Life and Memory Center

The New York Times (August 29, 2010) is running a series called “The Vanishing Mind” with the most recent installment titled “Years Latter; No Magic Bullet Against Alzheimer’s.”  The article is based on the conclusions reached by a “jury” of 15 medical scientists along with scientists at Duke University with no vested interests in Alzheimer’s research.  The National Institutes of Health convened this “court” to objectively evaluate the quality of research findings addressing the prevention of Alzheimer’s disease.  These studies covered all of the bases: exercise, mental stimulation, healthy diet, social engagement, nutritional supplements, anti-inflammatory drugs, drugs lowering cholesterol, amount of education, being married, and being a loner.

The panel’s conclusion was that “Currently, no evidence of even moderate scientific quality exists to support the association of any modifiable factor with reduced risk of Alzheimer’s disease.”   A week later a study that will appear in the journal Neurology concludes “A Rich Cognitive Life “Squares the Curve” of Decline Leading to Dementia.”  The message here is that participating in an engaging and challenging activity (i.e., following your passion or exercising) allows you to resist the impact of Alzheimer’s for a longer time than being disengaged and unchallenged intellectually (i.e., having a more sedentary and passive life style).  How can such opposite conclusions be reconciled?

First, consider the issue of “scientific quality” as judged by totally objective standards.  The highest quality of evidence from a scientific point of view is that, for example, engagement and stimulation (the “use it or lose it” hypothesis) cause a later onset of symptoms of Alzheimer’s or prevents the disease from developing.  The evidence that fits these criteria (i.e., high level of evidence) can only be found in longitudinal studies where participants are randomly assigned to treatment or control groups (no treatment and pseudotreatments) and followed over time.  There are no studies meeting this very strict criterion, hence the gloomy outlook in the article.  Indeed, such a study would require 30-50 years to provide a definitive answer for each variable of interest.

Instead, we have to rely on evidence from studies that do not meet this very strict standard.  The existing studies are correlational studies that allow us to make associations between factors such as age of onset of Alzheimer’s disease and exercise but do not permit conclusive statements about cause and effect.  But many of our current beliefs about health promotion and prevention are based on correlational studies.  For example, the belief that cigarette smoking causes cancer is based on correlational studies.  Do you want to be randomly assigned to a smoke or don’t smoke for 30 years to obtain the highest quality evidence for this belief?  Being unable to find cause and effect relationships does not imply that interventions like mental stimulation and exercise do not influence the course of Alzheimer’s disease as the tone of the article seems to imply.  You cannot make the strong assertion that something doesn’t work just because you can’t definitively say it works.  Next week, the discussion will turn to the meaning of prevention and summarize a different take on the existing evidence.

There was an article by Gary Small, a well known UCLA memory expert, titled “Paul McCartney’s memory lapses.”  Apparently, Paul McCartney (who is now 68 and too old to be a baby boomer) admitted that he has times such as during a recent concert at Fenway Park in Boston when he cannot recall the lyrics to his old songs – the ones he has been performing for years.  Dr. Small used the article to discuss “normal memory loss associated with aging.”  The article intrigued me, so I pursued other examples of singers experiencing memory lapses for lyrics. Interestingly, it is not only the aged rockers who forget lyrics.

The examples are legion.  I will only present a few.  Mick Jagger, 65 at the time, repeated a verse from Ruby Tuesday in a 2006 concert in Glasgow.   There is a nearly three minute YouTube video of Elvis (who was 42 when he died) being unable to recall the lyrics for a song he was performing.  Finally, Jenny McCarthy, aged 37, forgot the lyrics of the national anthem she was performing for a NASCAR race.  Apparently, you don’t have to be “old” to forget well rehearsed lyrics.  It is clear that age is not the common thread for this type of forgetting.  So don’t feel so badly if you temporarily forget your phone number or social security number – it happens to all of us.  These lapses are not “age-associated memory loss” and not signs of impending mental decline. Indeed, there is no such thing as normal memory loss.  Like with all things, aging reduces our efficiency not our competency.

As I pursued this further, I was pleased that most performers solve this problem by liberally using external memory supports or as I have called them the “one minute rule.” Simply stated the one minute rule states that anything given less than one minute of thought will fade from your memory.  One good way to reduce forgetting is to make a plan for remembering (e.g., a notation in a calendar).  Performers have clear and specific plans to help them remember during performances.  Paul McCartney compensates by using a teleprompter.  Mick Jagger uses an onstage monitor to prompt his lyrics – if needed.  He also wisely adds the name of the city where he is performing and cues for his ad –libs between songs.  Come to find out this is very common among performers as was pioneered by Frank Sinatra.  He used an onstage teleprompter to perform until he was 80 despite a failing memory.

These lapses are not the beginnings of Alzheimer’s disease.   Alzheimer’s disease starts with failure of new learning and is not the same as temporary memory lapses.  A good memory evaluation can tell the difference.  I don’t have to feel guilt any longer for using Power Point slides to pace and manage my talks.  I am in good company.

Do we really have a breakthrough in diagnosis and treatment of Alzheimer’s disease?  In our desperation for a cure, we have gotten ahead of biology and cast all of our hopes on the amyloid hypothesis ignoring the complexity of Alzheimer’s disease.  The amyloid hypothesis drives a multitude of clinical trials currently underway by pharmaceutical companies to find the cure for Alzheimer’s disease.  Simply stated, the hypothesis proposes that build up of beta amyloid, an abnormal protein in the brain, is the cause of Alzheimer’s disease.  Hence, treatments are sought that either stop or reverse the production of amyloid proteins in the brain.  One of the medications under investigation was semagacestat, a drug developed by Lilly Pharmaceuticals.

The trials had advanced to the point where there were 2600 patients enrolled in the clinical trials comparing semagacestat with a placebo.  This medication attacks the abnormal amyloid.  In theory this is a good thing.  However, the trials were terminated because the results indicated (1) that 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.  This led to many commentaries defending the amyloid hypothesis despite this important failure.  This is a natural reaction to information that goes contrary to one’s beliefs.  We regroup and find new ways to support our belief and minimize or ignore contrary evidence.

But in this case, the failure of semagacestat should cast doubt on the amyloid theory.  We need to pursue the science behind this theory and its failure but we need to be careful in moving ahead with a single minded theory.  This could be a costly blind alley.  As discussed in an earlier article, the amyloid hypothesis has a number of other problems.  For example, there are other data from clinical trials with amyloid drugs that reverse the buildup of beta amyloid but have no clinical benefit.  Furthermore, a substantial number of people develop enough plaques as they age that they meet the pathological criteria for Alzheimer’s disease on autopsy but have no symptoms of the disease.

There is a strong push to add expensive (e.g., brain scans to see the amyloids) and invasive (e.g., spinal taps to assay the amyloids) tests as routine diagnostic assessment for Alzheimer’s disease.  The failure of the Lilly drug makes me concerned about the path we are taking.  We still don’t know whether the abnormal amyloids are the cause or the effect of the disease.  These tests belong in the research lab not in the clinic.  Until we better understand the biology and can safely modify the disease, rigorous and sequential memory testing and direct treatment of memory should be as routine as annual physicals.  If you are going to develop Alzheimer’s disease, you must learn to implement memory and coping skills before your short-term memory fades too far to learn them.

I was recently confronted with a situation that has caused me to again rethink the use and abuse of the power that we have as professionals- especially those with the title of “doctor.”  In my line of work, I am often confronted with difficult and emotional decisions that involve personal rights and freedoms.  I provide opinions regarding the capacity of persons to drive, manage finances, and live independently.  Most of the cases I am involved with involve various degrees of memory loss, sometimes to the point of impairment known as dementia.   Dementia presents as an irreversible loss of ability and coping skills.  Depending on the severity of the dementia, rights such as the freedom to come and go as one pleases must be removed for safety.  These are often gut wrenching for both the afflicted individual and those who love them.

A recent case forced me to revisit these issues from a new perspective.  The case involved someone suffering from a delirium rather than a dementia.  A delirium is a temporary and reversible confusion with loss of judgment and decision-making ability and may involve danger to self or others.  The person I was working with induced a delirium by consuming a large amount of alcohol (alcohol intoxication/poisoning).  This person was clearly a profound danger to self and clearly fearful and stressed underneath the confusion and intoxication.  They were appropriately protected from harm by involuntary treatment (known as the Baker Act in Florida).  The Baker act serves to protect against harm and involves a 72 hour observation period.  If after 72 hours the person is no longer of harm to self, their rights are restored.  This is a legal protection we all have against overly restrictive and coercive treatment.

After sobering up, less than the 72 hours, this person was given the option of entering “voluntary” treatment for alcoholism as they had cleared of the delirium and were thinking clearly and of no immediate harm to self. The Baker Act was then appropriately lifted.  However, the person was coerced into treatment by the threat that if they did not pursue treatment as directed, they would again be subject to the Baker Act and involuntarily returned to treatment.  This was justified as therapy but not only violated the person’s rights but also was exploitive, deceptive, and abusive.  We have no right to abuse legal rules that protect individual rights even if we are trying to keep someone from making a poor decision again in the future.  This is not therapy but rather is dishonest and contrary to therapeutic needs – in this case to help the person regain control via therapeutic alliance rather than strong arming the person into treatment over which they had no control.  Fortunately this case was resolved without legal intervention but the added stress was quite unnecessary and inappropriate.

I hope I personally do better by those who work with me and trust my counsel.  Sometimes it is necessary to use “parenting techniques” and “exaggerated communication” for those who are confused to reduce stress and promote safety.  However, it is also important for professionals to tailor their interventions to the competent individual without coercion or exploitation of their vulnerability during times of intense stress.   It is also necessary to closely involve caring family members in the treatment from the start and to treat the person rather than the diagnostic label.  I don’t want to be treated as an alcoholic or an Alzheimer’s patient.  I want to be treated dignity and compassion individual no matter what the label or standard protocol.

A new study in the journal Neurology asserts that a spinal tap can accurately detect the development of Alzheimer’s disease before symptoms appear. As quoted in The New Republic, “The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that Alzheimer’s pathology is active and detectable earlier than has heretofore been envisioned.” The “AD signature” is the presence of a protein called beta-amyloid in the spinal fluid. The implication is that people can be accurately diagnosed with Alzheimer’s disease years before they develop symptoms.

This all sounds so neat and clean like genetic testing for neurological diseases such as Huntington’s chorea. As technologies like spinal taps and brain scans become more available outside of research settings, there seems to be increased interest in using them as diagnostic tools. But I feel we are getting ahead of what the data may actually mean. First, a finding of abnormal amyloids does not really mean that one will develop Alzheimer’s disease or become demented. Second, the results of the spinal fluid tests may vary by as much as 30% across different labs indicating a problem with reliability. Third, one often hears that the definitive test for Alzheimer’s disease is autopsy. But this is also not accurate. As many as 25% of elderly people who die and have autopsy studies of their brain have pathological Alzheimer’s disease but do not have memory problems or dementia. Fourth, spinal taps are quite invasive and carry risks that other tests do not. Spinal taps (lumbar puncture) produces headache in about 30% that may start several hours or days after the procedure and last for hours to more than a week. Other risks are for the development of back pain, bleeding, infection, and possible brainstem herniation.

I am all for continued efforts to seek diagnosis and proactive treatments for Alzheimer’s disease. However, spinal taps need to remain in research labs and clinical trials for now. For those who seek my counsel, I would suggest caution. The risks are too great and the useful information provided is too limited and unreliable for clinical purposes. The best clinical plan for diagnosis of memory disorders requires a good medical history (which requires time and informants such as family members who know you well), a work up for treatable causes of memory loss (blood work and imaging study), careful and rigorous memory and cognitive tests rather than screenings, and someone to spend the time to help you and family members understand the results and work out a treatment plan. The bottom line: having amyloid in the brain or being tested positive for Apolipoprotein E4 does not mean you will develop either Alzheimer’s disease or dementia.

We get so focused on Alzheimer’s disease that we often forget that there are many other possible causes of progressive cognitive decline and dementia.  One such disease that merits attention is Parkinson’s disease which is the third most common progressive neurodegenerative disorder behind Alzheimer’s and Lewy body disease.  There are an estimated one million people diagnosed with Parkinson’s disease and 50,000 new cases each year.  Parkinson’s disease is more common in men than women by a factor of about 2:1.  Age is the only known risk factor as the average age of onset is 60 and most cases of Parkinson’s disease occur in those 50 and older.  Family history does not appear to be a significant risk factor for developing Parkinson’s disease.

“Parkinsonism” is associated with a variety of causes including viral encephalitis, use of anti-psychotic medications, carbon monoxide poisoning, and multiple strokes.   However, 85% of cases of Parkinson’s disease have no known cause.  As many as 50% of cases of Parkinson’s disease may decline to dementia and over 80% show more subtle cognitive deficits.  Parkinson’s disease is characterized by both motor and nonmotor symptoms.  The classical motor symptoms include slowness of movement, slowed reaction time, muscle rigidity, tremor, and proneness to falls.  The nonmotor features include gastrointestinal dysfunction, urinary or sexual dysfunction, orthostatic hypotension, profuse sweating, sleep disorders (e.g., excessive daytime sleepiness, excessive movements in sleep), loss of sense of smell, depression, anxiety, psychosis, poor memory and disorders of judgment.  I could go on but I hope you get the point.  Alzheimer’s disease is not the only risk we run as we age nor is it necessarily the worst neurodegenerative disorder.

As with Alzheimer’s disease, managing Parkinson’s disease also requires a proactive approach including awareness of possible early signs, especially given that there are treatments for the motor symptoms.  Nonmotor symptoms may precede the motor symptoms of Parkinson’s disease and the constellation of excessive daytime sleepiness, reduced sense of smell, constipation, and slowed reaction times are correlated with greater risk.  Individuals with this constellation of symptoms should be assessed and followed closely as should those with REM sleep disorders.  Early presentations of Parkinson’s disease (as also happens with Alzheimer’s disease) may be in the form of late onset depression, anxiety, or psychosis.  Those afflicted with Parkinson’s disease may be especially sensitive to certain medications such as antipsychotic medications.

Early interventions such as exercise and dance (who says therapy can’t also be fun) may be especially helpful to those at all stages of Parkinson’s disease.  Persons with Parkinson’s disease also need to be followed for memory and other cognitive skills and caregivers need attention and support.  There is help through the Parkinson’s Association of Southwest Florida (call 417-3465) as well as through many of the services for Alzheimer’s disease.

There are four FDA approved medications available for treatment of Alzheimer’s disease: Aricept, Exelon, Razadyne, and Namenda.  The first three are in a class of medications known as cholinesterase inhibitors and the other, Namenda, is an NMDA receptor antagonist.  In simple terms, the cholinesterase inhibitors increase the amount of a neurotransmitter called acetylcholine whereas Namenda decreases the amount of a different neurotransmitter, glutamate.  Often Namenda is used together with one of the cholinesterase inhibitors as the combination appears to be more effective to boost cognition in moderate to severe Alzheimer’s disease than either medication used alone.

The news of the week is that the FDA has approved the use of a higher dose of Aricept for those with moderate to severe Alzheimer’s disease as indicated by a score of 20 or fewer of 30 possible points on the Mini-Mental State Exam.  Until now the standard for use of Aricept was to take 5 mg for the first month to build tolerance and then 10 mg thereafter, if tolerated.  Starting in August 2010, Aricept will also be available in a new 23 mg dose.  The approval of the higher dose is based on a study indicating that there are cognitive benefits of the 23 mg dose of Aricept when compared the standard 10 mg dose.  Participants in the study had been taking 10 mg of Aricept for a minimum of three months before taking the higher dose.

As with any medication, there are trade-offs for use of a higher dose.  First, there are more frequent side effects.   The 23 mg dose induces a greater frequency of nausea, vomiting, diarrhea, and loss of appetite than does the 10 mg dose.  Other common side effects to be aware of are dizziness, weight loss, muscle cramps, urinary incontinence, fatigue, difficulty sleeping, and headache among others.  Second, there are several at risk groups that need greater caution and closer monitoring if taking the higher dose.  For example, those at risk of stomach ulcers (Aricept may increase bleeding) or heart disease (Aricept may cause slowed heart rate and fainting), lung disease, bladder problems, or seizures should also be screened and monitored more carefully if given the higher dose.

Finally, there were improvements on a very specific cognitive test called the Severe Impairment Battery.  This test is not often used outside of research settings.  Screening tests like the Mini-Mental State Exam cannot be relied on to measure outcome.  Furthermore, those caring for persons using the 23 mg dose may not see any obvious effects of the higher dose.  Despite cognitive improvement on the Severe Impairment Battery there were no reliable improvements in either clinician or caregiver ratings of those on the 23 mg dose when compared to the 10 mg dose. The clinical benefits of the higher dose remain to be determined

I often get asked two very important questions. How do I know when I should seek a memory evaluation and who do I see? This is a more complicated question than it sounds. If you have concerns early in the stages of memory decline you will easily pass all of the brief screening tests now in use and be told that you are fine. I have interviewed hundreds of clients worried about their memory and I have a set of questions that I ask. If you answer yes to one of more of these issues listed below, seek further evaluation no matter what you score on screening tests.

• Frequently repetitive
• Trouble remembering recent conversations
• Trouble remembering recent events
• Trouble remembering appointments
• Frequently misplace objects
• Trouble performing tasks that require many steps such as balancing a checkbook, cooking a meal, using the computer
• Trouble organizing objects around the house
• Trouble finding his or her way around familiar and/or unfamiliar places
• Increasing difficulty with finding the words to express what he or she wants to say
• Someone who knows you well is concerned
• You are concerned about your self

Who do you see if you have any of these concerns? The most obvious answer is if you have concerns about your memory; consult with your primary care physician. This is a good place to start but there are problems with this approach for those with mild changes in memory. Your primary care physician has little time with you and is not trained to do memory evaluations. Many physicians believe that as there are no effective drug therapies there is nothing that can be done. Finally, there is a fear that they will make an incorrect diagnosis of dementia which stigmatizes the patient.

These beliefs among physicians make it difficult to help persons who are very early in memory loss seek adequate evaluation and start effective environmental and psychological treatments (such as more effective use of external memory supports and groups like the Minders Keepers that is run by the Alzheimer’s Support Network in Naples). We have made all of this too complicated. Don’t wait until you can be diagnosed with dementia – the medical goal. Seek evaluation and guidance when there are changes in your memory. Not all persons with declining memory will go on to develop a dementia but they are at higher risk. Be proactive and seek evaluation early. Talk to your primary care physician and ask for a through memory evaluation not just a screening. Alternatively, seek the council of a memory expert who can provide you with a detailed evaluation and description of your memory and related mental skills and can guide you toward an effective treatment plan.

There is a new concern arising as “boomers” are now dealing with cognitive decline in their aging parents. They are now asking “What about me?” This is to say that boomers are concerned about dealing with one possible outcome of their own aging – dementia. As always I suggest getting a plan in place before you need it.

We don’t wait until we are in our 70s to plan for financial needs in retirement – we purchase IRAs or 401Ks earlier in life. We don’t wait until we have cancer to act – we undergo cancer screenings from middle age. We don’t wait for medical problems to emerge – we have annual physicals. We are proactive about so many issues in life but remain reactive with our memory. There are several possible reasons for this. First, we treat decline in memory as an outcome of aging. Aging does not rob us of memory. Rather aging makes our memory less efficient.

Second, we treat brain functions as biology. This ignores the fact that the brain is a “learning sponge.” It masters experiences and wires its own unique circuits for everyone. This leads to greater wisdom with normal aging.

Third, we currently rely on medicine to determine how well our memory is functioning. Medicine does not have all of the answers. We manage diabetes better with insulin but we also need to be proactive, catch it early, and manage life style as well as biology. Indeed, this is the best level of intervention early for those at risk for diabetes. We rely on screenings to determine if we have memory decline. These can be as simple as someone listening to you or administering a screening “test” – most often the Mini-Mental State Exam. Neither approach allows you to know how our short-term memory is functioning. Neither allows you to be proactive. Rather these screenings allow you to be reactive.

The risk for progressive memory disorders like Alzheimer’s disease is easy to detect. The first sign of risk is decline in short-term memory which happens years before there is impairment in ability to manage one’s life. There are no medical tests (e.g., screenings, scans, blood tests) that can determine the strengths and weaknesses of memory. Short- term memory is the culprit. Short term memory is not like a muscle – you cannot exercise it. That’s why we use post it notes and calendars.

How do you know how your short-term memory is working? Take a challenging memory test that allows you to know for sure how your short-term memory works. If it is not normal for your age, you may be at risk in the future. The rub with short-term memory loss is that you have to stay ahead of the changes. You are open to having a colonoscopy to detect possible changes that may develop within 10 years into a cancer. Why do you short change your short-term memory? A memory evaluation is way more fun than a colonoscopy.