Age-related Iron Deposition in the Basal Ganglia: Quantitative Analysis in Healthy Subjects

Aquino, Domenico; Bizzi, Alberto; Grisoli, Marina; Garavaglia, Barbara; Bruzzone, Maria Grazia; Nardocci, Nardo; Savoiardo, M.; Chiapparini, Luisa

doi:10.1148/radiol.2522081399

Cited by 252 publications

(269 citation statements)

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“…The evidence presented here indicates that the relationship between T1 and age is not straightforward, with evidence of little change in older age and an increase in middle age. Interestingly, these findings reflect a previous observation which demonstrated that, in humans, gray matter T1 relaxation times were highest in middle age, with both younger and older subjects showing lower values (Aquino et al, 2009).…”

Section: Discussionsupporting

confidence: 89%

“…5c). However previous data indicated that T1 relaxation time was higher in 20-month-old rats than in younger animals and it has been reported by others that T1 relaxation time peaks at middle age (Aquino et al, 2009). To further evaluate this, data from several cohorts of rats were pooled and the findings support the contention that T1 relaxation time is age-dependent in hippocampus (Fig.…”

Section: Resultssupporting

confidence: 60%

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The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

Blau¹,

Cowley²,

O'Sullivan³

et al. 2012

Neurobiology of Aging

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In view of the increase in the aging population and the unavoidable parallel increase in the incidence of age-related neurodegenerative diseases, a key challenge in neuroscience is the identification of clinical signatures which change with age and impact on neuronal and cognitive function. Early diagnosis offers the possibility of early therapeutic intervention, thus magnetic resonance imaging (MRI) is potentially a powerful diagnostic tool. We evaluated age-related changes in relaxometry, blood flow, and blood-brain barrier (BBB) permeability in the rat by magnetic resonance imaging and assessed these changes in the context of the age-related decrease in synaptic plasticity. We report that T2 relaxation time was decreased with age; this was coupled with a decrease in gray matter perfusion, suggesting that the observed microglial activation, as identified by increased expression of CD11b, MHCII, and CD68 by immunohistochemistry, flow cytometry, or polymerase chain reaction (PCR), might be a downstream consequence of these changes. Increased permeability of the blood-brain barrier was observed in the perivascular area and the hippocampus of aged, compared with young, rats. Similarly there was an age-related increase in CD45-positive cells by flow cytometry, which are most likely infiltrating macrophages, with a parallel increase in the messenger mRNA expression of chemokines IP-10 and MCP-1. These combined changes may contribute to the deficit in long-term potentiation (LTP) in perforant path-granule cell synapses of aged animals.

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Section: Discussionsupporting

confidence: 89%

Section: Resultssupporting

confidence: 60%

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

Blau¹,

Cowley²,

O'Sullivan³

et al. 2012

Neurobiology of Aging

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“…However, the presence of conditions that increase macromolecules in sites which show negative correlations with age is less likely. Basal ganglia structures show hemosiderin deposition with age (8), and increased levels of hemosiderin reduce T2-relaxation values (12), perhaps resulting in the negative correlations found here. Whether age-related changes in iron deposition occur in the pons is unclear; however, the negative correlations may result from iron deposition in a neighboring brain site, the substantia nigra, which does show increased hemosiderin deposition with age in healthy adults (8,26).…”

Section: Discussionmentioning

confidence: 67%

“…Basal ganglia structures show hemosiderin deposition with age (8), and increased levels of hemosiderin reduce T2-relaxation values (12), perhaps resulting in the negative correlations found here. Whether age-related changes in iron deposition occur in the pons is unclear; however, the negative correlations may result from iron deposition in a neighboring brain site, the substantia nigra, which does show increased hemosiderin deposition with age in healthy adults (8,26). Several brain sites, including the frontal gray matter, basal ganglia, temporal and occipital white matter, thalamus, and cerebellar areas, showed reduced T2-relaxation values in female over male subjects, although no significant differences in age appeared between sexes.…”

Section: Discussionmentioning

confidence: 67%

Age‐related regional brain T2‐relaxation changes in healthy adults

Kumar

Delshad

Woo

et al. 2011

Magnetic Resonance Imaging

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Purpose: To determine normal T2-relaxation values from different brain areas in healthy adults, assess age-related T2-relaxation changes in those sites, and evaluate potential gender-related T2-relaxation value differences. Materials and Methods:We performed proton-density and T2-weighted imaging in 60 healthy adults (male: 38, age range ¼ 31-64 years, mean age 6 SD ¼ 46.1 6 9.3 years; female: 22, age range ¼ 37-66 years, mean age 6 SD ¼ 49.5 6 8.3 years), using a 3.0 Tesla MRI scanner. T2-relaxation values were calculated voxel-by-voxel from proton-density and T2-weighted images, and whole-brain T2-relaxation maps were constructed and normalized to a common space. A set of regions-of-interest were outlined within the basal ganglia, limbic, frontal, parietal, temporal, occipital, thalamic, hypothalamic, cerebellar, and pontine regions using mean background images derived from normalized and averaged T2-weighted images of all individuals, and regional T2-relaxation values were determined from these regions-of-interest and normalized T2-relaxation maps. Pearson's correlations were calculated between T2-relaxation values and age, and male-female differences evaluated with independent-samples t-tests.Results: T2-relaxation values typically increased with age in multiple brain sites; only a few regions showed declines, including the putamen and ventral pons. Sexrelated differences in T2-relaxation values appeared in basal ganglia, frontal, temporal, occipital, and cerebellar regions; males showed higher values over females in these sites.Conclusion: Establishment of normative adult T2-relaxation values over different brain areas, with age and sex as co-factors, offers baseline values against which diseaserelated tissue changes can be assessed. NONINVASIVE ASSESSMENT OF adult human brain changes resulting from neurologic, neuropsychological, and neurocognitive pathologies against normal age-related changes remains difficult (1-3). Myelin and neurons undergo slow degradation with age in adults (4,5), and these normative changes, as well as neurodegenerative processes inducing myelin and neuronal loss (6,7), increase free tissue water content. However, certain deep brain structures, including the basal ganglia, are known to show iron deposition with age in adult subjects (8), which can alter indications of normal progression of tissue changes in these sites. Pathological and treatment-related brain tissue alterations can be assessed accurately, but only after controlling for age-related changes, which mandates determination of normative values from gray and white matter regions over wide-spread brain areas.MR T2-relaxometry provides a quantitative surrogate marker of brain tissue changes in both health and disease by assessing free tissue water content (9) in the absence of diamagnetic and paramagnetic substances, which differs during pediatric development over normal patterns of aging in adult controls (5,10), and increases with disease processes (11). T2-relaxation values increase with increased free tissue water cont...

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“…The degree of hypointensity in the globus pallidus and substantia nigra is markedly more robust in 3T magnets. 9 In addition, the degree of hypointensity increases with age, consistent with an age-dependent iron deposition, 10,11 both in normal aging and in NBIA. To correctly identify excess iron clinically, one must thus have a working knowledge of both age-and field-dependent norms.…”

mentioning

confidence: 71%

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

Kruer¹,

Boddaert²,

Schneider³

et al. 2011

AJNR Am J Neuroradiol

185

161

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SUMMARY: NBIA characterizes a class of neurodegenerative diseases that feature a prominent extrapyramidal movement disorder, intellectual deterioration, and a characteristic deposition of iron in the basal ganglia. The diagnosis of NBIA is made on the basis of the combination of representative clinical features along with MR imaging evidence of iron accumulation. In many cases, confirmatory molecular genetic testing is now available as well. A number of new subtypes of NBIA have recently been described, with distinct neuroradiologic and clinical features. This article outlines the known subtypes of NBIA, delineates their clinical and radiographic features, and suggests an algorithm for evaluation.ABBREVIATIONS: ACP ϭ aceruloplasminemia; CNS ϭ central nervous system; FAHN ϭ fatty acid hydroxylase-associated neurodegeneration; INAD ϭ infantile neuroaxonal dystrophy; KRS ϭ KuforRakeb syndrome; NAD ϭ neuroaxonal dystrophy; NBIA ϭ neurodegeneration with brain iron accumulation; NFT ϭ neuroferritinopathy; PKAN ϭ pantothenate kinase-associated neurodegeneration; PLAN ϭ phospholipase-associated neurodegeneration; SENDA ϭ static encephalopathy of childhood with neurodegeneration in adulthood; WSS ϭ Woodhouse-Sakati syndrome B efore the widespread availability of MR imaging, a diagnosis of NBIA could be made only at the time of autopsy. In contrast, current diagnosis is facilitated by evaluation by using both T1-and T2-weighted sequences. As a paramagnetic substance, Fe 3ϩ catalyzes the nuclear spin relaxation of neighboring water protons. With standard clinical parameters, areas rich in iron appear hypointense on T2-weighted sequences, and isointense on T1 sequences. T2*-weighted acquisitions (gradient-echo sequences) may accentuate this degree of hypointensity ("blooming") and may be helpful in identifying NBIA disorders as may susceptibility-weighted images.1 In biologic iron-oxides, Fe 2ϩ typically has fewer unpaired electrons than Fe 3ϩ and is less effective in quenching T2-weighted signal intensity.2 Calcium may also appear isointense on T1 and hypointense on T2-weighted sequences, mimicking the appearance of iron. The 2 minerals are readily distinguished by CT, however, because Ca 2ϩ characteristically appears hyperintense to the surrounding brain parenchyma, while iron is isointense. In addition, iron typically appears markedly hypointense on both standard clinical diffusionweighted and apparent diffusion coefficient sequences. Other metals that may be deposited in neurodegenerative disorders, such as manganese and copper, have a distinct appearance on T1-and T2-weighted sequences, enabling a heuristic approach to diagnosis based on MR imaging parameters. The characteristics of these metals are summarized in Table 1. Despite the utility of MR imaging in this setting, it does not preclude the need for elemental analysis of neuropathologic specimens; rather, it enables putative diagnosis to be made during life.The radiographic appearance of the lesions themselves is of prime importance. Iron deposition occurs in mul...

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Age-related Iron Deposition in the Basal Ganglia: Quantitative Analysis in Healthy Subjects

Abstract: R2* measurements can be used to quantify brain iron accumulation and thus may allow better evaluation of neurodegenerative diseases associated with iron deposition.

Cited by 252 publications

References 44 publications

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

Age‐related regional brain T2‐relaxation changes in healthy adults

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

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