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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'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, A?, 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 (R 2 = 22%, ? = 0.202, and p = 0.017) and RAVLT scores (R 2 = 7.30%, ? = -0.178, and p = 0.043) and negatively correlated to ADAS-Cog13 (R 2 = 17.3%, ? = 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 A?. Further investigations are required to determine the source of CSF MTf and how brain MTf is regulated by cellular barriers, A? 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.

SUBMITTER: Ashraf A

PROVIDER: S-EPMC6419538 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Ashraf Azhaar A Alepuz Guillen Jose Andres JA Aljuhani Manal M Hubens Chantal C So Po-Wah PW

Frontiers in neuroscience 20190308

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 impa ...[more]

PMID: 30906244

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Project description:In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-?1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-?1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-? amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-?1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ?4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-?1-42 values and APOE ?2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-?1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-?1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.

Dataset Information

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

Publications

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

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