Sign of lipid peroxidation as measured in the urine of patients with probable Alzheimer’s disease
Introduction
It is estimated that at least 4 million people in the United States have been diagnosed with Alzheimer’s disease (AD) and that up to 50% of people over the age of 85 have AD [2]. There is extensive evidence indicating that oxidative stress, resulting in the destruction and death of neurons in the brain, is a contributing factor to the development and expression of AD [9].
Assessment of free radical-induced oxidative stress in the brains of patients with AD has revealed an increase in thiobarbituric acid-reactive substances in the hippocampus [6] and the temporal cortex 8, 11, indicative of significant lipid peroxidation. The aldehyde product of lipid peroxidation, 4-hydroxynonenal, is significantly increased in the amygdala, the hippocampus, and the parahippocampal gyrus of the AD brain and coincides in these areas with histopathology characteristic of AD [10]. Elevated levels of 4-hydroxynonenal are also found in the cerebrospinal fluid of patients with probable AD [7]. Oxidative degradation of protein is detected in the inferior parietal lobe and hippocampus of brains from patients diagnosed with AD [5] as is increased nitration of proteins and the presence of peroxynitrite 5, 22. A significant increase in oxidative damage to mitochondrial [12] and nuclear [4] DNA in brains of patients with AD is also observed. These findings strongly support the suggestion that the brains of patients with Alzheimer’s disease are in a state of oxidative stress.
F2-isoprostanes are formed by the non-enzymatic peroxidation of arachidonic acid in phospholipids and polyunsaturated fatty acids, by free radicals 15, 20. The F2-isoprostane, 8-isoprostaglandin F2α (iPF2α-III), has been quantified in human tissue, plasma, and urine, and is viewed as a reliable indicator of oxidative stress occurring in vivo 20, 21. In a study conducted post-mortem, a significant increase in iPF2α-III is found in the frontal and temporal poles of the brains of patients with AD as compared to brains of patients who were not reported to be demented prior to death and were without significant histological signs of AD upon autopsy [19]. A significant increase in iPF2α-III is also observed post-mortem, in the ventricular fluid of patients diagnosed with AD [14]. The direct measurement of a product of lipid peroxidation in the brain tissue and ventricular fluid of patients with AD provides important evidence of the occurrence of oxidative stress in the brain of AD patients.
In the present study, the hypothesis was tested that patients with dementia and probable AD are undergoing significant oxidative stress. This hypothesis was tested by comparing the concentration of iPF2α-III, a product of free radical-induced lipid peroxidation, in the urine of patients with mild to moderate dementia and a diagnosis of probable AD, with the concentration of iPF2α-III in the urine of non-demented control subjects, similar in age. Also compared between demented and non-demented subjects was the concentration of 2,3-dinor thromboxane B2 (dinor TXB2), a metabolite of TXB2, which is also detectable in the urine [23]. TXB2 is synthesized from arachidonic acid by an enzymatic process involving cyclooxygenase [21]. Measurements of dinor TXB2 allowed for a comparison of enzymatic metabolic activity with the non-enzymatic autoxidation associated with the generation of iPF2α-III by free radicals. The use of urine provided a non-invasive procedure for assessing the possibility that patients with dementia and probable AD were experiencing significant oxidative stress resulting in increased excretion of a biomarker indicative of this stress.
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Subjects
Participants in the study (non-demented and demented) were over the age of 65, were ambulatory, and were living in the community or residing in a nursing home. Participants were receiving medical care from physicians at the Center for Aging of the University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine. The diagnosis of dementia and probable AD was made according to NINDS/ADRDA criteria and evaluation of the patient by a geriatrician and a neurologist or geriatric
Results
A total of 71 patients were enrolled in the study. There were 33 control subjects and 38 subjects diagnosed with mild to moderate dementia. The mean age of the subjects in each group was similar, as was the relative distribution of female and male patients. Information on serum cholesterol and triglyceride levels, the use of non-steroidal anti-inflammatory drugs (NSAIDs), vitamin E, and alcohol were obtained, as were data on the occurrence of chronic obstructive pulmonary disease (COPD) and
Discussion
The present study demonstrated that the concentration of iPF2α-III measured in the urine of patients with mild to moderate dementia associated with probable AD, was significantly elevated as compared to non-demented control patients. Urinary levels of dinor TXB2 were also significantly increased in patients diagnosed with mild to moderate dementia associated with probable AD as compared to control subjects who were not demented.
Measurements made post-mortem reveal significant elevations of F2
Acknowledgements
The authors would like to acknowledge the assistance of Dr. T. P. Stein, for the use of his laboratory to perform certain procedures involved in this study. The assistance of Dr. Sherry Carol-Pomerantz in the statistical analysis of the data and Ms. Lisa Giffen for her help in collecting data from patient records, are also gratefully acknowledged. This work was supported in part, by a grant from the American Osteopathic Association (F99-2) to Dr. Tuppo.
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Present address: Western University of Health Sciences, College of Osteopathic Medicine, 302 Second Street, Pomona, CA 91766, USA.