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Iron accumulation in the brain is a phenomenon common to many neurodegenerative diseases, perhaps most notably Alzheimer’s disease (AD).We present here magnetic analyses of post-mortem brain tissue of patients who had severe Alzheimer’s disease, and compare the results with those from healthy controls. Isothermal remanent magnetization experiments were performed to assess the extent to which different magnetic carriers are affected by AD pathology and formalin fixation.While Alzheimer’s brain material did not show higher levels of magnetite/maghemite nanoparticles than corresponding controls, the ferrihydrite mineral, known to be found within the core of ferritin proteins and hemosiderin aggregates, almost doubled in concentration in patients with Alzheimer’s pathology, strengthening the conclusions of our previous studies. As part of this study, we also investigated the effects of sample preparation, by performing experiments on frozen tissue as well as tissue which had been fixed in formalin for a period of five months. Our results showed that the two different preparations did not critically affect the concentration of magnetic carriers in brain tissue, as observable by SQUID magnetometry.

Purpose: To employ an off-resonance saturation method to measure the mineral-iron pool in the postmortem brain, which is an endogenous contrast agent that can give information on cellular iron status. Methods: An off-resonance saturation acquisition protocol was implemented on a 7 Tesla 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. Mineral-iron maps were obtained from postmortem tissue of patients with neurological diseases characterized by brain iron accumulation, that is, Alzheimer disease, Huntington disease, and aceruloplasminemia, and validated with histology. Transverse relaxation rate and magnetic susceptibility values were used for comparison. Results: In postmortem tissue, the mineral-iron contrast colocalizes with histological iron staining in all the cases. Iron concentrations obtained via the off-resonance saturation method are in agreement with literature. Conclusions: Off-resonance saturation is an effective way to detect iron in gray matter structures and partially mitigate 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 diseases characterized by brain iron accumulation and can complement existing iron-sensitive parametric methods.

Highlights • Ferrihydrite-iron is the most abundant iron form in the aceruloplasminemia brain. • Iron concentrations over 1 mg/g are found in deep gray matter structures. • The deep gray matter contains over three times more iron than the temporal cortex. • Iron-sensitive MRI contrast is primarily driven by the amount of ferrihydrite-iron. • R2* is more illustrative of the pattern of iron accumulation than QSM at 7 T., Aims Aceruloplasminemia is an ultra-rare neurodegenerative disorder associated with massive brain iron deposits, of which the molecular composition is unknown. We aimed to quantitatively determine the molecular iron forms in the aceruloplasminemia brain, and to illustrate their influence on iron-sensitive MRI metrics. Methods The inhomogeneous transverse relaxation rate (R2*) and magnetic susceptibility obtained from 7 T MRI were combined with Electron Paramagnetic Resonance (EPR) and Superconducting Quantum Interference Device (SQUID) magnetometry. The basal ganglia, thalamus, red nucleus, dentate nucleus, superior- and middle temporal gyrus and white matter of a post-mortem aceruloplasminemia brain were studied. MRI, EPR and SQUID results that had been previously obtained from the temporal cortex of healthy controls were included for comparison. Results The brain iron pool in aceruloplasminemia detected in this study consisted of EPR-detectable Fe3+ ions, magnetic Fe3+ embedded in the core of ferritin and hemosiderin (ferrihydrite-iron), and magnetic Fe3+ embedded in oxidized magnetite/maghemite minerals (maghemite-iron). Ferrihydrite-iron represented above 90% of all iron and was the main driver of iron-sensitive MRI contrast. Although deep gray matter structures were three times richer in ferrihydrite-iron than the temporal cortex, ferrihydrite-iron was already six times more abundant in the temporal cortex of the patient with aceruloplasminemia compared to the healthy situation (162 µg/g vs. 27 µg/g), on average. The concentrations of Fe3+ ions and maghemite-iron in the temporal cortex in aceruloplasminemia were within the range of those in the control subjects. Conclusions Iron-related neurodegeneration in aceruloplasminemia is primarily associated with an increase in ferrihydrite-iron, with ferrihydrite-iron being the major determinant of iron-sensitive MRI contrast.

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.

IntroductionAceruloplasminemia is an ultra-rare neurodegenerative disorder associated with massive brain iron accumulation. It is unknown which molecular forms of iron accumulate in the brain of patients with aceruloplasminemia. As the disease is associated with at least a fivefold increase in brain iron concentration compared to the healthy brain, it offers a unique model to study the role of iron in neurodegeneration and the molecular basis of iron-sensitive MRI contrast.MethodsThe iron-sensitive MRI metrics inhomogeneous transverse relaxation rate (R2*) and magnetic susceptibility obtained at 7T were combined with Electron Paramagnetic Resonance (EPR) and Superconducting Quantum Interference Device (SQUID) magnetometry to specify and quantify the different iron forms per gram wet-weight in a post-mortem aceruloplasminemia brain, with focus on the basal ganglia, thalamus, red nucleus, dentate nucleus, superior-and middle temporal gyrus and white matter. MRI, EPR and SQUID results that had been previously obtained from the temporal cortex of healthy controls were included for comparison.ResultsThe brain iron pool in aceruloplasminemia consisted of EPR-detectable Fe3+ ions, magnetic Fe3+ embedded in the core of ferritin and hemosiderin (ferrihydrite-iron), and magnetic Fe3+ embedded in oxidized magnetite/maghemite minerals (maghemite-iron). Of all the studied iron pools, above 90% was made of ferrihydrite-iron, of which concentrations up to 1065 µg/g were detected in the red nucleus. Although deep gray matter structures in the aceruloplasminemia brain were three times richer in ferrihydrite-iron than the temporal cortex, ferrihydrite-iron in the temporal cortex of the patient with aceruloplasminemia was already six times more abundant compared to the healthy situation (162 µg/g vs. 27 µg/g). The concentration of Fe3+ ions and maghemite-iron were 1.7 times higher in the temporal cortex in aceruloplasminemia than in the control subjects. Of the two quantitative MRI metrics, R2* was the most illustrative of the pattern of iron accumulation and returned relaxation rates up to 0.49 ms-1, which were primarily driven by the abundance of ferrihydrite-iron. Maghemite-iron did not follow the spatial distribution of ferrihydrite-iron and did not significantly contribute to MRI contrast in most of the studied regions.ConclusionsEven in extremely iron-loaded cases, iron-related neurodegeneration remains primarily associated with an increase in ferrihydrite-iron, with ferrihydrite-iron being the major determinant of iron-sensitive MRI contrast.

We present a quantitative study of different molecular iron forms found in the temporal cortex of Alzheimer (AD) patients. Applying the methodology we developed in our previous work, we quantify the concentrations of non-heme Fe(III) by Electron Paramagnetic Resonance (EPR), magnetite/maghemite and ferrihydrite by SQUID magnetometry, together with the MRI transverse relaxation rate $$({{\rm{R}}}_{2}^{\ast })$$ ( R 2 ⁎ ) , to obtain a systematic view of molecular iron in the temporal cortex. Significantly higher values of $${{\rm{R}}}_{2}^{\ast }$$ R 2 ⁎ , a larger concentration of ferrihydrite, and a larger magnetic moment of magnetite/maghemite particles are found in the brain of AD patients. Moreover, we found correlations between the concentration of the iron detected by EPR, the concentration of the ferrihydrite mineral and the average iron loading of ferritin. We discuss these findings in the framework of iron dis-homeostasis, which has been proposed to occur in the brain of AD patients.

Although iron is crucial for neuronal functioning, many aspects of cerebral iron biology await clarification. The ability to quantify specific iron forms in the living brain would open new avenues for diagnosis, therapeutic monitoring, and understanding pathogenesis of diseases. A modality that allows assessment of brain tissue composition in vivo, in particular of iron deposits or myelin content on a submillimeter spatial scale, is magnetic resonance imaging (MRI). Multimodal strategies combining MRI with complementary analytical techniques ex vivo have emerged, which may lead to improved specificity. Interdisciplinary collaborations will be key to advance beyond simple correlative analyses in the biological interpretation of MRI data and to gain deeper insights into key factors leading to iron accumulation and/or redistribution associated with neurodegeneration.

Muon Spin Rotation is employed to investigate the spin dynamics of ferritin proteins isolated from the brain of an Alzheimer's disease (AD) patient and of a healthy control, using a sample of horse-spleen ferritin as a reference. A model based on the N\'eel theory of superparamagnetism is developed in order to interpret the spin relaxation rate of the muons stopped by the core of the protein. Using this model, our preliminary observations show that ferritins from the healthy control are filled with a mineral compatible with ferrihydrite, while ferritins from the AD patient contain a crystalline phase with a larger magnetocrystalline anisotropy, possibly compatible with magnetite or maghemite., Comment: 16 pages, 9 figures

Nuclear spin-lattice relaxation times are measured on copper using magnetic resonance force microscopy performed at temperatures down to 42 mK. The low temperature is verified by comparison with the Korringa relation. Measuring spin-lattice relaxation times locally at very low temperatures opens up the possibility to measure the magnetic properties of inhomogeneous electron systems realized in oxide interfaces, topological insulators and other strongly correlated electron systems such as high-Tc superconductors., Comment: We revised the manuscript by including the supplemental material. The manuscript is changed from a Letter to a Research Article after change of journal

We present nuclear magnetic resonance evidence that very slow $(\ensuremath{\le}1$ MHz) spin fluctuations persist into the overdoped regime of $\mathrm{Ba}({\mathrm{Fe}}_{1\ensuremath{-}x}{\mathrm{Rh}}_{x}){}_{2}{\mathrm{As}}_{2}$ superconductors. Measurements of the $^{75}\mathrm{As}$ spin echo decay rate, obtained both with Hahn Echo and Carr Purcell Meiboom Gill pulse sequences, show that the slowing down of spin fluctuations can be described by short-range diffusive dynamics, likely involving domain walls motions separating $(\ensuremath{\pi}/a,0)$ from $(0,\ensuremath{\pi}/a)$ correlated regions. This slowing down of the fluctuations is weakly sensitive to the external magnetic field and, although fading away with doping, it extends deeply into the overdoped regime.

We propose a novel combination of methods to study the physical properties of ferric ions and iron-oxide nanoparticles in post-mortem human brain, based on the combination of Electron Paramagnetic Resonance (EPR) and SQUID magnetometry. By means of EPR, we derive the concentration of the low molecular weight iron pool, as well as the product of its electron spin relaxation times. Additionally, by SQUID magnetometry we identify iron mineralization products ascribable to a magnetite/maghemite phase and a ferrihydrite (ferritin) phase. We further derive the concentration of magnetite/maghemite and of ferritin nanoparticles. To test out the new combined methodology, we studied brain tissue of an Alzheimer’s patient and a healthy control. Finally, we estimate that the size of the magnetite/maghemite nanoparticles, whose magnetic moments are blocked at room temperature, exceeds 40–50 nm, which is not compatible with the ferritin protein, the core of which is typically 6–8 nm. We believe that this methodology could be beneficial in the study of neurodegenerative diseases such as Alzheimer’s Disease which are characterized by abnormal iron accumulation in the brain.

$^{19}\mathrm{F}$ NMR measurements in optimally electron-doped ${\mathrm{La}}_{1\text{\ensuremath{-}}y}{\mathrm{Y}}_{y}{\mathrm{Fe}}_{1\text{\ensuremath{-}}x}{\mathrm{Mn}}_{x}{\mathrm{AsO}}_{0.89}{\mathrm{F}}_{0.11}$ superconductors are presented. The effect of Mn doping on the superconducting phase is studied for two series of compounds $(y=0$ and $y=0.2)$ where the chemical pressure is varied by substituting La with Y. In the $y=0.2$ series superconductivity is suppressed for Mn contents an order of magnitude larger than for $y=0$. For both series a peak in the $^{19}\mathrm{F}$ NMR nuclear spin-lattice relaxation rate $1/{T}_{1}$ emerges upon Mn doping and becomes significantly enhanced on approaching the quantum phase transition between the superconducting and magnetic phases. $^{19}\mathrm{F}$ NMR linewidth measurements show that for similar Mn contents magnetic correlations are more pronounced in the $y=0$ series, at variance with what one would expect for $\stackrel{P\vec}{Q}=(\ensuremath{\pi}/a,0)$ spin correlations. These observations suggest that Mn doping tends to reduce fluctuations at $\stackrel{P\vec}{Q}=(\ensuremath{\pi}/a,0)$ and to enhance other low-frequency modes. The effect of this transfer of spectral weight on the superconducting pairing is discussed along with the charge localization induced by Mn.

We investigate the degradation of the magnetic moment of a 300 nm thick FePt film induced by Focused Ion Beam (FIB) milling. A $1~\mu \mathrm{m} \times 8~\mu \mathrm{m}$ rod is milled out of a film by a FIB process and is attached to a cantilever by electron beam induced deposition. Its magnetic moment is determined by frequency-shift cantilever magnetometry. We find that the magnetic moment of the rod is $\mu = 1.1 \pm 0.1 \times 10 ^{-12} \mathrm{Am}^2$, which implies that 70% of the magnetic moment is preserved during the FIB milling process. This result has important implications for atom trapping and magnetic resonance force microscopy (MRFM), that are addressed in this paper., Comment: 4 pages, 4 figures

Using dynamic cantilever magnetometry, we study the vortex lattice and its corresponding melting transition in a micrometer-size crystallite of superconducting NbSe2. Measurements of the cantilever resonance frequency as a function of magnetic field and temperature respond to the magnetization of the vortex-lattice. The cantilever dissipation depends on thermally activated vortex creep motion, whose pinning energy barrier is found to be in good agreement with transport measurements on bulk samples. This approach reveals the phase diagram of the crystallite, and is applicable to other micro- or nanometer-scale superconducting samples., 5 pages, 4 figures

This work presents 75As NMR spin echo decay rate (1/T2) measurements in Ba(Fe1-xRhx)2As2 superconductors, for 0.041 < x < 0.094. It is shown that 1/T2 increases upon cooling, in the normal phase, suggesting the onset of an unconventional very low-frequency activated dynamic. The correlation times of the fluctuations and their energy barriers are derived. The motion is favored at large Rh content, while it is hindered by the application of a magnetic field perpendicular to the FeAs layers. The same dynamic is observed in the spin-lattice relaxation rate, in a quantitatively consistent manner. These results are discussed in the light of nematic fluctuations involving domain wall motion. The analogies with the behaviour observed in the cuprates are also outlined.

We measured the static uniform spin susceptibility of Ba(Fe$_{1-x}$Rh$_x$)$_2$As$_2$ iron-based superconductors, over a broad range of doping ($0.041\leq x\leq 0.094$) and magnetic fields. At small fields ($H \le$ 1 kOe) we observed, above the transition temperature $T_c$, the occurrence of precursor diamagnetism, which is not ascribable to the Ginzburg-Landau theory. On the contrary, our data fit a phase fluctuation model, which has been used to interpret a similar phenomenology occurring in the high-$T_c$ cuprate superconductors. On the other hand, in presence of strong fields the unconventional fluctuating diamagnetism is suppressed, whereas 3D fluctuations are found, in agreement with literature.

${}^{75}\phantom{\rule{-0.16em}{0ex}}$As NMR spin-lattice relaxation ($1/{T}_{1}$) and spin-echo decay ($1/{T}_{2}$) rate measurements were performed in a single crystal of Ba(Fe${}_{0.93}$Rh${}_{0.07}$)${}_{2}$As${}_{2}$ superconductor. Below the superconducting transition temperature ${T}_{c}$, when the magnetic field $\mathbf{H}$ is applied along the $c$ axes, a peak in both relaxation rates is observed. Remarkably that peak is suppressed for $\mathbf{H}\ensuremath{\perp}c$. Those maxima in $1/{T}_{1}$ and $1/{T}_{2}$ have been ascribed to the flux lines lattice motions and the corresponding correlation times and pinning energy barriers have been derived on the basis of a heuristic model. Further information on the flux lines motion was derived from the narrowing of ${}^{75}\phantom{\rule{-0.16em}{0ex}}$As NMR linewidth below ${T}_{c}$ and found to be consistent with that obtained from $1/{T}_{2}$ measurements. All the experimental results are described in the framework of thermally activated vortices motions.

$^{31}\mathrm{P}$ nuclear and muon spin-lattice relaxation-rate measurements in SrZnVO(PO${}_{4}$)${}_{2}$, a $S=1/2$ frustrated magnet on a square lattice, are presented. The temperature ($T$) dependence of the in-plane correlation length $\ensuremath{\xi}$ is derived and it is shown that the overall behavior is analogous to the one found for nonfrustrated systems but with a reduced spin stiffness. The temperature dependence of $\ensuremath{\xi}$ in SrZnVO(PO${}_{4}$)${}_{2}$ is compared to the one of other frustrated magnets on a square lattice with competing nearest neighbor (${J}_{1}$) and next-nearest-neighbor (${J}_{2}$) exchange couplings and it is shown that $\ensuremath{\xi}$ progressively decreases as the ratio ${J}_{2}/{J}_{1}$ approaches the critical value leading to the suppression of long-range magnetic order. In spite of the differences in the functional form of $\ensuremath{\xi}(T)$ found in different vanadates, it is pointed out that the characteristic energy scale describing spin correlations in all those compounds appears to scale as $|2{J}_{2}+{J}_{1}|$.

By using nuclear magnetic resonance and ac-susceptibility, the characteristic correlation times for the vortex dynamics, in an iron-based superconductor, have been derived. Upon cooling, the vortex dynamics displays a crossover consistent with a vortex glass transition. The correlation times, in the fast motions regime, merge onto a universal curve which is fit by the Vogel-Fulcher law, rather than by an Arrhenius law. Moreover, the pinning barrier shows a weak dependence on the magnetic field which can be heuristically justified within a fragile glass scenario. In addition, the glass freezing temperatures obtained by the two techniques merge onto the de Almeida-Thouless line. Finally the phase diagram for the mixed phase has been derived.