The computer industry uses version numbers to track the evolution of software. The first release after trial versions is called version 1.0. Major changes are reflected in the first digit of the version number, as in version 2.0. Any minor changes are reflected in the second digit, as in version 2.1. I’ve recently realized that this labeling scheme could apply to hormones as well. Think of it this way – each decade, along with its associated hormonal changes, is a major version change.
In the midst of writing about Alzheimer’s and dementia, I find myself in Hormones 4.9. So far, the transition into middle-aged versions is reflected more in my mental preoccupations than in any physical manifestations. All I think about is aging and dementia.
These topics dominate my conversations now, partly because most of my friends are somewhere near Version 5.0. My colleague Rebekah and I used to talk about technical specifications and industry gossip. But when she called me from Kansas City the other day, my favorite subjects came up. She was driving her dog Max to his acupuncturist appointment, for treatment of arthritis and irritable bowel syndrome. I told her about my scheme for labeling hormonal stages, and we wondered how it would work for dogs.
Then she told me her father-in-law had fallen at the nursing home. “Nine stitches and a bump the size of a prairie chicken egg,” she said. “I went to visit him yesterday, and said ‘That was really a nasty fall.’ ‘Fall!’ he said, ‘I didn’t fall – I was taken down by a mob in the bathroom! Then the lady who sits on people at football games got me….”
With a sense of humor and an occasional glass of wine, I figure we can handle Hormones 5.0. But I’m more worried about 6.0 and beyond. It seems no one is immune to serious problems such as Alzheimer’s, cancer, and heart disease. Maybe this is why when Gail Rae Hudson (The Mom and Me Journals) and her mother watched the movie Cocoon recently, they decided they would drink from the fountain of youth if they had the chance.
I thought of them when I watched 10 Years Younger yesterday [I had turned on the television for research purposes – really!]. During the program, image experts succeeded in moving a woman’s appearance from Hormones 4.9 back to Hormones 3.9 or so. But what good is looking like Version 3.9 if I can’t remember where I left my car?
Is there anything we can do to decrease our actual version numbers and avoid serious health problems? As far as I can tell, scientists don’t understand aging very well. The most popular idea about why we age is called the Free Radical Theory on Aging. According to this theory, breathing in air allows unstable molecules called oxygen free-radicals to build up in the body. These oxygen free-radicals then combine with other molecules, causing cell damage in a process similar to the way rust damages metal.
Researchers have shown that calorie restriction in mice and other organisms extends their lifespans. Fans of the Free Radical Theory think this may be because reducing food intake decreases the rate of metabolism and thus oxygen intake, and so the amount of free-radicals accumulating in the body also goes down. Some studies have contradicted this hypothesis, though. Even more discouraging, the anti-oxidant vitamins I thought might keep me in the equivalent of Hormones 4.9 for a few more years may not be effective. Maybe the Free Radical Theory of Aging won’t lead to Gail’s fountain of youth.
But Dr. Craig Atwood at the University of Wisconsin thinks a theory called the Reproductive-Cell Cycle Theory of Aging may eventually show the way. As discussed in an earlier post, he believes the same theory explains the chain of events leading to Alzheimer’s disease.
Dr. Atwood’s 2004 paper “Living and Dying for Sex: A Theory of Aging Based on the Modulation of Cell Cycle Signaling by Reproductive Hormones,” explains how calorie restriction might extend lifespans a bit differently than free radical [theorists, proponents]. The paper was co-authored by Dr. Richard Bowen of Voyager Pharmaceutical Corporation and published in Gerontology in 2004. It outlines the idea that when estrogen and testosterone levels go down in mid-life, the body cranks up other hormones (luteinizing hormone and follicle stimulating hormone, for example) in an attempt to maintain fertility.
“The increased levels of luteinizing hormone and follicle stimulating hormone signal bone, muscle, brain and other cells to divide inappropriately,” Dr. Atwood explains, “leading to cell dysfunction and death. This increased cell death leads to tissue dysfunction and disease, thereby killing less fertile older animals or people, preventing them from competing for resources with younger, more fertile individuals.”
Dr. Atwood thinks this theory better explains why stresses like extreme calorie restriction, exposure to cold, and “excessive” exercise appear to be associated with longer life, since calorie restriction has been shown to reduce reproductive hormones in female mammals. It may be the body interprets these stresses to mean that it’s not a good time to reproduce, and so decreases the amount of sex hormones it manufactures.
Maybe hormones hold the key to real anti-aging, rather than just changing appearances. But what about reports that hormone treatments may not prevent disease and dementia in women? In the U.S., the Women’s Health Initiative (WHI) hormone therapy trials were discontinued in 2002 because researchers found somewhat higher rates of some diseases in the group taking hormones. This same study also found that the estrogen plus progestin combination used in the trials didn’t prevent cognitive decline and actually seemed to increase dementia in some women over 65.
I asked Dr. Atwood if the results of the Women’s Health Initiative trials mean I shouldn’t consider taking hormones to decrease my risk of dementia. He said he feels that it’s very misleading to extrapolate the results of this study, in which Prempro and Premarin were used, to all forms of hormone replacement therapy. Prempro is a combination of conjugated equine estrogens and progestin in the form of the synthetic medroxyprogesterone acetate, and Premarin is made up of conjugated equine estrogens.
“Current hormone replacement therapies do not come close enough to replicating normal reproductive hormone levels,” he says, “since conjugated equine estrogens and medroxyprogesterone are not the major forms of sex steroids in the human body.” He points out that the WHI study contradicts results from numerous other animal and human studies showing that natural or bioidentical forms of these hormones protect neurons and may prevent dementia.
Hormones affect men too. A new study by researchers at the University of Washington Veterans Administration Puget Sound Health Care System found that low testosterone levels in men are associated with increased mortality rates. Looking specifically at dementia, the picture seems less clear. Scientists at the University Medical Center Utrecht in the Netherlands studied the link between reproductive hormones and Alzheimer’s disease (AD) in 2,974 men, aged 71 to 93 years for six years. They concluded “testosterone levels are not associated with risk for cognitive decline and AD, whereas higher estrogen levels increase risk for cognitive decline and AD”. In a small study at the University of California Los Angeles, testosterone supplementation in 16 men with Alzheimer’s improved their quality of life as reported by caregivers, but not their cognition.
It doesn’t seem to me there’s been enough research yet to know how various hormone replacement therapies will affect aging in general, let alone the risk of developing dementia. Dr. Atwood agrees that further research is needed. He and his colleagues are studying the neuroprotective effects of different formulations and delivery methods of female sex hormones.
He reminded me that research on aging and dementia has to have a broader focus than simply looking at estrogen and testosterone levels. “There are many other hormones that become dysregulated in the body following menopause and andropause,” he says, “and these have not been studied in any detail. Therefore, the dysregulation of estrogens and testosterone may be only part of the story.”
In the meantime, at least in theory, Gail and her mother could try to fool their bodies into keeping levels of luteinizing hormone and follicle stimulating hormone low by subjecting themselves to some of the stresses listed above. It’s hard to say whether this would slow their rate of progress to higher versions. For his part, Dr. Atwood doesn’t view calorie restriction as very attractive. “Rigorous exercise is the most practical anti-aging strategy until therapies that modulate reproductive hormones are developed,” he says.
I don’t think Gail will starve her mother, or sign her up for an Ironman race and the Polar Bear Club, but I guess this is the place to say that information in this post is not a substitute for medical advice. These measures could have life-threatening ill effects, particularly in older people.
With software, higher version numbers indicate greater stability and added functionality. Could this be true for life? Although I don’t want to develop dementia or another serious disease, I don’t really want to go back to Hormones 2.9 or even 3.9 either. So for now, I’ll watch for more research on the role of reproductive hormones in Alzheimer’s and aging, and head to the gym as often as I can. But I’m rebelling against the idea of looking “10 Years Younger”, and am growing my gray hair out. At least people will understand why I can’t find my car.
In a previous post, I wrote about how a history of depression may increase your risk of developing dementia. This connection is not well understood, and is further complicated by the fact that many Alzheimer’s patients are depressed, even when they have no previous history of depressive episodes. If my father had lived long enough, he might have been dealing with depression as well as cerebral amyloid angiopathy and probable Alzheimer’s.
“The rate of depression in people 65 and over is quite low – a few percent,” Dr. Zubenko says. “But somewhere between 30 and 50% of Alzheimer’s patients suffer from depression. Some of that is probably due to the realization that they’re losing mental capacity – major depressive episodes often seem to be triggered by stressful life events. The much higher rates of major depression in AD [Alzheimer’s disease] patients suggest that the emergence of MDD [Major Depressive Disorder] in AD is often the result of the neurodegenerative disorder.
George S. Zubenko, M.D., Ph.D.
It’s obvious that major depression increases the suffering of dementia patients and their caregivers. Dr. Zubenko points out that it also exaggerates the patients’ disabilities, makes institutionalization more likely, and may hasten death. For these reasons, it’s important to diagnose depression in dementia patients. Diagnosis can be tricky, though - doctors don’t agree on the definition of "depression" in AD, and it’s often difficult for dementia patients to communicate their symptoms.
To help diagnose and characterize depression in Alzheimer’s patients, Dr. Zubenko and his coworkers developed a diagnostic interview called Clinical Assessment for Depression in Dementia (CADD). He believes that “major depressive disorder in Alzheimer’s disease” is not the same as major depression in non-demented patients. When the CADD was administered to 243 patients with probable Alzheimer’s disease and 151 non-demented control patients, the data showed that Alzheimer’s-related depression had somewhat different symptoms than “regular” depression. In this study, depressed Alzheimer’s patients were less likely to have sleep disturbances or feelings of worthlessness or excessive guilt than non-demented depression patients, but were more likely to have problems concentrating or making decisions.
The results of this same study confirmed other research showing that the prevalence of major depression did not increase with the severity of Alzheimer’s disease. This may mean that major depression in Alzheimer’s is not related to the overall degeneration of the brain, but rather to degeneration in specific areas. In fact, several studies have shown that major depression in Alzheimer’s disease patients is associated with the degeneration of the areas of the brain stem that produce mood-regulating chemicals such as serotonin, noradrenaline, and dopamine. It’s unclear whether this is relevant for other types of dementia.
Dr. Zubenko is one of a group of scientists proposing that the next update of the Diagnostic and Statistical Manual of Mental Disorders (a reference manual used by doctors in the U.S.) include more accurate characterizations of various psychiatric symptoms in dementia, including depression. Better diagnosis would be another step towards understanding the causes of and treatment for depression in Alzheimer’s.
In the meantime, can doctors help AD patients with depression? Most clinical trials of anti-depressants for depression in Alzheimer’s have been relatively small and short term. At first glance, results look mixed, with some trials showing anti-depressants were more effective than placebo, and some not. In one larger study of 511 patients, an anti-depressant significantly improved both depression and memory. Research currently underway may yield more information. Israeli researchers are conducting a trial of Escitalopram (Lexapro, Cipralex)) for depressive syndrome in various dementias, and there’s also a U.S.-based trial of Zoloft for depression in Alzheimer’s disease.
But the published trial results are really more positive than it first appears, because many show large improvements in the patients taking antidepressants AND in those taking placebos. For example, researchers from the Raul Carrea Institute of Neurological Research in Argentina published the results of a trial of anti-depressants in 41 depressed Alzheimer’s patients. The symptoms of depression went away in 47% of patients treated with the anti-depressant, and in 33% of those treated with placebo. The large placebo effect may be due to non-drug factors such as the attention paid to patients and caregivers during clinical trials, or to the fact that depression in Alzheimer’s patients seems to come and go. Even though it’s not well understood, Dr. Zubenko says this finding means doctors can provide some assistance for AD patients with depression.
“The goals of most controlled clinical trials are somewhat different from the goals of clinical care,” he explains. “Most controlled clinical trials are designed to evaluate whether a particular treatment is effective. To accomplish this, the only difference between the treatment and control groups is the specific treatment whose potential benefit is being evaluated. These controlled trials are important because they provide scientific information from which healthcare professionals and caregivers can decide what treatments work for a particular condition and which do not. Doctors recommend treatment plans for individual patients based on this information, but are not limited to one particular treatment approach. In such cases, we often recommend multiple interventions to maximize the likelihood of a beneficial response, hopefully in an organized way, so that we can also infer which interventions are benefiting the patient. This practical approach is especially important when time is of the essence--e.g the patient's condition is deteriorating in ways that place them in harm's way, they are dangerous to others, or when other practical realities limit the available duration of treatment (such as often occurs in inpatient settings).”
Medications are helpful, but “nonspecific clinical interventions can have valuable effects on optimizing function and minimizing disability,” Dr. Zubenko says. “Patients who are in physical pain or discomfort, or are impaired in other ways by medical problems or medication side effects, commonly have secondary disturbances of mood and cognition. Performing a complete medical evaluation and optimizing general health care can have significant positive effects on level of function and the quality of life. Supportive care is also important-- improving nutrition among malnourished patients, addressing personal hygiene, normalizing and structuring daily activities, providing a safe environment with activities and aids that facilitate memory and promote normal functioning , and reevaluating these plans periodically to ensure that they remain appropriate to the patient's needs. Based on my clinical experience, major depression in AD patients usually responds best to a multimodal treatment approach.
It's also important to remember that the ongoing care of a patient with AD is a challenging task for the caregiver. Over the intermediate and long term, it is necessary to provide support, education, assistance, and resources to the caregivers as well. Proper attention and support reduces the stress on caregivers and decreases or delays the need for institutionalization. Failure to do so results in poorer outcomes for both patients and caregivers alike.”
So, major depression and dementia are closely linked, and our understanding of causes and treatments for both of these diseases is still incomplete. For depression sufferers around the world, there’s an increased risk of AD. And for Alzheimer’s patients around the world, there’s a potential depressive ripple effect, for both patients and caregivers.
Careful medical attention for both the patient and the caregiver may help, but I wonder how many patients and caregivers can get this attention. In my family’s experience, it was difficult to coordinate Dad’s care between his family physician and his neurologist, let alone “optimize” all the factors Dr. Zubenko talks about. If my father had lived long enough to need intensive caregiving, only minimal assistance and resources would have been available to us.
It’s hard to find the silver lining in this research, but Dr. Zubenko put it in perspective for me. “We’re trying to treat a complicated behavioral syndrome in the context of degenerative brain disease – any progress is remarkable, and efforts to optimize treatment are well worth it for patients and their family members,” he says.
Last week, I wrote about a dementia risk score developed by researchers at the Karolinska Institute in Sweden. To put the risk score in perspective, I checked in with Dr. Tiia Ngandu, co-author of the risk score article published in the September issue of Lancet Neurology. Here are her answers to my questions:
Q: Some background information: my dad died of a hemorrhagic stroke last November, and his autopsy showed severe cerebral amyloid angiopathy (CAA) along with probable Alzheimer's disease. He had few of the risk factors I think were involved in calculating the "dementia risk score": his cholesterol was always low, he was not at all overweight, his blood pressure was low, he exercised and had 16 years of education. So, in my father's case, anyway, he would have had a low score, and I think would have been a "false negative" in your study.
A: First of all, I would like to say that the aim of our risk score was not to say definitely that someone will develop dementia or someone will not. That would not be possible, since we are dealing with a disease that is as complex and multifactorial as Alzheimer's disease. Those persons who had more risk factors had a higher risk of developing dementia in 20 years time, but even among those who had the worst risk score, only 35 % developed dementia - that is to say that with our score it is not possible to "label" persons into future demented and nondemented. We hope that the risk score will be more used to inform both physicians and patients about the risk factors behind dementia in a very practical way. We believe that the persons with most risk factors and highest risk score might benefit from both lifestyle and pharmaceutical interventions.
Q: Was a fairly homogeneous population used for the study? [I asked this because results from one population may not apply to another.]
A: All the participants are from Eastern Finland, and they were fairly homogeneous population.
Q: Did you differentiate at all among the various types of dementia? What cognitive or other tests were used to detect dementia?
A: We differentiated between different types of dementia. The majority of patients had AD. The Mini Mental State Examination (MMSE) was used as a screening test, and after screening the patient went through both clinical and neuropsychological examinations. Due to the use of MMSE at the screening, we may have missed persons with mild dementia, especially early vascular dementia.
Q: Were there risk factors considered that were not found to be predictive in this study? Smoking? Family history of dementia? Tooth loss? Genetic status?
A: Risk factors that were considered but not found predictive were midlife smoking and diastolic blood pressure. We did not have information on family history of dementia or tooth loss. ApoE4 was predictive in this study and it was included in a second risk score model. (It was left out from the first one because we wanted to include only parameters that are easily available in primary care settings)
Q: What other risk factors may be considered while you refine the scoring process?
A: Other risk factors that should be considered in the future risk scores are at least diabetes and family history of dementia: those factors have quite a lot of evidence behind them at the moment.
Q: I saw an abstract of a presentation by researchers at Kings College London at the recent Alzheimer's conference in Madrid that says that in the Honolulu Asia-Aging Study, "cholesterol levels in men with dementia, and in particular those with Alzheimer’s disease, had declined at least 15 years before the diagnosis and remained lower than men without dementia throughout that period." Do you think this is true in other populations? How might this affect the cholesterol component of your risk score?
A: Some studies have shown that the cholesterol levels (as well as blood pressure levels) decline in demented patients, and that this decline begins already before the diagnosis of dementia can be made. This decline is probably due to the disease process rather than the decline in cholesterol increasing the risk of dementia. In the Honolulu-Asia Aging Study this kind of decline was observed already 15 years before diagnosis. Also the research group from the Honolulu study thought that the decline might be due to early stages of dementia. I don't see that these findings are in any way contradictory to our findings that high cholesterol levels at midlife would increase the risk of dementia. One should keep in mind the trajectories of cholesterol change with aging and in relation to chronic diseases.
Q: The audience for my blog is mostly middle-aged people, many of whom are caregivers for dementia patients. On a practical level, is there anything we should learn from the dementia risk score other than a confirmation that cardiovascular health and education levels appear to be linked to dementia?
A: What I believe that a middle-aged person could learn from our risk score is that there are several things one can do in order to reduce the risk of dementia. Especially the cardiovascular risk factors can be modified with both lifestyles and medications. I think it is quite good news for those who worry that they might become demented and would like to do something to prevent or postpone it. Of course there are still many other and also unknown factors influencing the development of dementia, but we believe that this is a step in the right direction.
Grand Rounds is up at Clinical Cases and Images - interesting reading, even for laypeople!
For most of his life, my father was calm and happy. “No sweat,” he’d say when the furnace blew up or the car wouldn’t start. Even when his retail lumberyard burned down, or when his parents died, he seemed to take a Zen attitude towards life. But after he retired, I thought he was more pessimistic than usual. Was this somehow related to his later dementia?
I didn’t think much about mood, depression and dementia until I realized it was a topic of discussion on some of the caregiver blogs. In The Yellow Wallpaper, Deb Peterson writes about how her mother’s depression after the death of several family members seemed to mark the beginning of her dementia. Paula Martinac (Dementia Blues) reports both her parents were depressed before their declines into dementia. But many people with Alzheimer’s disease or dementia have no history of depression. Gail Rae Hudson (The Mom & Me Journals), who describes her mother’s condition as “dementia lite,” doesn’t think her mom has ever been depressed.
Was the change in Dad’s mood [I wouldn’t call it depression] a normal reaction to retirement? Or was it an understandable reaction to subtle signs of dementia the rest of us didn’t see? It makes sense that some dementia patients become melancholy when they realize they’re having memory problems.
But rather than dementia causing depression, it seems to be more of a two-way process. Several studies show a history of depression may increase your risk of developing dementia later in life:
• A large retrospective study at the University of Limburg in the Netherlands (published in 1996) and another at the University of Copenhagen in Denmark (2003) found associations between a history of depression and dementia
• When researchers at Rush Alzheimer's Disease Center in Chicago followed Catholic clergy aged 65+ for seven years, they concluded that each depressive symptom reported over the seven year period increased the risk of developing Alzheimer’s disease by an average of 19%, and increased average cognitive decline by 24%.
• Scientists at Boston University School of Medicine found a significant association between depression symptoms and Alzheimer’s in 1953 patients with Alzheimer’s disease and 2093 of their non-demented relatives. The association was most significant when depression symptoms first occurred within one year of the onset of Alzheimer’s, but there was still a modest association even when depression first happened more than 25 years before the onset of Alzheimer’s. [free registration required to view this article]
Other studies have not been as definitive. University of Ottawa researchers found a weak, but not statistically significant association between a history of depression and Alzheimer’s disease after following more than 4600 Canadians aged 65 and older over a five year period.
This year, a team of researchers from the University of Miami Miller School of Medicine and the Wien Center for Alzheimer’s Disease and Memory Disorders at Mt. Sinai Medical Center published the results of a systematic review and analysis of the research on this topic. Analyzing data from over 100,000 patients in 22 studies, the researchers concluded that a history of depression does seem to increase the risk of developing Alzheimer’s, although the absolute risk is still small. Their data also showed relatively long times between depressive episodes and the onset of Alzheimer’s, suggesting that depression may be an independent risk factor for developing Alzheimer’s rather than signaling the onset of the disease.
For dementia patients with a previous history of depression, it’s also likely their dementia will be more severe than that of patients with no such history. In a recent study, pathologists compared the brains of Alzheimer’s patients who had lifelong histories of depression to the brains of Alzheimer’s patients who hadn’t had depression. The pathologists found that the brains of patients with a history of depression had more of the plaques and tangles associated with Alzheimer’s disease than those of patients who hadn’t had depression. This increase in plaques and tangles seemed to correlate with the severity of memory loss.
If depression and Alzheimer’s are linked, then maybe there’s a common underlying cause. Several studies point to cortisol, a stress hormone, as the possible culprit. The thinking is that stress causes the body to release cortisol, and that chronic stress leads to the chronically high levels of cortisol sometimes associated with cognitive impairment and shrinkage of some areas of the brain.
The obvious question is whether lowering cortisol improves memory. I’ve always had trouble navigating, and this problem gets worse when I’m upset. Could I take something to lower my levels of this hormone before I drive an unfamiliar route? It turns out that for rats, lowering cortisol levels does improve their performance in mazes.
I was disappointed to find it’s not so simple for humans. In a small trial of seventeen people, a team headed by researchers from McGill University in Canada found that manipulating cortisol levels did have an effect on memory in some people, but that effect was dependent on historical cortisol levels in each participant or person. If the individual patient had had moderate cortisol levels for a period of five years, blocking cortisol levels actually decreased memory, and adding back cortisol reversed this problem. For patients with historically high cortisol levels and existing memory problems, blocking cortisol didn’t improve memory, although increasing cortisol levels made their memory problems worse. This could be because it’s the cumulative, long-term exposure to high levels of cortisol that hurt the brain, rather than the level at any one time. Some scientists think problems are caused by the malfunctioning of the receptors for cortisol, rather than the hormone itself.
So, the cortisol and stress connection is intriguing, but at least so far, hasn’t yielded the magic formula to fix dementia.
One of reasons it’s hard to untangle the relationship of depression and dementia or Alzheimer’s disease is that both diseases may have multiple underlying causes. “I think the evidence shows that there may be complex relationships among stress, cortisol (and other neuroendocrine substances), inflammatory markers, cardiovascular disease, and cognition,” says Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine and the lead author of the scientific review of research on the topic. “Since cardiovascular disease may be related to Alzheimer's disease, it seems quite possible that stress, cortisol, inflammation, depression, and AD may all be related, but we don’t know how.”
Raymond L. Ownby, M.D., Ph.D., M.B.A.
But even if stress, cortisol and depression were only partially responsible for dementia, could they be considered “modifiable risk factors” for Alzheimer’s disease? I asked Dr. Ownby if treating depression could actually lessen a person’s chances of developing dementia.
“The possibility that treating depression might lower your risk for Alzheimer’s disease is intriguing,” he says, “but there simply isn't any evidence that I'm aware of on the subject, other than the possibility that antidepressants can lower levels of some chemicals that may be related to dementing illnesses.”
What about the idea that depression can masquerade as dementia? When I first started researching my father’s memory problems, several web sites mentioned “pseudo-dementia.” According to some of these sites, once you treat the depression, the dementia is reversed. But the diagnosis and prevalence of pseudo-dementia is now in question, and at least one study has shown that many people who seemed to have reversible dementia [their memory problems improved after their depression was treated] later developed [non-reversible] dementia.
Dad didn’t have a history of depression, and it’s pretty clear most of his dementia was related to cerebral amyloid angiopathy. But if he had lived long enough, depression might have been more of a problem. Treating any depression may have helped his dementia, at least for a while. I’ll talk more about that in my next post.
Sometimes the headlines about Alzheimer's research are dramatic, but the lives of dementia sufferers and their caregivers are pretty mundane. In fact, details like preparing meals, balancing a checkbook and bathroom visits take center stage.