The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
The Involvement of Iron in Traumatic Brain Injury and Neurodegenerative Disease.
Traumatic brain injury (TBI) consists of acute and long-term pathophysiological sequelae that ultimately lead to cognitive and motor function deficits, with age being a critical risk factor for poorer prognosis. TBI has been recently linked to the development of neurodegenerative diseases later in life including Alzheimer's disease, Parkinson's disease, chronic traumatic encephalopathy, and multiple sclerosis. The accumulation of iron in the brain has been documented in a number of neurodegenerative diseases, and also in normal aging, and can contribute to neurotoxicity through a variety of mechanisms including the production of free radicals leading to oxidative stress, excitotoxicity and by promoting inflammatory reactions. A growing body of evidence similarly supports a deleterious role of iron in the pathogenesis of TBI. Iron deposition in the injured brain can occur via hemorrhage/microhemorrhages (heme-bound iron) or independently as labile iron (non-heme bound), which is considered to be more damaging to the brain. This review focusses on the role of iron in potentiating neurodegeneration in TBI, with insight into the intersection with neurodegenerative conditions. An important implication of this work is the potential for therapeutic approaches that target iron to attenuate the neuropathology/phenotype related to TBI and to also reduce the associated risk of developing neurodegenerative disease.
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Galway Neuroscience Centre, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland
UPR Induction Prevents Iron Accumulation and Oligodendrocyte Loss in ex vivo Cultured Hippocampal Slices
The accumulation of iron within the brain occurs in many chronic disorders including Alzheimer's and Parkinson's disease and multiple sclerosis. Outside the CNS, a link between levels of iron and the unfolded protein response has already been established. To determine if such a relationship operates in within the brain, we used our ex vivo hippocampal slice-based model of iron accumulation. Ferrocene addition caused accumulation of iron within slices and loss of oligodendrocytes, an effect that was partially inhibited when ferrocene and ER stressor tunicamycin (Tm) were added together. An upward trend (not found to be statistically significant) in the expression of UPR transcripts in response to ferrocene was demonstrated using real-time PCR, while a significant upregulation of mRNA for B cell immunoglobulin-binding protein (BiP) and C/EBP homologous binding protein (CHOP) occurred following exposure to Tm. In silico analysis revealed consensus DNA-binding sequences for UPR-associated transcription factors within the promoter regions of eight iron-regulatory genes. In addition, dual-staining for CHOP and oligodendrocyte transcription factor 2 (OLIG2) or Ionized calcium binding adaptor molecule 1 (Iba1) showed nuclear expression of CHOP in some oligodendrocyte-lineage cells in response to Tm or Tm+ferrocene, but CHOP was rarely found in microglia. Co-expression of UPR-associated activated transcription factor 6 (ATF6) was detected in the nuclei of some oligodendrocyte-lineage cells exposed to Tm alone, or to Tm and ferrocene, but rarely in microglia. These data highlight the therapeutic potential of targeting UPR-associated proteins when developing novel treatments for chronic brain disorders that are affected by dysregulated iron.
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We have been discussing the association of iron with MS lesions on this forum for the past 15 years since 2004, nearly since the forum's inception.
- Iron and the Brain by Dignan posted Fri Nov 05, 2004.
- Iron deposits surrounding multiple sclerosis plaques.
Arch Pathol Lab Med. 1982 Aug;106(8):397-9.
Autopsy samples from cerebral areas of five brains from patients with multiple sclerosis (MS) and from six control brains were stained with Perls acid ferrocyanide to detect nonheme iron present as hemosiderin. Positive iron reactions were observed only in MS sections surrounding demyelinated plaques. Myelinated white matter near the lesion contained numerous iron-laden ovoid bodied and axons that stained positively for iron. Positive reactions were also found within blood vessels of gray matter near the lesion. A possible source of the iron was extravasated blood.
The above review paper published in December 2018 continues the discussion. We now know that iron in the brain is toxic. It potentiates a vicious cycle of inflammation, mitochondrial dysfunction and subsequent neurodegeneration leading to yet more iron deposition. Indeed, excessive iron accumulation in the brain is associated with a variety of neurodegenerative diseases, e.g., MS, Traumatic Brain Injury, Parkinson's Disease, Alzheimer's Disease, dementia, etc. With respect to MS, we now have just over 20 different forums dedicated to the various medical treatments available to MS patients. However, none of these treatments address iron's vicious cycle. Iron is the proverbial elephant in the room. This begs the obvious question, how do we get iron out of the brain? ...and do it safely without precipitating anemia or binding up useful metal cations, e.g., zinc, magnesium, calcium, etc. with chelation therapies?
Zinc Deficiency-induced Iron Accumulation... (2007)
A number of studies indicate that a diet deficient in zinc can result in the accumulation of iron in numerous tissues, including testes, liver, kidney, and spleen, as well as in fetuses of zinc-deficient dams (2-4).
related, but more recent and not previously posted here:
Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions (2017)
https://link.springer.com/article/10.10 ... 017-1696-8
"Metals are essential for the synthesis, stability, and maintenance of myelin [14, 29, 36, 63, 64], and are required for normal CNS functioning [36, 72]. ... This is the first systematic synchrotron X-ray fluorescence study to compare the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing white matter (normal appearing WM) and periplaque white matter (periplaque WM) from a given patient, and to assess the involvement of these metals in MS lesion pathogenesis.
We analyzed formalin-fixed paraffin-embedded archival autopsy tissue from 18 MS patients (Suppl. Table 1), with no known iron metabolism abnormalities.
The completely demyelinated inactive center (Fig. 2a) was devoid of iron in six smoldering lesions, while four lesions (three with and one without an iron ring, all from patients younger than 50 years of age) contained patchy subregions of iron accumulation and iron loss visible on XFI (Figs. 2b, h, k, 4a, b), and iron histochemistry (Fig. 2f, i). These iron-rich regions located within the inactive demyelinated center co-localized with areas of reactive astrogliosis and glial scaring (Fig. 2e). Iron within these patches was significantly increased when compared to the iron in the rest of the demyelinated center (p = 0.02), and there was a trend of increase relative to the rim iron (p = 0.06), but not compared to the periplaque WM iron (p = 0.55). Zinc was low in the inactive demyelinated center of smoldering lesions (Fig. 2c), except in one case where zinc was increased periventricularly (Fig. 2j).
Zinc in MS lesions is generally decreased, paralleling the myelin loss.
Whether there is a role for iron chelation in MS remains controversial [12, 61, 69] and is based on the premise that iron accumulates in lesions. We have generally observed the opposite, as chronic MS plaques tended to be deficient in iron.
Further studies are needed to determine whether MRI features reportedly associated with iron rims around smoldering and inactive plaques differ. Although our study focused on chronic non-active MS lesions, XFI-pathological correlative studies examining iron and zinc in actively demyelinating lesions are ongoing, to better define their role in early lesion formation. "
will have to have a scout around for those
pursue optimal self care at least as actively as a diagnosis
ask for referrals to preventive health care specialists eg dietitians
don't let suboptimal self care muddy any underlying diagnostic picture!
IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
Oxidative Stress Related to Iron Metabolism in Relapsing Remitting Multiple Sclerosis Patients With Low Disability.
Oxidative status may play a role in chronic inflammation and neurodegeneration which are considered critical etiopathogenetic factors in Multiple Sclerosis (MS), both in the early phase of the disease and in the progressive one. The aim of this study is to explore oxidative status related to iron metabolism in peripheral blood of stable Relapsing-Remitting MS with low disability. We studied 60 Relapsing-Remitting MS patients (age 37.2 ± 9.06, EDSS median 1.0), and 40 healthy controls (age 40.3 ± 10.86). We measured total hydroperoxides (dROMs test) and Total Antioxidant Status (TAS), along with the iron metabolism biomarkers: Iron (Fe), ferritin (Ferr), transferrin (Tf), transferrin saturation (Tfsat), and ceruloplasmin (Cp) panel biomarkers [concentration (iCp) and enzymatic activity (eCp), copper (Cu), ceruloplasmin specific activity (eCp:iCp), copper to ceruloplasmin ratio (Cu:Cp), non-ceruloplasmin copper (nCp-Cu)]. We computed also the Cp:Tf ratio as an index of oxidative stress related to iron metabolism. We found lower TAS levels in MS patients than in healthy controls (CTRL) and normal reference level and higher dROMs and Cp:Tf ratio in MS than in healthy controls. Cp and Cu were higher in MS while biomarkers of iron metabolism were not different between patients and controls. Both in controls and MS, dROMs correlated with iCp (CTRL r = 0.821, p < 0.001; MS r = 0.775 p < 0.001) and eCp (CTRL r = 0.734, p < 0.001; MS r = 0.820 p < 0.001). Moreover, only in MS group iCp correlated negatively with Tfsat (r = -0.257, p = 0.047). Dividing MS patients in "untreated" group and "treated" group, we found a significant difference in Fe values [F(2, 97) = 10.136, p < 0.001]; in particular "MS untreated" showed higher mean values (mean = 114.5, SD = 39.37 μg/dL) than CTRL (mean 78.6, SD = 27.55 μg/dL p = 0.001) and "MS treated" (mean = 72.4, SD = 38.08 μg/dL; p < 0.001). Moreover, "MS untreated" showed significantly higher values of Cp:Tf (mean = 10.19, SD = 1.77∗10-2; p = 0.015), than CTRL (mean = 9.03, SD = 1.46 ∗10-2). These results suggest that chronic oxidative stress is relevant also in the remitting phase of the disease in patients with low disability and short disease duration. Therefore, treatment with antioxidants may be beneficial also in the early stage of the disease to preserve neuronal reserve.
Department of Biochemistry, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey
Serum NADPH oxidase concentrations and the associations with iron metabolism in relapsing remitting multiple sclerosis.
Overproduction of reactive oxygen species (ROS) and impaired iron metabolism are considered to be possible factors in the pathogenesis of Multiple sclerosis (MS). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are the primary sources of regulated ROS production. The NADPH oxidase (NOX) family consists of seven catalytic homologues, NOX1-5 and two dual oxidases. NOX1 and NOX5 are associated with endothelial dysfunction and inflammation but NOX4 has a protective effect on vascular function. The aims of this study were to investigate the status of NOX1, NOX4 and NOX5 and its relationship with serum iron metabolism biomarkers in relapsing-remitting MS patients.
The study included 53 RRMS patients and 45 control subjects. Serum NOX1,4,5, ferritin, iron, unbound-iron binding capacity, C-reactive protein (CRP), white blood count (WBC) and erythrocyte sedimentation rate (ESR) levels were measured in all the study subjects.
Higher serum NOX5 (p < 0.0001), CRP (p = 0.014), ferritin (p = 0.040) and lower serum NOX4 (p < 0.0001) and iron (p = 0.013) concentrations were found in the patients than in controls. No correlation was found between NOXs, CRP, WBC, ESR and iron metabolism biomarkers in patients.
Our data suggest that increased NOX5 expression and decreased levels of NOX4 might be related with oxidative stress related vascular changes in MS patients. These findings provide future opportunities to combat MS with separately target individual NOX isoforms.
Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
Potential role of iron in repair of inflammatory demyelinating lesions.
Inflammatory destruction of iron-rich myelin is characteristic of multiple sclerosis (MS). Although iron is needed for oligodendrocytes to produce myelin during development, its deposition has also been linked to neurodegeneration and inflammation, including in MS. We report perivascular iron deposition in multiple sclerosis lesions that was mirrored in 72 lesions from 13 marmosets with experimental autoimmune encephalomyelitis. Iron accumulated mainly inside microglia/macrophages from 6 weeks after demyelination. Consistently, expression of transferrin receptor, the brain's main iron-influx protein, increased as lesions aged. Iron was uncorrelated with inflammation and postdated initial demyelination, suggesting that iron is not directly pathogenic. Iron homeostasis was at least partially restored in remyelinated, but not persistently demyelinated, lesions. Taken together, our results suggest that iron accumulation in the weeks after inflammatory demyelination may contribute to lesion repair rather than inflammatory demyelination per se.
Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo
Targeting Iron Dyshomeostasis for Treatment of Neurodegenerative Disorders.
While iron has an important role in the normal functioning of the brain owing to its involvement in several physiological processes, dyshomeostasis has been found in many neurodegenerative disorders, as evidenced by both histopathological and imaging studies. Although the exact causes have remained elusive, the fact that altered iron levels have been found in disparate diseases suggests that iron may contribute to their development and/or progression. As such, the processes involved in iron dyshomeostasis may represent novel therapeutic targets. There are, however, many questions about the exact interplay between neurodegeneration and altered iron homeostasis. Some insight can be gained by considering the parallels with respect to what occurs in healthy aging, which is also characterized by increased iron throughout many regions in the brain along with progressive neurodegeneration. Nevertheless, the exact mechanisms of iron-mediated damage are likely disease specific to a certain degree, given that iron plays a crucial role in many disparate biological processes, which are not always affected in the same way across different neurodegenerative disorders. Moreover, it is not even entirely clear yet whether iron actually has a causative role in all of the diseases where altered iron levels have been noted. For example, there is strong evidence of iron dyshomeostasis leading to neurodegeneration in Parkinson's disease, but there is still some question as to whether changes in iron levels are merely an epiphenomenon in multiple sclerosis. Recent advances in neuroimaging now offer the possibility to detect and monitor iron levels in vivo, which allows for an improved understanding of both the temporal and spatial dynamics of iron changes and associated neurodegeneration compared to post-mortem studies. In this regard, iron-based imaging will likely play an important role in the development of therapeutic approaches aimed at addressing altered iron dynamics in neurodegenerative diseases. Currently, the bulk of such therapies have focused on chelating excess iron. Although there is some evidence that these treatment options may yield some benefit, they are not without their own limitations. They are generally effective at reducing brain iron levels, as assessed by imaging, but clinical benefits are more modest. New drugs that specifically target iron-related pathological processes may offer the possibility to prevent, or at the least, slow down irreversible neurodegeneration, which represents an unmet therapeutic target.
Neurology B, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis.
Intrathecal inflammation, compartmentalized in cerebrospinal fluid (CSF) and in meningeal infiltrates, has fundamental role in inflammation, demyelination, and neuronal injury in cerebral cortex in multiple sclerosis (MS). Since the exact link between intrathecal inflammation and mechanisms of cortical pathology remains unknown, we aimed to investigate a detailed proteomic CSF profiling which is able to reflect cortical damage in early MS.
We combined new proteomic method, TRIDENT, CSF analysis, and advanced 3T magnetic resonance imaging (MRI), in 64 MS patients at the time of diagnosis and 26 controls with other neurological disorders. MS patients were stratified according to cortical lesion (CL) load.
We identified 227 proteins differently expressed between the patients with high and low CL load. These were mainly related to complement and coagulation cascade as well as to iron homeostasis pathway (30 and 6% of all identified proteins, respectively). Accordingly, in the CSF of MS patients with high CL load at diagnosis, significantly higher levels of sCD163 (P < 0.0001), free hemoglobin (Hb) (P < 0.05), haptoglobin (P < 0.0001), and fibrinogen (P < 0.01) were detected. By contrast, CSF levels of sCD14 were significantly (P < 0.05) higher in MS patients with low CL load. Furthermore, CSF levels of sCD163 positively correlated (P < 0.01) with CSF levels of neurofilament, fibrinogen, and B cell-related molecules, such as CXCL13, CXCL12, IL10, and BAFF.
Intrathecal dysregulation of iron homeostasis and coagulation pathway as well as B-cell and monocyte activity are strictly correlated with cortical damage at early disease stages.
Department of Neurology, Medical University of Vienna, Austria
Serum hepcidin levels in multiple sclerosis
Brain iron accumulation is associated with multiple sclerosis (MS). Hepcidin is the master regulator of iron homeostasis and distribution. Dysregulation of hepcidin is a feature of different chronic inflammatory diseases but has not been investigated in MS so far.
The aim of this study was to determine serum hepcidin levels of MS patients and healthy volunteers serving as controls and to investigate possible relations between hepcidin levels, disease activity and disease course.
In a cross-sectional design, we measured serum hepcidin levels in 71 MS patients and 16 healthy controls (HC). MS patients were sub-grouped in active relapsing-remitting MS (aRRMS), inactive (i)RRMS, active progressive MS (aPMS) and inactive (i)PMS. Blood parameters were measured by standard laboratory methods.
Median hepcidin levels were 26.9 ng/ml (confidence interval (CI) 22.8; 30.9) in MS and 17.3 ng/ml (CI 12.8; 23.4) in HC with significant age and sex effects. Hepcidin correlates were in line with hepcidin as an indicator of iron stores. After correction for age and sex, hepcidin was neither associated with MS subgroups nor degree of disability and occurrence of relapses.
Serum hepcidin levels are not associated with disease activity and disease course in MS.
Department of Ophthalmology & Bascom Palmer Eye Institute, University of Miami, Miami, Florida
Nuclear prelamin a recognition factor and iron dysregulation in multiple sclerosis
Dysregulation of iron metabolism and aberrant iron deposition has been associated with multiple sclerosis. However, the factors that contribute to this pathological state remain to be understood. In this study, human multiple sclerosis and mice brain samples were analyzed through mass spectrometry as well as histological and immunoblot techniques, which demonstrated that iron deposition is associated with increased levels of nuclear prelamin A recognition factor (NARF). NARF is a protein associated with the mitochondria which has also been linked to mitochondrial defects in multiple sclerosis. We report NARF to be associated in multiple sclerosis pathology and aberrant iron deposition.
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