Oxidative stress, defined as an imbalance between exposure to free radicals and antioxidant defenses, plays an important role in the development of neurological disease, including Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD)[1
]. Animal studies show age-related increases in oxidative damage in the hippocampus and frontal cortex homogenates due to products of lipid peroxidation [2
]. Lipid peroxidation is particularly toxic to the brain as it alters properties of the cell membrane and the function of membrane-bound receptors and enzymes [5
]. Over the past few years, F2
-IsoP) have gained attention as a reliable marker of oxidation. F2
-IsoPs are prostoglandin-like compounds produced through the auto-oxidation of arachidonic acid in vivo
that provide a valuable indicator of lipid peroxidation in humans. F2
-IsoPs are relatively stable molecules that can be detected in measurable quantities in all body tissues and fluids, and are considered to be a reliable non-invasive method to assess oxidation in vivo
(for review see [6
It is suggested that oxidant stress and the production of reactive oxygen species in the brain plays an important role in the pathogenesis of Alzheimer’s disease [8
]. Thus, recent studies have examined the relationship between F2
-IsoP levels and cognitive impairment. The majority of research has entailed case-control studies, examining F2
-IsoP levels in postmortem brains and in cerebral spinal fluid (CSF). Using gas chromatography-mass spectronomy assay, some postmortem studies have reported evidence of increased lipid peroxidation in AD brains compared to healthy controls [9
], while others have reported negative findings [11
]. Enhanced levels have been noted in frontal, temporal, and parietal cortex, and in the hippocampus of postmortem AD brains.
Studies that have analyzed F2
-IsoP in CSF consistently report that levels are increased in AD patients compared to healthy controls [13
]. Furthermore, F2
-IsoP levels are reported to increase with an increase in severity of dementia [11
] and are also reported to be higher in apolipoprotein E (APOE) e4 carriers compared to those without the e4 allele, suggesting that APOE status may influence how the brain responds to oxidative injury [15
]. In a longitudinal study that assessed the value of CSF F2
-IsoP as a biological markers in the progression from mild cognitive impairment (MCI) to AD, it was found that individuals who declined over time, either from normal to MCI and MCI to AD (n=8) displayed higher CSF F2
-IsoP levels at baseline compared to stable normal controls [13
]. It is reported that F2
-IsoP measured in CSF significantly improves the diagnostic accuracy and predictive outcomes over memory testing and quantitative magnetic resonance imaging (MRI) measurement [13
]. To this end, it has been suggested that F2
-IsoP may serve as a valuable biomarker in the early detection of AD pathology.
Although CSF closely corresponds to brain composition and is thus likely to provide the most consistent and reliable biomarker in the evaluation for dementia, CSF is an invasive procedure that is not routinely performed in practice. Identification of biomarker molecules in peripheral measures, such as blood, would provide a means for less invasive, expensive and time-consuming testing.
Studies that have evaluated peripheral F2
-IsoP markers are less consistent. One group reported that AD and MCI patients [16
] display elevated F2-IsoP in urine and in blood, compared to healthy controls. Conversely, negative findings have also been reported for both peripheral F2-IsoP measures [17
]. In a study that assessed plasma F2
-IsoP in normal controls, MCI, AD, and Parkinson patients, no group differences were observed. Further, authors reported that levels did not correlated with duration of disease or cognitive performance [18
]. However, the high frequency of anti-oxidant use among MCI and AD patients, which could potentially decrease F2
-IsoP levels, may have dampened any detectable group differences.
Despite growing evidence that oxidative stress is implicated in the development of dementia and cognitive impairment [13
], little research has assessed the relationship between less invasive peripheral measures of F2
-IsoP and prospective cognitive function in non-demented older adults. Although differences in biological markers are often found to differ between groups in case-control studies, biomarkers that can predict decline in cognitive function in the preclinical phase, years before dementia diagnosis, are of great value as they 1) add to the biology of the disease, 2) may help identify those at risk for AD or other dementias, and 3) emphasize that these diseases are a continuum. Furthermore, the elucidation of biomarkers that are non-invasive can have significant clinical implications for the detection and prevention of adverse cognitive decline.
Our goal was to examine the association between plasma F2-IsoP levels and change in cognitive function over eight years in a large biracial cohort of non-demented elderly men and women. Given previous findings in the dementia literature, we hypothesized that higher F2-IsoP levels in plasma would be observed in elderly displaying greater decline in cognitive function over eight years.