeta(1-42) plus the adjuvant cholera toxin (CT) results in high-titer Abeta antibodies (mainly of the Ig G1 class) and Abeta(1-42)-specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the Abeta(1-42) immunogen, suggesting that these unique innate immune cells participate in Abeta(1-42) antigen processing. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APPsw, PSEN1dE9) mice were immunized with aggregated Abeta(1-42) peptide plus CT. Similar to WT mice, PSAPP mice showed high Abeta antibody titers. Most importantly, t.c. immunization with Abeta(1-42) plus CT resulted in significant decreases in cerebral Abeta(1-40,42) levels coincident with increased circulating levels of Abeta(1-40,42), suggesting brain-to-blood efflux of Abeta. Reduction in cerebral amyloidosis was not associated with deleterious side effects, including brain T cell infiltration or cerebral microhemorrhage. Together, these data suggest that t.c. immunization constitutes an effective and potentially safe treatment strategy for AD.
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Project description:The aim of this protocol is to provide a detailed description of male and female rodent models of osteoporosis. In addition to indications on the methods of performing the surgical procedures, the choice of reliable and safe anaesthetics is also described. Post-operative care, including analgesia administration for pain management, is also discussed. Ovariectomy in rodents is a procedure where ovaries are surgically excised. Hormonal changes resulting from ovary removal lead to an oestrogen-deprived state, which enhances bone remodelling, causes bone loss and increases bone fracture risk. Therefore, ovariectomy has been considered as the most common preclinical model for understanding the pathophysiology of menopause-associated events and for developing new treatment strategies for tackling post-menopausal osteoporosis. This protocol also provides a detailed description of orchidectomy, a model for androgen-deficient osteoporosis in rodents. Endocrine changes following testes removal lead to hypogonadism, which results in accelerated bone loss, increasing osteoporosis risk. Orchidectomised rodent models have been proposed to mimic male osteoporosis and therefore remain a valuable tool for understanding androgen deficiency in aged men. Although it would have been particularly difficult to assemble an internationally acceptable description of surgical procedures, here we have attempted to provide a comprehensive guide for best practice in performing ovariectomy and orchidectomy in laboratory rodents. Research scientists are reminded that they should follow their own institution's interpretation of such guidelines. Ultimately, however, all animal procedures must be overseen by the local Animal Welfare and Ethical Review Body and conducted under licences approved by a regulatory ethics committee.
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