Oxidative stress may lead to neuronal damage and apoptosis. beta-amyloid neurotoxicity may be mediated in part by free radicals. Antioxidants may act as free radical scavengers, minimizing damage from lipid peroxidation and apoptosis. The brain is vulnerable to oxidative stress from many fronts. There is a demand for oxygen, an abundance of catecholamines and the possibility of auto-oxidation. Additionally, monoamine oxidase (MAO) formation of hydrogen peroxide (an oxidative compound), an abundance of iron (present in oxidative reactions) and relatively low concentration ofantioxidative enzymes (superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione reductase) place the brain in a susceptible position for oxidative damage.
Vitamin E
Several reviews have examined the role of vitamin E in AD. Basic evidence supports the role of vitamin E in protecting cell cultures from the toxic effects of beta-amyloid. The absorption of vitamin E is variable by the oral route. Bile is necessary for absorption and fat enhances absorption. Vitamin E is distributed to all tissues, although adipose tissue is the major storage site. It is hepatically metabolized, 70±80% in 1 week.
The major clinical study examining vitamin E in AD was a 2-year double-blind placebo-controlled trial in moderate to severe AD patients comparing vitamin E (2000 IU/day), selegeline (10 mg/day), the combination of the vitamin E and selegiline, and placebo. The outcome measures were nursing home placement, time to death, decline in well-defined ADL level and cognitive function. Neither selegiline nor vitamin E improved cognition compared to placebo. Although the trial was randomized, groups differed significantly in baseline cognition, as measured by MMSE. No difference between groups was found unless the baseline cognition was co-varied in the analysis. When this statistical manipulation was performed, the treatment groups all demonstrated benefits compared to placebo in some of the outcome measures (except cognition). There was no additive effect in the combination selegiline/vitamin E group.
Safety
Initial signs of toxicity are fatigue and weakness. Hepatotoxicity and ascites have been associated with vitamin E in infants. In adults, the risk of thrombophlebitis has been reported. In one study, 46 patients with an average age of 60 years had suspected or confirmed thrombophlebitis after vitamin E ingestion. The dose was less than 400 IU for two patients, 400±800 IU for 26 patients, 800 IU for 13 patients and not reported for five patients. Some patients developed thrombophlebitis again when rechallenged with vitamin E. Many of the patients had medical comorbidities that may have predisposed them to thrombophlebitis. There was no comparison group.
Coagulopathy is another potential adverse effect from vitamin E. The mechanism of this potential effect may be related to vitamin E's enhanced effects on oral anticoagulants, possibly secondary to interference with the effects of vitamin K on coagulation factor synthesis. Patients on oral anticoagulants with a dosage change of vitamin E greater than 300 IU/day should have prothrombin time (PT) or international normalized ratio (INR) closely monitored. Dosages greater than 300 mg/day may prolong PT. A case report described a 55-year old man who developed bleeding with warfarin and 1200 IU vitamin E per day for 2 months. The symptoms resolved after vitamin E was stopped, but returned after he was rechallenged with vitamin E 800 IU for 4 weeks. Additional support for potential coagulopathy is based on a possible hemorrhagic stroke in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
Prescription guidelines
Our practice is to prescribe vitamin E 1000 IU b.i.d to AD patients. Although the level of impairment of AD patients in the Sano study was moderate to severe, we empirically start vitamin E in the mild and moderate AD patients, believing that the potential benefit outweighs the risk. For patients on anticoagulants, we start on lower doses and titrate upward, closely monitoring the INR. Quality control is not similar for vitamin E preparations as FDA approved prescription drugs. This creates the potential risk of contamination, not knowing the actual ingredients in the preparation, and other unknown risks inherent in the manufacturing process of the compound. We advise our patients to use preparations that are listed in the United States Pharmacopeia. In the Sano study, the vitamin E preparation was made exclusively for the double-blind study and is not commercially available.
Selegiline
Selegiline is a MAO inhibitor that selectively inhibits MAO-B. Hepatic metabolism of the compound results in the production of desmethylselegiline, amphetamine and methamphetamine. Selegiline blocks free radical activity from oxidative species. Desmethylselegiline upregulates antiapoptotic molecules, glutathione and superoxide dismutase, providing additional protection.
In addition to having utility as an antidepressant agent, selegiline has demonstrated the ability to prevent animals from developing a parkinsonian syndrome induced by 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine (MPTP). In humans, selegiline dosed at 10 mg/day may delay the emergence of disability or signs and symptoms of Parkinson's disease.
Effectiveness and safety
In AD, selegiline was found to be superior to placebo in delaying time to death, and decline in ADLs. There was no benefit to cognition, no significant effect on institutionalization and no additive effect with vitamin E. In this clinical trial with AD patients, falls, dental events (an event that led to dental treatment) and syncope were the only categories of adverse events that differed between treatment group and placebo. In routine clinical use, CNS side effects associated with selegiline may include sleep disturbance, psychosis, agitation, confusion, hypotension, anorexia and dyskinesias. Additionally, selegiline has the potential to interact with other drugs. Concurrent use of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), or miperidine should be avoided, as fatalities have been reported with these medication combinations. Combining selegiline with bupropion has resulted in bupropion toxicity in animals, and the combination should be avoided. In addition, combining selegiline and buspirone should be avoided because of the risk of hypertensive crisis.
Prescription guidelines
Selegiline is not a first-line agent for the treatment of AD. It is more costly and has a more malignant side effect profile than vitamin E. Selegiline may be offered to patients who are unable to take vitamin E because of allergy, sensitivity or coagulopathy risk, but they should be well informed that selegiline is not a standard of care for AD.
Source: Dementia by Mario Maj and Norman Sartorius
