Jimmy Lätt

99mTc-Labeled Superparamagnetic Iron Oxide Nanoparticles for Multimodality SPECT/MRI of Sentinel Lymph Nodes

The purpose of this study was to develop multimodality SPECT/MRI contrast agents for sentinel lymph node (SLN) mapping in vivo. Methods: Nanoparticles with a solid iron oxide core and a polyethylene glycol coating were labeled with 99mTc. The labeling efficiency was determined with instant thin-layer chromatography and magnetic separation. The stability of the radiolabeled superparamagnetic iron oxide nanoparticles (SPIONs) was verified in both sterile water and human serum at room temperature 6 and 24 h after labeling. Five Wistar rats were injected subcutaneously in the right hind paw with 99mTc-SPIONs (25–50 MBq, ∼0.2 mg of Fe) and sacrificed 4 h after injection. Two animals were imaged with SPECT/MRI. All 5 rats were dissected; the lymph nodes, liver, kidneys, spleen, and hind paw containing the injection site were removed and weighed; and activity in the samples was measured. The microdistribution within the lymph nodes was studied with digital autoradiography. Results: The efficiency of labeling of the SPIONs was 99% 6 h after labeling in both water and human serum. The labeling yield was 98% in water and 97% in human serum 24 h after labeling. The SLN could be identified in vivo with SPECT/MRI. The accumulation of 99mTc-SPIONs (as the percentage injected dose/g [%ID/g]) in the SLN was 100 %ID/g, whereas in the liver and spleen it was less than 2 %ID/g. Digital autoradiography images revealed a nonhomogeneous distribution of 99mTc-SPIONs within the lymph nodes; nanoparticles were found in the cortical, subcapsular, and medullary sinuses. Conclusion: This study revealed the feasibility of labeling SPIONs with 99mTc. The accumulation of 99mTc-SPIONs in lymph nodes after subcutaneous injection in animals, verified by SPECT/MRI, is encouraging for applications in breast cancer and malignant melanoma.

Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain

Significance Parkinson’s disease is the most common movement disorder. Here we describe the histopathological analysis of a unique patient with Parkinson’s disease who underwent unilateral cell transplantation in the putamen with human embryonic mesencephalic tissue at 24 y before death. The patient enjoyed major clinical benefits for at least a decade after transplantation. After a quarter of a century, complete graft-derived dopaminergic reinnervation was still evident in the transplanted putamen. α-Synuclein–positive inclusions, some with the appearance of typical Lewy bodies, were present in 11–12% of the grafted dopaminergic neurons, reflecting spread of pathology from the host brain to the transplant. The clinical improvements were gradually lost from 14 y posttransplantation, indicating that even extensive graft-derived dopaminergic reinnervation loses its efficacy in a severely degenerating brain. Clinical trials using cells derived from embryonic ventral mesencephalon have shown that transplanted dopaminergic neurons can survive and function in the long term, as demonstrated by in vivo brain imaging using 18F-fluorodopa and 11C-raclopride positron emission tomography. Here we report the postmortem analysis of a patient with Parkinson’s disease who 24 y earlier underwent unilateral transplantation of embryonic dopaminergic neurons in the putamen and subsequently exhibited major motor improvement and recovery of striatal dopaminergic function. Histopathological analysis showed that a dense, near-normal graft-derived dopaminergic reinnervation of the putamen can be maintained for a quarter of a century despite severe host brain pathology and with no evidence of immune response. In addition, ubiquitin- and α-synuclein–positive inclusions were seen, some with the appearance of typical Lewy bodies, in 11–12% of the grafted dopaminergic neurons, reflecting the spread of pathology from the host brain to the transplants. Because the clinical benefits induced by transplantation in this patient were gradually lost after 14 y posttransplantation, our findings provide the first reported evidence, to our knowledge, that even a viable dopaminergic graft giving rise to extensive striatal reinnervation may lose its efficacy if widespread degenerative changes develop in the host brain.

Noninvasive mapping of water diffusional exchange in the human brain using filter-exchange imaging.

We present the first in vivo application of the filter‐exchange imaging protocol for diffusion MRI. The protocol allows noninvasive mapping of the rate of water exchange between microenvironments with different self‐diffusivities, such as the intracellular and extracellular spaces in tissue. Since diffusional water exchange across the cell membrane is a fundamental process in human physiology and pathophysiology, clinically feasible and noninvasive imaging of the water exchange rate would offer new means to diagnose disease and monitor treatment response in conditions such as cancer and edema. The in vivo use of filter‐exchange imaging was demonstrated by studying the brain of five healthy volunteers and one intracranial tumor (meningioma). Apparent exchange rates in white matter range from 0.8 ± 0.08 s−1 in the internal capsule, to 1.6 ± 0.11 s−1 for frontal white matter, indicating that low values are associated with high myelination. Solid tumor displayed values of up to 2.9 ± 0.8 s−1. In white matter, the apparent exchange rate values suggest intra‐axonal exchange times in the order of seconds, confirming the slow exchange assumption in the analysis of diffusion MRI data. We propose that filter‐exchange imaging could be used clinically to map the water exchange rate in pathologies. Filter‐exchange imaging may also be valuable for evaluating novel therapies targeting the function of aquaporins. Magn Reson Med, 2013.

The role of tissue microstructure and water exchange in biophysical modelling of diffusion in white matter

Biophysical models that describe the outcome of white matter diffusion MRI experiments have various degrees of complexity. While the simplest models assume equal-sized and parallel axons, more elaborate ones may include distributions of axon diameters and axonal orientation dispersions. These microstructural features can be inferred from diffusion-weighted signal attenuation curves by solving an inverse problem, validated in several Monte Carlo simulation studies. Model development has been paralleled by microscopy studies of the microstructure of excised and fixed nerves, confirming that axon diameter estimates from diffusion measurements agree with those from microscopy. However, results obtained in vivo are less conclusive. For example, the amount of slowly diffusing water is lower than expected, and the diffusion-encoded signal is apparently insensitive to diffusion time variations, contrary to what may be expected. Recent understandings of the resolution limit in diffusion MRI, the rate of water exchange, and the presence of microscopic axonal undulation and axonal orientation dispersions may, however, explain such apparent contradictions. Knowledge of the effects of biophysical mechanisms on water diffusion in tissue can be used to predict the outcome of diffusion tensor imaging (DTI) and of diffusion kurtosis imaging (DKI) studies. Alterations of DTI or DKI parameters found in studies of pathologies such as ischemic stroke can thus be compared with those predicted by modelling. Observations in agreement with the predictions strengthen the credibility of biophysical models; those in disagreement could provide clues of how to improve them. DKI is particularly suited for this purpose; it is performed using higher b-values than DTI, and thus carries more information about the tissue microstructure. The purpose of this review is to provide an update on the current understanding of how various properties of the tissue microstructure and the rate of water exchange between microenvironments are reflected in diffusion MRI measurements. We focus on the use of biophysical models for extracting tissue-specific parameters from data obtained with single PGSE sequences on clinical MRI scanners, but results obtained with animal MRI scanners are also considered. While modelling of white matter is the central theme, experiments on model systems that highlight important aspects of the biophysical models are also reviewed.

The importance of axonal undulation in diffusion MR measurements: a Monte Carlo simulation study

Many axons follow wave‐like undulating courses. This is a general feature of extracranial nerve segments, but is also found in some intracranial nervous tissue. The importance of axonal undulation has previously been considered, for example, in the context of biomechanics, where it has been shown that posture affects undulation properties. However, the importance of axonal undulation in the context of diffusion MR measurements has not been investigated. Using an analytical model and Monte Carlo simulations of water diffusion, this study compared undulating and straight axons in terms of diffusion propagators, diffusion‐weighted signal intensities and parameters derived from diffusion tensor imaging, such as the mean diffusivity (MD), the eigenvalues and the fractional anisotropy (FA). All parameters were strongly affected by the presence of undulation. The diffusivity perpendicular to the undulating axons increased with the undulation amplitude, thus resembling that of straight axons with larger diameters. Consequently, models assuming straight axons for the estimation of the axon diameter from diffusion MR measurements might overestimate the diameter if undulation is present. FA decreased from approximately 0.7 to 0.5 when axonal undulation was introduced into the simulation model structure. Our results indicate that axonal undulation may play a role in diffusion measurements when investigating, for example, the optic and sciatic nerves and the spinal cord. The simulations also demonstrate that the stretching or compression of neuronal tissue comprising undulating axons alters the observed water diffusivity, suggesting that posture may be of importance for the outcome of diffusion MRI measurements. Copyright

MRI with diffusion tensor imaging post-mortem at 3.0 T in a patient with frontotemporal dementia.

The formalin-fixed brain of a patient with clinically diagnosed frontotemporal dementia (FTD) was examined post-mortem using magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) at 3.0 T. Frontotemporal atrophy as well as bilateral frontal white matter abnormalities were seen. The white matter changes were slightly more extensive on DTI than on conventional MRI. Correlation with histopathology of the corresponding regions revealed typical frontal lobe degeneration of non-Alzheimer type, with mild frontotemporal degeneration in the outer cortical layers and a moderate frontal white matter gliosis with demyelination. Post-mortem MRI/DTI with histopathologic correlation will enhance our understanding of the basis of white matter changes observed in dementia patients and may improve the in vivo MRI/DTI diagnostic assessment in FTD.

On the effects of a varied diffusion time in vivo: is the diffusion in white matter restricted?

The aim of this work was to study the diffusion-related signal attenuation curves (signal-vs.-b curves) measured perpendicular and parallel to the neuronal fibers of the corticospinal tract in vivo and to determine whether effects of restricted diffusion could be observed when varying the diffusion time (T(D)). A biexponential model and a two-compartment model including exchange according to the Kärger formalism were employed to analyze the signal-vs.-b curves. To validate the two-compartment model, restricted diffusion with exchange was simulated for uniformly sized cylinders, using different diameters and exchange times. The model was shown to retrieve the simulated parameters well, also when the short gradient pulse approximation was not met. The in vivo measurements performed perpendicular to the tracts, using b values up to 28000 s/mm(2) and T(D) values between 64 and 256 ms, did not show the effects of restricted diffusion as expected from previous ex vivo studies. The applied two-compartment model yielded an average axonal diameter of about 4 mum and an intracellular exchange time of about 300 ms, but did not fit statistically well to the data. In conclusion, this study indicates that if the diffusion is modeled as two compartments, of which one is restricted, exchange must be included in the model.

Magnetic resonance imaging artifacts caused by aneurysm clips and shunt valves: Dependence on field strength (1.5 and 3 T) and imaging parameters

To evaluate artifact sizes at 3 T compared to at 1.5 T, and to evaluate the influence of scanning parameters with respect to artifact size on a 3‐T magnetic resonance imaging (MRI) system.

Tumor extension in high-grade gliomas assessed with diffusion magnetic resonance imaging: values and lesion-to-brain ratios of apparent diffusion coefficient and fractional anisotropy.

Purpose: To determine whether the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) can distinguish tumor-infiltrated edema in gliomas from pure edema in meningiomas and metastases. Material and Methods: Thirty patients were studied: 18 WHO grade III or IV gliomas, 7 meningiomas, and 5 metastatic lesions. ADC and FA were determined from ROIs placed in peritumoral areas with T2-signal changes, adjacent normal appearing white matter (NAWM), and corresponding areas in the contralateral healthy brain. Values and lesion-to-brain ratios from gliomas were compared to those from meningiomas and metastases. Results: Values and lesion-to-brain ratios of ADC and FA in peritumoral areas with T2-signal changes did not differ between gliomas, meningiomas, and metastases (P = 0.40, P = 0.40, P = 0.61, P = 0.34). Values of ADC and FA and the lesion-to-brain ratio of FA in the adjacent NAWM did not differ between tumor types (P = 0.74, P = 0.25, and P = 0.31). The lesion-to-brain ratio of ADC in the adjacent NAWM was higher in gliomas than in meningiomas and metastases (P = 0.004), but overlapped between tumor types. Conclusion: Values and lesion-to-brain ratios of ADC and FA in areas with T2-signal changes surrounding intracranial tumors and adjacent NAWM were not helpful for distinguishing pure edema from tumor-infiltrated edema when data from gliomas, meningiomas, and metastases were compared.

Denoising of complex MRI data by wavelet-domain filtering: Application to high-b-value diffusion-weighted imaging.

The Rician distribution of noise in magnitude magnetic resonance (MR) images is particularly problematic in low signal‐to‐noise ratio (SNR) regions. The Rician noise distribution causes a nonzero minimum signal in the image, which is often referred to as the rectified noise floor. True low signal is likely to be concealed in the noise, and quantification is severely hampered in low‐SNR regions. To address this problem we performed noise reduction (or denoising) by Wiener‐like filtering in the wavelet domain. The filtering was applied to complex MRI data before construction of the magnitude image. The noise‐reduction algorithm was applied to simulated and experimental diffusion‐weighted (DW) images. Denoising considerably reduced the signal standard deviation (SD, by up to 87% in simulated images) and decreased the background noise floor (by approximately a factor of 6 in simulated and experimental images). Magn Reson Med, 2006.