Reliability of quantitative multiparameter maps is high for MT and PD but attenuated for R1 and R2* in healthy young adults

We investigate the reliability of individual differences of four quantities measured by magnetic resonance imaging based multiparameter mapping (MPM): magnetization transfer (MT), proton density (PD), longitudinal relaxation rate (R1), and effective transverse relaxation rate (R2*). A total of four MPM datasets, two on each of two consecutive days, were acquired in healthy young adults. On Day 1, no repositioning occurred; on Day 2, participants were repositioned between MPM datasets. Using intra-class correlation effect decomposition (ICED), we assessed the contributions of session-specific, day-specific, and residual sources of measurement error. For whole-brain gray and white matter, all four MPM parameters showed high reproducibility and high reliability, as indexed by the coefficient of variation (CoV) and the intra-class correlation (ICC). However, MT, PD, R1, and R2* differed markedly in the extent to which reliability varied across brain regions. MT and PD showed high reliability in almost all regions. In contrast, R1 and R2* showed low reliability in some regions outside the basal ganglia, such that the sum of the measurement error estimates in our structural equation model was higher than estimates of between-person differences. In sum, in this sample of healthy young adults, the four MPM parameters showed very little variability over four measurements over two days but differed in how well they could assess between-person differences. We conclude that R1 and R2* might carry only limited person-specific information in samples of healthy young adults, and, by implication, might be of restricted utility for studying associations to between-person differences in behavior.

Combining Navigator and Optical Prospective Motion Correction for High-Quality 500 μm Resolution Quantitative Multi-Parameter Mapping at 7T

PURPOSEHigh-resolution quantitative multi-parameter mapping shows promise for non-invasively characterizing human brain microstructure but is limited by physiological artifacts. We implemented corrections for rigid head movement and respiration-related B0-fluctuations and evaluated them in healthy volunteers and dementia patients.METHODSCamera-based optical prospective motion correction (PMC) and free-induction decay (FID) navigator correction were implemented in a gradient and RF-spoiled multi-echo 3D gradient echo sequence for mapping proton density (PD), longitudinal relaxation rate (R1) and effective transverse relaxation rate (R2*). We studied their effectiveness separately and in concert in young volunteers and then evaluated the navigator correction (NAVcor) with PMC in a group of elderly volunteers and dementia patients. We used spatial homogeneity within white matter (WM) and gray matter (GM) and scan-rescan measures as quality metrics.RESULTSNAVcor and PMC reduced artifacts and improved the homogeneity and reproducibility of parameter maps. In elderly participants, NAVcor improved scan-rescan reproducibility of parameter maps (coefficient of variation decreased by 14.7% and 11.9% within WM and GM respectively). Spurious inhomogeneities within WM were reduced more in the elderly than in the young cohort (by 9% vs 2%). PMC increased regional GM/WM contrast and was especially important in the elderly cohort, which moved twice as much as the young cohort. We did not find a significant interaction between the two corrections.CONCLUSIONNavigator correction and PMC significantly improved the quality of PD, R1 and R2* maps, particularly in less compliant elderly volunteers and dementia patients.

Magnetic Agarose Microspheres/Hyaluronic Acid Hydrogel as a Trackable Bulking Agent for Vesicoureteral Reflux Treatment

Vesicoureteral reflux (VUR) is one of the most common congenital anomalies in the kidney and the urinary tract. Endoscopic subureteral injection of a bulking agent has become popular in VUR treatment due to its high success rates, few complications, and a straightforward procedure. In this study, a novel magnetic bulking agent was prepared by embedding Fe3O4 magnetic nanoparticles in cross-linked agarose microspheres with diameters of 80–250 μm and dispersing the magnetic microspheres in a hyaluronic acid hydrogel. The bulking agent has good biocompatibility and biosecurity validated by the tests of cytotoxicity, in vitro genotoxicity, animal irritation, skin sensitization, acute systemic toxicity, and pathological analysis after the injection of the bulking agent extract solution into healthy mice as well as injection of the bulking agent into VUR rabbits. The VUR rabbits were created by incising the roof of the intravesical ureter to enlarge the ureteral orifice. The success rate of the bulking agent in treating VUR rabbits using a subureteral transurethral injection technique was 67% (4/6) or 80% (4/5, excluding the unfinished rabbit), and no migrated particles were found in the organs of the rabbits. The transverse relaxation rate of the bulking agent was 104 mM−1s−1. After injection, the bulking agent was long-term trackable through magnetic resonance imaging that can help clinicians to inspect the VUR treatment effect. For the first time, this study demonstrates that the bulking agent with a long-term stable tracer is promising for endoscopic VUR treatment.

1H R1ρ relaxation dispersion experiments in aromatic side chains

Aromatic side chains are attractive probes of protein dynamic, since they are often key residues in enzyme active sites and protein binding sites. Dynamic processes on microsecond to millisecond timescales can be studied by relaxation dispersion experiments that attenuate conformational exchange contributions to the transverse relaxation rate by varying the refocusing frequency of applied radio-frequency fields implemented as either CPMG pulse trains or continuous spin-lock periods. Here we present an aromatic 1H R1ρ relaxation dispersion experiment enabling studies of two to three times faster exchange processes than achievable by existing experiments for aromatic side chains. We show that site-specific isotope labeling schemes generating isolated 1H–13C spin pairs with vicinal 2H–12C moieties are necessary to avoid anomalous relaxation dispersion profiles caused by Hartmann–Hahn matching due to the 3JHH couplings and limited chemical shift differences among 1H spins in phenylalanine, tyrosine and the six-ring moiety of tryptophan. This labeling pattern is sufficient in that remote protons do not cause additional complications. We validated the approach by measuring ring-flip kinetics in the small protein GB1. The determined rate constants, kflip, agree well with previous results from 13C R1ρ relaxation dispersion experiments, and yield 1H chemical shift differences between the two sides of the ring in good agreement with values measured under slow-exchange conditions. The aromatic1H R1ρ relaxation dispersion experiment in combination with the site-selective 1H–13C/2H–12C labeling scheme enable measurement of exchange rates up to kex = 2kflip = 80,000 s–1, and serve as a useful complement to previously developed 13C-based methods.

Polypyrrole-Coated Magnetite Vortex Nanoring for Hyperthermia-Boosted Photothermal/Magnetothermal Tumor Ablation Under Photoacoustic/Magnetic Resonance Guidance

Photothermal/magnetothermal-based hyperthermia cancer therapy techniques have been widely investigated, and associated nanotechnology-assisted treatments have shown promising clinical potentials. However, each method has some limitations, which have impeded extensive applications. For example, the penetration ability of the photothermal is not satisfactory, while the heating efficiency of the magnetothermal is very poor. In this study, a novel magnetite vortex nanoring nanoparticle-coated with polypyrrole (denoted as nanoring Fe3O4@PPy-PEG) was first synthesized and well-characterized. By combining photothermal and magnetothermal effects, the performance of the dual-enhanced hyperthermia was significantly improved, and was thoroughly examined in this study. Benefiting from the magnetite vortex nanoring and polypyrrole, Fe3O4@PPy-PEG showed excellent hyperthermia effects (SAR = 1,648 Wg–1) when simultaneously exposed to the alternating magnetic field (300 kHz, 45 A) and near-infrared (808 nm, 1 W cm–2) laser. What is more, nanoring Fe3O4@PPy-PEG showed a much faster heating rate, which can further augment the antitumor effect by incurring vascular disorder. Besides, Fe3O4@PPy-PEG exhibited a high transverse relaxation rate [60.61 mM–1 S–1 (Fe)] at a very low B0 field (0.35 T) and good photoacoustic effect. We believe that the results obtained herein can significantly promote the development of multifunctional nanoparticle-mediated magnetic and photo induced efficient hyperthermia therapy.

Physical activity, brain tissue microstructure, and cognition in older adults

Objective To test whether postmortem MRI captures brain tissue characteristics that mediate the association between physical activity and cognition in older adults. Methods Participants (N = 318) were older adults from the Rush Memory and Aging Project who wore a device to quantify physical activity and also underwent detailed cognitive and motor testing. Following death, cerebral hemispheres underwent MRI to quantify the transverse relaxation rate R2, a metric related to tissue microstructure. For analyses, we reduced the dimensionality of the R2 maps from approximately 500,000 voxels to 30 components using spatial independent component analysis (ICA). Via path analysis, we examined whether these R2 components attenuated the association between physical activity and cognition, controlling for motor abilities and indices of common brain pathologies. Results Two of the 30 R2 components were associated with both total daily physical activity and global cognition assessed proximate to death. We visualized these components by highlighting the clusters of voxels whose R2 values contributed most strongly to each. One of these spatial signatures spanned periventricular white matter and hippocampus, while the other encompassed white matter of the occipital lobe. These two R2 components partially mediated the association between physical activity and cognition, accounting for 12.7% of the relationship (p = .01). This mediation remained evident after controlling for motor abilities and neurodegenerative and vascular brain pathologies. Conclusion The association between physically activity and cognition in older adults is partially accounted for by MRI-based signatures of brain tissue microstructure. Further studies are needed to elucidate the molecular mechanisms underlying this pathway.

Microstructural plasticity in nociceptive pathways after spinal cord injury

ObjectiveTo track the interplay between (micro-) structural changes along the trajectories of nociceptive pathways and its relation to the presence and intensity of neuropathic pain (NP) after spinal cord injury (SCI).MethodsA quantitative neuroimaging approach employing a multiparametric mapping protocol was used, providing indirect measures of myelination (via contrasts such as magnetisation transfer (MT) saturation, longitudinal relaxation (R1)) and iron content (via effective transverse relaxation rate (R2*)) was used to track microstructural changes within nociceptive pathways. In order to characterise concurrent changes along the entire neuroaxis, a combined brain and spinal cord template embedded in the statistical parametric mapping framework was used. Multivariate source-based morphometry was performed to identify naturally grouped patterns of structural variation between individuals with and without NP after SCI.ResultsIn individuals with NP, lower R1 and MT values are evident in the primary motor cortex and dorsolateral prefrontal cortex, while increases in R2* are evident in the cervical cord, periaqueductal grey (PAG), thalamus and anterior cingulate cortex when compared with pain-free individuals. Lower R1 values in the PAG and greater R2* values in the cervical cord are associated with NP intensity.ConclusionsThe degree of microstructural changes across ascending and descending nociceptive pathways is critically implicated in the maintenance of NP. Tracking maladaptive plasticity unravels the intimate relationships between neurodegenerative and compensatory processes in NP states and may facilitate patient monitoring during therapeutic trials related to pain and neuroregeneration.

Off-resonance saturation as an MRI method to quantify ferritin-bound iron in the post-mortem brain

PurposeTo employ an Off-Resonance Saturation (ORS) method to measure the ferritin-bound iron pool, which is an endogenous contrast agent which can give information on cellular iron status.MethodsAn ORS acquisition protocol was implemented on a 7T preclinical scanner and the contrast maps were fitted to an established analytical model. The method was validated by correlation and Bland-Altman analysis on a ferritin-containing phantom. Ferritin-iron maps were obtained from post-mortem tissue of patients with neurological diseases characterized by brain iron accumulation, i. e. Alzheimer’s disease, Huntington’s disease and aceruloplasminemia, and validated with histology. Transverse relaxation rate and magnetic susceptibility values were also obtained for comparison.ResultsIn post-mortem tissue, the ferritin-iron contrast strongly co-localizes with histological iron staining, in all the cases. Quantitative iron values obtained via the ORS method are in agreement with literature.ConclusionsOff-resonance saturation is an effective way to detect iron in grey matter structures, while mitigating for the presence of myelin. If a reference region with little iron is available in the tissue, the method can produce quantitative iron maps. This method is applicable in the study of brain diseases characterized by brain iron accumulation and complement existing iron-sensitive parametric methods.

HFE H63D Limits Nigral Vulnerability to Paraquat in Agricultural Workers

Paraquat is an herbicide whose use is associated with Parkinson’s disease (PD), a neurodegenerative disorder marked by neuron loss in the substantia nigra pars compacta (SNc). We recently observed that the murine homolog to the human H63D variant of the homeostatic iron regulator (HFE) may decrease paraquat-associated nigral neurotoxicity in mice. The present study examined the potential influence of H63D on paraquat-associated neurotoxicity in humans. Twenty-eight paraquat-exposed workers were identified from exposure histories and compared with 41 unexposed controls. HFE genotypes, and serum iron and transferrin were measured from blood samples. MRI was used to assess the SNc transverse relaxation rate (R2*), a marker for iron, and diffusion tensor imaging scalars of fractional anisotropy (FA) and mean diffusivity, markers of microstructural integrity. Twenty-seven subjects (9 exposed and 18 controls) were H63D heterozygous. After adjusting for age and use of other PD-associated pesticides and solvents, serum iron and transferrin were higher in exposed H63D carriers than in unexposed carriers and HFE wildtypes. SNc R2* was lower in exposed H63D carriers than in unexposed carriers, whereas SNc FA was lower in exposed HFE wildtypes than in either unexposed HFE wildtypes or exposed H63D carriers. Serum iron and SNc FA measures correlated positively among exposed, but not unexposed, subjects. These data suggest that H63D heterozygosity is associated with lower neurotoxicity presumptively linked to paraquat. Future studies with larger cohorts are warranted to replicate these findings and examine potential underlying mechanisms, especially given the high prevalence of the H63D allele in humans.

Quantitative Multi-Parameter Mapping Optimized for the Clinical Routine

Using quantitative multi-parameter mapping (MPM), studies can investigate clinically relevant microstructural changes with high reliability over time and across subjects and sites. However, long acquisition times (20 min for the standard 1-mm isotropic protocol) limit its translational potential. This study aimed to evaluate the sensitivity gain of a fast 1.6-mm isotropic MPM protocol including post-processing optimized for longitudinal clinical studies. 6 healthy volunteers (35±7 years old; 3 female) were scanned at 3T to acquire the following whole-brain MPM maps with 1.6 mm isotropic resolution: proton density (PD), magnetization transfer saturation (MT), longitudinal relaxation rate (R1), and transverse relaxation rate (R2*). MPM maps were generated using two RF transmit field (B1+) correction methods: (1) using an acquired B1+ map and (2) using a data-driven approach. Maps were generated with and without Gibb's ringing correction. The intra-/inter-subject coefficient of variation (CoV) of all maps in the gray and white matter, as well as in all anatomical regions of a fine-grained brain atlas, were compared between the different post-processing methods using Student's t-test. The intra-subject stability of the 1.6-mm MPM protocol is 2–3 times higher than for the standard 1-mm sequence and can be achieved in less than half the scan duration. Intra-subject variability for all four maps in white matter ranged from 1.2–5.3% and in gray matter from 1.8 to 9.2%. Bias-field correction using an acquired B1+ map significantly improved intra-subject variability of PD and R1 in the gray (42%) and white matter (54%) and correcting the raw images for the effect of Gibb's ringing further improved intra-subject variability in all maps in the gray (11%) and white matter (10%). Combining Gibb's ringing correction and bias field correction using acquired B1+ maps provides excellent stability of the 7-min MPM sequence with 1.6 mm resolution suitable for the clinical routine.