The Tangled Neuron

Surgery, Anesthesia and Memory Loss

Summary:  After surgery, many people experience short-term delirium and/or longer-term cognitive decline.  Scientists are still studying how to prevent these problems.

Doctors, families and patients report that surgery seems to cause short-term delirium and/or longer term memory loss in some people.

In a recent Duke University study of 1064 patients undergoing major surgery (but not heart surgery), neuropsychological tests showed the following rates of post-operative cognitive dysfunction or POCD:

Age range                  Leaving hospital      3 Months After Surgery

18-39 year olds                 37%                                 6%     

40-59 year olds                 30%                                 6%

60 or older                         41%                               13%

Zhongcong Xie, M.D., Ph.D.

Even higher rates of POCD have been reported after heart surgery, but scientists still don't agree on how to measure these problems, or on whether the heart patients also had memory loss before their surgeries.

Dr. Zhongcong Xie, Assistant Professor at Massachusetts General Hospital and Harvard Medical School, is working with his colleagues to determine what causes POCD.

POCD seems to be worse among the elderly, but "the reason why age is a risk factor for POCD remains to be determined," Dr. Xie says.  In his lab, he and his colleagues are researching

Does Depression Increase Your Risk of Memory Loss?

Summary: A new study provides more evidence that depression may be a risk factor for Alzheimer’s.

People with dementia often report they suffered from depression before they developed serious problems with memory and thinking. Study after study has shown a link between depression and memory loss. Researchers continue to debate whether depression increases the risk of developing serious memory loss or is simply a sign of brain changes underlying Alzheimer’s or other dementias.

Robert S. Wilson, Ph. D.

Dr. Robert Wilson, Professor of Neurological Sciences and Psychology at Rush University Medical Center, studies the neurobiology of the connection between depression and dementia. In an article in a recent issue of the Archives of General Psychiatry, he and his colleagues provide more evidence that depression may be a risk factor for Alzheimer’s.

Antipsychotic Medications and Alzheimer's

Throughout his life, my father laughed away any worries. He never locked doors; he trusted everyone. When lightening struck a transformer ten feet from where he stood, he brushed it off. Nothing kept him awake at night.

But when I visited my parents for Dad’s 73rd birthday last year, he was confused and seemed to be hallucinating. “Where are the others?” he asked over and over. “They were here a little while ago – I’m sure I saw them.” I had flown up by myself, and no one was with us in the house.

Later that week, he told Mom he couldn’t sleep because he thought the vibrating box fan in the doorway of the bedroom was going to attack him. He was upset, and it was hard for my mother to reassure him.

Symptoms like Dad’s are common in Alzheimer’s patients, and add to caregivers’ burdens. According to the U.S. National Institute for Mental Health (NIMH), antipsychotic drugs are widely used to treat psychiatric symptoms in people with Alzheimer’s. More than 27% of patients in American nursing homes receive these drugs, which were initially developed for schizophrenia. But, at least in the U.S., these drugs carry “black-box” warnings that they are not approved for the treatment of patients with dementia-related psychosis.

Results of a five year study of antipsychotic medicines in Alzheimer’s patients were published earlier this month in the New England Journal of Medicine. The “Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Alzheimer’s Disease” study tested three antipsychotic medications against a placebo in 421 Alzheimer’s patients living in their own homes, in family members’ homes, or in assisted living. The medications tested were:

- olanzapine (Zyprexa)
- quetiapine (Seroquel) and
- risperidone (Risperdal).

Input from caregivers was used to help with doctors’ assessments of any improvements or side effects. Although these drugs showed some benefit for some patients, the researchers concluded that “adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer’s disease.”
Side effects seen in some patients included problems with coordination of movement, sedation, confusion and psychotic symptoms. Antipsychotic medicines have also been shown to increase the risk of developing diabetes and stroke.

Despite recent headlines about this research (“Little Benefit Seen in Antipsychotics Used in Alzheimer's,” etc.), it’s hard to say what the study results mean for each individual patient. Dr. Constantine Lyketsos, Chair of Psychiatry at Johns Hopkins Bayview and Vice Chair of Psychiatry at Johns Hopkins Medicine, co-authored the study. “Neither the CATIE study nor other studies suggest that these medicines shouldn’t be used,” he says. “If you look at the CATIE study, it’s not that the medicines weren’t effective, but the risk/benefit ratio has changed. For the sub-groups of trial participants for whom the medications weren’t discontinued because of side effects, they were more effective than placebo. If a patient’s symptoms are high-risk, then doctors can try antipsychotics with careful safety monitoring. If one of these drugs is well-tolerated, then I can tell you from clinical practice that it’s often effective.”

Constantine (Kostas) G. Lyketsos, M.D., MPH

“I think it would be unfortunate if everyone stopped prescribing any medication solely on the basis of one study,” agrees Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine. “Contrary to what many people believe about the study results (and I'll agree that the presentation is confusing), I would not argue that it shows that antipsychotics don't work. It simply shows that antipsychotics aren't enormously effective and that they have lots of side effects. Physicians should prescribe what's appropriate for their individual patients while being aware of the risks and benefits of any given treatment.”

In a “Question and Answer” page on this study, the NIMH recommends caution in prescribing these drugs:

Although some patients may benefit greatly from these medications, the evidence from this study suggests these medications hold limited value for the majority of patients. These results further emphasize the challenge of managing behavioral problems in Alzheimer's patients. Prior to prescribing these medications, clinicians must ensure that agitation or aggression in their Alzheimer's patients are not related to medical, social, or environmental factors (e.g., fever from an infection, side effects from another medication) which might be mitigated without resorting to psychotropic medications.

In a future post, I’ll write about potential alternatives to these drugs, and efforts to develop antipsychotic medications with fewer side effects. But right now, there are no easy answers for doctors or for caregivers.

In the weeks after Dad’s birthday, things got better. Although he was still confused sometimes, he didn’t seem to be hallucinating, and wasn’t as agitated. His doctor thought maybe his symptoms were the result of heat exhaustion (he had mowed the lawn in the summer heat just before these incidents). I now wonder if he’d had a small hemorrhagic stroke that day. If my father had lived longer, he might have gone through more periods when he was anxious, agitated and confused. As the anniversary of his death approaches, we all miss him terribly. But I’m glad we didn’t have to agonize over whether antipsychotic medicines would help him or hurt him.

Stress, Depression and Alzheimer's, Part 2

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.

Dr. George Zubenko, Professor of Psychiatry at the University of Pittsburgh School of Medicine, spent some time last week helping me make sense of all this.

“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.

Stress, Depression and Alzheimer's, Part 1

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.