Dementia: Update for the Practitioner

There is an ongoing discussion about the mechanisms of oxidative damage in Alzheimer's disease, and there are many ways in which oxidative damage can impact cell function and play a role in Alzheimer's disease. Because of this, clinical trials have examined antioxidants as treatment mechanisms.


	Mechanisms of Oxidative Damage in Alzheimer's Disease


	There are many ways in which oxidative damage can impact cell dysfunction and play a role in Alzheimer's disease. Courtesy of Dr. Mary Sano

One trial used vitamin E and selegiline in individuals who had moderate to severe impairment with Alzheimer's disease. Vitamin E, or alpha-tocopherol, is known to limit free radical formation, lipid peroxidation, and oxidative stress, while selegiline is a selective MAO-B inhibitor with antioxidant properties that increases brain catecholamines. The primary outcome for patients entered in the study, unlike the outcome in studies of cholinesterase inhibitors, was clinical deterioration marked by reaching one of a set of end points: moving from moderate dementia to severe dementia, relatively total loss of basic activities of daily living, the need for institutionalization, or death.

In this two-year period, either vitamin E or selegiline or the combination delayed those outcomes. One caveat to this study is that, though it was not a primary outcome measure, cognition was measured, and there was no evidence of benefit on cognition in this population with these agents, either alone or in combination.


	Selegiline and Vitamin E: Delay in Clinical Progression of Alzheimer's Disease


	The effect on delay of progression to AD of vitamin E and selegiline in individuals who had moderate to severe impairment with Alzheimer's disease. Courtesy of Dr. Mary Sano. Source of data: M. Sano et al., "A Controlled Trial of Selegiline, Alpha-Tocopherol, or Both as Treatment for Alzheimer's Disease," New England Journal of Medicine 336, no. 17 (April 24, 1997): 1216–22.


	Selegiline and Vitamin E: Delay in Nursing-Home Placement


	The effect on delay in nursing-home placement of vitamin E and selegiline in individuals who had moderate to severe impairment with Alzheimer's disease. Courtesy of Dr. Mary Sano. Source of data: M. Sano et al., "A Controlled Trial of Selegiline, Alpha-Tocopherol, or Both as Treatment for Alzheimer's Disease," New England Journal of Medicine 336, no. 17 (April 24, 1997): 1216–22.


	Ginkgo Biloba (Meta-analysis) Reviewed randomized, double-blind, placebo-controlled studies Four studies with 212 subjects in each placebo and drug groups using EGb 761 120–240 mg/day Results: small but significant effect of 3–6 month treatment 120–240 mg of Gingko biloba extract on objective measures of cognitive function Side effects: four reports of hemorrhage Caution: in patients taking anticoagulants, antiplatelets or with bleeding diathesis

	A summary of a meta-analysis of published data on the effect of ginkgo biloba on cognitive function. Courtesy of Dr. Mary Sano. Source of data: Barry S. Oken et al., "The Efficacy of Ginkgo biloba on Cognitive Function in Alzheimer's Disease," Archives of Neurology 55, no. 11 (1998): 1409–15.


	Ginkgo Biloba

Another mechanism is the target of the agent memantine, which is believed to block the NMDA receptor and reduce glutamate excitotoxicity. This mechanism is thought to permit amplification of the transmission of a neuronal impulse that would improve learning.


	Selegiline and Vitamin E: Delay in Nursing-Home Placement


	Memantine is believed to block the NMDA receptor and reduce glutamate excitotoxicity. This mechanism is thought to permit amplification of the transmission of a neuronal impulse that would improve learning. Courtesy of Dr. Mary Sano

The initial European study of memantine suggested an improvement in CGI in patients with severe dementia. More recently, in the New England Journal of Medicine, memantine was described in the treatment of individuals with moderate to severe Alzheimer's disease. There was significant improvement of the intent-to-treat analysis on the severe impairment battery tests (which were used instead of the ADAS-cog because these patients were advanced), but no significant effect in the clinical global measure. In general, there is enthusiasm for the agent and the safety seems to be acceptable.


	Memantine in Moderate to Severe Alzheimer's Disease


	Results of an efficacy analysis of memantine in moderate to severe Alzheimer's disease. Courtesy of Dr. Mary Sano. Source of data: Barry Reisberg et al., "Memantine in Moderate-to-Severe Alzheimer's Disease," New England Journal of Medicine 348, no. 14 (April 3, 2003): 1333–41.

Recent trials suggest that memantine may have a benefit when given in combination with donepezil, suggesting that memantine as an added agent may provide additional benefit. We need to find out whether this additive benefit might be apparent with other cholinesterase inhibitors. The magnitude of the effect of cholinesterase inhibitors on cognition is smallest with donepezil and larger with the other approved agents. It would be important to know if the additive effect of memantine can also be seen with galantamine and rivastigmine. It is not clear if the market will bear the price of two drugs. These are important points to consider when deciding how to start or initiate your treatment with these agents.

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