CSF proteomic analysis reveals persistent iron deficiency‐induced alterations in non‐human primate infants

Geguchadze, Ramaz; Coe, Christopher L.; Lubach, Gabriele R.; Clardy, Thomas; Beard, John L.; Connor, James R.

doi:10.1111/j.1471-4159.2007.05113.x

Cited by 25 publications

(29 citation statements)

References 44 publications

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“…In the ID individual, there may be a further prioritizing of iron to bone marrow, liver, spleen, and red blood cells, which may be placing the brain needs for iron in jeopardy. Our finding of a delayed but sustained effect on the CNS also concurs with a prior proteomic analysis of CSF from a different group of ID monkeys, which indicated that their iron regulatory proteins were increased and the intrathecal proteome disturbed for at least 4 months after the period of anemia had ended (Geguchadze, Coe, Lubach, Clardy, Beard, & Connor, 2008). …”

Section: Discussionsupporting

confidence: 90%

A history of iron deficiency anemia during infancy alters brain monoamine activity later in juvenile monkeys

Coe

Lubach

Bianco

et al. 2009

Developmental Psychobiology

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Both during and after a period of iron deficiency (ID), iron-dependent neural processes are affected, which raises the potential concern that the anemia commonly experienced by many growing infants could have a protracted effect on the developing brain. To further investigate the effects of ID on the immature brain, 49 infant rhesus monkeys were evaluated across the first year of life. The mothers, and subsequently the infants after weaning, were maintained on a standardized diet containing 180 mg/kg of iron and were not provided other iron-rich foods as treats or supplements. As the infants grew, they were all screened with hematological tests, which documented that 16 (33.3%) became markedly ID between 4-to-8 months of age. During this anemic period and subsequently at one year of age, cerebrospinal fluid (CSF) specimens were collected to compare monoamine activity in the ID and iron-sufficient infants. Monoamine neurotransmitters and metabolite levels were normal at 4 and 8 months of age, but by one year the formerly anemic monkeys had significantly lower dopamine and significantly higher norepinephrine levels. These findings indicate that ID can affect the developmental trajectory of these two important neurotransmitter systems, which are associated with emotionality and behavioral performance, and further that the impact in the young monkey was most evident during the period of recovery.

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Section: Discussionsupporting

confidence: 90%

A history of iron deficiency anemia during infancy alters brain monoamine activity later in juvenile monkeys

Coe

Lubach

Bianco

et al. 2009

Developmental Psychobiology

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“…One protein identified by our iTRAQ study that was also altered in our previous study [19] was prostaglandin H2-D-isomerase, which is also referred to as prostaglandin D2 synthase (PGDS), and functions to catalyze the conversion of prostaglandin H2 to PGD2. PGDS is produced in the leptomeninges and choroid plexus, and the enzymatic product PGD2 is a neuromodulator as well as a trophic factor in the CNS.…”

Section: Discussionmentioning

confidence: 78%

“…The iTRAQ methodology was chosen because it not only identifies proteins of interest, but also permits accurate quantification, allowing for key comparisons in a systematic manner. A previous study of IDA in infant monkeys using 2D analyses [19] revealed that a distinct CSF protein profile persisted for over 4 months after the period of anemia, and it was still evident in infants that received 2 months of ferrous sulfate treatment. The current results confirm and extend those findings.…”

Section: Discussionmentioning

confidence: 99%

“…Although serum would be the most convenient source for routine, noninvasive testing, cerebrospinal fluid (CSF) is more likely to provide an accurate reflection of depleted iron stores in the brain [19–21]. Several recent studies have documented that there is a selective prioritization and partitioning of iron across different tissues in the anemic state, and thus hematological indices do not sensitively reflect the full extent of the CNS depletion [19]. One other advantage of CSF as the biological medium for the proteomic approach used in the current research is that CSF is sequestered behind both the blood-brain and brain-CSF barriers.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Proteomic Analyses of Cerebrospinal Fluid Using iTRAQ in a Primate Model of Iron Deficiency Anemia

et al. 2012

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Iron deficiency affects nearly 2 billion people worldwide, with pregnant women and young children being most severely impacted. Sustained anemia during the first year of life can cause cognitive, attention and motor deficits, which may persist despite iron supplementation. We conducted iTRAQ analyses on cerebrospinal fluid (CSF) from infant monkeys (Macaca mulatta) to identify differential protein expression associated with early iron deficiency. CSF was collected from 5 iron-sufficient and 8 iron-deficient anemic monkeys at weaning age (6–7 months) and again at 12–14 months. Despite consumption of iron-fortified food after weaning, which restored hematological indices into the normal range, expression of 5 proteins in the CSF remained altered. Most of the proteins identified are involved in neurite outgrowth, migration or synapse formation. The results reveal novel ways in which iron deficiency undermines brain growth and results in aberrant neuronal migration and connections. Taken together with gene expression data from rodent models of iron deficiency, we conclude that significant alterations in neuroconnectivity occur in the iron-deficient brain, which may persist even after resolution of the hematological anemia. The compromised brain infrastructure could account for observations of behavioral deficits in children during and after the period of anemia.

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“…This expression pattern for Tf and ferritin when seen in the serum is considered an indicator of systemic iron deficiency. Elevated CSF Tf levels also were observed in a developmental non-human primate model of iron deficiency, despite supplementation with iron and resolution of hematological iron deficiency [27]. The persistence of elevated Tf in CSF despite repletion of systemic iron brings up the possibility that a set point for iron status in the brain was altered during development that may render the brain sensitive to iron challenges into adulthood.…”

Section: Introductionmentioning

confidence: 99%

Iron and restless legs syndrome: treatment, genetics and pathophysiology

Connor

Patton

Oexle³

et al. 2017

Sleep Medicine

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In this article, we review the original findings from MRI and autopsy studies that demonstrated brain iron status is insufficient in individuals with restless legs syndrome (RLS). The concept of deficient brain iron status is supported by proteomic studies from cerebrospinal fluid (CSF) and from the clinical findings where intervention with iron, either dietary or intravenous, can improve RLS symptoms. Therefore, we include a section on peripheral iron status and how peripheral status may influence both the RLS symptoms and treatment strategy. Given the impact of iron in RLS, we have evaluated genetic data to determine if genes are directly involved in iron regulatory pathways. The result was negative. In fact, even the HFE mutation C282Y could not be shown to have a protective effect. Lastly, a consistent finding in conditions of low iron is increased expression of proteins in the hypoxia pathway. Although there is lack of clinical data that RLS patients are hypoxic, there are intriguing observations that environmental hypoxic conditions worsen RLS symptoms; in this chapter we review very compelling data for activation of hypoxic pathways in the brain in RLS patients. In general, the data in RLS point to a pathophysiology that involves decreased acquisition of iron by cells in the brain. Whether the decreased ability is genetically driven, activation of pathways (eg, hypoxia) that are designed to limit cellular uptake is unknown at this time; however, the data strongly support a functional rather than structural defect in RLS, suggesting that an effective treatment is possible.

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CSF proteomic analysis reveals persistent iron deficiency‐induced alterations in non‐human primate infants

Cited by 25 publications

References 44 publications

A history of iron deficiency anemia during infancy alters brain monoamine activity later in juvenile monkeys

A history of iron deficiency anemia during infancy alters brain monoamine activity later in juvenile monkeys

Quantitative Proteomic Analyses of Cerebrospinal Fluid Using iTRAQ in a Primate Model of Iron Deficiency Anemia

Iron and restless legs syndrome: treatment, genetics and pathophysiology

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