Sano M., Ernesto C., et al. A Controlled Trial of Selegiline,
Alpha-Tocopherol, or Both as Treatment for Alzheimer's Disease.
N Engl J Med 1997; 336:1216-22.

Bruce Robinson, M.D.
May 2, 1997

Clinical Scenario
A 76-year-old man whom you diagnosed several months ago with Alzheimer's dementia
comes to your clinic with his wife and family. The patient lives at home, but over time has
required increased and now full-time supervision. On exam, as before, he has flat affect but
becomes anxious when questioned. He is unable to answer many simple questions, and his
short-term memory is poor. He makes mild aphasic errors. He has a palmomental reflex.
Neurologic exam is otherwise unremarkable. Your patient's family, excited about what they
had recently read in the newspaper, asks you how beneficial the vitamin E that they bought
for him will be

Background

Alzheimer's Disease

Neuropathology: Cerebral cortical neurofibrillary tangles and senile plaques, impaired synaptic function, and cell loss. Prominent loss of cholinergic, noradrenergic, and dopaminergic neurons.
Cause: Unknown, but may involve oxidative stress and the accumulation of free radicals, which leads to excessive lipid peroxidation and neuronal degeneration.

Antioxidants

Proposed neuroprotection by reduction of oxidant stress.
Agents:

Selegiline-monoamine oxidase inhibitor that inhibits oxidative deamination and also facilitates catecholamine activity.

Alpha-tocopherol-lipid-soluble vitamin that traps oxygen free radicals.

Past findings:

In animals, selegiline is associated with increased active lifespan; alpha-tocopherol reduces neuronal death after ischemia

In Parkinson's disease, DATATOP trial suggested that selegiline, but not alpha-tocopherol,significantly delayed the need for levodopa, as reported in N Engl J Med 1993;328.Benefit, however, was not sustained during follow-up.

In Alzheimer's dementia, short-term trials of selegiline have shown significant benefit in cognition.

Evidence
Methods

Double-blind, placebo-controlled, randomized, multicenter trial.

Population: 341 patients with probable Alzheimer's disease of moderate severity (Clinical Dementia Rating 2) were recruited from 23 centers participating in the Alzheimer's Disease Cooperative Study. Subjects were free of other central nervous system disease,were taking no psychoactive medication, and were not residing in a skilled nursing facility.

Intervention: Randomly assigned to receive selegiline, alpha-tocopherol, selegiline and alpha-tocopherol, or placebo. Treated and followed for two years.

Outcome Measures:

Primary--Clinical deterioration, as measured by time to the occurrence of death, institutionalization, loss of ability to perform 2 of 3 basic activities of daily living (eating, grooming, using the toilet), or severe dementia (Clint Dementia Rating 3)

Secondary--Objective measures of cognition, function, behavior; as well as evaluation for extrapyramidal signs.

Other--Medical events occurring during the treatment period.

Results

Despite random assignment, the baseline score on the Mini-Mental State Exam was modestly higher in the placebo group.

Unadjusted Analyses: The unadjusted median primary event-free survival was 526 days in the placebo group, 597 days for the patients receiving alpha-tocopherol, 628 days for significant differences were found among the four groups.

Adjusted Analyses: When baseline score on the Mini-Mental State Exam was included as a covariate..

(1) the estimated median primary event-free survival was 440 days in the placebo group, 670 days for the patients receiving alpha-tocopherol (p=0.001 vs. placebo), 655 days for those receiving selegiline (p=0.012 vs. placebo) and 585 days for those receiving both (p=0.049 vs. placebo).

(2) no significant difference was noted between alpha-tocopherol, selegiline, and combination groups.

(3) no significant treatment effect was noted for the individual endpoints in the primary outcome measure, except for a delay in institutionalization associated with alpha-tocoperol versus placebo (p=0.03)

Secondary Outcome Measures: No difference in worsening over time of cognitive, functional, or behavioral test scores or of extrapyramidal signs between the treatment and placebo groups.

Safety Data: Falls, syncope, and dental events were significantly more common in the treatment groups than in the placebo groups. The frequency of 46 other adverse medical events did not differ significantly between the groups.

Conclusion

According to authors, treatment with selegiline or alpha-tocopherol or both was beneficial in delaying disease progression.

Comments

Strengths of the Study:

Significant findings in a double-blind, placebo-controlled, randomized trial.

Functional and occupational measures may be more meaningful indicators of disease progression to clinicians and family than are psychometric measures.

Potential Weaknesses of the Study:

Limited study population -- Patients enrolled had moderate dementia, not mild cognitive impairment, early dementia, or late-stage Alzheimer's.

Were the end points used reliable clinical markers of disease progression?

Were the statistical adjustments reasonable? Compensation (by the Cox model) for baseline differences between randomly selected treatment groups resulted in dramatic changes in outcome.

Were the results internally consistent? The lack of effect of treatment on objective measures is puzzling. Did improved function without improved cognition represent some other health benefit?

Should we prescribe antioxidants in Alzheimer's?

Data is limited and inconclusive.

Alpha-tocopherol is inexpensive, has low side-effect profile, and has other possible health benefits.

Treatment may help the family as they deal with this difficult disease.

After informed discussion with patient/caretakers, medication trial is reasonable.

References

Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med 1997;336:1216-22.

Drachman DA, Leber P. Treatment of Alzheimer's disease--Searching for a breakthrough, settling for less. N Engl J Med 1997; 336: 1245-47.

The Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1993; 328: 176-83.