Low Cerebrospinal Fluid Levels of Melanotransferrin Are Associated With Conversion of Mild Cognitively Impaired Subjects to Alzheimer's Disease

Azhaar Ashraf; Jose Andres Alepuz Guillen; Manal Aljuhani; Chantal Hubens; Po-Wah So

doi:10.3389/fnins.2019.00181

Low Cerebrospinal Fluid Levels of Melanotransferrin Are Associated With Conversion of Mild Cognitively Impaired Subjects to Alzheimer's Disease

Azhaar Ashraf, Jose Andres Alepuz Guillen, Manal Aljuhani, Chantal Hubens, Po-Wah So

Neuroimaging

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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Abstract

The disruption of iron metabolism and iron transport proteins have been implicated in the pathogenesis of Alzheimer’s disease (AD). Serum melanotransferrin (MTf), a transferrin homolog capable of reversibly binding iron, has been proposed as a biochemical marker of AD. MTf has also been shown to be elevated in iron-rich reactive microglia near amyloid plaques in AD. We examined the association of CSF MTf to hippocampal volumes and cognitive tests in 86 cognitively normal, 135 mild cognitive impairment (MCI) and 66 AD subjects. CSF was collected at baseline for MTf, Aβ, total-tau and phosphorylated-tau measurements. Serial cognitive testing with ADAS-Cog13, Rey’s auditory visual learning test (RAVLT), mini-mental state examination (MMSE) were performed alongside hippocampal MRI volumetric analysis for up to 10 years after baseline measurements. High levels of baseline CSF MTf were positively associated with baseline hippocampal volume (R2 = 22%, β = 0.202, and p = 0.017) and RAVLT scores (R2 = 7.30%, β = -0.178, and p = 0.043) and negatively correlated to ADAS-Cog13 (R2 = 17.3%, β = 0.247, and p = 0.003) scores in MCI subjects. Interestingly, MCI subjects that converted to AD demonstrated significantly lower levels of CSF MTf (p = 0.020) compared to MCI non-converters at baseline. We suggest the diminished CSF MTf observed in MCI-converters to AD may arise from impaired transport of MTf from blood into the brain tissue/CSF and/or increased MTf export from the CSF into the blood arising from attenuated competition with reduced levels of CSF Aβ. Further investigations are required to determine the source of CSF MTf and how brain MTf is regulated by cellular barriers, Aβ and activated microglia that surround plaques in AD pathophysiology. In conclusion, low CSF MTf may identify those MCI individuals at risk of converting to AD.

Original language	English
Pages (from-to)	181
Journal	Frontiers in Neuroscience
Volume	13
DOIs	https://doi.org/10.3389/fnins.2019.00181
Publication status	Published - 8 Mar 2019

Keywords

Alzheimer's disease
CSF
iron
MCI
melanotransferrin
microglia

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Low Cerebrospinal Fluid Levels_ASHRAF_Accepted14February2019_GOLD VoRFinal published version, 745 KBLicence: CC BY

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@article{d62d52cdbe1d4dfd9a374bcfa1037fef,

title = "Low Cerebrospinal Fluid Levels of Melanotransferrin Are Associated With Conversion of Mild Cognitively Impaired Subjects to Alzheimer's Disease",

abstract = "The disruption of iron metabolism and iron transport proteins have been implicated in the pathogenesis of Alzheimer{\textquoteright}s disease (AD). Serum melanotransferrin (MTf), a transferrin homolog capable of reversibly binding iron, has been proposed as a biochemical marker of AD. MTf has also been shown to be elevated in iron-rich reactive microglia near amyloid plaques in AD. We examined the association of CSF MTf to hippocampal volumes and cognitive tests in 86 cognitively normal, 135 mild cognitive impairment (MCI) and 66 AD subjects. CSF was collected at baseline for MTf, Aβ, total-tau and phosphorylated-tau measurements. Serial cognitive testing with ADAS-Cog13, Rey{\textquoteright}s auditory visual learning test (RAVLT), mini-mental state examination (MMSE) were performed alongside hippocampal MRI volumetric analysis for up to 10 years after baseline measurements. High levels of baseline CSF MTf were positively associated with baseline hippocampal volume (R2 = 22%, β = 0.202, and p = 0.017) and RAVLT scores (R2 = 7.30%, β = -0.178, and p = 0.043) and negatively correlated to ADAS-Cog13 (R2 = 17.3%, β = 0.247, and p = 0.003) scores in MCI subjects. Interestingly, MCI subjects that converted to AD demonstrated significantly lower levels of CSF MTf (p = 0.020) compared to MCI non-converters at baseline. We suggest the diminished CSF MTf observed in MCI-converters to AD may arise from impaired transport of MTf from blood into the brain tissue/CSF and/or increased MTf export from the CSF into the blood arising from attenuated competition with reduced levels of CSF Aβ. Further investigations are required to determine the source of CSF MTf and how brain MTf is regulated by cellular barriers, Aβ and activated microglia that surround plaques in AD pathophysiology. In conclusion, low CSF MTf may identify those MCI individuals at risk of converting to AD.",

keywords = "Alzheimer's disease, CSF, iron, MCI, melanotransferrin, microglia",

author = "Azhaar Ashraf and {Alepuz Guillen}, {Jose Andres} and Manal Aljuhani and Chantal Hubens and Po-Wah So",

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doi = "10.3389/fnins.2019.00181",

language = "English",

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T1 - Low Cerebrospinal Fluid Levels of Melanotransferrin Are Associated With Conversion of Mild Cognitively Impaired Subjects to Alzheimer's Disease

AU - Ashraf, Azhaar

AU - Alepuz Guillen, Jose Andres

AU - Aljuhani, Manal

AU - Hubens, Chantal

AU - So, Po-Wah

PY - 2019/3/8

Y1 - 2019/3/8

N2 - The disruption of iron metabolism and iron transport proteins have been implicated in the pathogenesis of Alzheimer’s disease (AD). Serum melanotransferrin (MTf), a transferrin homolog capable of reversibly binding iron, has been proposed as a biochemical marker of AD. MTf has also been shown to be elevated in iron-rich reactive microglia near amyloid plaques in AD. We examined the association of CSF MTf to hippocampal volumes and cognitive tests in 86 cognitively normal, 135 mild cognitive impairment (MCI) and 66 AD subjects. CSF was collected at baseline for MTf, Aβ, total-tau and phosphorylated-tau measurements. Serial cognitive testing with ADAS-Cog13, Rey’s auditory visual learning test (RAVLT), mini-mental state examination (MMSE) were performed alongside hippocampal MRI volumetric analysis for up to 10 years after baseline measurements. High levels of baseline CSF MTf were positively associated with baseline hippocampal volume (R2 = 22%, β = 0.202, and p = 0.017) and RAVLT scores (R2 = 7.30%, β = -0.178, and p = 0.043) and negatively correlated to ADAS-Cog13 (R2 = 17.3%, β = 0.247, and p = 0.003) scores in MCI subjects. Interestingly, MCI subjects that converted to AD demonstrated significantly lower levels of CSF MTf (p = 0.020) compared to MCI non-converters at baseline. We suggest the diminished CSF MTf observed in MCI-converters to AD may arise from impaired transport of MTf from blood into the brain tissue/CSF and/or increased MTf export from the CSF into the blood arising from attenuated competition with reduced levels of CSF Aβ. Further investigations are required to determine the source of CSF MTf and how brain MTf is regulated by cellular barriers, Aβ and activated microglia that surround plaques in AD pathophysiology. In conclusion, low CSF MTf may identify those MCI individuals at risk of converting to AD.

AB - The disruption of iron metabolism and iron transport proteins have been implicated in the pathogenesis of Alzheimer’s disease (AD). Serum melanotransferrin (MTf), a transferrin homolog capable of reversibly binding iron, has been proposed as a biochemical marker of AD. MTf has also been shown to be elevated in iron-rich reactive microglia near amyloid plaques in AD. We examined the association of CSF MTf to hippocampal volumes and cognitive tests in 86 cognitively normal, 135 mild cognitive impairment (MCI) and 66 AD subjects. CSF was collected at baseline for MTf, Aβ, total-tau and phosphorylated-tau measurements. Serial cognitive testing with ADAS-Cog13, Rey’s auditory visual learning test (RAVLT), mini-mental state examination (MMSE) were performed alongside hippocampal MRI volumetric analysis for up to 10 years after baseline measurements. High levels of baseline CSF MTf were positively associated with baseline hippocampal volume (R2 = 22%, β = 0.202, and p = 0.017) and RAVLT scores (R2 = 7.30%, β = -0.178, and p = 0.043) and negatively correlated to ADAS-Cog13 (R2 = 17.3%, β = 0.247, and p = 0.003) scores in MCI subjects. Interestingly, MCI subjects that converted to AD demonstrated significantly lower levels of CSF MTf (p = 0.020) compared to MCI non-converters at baseline. We suggest the diminished CSF MTf observed in MCI-converters to AD may arise from impaired transport of MTf from blood into the brain tissue/CSF and/or increased MTf export from the CSF into the blood arising from attenuated competition with reduced levels of CSF Aβ. Further investigations are required to determine the source of CSF MTf and how brain MTf is regulated by cellular barriers, Aβ and activated microglia that surround plaques in AD pathophysiology. In conclusion, low CSF MTf may identify those MCI individuals at risk of converting to AD.

KW - Alzheimer's disease

KW - CSF

KW - iron

KW - MCI

KW - melanotransferrin

KW - microglia

U2 - 10.3389/fnins.2019.00181

DO - 10.3389/fnins.2019.00181

M3 - Article

C2 - 30906244

SN - 1662-453X

VL - 13

SP - 181

JO - Frontiers in Neuroscience

JF - Frontiers in Neuroscience

ER -

Low Cerebrospinal Fluid Levels of Melanotransferrin Are Associated With Conversion of Mild Cognitively Impaired Subjects to Alzheimer's Disease

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Keywords

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