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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 5 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.

Neuroinflammation has been implicated in frontotemporal lobar degeneration (FTLD) pathophysiology, including in genetic forms with microtubule‐associated protein tau (MAPT) mutations (FTLD‐MAPT) or chromosome 9 open reading frame 72 (C9orf72) repeat expansions (FTLD‐C9orf72). Iron accumulation as a marker of neuroinflammation has, however, been understudied in genetic FTLD to date. To investigate the occurrence of cortical iron accumulation in FTLD‐MAPT and FTLD‐C9orf72, iron histopathology was performed on the frontal and temporal cortex of 22 cases (11 FTLD‐MAPT and 11 FTLD‐C9orf72). We studied patterns of cortical iron accumulation and its colocalization with the corresponding underlying pathologies (tau and TDP‐43), brain cells (microglia and astrocytes), and myelination. Further, with ultrahigh field ex vivo MRI on a subset (four FTLD‐MAPT and two FTLD‐C9orf72), we examined the sensitivity of T2*‐weighted MRI for iron in FTLD. Histopathology showed that cortical iron accumulation occurs in both FTLD‐MAPT and FTLD‐C9orf72 in frontal and temporal cortices, characterized by a diffuse mid‐cortical iron‐rich band, and by a superficial cortical iron band in some cases. Cortical iron accumulation was associated with the severity of proteinopathy (tau or TDP‐43) and neuronal degeneration, in part with clinical severity, and with the presence of activated microglia, reactive astrocytes and myelin loss. Ultra‐high field T2*‐weighted MRI showed a good correspondence between hypointense changes on MRI and cortical iron observed on histology. We conclude that iron accumulation is a feature of both FTLD‐MAPT and FTLD‐C9orf72 and is associated with pathological severity. Therefore, in vivo iron imaging using T2*‐weighted MRI or quantitative susceptibility mapping may potentially be used as a noninvasive imaging marker to localize pathology in FTLD.

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 ( R 2 ⁎ ) , to obtain a systematic view of molecular iron in the temporal cortex. Significantly higher values of 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.

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.

Non-invasive measures of brain iron content would be of great benefit in neurodegeneration with brain iron accumulation (NBIA) to serve as a biomarker for disease progression and evaluation of iron chelation therapy. Although magnetic resonance imaging (MRI) provides several quantitative measures of brain iron content, none of these have been validated for patients with a severely increased cerebral iron burden. We aimed to validate R2* as a quantitative measure of brain iron content in aceruloplasminemia, the most severely iron-loaded NBIA phenotype. Tissue samples from 50 gray- and white matter regions of a postmortem aceruloplasminemia brain and control subject were scanned at 1.5 T to obtain R2*, and biochemically analyzed with inductively coupled plasma mass spectrometry. For gray matter samples of the aceruloplasminemia brain, sample R2* values were compared with postmortem in situ MRI data that had been obtained from the same subject at 3 T – in situ R2*. Relationships between R2* and tissue iron concentration were determined by linear regression analyses. Median iron concentrations throughout the whole aceruloplasminemia brain were 10 to 15 times higher than in the control subject, and R2* was linearly associated with iron concentration. For gray matter samples of the aceruloplasminemia subject with an iron concentration up to 1000 mg/kg, 91% of variation in R2* could be explained by iron, and in situ R2* at 3 T and sample R2* at 1.5 T were highly correlated. For white matter regions of the aceruloplasminemia brain, 85% of variation in R2* could be explained by iron. R2* is highly sensitive to variations in iron concentration in the severely iron-loaded brain, and might be used as a non-invasive measure of brain iron content in aceruloplasminemia and potentially other NBIA disorders.

We performed depth-dependent low-energy muon spin spectroscopy (\\(\\)SR) studies on three palladium 100 nm thin films, both undoped and doped with 170 ppm of iron. Muons implanted in the surface and substrate interface region probe an increased local magnetic field compared to the inner part of the sample. The field increase extends over a few nanometers, it is temperature-independent (in the range of 3.7 - 100 K), stronger for the iron-doped samples and accompanied by an increase in local field inhomogeneity. We consider various potential origins for this magnetic surface state, such as adsorbents and supressed d-states. Our conclusion is that orbital moments induced at the surface / interface by localized spins and charges are the most likely explanation, potentially accompanied by magnetic moments due to crystal irregularities.

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. Competing Interest Statement The authors have declared no competing interest.

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 Néel 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.

Abstract Purpose To 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. Methods An 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. Results In 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. Conclusions Off-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. Competing Interest Statement The authors have declared no competing interest.