EVALUATION OF THE SAFETY, TOLERABILITY AND IMPACT ON BIOMARKERS OF ANTI-OXIDANT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer's Disease (AD), a progressive degenerative disease of the brain resulting in impaired memory and loss of cognitive and functional abilities, is the most common cause of dementia in the elderly. It poses a huge public health problem, particularly as life expectancy continues to increase. In the US, the direct and indirect costs of AD were estimated at over $100 billion per year (Ernst 1994). Currently approved treatment for AD includes acetylcholinesterase inhibitors and memantine, both of which target neurotransmitter systems and show symptomatic benefits. There is no disease-modifying treatment to prevent AD or to slow its progression. A major hypothesis about the etiology of AD is that beta-amyloid (A?) aggregates and is deposited in the brain, which leads to neuronal damage and ultimately to AD (reviewed in Hardy 1997). A? ending at residue 42 (A?42) is thought to be the key initiator because A?42 predominates in early amyloid deposits in the brain and has a greater propensity to aggregate, form fibrils, and lead to cellular toxicity than A? ending at residue 40 (A?40) or shorter forms of A?. Oxidative damage is a key factor implicated in the neurodegeneration of AD (Behl 1999) and can be linked to A? (Pratico 1999, Lustbader 2004). The defining neuropathological changes in AD are senile plaques (SP) and neurofibrillary tangles (NFT) made up of paired helical filaments (PHF) comprising insoluble aggregates of the microtubule-associated protein tau. Plaques are surrounded by reactive microglia and astrocytes. Oxidative damage to DNA, lipids, and proteins is readily detected in the brain in AD (Markesbery 1999). Mitochondrial as well as somatic DNA undergoes damage, and the burden of damaged DNA increases with age. Oxidative damage may impair critical neuronal functions in many ways, for example, loss of membrane homeostasis, mitochondrial damage, damage to DNA, and promoting aggregation of proteins such as A? and tau. In addition, reactive oxygen species may act as mediators of apoptosis or programmed cell death, which has been implicated in AD. Many biochemical markers of oxidative damages have been studied, such as nitrated proteins, 8-hydroxy modified forms of DNA or RNA, and 4-OH-nonenal. Among the most stable are isoprostanes, which are forms of prostaglandins produced in response to oxidative stress (Pratico 1999). The F-2 group of isoprostanes is produced in response to oxidative damage to the brain, and reflects lipid peroxidation. Levels of F-2 isoprostanes are increased in the brains of patients with AD, in transgenic mouse models of amyloid deposition, and in the cerebrospinal fluid in AD (Montine 1999 & 2001; Pratico 2000). A specific isoprostane in this group, 8,12-iso iPF2?6, was reported to be increased in plasma and urine in AD (Pratico 2000). Data from many but not all epidemiological studies suggest that dietary or supplemental antioxidants can decrease the risk of AD (e.g. Morris 1998, Paleologos 1998). Although the doses and duration of exposure to antioxidant vitamins varied markedly among participants, the overall effect was in the direction of lower risk of dementia. In the Cache County epidemiological survey, a recent study found that combined use of vitamin E and vitamin C, but not either one alone, was associated with a decreased hazard ration for prevalent and incident AD (Zandi 2004). Some studies have found decreased levels of antioxidants, including vitamin C and E, in patients with AD compared to controls (Polidori 2004). A multi-center controlled clinical trial of patients with moderate to severe AD showed that treatment with 2000 i.u./day of vitamin E (?-tocopherol) delayed the time to reach clinical milestones such as institutionalization, death and loss of activities of daily living (ADL) relative to placebo (Sano 1997). However a recent ADCS clinical trial of patients with MCI found no difference in treatment with vitamin E 2000 i.u./day in delaying clinical progression to AD, compared to placebo. There are many candidate antioxidants, including combinations, which could be neuroprotective in established AD or could have efficacy in prevention of AD. However, testing each of the possibilities in standard clinical trials would be prohibitively expensive. We have therefore decided to examine antioxidant supplements or vitamins which target specific cellular compartments, and look for evidence of biologically relevant effects in AD by measurement of biomarkers in CSF. Combinations of antioxidants: Combinations of antioxidants have been found to be useful in ameliorating oxidative damage in cell culture models and aged dogs (Bondy 2002). In rat cerebral synaptosomes, a combination of ?-tocopherol and vitamin C was more effective in inhibiting formation of isoprostanes than either alone (Montine 2003). Aged dogs develop cognitive changes, accompanied by markers of oxidative damage in their brain, and amyloid deposition in the form of diffuse deposits. In a dog colony studied by Carl Cotman and associates at UC Irvine, a marked decrease in age-associated oxidative markers, as well as lower amyloid load, were seen in the brains of dogs fed a chow supplemented with a combination of antioxidants. Aged dogs who received the supplemented chow showed improvement in their ability to acquire progressively more difficult tasks (e.g. oddity discrimination learning) (Milgram 2002). Support for antioxidant combinations is provided by data from human studies (e.g. Mosci 2002) in which markers of oxidative stress in lymphocytes of older subjects were ameliorated by a combination of antioxidants. Cotman and associates have recently carried out a safety study of vitamin E (?-tocopherol) 800 mg, vitamin C 200 mg and ?-lipoic acid 600 mg given in combination once per day to healthy older individuals for 6 months. No significant adverse events were encountered and the combination was well-tolerated (Cotman, personal communication). Two general cellular compartments where antioxidant supplements may act are the cytosol and mitochondria. While a cocktail of antioxidants that includes both targets would be worth testing, after several rounds of discussions with the ADCS Scientific Advisory panel, we have decided to separately study a combination of antioxidants that act primarily at cytosolic sites (vitamin E + C + ?-lipoic acid) and a single mitochondrial antioxidant, coenzyme Q10.