Life and Memory Center

Type 2 diabetes mellitus is associated with Mild Cognitive Impairment (often presenting as short-term memory loss that is either subjective or confirmed by rigorous memory tests) as well as dementia (moderate to severe short-term memory loss that causes a lack of independence). Furthermore, insulin resistance, the hall mark of adult onset or type 2 diabetes, increases the risk of developing Alzheimer’s disease.

Results from the Honolulu aging study provide an example of the association of the balance of glucose and insulin with risk of dementia. Study participants who had either very high or very low levels of serum insulin were more likely than those in between to become demented over the course of 5 years. Other studies, but not all, have shown this link between insulin resistance, impaired glucose metabolism, diabetes and dementia.

You have probably read the headlines generated by a recently published study demonstrating that intranasally administered insulin improved memory and “may be a potential treatment for Alzheimer’s disease.” The study recruited 104 adults with an average age of 72 who had a diagnosis of either mild cognitive impairment (66% of total number of subjects) or mild to moderate Alzheimer’s disease (33%). Participants were treated with either 20 or 40 IU of insulin intranasal for 4 months. Those treated with the lower dose showed improved memory over the course of the study whereas those treated with placebo got worse. The effects were statistically significant but small.

These results are intriguing but very preliminary. For example, the number of participants was small and already had cognitive decline to be included in the study. Alzheimer’s disease unfolds over a course of decades. This study lasted only 4 months. As with studies of the effects of blood sugar on memory, there appears to be a reversed “U” shaped relationship. Too much or too little insulin or blood sugar does not improve memory. Finally, there is a special device needed to administer the insulin through the nose. This device is not available.

While we wait for all of this to be sorted out, we all need attend to risk factors for type 2 diabetes. Risk factors include a family history of diabetes; being older than 45; hypertension; metabolic syndrome; “good” cholesterol less than 35 mg/dl and/or triglycerides greater than 250 mg. dl; history of gestational diabetes; polycystic ovary syndrome; inactive (exercise less than three times per week); and ethnicity (black, Hispanic/Latino, Native American, or Asian). If you have any of these risk factors, monitor blood sugars and get a baseline measure of your memory. Those who develop type 2 diabetes and changes in memory are at risk of cognitive decline.

There are currently five drugs approved for the treatment of Alzheimer’s disease: tacrine (not used because of toxicity to the liver), donepezil (Aricept), Rivastigmine (Exelon), galantamine (Razadyne), and memantine (Namenda). The first three are called cholinesterase inhibitors and have been around since the mid 1990s. All three medications are effective for mild to severe Alzheimer’s disease. There does not appear to be a difference in efficacy among the three medications. All of these treatments produce statistically significant effects but the effects are usually small.

There are many clinical trials attempting to find more effective treatments. The trials are mostly developed around four strategies: reduce amyloids (reduce plaques), modify tau (reduce tangles), treat with antioxidants, improve ion regulation, reduce inflammation, and improve cholesterol regulation.

Treatments to reverse or lessen the amount of amyloids (anti-amyloid aggregation) have been the main stay of clinical trials to date. The best known of these drugs is Alzmed. Unfortunately, trials have been a failure so far. For example, last year, the Lilly drug, semagacestat, terminated clinical trials because (1) the medication did not slow the disease as expected, (2) the medication made cognition worse, and (3) the medication made treated patients less able to care for their personal needs. The other anti-amyloid strategy has been to develop vaccinations. These medications have also failed to live up to their promise and the original vaccine produced unacceptable side effects. The conclusion from this line of research is that removing plaques is not enough.

The other, less researched approach is to halt or stop tangles from forming. The best known of these medications is methylene blue. Methylene blue improved cognitive scores but there were problems with the placebo group as the medication turns urine blue making blinding difficult. If your urine turns blue you know you are not taking a placebo. Attacking tangle formation is a direction for further exploration.

Other strategies have also had discouraging results so far. Attempts to reduce oxidative damage have focused on lowering homocysteine with high doses of folate and B vitamins. A completed trial showed no benefits on cognition. The same findings are true for trials with vitamin E, ginkgo balboa and omega 3 fatty acids. Trials of anti-inflammatory drugs have also failed and these medications produce unacceptable side effects. Available trials of chelation therapies have not produced lasting benefits. Finally, a study of the effects of Lipitor (a statin or cholesterol lowering drug) also proved to be ineffective.

Despite extensive efforts to develop treatments that modify the assumed pathology or pathologies underlying Alzheimer’s disease, most have proved unsuccessful to date (modifying the development of tangles is the exception). The clearest conclusion is that removing plaques does not appear to help and may do harm. This should question the amyloid hypothesis of Alzheimer’s disease. There are still many ongoing clinical trials but early identification and intervention is still the best way to protect your future.

Dr. Beckwith will conduct a three hour workshop (fee $100 per person/$150 per couple – limited seating) in Naples October 17 (call 591-6226 to register).

Placebos have powerful effects on the mind and the body. They can produce improvements, cause side effects, and reverse the actions of medications. Indeed, placebos are so powerful that medications are approved by the FDA only if they are proven better than placebos in clinical trials. For example, Namenda was not approved for treatment of mild to moderate Alzheimer’s disease because it did not do better than placebo. But treatment versus placebo effects is complicated as is demonstrated by teasing out whether antidepressants work better than placebos in treating depression.

Irving Kirsch (2008) completed a technical review (called a metaanalysis) of antidepressants and placebos as they are compared to no treatment. Among his findings were that some get better by treatment with active medications. Some get better with placebos (as many as 30% of study participants by some estimates). The difference between the effects of placebos and antidepressants is very small.

The effects of antidepressants are often below standards of clinical significance (make you actually feel better) when compared to placebos for those with moderate levels of depression. Clinically significant differences are only found in smaller studies and only for those with severe depression. On average, placebos produce effects when compared to no treatment that are twice the size of effects of the active medications compared to placebo effects.

The issue is that for any drug when there is a response to a drug it may be due to the placebo effect and not a result of the chemical composition of the drug. All treatments need to be proven better than both no treatment and a placebo to be considered effective. This is true of medications as well as supplements (where the FDA has no control). But there’s more to the story.

As Kirsch points out his analysis does not prove that antidepressants don’t work. His review only proves that the effects of the medication compared to placebo are small. This is not an inherent problem with the medications but rather a limitation of clinical trials. They are flawed by several factors such as short duration, unrepresentative samples, and breaking “blind” as researchers and subjects can tell active treatment by the side effects. We need better designed studies that explore who benefits (e.g., women versus men, older versus younger) and then be able to target medications.

So should you take an antidepressant? Unless your depression is severe, there is no clear answer. Does it really matter if it is a placebo effect or a treatment effect if you feel better? We need to better understand and use the power of placebos.

Improving your memory is deceptively simple. Don’t forget the “One Minute Rule.” Anything given less than one minute of thought will fade from your memory. We have known this for years but as we get busy we ignore the truth that we knew when we were in school. We took notes at lectures and from reading and we reviewed them often. Notes allow us to think longer (the One Minute Rule) about the point we feel is important and they focus our attention. Additionally, taking notes allows us to review the important facts which again give more time to learn and later remember what’s important.

In a world filled with massive and multiple sources of information we often ignore the fact that we learn most things well by spending time with the skill or information we want to remember. Human memory is not like computer memory, it does not work as the save command. For most of us, it takes time and effort to learn, understand, and recall. Human memory systems evolved long before computers and still need repetition, routine, and effort. The more minutes you spend focusing, the better you will remember. Malcolm Gladwell, author of Outliers, points out that it takes 10,000 hours of practice to become an expert. This is true for all learning and memory skills such as driving, skiing, bridge, chess, painting, sculpting, writing, speaking, or growing orchids.

The One Minute Rule also applies to situations that we encounter every day at home and at work. How many times have you looked for your car in the parking lot? Don’t forget the One Minute Rule. You run from your car to a meeting and want to be on time. You are reviewing who will be at the meeting and what the agenda is. What you don’t do is to stand by your car for a minute and spend the time thinking only of where it is located.

Consider the pervasive frustration with learning new names. Learning new names is a very complex memory skill. Some are very good at this and others have to work at it. But if you want to be better at remembering new names, you must spend the time up front. Repeat the name as you are talking to the person. If you are good at imaging, think of a visual association such as trying to remember my name by imaging a duck to represent Bill. When you sit at a table with new acquaintances, make a seating chart on your napkin of the names as they introduce themselves and use their names frequently.

Make notes. The act of making a note makes you think longer about the information. Put a notepad and pen next to every phone and repeat back what you write to the person providing the message. Make a Post-It note to remember to take Kleenex to work and place the note on the door going to the garage.

Most memories do not form instantly. Remembering requires time to find, review, understand, and finally to recall. The time we put in pays massive dividends later. Trying to remember doesn’t work. Make a plan for how you will remember. Don’t forget the One Minute Rule.

I recall where I was when I heard about the attacks of “9/11.” I was with a client who told me of the events and I recall my disbelief and confusion. I recall the look on her face. I recall what seemed like forever for the reality to actually set in. Finally, I recall my wife’s call and insistence that I cancel a talk that I had in the afternoon.

9/11 and other powerful events bring to mind vivid memories that feel as if they are formed instantly and in great detail. The explosion of the challenger, the OJ Simpson trial, and the assassination of President Kennedy are examples of these intensely felt memories. This type of memory was first described by Roger Brown and James Kulik in 1977 as “flashbulb” memory. These memories are stored and have the feeling as if they are photographs. They feel more vivid, complete, and accurate than do everyday memories.

But ten years after 911, research has clearly indicated that flashbulb memories are not as accurate as they feel unless one was actually at the event. Those in Manhattan at the time of the attacks can recount every sight, sound, and smell. The rest of us are more likely to forget or misremember the details and emotional reactions we had at the time. For example, my wife and were recently discussing the attack and I had forgotten there were four planes rather than two.

As with most long-term memories, flashbulb memories erode over time. They are subject to distortion both of the facts about how we first learned of the events and the actual details of the events. Duke University researchers assessed students’ recall both of 9/11 and of everyday events immediately after the attack. A third of the students was asked to recall both 9/11 and everyday events again a week later, another third after six weeks, and the final third after 32 weeks. Both flashbulb and everyday memories changed in consistency and accuracy over time. However, flashbulb memories felt as if they were more accurate and consistent than regular memories.

Flashbulb memories are not necessarily more accurate but we perceive them to be. Everyday memories are processed through the hippocampus (circuit of short-term memory) which allows new learning of things like names, what we have to do at 3:00 today, or what we did last night. Emotional memories side step this circuit. Strongly emotional events activate the amygdala which labels an event as emotionally important. The events that trigger the amygdala are related to survival (either real or perceived threats) or strong negative (e.g., personal attack or loss) or positive emotions (e.g., falling in love or seeing the Grand Canyon for the first time).

Emotional memories continue to still function in many with progressive dementing disorders. For example, seeing a sad movie sets an emotionally sad tone for the day in nursing home residents whereas viewing an uplifting movie sets a positive tone. However, in both cases the residents have no recollection of having even seen a film and cannot tell you why they are having their feelings. Emotional memory is processed quite differently from factual memory and keeps working well into progressive dementias.

Behavioral problems like aggression, agitation, and hallucinations are often treated with medications called “antipsychotics” or “neuroleptics.” Newer medications in this class include Risperdal, Zyprexa, Geodon, Seroquel, and Abilify. Older medications, including Thorazine, Haldol, and Melleril, are not widely used today.

The benefits of these medications are modest at best. However, the list of adverse effects continues to grow. A recent study adds to the concerns with use of these medications to treat behavioral problems associated with dementia. Antipsychotic medications caused significant decline in remaining cognitive skills. There was a significant drop in neuropsychological test scores when compared to placebo after 12 weeks of treatment. It is unclear from the results whether the decline is permanent and would be reversed by cessation of the drugs.

This adds another element to the growing concern over the use of antipsychotic medications to manage behavioral problems in people with a diagnosis of dementia.
The FDA has already added a “black box” warning that antipsychotic medications produce significant risk of life threatening side effects. Older as well as newer medications increase the risk of death – especially at higher doses.

Treatment with antipsychotics (including newer medications) has been associated with weight grain, hyperglycemia (high blood sugars), increased risk for stroke and transient ischemic attacks (TIAs), dysfunctions of cardiac conduction, pneumonia, movement disorders such as tardive dyskinesia, hyperlipidemia (high blood fats), worsening of diabetes, and increased risk for metabolic syndrome and diabetes. These finding raise questions about the relative benefits and costs of these medications.

Currently, only Risperdal is approved for use with dementia patients and only in low doses for up to 6 weeks. Other medications are “off label” for this use and at the discretion of a physician. Antipsychotic medications should be used with caution and vigilance and only if other nonmedication approaches have been shown not to work or if the behavioral issues cause danger to self or others. Antipsychotics should be used only after careful consultation with your physician and only with the informed consent of legal representatives.

Careful cardiac evaluation needs to be done before and after prescribing antipsychotic medications to better determine the risk versus the benefits of use. Blood sugars, lipids and weight should be monitored prior to and subsequent to prescribing these medications. Family members should be vigilant for over sedation or gait changes. Antipsychotic medications should be carefully discontinued when they are no longer needed as there may withdrawal effects and these medications should not be suddenly discontinued.

Difficult behaviors need to be managed through environmental (e.g., keeping people with memory loss engaged, confrontation only if the behavior causes a risk) and behavioral control interventions (e.g., calming voice, redirection toward peaceful activity). These interventions are not as convenient but are much safer.

Pat Summitt is a legendary coach and achiever. She has won more major college basketball games than any other coach in the history of the game. She announced yesterday that she has had memory problems, at least over the past year. Furthermore, she announced that she has a family history of dementia. Her story will hopefully encourage others to seek early assessment and treatment for memory issues.

However, the condition she described is not a dementia. Dementia means cognitive impairment that compromises the ability to work and live independently. Ms. Summitt would not be able to continue to coach if she were already demented. Her condition would be more appropriately referred to as a confusional state or forgetfulness. She is still in control of her future and can plan to compensate for memory changes and continue to work. She has a substantial risk of becoming demented in time. I am concerned that using the word dementia in articles written about her will scare others from seeking assessment as there is an implication of hopelessness.

It is interesting how we tend to avoid assessing the health of our memory. It is common to get annual physicals but people shy away from assessing how their memory is actually working. A thorough memory assessment should be as routine as an annual physical. There is so much you can do if you catch changes early when you are still in control of your future. I hope Ms. Summitt’s revelation helps us all treat our memory as we would our blood sugars. It is important to assess, monitor, and make a proactive plan to protect your future.

If you are 60 or older, have a memory assessment – not a screening – by a memory expert. If you have significant risk factors such as family history (especially with early onset) or past head injury, consider assessing your memory at an earlier age. This establishes a baseline for future monitoring. Early in the course of progressive memory disorders, memory may be better than norms but poorer than is used to be. For example, a client came to me for a memory assessment because of having Alzheimer’s disease in her family. On the first assessment, she was able to recall all of the words from a long list. Over the course of the next ten years, we monitored her memory and it progressively declined to the point of her having a normal memory – a progressive decline. We would never have known if we did not have a baseline and compared scores over the succeeding years.

I often hear that there is no point knowing as there is nothing you can do. Ms. Summit proves this wrong. She is acting before she forgets that she forgets. She is planning strategies for working longer than if she just let things happen because she did not sit back and wait. She is taking control while she still can. Hopefully, her plan includes directions for living a good life even when she can no longer coach and she can make the decision of when it is time to retire rather than be told it’s time. I hope she provides a role model for early detection and proactive planning. Memory assessments are as necessary as annual physicals.

Undergoing general anesthesia may cause cognitive decline especially in the elderly. Delirium and postoperative cognitive decline are the two most common untoward effects of surgery. Delirium is transient and obvious but may last days to weeks. Delirium may occur in 10% of postoperative patients. Postoperative cognitive decline is a more long lasting condition, often subtle, and neuropsychological testing is necessary to detect these changes.

One recent study estimates that postoperative cognitive decline occurs in 35% of those under 40, 56% of those 40-59, and 69% of those 60 and older at one week after surgery. By three months the rates decline to about 7% in those under 40, 13% in those 40-59, and 24% of those 60 and older. Another study indicated that about 25% of all surgery patients experience postoperative cognitive decline at one week. Fortunately, this rate drops to about 10% after three months.

Age is clearly a risk factor for postoperative cognitive decline. Other risk factors include cardiopulmonary bypass surgery, duration of anesthesia, respiratory complications, infection, history of alcohol abuse, and a second surgery. Heart surgery produces greater risk for produce postoperative cognitive decline at one week after surgery but is no different from other surgeries (e.g., hip replacement, knee replacement) at three months. Hip or knee replacement produces similar rates of postoperative cognitive decline with either regional or general anesthesia.

Protective factors include education and hypothermic cardiopulmonary surgery. Postoperative cognitive decline is less likely in those with more education. Hypothermic cardiopulmonary bypass surgery reduces the rate of postoperative cognitive decline. So far, studies linking Alzheimer’s disease to anesthesia exposure are contradictory.

The cause of postoperative cognitive decline is unknown. One theory is that those with pre-existing cognitive disorders are at great risk. Other theories suggest possible inflammatory response to surgery or anesthesia induced neurodegeneration. More research needs to be done to clarify the risks of anesthesia and surgery and to tease out possible protective factors.

It is clear that anesthetic agents may be neurotoxic for some and more so after 60. The decision of whether or not to have surgery becomes more complex as we age and needs to weight potential gains and costs. The clearest advice is to avoid purely elective surgical procedures especially in the elderly.

The Alzheimer’s Association International Conference met in Paris in August, 2011. This is an annual meeting that brings out all of the latest research findings.

The first results from the Dominant Inherited Alzheimer’s disease study indicated that that there are measurable changes in cognition, biochemistry, and imaging up to 20 years before symptoms appear. These results are based on studies of high risk individuals who are carriers of a mutant gene that induces early onset Alzheimer’s disease that may develop as early as the 30s and 40s. These findings again confirm that Alzheimer’s disease comes on over the course of decades and that treatment approaches must be proactive. If you wait for symptoms, you lose your advantage.

New research suggests that traumatic brain injury doubles the risk of dementia. These findings are based on a retrospective study of older (55 years or older) veterans. Another related finding was that 35 % of retired NFL players who sustain repetitive head traumas with an average age of 61 had cognitive impairment. This rate far exceeds the rate in the general population (there is an estimated 10% prevalence in those over 65). The relationship between traumatic brain injury and dementia remains controversial as some studies find an association and some don’t (as is true of most areas of science). But what is clear is that those who have sustained head injuries should be followed very carefully as they age for changes in cognitive skills.

Falls in older persons who appear physically and cognitively healthy may be a sign of early Alzheimer’s disease (or other neurological conditions). Progressive neurological disorders don’t always appear at first as cognitive decline. A history of recent falls should be assessed and, if there are falls, a thorough cognitive evaluation should also be conducted.

One headline reads “Modifying Risk Factors May Prevent Alzheimer’s Disease.” The risk factors are smoking, physical inactivity, midlife obesity, midlife hypertension, depression, diabetes, and cognitive inactivity. These factors are not new to those who follow information for “preventing” cognitive decline. The problem is with the word prevention. These factors are correlated with cognitive decline as we age but they don’t cause the decline. There are a number of excellent reasons to attend to these risk factors (e.g., improve overall health and quality of life, reduce medical expenses, and better manage heart disease and cancer) but there is, as yet no evidence that attending to these factor prevents Alzheimer’s disease.

Current beliefs point toward the slowing of brain processes as causing progressive decline in diseases such as Alzheimer’s disease. Preliminary results suggested that this may not be true. Low doses (lower than is used for treating seizures) of Keppra (levetiracetam) slowed the progression of mild cognitive impairment and improved memory. These findings suggest that it is increased activity that may speed progression and that slowing neuroactivity may help slow progression. An interesting new direction to pursue.

Finally, the emphasis in clinical trials has been on drugs that lower amyloids in the brain. These trails have used either immunotherapy or enzymes that remove amyloids. The new finding is that agents that remove amyloids produce edema and microhemorrhages in neurons. This is clearly an adverse effect of amyloid-lowering treatments and may contribute to further neuronal damage. The jury is still out, but I sense a need for caution in moving forward with these classes of drugs.