Quantification of different iron forms in the aceruloplasminemia brain to explore iron-related neurodegeneration

AbstractIntroductionAceruloplasminemia 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.

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Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph12020093 ◽

2019 ◽

Vol 12 (2) ◽

pp. 93 ◽

Cited By ~ 12

Author(s):

Shashank Masaldan ◽

Abdel Ali Belaidi ◽

Scott Ayton ◽

Ashley I. Bush

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hydroxyl Radicals ◽

Iron Accumulation ◽

Brain Iron ◽

Dependent Cell ◽

Cellular Dysfunction ◽

The Impact ◽

The Brain

Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.

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Quantitative assessment of brain iron by R2* relaxometry in patients with clinically isolated syndrome and relapsing–remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458509106609 ◽

2009 ◽

Vol 15 (9) ◽

pp. 1048-1054 ◽

Cited By ~ 92

Author(s):

M Khalil ◽

C Enzinger ◽

C Langkammer ◽

M Tscherner ◽

M Wallner-Blazek ◽

...

Keyword(s):

Multiple Sclerosis ◽

Basal Ganglia ◽

Quantitative Assessment ◽

Disease Duration ◽

Clinically Isolated Syndrome ◽

Iron Accumulation ◽

Iron Deposition ◽

Relaxation Rates ◽

Brain Iron ◽

Relapsing Remitting

Background Increased iron deposition has been implicated in the pathophysiology of multiple sclerosis (MS), based on visual analysis of signal reduction on T2-weighted images. R2* relaxometry allows to assess brain iron accumulation quantitatively. Objective To investigate regional brain iron deposition in patients with a clinically isolated syndrome (CIS) or relapsing–remitting MS (RRMS) and its associations with demographical, clinical, and conventional magnetic resonance imaging (MRI) parameters. Methods We studied 69 patients (CIS, n = 32; RRMS, n = 37) with 3T MRI and analyzed regional R2* relaxation rates and their correlations with age, disease duration, disability, T2 lesion load, and normalized brain volumes. Results Basal ganglia R2* relaxation rates increased in parallel with age ( r = 0.3–0.6; P < 0.01) and were significantly higher in RRMS than in CIS ( P < 0.05). Using multivariate linear regression analysis, the rate of putaminal iron deposition was independently predicted by the patients’ age, disease duration, and gray matter atrophy. Conclusions Quantitative assessment by R2* relaxometry suggests increased iron deposition in the basal ganglia of MS patients, which is associated with disease duration and brain atrophy. This technique together with long-term follow-up thus appears suited to clarify whether regional iron accumulation contributes to MS morbidity or merely reflects an epiphenomenon.

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Case of phenotype of optic nerve atrophy due to mutation in С19orf12 gene (neurodegeneration with the brain iron accumulation (nbia))

Clinical ophthalmology ◽

10.32364/2311-7729-2020-20-1-32-36 ◽

2020 ◽

pp. 32-36

Author(s):

M.E. Ivanova ◽

◽

V.V. Kadyshev ◽

D.S. Atarshchikov ◽

I.V. Zolnikova ◽

...

Keyword(s):

Optic Nerve ◽

Iron Accumulation ◽

Brain Iron ◽

Optic Nerve Atrophy ◽

The Brain

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Aging is associated with increased brain iron through brain-derived hepcidin expression

10.1101/2021.09.06.459092 ◽

2021 ◽

Author(s):

Hossein Ardehali ◽

Tatsuya Sato ◽

Jason Solomon Shapiro ◽

Hsiang-Chun Chang ◽

Richard A Miller

Keyword(s):

Heme Iron ◽

Iron Accumulation ◽

Biological Processes ◽

Brain Iron ◽

Cellular Compartment ◽

Hepcidin Expression ◽

Non Heme Iron ◽

Oxidative Effects ◽

The Brain ◽

Hepcidin Mrna

Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrate that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, feroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.

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

10.1101/2021.03.22.436424 ◽

2021 ◽

Author(s):

Lucia Bossoni ◽

Ingrid Hegeman-Kleinn ◽

Sjoerd G. van Duinen ◽

Lena H. P. Vroegindeweij ◽

Janneke G. Langendonk ◽

...

Keyword(s):

Neurological Diseases ◽

Iron Status ◽

Iron Accumulation ◽

Brain Diseases ◽

Transverse Relaxation Rate ◽

Post Mortem ◽

Brain Iron ◽

Resonance Saturation ◽

Ferritin Iron ◽

Iron Pool

AbstractPurposeTo 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.

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Adult-Onset Case of Undiagnosed Neurodegeneration with Brain Iron Accumulation with Psychotic Symptoms

Case Reports in Psychiatry ◽

10.1155/2014/742042 ◽

2014 ◽

Vol 2014 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Luigi Attademo ◽

Enrico Paolini ◽

Francesco Bernardini ◽

Roberto Quartesan ◽

Patrizia Moretti

Keyword(s):

Brain Mri ◽

Mood Stabilizer ◽

Iron Accumulation ◽

Psychotic Symptoms ◽

Adult Onset ◽

Brain Iron ◽

Radiographic Evidence ◽

Rate Of Progression ◽

Hypointense Signal ◽

The Brain

Neurodegeneration with brain iron accumulation (NBIA) is a collective term to indicate a group of neurodegenerative diseases presenting accumulation of iron in the basal ganglia. These disorders can result in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Onset age ranges from infancy to late adulthood and the rate of progression is very variable. So far, the genetic bases of nine types of NBIA have been identified, pantothenate-kinase-associated neurodegeneration (PKAN) being the most frequent type. The brain MRI “eye-of-the-tiger” sign, T2-weighted hypointense signal in theglobus palliduswith a central region of hyperintensity, has been considered virtually pathognomonic for PKAN but recently several reports have denied this. A significant percentage of individuals with clinical and radiographic evidence of NBIA do not have an alternate diagnosis or mutation of one of the nine known NBIA-associated genes (idiopathic NBIA). Here we present an adult-onset case of “undiagnosed” NBIA with the brain MRI “eye-of-the-tiger” sign, and with psychotic symptoms which were successfully treated with antipsychotic and mood stabilizer medications. Here, the term “undiagnosed” is used because the patient has not been screened for all known NBIA genes, but only for two of them.

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Excess iron harms the brain: the syndromes of neurodegeneration with brain iron accumulation (NBIA)

Journal of Neural Transmission ◽

10.1007/s00702-012-0922-8 ◽

2012 ◽

Vol 120 (4) ◽

pp. 695-703 ◽

Cited By ~ 30

Author(s):

Susanne A. Schneider ◽

Kailash P. Bhatia

Keyword(s):

Iron Accumulation ◽

Brain Iron ◽

Excess Iron ◽

The Brain

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Aging is associated with increased brain iron through cortex-derived hepcidin expression

eLife ◽

10.7554/elife.73456 ◽

2022 ◽

Vol 11 ◽

Author(s):

Tatsuya Sato ◽

Jason Solomon Shapiro ◽

Hsiang-Chun Chang ◽

Richard A Miller ◽

Hossein Ardehali

Keyword(s):

Heme Iron ◽

Iron Accumulation ◽

Brain Iron ◽

Cellular Compartment ◽

Hepcidin Expression ◽

Non Heme Iron ◽

Ferroportin 1 ◽

Oxidative Effects ◽

The Brain ◽

Hepcidin Mrna

Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrated that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain cortex exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, ferroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.

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