Publications by authors named "Timo Liimatainen"

56 Publications

Pulmonary Artery Dilatation Is a Common Finding in a Coronary Artery CT Angiography Population.

In Vivo 2021 Jul-Aug;35(4):2177-2185

Department of Clinical Radiology, Kuopio University Hospital, Clinical Imaging Center, Kuopio, Finland.

Background/aim: Dilatation of the main pulmonary artery (mPA) is a common incidental finding in chest imaging and often leads to consultation. The aim of this study was to determine the prevalence of mPA dilatation in a coronary artery CT angiography (CCTA) population.

Patients And Methods: The study investigated 985 consecutive patients scheduled for diagnostic CCTA. The transverse axial diameter of the mPA was measured. The prevalence of mPA dilatation was estimated using different reference values (Framingham Heart Study: 28.9 mm for males and 26.9 mm for females, Bozlar: 29.5 mm for both genders and Karazincir: 32.6 mm for males and 31.9 mm for females).

Results: The patient mean age was 53.0±9.7 years (66.5% were women). Body surface area (BSA) correlated moderately with the mPA diameter (r=0.423, p<0.001). The prevalence of mPA dilatation varied from 5.9% (Karazincir) to 33.7% (Framingham Heart Study) in the overall study population.

Conclusion: The prevalence of mPA dilatation is high in a CCTA patient population when using a cut-off value from the Framingham Heart Study.
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http://dx.doi.org/10.21873/invivo.12489DOI Listing
June 2021

Statistical Evaluation of Different Mathematical Models for Diffusion Weighted Imaging of Prostate Cancer Xenografts in Mice.

Front Oncol 2021 26;11:583921. Epub 2021 May 26.

Department of Radiology, University of Turku, Turku, Finland.

Purpose: To evaluate fitting quality and repeatability of four mathematical models for diffusion weighted imaging (DWI) during tumor progression in mouse xenograft model of prostate cancer.

Methods: Human prostate cancer cells (PC-3) were implanted subcutaneously in right hind limbs of 11 immunodeficient mice. Tumor growth was followed by weekly DWI examinations using a 7T MR scanner. Additional DWI examination was performed after repositioning following the fourth DWI examination to evaluate short term repeatability. DWI was performed using 15 and 12 b-values in the ranges of 0-500 and 0-2000 s/mm, respectively. Corrected Akaike information criteria and F-ratio were used to evaluate fitting quality of each model (mono-exponential, stretched exponential, kurtosis, and bi-exponential).

Results: Significant changes were observed in DWI data during the tumor growth, indicated by ADC, ADC, and ADC. Similar results were obtained using low as well as high b-values. No marked changes in model preference were present between the weeks 1-4. The parameters of the mono-exponential, stretched exponential, and kurtosis models had smaller confidence interval and coefficient of repeatability values than the parameters of the bi-exponential model.

Conclusion: Stretched exponential and kurtosis models showed better fit to DWI data than the mono-exponential model and presented with good repeatability.
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http://dx.doi.org/10.3389/fonc.2021.583921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188898PMC
May 2021

Lentivirus vector‑mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain.

Mol Med Rep 2021 06 13;23(6). Epub 2021 Apr 13.

A.I Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI‑70211 Kuopio, Finland.

Translation of promising experimental therapies from rodent models to clinical success has been complicated as the novel therapies often fail in clinical trials. Existing rodent glioma models generally do not allow for preclinical evaluation of the efficiency of novel therapies in combination with surgical resection. Therefore, the aim of the present study was to develop a larger animal model utilizing lentivirus vector‑mediated oncogenic transformation in the rabbit brain. Lentiviruses carrying constitutively active AKT and H‑Ras oncogenes, and p53 small interfering (si)RNA were introduced into newborn rabbit neural stem cells (NSCs) and intracranially implanted into rabbits' brains to initiate tumor formation. In one of the ten rabbits a tumor was detected 48 days after the implantation of transduced NSCs. Histological features of the tumor mimic was similar to a benign Grade II ganglioglioma. Immunostaining demonstrated that the tissues were positive for AKT and H‑Ras. Strong expression of GFAP and Ki‑67 was also detected. Additionally, p53 expression was notably lower in the tumor area. The implantation of AKT, H‑Ras and p53 siRNA transduced NSCs for tumor induction resulted in ganglioglioma formation. Despite the low frequency of tumor formation, this preliminary data provided a proof of principle that lentivirus vectors carrying oncogenes can be used for the generation of brain tumors in rabbits. Moreover, these results offer noteworthy insights into the pathogenesis of a rare brain tumor, ganglioglioma.
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http://dx.doi.org/10.3892/mmr.2021.12061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047887PMC
June 2021

Whole Brain Adiabatic T and Relaxation Along a Fictitious Field Imaging in Healthy Volunteers and Patients With Multiple Sclerosis: Initial Findings.

J Magn Reson Imaging 2021 Mar 6. Epub 2021 Mar 6.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Background: In preclinical models of multiple sclerosis (MS), both adiabatic T (T ) and relaxation along a fictitious field (RAFF) imaging have demonstrated potential to noninvasively characterize MS.

Purpose: To evaluate the feasibility of whole brain T and RAFF imaging in healthy volunteers and patients with MS.

Study Type: Single institutional clinical trial.

Subjects: 38 healthy volunteers (24-69 years) and 21 patients (26-59 years) with MS. Five healthy volunteers underwent a second MR examination performed within 8 days. Clinical disease severity (The Expanded Disability Status Scale [EDSS] and The Multiple Sclerosis Severity Score [MSSS]) was evaluated at baseline and 1-year follow-up (FU).

Field Strength/sequence: RAFF in second rotating frame of reference (RAFF2) was performed at 3 T using 3D-fast-field echo with magnetization preparation, RF amplitude of 11.74 μT while the corresponding value for T was 13.50 μT. T -, T -, and FLAIR-weighted images were acquired with reconstruction voxel size 1.0 × 1.0 × 1.0 mm .

Assessment: The parametric maps of T and RAFF2 (T ) were calculated using a monoexponential model. Semi-automatic segmentation of MS lesions, white matter (WM), and gray matter (GM), and WM tracks was performed using T -, T -, and FLAIR-weighted images.

Statistical Tests: Regression analysis was used to evaluate correlation of T and T with age and disease severity while a Friedman test followed by Wilcoxon Signed Rank test for differences between tissue types. Short-term repeatability was evaluated on voxel level.

Results: Both T and T demonstrated good short-term repeatability with relative differences on voxel level in the range of 6.1%-11.9%. Differences in T and T between the tissue types in MS patients were significant (P < 0.05). T and T correlated (P < 0.001) with baseline EDSS/MSSM and disease progression at FU (P < 0.001).

Data Conclusion: Whole brain T and T at 3 T was feasible with significant differences in T and T values between tissues types and correlation with disease severity.

Evidence Level: 1 TECHNICAL EFFICACY: Stage 1.
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http://dx.doi.org/10.1002/jmri.27586DOI Listing
March 2021

Docetaxel chemotherapy response in PC3 prostate cancer mouse model detected by rotating frame relaxations and water diffusion.

NMR Biomed 2021 04 4;34(4):e4483. Epub 2021 Feb 4.

A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.

MRI is a common method of prostate cancer diagnosis. Several MRI-derived markers, including the apparent diffusion coefficient (ADC) based on diffusion-weighted imaging, have been shown to provide values for prostate cancer detection and characterization. The hypothesis of the study was that docetaxel chemotherapy response could be picked up earlier with rotating frame relaxation times T and T than with the continuous wave T , adiabatic T , adiabatic T , T , T or water ADC. Human PC3 prostate cancer cells expressing a red fluorescent protein were implanted in 21 male mice. Docetaxel chemotherapy was given once a week starting 1 week after cell implantation for 10 randomly selected mice, while the rest served as a control group (n = 11). The MRI consisted of relaxation along a fictitious field (RAFF) in the second (RAFF2) and fourth (RAFF4) rotating frames, T and T , continuous wave T , adiabatic T and adiabatic T relaxation time measurements and water ADC. MRI was conducted at 7 T, once a week up to 4 weeks from cell implantation. The tumor volume was monitored using T -weighted MRI and optical imaging. The histology was evaluated after the last imaging time point. Significantly reduced RAFFn, T T and conventional relaxation times 4 weeks after tumor implantation were observed in the treated tumors compared with the controls. The clearest short- and long-term responses were obtained with T , while no clear improvement in response to treatment was detected with novel methods compared with conventional methods or with RAFFn compared with all others. The tumor volume decreased after a two-week time point for the treated group and increased significantly in the control group, which was supported by increasing red fluorescent light emission in the control tumors. Decreased relaxation times were associated with successful chemotherapy outcomes. The results indicate altered relaxation mechanisms compared with higher dose chemotherapies previously published.
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http://dx.doi.org/10.1002/nbm.4483DOI Listing
April 2021

Prediction of prostate cancer aggressiveness using F-Fluciclovine (FACBC) PET and multisequence multiparametric MRI.

Sci Rep 2020 06 10;10(1):9407. Epub 2020 Jun 10.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

The aim of this prospective single-institution clinical trial (NCT02002455) was to evaluate the potential of advanced post-processing methods for F-Fluciclovine PET and multisequence multiparametric MRI in the prediction of prostate cancer (PCa) aggressiveness, defined by Gleason Grade Group (GGG). 21 patients with PCa underwent PET/CT, PET/MRI and MRI before prostatectomy. DWI was post-processed using kurtosis (ADC, K), mono- (ADC), and biexponential functions (f, D, D) while Logan plots were used to calculate volume of distribution (V). In total, 16 unique PET (V, SUV) and MRI derived quantitative parameters were evaluated. Univariate and multivariate analysis were carried out to estimate the potential of the quantitative parameters and their combinations to predict GGG 1 vs >1, using logistic regression with a nested leave-pair out cross validation (LPOCV) scheme and recursive feature elimination technique applied for feature selection. The second order rotating frame imaging (RAFF), monoexponential and kurtosis derived parameters had LPOCV AUC in the range of 0.72 to 0.92 while the corresponding value for V was 0.85. he best performance for GGG prediction was achieved by K parameter of kurtosis function followed by quantitative parameters based on DWI, RAFF and F-FACBC PET. No major improvement was achieved using parameter combinations with or without feature selection. Addition of F-FACBC PET derived parameters (V, SUV) to DWI and RAFF derived parameters did not improve LPOCV AUC.
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http://dx.doi.org/10.1038/s41598-020-66255-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287051PMC
June 2020

A smaller heart-aorta-angle associates with ascending aortic dilatation and increases wall shear stress.

Eur Radiol 2020 Sep 22;30(9):5149-5157. Epub 2020 Apr 22.

Department of Clinical Radiology, Clinical Imaging Center, Kuopio University Hospital, Kuopio, Finland.

Objectives: The aim of this study was to evaluate whether the orientation of the heart, measured as an angle between the long axis of the heart and ascending aorta midline (heart-aorta-angle, HAA), associates with ascending aortic (AA) dilatation. Furthermore, the association between HAA and wall shear stress (WSS) was studied.

Methods: HAA was retrospectively measured in 1000 consecutive coronary artery computed tomographic angiography (CCTA) images in patients with low-to-moderate pretest probability for coronary artery disease (CAD). To evaluate the effects of HAA on AA flow, 4D flow MRI was performed for 28 patients with AA dilatation (> 40 mm) and WSS was analyzed.

Results: The mean age of patients undergoing CCTA was 52.9 ± 9.8 years; 66.5% were women. Their median HAA was 128.7° and interquartile range 123.3-134.1°. HAA was significantly smaller in patients with dilated AA (median 126.7° [121.3-130.8°]) compared with the patients with normal AA (median 129.5° [124.3-135.3°], p < 0.001). HAA was smaller in males (p < 0.001) and in patients with diabetes (p = 0.016), hypertension (p = 0.001), CAD (p = 0.003), hypercholesterolemia (p < 0.001), and bicuspid aortic valve (p = 0.025) than without these factors. In a subpopulation without any of these underlying diseases (n = 233), HAA was still significantly smaller in the patients with dilated AA (median 127.9° [124.3-134.3°]) compared with patients with normal AA (median 131.9° [127.6-136.9°], p = 0.013). In 4D flow MRI, a smaller HAA correlated with increased total WSS in the outer curvature of the proximal AA (r = - 0.510, p = 0.006).

Conclusion: A smaller HAA associates with AA dilatation and affects the blood flow in the proximal AA.

Key Points: • A smaller angle between the long axis of the heart and ascending aorta midline associated with ascending aortic dilatation. • A smaller heart-aorta-angle correlated with increased total wall shear stress in the outer curvature of the proximal ascending aorta.
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http://dx.doi.org/10.1007/s00330-020-06852-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431431PMC
September 2020

High prevalence of ascending aortic dilatation in a consecutive coronary CT angiography patient population.

Eur Radiol 2020 Feb 16;30(2):1079-1087. Epub 2019 Sep 16.

Department of Clinical Radiology, Clinical Imaging Center, Kuopio University Hospital, PO Box 100, Puijonlaaksontie 2, 70029, Kuopio, KYS, Finland.

Objectives: To clarify the prevalence and risk factors of ascending aortic (AA) dilatation according to ESC 2014 guidelines.

Methods: This study included 1000 consecutive patients scheduled for diagnostic coronary artery computed tomographic angiography. AA diameter was retrospectively measured in 3 planes: sinus valsalva, sinotubular junction, and tubular part. The threshold for AA dilatation was set to > 40 mm which has been suggested as an upper normal limit for AA diameter in ESC 2014 guidelines on aortic diseases. Aortic size index (ASI) using the ratio between aortic diameter and body surface area (BSA) was applied as a comparative measurement. The threshold for AA dilatation was set to the upper limit of normal distribution exceeding two standard deviations (95%). Risk factors for AA dilatation were collected from medical records.

Results: The patients' mean age was 52.9 ± 9.8 years (66.5% women). The prevalence of AA dilatation was 23.0% in the overall study population (52.5% males) and 15.1% in the subgroup of patients with no coronary artery disease or bicuspid (BAV)/mechanical aortic valve (n = 365). According to the normal-distributed ASI values, the threshold for sinus valsalva was defined as 23.2 mm/m and for tubular part 22.2 mm/m in the subgroup. Higher BSA was associated with larger AA dimensions (r = 0.407, p < 0.001). Male gender (p < 0.001), BAV (p < 0.001), hypertension (p = 0.009) in males, and smoking (p < 0.001) appeared as risk factors for AA dilatation.

Conclusions: The prevalence of AA dilatation is high with current ESC guidelines for normal AA dimension, especially in males. Body size is strongly associated with AA dimensions; it would be more reliable to use BSA-adjusted AA diameters for the definition of AA dilatation.

Key Points: • The prevalence of AA dilatation is high in patients who are candidates for coronary CT angiography. • Body size is strongly associated with AA dimensions.
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http://dx.doi.org/10.1007/s00330-019-06433-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957537PMC
February 2020

Characterizing valve dynamics in mice by high-resolution cine-MRI.

NMR Biomed 2019 08 21;32(8):e4108. Epub 2019 May 21.

School of Pharmacy, University of Eastern Finland, Kuopio, Finland.

Aims: In calcific aortic valve disease (CAVD), progressive valvular sclerosis and calcification cause narrowing of the orifice and an impairment of the valve's function. We applied high-resolution cine-MRI to perform quantitative analysis of the dynamics of the aortic valve in a mice model of CAVD.

Methods And Results: LDLr ApoB mice were fed a Western diet (WD) or a standard diet (control) for 22 weeks. The mice were imaged in a 7 T horizontal MRI scanner, and aortic valve dynamics was examined by imaging the cross-section of the aorta at valve level using cine sequences. From these images, the area of the aortic valve orifice was determined during the heart cycle. MRI results were compared with echocardiographic and histopathologic results. The data revealed evidence of clear aortic valve dysfunction in WD mice as compared with control mice (interaction P < 0.001). MRI showed narrowing (14%, P < 0.05) of the orifice area, and this was also seen in histology (34%, P < 0.05), indicating more severe aortic stenosis after WD than in controls. Additionally, MRI revealed a reduction in the ejection fraction (EF) (-11%, P < 0.01), a result confirmed with echocardiography (-27%, P < 0.001) in mice fed with WD. EF detected by MRI and echocardiography also correlated strongly with the degree of stenosis assessed by histology.

Conclusions: Cine-MRI can be used for quantitative analysis of the aortic valve orifice over the cardiac cycle in mice. MRI showed the cusps clearly, and we were able to detect aortic valve dysfunction over time through the cardiac cycle.
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http://dx.doi.org/10.1002/nbm.4108DOI Listing
August 2019

Aortic dilatation associates with flow displacement and increased circumferential wall shear stress in patients without aortic stenosis: A prospective clinical study.

J Magn Reson Imaging 2019 07 18;50(1):136-145. Epub 2019 Jan 18.

Department of Clinical Radiology, Kuopio University Hospital, Imaging Center, Kuopio, Finland.

Background: The relationship between blood flow characteristics and ascending aortic (AA) dilatation has not been studied in patients with a tricuspid aortic valve (TAV) without aortic stenosis.

Purpose: To evaluate whether 4D flow characteristics determined in MRI are related to AA dilatation by comparing dilated AA and nondilated AA subjects with TAV.

Study Type: Prospective.

Population: Twenty patients with dilated AA and 20 age-matched patients with nondilated AA.

Field Strength/sequence: 1.5T/4D flow, 2D flow, and anatomic images.

Assessment: Altogether, 16 different 4D flow parameters were assessed in 10 planes in the thoracic aorta. Intra- and interobserver reproducibility were analyzed.

Statistical Tests: Independent t-test for normally distributed and the Mann-Whitney test for skewed distributed parameters were used. A paired-samples t-test was used to compare 2D and 4D flow parameters. Intraclass correlation coefficient (ICC) was used in intra- and interobserver reproducibility analysis.

Results: Aortic flow was displaced from the centerline of the aorta in the proximal and tubular planes. Flow displacement (FD) was greatest in the proximal plane of AA and was higher in dilated AA (4.5%, range 3.0-5.8%) than in nondilated AA (2.0%, 1.0-3.0%, P < 0.001). Total wall shear stress (WSS) values were 1.3 ± 0.4 times higher on the displaced side than on the opposite side of the aorta (P < 0.01). The circumferential WSS (WSS ) ratio to total WSS was greater in dilated AA, being 0.48 ± 0.11 vs. 0.32 ± 0.09 in the inner curvature of the proximal AA (P < 0.001) and 0.37 ± 0.11 vs. 0.26 ± 0.07 in the whole aortic ring in the distal AA (P < 0.001). Depending on 4D flow parameters, reproducibility varied from excellent (ICC = 0.923) to very low (ICC = 0.204).

Data Conclusion: The present study demonstrates that 4D flow measurements help to visualize the pathological flow patterns related to aortic dilatation. Flow displacement and an increased WSSc/WSS ratio are significantly associated with AA dilatation.

Level Of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:136-145.
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http://dx.doi.org/10.1002/jmri.26655DOI Listing
July 2019

Downregulation of VEGFR3 signaling alters cardiac lymphatic vessel organization and leads to a higher mortality after acute myocardial infarction.

Sci Rep 2018 11 12;8(1):16709. Epub 2018 Nov 12.

A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.

Heart has a wide lymphatic network but the importance of cardiac lymphatic system in heart diseases has remained unclear. Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) is a key molecule in the development and maintenance of cardiac lymphatic vessels. Here we characterized the role of VEGFR3 in healthy hearts and after myocardial infarction (MI) by using sVEGFR3 transgenic mice expressing a soluble decoy VEGFR3 under K14 promoter and Chy mice which have an inactivating mutation in the VEGFR3 gene. Cardiac lymphatic vessels were significantly dilated in the healthy hearts of sVEGFR3 mice when compared to controls. Lymphatic vessels formed large sheet-like structures in Chy mice. Attenuated VEGFR3 signaling led to a more severe MI predisposing to a significantly higher mortality in sVEGFR3 mice than in control mice. sVEGFR3 mice displayed intramyocardial hemorrhages in the infarcted area indicating hyperpermeability of the vasculature. Furthermore, novel MRI methods TRAFF2 and TRAFF4 and histological analysis revealed a modified structure of the fibrotic infarcted area in sVEGFR3 mice. In conclusion, the downregulation of VEGFR3 signaling modifies the structure of cardiac lymphatic network and causes vascular leakiness and increased mortality after MI.
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http://dx.doi.org/10.1038/s41598-018-34770-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232169PMC
November 2018

Capturing exchange using periodic radiofrequency irradiation.

J Magn Reson 2018 11 5;296:79-84. Epub 2018 Sep 5.

Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, USA.

The dynamics of spin system coupled by chemical exchange between two sites with different chemical shifts during periodic radiofrequency (RF) irradiation was here investigated. When the instantaneous π-flip of effective frequency during the course of frequency sweep was applied, a significant increase of exchange-induced relaxation rate constants was observed for small tip angle of magnetization in the laboratory frame of reference. This increase of the rate constants corresponds to the side bands generated by the periodic irradiation during the RF pulses. The exchange - induced relaxation rate constants depend on the exchange conditions, the RF power and the irradiation period. The described phenomenon promises applications for studying protein dynamics and for generating exchange specific relaxation contrasts in MRI.
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http://dx.doi.org/10.1016/j.jmr.2018.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661253PMC
November 2018

Macrophage Infiltration in the Saccular Intracranial Aneurysm Wall as a Response to Locally Lysed Erythrocytes That Promote Degeneration.

J Neuropathol Exp Neurol 2018 10;77(10):890-903

Neurosurgery Research Group, Biomedicum, Helsinki, Finland.

Saccular intracranial aneurysm (sIA) rupture is often fatal. Rupture-prone sIA walls are infiltrated by macrophages expressing hemoglobin-receptor CD163, suggesting a role for erythrocyte lysis in the degenerative remodeling predisposing to rupture. We therefore studied erythrocyte remnants in 16 unruptured and 20 ruptured sIA walls using histology and immunohistochemistry. Glycophorin A (GPA), an erythrocyte membrane protein, was present in 34/36 (94%) sIA walls and correlated with loss of αSMA+ cells, reflecting loss of mural smooth muscle cells ([SMCs]; r = -0.592, p < 0.001), wall degeneration (p = 0.008), and rupture (p = 0.005). GPA correlated with high numbers of CD163+ and CD68+ phagocytes (r = 0.65 and r = 0.54, p ≤ 0.001 for both). CD163+ phagocytes were mostly HLA-DR-. Interestingly, single SMCs expressed HLA-DR and also CD163 was expressed in sporadic SMCs, which may reflect their response to hemoglobin accumulation. GPA associated with iron (p = 0.014) was detectable by MRI. An additional 11 sIAs were therefore imaged ex vivo with a 4.7 T MRI prior to histology. In the sIA walls, high GPA and iron accumulation associated with signal intensity in T1-weighted gradient echo MRI. We conclude that accumulation of lysed erythrocytes is a potential driver of inflammatory response in the sIA walls and is associated with the degenerative wall remodeling, thereby predisposing to rupture.
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http://dx.doi.org/10.1093/jnen/nly068DOI Listing
October 2018

Quantification of myocardial infarct area based on T relaxation time maps - comparison with cardiovascular magnetic resonance late gadolinium enhancement, T and T in vivo.

J Cardiovasc Magn Reson 2018 06 7;20(1):34. Epub 2018 Jun 7.

Research Unit of Medical Imaging, Physics and Technology, University of Oulu, Oulu, Finland.

Background: Two days after myocardial infarction (MI), the infarct consists mostly on necrotic tissue, and the myocardium is transformed through granulation tissue to scar in two weeks after the onset of ischemia in mice. In the current work, we determined and optimized cardiovascular magnetic resonance (CMR) methods for the detection of MI size during the scar formation without contrast agents in mice.

Methods: We characterized MI and remote areas with rotating frame relaxation time mapping including relaxation along fictitious field in n rotating frame (RAFFn), T and T relaxation time mappings at 1, 3, 7, and 21 days after MI. These results were compared to late gadolinium enhancement (LGE) and Sirius Red-stained histology sections, which were obtained at day 21 after MI.

Results: All relaxation time maps showed significant differences in relaxation time between the MI and remote area. Areas of increased signal intensities after gadolinium injection and areas with increased T relaxation time were highly correlated with the MI area determined from Sirius Red-stained histology sections (LGE: R = 0.92, P < 0.01, T: R = 0.95, P < 0.001). Infarct area determined based on T relaxation time correlated highly with Sirius Red histology sections (R = 0.97, P < 0.01). The smallest overestimation of the LGE-defined MI area was obtained for T (5.6 ± 4.2%) while for T overestimation percentage was > 9% depending on T pulse power.

Conclusion: T and T relaxation time maps can be used to determine accurately MI area at various time points in the mouse heart. Determination of MI size based on T relaxation time maps could be performed without contrast agents, unlike LGE, and with lower specific absorption rate compared to on-resonance T relaxation time mapping.
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http://dx.doi.org/10.1186/s12968-018-0463-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992705PMC
June 2018

T , T and T detect early regenerative changes in mouse ischemic skeletal muscle.

NMR Biomed 2018 05 23;31(5):e3909. Epub 2018 Mar 23.

A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.

The identification of areas with regenerative potential in ischemic tissues would allow the targeting of treatments supporting tissue recovery. The regeneration process involves the activation of several cellular and molecular responses which could be detected using magnetic resonance imaging (MRI). However, to date, magnetic resonance (MR) relaxation parameters have received little attention in the diagnosis and follow-up of limb ischemia. The purpose of this study was to evaluate the feasibility of different MRI relaxation and diffusion tensor imaging parameters in the detection of areas showing early signs of regeneration in ischemic mouse skeletal muscles. T and T relaxation time constants, together with T , T and diffusion tensor imaging, were evaluated to differentiate areas of regeneration in a mouse hind limb ischemia model before and 0, 1, 4, 7, 14 and 30 days after ischemia. All the measured relaxation times were longer in the areas of early regeneration compared with normal muscle tissue. The relaxation times increased after ischemia in the ischemic muscles, reaching a maximum at 4-7 days after occlusion, coinciding with the appearance of early signs of regeneration. Fractional anisotropy decreased significantly (p < 0.05) on days 1-4, whereas mean diffusivity, λ and λ decreased later, starting at day 7 after ischemia compared with the pre-operational time point. The percentages of areas with different tissue morphologies were determined based on histological analysis of the ischemic muscle cross-sections, and correlations between the percentages obtained and different relaxation times were calculated. The highest correlation between relaxation times and histology was achieved with T , T and T (R = 0.96, R = 0.92 and R = 0.84, respectively, p < 0.01) Early regenerative changes were visible using T , T and T MR relaxation time constants in skeletal muscle after ischemia. These markers could potentially be used for the identification of targets for therapies supporting muscle regeneration after ischemic injury.
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http://dx.doi.org/10.1002/nbm.3909DOI Listing
May 2018

Gadoterate meglumine decreases ADC values of breast lesions depending on the b value combination.

Sci Rep 2018 01 8;8(1):87. Epub 2018 Jan 8.

Kuopio University Hospital, Diagnostic Imaging Centre, Department of Clinical Radiology, Kuopio University Hospital, PO Box 100, Puijonlaaksontie 2, 70029, Kuopio, Finland.

To retrospectively evaluated the influence of administration of the gadolinium based intravenous contrast agent (G-CA) on apparent diffusion coefficient (ADC) values in ADC maps generated using multiple b value combinations. A total of 106 women underwent bilateral 3.0 T breast MRI. As an internal validation, diffusion-weighted imaging (b values of 0, 200, 400, 600, 800 s/mm) was performed before and after the G-CA (gadoterate meglumine (0.2 ml/kg, 3 ml/s)). Whole lesion and fibroglandular tissue (FGT) covering region-of-interests (ROIs) were drawn on the b = 800 s/mm images; ROIs were then propagated to multiple retrospectively generated ADC maps. Twenty-seven patients (mean age 55.8 ± 10.8 years) with 32 mass-like enhancing breast lesions including 25 (78.1 %) histopathologically malignant lesions were enrolled. Lesion ADC values were statistically significantly higher in pre-G-CA than post-G-CA ADC maps (ADC: 1.05 ± 0.35 × 10 mm/s vs. 1.02 ± 0.36 × 10 mm/s (P < 0.05); ADC: 1.25 ± 0.42 × 10 mm/s vs. 1.20 ± 0.35 × 10 mm/s (P < 0.05)). ADC values between pre- and post-contrast maps were not statistically different when the maps were generated using other b value combinations. Contrast agent administration did not affect the FGT ADC values. G-CA statistically significantly reduced the ADC values of breast lesions on ADC maps generated using the clinically widely utilized b values.
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http://dx.doi.org/10.1038/s41598-017-18035-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758819PMC
January 2018

The follow-up of progressive hypertrophic cardiomyopathy using magnetic resonance rotating frame relaxation times.

NMR Biomed 2018 02 15;31(2). Epub 2017 Dec 15.

Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.

Magnetic resonance rotating frame relaxation times are an alternative non-contrast agent choice for the diagnosis of chronic myocardial infarct. Fibrosis typically occurs in progressive hypertrophic cardiomyopathy. Fibrosis has been imaged in myocardial infarcted tissue using rotating frame relaxation times, which provides the possibility to follow up progressive cardiomyopathy without contrast agents. Mild and severe left ventricular hypertrophy were induced in mice by transverse aortic constriction, and the longitudinal rotating frame relaxation times (T ) and relaxation along the fictitious field (T , T ) were measured at 5, 10, 24, 62 and 89 days after transverse aortic constriction in vivo. Myocardial fibrosis was verified using Masson's trichrome staining. Increases in the relative relaxation time differences of T , together with T and T , between fibrotic and remote tissues over time were observed. Furthermore, T and T showed higher relaxation times overall in fibrotic tissue than T . Relaxation time differences were highly correlated with an excess of histologically verified fibrosis. We found that T and T are more sensitive than T to hypertrophic cardiomyopathy-related tissue changes and can serve as non-invasive diagnostic magnetic resonance imaging markers to follow up the mouse model of progressive hypertrophic cardiomyopathy.
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http://dx.doi.org/10.1002/nbm.3871DOI Listing
February 2018

Quantitative Volumetric K-Means Cluster Segmentation of Fibroglandular Tissue and Skin in Breast MRI.

J Digit Imaging 2018 08;31(4):425-434

Department of Clinical Radiology, Diagnostic Imaging Centre, Kuopio University Hospital, Kuopio, Finland.

Mammographic breast density (MBD) is the most commonly used method to assess the volume of fibroglandular tissue (FGT). However, MRI could provide a clinically feasible and more accurate alternative. There were three aims in this study: (1) to evaluate a clinically feasible method to quantify FGT with MRI, (2) to assess the inter-rater agreement of MRI-based volumetric measurements and (3) to compare them to measurements acquired using digital mammography and 3D tomosynthesis. This retrospective study examined 72 women (mean age 52.4 ± 12.3 years) with 105 disease-free breasts undergoing diagnostic 3.0-T breast MRI and either digital mammography or tomosynthesis. Two observers analyzed MRI images for breast and FGT volumes and FGT-% from T1-weighted images (0.7-, 2.0-, and 4.0-mm-thick slices) using K-means clustering, data from histogram, and active contour algorithms. Reference values were obtained with Quantra software. Inter-rater agreement for MRI measurements made with 2-mm-thick slices was excellent: for FGT-%, r = 0.994 (95% CI 0.990-0.997); for breast volume, r = 0.985 (95% CI 0.934-0.994); and for FGT volume, r = 0.979 (95% CI 0.958-0.989). MRI-based FGT-% correlated strongly with MBD in mammography (r = 0.819-0.904, P < 0.001) and moderately to high with MBD in tomosynthesis (r = 0.630-0.738, P < 0.001). K-means clustering-based assessments of the proportion of the fibroglandular tissue in the breast at MRI are highly reproducible. In the future, quantitative assessment of FGT-% to complement visual estimation of FGT should be performed on a more regular basis as it provides a component which can be incorporated into the individual's breast cancer risk stratification.
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http://dx.doi.org/10.1007/s10278-017-0031-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113149PMC
August 2018

Aggravated Postinfarct Heart Failure in Type 2 Diabetes Is Associated with Impaired Mitophagy and Exaggerated Inflammasome Activation.

Am J Pathol 2017 Dec 19;187(12):2659-2673. Epub 2017 Sep 19.

Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, Kuopio University Hospital, Kuopio, Finland; Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland. Electronic address:

Type 2 diabetes mellitus (T2DM) is a major risk factor for heart disease. Mortality rates after myocardial infarction (MI) are significantly increased in T2DM patients because of dysfunctional left ventricle (LV). However, molecular pathways underlying accelerated heart failure (HF) after MI in T2DM remain unclear. We investigated the underlying mechanisms by inducing MI in a well-established model of T2DM and control mice. Cardiac imaging revealed a significantly decreased global left ventricular ejection fraction in parallel with increased mortality after MI in T2DM mice compared with control mice. Genome-wide mRNA sequencing, immunoblot, electron microscopy, together with immunofluorescence staining for LC3 and p62 indicated an impaired mitophagy in peri-infarct regions of LV in T2DM mice compared with control mice. Furthermore, defective mitophagy was associated with an increased release of mitochondrial DNA, resulting in Aim2 and NLRC4 inflammasome and caspase-I hyperactivation in cardiomyocytes and cardiac macrophages in peri-infarct regions of LV in T2DM mice. Consistent with inflammasome and caspase-I hyperactivation, cardiomyocyte death and IL-18 secretion were increased in T2DM mice. Our results indicate that T2DM aggravates HF after MI through defective mitophagy, associated exaggerated inflammasome activation, cell death, and IL-18 secretion, suggesting that restoring mitophagy and inhibiting inflammasome activation may serve as novel targets for the prevention and treatment of HF in T2DM.
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http://dx.doi.org/10.1016/j.ajpath.2017.08.023DOI Listing
December 2017

Combined Gene Therapy Using AdsVEGFR2 and AdsTie2 With Chemotherapy Reduces the Growth of Human Ovarian Cancer and Formation of Ascites in Mice.

Int J Gynecol Cancer 2017 06;27(5):879-886

*Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, and †Institute of Clinical Medicine, Gynecology, and Pathology and Forensic Medicine, University of Eastern Finland; ‡Department of Gynecology, Kuopio University Hospital; §NMR Research Group, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland; ∥Department of Pathology and ¶Gene Therapy Unit, Kuopio University Hospital; and #Science Service Center, Kuopio University Hospital, Kuopio, Finland.

Objectives: Ovarian cancer is highly dependent on tumor microvessels and angiogenesis regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) and angiopoietins (Ang) and their Tie receptors. We studied the efficacy of adenoviral (Ad) gene therapy with soluble VEGFR2 and Tie2 combined with paclitaxel and carboplatin for the treatment of ovarian cancer.

Methods: An intraperitoneal human ovarian cancer xenograft model in nude mice (n = 44) was used in this study. Gene therapy was given intravenously when the presence of sizable tumors was confirmed in magnetic resonance imaging. The study groups were as follows: AdCMV as a control (group I), AdCMV with chemotherapy (group II), AdsVEGFR2 and AdsTie2 (group III), and AdsVEGFR2 and AdsTie2 with chemotherapy (group IV). Antitumor effectiveness was assessed by overall tumor growth, ascites, immunohistochemistry, microvessel density, and sequential magnetic resonance imaging analyses.

Results: AdsVEGFR2 and AdsTie2 gene therapy (group III) significantly reduced tumor weights as compared with group II (P = 0.007). Accumulation of ascites was significantly reduced when the mice were treated with AdsVEGFR2 and AdsTie2 gene therapy or with combined gene therapy and chemotherapy as compared with controls (P = 0.029 and P = 0.010, respectively). Vascular endothelial growth factor and Ang2 levels in ascites fluid were elevated after the gene therapy.

Conclusions: Combined inhibition of VEGF/VEGFR2 and Ang/Tie2 pathways provided efficient therapy for ovarian cancer in mice. In addition, antiangiogenic gene therapy has potential as a treatment for the accumulation of ascites.
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http://dx.doi.org/10.1097/IGC.0000000000000973DOI Listing
June 2017

Left ventricular remodeling leads to heart failure in mice with cardiac-specific overexpression of VEGF-B: echocardiography and magnetic resonance imaging study.

Physiol Rep 2017 Mar;5(6)

Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

Cardiac-specific overexpression of vascular endothelial growth factor (VEGF)-B is known to induce left ventricular hypertrophy due to altered lipid metabolism, in which ceramides accumulate to the heart and cause mitochondrial damage. The aim of this study was to evaluate and compare different imaging methods to find the most sensitive way to diagnose at early stage the progressive left ventricular remodeling leading to heart failure. Echocardiography and cardiovascular magnetic resonance imaging were compared for imaging the hearts of transgenic mice with cardiac-specific overexpression of VEGF-B and wild-type mice from 5 to 14 months of age at several time points. Disease progression was verified by molecular biology methods and histology. We showed that left ventricular remodeling is already ongoing at the age of 5 months in transgenic mice leading to heart failure by the age of 14 months. Measurements from echocardiography and cardiovascular magnetic resonance imaging revealed similar changes in cardiac structure and function in the transgenic mice. Changes in histology, gene expressions, and electrocardiography supported the progression of left ventricular hypertrophy. Longitudinal relaxation time in rotating frame (T ) in cardiovascular magnetic resonance imaging could be suitable for detecting severe fibrosis in the heart. We conclude that cardiac-specific overexpression of VEGF-B leads to left ventricular remodeling at early age and is a suitable model to study heart failure development with different imaging methods.
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http://dx.doi.org/10.14814/phy2.13096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371547PMC
March 2017

Tailored Dual PEGylation of Inorganic Porous Nanocarriers for Extremely Long Blood Circulation in Vivo.

ACS Appl Mater Interfaces 2016 Dec 23;8(48):32723-32731. Epub 2016 Nov 23.

Institute of Biochemistry, Vilnius University , Saulėtekio al. 7, LT-10257 Vilnius, Lithuania.

Drug carrier systems based on mesoporous inorganic nanoparticles generally face the problem of fast clearance from bloodstream thus failing in passive and active targeting to cancer tissue. To address this problem, a specific dual PEGylation (DPEG) method for mesoporous silicon (PSi) was developed and studied in vitro and in vivo. The DPEG coating changed significantly the behavior of the nanoparticles in vivo, increasing the circulation half-life from 1 to 241 min. Furthermore, accumulation of the coated particles was mainly taking place in the spleen whereas uncoated nanoparticles were rapidly deposited in the liver. The protein coronas of the particles differed considerably from each other. The uncoated particles had substantially more proteins adsorbed including liver and immune active proteins, whereas the coated particles had proteins capable of suppressing cellular uptake. These reasons along with agglomeration observed in blood circulation were concluded to cause the differences in the behavior in vivo. The biofate of the particles was monitored with magnetic resonance imaging by incorporating superparamagnetic iron oxide nanocrystals inside the pores of the particles making dynamic imaging of the particles feasible. The results of the present study pave the way for further development of the porous inorganic delivery system in the sense of active targeting as the carriers can be easily chemically modified allowing also magnetically targeted delivery and diagnostics.
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http://dx.doi.org/10.1021/acsami.6b12481DOI Listing
December 2016

Multi-parametric MRI characterization of enzymatically degraded articular cartilage.

J Orthop Res 2016 07 31;34(7):1111-20. Epub 2015 Dec 31.

Research Unit of Medical Imaging, Physics, and Technology, University of Oulu, Oulu, Finland.

Several laboratory and rotating frame quantitative MRI parameters were evaluated and compared for detection of changes in articular cartilage following selective enzymatic digestion. Bovine osteochondral specimens were subjected to 44 h incubation in control medium or in collagenase or chondroitinase ABC to induce superficial collagen or proteoglycan (glycosaminoglycan) alterations. The samples were scanned at 9.4 T for T1 , T1 Gd (dGEMRIC), T2 , adiabatic T1 ρ , adiabatic T2 ρ , continuous-wave T1 ρ , TRAFF2 , and T1 sat relaxation times and for magnetization transfer ratio (MTR). For reference, glycosaminoglycan content, collagen fibril orientation and biomechanical properties were determined. Changes primarily in the superficial cartilage were noted after enzymatic degradation. Most of the studied parameters were sensitive to the destruction of collagen network, whereas glycosaminoglycan depletion was detected only by native T1 and T1 Gd relaxation time constants throughout the tissue and by MTR superficially. T1 , adiabatic T1 ρ , adiabatic T2 ρ , continuous-wave T1 ρ , and T1 sat correlated significantly with the biomechanical properties while T1 Gd correlated with glycosaminoglycan staining. The findings indicated that most of the studied MRI parameters were sensitive to both glycosaminoglycan content and collagen network integrity, with changes due to enzymatic treatment detected primarily in the superficial tissue. Strong correlation of T1 , adiabatic T1ρ , adiabatic T2 ρ , continuous-wave T1 ρ , and T1 sat with the altered biomechanical properties, reflects that these parameters were sensitive to critical functional properties of cartilage. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1111-1120, 2016.
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http://dx.doi.org/10.1002/jor.23127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903086PMC
July 2016

Relaxation along fictitious field, diffusion-weighted imaging, and T2 mapping of prostate cancer: Prediction of cancer aggressiveness.

Magn Reson Med 2016 May 22;75(5):2130-40. Epub 2015 Jun 22.

Department of Radiology, University of Turku, Turku, Finland.

Purpose: To evaluate the performance of relaxation along a fictitious field (RAFF) relaxation time (TRAFF ), diffusion-weighted imaging (DWI)-derived parameters, and T2 relaxation time values for prostate cancer (PCa) detection and characterization.

Methods: Fifty patients underwent 3T MR examination using surface array coils before prostatectomy. DWI was performed using 14 and 12 b values in the ranges of 0-500 s/mm(2) and 0-2000 s/mm(2) , respectively. Repeated MR examination was performed in 16 patients. TRAFF , DWI-derived parameters (monoexponential, kurtosis, biexponential models), and T2 values were measured and averaged over regions of interest placed in PCa and normal tissue. Repeatability of TRAFF and DWI-derived parameters were assessed by coefficient of repeatability and intraclass correlation coefficient ICC(3,1). Areas under the receiver operating characteristic curve (AUCs) for PCa detection and Gleason score classification were estimated. The parameters were correlated with Gleason score groups using Spearman correlation coefficient (ρ).

Results: ICC(3,1) values for TRAFF were in the range of 0.82-0.92. TRAFF values had higher AUC values for Gleason score classification compared with DWI-derived parameters and T2 . The RAFF method demonstrated the highest ρ value (-0.65).

Conclusion: In a quantitative region of interest-based analysis, RAFF outperformed DWI ("low" and "high" b values) and T2 mapping in the characterization of PCa.
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http://dx.doi.org/10.1002/mrm.25808DOI Listing
May 2016

Rotating frame relaxation imaging of prostate cancer: Repeatability, cancer detection, and Gleason score prediction.

Magn Reson Med 2016 Jan 2;75(1):337-44. Epub 2015 Mar 2.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Purpose: To investigate relaxation along a fictitious field (RAFF) and continuous wave (cw) T1ρ imaging of prostate cancer (PCa) in the terms of repeatability, PCa detection, and characterization.

Methods: Thirty-six patients (PSA 11.6 ± 7.6 ng/mL, mean ± standard deviation) with histologically confirmed PCa underwent two repeated 3T MR examinations using surface array coils before prostatectomy. Relaxation along fictitious field, cw T1ρ, and T2 relaxation times (TRAFF, T1ρcw, T2) were measured and averaged over regions of interest placed in PCa, normal peripheral zone (PZ), and normal central gland (CG) positioned using whole-mount prostatectomy sections and anatomical T2-weighted images. Receiver operating characteristic curve analysis with area under the curve (AUC) was calculated to distinguish PCa from PZ/CG and PCa with Gleason score (GS) of 3+3 from GS of 3+4/≥ 3+4.

Results: TRAFF and T1ρcw relaxation times were repeatable with coefficients of repeatability as a percentage of median value in the range of 7.8-23.2%. AUC (mean, 95% confidence interval) in the differentiation of PCa with GS of 3+3 from PCa with CS of ≥ 3+4 were 0.88 (0.72-0.99), 0.69 (0.46-0.90), and 0.68 (0.45-0.88), for TRAFF, T1ρcw, and T2, respectively.

Conclusion: In quantitative region of interest based analysis, TRAFF outperformed T1ρcw and T2 in PCa detection and characterization.
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http://dx.doi.org/10.1002/mrm.25647DOI Listing
January 2016

Assessment of dysmyelination with RAFFn MRI: application to murine MPS I.

PLoS One 2015 13;10(2):e0116788. Epub 2015 Feb 13.

Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, United States of America.

Type I mucopolysaccharidosis (MPS I) is an autosomal recessive lysosomal storage disorder with neurological features. Humans and laboratory animals with MPS I exhibit various white matter abnormalities involving the corpus callosum and other regions. In this study, we first validated a novel MRI technique, entitled Relaxation Along a Fictitious Field in the rotating frame of rank n (RAFFn), as a measure of myelination and dysmyelination in mice. We then examined differences between MPS I mice and heterozygotes using RAFF5 and histology. RAFF5 (i.e., RAFFn with n = 5) relaxation time constants were highly correlated with histological myelin density (R2 = 0.68, P<0.001), and RAFF5 clearly distinguished between the hypomyelinated and dysmyelinated shiverer mouse and the wild-type mouse. Bloch-McConnell theoretical analysis revealed slower exchange correlation times and smaller exchange-induced relaxation rate constants for RAFF4 and RAFF5 compared to RAFF1-3, T1ρ, and T2ρ. These data suggest that RAFF5 may assess methylene protons in myelin lipids and proteins, though other mechanisms (e.g. detection of myelin-bound water) may also explain the sensitivity of RAFF5 to myelin. In MPS I mice, mean RAFF5 relaxation time constants were significantly larger for the striatum (P = 0.004) and internal capsule (P = 0.039), and marginally larger for the fornix (P = 0.15). Histological assessment revealed no differences between MPS I mice and heterozygotes in myelin density or corpus callosum thickness. Taken together, these findings support subtle dysmyelination in the brains of mice with MPS I. Dysmyelination may result from myelin lipid abnormalities caused by the absence of α-L-iduronidase. Our findings may help to explain locomotor and cognitive deficits seen in mice with MPS I.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116788PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334512PMC
January 2016

MRI relaxation in the presence of fictitious fields correlates with myelin content in normal rat brain.

Magn Reson Med 2016 Jan 3;75(1):161-8. Epub 2015 Feb 3.

A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.

Purpose: Brain myelin plays an important role in normal brain function. Demyelination is involved in many degenerative brain diseases, thus quantitative imaging of myelin has been under active investigation. In previous work, we demonstrated the capability of the method known as Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank n (RAFFn) to provide image contrast between white and gray matter in human and rat brains. Here, we provide evidence pointing to myelin being the major source of this contrast.

Methods: RAFFn relaxation time constant (TRAFFn) was mapped in rat brain ex vivo. TRAFFn was quantified in 12 different brain areas. TRAFFn values were compared with multiple other MRI metrics (T1, T2 , continuous wave T1ρ, adiabatic T1ρ and T2ρ, magnetization transfer ratio), and with histologic measurements of cell density, myelin and iron content.

Results: Highest contrast between white and grey matter was obtained with TRAFFn in the rotating frames of ranks n = 4 and 5. TRAFFn values correlated strongly with myelin content, whereas no associations between TRAFFn and iron content or cell density were found.

Conclusion: TRAFFn with n = 4 or 5 provides a high sensitivity for selective myelin mapping in the rat brain.
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http://dx.doi.org/10.1002/mrm.25590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523459PMC
January 2016

Exchange-induced relaxation in the presence of a fictitious field.

J Magn Reson 2014 Aug 13;245:12-6. Epub 2014 May 13.

Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN, USA. Electronic address:

In the present study we derive a solution for two site fast exchange-induced relaxation in the presence of a fictitious magnetic field as generated by amplitude and frequency modulated RF pulses. This solution provides a means to analyze data obtained from relaxation experiments with the method called RAFFn (Relaxation Along a Fictitious Field of rank n), in which a fictitious field is created in a coordinate frame undergoing multi-fold rotation about n axes (rank n). The RAFF2 technique is relevant to MRI relaxation methods that provide good contrast enhancement for tumor detection. The relaxation equations for n=2 are derived for the fast exchange regime using density matrix formalism. The method of derivation can be further extended to obtain solutions for n>2.
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http://dx.doi.org/10.1016/j.jmr.2014.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4308052PMC
August 2014

Assessing Myocardial Disease Using T MRI.

Curr Cardiovasc Imaging Rep 2014 Feb;7(2):9248

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Smilow Center for Translational Research, 3400 Civic Center Blvd, Bldg 421, 7th floor, Rm 103, Philadelphia, PA 19104, USA.

There is great interest to use magnetic resonance imaging (MRI) for non-invasive assessment of myocardial disease in ischemic and non-ischemic cardiomyopathies. Recently, there has been a renewed interest to use a magnetic resonance imaging (MRI) technique utilizing spin locking radiofrequency (RF) pulses, called T MRI. The spin locking RF pulse creates sensitivity to some mechanisms of nuclear relaxation such as H exchange between water and amide, amine and hydroxyl functional groups in molecules; consequently, there is the potential to non-invasively, and without exogenous contrast agents, obtain important molecular information from diseased myocardial tissue. The purpose of this article is to review and critically examine the recent published literature in the field related to T MRI of myocardial disease.
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http://dx.doi.org/10.1007/s12410-013-9248-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968806PMC
February 2014

Epigenetic upregulation of endogenous VEGF-A reduces myocardial infarct size in mice.

PLoS One 2014 26;9(2):e89979. Epub 2014 Feb 26.

Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland ; Research Unit and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland.

"Epigenetherapy" alters epigenetic status of the targeted chromatin and modifies expression of the endogenous therapeutic gene. In this study we used lentiviral in vivo delivery of small hairpin RNA (shRNA) into hearts in a murine infarction model. shRNA complementary to the promoter of vascular endothelial growth factor (VEGF-A) was able to upregulate endogenous VEGF-A expression. Histological and multiphoton microscope analysis confirmed the therapeutic effect in the transduced hearts. Magnetic resonance imaging (MRI) showed in vivo that the infarct size was significantly reduced in the treatment group 14 days after the epigenetherapy. Importantly, we show that promoter-targeted shRNA upregulates all isoforms of endogenous VEGF-A and that an intact hairpin structure is required for the shRNA activity. In conclusion, regulation of gene expression at the promoter level is a promising new treatment strategy for myocardial infarction and also potentially useful for the upregulation of other endogenous genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089979PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935957PMC
October 2014