Ask the Experts - Is the Concept of a Neuroprotective Drug Viable for...
Is the concept of a neuroprotective drug viable for dementia? When is the best time to give a drug like that? What are the options?

This is a great question that taps into the future of dementia research and treatment!

First, it is important to remember that "dementia" is not a diagnosis, but rather a syndrome, indicating a progressive decline in cognitive abilities that interferes with normal life. The syndrome of dementia may be caused by Alzheimer's disease (AD), strokes, depression, medications, or a number of other neurologic diseases. In any patient with memory or thinking problems, it is always essential to determine the cause of a particular dementia before proceeding, because the prognosis and the treatment will vary, depending upon the cause.

The concept of an intervention to biologically prevent or protect someone before the disease develops is a powerful and popular concept in dementia. It is obviously more salient for some of these causes than others. For example, finding a substance to protect the brain from injury is not as relevant for overmedication or depression as it might be for strokes and degenerative diseases.

The most common cause of dementia is AD, accounting for at least 70% of all cases of dementia in this country. In the response below, I will concentrate on the possibility of preventing or delaying the progression of AD by administering neuroprotective treatments.
Neuroprotection and AD
The leading theories of the cause of Alzheimer's suggest that the gradual deposition of abnormal beta-amyloid leads to the death of brain cells, or neurons. Typically the disease begins in regions of the brain that subsume memory and executive function, and then progresses over years or decades to other brain areas while the clinical symptoms gradually impair all cognitive functions. Many scientists have proposed that it would be far more difficult to devise treatments to repair the brain than it would be to find treatments to prevent the disease from occurring or progressing, and strategies to discover neuroprotective agents have been a high priority for research over the past 10 years.

All currently available medications for AD are cholinesterase inhibitors, which provide modest symptomatic improvement and can delay the loss of functional abilities. However, there is no convincing evidence that they slow the biological progression of the disease. A number of potential neuroprotective agents have been identified through basic research, or through epidemiologic studies, and are currently in clinical trials.

Brain cells of patients with AD may be more susceptible to "oxidative stress" and subsequent cell death by virtue of increased monoamine oxidase (MAO) activity. Free radicals, the byproducts of the metabolic processes such as oxidative metabolism, may accumulate, leading to excessive lipid peroxidation and neuronal degeneration in the brain. MAO inhibitors can reduce oxidative deamination and may prevent the formation of free radicals, preserving neuronal integrity; they can also produce a selective augmentation of monoaminergic transmission. Alpha-tocopherol (vitamin E), a lipid soluble vitamin that can block lipid peroxidation, may also reduce oxidative damage.

Small trials of MAO inhibitors have suggested efficacy in patients with AD. In a large 2-year, multicenter, double-blind, placebo-controlled trial, 341 patients with moderate to severe AD received the MAO inhibitor selegiline and alpha-tocopherol (vitamin E), either alone or in combination, or placebo. Outcome measures were death, institutionalization, loss of ability to perform at least 3 activities of daily living, and severe dementia. Over the course of the 2-year trial, neither of the compounds provided cognitive improvement, but all treated groups showed less decline on an activities of daily living scale when compared with placebo. Vitamin E appeared to delay progression to the mixed end point by approximately 25% over the 2 years of the study. This study required statistical adjustment to equate the initially nonequivalent treatment groups, and should not be considered definitive until reproduced. However, this design has signaled a new era of treatment for AD designed to slow progression or even to provide primary prevention to at-risk populations, and has prompted many clinicians to treat their AD patients with daily doses of vitamin E.

For those clinicians who recommend vitamin E to their patients, or for individuals who hope to avoid AD in the future, the dosage remains unclear. The study described was the only such large-scale treatment study and used 2000 IU of vitamin E daily, but this dosage could theoretically cause anticoagulation and bleeding problems in some patients. Therefore, clinicians who recommend vitamin E either for patients with AD or for those seeking its neuroprotective properties suggest a wide variety of dosages without a lot of evidence for them.

The extract of the ginkgo biloba, derived from the leaves of a subtropical tree, is also believed to act as an antioxidant. Two small studies and 1 larger clinical trial have suggested that ginkgo biloba may provide a small beneficial effect on cognitive measures of patients with AD. In the most highly publicized of these trials, a large number of drop-outs raise questions about the validity of the results, and large-scale trials to evaluate efficacy are under way. Since ginkgo biloba is sold as a health supplement, it is not subject to the same purity standards or marketing restrictions that govern Food and Drug Administration-approved treatments and is not recommended by most memory experts at this time.

Along with the deposition of abnormal amyloid, there is considerable evidence that immune and inflammatory reactions occur in the brains of AD patients, including the activation of complement cascades and inflammatory cytokines. Furthermore, epidemiologic evidence from observational studies has shown that patients exposed to long-term anti-inflammatory medications may be protected from developing AD.

In pilot studies, the glucocorticoid prednisone, which should suppress both acute-phase response and the complement pathway, resulted in no improvement in either behavior or cognition in 19 AD patients over a 7-week period, whereas improvements were seen in a relatively small trial of indomethacin in patients with AD. However, a well-designed 1-year trial of prednisone in patients with AD yielded negative results.

Other anti-inflammatory drugs currently in development are the cyclooxygenase (COX) inhibitors, specifically those directed at COX-2, which is activated by inflammatory stimuli. Selective COX-2 inhibitors may have a potential for both prevention and treatment of AD, and several large-scale, placebo-controlled trials of these compounds are under way. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) is a National Institutes of Health-funded project designed to determine whether anti-inflammatory medications can protect the brain and prevent the onset of AD in first-degree relatives of patients with AD. (For further information, see the ADAPT Web site at www.2stopAD.org.)

At this time, no anti-inflammatory therapies are recommended for persons with AD or for those who are concerned about developing it, because these therapies have potentially dangerous side effects and efficacy has not been demonstrated.

Estrogen-sensitive neurons are present in both male and female brains and may play an important role in neurocognitive function, both in normal aging and AD. The mechanisms through which hormones might exert these effects are varied, but could include such neuroprotective mechanisms as improved glucose transport in the hippocampus, promotion of neuronal viability and synaptic integrity, enhanced choline uptake, increased cerebral blood flow, modification of amyloid precursor protein processing and plaque formation, and/or regulation of nerve growth factor (NGF) and NMDA receptors.

The term hormone replacement therapy (HRT) encompasses estrogen replacement therapy (ERT) with and without progestins. The progestin is prescribed to prevent endometrial cancer and therefore is not necessary in women who have had a hysterectomy. Selective estrogen receptor modulators (SERMs) are synthetic compounds that can act both as an agonist and as an antagonist at the estrogen receptor.

Interest in HRT to treat or prevent AD arose because hormone replacement may improve cognition in nondemented postmenopausal women, and because some (but not all) observational studies have suggested that HRT in postmenopausal women with AD may be associated with improved cognition, later onset, or slower rate of progression. In particular, 2 cohort studies have reported significant odds ratios of 0.5, suggesting substantial protection.

HRT is not recommended for patients with AD because 2 studies have now demonstrated no clear benefit over placebo in prospective trials. Since observational studies of estrogen efficacy are notoriously vulnerable to various sources of bias, HRT is not specifically recommended for patients at risk for AD, although several large clinical trials of HRT in women at risk for AD are under way. (For more information, see study Web site at www.delay-AD.org.) No large-scale AD trials with SERMs have been conducted.

An enormous number of strategies that might be considered "neuroprotective" are under investigation for their potential as treatment or preventive agents in persons with, or at risk for, AD. These include therapies to decrease the production or deposition of beta-amyloid, therapies to immunize the body against the accumulation of beta-amyloid, and therapies utilizing NGF to preserve the viability of vulnerable cholinergic neurons. Neither of these strategies is yet in large-scale clinical trials.

It should also be noted that there is a huge industry of health food products that are marketed under catchy brand names to improve or prevent memory problems, but have absolutely no large-scale clinical trials to support their claims of efficacy. These products exploit a regulatory loophole in that they are sold as dietary supplements rather than pharmaceuticals, and therefore escape FDA oversight, production and purity controls, and the requirement that efficacy be demonstrated in valid clinical trials. Most experts consider them to be, at best, completely unproven, and at worst, a fraudulent and potentially dangerous waste of money.

It is frustrating to realize that there is so much information about neuroprotective agents, but so little is actually known with certainty! My recommendation would be that until prospective clinical trials are completed, neither anti-inflammatory medication, nor hormone replacement in women, nor any of the food supplements or "nutraceuticals" (including ginkgo) should be used to protect against AD. They simply haven't yet been proven, and each is accompanied by potentially serious side effects.

I do recommend vitamin E and take it myself. While the data about the neuroprotective effects of vitamin E are not yet definitive, it is inexpensive and has no side effects in those without liver problems or clotting disorders. As noted, the only factual information about dosage comes from the study cited that used 2000 IU each day, and many people who are "hedging their bets" by taking vitamin E currently take a lower dose, for example 400-800 IU twice daily) without firm evidence that this is effective.

The good news is that neuroprotective agents are thought to be the wave of the future and are undergoing intensive research at centers all over the world. Within the next few years, I think we will be hearing about, and maybe even using, exciting new compounds to help prevent AD.