Journal
FRONTIERS IN NEUROSCIENCE
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fnins.2019.00181
Keywords
Alzheimer's disease; CSF; iron; MCI; melanotransferrin; microglia
Categories
Funding
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- Fujirebio
- Johnson & Johnson Pharmaceutical Research and Development LLC.
- Merck Co., Inc.
- Meso Scale Diagnostics
- NeuroRx Research
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Takeda Pharmaceutical Company
- Canadian Institutes of Health Research
- ADNI clinical sites in Canada
- Foundation for the National Institutes of Health
- Northern California Institute for Research and Education
- Laboratory for Neuro Imaging at the University of Southern California - National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London
- Biotechnology and Biological Sciences Research Council (BBSRC), King's College London and Perspectum Diagnostics Ltd.
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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 beta, 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%, beta = 0.202, and p = 0.017) and RAVLT scores (R-2 = 7.30%, beta = -0.178, and p = 0.043) and negatively correlated to ADAS-Cog13 (R-2 = 17.3%, beta = 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 beta. Further investigations are required to determine the source of CSF MTf and how brain MTf is regulated by cellular barriers, A beta 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.
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