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

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

10.1101/2020.10.15.20206102 ◽

2020 ◽

Author(s):

Lena H.P. Vroegindeweij ◽

Lucia Bossoni ◽

Agnita J.W. Boon ◽

J.H. Paul Wilson ◽

Marjolein Bulk ◽

...

Keyword(s):

Red Nucleus ◽

Temporal Cortex ◽

Iron Accumulation ◽

Molecular Forms ◽

Transverse Relaxation Rate ◽

Relaxation Rates ◽

Brain Iron ◽

Mri Contrast ◽

The Brain ◽

Iron Forms

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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Treatment of nervous syphilis with bismuth

Kazan medical journal ◽

10.17816/kazmj58876 ◽

1926 ◽

Vol 22 (4) ◽

pp. 466

Author(s):

V. S.

Keyword(s):

Optic Nerve ◽

Optic Nerve Atrophy ◽

The Brain

SN Sharavsky (Sovr Psychonevr., 1925, No. 8) performed such treatment in 19 cases of nervous syphilis, among which there were 4 cases. dorsal tabes (3 of them with optic nerve atrophy), 1 case. progressive paralysis, 4 words. basal meningitis, 6 cases. syphilis of the brain (2 of them with epilepsy), 2 cases. spinal syphilis and 2 - syphilitic meningo-myelitis.

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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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Panhypopituitarism Presenting as Progressive Visual Acuity Deterioration Secondary to Suprasellar Germinoma

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1215 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A596-A596

Author(s):

Rainer Wandrew Young Po ◽

Monica Therese B Cating-Cabral

Keyword(s):

Visual Acuity ◽

Optic Nerve ◽

Optic Disc ◽

Clinical Sign ◽

External Beam Radiation ◽

Optic Nerve Atrophy ◽

Beam Radiation ◽

Intracranial Mass ◽

The Right ◽

The Brain

Abstract Background: Overall the incidence of germ cell tumors worldwide is 0.1% with 60% comprising of germinomas. These may present in the suprasellar region a third of the time and thus impart variability in its presenting characteristics. Clinical Case: A 27-year male presented with progressive blurring of vision with incongruent visual acuity and refraction grade with optic disc pallor assessed with normal angiography. Patient also presented with increasing docility, sluggishness and more withdrawn behavior paired with polyuria, polydipsia and cold intolerance. Progressive worsening of vision led to cranial CT revealing an enhancing hyper density in the right caudate head later elucidated via MRI with several interspersed non-enhancing foci in the right caudate nucleus, both internal capsules with associated mild mass effect. The largest component located in the right capsular region with measurement of 21 x 21 x 16 mm with enhancing lesions in the hypothalamus and pituitary stalk. Endocrine evaluation revealed low serum cortisol at 91.03nmol/L (NV 138-685 nmol/L), responsive to ACTH stimulation test (65.94nmol/L to 387nmol/L), high prolactin at 856.9 mIU/L (42.4-296.8mIU/L) and low FT4 8.62pmol/l (9.01-19.05 pmol/L) despite normal TSH 1.528uIU/ml (0.35-4.94 uIU/mL). Optic nerve atrophy was now attributed to compressive intracranial mass. Secondary adrenal insufficiency was managed with hydrocortisone 50mgIV every 8 hours, and central hypothyroidism was managed with levothyroxine 75mcgtab 1tab once a day. Increased urinary output assessed as diabetes insipidus was given desmopressin 60mcg/tab ½ tab 2x a day at this time. Stereotactic biopsy of the brain revealed a germinoma of the right caudate lobe. Given the nature of the intracranial mass with high sensitivity to chemotherapeutic and radiotherapy, a multidisciplinary approach to treatment was taken with radiotherapy, hormonal and steroid replacement. Patient underwent external beam radiation therapy of the brain and spine for a total of 51 treatments allowing for improvement of visual acuity to counting, with polyuria less than 2-3 diaper changes per day. Conclusion: Optic disc pallor is a clinical sign that indicates optic nerve atrophy reflective of the optic tract. This may be an important clinical sign to increase clinical suspicion for intracranial mass lesion especially with correlation to manifestation of pituitary hormone deficiencies.

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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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