In the Grey Zone

When I went to medical school, the condition “mild cognitive impairment” had not been recognized. Patients either had dementia (which was often referred to as “senility” or “senile dementia” or “senile dementia of the Alzheimer’s type”) or they didn’t. Now we believe that dementia may be twenty years in the making. This makes a lot of sense for Alzheimer’s disease, the most common form of dementia, because Alzheimer’s is due to the abnormal deposition of a normally occurring protein called beta amyloid. If too much beta amyloid accumulates in the brain—and it tends to build up in the part of the brain particularly involved in memory, the hippocampus—the result is amyloid plaques. These plaques are something like dental plaque, but unfortunately there is no easy way to get rid of them. They can’t just be scraped off. In fact, Alzheimer’s disease may result from an imbalance between the deposition of amyloid and its removal. It takes a good long time for enough plaque to build up to result in the problems with memory, thinking, and behavior that constitute Alzheimer’s disease. So it’s not surprising that somewhere along the line, as the process develops, a person might have enough beta amyloid to experience mild memory loss without having enough amyloid to meet the criteria for dementia.

Mild cognitive impairment, or MCI, has been a hot topic of research. Clinicians have tried to define just exactly what MCI is. They have sought to distinguish it from “age-associated memory impairment,” the very slight degree of memory loss that is typically found when comparing old people (especially very old people) to young adults. MCI is now defined as a condition in which patients or families report memory problems which are not sufficient to interferer with daily life. (See R. Petersen, J. Stevens, M. Ganguli et al, “Practice Parameter: Early Detection of Dementia: Mild Cognitive Impairment,” Neurology 2001; 56: 1133.)

Researchers have also tried to figure out whether everyone with MCI is destined to develop dementia. Studies have varied in their findings, but the rate of progression to dementia is somewhere between 6 and 25% per year. Finally, investigators have studied whether any interventions can prevent the development of full blown dementia in people with MCI. One study evaluated the use of Vitamin E and of Donepezil (Aricept), two drugs that are used in the treatment of Alzheimer’s. Unfortunately, Vitamin E had no effect. Donepezil was associated with a lower rate of progression to Alzheimer’s in the first year of treatment, but not subsequently. (See R. Petersen, R. Thomas, M. Grundman et al: “Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment,” New England Journal of Medicine 2005; 352: 2379.)

How should physicians approach patients with MCI? What should families do? What should patients do if they are given this intimidating diagnosis? Right now there is no reliable way to predict who will go on to develop dementia. Magnetic Resonance Imaging (MRI) is a promising technology: patients with degeneration in the hippocampus are at risk of progression to Alzheimer’s. So too are patients with abnormal metabolism in the temporal lobe as measured on a Positron Emission Tomography (PET) scan. But these tests cannot determine with certainty who will progress and who will not. (See K. Blennow, M. de Leon, H. Zetterberg, “Alzheimer’s Disease,” The Lancet 2006; 368: 387.) Until we have treatment that will effectively prevent MCI from progressing, there is little point in trying to predict who is going to get the disease. Patients with MCI should be evaluated regularly, however, to see if they have developed Alzheimer’s or another form of dementia. At that point, treatment may be beneficial. In the mean time, patients with MCI should be sure to appoint a health care proxy to make decisions for them if they lose the capacity to make decisions themselves. And they should take the opportunity to tell their proxy what matters to them—just in case.

Alzheimer’s Centennial

On November 6, 1906, Alois Alzheimer presented a paper to his medical colleagues describing a patient, Auguste D, who had a progressive, ultimately fatal form of dementia. He studied her brain tissue under the microscope after she died, describing the tangles and plaques that would become the hallmarks of the disease. Her illness, which he distinguished from the “senility” found so often in elderly patients—Auguste D was only 51—would become known as Alzheimer’s disease.

It would take more than half a century until we recognized that “senile dementia” and “Alzheimer’s disease” were one and the same. Most people who develop this dread condition, marked by cognitive changes (memory loss being the earliest and most striking example), behavioral changes (agitation and often paranoia), and ultimately, total dependence on others for the most basic functions of daily life, are in their seventies or eighties. Less commonly, they develop the same symptoms at a much younger age. Often these individuals have a hereditary form of the disease—but it is fundamentally exactly the same disorder.

How much progress have we made in understanding and treating Alzheimer’s disease in the past 100 years? An article in the British periodical, The Lancet, (Konrad Maurer, Ian McKeith, Jeffrey Cummings et al, “Has the Management of Alzheimer’s Disease Changed Over the Past 100 Years?” Lancet 2006; 368: 1619-1621) argues that many of the basic approaches to care remain unchanged, though the number of available medications has increased enormously. The authors indicate that already a century ago, Alzheimer understood that a key element of care was the environment. Patients with dementia need calm and compassionate caregivers and an atmosphere that is distracting but not excessively stimulating.

But what about all those medications we use today—Donezpezil (Aricept) and Memantine (Namenda) and drugs such as Risperidone (Risperdal) and Olanzapine (Zyprexa)? Just how much better are they than the small doses of alcohol and sedatives such as chloral hydrate and paraldehyde that were used in Alois Alzheimer’s day? Today’s pharmacologic agents may have fewer side effects than their predecessors, certainly an important consideration, but they are far from benign—the antipsychotics, for example, have been associated with an increased risk of stroke.

What concerns me is that the effectiveness of the medications we routinely and liberally use in Alzheimer’s disease is regrettably only modest. The cholinesterase inhibitors (such as Aricept) result in a statistically significant improvement in measures of global function—but it’s far from clear that they make a real difference in the daily lives of most patients and their caregivers. A review of all studies on these drugs by the British National Institute for Health and Clinical Excellence concluded the evidence for real benefit was so questionable that they should not be considered the standard of care (see my blog posting, “Americans, Alzheimer’s, and Aricept..”) The antipsychotic drug that are commonly used for agitation, restlessness, paranoia and other major behavioral features of Alzheimer’s have just been examined at in the most sophisticated and careful study to date. Unfortunately, the conclusion of this study is that these medicines are usually no more effective than placebo (See Lois Schneider, Pierre Tariot, Karen Dagerman et al, “Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer’s Disease,” New England Journal of Medicine 2006; 355:1525-1538). And the glutamatergic antagonists (ie Memantine) have been shown to slow the progression of disease in patients whose dementia is already advanced—an effect which some might regard as tantamount to leaving patients suspended in a condition worse than death. (See Barry Reisenberg, Rachelle Doody, Albrecht Stoffler et al, “Memantine in Moderate-to-Severe Alzheimer’s Disease,” New England Journal of Medicine 2003; 343:1333-41).

Scientists have made remarkable strides in understanding the genetic and biochemical underpinnings of Alzheimer’s disease. Several promising avenues of research into treatment are being vigorously pursued—a vaccine, tested in mice, has led to dramatic regression of plaques in the brain. But bran diseases are extraordinarily complicated and those affecting thinking are particularly recalcitrant to treatment. Perhaps we should spend as much effort on designing more humane environments in which to care for people with dementia as we do searching for a pharmacologic fix.

A Time to Be Born, A Time to Die

On September 6, the Food and Drug Administration (FDA) approved the use of the artificial heart. The AbioCor heart, the device that was approved, has been used in 14 people. Their experience formed the basis of the FDA decision. All 14 had very advanced heart failure at the time of the surgery, so advanced they were not expected to live for more than a month. They could scarcely walk without getting short of breath and they were not candidates for a heart transplant (typically because of their age or other medical conditions). All 14 have died: 2 died during surgery, and 6 of the survivors suffered strokes. They lived an average of 5.2 months with the surgery, including one subject who lived for 17 months. However, only one was discharged home. Ten left the hospital only with short passes, and 1 moved to a hotel near the hospital. The cost of the device has been set at $250,000 by AbioMed, its manufacturer. The hospital charge for the insertion (not counting the cost of the prolonged hospital stays that have been required to date) is estimated at $100,000.

A little over a year ago, the scientific advisory panel to the FDA recommended against approving the device. FDA approval is contingent on a device being “safe and effective.” The artificial heart was deemed “effective,” since it prolonged life from an expected one month to an average of 5.2 months. The advisory panel, by a 7:6 vote, concluded they could not consider a device which led to major strokes in 50% of the recipients and which kept almost all patients hospitalized until their deaths “safe.” Usually, the FDA heeds the recommendation of its advisory panel. In this instance, without any engineering modifications since the advisory panel met in June, 2005, the FDA nonetheless approved the device. What happened?

The story of just who put pressure on whom to win approval of the device has yet to be researched. Interestingly, back in 1976, the director of the National Heart, Lung and Blood Institute tried to pull its contracts with 4 firms for designing and manufacturing the total artificial heart on the grounds that the technology was too flawed and too expensive. He didn’t expect anticipate the response from 2 powerful senators, Orrin Hatch of Utah and Edward Kennedy of Massachusetts, in whose states several of the firms were based. At their insistence, the contracts were reinstated—including the one to Abiomed, the Danvers, Massachusetts firm that produces today’s AbioCor heart. (For further insights on the history of the AbioCor heart, see the article by Renee Fox and Judith Swazey, “He Knows That Machine is His Mortality: Old and New Social and Cultural Patterns in the Clinical Trial of the AbioCor Artificial Heart,” Perspectives in Biology and Medicine 2004; 47:74-93).

What we know today is that the FDA decided not to grant full approval, but to allow use of the device under its “humanitarian exception” provision.” The standard in these cases is that the device be “safe and probably beneficial” and that the condition for which it is used afflicts fewer than 4000 individuals per year. The FDA, to be fair, has a tough job. It has to weigh the risks and the benefits of a new device. It has no clear calculus for doing this. In clinical practice, we typically offer treatments that “work” and expect patients to figure out, using their own personal values, whether the potential advantages of the treatment outweigh the disadvantages. When the treatment (whether drug or device) simply doesn’t do what it’s supposed to do, the job is fairly easy. When it does what it’s alleged to do, but there’s a safer alternative, the job of deciding on approval is also fairly straightforward. In the case of the artificial heart, it seems to “work,” if we define working as, on average, prolonging life. But the cost to the individual is enormous. Tom Christenson, the one subject who lived for 18 months after the implant, developed a fever to 107, kidney and liver failure and respiratory problems. He actually made it home for a few months, only to be readmitted to the hospital at which point the decision was made to disconnect the power source of the device and allow him to die.

Just because the FDA has approved use of the device doesn’t mean that it will automatically be paid for by the major health insurers. Medicare, for instance, has a process for making coverage decisions for controversial technologies such as the artificial heart. Medicare is required by law to make available to enrollees in the Medicare program any medical intervention that is “reasonable and necessary,” a phrase even less well-defined than the FDA’s “safe and effective.” Officially, Medicare is not supposed to take cost into consideration. This has become increasingly problematic as more and more expensive and only marginally useful procedures have entered medical practice, such as lung volume reduction surgery (an operation in which parts of the lung are cut out of patients with emphysema), the implantable defibrillator (a device that automatically shocks the heart if it detects a potentially dangerous heart rhythm), and the left ventricular assist device (another device used for patients suffering from very advanced heart failure, one that boosts the function of the heart rather than replacing the heart entirely). As a result, the Centers for Medicare and Medicaid Services has begun setting the price it will pay for certain procedures far below their actual cost—the left ventricular assist device was initially reimbursed at $70,000 even though the device alone cost $65,000 and the surgery to insert it typically cost over $200,000. With the AbioCor Heart, if Medicare does agree to cover the device, it will no doubt employ a similar strategy: it will choose to permit use of the device but pay something like $150,000—roughly what it pays for a heart transplant but less than half the cost of the new procedure—a strategy that will no doubt put a crimp on actual use of the procedure. (See my article, “Medicare Coverage for Technological Intervention: Time for New Criteria? Published in the New England Journal of Medicine 2004; 350: 199-203).

Replacing the human heart has been the American dream since the National Institutes of Health established an Artificial Heart Program in 1965. Originally granted $600,000 and 5 years to achieve its goal, the project has continued for over 40 years. Along the way, it has been critically reviewed multiple times, sometimes with the recommendation that the work continue only if the technology is expected to be cost-effective, or a good “value for the money.” At $350,000 to implant the AbioCor heart—and this figure does not take into account the full cost of hospitalization for these patients (all but 2 of the initial 14 cases spent the rest of their lives in the hospital)—it is surely not a good value. Heart disease is a critically important problem in America, afflicting some 5 million people. Perhaps it’s time to focus on preventing this disease—which we can do, if we do a better job on the prevention of high blood pressure, diabetes, and cigarette smoking. For those patients who do develop heart failure and who are dying of their heart failure, palliative care is an excellent means of addressing their symptoms and supporting them and their families in their final days.

Dutch Treat

The Framingham Study is probably the most famous long-term medical study ever designed. Founded in 1948 to identify risk factors for heart disease, it began by following 5209 people from the city of Framingham, Massachusetts. It was so successful, definitively showing the importance of smoking, high blood pressure, cholesterol, diabetes, and inactivity in causing coronary heart disease, that a second group of about 5000 people were added in 1971—the children of the first group, along with their spouses. Less well-known, but also teeming with useful insights is another epidemiological study, this one conducted in a suburb of Rotterdam, Holland (A. Hofman, P. deJong, C. van Duijn et al, “Epidemiology of Neurologic Diseases in Elderly People: What Did We Learn from the Rotterdam Study?” Lancet Neurology 2006; 5: 545-50).

The Rotterdam Study has been following a group of men and women since 1990 and is concerned with finding potentially modifiable factors that put older people at risk of debilitating chronic disease. It recruited just under 8000 people over the age of 55, with the oldest participant age 106. Each study member was put through a 2-hour interview at home and a 5-hour battery of tests. On average the examinations were repeated every 3 years, focusing on the heart, the blood vessels, eyes, skeleton, and brain.

Just as the Framingham Study was particularly concerned with heart disease, the Rotterdam Study was especially interested in understanding more about neurologic disease (such as dementia and Parkinson’s disease), visual problems (mainly macular degeneration), and problems with mobility (arising principally from osteoporosis and fractures). The investigators found that by age 85, about 20% of the study group had dementia, and by age 95, the percentage had risen to over 40%. But they also found that the same factors that are associated with heart disease—high blood pressure, cholesterol, and cigarette smoking, along with diabetes—are associated with dementia. And those factors appeared to be important not just for the development of “vascular dementia,” or the dementia arising from multiple strokes, but also for producing Alzheimer’s disease.

The good news from Rotterdam, confirming earlier findings from smaller studies, is that we may be able to prevent dementia in the elderly, or at least delay its clinical manifestations, by treating high blood pressure, lowering cholesterol, avoiding smoking, and preventing or treating diabetes. It remains to be demonstrated that actually doing all these things will in fact make a difference, but it seems well worth a try.

Thinking About Long-Term Care Insurance

I’ve always dreaded when people ask me whether they should buy long term care insurance. They assume that as a physician specializing in the care of geriatric patients, I should know the answer, or at least have an opinion. There are so many different policies and people’s circumstances vary so much that I’ve never known what to say. Now the AARP (American Association of Retired Persons) Public Policy Institute has commissioned a report that sheds considerable light on the subject: “Comparing Long-Term Care Insurance Policies: Bewildering Choices for Consumers” (May, 2006). I still don’t have an answer, but at least I understand the issues better.

By way of background, we should all recognize that we face a substantial risk of needing nursing home care. Nearly 50% of people who recently turned 65 can expect to spend some time in a nursing home before they die. For many this will be the last place they live in; for some, it will be a facility where they stay for rehabilitation after hospitalization. The majority of people over age 80 need some form of long term care—fully 68% of men and 77% of women who live at home need assistance with everyday activities (see Wan He, Manisha Sengupta, Victoria Velkoff, and Kimberly DeBarros: US Census Bureau, Current Population Reports, P23-209, 65+ in the United States: 2005. US GPO, Washington, DC, 2005.

We should also be aware that Medicare pays for only a small fraction of our long- term care needs. Medicare covers up to 100 days of skilled nursing home care each “benefit period,” (where a benefit period typically starts at the time of hospitalization). But this kind of “skilled nursing home” care involves short-term rehab after a hospital stay only. Medicare may also pay for a home health aide or homemaker for a limited time after an acute illness. It does not pay for the kind of ongoing care than an older person with one or more chronic diseases may need. Medicaid, the insurance program for the poor and the disabled, does pay for nursing home care or services in the home for those who have used up most of their resources. The actual Medicaid eligibility criteria vary considerably from state to state since Medicaid is a joint federal-state program.

If you think you want to get long term care insurance, you typically need to choose among policies that only cover care in institutional settings, policies that only cover care at home, and comprehensive policies that provide both. While some people figure that the point of a policy is to be able to pay for home care so as to avoid going into a nursing home and therefore are interested only in a home-care policy, the coverage provided is likely to be inadequate to pay for full time help. Many people decide that if they’re going to get long-term care insurance, they may as well guard against all eventualities.

Finally, consumers should be aware that their premiums can increase. Insurance companies cannot single out particular individuals for increases based on their particular circumstances, such as their health. They can, however, raise premiums to entire groups of people, for example those over age 75. Here are some of the specific questions you need to ask if you are looking at a LTC policy:

Does it cover assisted living?

State laws often require that those LTC policies that cover “facility care” provide coverage for assisted living facilities. However, there is no standard definition of assisted living, so insurers can claim that a particular assisted living facility does not qualify.

What level of disability is needed to qualify?

LTC policies only kick in if the insured meets a specified level of disability. Most (but not all) policies accept the standard of impairment in at least 2 activities of daily living (such as dressing, bathing, or going to the bathroom). However, insurance companies can choose how they will determine if you are dependent in these areas.

What is the daily benefit?

The daily benefit amount provided can be as low as $50 a day or over $300 per day. In some cases, if your benefit ceiling is $150/day and your costs are $100/day, you effectively forfeit the difference, even if the following year you enter a nursing home and your costs go up. Another approach is to use a “pool of money.” The total benefit is then the daily benefit times the number of days of coverage (ie the duration of the policy). The pool can be spent for any combination of services: it might be spent slowly (if your only needs are modest home care) or more quickly (in a nursing home).

How long is the waiting period?

Once a person has met the policy’s “disability trigger,” the waiting period is the time before the benefit actually begins. If you have a 100-day waiting period, and nursing home care costs $150/day, you will have to pay $15,000 before the insurance company starts to pay.

What is the duration of the benefit?

Once you start using the LTC benefit, you may have anywhere between 1 year’s worth of coverage and a lifetime’s worth. Most people who need long-term care need it for several years.

Does it have inflation protection?

Unless you have inflation protection, the daily benefit will lose in value relative to the cost of care. This is an especially severe problem for younger purchasers whose benefit may be inadequate to cover the costs of care years later.

Summary

As the AARP report suggests, it would be very helpful if the government mandated standard policy benefits and provisions, just as is the case for supplemental Medicare policies. In addition, it would be desirable to require companies to offer to pay family caregivers. Finally, LTC policies that pay benefits for multiple types of care should make the total value of all benefits available in any covered setting.

Until such regulations are passed, consumers are faced with a confusing array of possibilities. If you decide you want to buy LTC insurance, you should generally choose a comprehensive policy. You should make sure that by “comprehensive” it in fact does cover assisted living facilities. You probably will want a policy that specifies the maximum total amount it will pay out and that allows you to allocate that amount between home care, assisted living, and nursing home care, as you see fit. You should be sure that the benefit will go into effect once you are dependent in 2 activities of daily living, that the waiting period if no more than 100 days, and that the duration of coverage is at least 3 years. The cost of the premium for such a policy may be very high. Once the insurance agent quotes you a premium, you will need to consider whether you would be better off setting aside money regularly as a special LTC fund for yourself.

Washington Post Review

The following review appeared in the Washington Post on Sunday. It's perhaps a bit overstated, but positive nonetheless.

In The Denial of Aging: Perpetual Youth, Eternal Life, and Other Dangerous Fantasies (Harvard Univ., $25.95), Muriel R. Gillick whacks all the major players orchestrating the Last Dance of America's senior citizens. Medicare is misguided, she argues. Nursing homes are like prisons. Assisted living facilities are too often motivated by greed. Doctors (Gillick is a physician, by the way) are too willing to extend life at any cost. Relatives often have lousy judgment about what's best for a loved one. Even those facing their own finality are too focused on themselves.

In assessing the nation's retirement and health care institutions, Gillick is not the first to see flaws that are ruinous both for the seniors receiving aid and for those of us receiving huge bills for that aid. For example, she notes that while most people want to spend their last days at home, only a quarter of people over age 65 do so. Twice as many die in hospitals, which are so focused on keeping patients alive that they haven't mastered the art of respectfully allowing those near death to leave this world.

For those who need medical care, Gillick would deliver more of it at home, via phone calls, visits from practitioners and other simple measures that have proved effective and efficient. But don't mistake Gillick for a heartless advocate of rationed care. She wants to keep old people alive and well for however long each person can thrive. But she views many efforts to protect nursing-home residents as more of a problem than a solution. By focusing on statistics and standards aimed at ensuring quality of care for these people, she contends, the government is actually prompting these institutions to ignore quality of life.

Gillick challenges Baby Boomers to reengineer nursing homes, first into true homes where elders can thrive and, when necessary, into places providing the care they need to either recover or spend their final days in comfort. More broadly, she challenges her generation to embrace the inevitability of aging and to make the most of it. That would be quite a legacy for the Baby Boomers to leave their children.

--Tom Graham

When More is Less

Last week, Dartmouth’s Center for the Evaluative Clinical Sciences released the latest version of its “atlas” of medical care in the U.S. Since 1993, the Dartmouth Atlas Project has produced a fascinating series of studies examining the geographic variability in health care resources and their utilization. A consistent theme throughout the life of the project has been that the availability of resources drives their use: surgical rates—even for elective surgery—are higher in communities with more surgeons; hospitalization rates are higher in areas with more hospital beds. The newest report, called “The Care of Patients with Severe Chronic Illness: A Report on the Medicare Program by the Dartmouth Atlas Project” draws the same conclusions about the care for people with chronic disease (available in entirety online here)

Chronic disease—conditions such as diabetes, cancer, and heart disease—is the major health problem among Americans today, afflicting some 90 million people and accounting for 7 out of 10 deaths. The care of people with chronic illness accounts for over 75% of all U.S. health care expenditures. And most of the people with chronic conditions are elderly.

The principal finding of the Dartmouth study is that Medicare spends much more per enrollee in some states than in others. Spending for patients with severe chronic illness during their last 2 years of life ranges from almost $40,000/person in New Jersey, Washington, D.C., California, New York and Maryland, to under $25,000 in states including Idaho, Iowa, West Virginia and North Dakota. The variability is not due to higher rates of sickness in some regions. In fact, differences in illness levels are “virtually unrelated to differences in spending.” The other disturbing finding of the study is that the extra spending does not buy longer life or better quality of life. On the contrary, those with chronic illness in high spending regions have shorter life expectancies and less satisfaction with their care.

Spending on chronic illness varies by state, with those states that have greater reliance on primary care than on specialists spending less money and depending less on intensive care units. In Florida, for instance, Medicare patients who died spend an average of 4.7 days in the ICU during the last 6 months of life (a marker of the aggressiveness of care), whereas patients in North Dakota spend only 1.5 days. Academic medical centers also vary in the way they manage chronic illness: during the last 6 months of life, for example, patients who use New York University Hospital have an average of 76 physician visits, compared to 24 visits for patients who use the Mayo Clinic. In general, acute hospitals are dramatically over-used (in Hawaii, patients spend an average of 16.4 days in the hospital during their last 6 months of life, compared to 7.3 days in Utah) and hospice care is under-utilized (while in Arizona, 44.7% of dying patients are enrolled in hospice, in Alaska it is only 6.7% and the national average is 27.2%).

The authors conclude that what we need is “a population-based, community wide integrated system for managing severe chronic illness.” I agree. Specialists have no incentive to refer patients to hospice care; they do have incentives to order diagnostic tests and to use ICU care. Hospitals likewise, unless they are part of a network of care, have no incentive to enable patients to die at home; they benefit if their beds are filled. If we had a comprehensive system—and the closest that any segment of the U.S. comes to such an approach is the Veterans Administration system—Medicare would reduce its costs on patients with chronic disease by 30%, while simultaneously improving care.

Aricept Redux

Three months ago I wrote a column arguing that in the U.S. we over-use donepezil (Aricept), a drug widely touted as helpful in early Alzheimer’s disease (“Americans, Alzheimer’s, and Aricept,” February 1, 2006). In Britain, by contrast, careful review of all the available studies led to the recommendation by NICE (the independent National Institute for Health and Clinical Excellence) against routine use of this medication. Now a new study suggests that donepezil may help patients with advanced Alzheimer’s disease, people who need help with basic tasks such as bathing and dressing and who have profound cognitive impairment (see B. Winblad, L. Kilanter, S. Erikkson et al, “Donepezil in Patients with Severe Alzheimer’s Disease: Double-Blind, Parallel Group, Placebo-Controlled Study,” Lancet 2006; 367:1057-65). How can this be? Are we seeing an attempt to find some use, any use, for this drug, which does not appear to be tremendously useful in early Alzheimer’s patients, the group in whom it was initially targeted?

The new study was carried out in Swedish nursing homes. Subjects were randomized to receive either donepezil or placebo and they were treated for 6 months. The treated group showed slight improvement in tests of mental function and a lower rate of deterioration in basic activities of daily living compared to controls. But before families rush to request donepezil for their relatives, we should consider the intriguing possibility raised by the study’s authors: perhaps what the donezpezil did was to counteract the negative effects of the many other medications these individuals were taking. Virtually all the people in the study (99%) were taking other medications, and 80% were on psychoactive medications intended to control their behavior. We know that the brains of individuals with dementia are very sensitive to chemicals that affect the nervous system—they are very prone to developing delirium, or an acute confusional state. Before concluding that all patients with severe dementia should be given donepezil, we need to study its effectiveness in demented persons who are on no other medications. Only then can we figure out whether we should dole out more donepezil (assuming that the “statistically significant” benefits are in fact clinically meaningful)—or give patients a drug holiday, discontinuing the many potentially toxic medicines they are currently taking.

The Skinny on Longevity

It’s been known for some time that skinny rats live longer than fat rats. They have to be extremely svelte for this effect to kick in: laboratory rats that consume 60% of the usual rat diet live 30% longer than the average rat. Studies are underway in primates, but because monkeys live for many years, the results of “caloric restriction,” as the intervention is called, on their longevity is not yet know. But a new study in the Journal of the American Medical Association suggests that a comparable phenomenon is at work in people.

A team of researchers from Louisiana State University in Baton Rouge and the Garvan Institute for Medical Research in Darlinghurst, Australia reported on a randomized study involving 48 people (see Leonie Heilbron, Lilian de Jonge, Madlyn Frisard et al, “Effect of 6-Month Calorie Restriction in Biomarkers of Longevity, Metabolic Adaptation, and Oxidative Stress in Overweight Individuals,” Journal of the American Medical Association 2006; 295:1539-48). The 48 people included men under 50 and women under 45 who were healthy but sedentary and overweight but not obese. It was hard to find people to participate: of 599 people who were screened for participation, 460 failed to meet the criteria. Another 91 people decided as they were being screened that they weren’t interested in participating. For the 48 people who did enroll, 12 served as controls and were kept on a weight-maintenance diet; 12 were assigned to a calorie restricted diet (25% restriction of their baseline energy requirements); 12 were assigned to a combination of calorie restriction and exercise (12.5% calorie restriction and 12.5% increase in energy expenditure through exercise); and 12 were assigned to a very low calorie group (890 kcal/day). Midway through the study and then at the end of the 6-month study period, all sorts of measurements were performed, including tests reflecting metabolism, tests of DNA damage, and of course weight.

What the authors found was that after six months of the prescribed regime, insulin levels and core body temperature were decreased in the intervention groups, both of which are “biomarkers of longevity.” They also found evidence of “metabolic adaptations,” i.e. lower energy expenditure in the groups on the special diets. While they could not conclude anything about whether these changes would persist if the subjects continued on their diets indefinitely and they certainly could not conclude that the subjects would live longer if they kept up the diet, they found the results “suggestive.”

The interesting aspect of this work is the possibility not that we could live longer if we starved ourselves, but rather that the aging process might be slowed down if we could find ways to emulate the effects of caloric restriction. Nobody seriously believes that large numbers of people are going to go on an 890 calorie diet indefinitely in a society where we cannot even find ways to prevent obesity or to help markedly overweight individuals lose weight. Most people aren’t really interested in living to be 100, particularly not if it means a long period of physical frailty and cognitive impairment. But if scientists could design chemicals that mimic the effects of calorie restriction and if these chemicals are able to delay aging, then conceivably all the major disorders of old age—heart disease, cancer, dementia—would have a later age of onset.

Of course it’s far from clear from a study of 48 people conducted over a mere 6 months that caloric restriction will have the desired age-delaying effect. And even if caloric restriction does prove effective, it will be a long way to finding a pill that produces the desirable consequences of caloric restriction without any significant side effects.

Before any older individuals cut down on food in the hope of preventing disability, it’s critically important to note that among older people today, malnutrition rather than obesity is a major problem. In the National Health and Nutrition Examination Survey, a study conducted periodically by the federal government, the incidence of malnutrition is reported to range between 12 and 50% among hospitalized older people and from 23-60% among institutionalized older adults. In the community, where malnutrition rates are lower, it remains a problem among people with low income, difficulty digesting or chewing food, and people who have trouble shopping or cooking (See Carol Evans, “Malnutrition in the Elderly: A Multifactorial Failure to Thrive,” Permanente Journal 2005; 9:3).

Facing our mortality is not easy. But phantasmagorical dreams of perpetual life are not the answer. What I argue in my book, The Denial of Aging: Perpetual Youth, Eternal Life, and Other Dangerous Fantasies is that immortality projects are better ways to cope with knowledge of our finitude than are searches for the elixir of life. Immortality projects—whether a book we write, a company we found, or the children we nurture—help us transform our painful awareness of our own limits into enduring memories. They are the way we leave a mark on the world, even after we ourselves have departed.

Newsweek Interview

Here's an interview Newsweek did a few days ago.