The DOI matches its Crossref record; 228 of the 228 references it cites were found in a registry or an index; 6 of the 285 sources its claims cite were checked for support.
The role of iron in brain ageing and neurodegenerative disorders
Open accessAbstract
In the CNS, iron in several proteins is involved in many important processes such as oxygen transportation, oxidative phosphorylation, myelin production, and the synthesis and metabolism of neurotransmitters. Abnormal iron homoeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation and modification of lipids, proteins, carbohydrates, and DNA. During ageing, different iron complexes accumulate in brain regions associated with motor and cognitive impairment. In various neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, changes in iron homoeostasis result in altered cellular iron distribution and accumulation. MRI can often identify these changes, thus providing a potential diagnostic biomarker of neurodegenerative diseases. An important avenue to reduce iron accumulation is the use of iron chelators that are able to cross the blood–brain barrier, penetrate cells, and reduce excessive iron accumulation, thereby affording neuroprotection.
Overview
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Written from the paper’s full text.
TL;DR
This review summarizes how iron homeostasis in the CNS changes with ageing and in neurodegenerative disorders, emphasizing oxidative damage, regional iron accumulation, MRI detection, and iron-chelation therapy. It argues that brain iron changes may contribute to disease pathogenesis and that MRI and chelators are promising but still limited diagnostic and therapeutic tools.
Key findings
- Iron is essential for oxygen transport, mitochondrial respiration, myelin synthesis, and neurotransmitter metabolism, but excess labile iron can generate hydroxyl radicals and damage lipids, proteins, carbohydrates, and DNA. During ageing, total iron increases selectively in the substantia nigra, putamen, globus pallidus, caudate nucleus, and cortices; highest adult brain iron is in basal ganglia, with lowest in pons, locus coeruleus, and medulla.
- In Alzheimer’s disease, iron, copper, and zinc accumulate in amyloid plaques and neurofibrillary tangles; iron can modulate APP processing via furin and IRP/IRE interactions, and hippocampal T2* MRI changes are proposed as a potential early biomarker. In Parkinson’s disease, total iron increases in the substantia nigra with disease severity, ferritin is decreased, and redox-active iron accumulates in Lewy bodies and neuromelanin; transcranial sonography shows substantia nigra hyperechogenicity in about 90% of patients.
- Other disorders show distinct iron patterns: multiple sclerosis has deep grey matter and inflammatory white matter iron deposits; Friedreich’s ataxia has prevalence of one case in 50,000 in the white population, with the common GAA expansion in about 96% of patients and iron accumulation in cerebellar dentate nuclei; aceruloplasminaemia can show up to a ten-times increase in iron in neurons and microglia; Huntington’s disease affects about one in 10,000 individuals, with 36–121 CAG repeats versus 6–34 in wild type; restless legs syndrome involves decreased substantia nigra iron.
- Iron chelation studies report some benefits: deferiprone 30 mg/kg per day improved symptoms and Unified Parkinson’s Disease Rating Scale scores in a Parkinson’s disease case and reduced substantia nigra iron on T2*-weighted MRI; in one trial, 3 of 40 patients developed neutropenia or agranulocytosis that resolved after stopping deferiprone. In a 78-patient Alzheimer’s disease trial, PBT2 250 mg/day reduced CSF Aβ and showed some executive-function improvement; deferiprone reduced dentate nuclei iron and improved some neurological measures in nine Friedreich’s ataxia patients aged 14–23 years.
Methods
- Narrative review of cellular and molecular iron distribution in healthy ageing, neurodegenerative diseases, MRI/sonography, and iron-chelation therapy.
- Evidence synthesized includes human post-mortem and MRI/ultrasound studies, animal models, in-vitro studies, and clinical trials or case reports.
- No primary data collection or systematic quantitative analysis is reported; the paper integrates existing literature and proposes future directions.
Limitations
- The paper states that how different brain regions maintain iron concentrations normally, with ageing, and after inflammation is not known; whether iron accumulation in neurodegenerative disease is primary or secondary is unclear; and disease-by-disease mechanisms remain poorly understood.
- The paper states that current knowledge relies heavily on young healthy rodents, which differ from elderly human brains, and that it is difficult to relate tissue iron concentrations to specific cell types; MRI cannot measure concentrations of specific iron molecules in particular cells.
- The paper states that whether chelators can remove iron from conjugated proteins/molecules such as neuromelanin is unknown. Evident from the text: this is a narrative review without systematic search or meta-analysis, and several chelation findings come from small studies, case reports, or preliminary/abstracted trial data.
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Claims the paper makes
160 Not checked yet · 7 Own interpretation · 6 No basis given · 3 Supported · 1 Partly supported · 1 Not supported · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“Gene knock-out studies on mice have shown that IRP2 is particularly important in cellular iron homoeostasis.24”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Supportedcites [24] Cooperman, 2005, Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2, Blood source
The Discussion states that IRP2 is the dominant regulator of iron-related targets such as transferrin receptor and ferritin in intact animals, and that its loss misregulates these targets in multiple tissues. The Abstract reports these effects in mice with targeted IRP2 deletion. This supports the claim that mouse knockout studies show IRP2 is particularly important in cellular iron homeostasis. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“To summarise, inflammatory stimuli and hepcidin induced iron accumulation in only neurons and microglia.36”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Supportedcites [36] Urrutia, 2013, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells, J Neurochem source
The Microglia section’s Fig. 6 caption states that the net result of inflammatory stimuli and hepcidin mediation is iron accumulation in neurons and microglia, but not astrocytes. This directly supports the citing sentence’s restriction to those two cell types. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Iron concentrations increase in many deep grey matter structures as multiple sclerosis progresses.156,157”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Multiple sclerosis
What the sources say
- Partly supportedcites [156] Neema, 2009, Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis, J Neuroimaging sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports worsening T2-hypointensity in the putamen and thalamus over four years and says excessive iron deposition is its most likely cause. The paper measured MRI signal rather than iron concentrations directly, and it does not establish increasing iron concentrations in many structures as MS progresses. (LLM, conf=0.86)
- Partly supportedcites [157] Ropele, 2011, MRI assessment of iron deposition in multiple sclerosis, J Magn Reson Imaging sourceExperimental — accuracy not yet measured
The Summary and Outlook (page unavailable) says iron accumulation is most pronounced in deep gray matter and seems associated with disease severity and duration. The conventional MRI section reports correlations with disease duration in the thalamus, putamen, and caudate, but these are MRI measures rather than direct evidence that iron concentrations increase in many structures as an individual's MS progresses. The claim states that progression more definitively than the review does. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Neurodegeneration with brain iron accumulation is associated with excess iron accumulation in deep grey matter nuclei.169”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Supportedcites [169] Schipper, 2012, Neurodegeneration with brain iron accumulation–clinical syndromes and neuroimaging, Biochim Biophys Acta source
Section 1 describes NBIA as a group of disorders involving pathological brain iron deposition. Section 3 reports basal ganglia abnormalities in the vast majority of cases, and the neuroferritinopathy subsection describes prominent iron accumulation in the globus pallidus, a deep grey matter nucleus. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
In the paper
“Incubation with interferon β reverted the cytokine-dependent induction of HO-1 and the subsequent incorporation of iron into mitochondria.162”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Multiple sclerosis
What the sources say
- Not checked yetcites [162] Mehindate, 2001, Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis, J Neurochem source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“In-vitro studies of rat astroglial cultures showed that proinflammatory cytokines (ie, interleukin 1β and tumour necrosis factor α) increased HO-1 expression after 6 days of incubation.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Multiple sclerosis
What the sources say
- Not checked yetcites [162] Mehindate, 2001, Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis, J Neurochem source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“Increased HO-1 expression promoted the sequestration of non-transferrin iron into the astroglial mitochondrial compartment, as assayed by 55Fe incorporation.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Multiple sclerosis
What the sources say
- Not checked yetcites [162] Mehindate, 2001, Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis, J Neurochem source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“Brain imaging shows iron accumulation in the substantia nigra and globus pallidus of patients with β-propeller protein-associated neurodegeneration.183”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Not checked yetcites [183] Hayflick, 2013, β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation, Brain source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Histological studies and MRI suggest that in human brains the highest iron accumulation occurs in the dentate nuclei of the cerebellum.166,167”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Friedreich’s ataxia
What the sources say
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“The severity is dependent on the number of nucleotide repeats.163”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Friedreich’s ataxia
What the sources say
- Not checked yetcites [163] Campuzano, 1996, Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 86
- Probably not a substantial claim. 3
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“In these iron overloaded areas of the brain, up to a ten-times increase was recorded in neurons and microglia, but widespread brain iron deposition can occur.170,175”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Disputedcites [170] Rouault, 2013, Iron metabolism in the CNS: implications for neurodegenerative diseases, Nat Rev Neurosci sourceExperimental — accuracy not yet measured
In “NBIA caused by defective iron metabolism” (page unavailable), the review locates marked iron overload in astrocytes in affected regions of aceruloplasminaemia, particularly the basal ganglia. It reports neuronal loss and says that the Purkinje and deep cerebellar neurons examined do not manifest iron overload. It does not report a tenfold increase in neurons and microglia or widespread deposition in this disease. (LLM, conf=0.84)
Checked by a reasoning model — may be wrong.
- Not checked yetcites [175] Kruer, 2012, Neuroimaging features of neurodegeneration with brain iron accumulation, AJNR Am J Neuroradiol source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
- Disputed
In the paper
“The inflammatory milieu associated with multiple sclerosis includes the activation of microglia and subsequent release of proinflammatory cytokines and ROS, inducing oxidative stress.40”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Multiple sclerosis
What the sources say
- Not checked yetcites [40] Williams, 2012, Pathogenic implications of iron accumulation in multiple sclerosis, J Neurochem source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In other rare genetic diseases of this group, such as pantothenate kinase-associated neurodegeneration, phospholipase A2G6-associated neurodegeneration, and Kufor-Rakeb disease, mutations disrupt proteins with cellular functions different from iron metabolism, and the mechanisms that result in brain iron overload are undefined.169–173”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Not checked yetcites [169] Schipper, 2012, Neurodegeneration with brain iron accumulation–clinical syndromes and neuroimaging, Biochim Biophys Acta source
- Not checked yetcites [170] Rouault, 2013, Iron metabolism in the CNS: implications for neurodegenerative diseases, Nat Rev Neurosci source
- Not checked yetcites [171] Dusek, 2012, Neurodegeneration with brain iron accumulation, Curr Opin Neurol source
- Not checked yetcites [172] Gregory, 2011, Genetics of neurodegeneration with brain iron accumulation, Curr Neurol Neurosci Rep source
- Not checked yetcites [173] Schneider, 2013, Genetics and pathophysiology of neurodegeneration with brain iron accumulation (NBIA), Curr Neuropharmacol
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Pantothenate kinase-associated neurodegeneration is characterised by an excess of iron especially in the globus pallidus, leading to a typical MRI pattern called eye of the tiger, and to a lesser extent, and later in the disease, in the substantia nigra.174,175”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The major consequences of frataxin deficiencies include the impairment of mitochondrial biosynthesis of proteins containing iron–sulphur clusters (eg, aconitase), deficiency of respiratory chain electron transporters on complexes I–III, iron overload in mitochondria, oxidative stress, and free radical accumulation leading to changes in cellular iron metabolism.164,165”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Friedreich’s ataxia
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Typical iron accumulation in phospholipase A2G6-associated neurodegeneration often occurs in the globus pallidus and might affect the substantia nigra.178”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Not checked yetcites [178] Kurian, 2008, Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN), Neurology source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“MRI iron patterns in Kufor-Rakeb disease are controversial, with iron deposition in the putamen and caudate nucleus in some cases,181 or without discernible iron deposition in other individuals.182”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Fatty acid hydroxylase-associated neurodegeneration leads to iron accumulation in the globus pallidus, with the substantia nigra possibly less affected.172”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Not checked yetcites [172] Gregory, 2011, Genetics of neurodegeneration with brain iron accumulation, Curr Neurol Neurosci Rep source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Iron misregulation is implicated in the pathology of restless leg syndrome, so that concentrations of TFR, IRP1, DMT1, ferroportin, and heavy-chain ferritin are decreased in dopaminergic neurons of the substantia nigra.198–200”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Restless legs syndrome
What the sources say
- Not checked yetcites [198] Allen, 2007, The role of iron in restless legs syndrome, Mov Disord source
- Not checked yetcites [199] Connor, 2003, Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome, Neurology source
- Not checked yetcites [200] Connor, 2004, Decreased transferrin receptor expression by Neuromelanin cells in restless legs syndrome, Neurology source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Iron deficit conditions worsen symptomatology, whereas iron replacement therapy improves symptoms.198,201”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Restless legs syndrome
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In embryonic stem cells, huntingtin is iron-regulated and also involved in iron homoeostasis regulation.193”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Huntington’s disease
What the sources say
- Not checked yetcites [193] Hilditch-Maguire, 2000, Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles, Hum Mol Genet source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“By contrast, a more general involvement of deep grey matter nuclei (and grey matter in general) with respect to iron accumulation is seen in aceruloplasminaemia, but without evidence of cystic processes.191”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Not checked yetcites [191] Fasano, 2008, Aceruloplasminemia: a novel mutation in a family with marked phenotypic variability, Mov Disord source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“MRI studies of neuroferritinopathy have suggested that the greatest accumulation of iron is in the basal ganglia and dentate nuclei, but thalamus and red nuclei can also be affected.185,189,190”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Not checked yetcites [185] Chinnery, 2007, Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation, Brain source
- Not checked yetcites [189] Ohta, 2012, MRI findings in neuroferritinopathy, Neurol Res Int source
- Not checked yetcites [190] McNeill, 2012, Progressive brain iron accumulation in neuroferritinopathy measured by the thalamic T2* relaxation rate, AJNR Am J Neuroradiol source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“High-field MRI amplifies the paramagnetic effect of iron on T2* relaxation, leading to improved sensitivity, resolution,202 and a better resolution of confounding factors.”
§ The role of iron in brain ageing and neurodegenerative disorders > Developments in MRI for brain iron detection
What the sources say
- Not checked yetcites [202] Duyn, 2012, The future of ultra-high field MRI and fMRI for study of the human brain, Neuroimage source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Mouse models of neuroferritinopathy show iron overload, neurodegeneration, and DNA damage.187,188”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Not checked yetcites [187] Vidal, 2008, Expression of a mutant form of the ferritin light chain gene induces neurodegeneration and iron overload in transgenic mice, J Neurosci source
- Not checked yetcites [188] Deng, 2010, Accumulation of oxidative DNA damage in brain mitochondria in mouse model of hereditary ferritinopathy, Neurosci Lett source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Myelin and iron decrease T2*, but have an opposing effect on frequency owing to the diamagnetic properties of myelin (as opposed to iron’s paramagnetic properties).204”
§ The role of iron in brain ageing and neurodegenerative disorders > Developments in MRI for brain iron detection
What the sources say
- Not checked yetcites [204] Duyn, 2013, MR susceptibility imaging, J Magn Reson source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Patients receiving 250 mg/day showed a substantial reduction in CSF of Aβ concentration, and some cognitive improvement (executive function) was noted.219”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron chelation as a potential therapy > Alzheimer’s disease
What the sources say
- Not checked yetcites [219] Lannfelt, 2008, Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial, Lancet Neurol source
plaindirectn = 29- Asserted: passes — The authors put it forward as true.
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In the paper
“After 6 months many of the symptoms had improved, and after 1 year an improvement was recorded in the Unified Parkinson’s Disease Rating Scale score. T2*-weighted MRI showed a rapid decrease in iron accumulation in the bilateral dentate nuclei, with a milder and later reduction in the substantia nigra, but no significant changes in the red nuclei.213”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron chelation as a potential therapy > Parkinson’s disease
What the sources say
- Not checked yetcites [213] Kwiatkowski, 2012, Long-term improvement under deferiprone in a case of neurodegeneration with brain iron accumulation, Parkinsonism Relat Disord source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“In-vivo and post-mortem investigations suggest focal iron accumulation in the white matter in multiple sclerosis160,161,206 and focal iron accumulation in the cortex in amyotrophic lateral sclerosis207 co-localise with microglia (appendix).160,207”
§ The role of iron in brain ageing and neurodegenerative disorders > Developments in MRI for brain iron detection
What the sources say
- Not checked yetcites [160] Bagnato, 2011, Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla, Brain source
- Not checked yetcites [161] Yao, 2012, Chronic multiple sclerosis lesions: characterization with high-field-strength MR imaging, Radiology source
- Not checked yetcites [206] Bian, 2013, A serial in vivo 7T magnetic resonance phase imaging study of white matter lesions in multiple sclerosis, Mult Scler source
- Not checked yetcites [207] Kwan, 2012, Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 tesla MRI and pathology, PLoS One source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In the second clinical trial of deferiprone, patients with Parkinson’s disease received 20 mg/kg per day or 30 mg/kg per day for 6 months; both doses were well tolerated, there were minimum toxic effects, and decreases in iron in specific brain regions were detected by T2*-weighted MRI.216”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron chelation as a potential therapy > Parkinson’s disease
What the sources say
- Not checked yetcites [216] Dexter, 2013, Altered brain iron homeostasis in Parkinson's disease and potential for iron chelation therapy, Am J Hematol
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Chelation therapy has been reported to provide improvements, notably with deferiprone, and particularly for other neurodegeneration with brain iron accumulation diseases, but no improvement was seen in two patients with neuroferritinopathy.185”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron chelation as a potential therapy > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Not checked yetcites [185] Chinnery, 2007, Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation, Brain source
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In the paper
“deferoxamine (20 mg/kg per day for 5 days a week for 8 months by subcutaneous bolus injection) evoked an increase in urinary iron excretion, a decrease in serum ferritin concentrations, and decreases in haemoglobin iron and serum iron.224 By contrast, deferiprone 75 mg/kg per day for 6 months had no effect; no MRI changes were seen in the brain regions after either chelation therapy.224”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron chelation as a potential therapy > Aceruloplasminaemia and neuroferritonopathy
What the sources say
- Not checked yetcites [224] Mariani, 2004, Iron chelation therapy in aceruloplasminaemia: study of a patient with a novel missense mutation, Gut source
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In the paper
“Velasco-Sanchez and colleagues220 administered deferiprone (20 mg/kg per day) and the antioxidant idebenone for 11 months to 20 patients with Friedreich’s ataxia aged between 8 and 25 years. MRI values in the dentate nuclei of participants showed a significant reduction of iron that was associated with significant recovery of kinetic functions, although gait and posture scores worsened.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron chelation as a potential therapy > Friedreich’s ataxia
What the sources say
- Not checked yetcites [220] Velasco-Sánchez, 2011, Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia, Cerebellum source
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In the paper
“A reduction in iron content was seen after 2 months of treatment and the effect was proportional to the concentration of initial accumulated iron.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron chelation as a potential therapy > Friedreich’s ataxia
What the sources say
- Not checked yetcites [210] Boddaert, 2007, Selective iron chelation in Friedreich ataxia: biologic and clinical implications, Blood source
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In the paper
“Treatment with 20 mg/kg per day or 30 mg/kg per day deferiprone for 6 months in nine patients with Friedreich’s ataxia aged between 14 and 23 years reduced the iron content in the dentate nuclei. This reduction was associated with neurological improvements in manipulative dexterity, speech fluency, and a reduction in neuropathy and ataxia gait, particularly in the youngest patients.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron chelation as a potential therapy > Friedreich’s ataxia
What the sources say
- Not checked yetcites [210] Boddaert, 2007, Selective iron chelation in Friedreich ataxia: biologic and clinical implications, Blood source
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In the paper
“Three of the 40 patients in the first study developed neutropenia or agranulocytosis, which were resolved rapidly with cessation of deferiprone.214,215”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron chelation as a potential therapy > Parkinson’s disease
What the sources say
- Not checked yetcites [214] Devos, 2012, Disease modifying strategy based upon iron chelation in Parkinson's disease: a translational study, Neurology
- Not checked yetcites [215] Moreau, 2013, Targeting brain chelatable iron as a therapeutic strategy for Parkinson's disease. Translational and clinical studies, Am J Hematol
plaindirectn = 40- Asserted: passes — The authors put it forward as true.
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In the paper
“An absence of ceruloplasmin can result in iron accumulation in the brain and neurodegeneration.17”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [17] Jeong, 2003, Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system, J Biol Chem source
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In the paper
“Iron is involved in many fundamental biological processes in the brain including oxygen transportation, DNA synthesis, mitochondrial respiration, myelin synthesis, and neurotransmitter synthesis and metabolism.1”
§ The role of iron in brain ageing and neurodegenerative disorders > Introduction
What the sources say
- Not checked yetcites [1] Crichton, 2009
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In the paper
“Two cytosolic iron sensors, the iron regulatory proteins (IRPs) IRP1 and IRP2 (panel; appendix), regulate iron metabolism post-transcriptionally.12”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Peripheral iron uptake
What the sources say
- Not checked yetcites [12] Wallander, 2006, Molecular control of vertebrate iron homeostasis by iron regulatory proteins, Biochim Biophys Acta source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Neurons are thought to acquire most of their iron via the transferrin–TFR system, and it is likely that they can export iron via ferroportin because many neurons co-express TFR and ferroportin.22”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [22] Boserup, 2011, Heterogenous distribution of ferroportin-containing neurons in mouse brain, Biometals source
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In the paper
“Iron crosses the vascular endothelial cells of the blood–brain barrier, mainly bound to transferrin via the transferrin–TFR1 system; TFR1 is highly expressed on the luminal side of endothelial cells.20”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [20] Jefferies, 1984, Transferrin receptor on endothelium of brain capillaries, Nature source
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In the paper
“Iron released in the extracellular compartment could then be taken up by other cells, such as astrocytes and neurons, either as low molecular weight complexes (eg, citrate, ATP, ascorbate) or after binding to transferrin via the transferrin–TFR pathways in neurons.16”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [16] Leitner, 2012, Functional roles of transferrin in the brain, Biochim Biophys Acta source
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In the paper
“In healthy ageing, selective accumulation of iron occurs in several brain regions and cell types, with iron mainly bound within ferritin and neuromelanin (panel).5,6”
§ The role of iron in brain ageing and neurodegenerative disorders > Introduction
What the sources say
- Not checked yetcites [5] Zecca, 2001, Iron, Neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes, J Neurochem source
- Not checked yetcites [6] Zecca, 2004, The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging, Proc Natl Acad Sci USA source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Astrocytes do not express TFR, but might take up iron at the blood–brain barrier via DMT1, which is expressed at the end-foot processes associated with the blood–brain barrier.26”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [26] Xu, 1994, Studies of the ultrastructure and permeability of the blood-brain barrier in the developing corpus callosum in postnatal rat brain using electron dense tracers, J Anat
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In the paper
“Transferrin is synthesised in the brain by the choroid plexus and by oligodendrocytes, but is only secreted in the choroid plexus.16”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [16] Leitner, 2012, Functional roles of transferrin in the brain, Biochim Biophys Acta source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Peripheral cellular iron uptake mainly involves endocytosis of the diferric transferrin–transferrin receptor 1 (TFR1; panel) complex; iron is then transported from the endosomes into the cell cytoplasm via the divalent metal ion transporter 1 (DMT1; panel).”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Peripheral iron uptake
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Iron continually moves between neurons, microglia, and astrocytes, but how these cells acquire and release iron is not fully understood.21”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [21] Zucca, 2011, The role of iron in neurodegeneration
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“When iron concentrations exceed the cellular iron sequestration capacity of storage proteins or other molecules, the concentration of iron in the labile iron pool (panel) can increase, which could be harmful and lead to oxidative damage and cell death.4”
§ The role of iron in brain ageing and neurodegenerative disorders > Introduction
What the sources say
- Not checked yetcites [4] Kruszewski, 2003, Labile iron pool: the main determinant of cellular response to oxidative stress, Mutat Res source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In many mammalian tissues (eg, hepatocytes and macrophages), cellular iron homoeostasis is regulated at the level of the translation of the mRNAs of proteins involved in iron metabolism, such as TFR1, DMT1, ferritin, and ferroportin.11”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Peripheral iron uptake
What the sources say
- Not checked yetcites [11] Muckenthaler, 2008, Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network, Annu Rev Nutr source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MRI can often identify these changes, thus providing a potential diagnostic biomarker of neurodegenerative diseases.”
§ The role of iron in brain ageing and neurodegenerative disorders > Abstract
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In the paper
“As circulating iron concentrations decrease, hepcidin synthesis decreases, and iron exportation by ferroportin resumes.1,9,10”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Peripheral iron uptake
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, hepcidin concentrations rapidly increased in astrocytes and microglia after activation with the inflammatory stimuli, although hepcidin was undetectable in neurons.”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [36] Urrutia, 2013, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells, J Neurochem source
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In the paper
“No change in iron content was detected in astrocytes, although DMT1 increased after stimulus, and only lipopolysaccharide induced a small decrease in ferroportin concentrations.36”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [36] Urrutia, 2013, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells, J Neurochem source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Glial iron accumulation can also induce an inflammatory state through an increased release of pro-inflammatory cytokines40 and result in a self-propelling cycle of neuroinflammation and neurodegeneration.41”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron changes in brain ageing
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In the substantia nigra, ferritin heavy chain and ferritin light chain concentrations increase with age, whereas these are constant in the locus coeruleus; therefore iron could contribute to neurodegeneration in the substantia nigra more than in the locus coeruleus.5,6”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron changes in brain ageing
What the sources say
- Not checked yetcites [5] Zecca, 2001, Iron, Neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes, J Neurochem source
- Not checked yetcites [6] Zecca, 2004, The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging, Proc Natl Acad Sci USA source
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In the paper
“In healthy individuals, total iron concentration in the locus coeruleus remains stable throughout life and is lower than in the substantia nigra, in which there is a linear increase in total iron concentration with age.6,52”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron changes in brain ageing
What the sources say
- Not checked yetcites [6] Zecca, 2004, The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging, Proc Natl Acad Sci USA source
- Not checked yetcites [52] Zucca, 2006, Neuromelanin and iron in human locus coeruleus and substantia nigra during aging: consequences for neuronal vulnerability, J Neural Transm source
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In the paper
“Regional heterogeneity of brain iron and its change with age have both been confirmed in vivo by MRI.48–51”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron changes in brain ageing
What the sources say
- Not checked yetcites [48] Bartzokis, 2007, Brain ferritin iron may influence age- and gender-related risks of neurodegeneration, Neurobiol Aging source
- Not checked yetcites [49] Aquino, 2009, Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects, Radiology source
- Not checked yetcites [50] Bartzokis, 2011, Gender and iron genes may modify associations between brain iron and memory in healthy aging, Neuropsychopharmacology source
- Not checked yetcites [51] Bilgic, 2012, MRI estimates of brain iron concentration in normal aging using quantitative susceptibility mapping, Neuroimage source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Little is known about iron metabolism in microglia but, in the course of microglial activation, iron uptake is thought to increase and iron exportation is down-regulated.31,32”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [31] Crichton, 2006
- Not checked yetcites [32] Rathore, 2012, Iron homeostasis in astrocytes and microglia is differentially regulated by TNF-α and TGF-β1, Glia source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“After 6 h, secreted hepcidin provoked a decrease of ferroportin in astrocytes, microglia, and neurons and an increase in DMT1 in microglia.”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [36] Urrutia, 2013, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells, J Neurochem source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This accumulation is associated with changes in the two iron transporters, DMT1 and ferroportin; stimulated hippocampal neurons showed substantial increases in DMT1 and decreased concentrations of ferroportin, whereas microglia showed increased DMT1 protein concentrations but no changes in ferroportin.”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [36] Urrutia, 2013, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells, J Neurochem source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Regional distribution of total iron in a healthy adult brain is heterogeneous; the highest iron concentrations were detected in the basal ganglia (putamen, globus pallidus, and caudate nucleus), whereas low concentrations were detected in the cortical grey matter, white matter, midbrain, and cerebellum, and the lowest iron concentrations were in the pons, locus coeruleus, and medulla.6,43,45–47”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron changes in brain ageing
What the sources say
- Not checked yetcites [6] Zecca, 2004, The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging, Proc Natl Acad Sci USA source
- Not checked yetcites [43] Ramos, 2014, Iron levels in the human brain: a post-mortem study of anatomical region differences and age-related changes, J Trace Elem Med Biol source
- Not checked yetcites [45] Zecca, 1996, Interaction of Neuromelanin and iron in substantia nigra and other areas of human brain, Neuroscience source
- Not checked yetcites [46] Zecca, 2001, The determination of iron and other metals by INAA in cortex, cerebellum and putamen of human brain and in their neuromelanins, J Radioanal Nucl Chem source
- Not checked yetcites [47] House, 2012, Aluminium, iron and copper in human brain tissues donated to the Medical Research Council's Cognitive Function and Ageing Study, Metallomics source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Iron is mostly found as ferritin and transferrin in oligodendrocytes,28,33 whereas, in astrocytes and microglia the iron form remains undefined.29”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [28] Connor, 1990, Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains, J Neurosci Res source
- Not checked yetcites [33] Connor, 1995, Cellular management of iron in the brain, J Neurol Sci source
- Not checked yetcites [29] Badaracco, 2010, Oligodendrogenesis: the role of iron, Biofactors source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“There is an increased pro-inflammatory state in the brains of the elderly. Glial cell numbers increase in the normal ageing brain, and there is increased immunoreactivity of astrocytic and microglial markers.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron changes in brain ageing
What the sources say
- Not checked yetcites [37] Conde, 2006, Microglia in the aging brain, J Neuropathol Exp Neurol source
- Not checked yetcites [38] Farrall, 2009, Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis, Neurobiol Aging source
- Not checked yetcites [54] Block, 2007, Microglia-mediated neurotoxicity: uncovering the molecular mechanisms, Nat Rev Neurosci source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“During neuroinflammation, glial cells are activated, which perturbs iron homoeostasis.34,35”
§ The role of iron in brain ageing and neurodegenerative disorders > Regulation of cellular iron > Brain iron uptake
What the sources say
- Not checked yetcites [34] Lee, 2004, The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and beta 2-microglobulin-deficient hepatocytes, Proc Natl Acad Sci USA source
- Not checked yetcites [35] Nemeth, 2004, IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin, J Clin Invest source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In the elderly brain, there is a subpopulation of ferritin-positive microglia cells and most of these cells have aberrant dystrophic-type morphology.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron changes in brain ageing
What the sources say
- Not checked yetcites [55] Lopes, 2008, Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity, Glia source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Although haem oxygenase 1 (HO-1) is considered to be cytoprotective, up-regulation of this enzyme in glia might contribute to neurodegeneration: as brains age, the prolonged action of HO-1 in astrocytes is likely to be involved in iron sequestration, intracellular oxidative stress, and mitochondrial insufficiency.56”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron changes in brain ageing
What the sources say
- Not checked yetcites [56] Schipper, 2009, Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement, J Neurochem source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Neurodegeneration that results from iron toxicity can lead to apoptosis73 and ferroptosis, an iron-specific form of non-apoptotic cell death.74”
§ The role of iron in brain ageing and neurodegenerative disorders > Neurodegenerative mechanisms involving iron
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ROS can damage DNA and mtDNA,58 affect DNA expression by epigenetic mechanisms,59 and oxidise proteins.”
§ The role of iron in brain ageing and neurodegenerative disorders > Neurodegenerative mechanisms involving iron
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Oligodendrocytes contain the largest amount of iron, stored mainly as ferritin and transferrin, and concentration remains constant as people age.28”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron changes in brain ageing
What the sources say
- Not checked yetcites [28] Connor, 1990, Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains, J Neurosci Res source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Inclusion bodies containing damaged or aggregated proteins could cause endoplasmic reticulum stress, which is a common feature of several neurodegenerative diseases.72”
§ The role of iron in brain ageing and neurodegenerative disorders > Neurodegenerative mechanisms involving iron
What the sources say
- Not checked yetcites [72] Liu, 2012, Iron and ER stress in neurodegenerative disease, Biometals source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“IRP binding to IRE might interfere with APP translation and translocation across the endoplasmic reticulum membrane; the interference could be substantial because α secretase activity needs membrane-bound APP.81”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Alzheimer’s disease
What the sources say
- Not checked yetcites [81] Rogers, 2002, An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript, J Biol Chem source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Microtubule-associated protein tau (MAPT) deficiency induces intracellular iron accumulation, which causes degeneration of dopaminergic neurons, leading to parkinsonism with dementia in mice.85”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Alzheimer’s disease
What the sources say
- Not checked yetcites [85] Lei, 2012, Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export, Nat Med source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“By contrast, iron deficiency will increase furin activity, thereby enhancing α secretase and stimulating the non-amyloidogenic pathway.78,80”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Alzheimer’s disease
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Increased iron concentrations accompany Aβ aggregation in areas initially affected in Alzheimer’s disease and offer an opportunity for a MRI-based diagnosis.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Alzheimer’s disease
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“APP was suggested to have ferroxidase activity,82 but this has not been confirmed by in-vitro studies with a peptide containing the iron-binding REXXE motif and the full-length protein.83,84”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Alzheimer’s disease
What the sources say
- Not checked yetcites [82] Duce, 2010, Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease, Cell source
- Not checked yetcites [83] Ebrahimi, 2012, A synthetic peptide with the putative iron binding motif of amyloid precursor protein (APP) does not catalytically oxidize iron, PLoS One source
- Not checked yetcites [84] Honarmand Ebrahimi, 2013, The amyloid precursor protein (APP) does not have a ferroxidase site in its E2 domain, PLoS One source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Abnormal homoeostasis of zinc, copper, and iron metal ions has been implicated in the misfolding process associated with the production of amyloid β (Aβ), from amyloid precursor protein (APP), hyperphosphorylated tau (found in the plaques and tangles), and contributing to neuronal oxidative stress.76”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Alzheimer’s disease
What the sources say
- Not checked yetcites [76] Sayre, 2000, In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals, J Neurochem source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Excessive amounts of total iron will decrease furin activity because transcription of furin is modulated by cellular concentrations of iron, leading to decreased furin protein concentrations which thereby favours β secretase activity and enhances the amyloidogenic pathway.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Alzheimer’s disease
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although MRI resolution is not sufficient to detect individual plaques, T2* abnormalities that result from plaque aggregates might be detected with MRI.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Alzheimer’s disease
What the sources say
- Not checked yetcites [88] Jack, 2005, In vivo magnetic resonance microimaging of individual amyloid plaques in Alzheimer's transgenic mice, J Neurosci source
- Not checked yetcites [89] Nabuurs, 2011, High-field MRI of single histological slices using an inductively coupled, self-resonant microcoil: application to ex vivo samples of patients with Alzheimer's disease, NMR Biomed source
- Not checked yetcites [90] Antharam, 2012, High field magnetic resonance microscopy of the human hippocampus in Alzheimer's disease: quantitative imaging and correlation with iron, Neuroimage source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Increased redox-active iron is higher in patients with the most severe neuronal loss and is absent in neurons without neuromelanin.122–124”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [122] Jellinger, 1992, Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis, J Neurochem source
- Not checked yetcites [123] Good, 1992, Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study, Brain Res source
- Not checked yetcites [124] Faucheux, 2003, Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease, J Neurochem source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Iron deposits in presenilin/APP transgenic mice models of Alzheimer’s disease93 colocalise with Aβ plaques,94,95 and increases in total brain iron coincide with early plaque formation.96”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Alzheimer’s disease
What the sources say
- Not checked yetcites [93] Holcomb, 1998, Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes, Nat Med source
- Not checked yetcites [94] Smith, 1998, Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress, J Neurochem source
- Not checked yetcites [95] Falangola, 2005, Histological co-localization of iron in Abeta plaques of PS/APP transgenic mice, Neurochem Res source
- Not checked yetcites [96] Leskovjan, 2011, Increased brain iron coincides with early plaque formation in a mouse model of Alzheimer's disease, Neuroimage source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In patients with Parkinson’s disease, semi-quantitative histochemical methods showed that iron deposits were present in the neurons and glia of the substantia nigra, putamen, and globus pallidus, with an increase of ferritin-loaded microglia cells in the substantia nigra.112”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [112] Jellinger, 1990, Brain iron and ferritin in Parkinson's and Alzheimer's diseases, J Neural Transm Park Dis Dement Sect source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Investigations have shown an increase in redox-active iron associated with neuromelanin in substantia nigra neurons of patients with Parkinson’s disease, probably as a result of decreased ferritin synthesis.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [122] Jellinger, 1992, Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis, J Neurochem source
- Not checked yetcites [123] Good, 1992, Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study, Brain Res source
- Not checked yetcites [124] Faucheux, 2003, Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease, J Neurochem source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“HO-1 is up-regulated in the hippocampus and temporal cortex of patients with Alzheimer’s disease or mild cognitive impairment, which further implicates this haem-degrading enzyme in the pathogenesis of Alzheimer’s disease.98,99”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Alzheimer’s disease
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In-vitro and in-vivo studies have confirmed the ability of neuromelanin to activate microglia and induce death of dopamine neurons.127,128”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [127] Zecca, 2008, Human Neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease, Acta Neuropathol source
- Not checked yetcites [128] Zhang, 2011, Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson's disease, Neurotox Res source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“High concentrations of iron detected in the substantia nigra of individuals with Parkinson’s disease might exceed the iron-buffering capacity of complexes, such as neuromelanin and ferritin, and could induce neurotoxicity.124”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [124] Faucheux, 2003, Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease, J Neurochem source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“A contributing factor to the increased iron accumulation in Parkinson’s disease might be increased DMT1 activity or decreased ferroxidase activity of ceruloplasmin, both of which would increase total intracellular iron, as reported in an animal model of Parkinson’s disease109 and in patients.131–134”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [109] Salazar, 2008, Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease, Proc Natl Acad Sci USA source
- Not checked yetcites [131] Boll, 1999, Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease, Neurosci Lett source
- Not checked yetcites [132] Boll, 2008, Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NO(x) content in the CSF. A different marker profile in four neurodegenerative diseases, Neurochem Res source
- Not checked yetcites [133] Martínez-Hernández, 2011, Plasma ceruloplasmin ferroxidase activity correlates with the nigral sonographic area in Parkinson's disease patients: a pilot study, Neurochem Res source
- Not checked yetcites [134] Olivieri, 2011, Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention, J Neurosci source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Reduced ferroxidase activity of ceruloplasmin was noted in the CSF of patients with Parkinson’s disease together with increased CSF copper concentrations by comparison with controls,131 a condition which could contribute to the increased mobilisation of reactive iron and oxidative stress reported in Parkinson’s disease.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [131] Boll, 1999, Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease, Neurosci Lett source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“MRI measures generally have been found to correlate with disability and thus might be used to monitor disease progression.104,144,145”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [104] Péran, 2010, Magnetic resonance imaging markers of Parkinson's disease nigrostriatal signature, Brain source
- Not checked yetcites [144] Gorell, 1995, Increased iron-related MRI contrast in the substantia nigra in Parkinson's disease, Neurology source
- Not checked yetcites [145] Martin, 2008, Midbrain iron content in early Parkinson disease: a potential biomarker of disease status, Neurology source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This increased risk is likely to be due to the need for adequate supplies of iron for the synthesis of neurotransmitters, such as dopamine, because iron is a cofactor of tyrosine hydroxylase (the key enzyme of dopamine synthesis).”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Despite the aforementioned increases of total and reactive iron content in brain areas of patients with Parkinson’s disease, increased concentrations of total serum iron are causally associated with a decreased risk of developing Parkinson’s disease, thus showing a potentially protective effect of peripheral iron.138,139”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Transcranial sonography might be a helpful technique in the diagnosis of Parkinson’s disease, Friedreich’s ataxia, Huntington’s disease, and restless leg syndrome and might be useful to differentiate between idiopathic Parkinson’s disease and atypical parkinsonian syndromes.152”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [152] Bouwmans, 2010, Transcranial sonography for the discrimination of idiopathic Parkinson's disease from the atypical parkinsonian syndromes, Int Rev Neurobiol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“In Parkinson’s disease, loss of neuromelanin and an increase in iron concentration is noted in the substantia nigra.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [153] Zecca, 2005, In vivo detection of iron and Neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage, Mov Disord source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Overexpression of DMT1 and iron accumulation was noted in the mesencephalon of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine animal models of Parkinson’s disease.109”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [109] Salazar, 2008, Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease, Proc Natl Acad Sci USA source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“A positive association between iron and ferritin concentrations, and a negative association of neuromelanin content with the area of echogenicity of the substantia nigra could therefore provide a basis for diagnosis and therapeutic follow-up studies in patients with Parkinson’s disease.153”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [153] Zecca, 2005, In vivo detection of iron and Neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage, Mov Disord source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Ultrasound investigation of post-mortem brains from healthy individuals showed a positive correlation between the echogenic area of the substantia nigra and concentration of iron and heavy and light chain ferritin, and a negative correlation between echogenicity and neuromelanin content of the substantia nigra.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [153] Zecca, 2005, In vivo detection of iron and Neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage, Mov Disord source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Preliminary reports state that identification of neuromelanin (rather than iron) by MRI might be feasible in patients with Parkinson’s disease.148,149”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [148] Nakane, 2008, Visualization of neuromelanin in the substantia nigra and locus ceruleus at 1·5T using a 3D-gradient echo sequence with magnetization transfer contrast, Magn Reson Med Sci source
- Not checked yetcites [149] Sasaki, 2008, Neuromelanin-sensitive MRI. Basics, technique and clinical applications, Clin Neuroradiol source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Increased amounts of iron were assayed in the brains of both the 6-hydroxydopamine and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine animal model of Parkinson’s disease,109,154 consistent with the increased expression of a DMT1 isoform (+IRE) reported in the substantia nigra of patients with Parkinson’s disease.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Parkinson’s disease
What the sources say
- Not checked yetcites [109] Salazar, 2008, Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease, Proc Natl Acad Sci USA source
- Not checked yetcites [154] Song, 2010, Ferroportin 1 but not hephaestin contributes to iron accumulation in a cell model of Parkinson's disease, Free Radic Biol Med source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“frataxin probably regulates iron handling in mitochondria, and prevents iron from generating oxidative stress.”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron in neurodegenerative disorders > Friedreich’s ataxia
What the sources say
- Not checked yetcites [57] Crichton, 2014
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“PBT2 binds excesses of copper and zinc and possibly iron in the brain, thereby diminishing the amount of amyloid plaque formation and relocating these metal ions to depleted cellular and neuronal compartments.218”
§ The role of iron in brain ageing and neurodegenerative disorders > Iron chelation as a potential therapy > Alzheimer’s disease
What the sources say
- Not checked yetcites [218] Crouch, 2011, The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity, J Neurochem source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper relies on this without support.
Ageing is the major risk factor for neurodegeneration.
“Ageing is the major risk factor for neurodegeneration.”
The paper relies on this without support.
Iron accumulation in specific brain regions greater than that reported in healthy ageing occurs in many neurodegenerative diseases and is often associated with oxidative stress and cellular damage.
“However, the accumulation of iron in specific brain regions, greater than that reported in healthy ageing, occurs in many neurodegenerative diseases and is often associated with oxidative stress and cellular damage.”
The paper relies on this without support.
In peripheral iron-loading diseases, such as thalassaemias and haemochromatosis, there is no increased incidence of neurodegeneration or elevated concentrations of brain iron despite massive iron deposition in parenchymal tissues.
“In peripheral iron-loading diseases, such as thalassaemias and haemochromatosis, no evidence has been reported of an increased incidence of neurodegeneration, nor of elevated concentrations of brain iron, despite the massive iron deposition in parenchymal tissues.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“Iron accumulation is also observed in other neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease (68, 69), although a causal link between iron overload and neurodegeneration has not been established.”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [68]
In the citing paper
“several lines of evidence suggest that excessive iron accumulation can be detrimental to brain structures and could be associated with brain ageing and neurodegenerative disorders [207].”
From Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence (2020) · cites this paper as [207]
Citations
Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691
Astrocyte-endothelial interactions at the blood-brain barrier
Abbott, N. J., Rönnbäck, L., & Hansson, E. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1824 · Cited by 5,595
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
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Metadata
- Authors
- Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R., & Zecca, L.
- Affiliations
- Hammersmith Hospital (GB)
- Institute of Biomedical Technologies (IT)
- National Institutes of Health (US)
- UCLouvain (BE)
- Corresponding author
- Zecca, Luigi
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 13
- Issue
- 10
- Pages
- 1045-1060
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC5672917
- OpenAlex
- W2112867510
- Semantic Scholar
- 678eb5fafcfe5243b063a7040e2aac9a04dee675
- Cited by
- 1,819
- References
- 228
- Citations by year
- 2026: 154 · 2025: 233 · 2024: 231 · 2023: 208 · 2022: 203 · 2021: 208 · 2020: 147 · 2019: 150 · 2018: 94 · 2017: 70 · 2016: 62 · 2015: 57 · 2014: 1
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Libraries (submittedVersion)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca (RBNE08ZZN7)
- Consiglio Nazionale delle Ricerche (PB·P05)
- Topics
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- brain iron, iron homeostasis, brain aging, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, iron accumulation, oxidative stress, hydroxyl radicals, iron chelators, blood-brain barrier, MRI biomarkers, neuroprotection
- MeSH terms
- Aging, Animals, Brain, Brain Chemistry, Humans, Iron, Iron Chelating Agents, Magnetic Resonance Imaging, Biomarkers, Neuroprotective Agents, Nonheme Iron Proteins, Neurodegenerative Diseases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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