PURPOSE: Focused ultrasound-induced blood-brain barrier (BBB) opening is a promising method for neurotherapeutic delivery. The standard for quantifying induced BBB permeability is the K trans $$ {K}^{\mathrm{trans}} $$ parameter, which reflects both permeability and plasma flow. The influence of plasma flow can be eliminated by estimating the PS parameter. However, this parameter has been largely unexplored in this application. This study aims to compare permeability estimates based on K trans $$ {K}^{\mathrm{trans}} $$ and PS in focused ultrasound-induced BBB opening experiments. METHODS: We used the extended Tofts model (ETM) and the two-compartment exchange model (2CXM) to estimate K trans $$ {K}^{\mathrm{trans}} $$ and PS parameters, respectively. Permeability estimates were compared using simulated concentration curves, simulated DCE-MRI data, and real datasets. We explored the influence of spatially-regularized model fitting on the results. RESULTS: For opened BBB, K trans $$ {K}^{\mathrm{trans}} $$ was minimally influenced by plasma flow under the tested conditions. However, fitting the ETM often introduced outliers in K trans $$ {K}^{\mathrm{trans}} $$ estimates in regions with closed BBB. The 2CXM outperformed the ETM at high signal-to-noise ratios, but its higher complexity led to lower precision at low signal-to-noise ratios. Both these issues were successfully compensated by spatially-regularized model fitting. CONCLUSION: Both K trans $$ {K}^{\mathrm{trans}} $$ and PS seem to be eligible options for the quantification of BBB opening, and the correct choice depends on the specifics of the acquired DCE-MRI data. Additionally, spatial regularization has demonstrated its importance in enhancing the accuracy and reproducibility of results for both models.
- Klíčová slova
- BBB opening, DCE‐MRI, focused ultrasound, perfusion analysis, simulation,
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Major depressive disorder (MDD) is a mental illness with a high worldwide prevalence and suboptimal pharmacological treatment, which necessitates the development of novel, more efficacious MDD medication. Nuclear magnetic resonance (NMR) can non-invasively provide insight into the neurochemical state of the brain using proton magnetic resonance spectroscopy (1H MRS), and an assessment of regional cerebral blood flow (rCBF) by perfusion imaging. These methods may provide valuable in vivo markers of the pathological processes underlying MDD. METHODS: This study examined the effects of the chronic antidepressant medication, citalopram, in a well-validated MDD model induced by bilateral olfactory bulbectomy (OB) in rats. 1H MRS was utilized to assess key metabolite ratios in the dorsal hippocampus and sensorimotor cortex bilaterally, and arterial spin labelling was employed to estimate rCBF in several additional brain regions. RESULTS: The 1H MRS data results suggest lower hippocampal Cho/tCr and lower cortical NAA/tCr levels as a characteristic of the OB phenotype. Spectroscopy revealed lower hippocampal Tau/tCr in citalopram-treated rats, indicating a potentially deleterious effect of the drug. However, the significant OB model-citalopram treatment interaction was observed using 1H MRS in hippocampal mI/tCr, Glx/tCr and Gln/tCr, indicating differential treatment effects in the OB and control groups. The perfusion data revealed higher rCBF in the whole brain, hippocampus and thalamus in the OB rats, while citalopram appeared to normalise it without affecting the control group. CONCLUSION: Collectively, 1H MRS and rCBF approaches demonstrated their capacity to capture an OB-induced phenotype and chronic antidepressant treatment effect in multiple brain regions.
- Klíčová slova
- Brain metabolites, Cerebral perfusion, Citalopram, Depression, Olfactory bulbectomy, Rats,
- MeSH
- bulbus olfactorius metabolismus chirurgie účinky léků MeSH
- citalopram * farmakologie MeSH
- deprese farmakoterapie metabolismus MeSH
- depresivní porucha unipolární farmakoterapie metabolismus MeSH
- hipokampus metabolismus účinky léků MeSH
- krysa rodu Rattus MeSH
- magnetická rezonanční spektroskopie metody MeSH
- modely nemocí na zvířatech * MeSH
- mozek * metabolismus účinky léků MeSH
- mozkový krevní oběh * účinky léků MeSH
- potkani Sprague-Dawley MeSH
- protonová magnetická rezonanční spektroskopie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- citalopram * MeSH
BACKGROUND: Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related cardiovascular morbidity are common, and current pharmacological strategies for their management are unsatisfactory. Glucagon-like 1 peptide receptor agonists (GLP-1 RAs) are approved for the treatment of type 2 diabetes and obesity hold promise for the management of antipsychotic-associated adverse metabolic effects. METHODS: To characterize the molecular effects and identify biomarkers for GLP-1 RA preventive treatment, Sprague-Dawley female rats were treated with long-acting formulations of the antipsychotic olanzapine and the GLP-1 RA dulaglutide for 8 days. A pair-feeding protocol evaluated the combined effects of dulaglutide and food restriction on an olanzapine-induced metabolic phenotype. Body weight and food consumption were recorded. Biochemical analysis included a lipid profile, a spectrum of gastrointestinal and adipose tissue-derived hormones, and fibroblast growth factor 21 serum levels. RESULTS: Olanzapine induced hyperphagia, weight gain, increased serum triglycerides and HDL cholesterol. Food restriction affected the OLA-induced phenotype but not serum markers. Dulaglutide led to a modest decrease in food intake, with no effect on weight gain, and did not reverse the OLA-induced changes in serum lipid parameters. Concomitant dulaglutide and food restriction resulted in weight loss, decreased feed efficiency, and lower total and HDL cholesterol. CONCLUSIONS: A combined strategy of dulaglutide and food restriction manifested a massive synergistic benefit. GLP-1RAs represent a promising strategy and deserve thorough future research. Our findings underline the potential importance of lifestyle intervention in addition to GLP-1 RA treatment.
- Klíčová slova
- Antipsychotic, GLP-1 receptor agonist, Olanzapine, metabolic adverse effects, Schizophrenia,
- MeSH
- agonisté receptoru pro glukagonu podobný peptid 1 MeSH
- antipsychotika farmakologie škodlivé účinky MeSH
- benzodiazepiny farmakologie škodlivé účinky MeSH
- glukagonu podobné peptidy * analogy a deriváty farmakologie MeSH
- hmotnostní přírůstek účinky léků MeSH
- imunoglobuliny - Fc fragmenty * farmakologie MeSH
- kalorická restrikce metody MeSH
- krysa rodu Rattus MeSH
- modely nemocí na zvířatech MeSH
- olanzapin * farmakologie škodlivé účinky MeSH
- potkani Sprague-Dawley * MeSH
- přijímání potravy účinky léků MeSH
- receptor pro glukagonu podobný peptid 1 metabolismus MeSH
- rekombinantní fúzní proteiny * farmakologie MeSH
- tělesná hmotnost účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- agonisté receptoru pro glukagonu podobný peptid 1 MeSH
- antipsychotika MeSH
- benzodiazepiny MeSH
- dulaglutide MeSH Prohlížeč
- glukagonu podobné peptidy * MeSH
- imunoglobuliny - Fc fragmenty * MeSH
- olanzapin * MeSH
- receptor pro glukagonu podobný peptid 1 MeSH
- rekombinantní fúzní proteiny * MeSH
PURPOSE: The aim of this study is to design a method of myocardial T1 quantification in small laboratory animals and to investigate the effects of spatiotemporal regularization and the needed acquisition duration. METHODS: We propose a compressed-sensing approach to T1 quantification based on self-gated inversion-recovery radial two/three-dimensional (2D/3D) golden-angle stack-of-stars acquisition with image reconstruction performed using total-variation spatiotemporal regularization. The method was tested on a phantom and on a healthy rat, as well as on rats in a small myocardium-remodeling study. RESULTS: The results showed a good match of the T1 estimates with the results obtained using the ground-truth method on a phantom and with the literature values for rats myocardium. The proposed 2D and 3D methods showed significant differences between normal and remodeling myocardium groups for acquisition lengths down to approximately 5 and 15 min, respectively. CONCLUSIONS: A new 2D and 3D method for quantification of myocardial T1 in rats was proposed. We have shown the capability of both techniques to distinguish between normal and remodeling myocardial tissue. We have shown the effects of image-reconstruction regularization weights and acquisition length on the T1 estimates.
- Klíčová slova
- MRI, T1, cardiac, fibrosis, quantification, remodeling, retrospective gating,
- MeSH
- fantomy radiodiagnostické MeSH
- krysa rodu Rattus MeSH
- magnetická rezonanční tomografie metody MeSH
- myokard * MeSH
- počítačové zpracování obrazu metody MeSH
- reprodukovatelnost výsledků MeSH
- zobrazování trojrozměrné * metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVES: Pilot study validating the animal model of depression - the bilateral olfactory bulbectomy in rats - by two nuclear magnetic resonance methods, indirectly detecting the metabolic state of the brain. Furthermore, the study focussed on potential differences in brain laterality. METHODS: Arterial spin labelling assessed cerebral brain flow in prefrontal, sensorimotor, and piriform cortices, nucleus accumbens, hippocampus, thalamus, circle of Willis, and whole brain. Proton magnetic resonance spectroscopy provided information about relative metabolite concentrations in the cortex and hippocampus. RESULTS: Arterial spin labelling found no differences in cerebral perfusion in the group comparison but revealed lateralisation in the thalamus of the control group and the sensorimotor cortex of the bulbectomized rats. Lower Cho/tCr and Cho/NAA levels were found in the right hippocampus in bulbectomized rats. The differences in lateralisation were shown in the hippocampus: mI/tCr in the control group, Cho/NAA, NAA/tCr, Tau/tCr in the model group, and in the cortex: NAA/tCr, mI/tCr in the control group. CONCLUSION: Olfactory bulbectomy affects the neuronal and biochemical profile of the rat brain laterally and, as a model of depression, was validated by two nuclear magnetic resonance methods.
- Klíčová slova
- Arterial spin labelling, depression, magnetic resonance spectroscopy, olfactory bulbectomy, rats,
- MeSH
- cholin metabolismus MeSH
- kreatin metabolismus MeSH
- krysa rodu Rattus MeSH
- kyselina aspartová metabolismus MeSH
- magnetická rezonanční spektroskopie metody MeSH
- magnetická rezonanční tomografie * MeSH
- mozek * patologie MeSH
- pilotní projekty MeSH
- receptory antigenů T-buněk metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cholin MeSH
- kreatin MeSH
- kyselina aspartová MeSH
- receptory antigenů T-buněk MeSH
Aims: Gross pathology inspection (patho) is the gold standard for the morphological evaluation of focal myocardial pathology. Examination with 9.4 T magnetic resonance imaging (MRI) is a new method for very accurate display of myocardial pathology. The aim of this study was to demonstrate that lesions can be measured on high-resolution MRI images with the same accuracy as on pathological sections and compare these two methods for the evaluation of radiofrequency (RF) ablation lesion dimensions in swine heart tissue during animal experiment. Methods: Ten pigs underwent radiofrequency ablations in the left ventricle during animal experiment. After animal euthanasia, hearts were explanted, flushed with ice-cold cardioplegic solution to relax the whole myocardium, fixed in 10% formaldehyde and scanned with a 9.4 T magnetic resonance system. Anatomical images were processed using ImageJ software. Subsequently, the hearts were sliced, slices were photographed and measured in ImageJ software. Different dimensions and volumes were compared. Results: The results of both methods were statistically compared. Depth by MRI was 8.771 ± 2.595 mm and by patho 9.008 ± 2.823 mm; p = 0.198. Width was 10.802 ± 2.724 mm by MRI and 11.125 ± 2.801 mm by patho; p = 0.049. Estuary was 2.006 ± 0.867 mm by MRI and 2.001 ± 0.872 mm by patho; p = 0.953. The depth at the maximum diameter was 4.734 ± 1.532 mm on MRI and 4.783 ± 1.648 mm from the patho; p = 0.858. The volumes of the lesions calculated using a formula were 315.973 ± 257.673 mm3 for MRI and 355.726 ± 255.860 mm3 for patho; p = 0.104. Volume directly measured from MRI with the "point-by-point" method was 671.702 ± 362.299 mm3. Conclusion: Measurements obtained from gross pathology inspection and MRI are fully comparable. The advantage of MRI is that it is a non-destructive method enabling repeated measurements in all possible anatomical projections.
Clinical diagnosis of Parkinson's disease (PD) occurs typically when a substantial proportion of dopaminergic neurons in the substantia nigra (SN) already died, and the first motor symptoms appear. Therefore, tools enabling the early diagnosis of PD are essential to identify early-stage PD patients in which neuroprotective treatments could have a significant impact. Here, we test the utility and sensitivity of the diffusion kurtosis imaging (DKI) in detecting progressive microstructural changes in several brain regions of mice exposed to chronic intragastric administration of rotenone, a mouse model that mimics the spatiotemporal progression of PD-like pathology from the ENS to the SN as described by Braak's staging. Our results show that DKI, especially kurtosis, can detect the progression of pathology-associated changes throughout the CNS. Increases in mean kurtosis were first observed in the dorsal motor nucleus of the vagus (DMV) after 2 months of exposure to rotenone and before the loss of dopaminergic neurons in the SN occurred. Remarkably, we also show that limited exposure to rotenone for 2 months is enough to trigger the progression of the disease in the absence of the environmental toxin, thus suggesting that once the first pathological changes in one region appear, they can self-perpetuate and progress within the CNS. Overall, our results show that DKI can be a useful radiological marker for the early detection and monitoring of PD pathology progression in patients with the potential to improve the clinical diagnosis and the development of neuroprotective treatments.
- Klíčová slova
- MRI, Parkinson, alpha synuclein, diffusion kurtosis imaging, rotenone, s disease, tract-based spatial statistics,
- MeSH
- aplikace orální MeSH
- bludiště - učení účinky léků fyziologie MeSH
- časové faktory MeSH
- dopaminergní neurony účinky léků patologie MeSH
- insekticidy toxicita MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- parkinsonské poruchy chemicky indukované diagnostické zobrazování patologie MeSH
- progrese nemoci * MeSH
- rotenon aplikace a dávkování toxicita MeSH
- zobrazování difuzních tenzorů metody MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- insekticidy MeSH
- rotenon MeSH
Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.
- Klíčová slova
- Arterial Spine Labelling, Cannabidiol, Dopamine D3 receptor, MAM model, Molecular Dynamics, Schizophrenia,
- MeSH
- antipsychotika farmakologie MeSH
- haloperidol chemie farmakologie MeSH
- kanabidiol chemie farmakologie MeSH
- magnetická rezonanční tomografie MeSH
- methylazoxymethanolacetát toxicita MeSH
- modely nemocí na zvířatech MeSH
- molekulární modely MeSH
- mozek diagnostické zobrazování účinky léků MeSH
- mozkový krevní oběh MeSH
- potkani Sprague-Dawley MeSH
- puberta MeSH
- receptory dopaminu D2 chemie genetika metabolismus MeSH
- receptory dopaminu D3 chemie genetika metabolismus MeSH
- regulace genové exprese MeSH
- schizofrenie chemicky indukované diagnostické zobrazování farmakoterapie genetika MeSH
- simulace molekulární dynamiky MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antipsychotika MeSH
- DRD2 protein, mouse MeSH Prohlížeč
- haloperidol MeSH
- kanabidiol MeSH
- methylazoxymethanolacetát MeSH
- receptory dopaminu D2 MeSH
- receptory dopaminu D3 MeSH
Methamphetamine (METH) abuse is known to increase the risk of Parkinson's disease (PD) due to its dopaminergic neurotoxicity. This is the rationale for the METH model of PD developed by toxic METH dosing (10 mg/kg four times every 2 h) which features robust neurodegeneration and typical motor impairment in mice. In this study, we used diffusion kurtosis imaging to reveal microstructural brain changes caused by METH-induced neurodegeneration. The METH-treated mice and saline-treated controls underwent diffusion kurtosis imaging scanning using the Bruker Avance 9.4 Tesla MRI system at two time-points: 5 days and 1 month to capture both early and late changes induced by METH. At 5 days, we found a decrease in kurtosis in substantia nigra, striatum and sensorimotor cortex, which is likely to indicate loss of DAergic neurons. At 1 month, we found an increase of kurtosis in striatum and sensorimotor cortex and hippocampus, which may reflect certain recovery processes. Furthermore, we performed tract-based spatial statistics analysis in the white matter and at 1 month, we observed increased kurtosis in ventral nucleus of the lateral lemniscus and some of the lateral thalamic nuclei. No changes were present at the early stage. This study confirms the ability of diffusion kurtosis imaging to detect microstructural pathological processes in both grey and white matter in the METH model of PD. The exact mechanisms underlying the kurtosis changes remain to be elucidated but kurtosis seems to be a valuable biomarker for tracking microstructural brain changes in PD and potentially other neurodegenerative disorders.
- Klíčová slova
- Behaviour, Diffusion kurtosis imaging, MRI, Methamphetamine, Mice, Parkinson’s disease, Tract-based spatial statistics,
- MeSH
- chování zvířat účinky léků MeSH
- difuzní magnetická rezonance MeSH
- dopaminové látky toxicita MeSH
- methamfetamin toxicita MeSH
- modely nemocí na zvířatech MeSH
- mozek diagnostické zobrazování účinky léků patologie MeSH
- myši inbrední C57BL MeSH
- Parkinsonova nemoc sekundární diagnostické zobrazování patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- dopaminové látky MeSH
- methamfetamin MeSH
PURPOSE: One of the main obstacles for reliable quantitative dynamic contrast-enhanced (DCE) MRI is the need for accurate knowledge of the arterial input function (AIF). This is a special challenge for preclinical small animal applications where it is very difficult to measure the AIF without partial volume and flow artifacts. Furthermore, using advanced pharmacokinetic models (allowing estimation of blood flow and permeability-surface area product in addition to the classical perfusion parameters) poses stricter requirements on the accuracy and precision of AIF estimation. This paper addresses small animal DCE-MRI with advanced pharmacokinetic models and presents a method for estimation of the AIF based on blind deconvolution. METHODS: A parametric AIF model designed for small animal physiology and use of advanced pharmacokinetic models is proposed. The parameters of the AIF are estimated using multichannel blind deconvolution. RESULTS: Evaluation on simulated data show that for realistic signal to noise ratios blind deconvolution AIF estimation leads to comparable results as the use of the true AIF. Evaluation on real data based on DCE-MRI with two contrast agents of different molecular weights showed a consistence with the known effects of the molecular weight. CONCLUSION: Multi-channel blind deconvolution using the proposed AIF model specific for small animal DCE-MRI provides reliable perfusion parameter estimates under realistic signal to noise conditions.
- Klíčová slova
- Arterial input function, Blind deconvolution, DCE-MRI,
- MeSH
- algoritmy MeSH
- arterie diagnostické zobrazování MeSH
- farmakokinetika MeSH
- kontrastní látky farmakokinetika MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- nekróza patologie MeSH
- perfuze MeSH
- počítačová simulace MeSH
- počítačové zpracování obrazu metody MeSH
- poměr signál - šum MeSH
- regresní analýza MeSH
- reprodukovatelnost výsledků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- kontrastní látky MeSH
