Neuroinflammation has been implicated in frontotemporal lobar degeneration (FTLD) pathophysiology, including in genetic forms with microtubule-associated protein tau (MAPT) mutations (FTLD-MAPT) or... Show moreNeuroinflammation 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. Show less
Aims: 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... Show moreAims: 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 R 2 * as a quantitative measure of brain iron content in aceruloplasminemia, the most severely iron-loaded NBIA phenotype. Methods: 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 R 2 * , and biochemically analyzed with inductively coupled plasma mass spectrometry. For gray matter samples of the aceruloplasminemia brain, sample R 2 * values were compared with postmortem in situ MRI data that had been obtained from the same subject at 3 T - in situ R 2 * . Relationships between R 2 * and tissue iron concentration were determined by linear regression analyses. Results: Median iron concentrations throughout the whole aceruloplasminemia brain were 10 to 15 times higher than in the control subject, and R 2 * 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 R 2 * could be explained by iron, and in situ R 2 * at 3 T and sample R 2 * at 1.5 T were highly correlated. For white matter regions of the aceruloplasminemia brain, 85% of variation in R 2 * could be explained by iron. Conclusions: R 2 * 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. Show less
Aims: 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... Show moreAims: 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 R 2 * as a quantitative measure of brain iron content in aceruloplasminemia, the most severely iron-loaded NBIA phenotype. Methods: 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 R 2 * , and biochemically analyzed with inductively coupled plasma mass spectrometry. For gray matter samples of the aceruloplasminemia brain, sample R 2 * values were compared with postmortem in situ MRI data that had been obtained from the same subject at 3 T - in situ R 2 * . Relationships between R 2 * and tissue iron concentration were determined by linear regression analyses. Results: Median iron concentrations throughout the whole aceruloplasminemia brain were 10 to 15 times higher than in the control subject, and R 2 * 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 R 2 * could be explained by iron, and in situ R 2 * at 3 T and sample R 2 * at 1.5 T were highly correlated. For white matter regions of the aceruloplasminemia brain, 85% of variation in R 2 * could be explained by iron. Conclusions: R 2 * 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. Show less
Bossoni, L.; Hegeman-Kleinn, I.; Duinen, S.G. van; Bulk, M.; Vroegindeweij, L.H.P.; Langendonk, J.G.; ... ; Weerd, L. van der 2021
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... Show morePurpose 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. Show less
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... Show moreAims: 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 & micro;g/g vs. 27 & micro;g/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. Show less
Weerd, L. van der; Lefering, A.; Webb, A.; Egli, R.; Bossoni, L. 2020
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... Show moreIron 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. Show less
