Cerebrospinal Fluid Aβ42, Tau, and F2-Isoprostane Concentrations in Patients With Alzheimer Disease, Other Dementias, and in Age-Matched Controls

Montine, Thomas J.; Kaye, J. A.; Montine, Kathleen S.; McFarland, Lynne L.; Morrow, Jason D.; Quinn, Joseph F.

doi:10.5858/2001-125-0510-cfataf

Cited by 110 publications

(15 citation statements)

References 14 publications

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“…The more iron in the cell, the greater the vulnerability toward ferroptosis. Lipid peroxides in ferroptosis lead to downstream products such as hydroxynonenal, malondialdehyde, F 2 ‐isoprostanes, acrolein, with subsequent depletion of long‐chain PUFA depletion—all changes that are reported for AD brain tissue 70–76 . The sites of putative therapeutics are noted.…”

Section: New or Updated Hypothesismentioning

confidence: 87%

Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance

Ayton

Portbury

Kalinowski

et al. 2021

Alzheimer's & Dementia

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Objective This paper is a proposal for an update of the iron hypothesis of Alzheimer's disease (AD), based on large‐scale emerging evidence. Background Iron featured historically early in AD research efforts for its involvement in the amyloid and tau proteinopathies, APP processing, genetics, and one clinical trial, yet iron neurochemistry remains peripheral in mainstream AD research. Much of the effort investigating iron in AD has focused on the potential for iron to provoke the onset of disease, by promoting proteinopathy though increased protein expression, phosphorylation, and aggregation. New/updated hypothesis We provide new evidence from a large post mortem cohort that brain iron levels within the normal range were associated with accelerated ante mortem disease progression in cases with underlying proteinopathic neuropathology. These results corroborate recent findings that argue for an additional downstream role for iron as an effector of neurodegeneration, acting independently of tau or amyloid pathologies. We hypothesize that the level of tissue iron is a trait that dictates the probability of neurodegeneration in AD by ferroptosis, a regulated cell death pathway that is initiated by signals such as glutathione depletion and lipid peroxidation. Major challenges for the hypothesis While clinical biomarkers of ferroptosis are still in discovery, the demonstration of additional ferroptotic correlates (genetic or biomarker derived) of disease progression is required to test this hypothesis. The genes implicated in familial AD are not known to influence ferroptosis, although recent reports on APP mutations and apolipoprotein E allele (APOE) have shown impact on cellular iron retention. Familial AD mutations will need to be tested for their impact on ferroptotic vulnerability. Ultimately, this hypothesis will be substantiated, or otherwise, by a clinical trial of an anti‐ferroptotic/iron compound in AD patients. Linkage to other major theories Iron has historically been linked to the amyloid and tau proteinopathies of AD. Tau, APP, and apoE have been implicated in physiological iron homeostasis in the brain. Iron is biochemically the origin of most chemical radicals generated in biochemistry and thus closely associated with the oxidative stress theory of AD. Iron accumulation is also a well‐established consequence of aging and inflammation, which are major theories of disease pathogenesis.

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Section: New or Updated Hypothesismentioning

confidence: 87%

Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance

Ayton

Portbury

Kalinowski

et al. 2021

Alzheimer's & Dementia

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“…Clear-cut experimental evidence shows that inflammatory responses are closely associated with the development of insulin resistance in obesity and T2DM ( 81 ), increasing the risk of AD. Accordingly, in the cerebrospinal fluid (CSF) of patients with AD, high concentrations of interleukin 6 (IL-6) have been reported ( 82 ). Studies on experimental animals suggest that inflammation interacts with the processing and deposition of β-amyloid peptide ( 83 ).…”

Section: Alterations In Glucose and Insulin Metabolism In Neurologica...mentioning

confidence: 99%

Significance of Brain Glucose Hypometabolism, Altered Insulin Signal Transduction, and Insulin Resistance in Several Neurological Diseases

et al. 2022

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Several neurological diseases share pathological alterations, even though they differ in their etiology. Neuroinflammation, altered brain glucose metabolism, oxidative stress, mitochondrial dysfunction and amyloidosis are biological events found in those neurological disorders. Altered insulin-mediated signaling and brain glucose hypometabolism are characteristic signs observed in the brains of patients with certain neurological diseases, but also others such as type 2 diabetes mellitus and vascular diseases. Thus, significant reductions in insulin receptor autophosphorylation and Akt kinase activity, and increased GSK-3 activity and insulin resistance, have been reported in these neurological diseases as contributing to the decline in cognitive function. Supporting this relationship is the fact that nasal and hippocampal insulin administration has been found to improve cognitive function. Additionally, brain glucose hypometabolism precedes the unmistakable clinical manifestations of some of these diseases by years, which may become a useful early biomarker. Deficiencies in the major pathways of oxidative energy metabolism have been reported in patients with several of these neurological diseases, which supports the hypothesis of their metabolic background. This review remarks on the significance of insulin and brain glucose metabolism alterations as keystone common pathogenic substrates for certain neurological diseases, highlighting new potential targets.

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“…In AD, isoprostane (8,12-iso-iPF2alpha-VI and others) in the CSF is increased. [27][28][29][30][31][32] Isoprostane level is increased in the brain of AD patients. 33…”

Section: F2-isoprostane (812-iso-ipf2alpha-vi Etc)mentioning

confidence: 99%

“…It is the most abundant isoprostane product that is formed during lipid peroxidation and is used as a biomarker for oxidative stress. In AD, isoprostane (8,12‐iso‐iPF2alpha‐VI and others) in the CSF is increased 27‐32 . Isoprostane level is increased in the brain of AD patients 33 …”

Section: Csf Oxidative Stress Markers In Ad In Vivomentioning

confidence: 99%

Cerebrospinal fluid oxidative stress markers in Alzheimer's disease

Sakakibara

Kawai

2020

Neurology & Clinical Neurosc

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Oxidative stress has a significant impact on neurodegenerative diseases. The present paper reviewed the role of oxidative stress in disease progression of Alzheimer's disease (AD) and measurement of the oxidative stress markers in cerebrospinal fluid (CSF) in AD in vivo. Oxidative stress measurement in CSF in AD provides knowledge of underlying pathophysiology, to be a counterpart of oxidative stress neuroimaging, and to help differentiating AD from other neurodegenerative diseases. In addition, these findings warrant future studies to see whether antioxidant intervention might help preventing progression of neurodegenerative diseases including AD.

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Cerebrospinal Fluid Aβ42, Tau, and F2-Isoprostane Concentrations in Patients With Alzheimer Disease, Other Dementias, and in Age-Matched Controls

Cited by 110 publications

References 14 publications

Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance

Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance

Significance of Brain Glucose Hypometabolism, Altered Insulin Signal Transduction, and Insulin Resistance in Several Neurological Diseases

Cerebrospinal fluid oxidative stress markers in Alzheimer's disease

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