Correlation of proton transverse relaxation rates (<i>R</i><sub>2</sub>) with iron concentrations in postmortem brain tissue from alzheimer's disease patients

House, Michael J.; Pierre, Timothy G. St.; Kowdley, Kris V.; Montine, Thomas J.; Connor, James R.; Beard, John L.; Berger, Jose; Siddaiah, Narendra; Shankland, Eric G.; Jin, Lee Way

doi:10.1002/mrm.21118

Cited by 98 publications

(95 citation statements)

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“…90 In a separate study using highresolution 4.7T MRI, this same group of investigators showed a direct correlation between R2 and iron concentrations in postmortem brain tissue obtained from patients with AD. 11 The study also corroborates previous studies demonstrating increased basal ganglia iron levels in patients with AD. 30,32 Collectively these studies suggest that brain gray matter iron deposition may facilitate some of the early neurodegenerative changes seen in AD.…”

Section: Alzheimer's Diseasesupporting

confidence: 90%

“…3 A growing body of data suggests that brain iron accumulation in vivo may contribute to tissue damage in a variety of chronic neurological disorders. Histological and magnetic resonance imaging (MRI) data have suggested increases in iron levels in the gray matter in Parkinson's disease (PD), 4 -10 Alzheimer's disease (AD), [11][12][13][14][15][16][17] multiple sclerosis (MS), 18 -21 and a host of other chronic neurological disorders. 22 Consequently, there is a growing interest in optimizing the ability of MRI to estimate iron deposition in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

et al. 2007

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Summary:Iron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurological disorders including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathological processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article, we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development.

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Section: Alzheimer's Diseasesupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

et al. 2007

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“…Given that R2* reflects brain iron content in postmortem samples and in vivo [6][7][8][9][10] , the progressive increase in thalamic R2* is likely to reflect ongoing iron accumulation in neuroferritinopathy, detectable during a 6-to 12-month period. Moreover, the correlation of thalamic R2* with dystonia severity scores supports the use of quantitative MR imaging both to monitor natural history and to study the effects of any treatment aimed at modulating brain iron stores.…”

Section: Discussionmentioning

confidence: 99%

“…Iron decreases the MR T2 decay time and therefore increases the R2 (R2 ϭ 1 /T2), which correlates with iron content in postmortem brain tissue in healthy controls and in neurologic disease. [6][7][8][9][10][11] The R2*(R2* ϭ 1 /T2*) has been shown to be more sensitive than conventional MR imaging in detecting brain iron accumulation. 11 Here we used 3T MR imaging to assess structural changes during a 12-month period on T1 and T2-weighted images and to examine the ability of quantitative R2* (R2* ϭ 1 /T2*) measurement to track iron accumulation in neuroferritinopathy.…”

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confidence: 99%

Progressive Brain Iron Accumulation in Neuroferritinopathy Measured by the Thalamic T2* Relaxation Rate

McNeill

Gorman

Khan

et al. 2012

AJNR Am J Neuroradiol

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SUMMARY Neuroferritinopathy is an autosomal dominant extrapyramidal movement disorder, caused by FTL gene mutations. Iron decreases the MR T2* decay time, therefore increasing the R2* (R2* = 1 /T2*), which correlates with brain tissue iron content. 3T structural and quantitative MR imaging assessment of R2* in 10 patients with neuroferritinopathy demonstrated a unique pattern of basal ganglia cavitation involving the substantia nigra in older patients and increasing thalamic R2* signal intensity detectable during 6 months. Increasing R2* signal intensity in the thalamus correlated with progression on a clinical rating scale measuring dystonia severity. Thalamic R2* signal intensity is a clinically useful method of objectively tracking disease progression in this form of neurodegeneration with brain iron accumulation.

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“…Its effect on susceptibilityweighted gradient echo MRI techniques increases with field strength (Abduljalil et al, 2003;Duyn et al, 2007). Studies on healthy brains both in vivo and post-mortem suggest that magnetic susceptibility contrast has several contributors, such as myelin (Duyn et al, 2007;Li et al, 2009;Fukunaga et al, 2010), calcium and phospholipid (He and Yablonskiy, 2009), haem-iron (deoxyhaemoglobin) and non-haem iron (Bizzi et al, 1990;Schenck 1995;Gelman et al, 1999;St Pierre et al, 2005;House et al, 2006House et al, , 2007House et al, , 2010; Lee et al, 2009Lee et al, , 2010aShmueli et al, 2009;Yao et al, 2009;Fukunaga et al, 2010). Of these factors, non-haem iron and myelin are both particularly relevant with respect to multiple sclerosis pathology.…”

Section: Introductionmentioning

confidence: 99%

Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

Bagnato

Hametner²,

Yao³

et al. 2011

Brain

312

346

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Previous authors have shown that the transverse relaxivity R 2 * and frequency shifts that characterize gradient echo signal decay in magnetic resonance imaging are closely associated with the distribution of iron and myelin in the brain's white matter. In multiple sclerosis, iron accumulation in brain tissue may reflect a multiplicity of pathological processes. Hence, iron may have the unique potential to serve as an in vivo magnetic resonance imaging tracer of disease pathology. To investigate the ability of iron in tracking multiple sclerosis-induced pathology by magnetic resonance imaging, we performed qualitative histopathological analysis of white matter lesions and normal-appearing white matter regions with variable appearance on gradient echo magnetic resonance imaging at 7 Tesla. The samples used for this study derive from two patients with multiple sclerosis and one non-multiple sclerosis donor. Magnetic resonance images were acquired using a whole body 7 Tesla magnetic resonance imaging scanner equipped with a 24-channel receive-only array designed for tissue imaging. A 3D multi-gradient echo sequence was obtained and quantitative R 2 * and phase maps were reconstructed. Immunohistochemical stainings for myelin and oligodendrocytes, microglia and macrophages, ferritin and ferritin light polypeptide were performed on 3-to 5-mm thick paraffin sections. Iron was detected with Perl's staining and 3,3 0 -diaminobenzidine-tetrahydrochloride enhanced Turnbull blue staining.In multiple sclerosis tissue, iron presence invariably matched with an increase in R 2 *. Conversely, R 2 * increase was not always associated with the presence of iron on histochemical staining. We interpret this finding as the effect of embedding, sectioning and staining procedures. These processes likely affected the histopathological analysis results but not the magnetic resonance imaging that was obtained before tissue manipulations. Several cellular sources of iron were identified. These sources included oligodendrocytes in normal-appearing white matter and activated macrophages/microglia at the edges of white matter lesions. Additionally, in white matter lesions, iron precipitation in aggregates typical of microbleeds was shown by the Perl's staining. Our combined imaging and pathological study shows that multi-gradient echo magnetic resonance imaging is a sensitive technique for the identification of iron in the brain tissue of patients with multiple sclerosis. However, magnetic resonance doi:10.1093/brain/awr278 imaging-identified iron does not necessarily reflect pathology and may also be seen in apparently normal tissue. Iron identification by multi-gradient echo magnetic resonance imaging in diseased tissues can shed light on the pathological processes when coupled with topographical information and patient disease history.

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Correlation of proton transverse relaxation rates (R₂) with iron concentrations in postmortem brain tissue from alzheimer's disease patients

Cited by 98 publications

References 35 publications

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

Progressive Brain Iron Accumulation in Neuroferritinopathy Measured by the Thalamic T2* Relaxation Rate

Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

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Correlation of proton transverse relaxation rates (R2) with iron concentrations in postmortem brain tissue from alzheimer's disease patients

Cited by 98 publications

References 35 publications

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

Progressive Brain Iron Accumulation in Neuroferritinopathy Measured by the Thalamic T2* Relaxation Rate

Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

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Correlation of proton transverse relaxation rates (R₂) with iron concentrations in postmortem brain tissue from alzheimer's disease patients