The cholinesterase inhibitors like Aricept (i.e., donepezil, rivastigmine, and galantamine) have been available for treatment of dementias such as Alzheimer’s disease since the mid 1990s. These medications slow the progression of Alzheimer’s disease (in those who tolerate them) and discontinuing them after extended use may induce a rapid decline even in those so impaired that they are in skilled nursing facilities. Despite these facts, the cholinesterase inhibitors are often maligned, not used, or discontinued too soon because they do not produce dramatic effects and do not arrest or reverse decline.

Although Alzheimer’s and similar dementias are classified as memory disorders, they actually have an impact on many brains skills or domains. In addition to memory, Alzheimer’s disease may produce impairments in attention, language such as word finding, visuospatial skills like drawing/handiwork, personality, mood, and/or executive functions. All of these skills are affected by changes in acetylcholine, the neurotransmitter that is increased by use of cholinesterase inhibitors. If we were to understand the benefits of these medications as consumers, it would be helpful to know what specific domains of possible benefits to expect.

This was the question addressed by “Treatment effects in multiple cognitive domains in Alzheimer’s disease: a two-year cohort study (Alzheimer’s Research and Therapy, 2014, 6, 48-60, PMID 25484926). As pointed out by the authors, there have been 4 large clinical trials demonstrating the benefits of cholinesterase inhibitors on global cognitive functioning (such as changes in the total score on the MMSE) for at least two years when compared to untreated matched control cases. However, there has been very little study of the specific domains or brain skills that respond to this treatment. It is especially important to understand the effects on executive functions as they are strongly correlated with activities such as cooking, driving, shopping, and managing the checkbook.

The focus of the study was to determine the effects of cholinesterase inhibitors on treated and untreated persons with Alzheimer’s disease for up to two years. Both measures of global functioning (MMSE and Dementia Rating Scale (DRS) total scores) and domain specific (e.g., memory, executive function) scores were obtained. The two groups were well matched in terms of age, education, and beginning MMSE and DRS scores. Treatment produced benefits on total score on both the MMSE and the DRS. For example; the average MMSE score began at 24.2 and declined to 20.2 in the treated group but declined from 22.9 to 16.4 in the untreated group.

More importantly, the major effects of treatment were in the domains of attention, visuoconstructive skills, and executive function. Despite being thought of as memory enhancers, these medications had little benefit on memory. In short, cholinesterase inhibitors do not improve short-term memory. Rather they slow the rate of decline in critical skills such as word finding, engaging in the world, and thinking abstractly. They reduce the burden of care by keeping together routines and self care skills longer than in the absence of treatment. These are important benefits despite the progressive nature of these dementias; treatment with cholinesterase inhibitors buys time.

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Alzheimer’s disease and other progressive dementias are not the only cause of cognitive impairment. It is commonly known that as the heart goes, so goes the brain. An estimated 5 million Americans suffer from heart failure and this number is expected to double over the next 40 years (“Heart failure and cognitive dysfunction,” International Journal of Cardiology, 2014, 178, 12-23, PMID 25464210). Cognitive impairment is common in those with heart failure with a prevalence ranging from 25% to 75% with greater degree of heart failure associated with higher levels of cognitive impairment. Those in heart failure with a left ventricular ejection fraction of less than 45% are especially prone to cognitive impairment that is at least mild.

Cognitive impairment may involve any one or all of several brain functions. These include attention, memory, executive function, language, speed of thinking, and/or constructive ability. Heart failure causes hypoperfusion (decreased blood flow) of the brain, which reduces oxygen and delivery of glucose to the brain. This in turn may lead to the destruction of neurons. The risk for cognitive impairment in heart failure is greatest for those with diabetes, systolic blood pressure of greater than 180, or diastolic blood pressure less than 65. There does not appear to be an association with low systolic or high diastolic blood pressure.

There are a multitude of secondary effects of heart failure that may contribute alone or together to increase cognitive impairment. Among these factors is depression, which may be severe or mild. Many medications that regulate blood pressure and heart function have anticholinergic side effects that are notorious for inducing confusion. Diabetes is known to induce cardiomyopathy, heart disease, and hypoglycemia. Inflammatory cytokines are released and are associated with cognitive impairment. Homocysteine, an amino acid, is elevated in heart failure and associated with cognitive impairment and decline. Finally, atrial fibrillation is strongly associated with cognitive and functional decline if left untreated.

Cognitive impairment associated with heart failure has a number of consequences. It compromises the skills necessary to manage a complicated treatment routine including managing medications, tracking follow up appointments, and managing heart healthy diet. It also may compromise the ability to recognize symptoms in oneself. On a practical level these changes may impair IADLs like driving, managing finances, paying bills, or preparing meals. In the extreme, cognitive impairment may lead to hospitalization and increased mortality in heart patients, mortality in heart failure with cognitive impairment is 18% at one year versus 3% in those with normal mentation.

The bottom line is that heart disease adds cognitive burden that affects treatment and outcome. The cognitive changes may be subtle or obvious, temporary or persisting. Assessment of cognitive function is an essential component in managing and treating heart disease.

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Alzheimer’s disease does not develop suddenly. It emerges over the course of decades. There is a history of short-term memory loss that often dates back a decade before more obvious symptoms arise. Onset is subtle. How many of us have had senior moments? How do we know if they are benign or the hallmark of progressive cognitive decline? Changes are complex and differ across individuals depending on the region of the brain that is affected.

One way to make sense of these complicated pathways is to have a category that reflects significant changes in memory that fall short of a dementia. The solution has been to create a category – diagnosis if you like – for individuals who have memory changes but are not demented. This is Mild Cognitive Impairment (MCI) (“Mild cognitive impairment and mild dementia: a clinical perspective,” David Knopman and Ronald Peterson, Mayo Clinic Proceedings, 2014, 89, 1452-1459, PMID 25282431).

MCI (the amnestic type) is memory decline that is greater than the inefficiencies of normal aging. It is marked by cognitive impairment that falls short of a dementia. The afflicted person remains independent but there are concerns as well as performance on objective tests that are lower than expected from those with similar age and education. A person with MCI can still pay bills, shop, and prepare meals. MCI marks the risk of future decline that is greater than for those with normal memory.

How is MCI different from mild dementia? Those with mild dementia also have poorer memory than either those who age normally or those with MCI. Mild dementia is marked by substantial decline at work or at home in abilities such as paying bills, shopping, or taking medications. However, personal care like dressing, preparing snacks, and grooming are fine. Persons with mild dementia almost always decline over time whereas some with MCI do not.

How are these conditions diagnosed? Mostly by a careful history obtained from the person of concern and an informant such as a family member or close friend. Despite the advancements in imaging techniques, a good clinical interview and objective cognitive tests are the gold standard for diagnosing MCI and mild dementias. If these assessments suggest decline further medical evaluation is necessary to determine if the problems are a result of a medical disorder such as stroke, thyroid disorder, or diabetes.

What should you look for in everyday life to indicate that someone may be at risk for progressive decline? Mostly the early signs will show as functional changes. Look at abilities like paying bills, balancing the checkbook, getting taxes ready, managing affairs, organizing papers, being able to shop alone, preparing meals, tracking current events/interests, following movies/TV shows, taking medications, finding one’s way around. If any of these skills are of concern, seek assessment.

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Treatment of Alzheimer’s disease begins with early detection of memory loss, well before any serious symptoms are present and there is an impact on independence. In other words, we need to have a reliable, valid way to detect minor changes in memory that exceed the inefficiencies of aging. At the present time we rely on medical screening with a test that is very insensitive to mild decline in memory – the Mini-Mental State Exam. The major problem with this approach is that it misses all but the most obvious changes in memory. Alternatively, we can seek neuropsychological evaluation to thoroughly measure and describe cognitive skills. This approach is much more sensitive but involves greater time and expense.

More simply we can ask the simple question, “How’s your memory?” After all, most medical and psychological evaluation begins with self-report and a good history. Some are very aware of their own changes in memory. The problem here is that we are asking someone who may be very forgetful to remember. In many memory loss clients, the problem is that they forget that they forget. They are not aware of their problem and will be unable to have insight into their deficits. The technical term for this is anosagnosia.

There is a good supplemental source of information that is easy to use and quite reliable and valid. One can ask family members for their appraisal. I am surprised how often spouses are not an integral part of memory assessment. After all memory loss is a family problem – affects not only the forgetful but also those who live with them. The point of assessment is to help those who are or may become caregivers to better understand what they are dealing with – I always involve family in all of my evaluations.

For example, one could give both the client and the spouse a questionnaire like the PRMQ (Prospective and Retrospective Memory Questionnaire). This is a simple set of questions about memory issues like being able to remember appointments, being able to remember to take medications, or being able to remember to do chores. Indeed, informant corroborated memory loss is superior to self-reported memory loss in assessing memory function in Alzheimer’s disease (The clinical utility of informant appraisals on prospective and retrospective memory in patients with Alzheimer’s disease, PloS One, 2014 19, E112210, PMID 25383950).

Informant’s ratings are highly correlated with objective measures of memory and overall cognitive ability. Informant’s ratings have good specificity and sensitivity for memory loss. Finally, informant’s ratings provide incremental value to both objective test scores and demographics. We need to paint a broader and more accurate picture of the range and scope of memory loss if we are to develop and implement better treatments. We have to include the family in all steps of the evaluation process.

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There has been a long standing debate about whether undergoing anesthesia can trigger dementia (see article by Roni Jacobson in Scientific American, October, 2014). Despite large, well-publicized studies claiming there is no significant association between anesthesia and dementia, there are too many cases to dismiss the phenomenon as coincidence. The cases appear to be statistical outliers in that they are not the norm.
However, that does not make them any less real just infrequent.

What is widely accepted is that a portion of those who undergo general anesthesia experience what is called “postoperative cognitive decline.” This marked by lapses of memory and attention (mild to severe delirium) that lasts from a few hours to a few weeks before it clears. Most who experience anesthesia do not show these effects for more than a very brief time and do not go on to experience a progressive, irreversible dementia (disability and loss of independence).

The question is whether anesthesia causes or is the first link in those who experience progressive decline after anesthesia. One obstacle to answering this question is that we still do not understand how anesthesia really works. The effects are very diffuse and produced by the deactivation of proteins that modulate sleep, attention, memory, and learning. Anesthesia targets sleep and arousal by deactivating neural networks that allow various brain systems to communicate. Like any drug, anesthetics can trigger unforeseen adverse events or side effects that have nothing to do with anesthesia per se. Drugs are never as specific in action as many might think.

Animal studies have shown that anesthetics can increase the levels of toxic amyloid proteins in the brain. Furthermore, they can also inflame brain tissues. But it is a long way from animal models to human brain function. Epidemiological studies with humans so far have not clearly shown a link between anesthesia and triggering of dementia.

That being said, there are many complicating factors in pursuing answers to the question of casual links between anesthetics and dementia. There may be many individual differences in susceptibility to adverse effects of anesthesia. What are the factors that cause some of us to be more affected? Are there preexisting conditions that put some at risk for dementia? We know that postoperative decline is more likely with cardiac surgery. It is also more likely in the aged, the diabetic, and the hypertensive. Are there medical factors that predispose to dementia after anesthesia? How do we separate the effects of anesthesia from the general effects of the trauma of surgery?

We have few practical answers regarding the link between anesthesia and dementia so far. The best concrete advice given the risks and uncertainty is to avoid elective surgeries. Also, carefully consider the risks and benefits of any surgery.

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Here are some of my favorite myths regarding the brain and how memory works.

  1. - Listening to Mozart or classical music improves intelligence.  This belief is based on  the “Mozart Effect” from a 1993 study suggesting that listening to Mozart may improve intelligence.  However, subsequent research demonstrated that the effect was restricted to spatial intelligence and is temporary.  The effect is not restricted to classical music and is probably has to do with improved mood and enjoyment.

  2. - The right brain is creative whereas the left brain is logical.  This long-standing belief stems from the fact that the brain has two hemispheres that have different functions.  The right  brain controls left sided motor/sensory function whereas the left brain controls right side motor/sensory function.  Furthermore, there is a long standing debate about localized versus distributed brain functions based on injuries (e.g., a left brain stroke produces language deficits) and the effects of “split brain” surgery that cuts the corpus collosum (the communication channel between the hemispheres).  Clearly the intact brain uses both hemispheres in a collaborative manner.  Creativity involves integrity of both hemispheres.

  3. - You only use 10% of your brain capacity.  This makes for interesting science fiction such as the movie Lucy but we use all parts of our brain even for simple tasks.  This belief probably is based on trying to motivate students to give more effort in school.

  4. - Adults do not make new brain cells.  This myth arises from many early studies and theories that we are fixed in abilities either in childhood or early adulthood.  The definitive study was completed in 1998 and demonstrated that adult’s brains are capable of “neural plasticity.”  You can teach an old dog new tricks.  As long as we retain awareness our brains are programed to elaborate circuits based on experience and practice.

  5. - Memories are accurate and we store all details of experience.  This myth arose from early neurosurgery findings that stimulating specific places in the brain produced what appeared to be recollections of specific events and facts as well as our attempts to use computers to model how the brain works.  Indeed,  the accuracy of these memories is very unreliable when facts were checked.  For most of us memory is full of errors, gaps, approximations, and susceptible to suggestion.  There are very few who have “photographic memory.”  Memory is a reconstructive process based on storing the “”gist” of events and filling in gaps.

  6. - Playing games, doing mentally challenging tasks, and mental exercise improves short-term memory.  Doing challenging or stimulating activities improves brain function due to increasing alertness or arousal and taking advantage of neuroplasticity also known as learning to learn.  We build knowledge, expertise, and skills by practice and repetition.   However, this is long-term memory and problem solving.  Short-term memory does not respond to practice but rather is like the “save” button on a computer.  Short-term memory relies on planning strategies to remember.  It takes effort and time.  We remember best what we spend the time to truly understand.  Short-term memory works by the One Minute Rule – anything given less than one minute of thought will fade from memory.

 

 

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The cholinesterase inhibitors like Aricept (i.e., donepezil) have been available for treatment of dementias such as Alzheimer’s disease since the mid 1990s. It is clear that long term use of these medications slows the progression of Alzheimer’s disease (in those who tolerate them) and that discontinuing the medication after extended use produces a more rapid decline even in those so impaired that they are in skilled nursing facilities. Despite these findings, the cholinesterase inhibitors are often maligned, not used, or discontinued too soon because they do not produce dramatic effects and do not stop or reverse decline.

One way to determine the efficacy of these medications is to determine if treatment reduces the burden that caregivers express (“Effects on caregiver burden of donepezil hydrochloride dosage increase to 10 mg in patients with Alzheimer’s disease,” Nakamura et al. Patient Preference and Adherence, 2014, 8, 1223-1228, PMID: 25258516). Normally, Aricept is initially given at a dose of 5 mg and increased to 10 mg after about 4 weeks. This study followed 27 Japanese patients (who tolerated treatment) (average age = 86.5) with moderate to severe Alzheimer’s disease. Participants were assessed before and after being switched to 10 mg donepezil and observed for 16 weeks. Assessments were made of severity of disease (i.e., orientation, speech, bathing, toileting, and dressing), caregiver burden, and swallowing at week 4, 8 12, &16. All study participants were still cared for at home.

The increase in dose from 5 to 10 mg. had no statistically significant effect on severity of the disease. However, the higher dose significantly reduced self-report of caregiver strain. The increased dose also produced small improvements in dressing, bathing, and toileting. Finally, the higher dose of donepezil improved swallowing in those participants that had swallowing problems at the beginning of the study.

Of course, this was a small study that did not include a placebo treatment and was only carried out over the course of 6 weeks. However it makes clear that rather than relying on impressionistic feelings, we need simple objective rating scales other than just the Mini Mental State Exam to gather data to inform clinical decision-making. A small increase in dose of Aricept improved both caregiver distress and self-care/swallowing in patients. Although cholinesterase inhibitors do not have dramatic actions or cure dementia, they do have a positive effect for many who tolerate them.

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We often get so focused on Alzheimer’s disease that we neglect other causes of memory loss and cognitive dysfunction.  Stroke is the second most likely cause of cognitive dysfunction after Alzheimer’s disease in the elderly.  Furthermore, there is a complex interaction between cerebrovascular health and Alzheimer’s disease.

 Post-stroke cognitive impairment may affect several domains of cognitive abilities such as attention (tracking the moment), memory (recalling new information and/or details of personal history), language (expressive and/or receptive speech), orientation (for time, place, and/or person), and executive functions (planning. judgment, reasoning, and/or social graces).  The effects of stroke may be temporary (e.g., TIA) or persisting depending on the size of the lesion and timing of treatment.  The effects may be severe (e.g., cause dementia) or mild (e.g., cause mild cognitive impairment) and may affect single skills or multiple skills.

There are three basic types of stroke.  Ischemic stroke caused by blood clots (i.e., embolic) or by fat deposits (i.e., thrombotic).  Stroke may also be caused by ruptured blood vessels (i.e., hemorrhagic).  This distinction is critical in that treatment for the former is via blood thinners whereas the later are made worse by blood thinners.  TIAs are “transient” or temporary events that may resolve within minutes to hours.  Strokes may be single events or recurrent and cumulative.  Stroke is evaluated and diagnosed by means of symptoms and signs such as one-sided weakness along with a physical exam, blood work, and imaging such as MRI.

There are a number of risk factors for stroke that are fixed and cannot be modified such as age, genetics, ethnicity, and sex. However, there are also a number of factors that are modifiable or manageable to reduce risk.  These factors include cerebrovascular disease (e.g., hypertension), heart disease (e.g., infarcts, atrial fibrillation), diabetes mellitus, hyperlipidemia, cigarette smoking, and alcohol abuse.

Not all stokes cause severe enough damage to produce dementia.  Some cause minor damage.  Vascular dementia is a permanent and irreversible condition where stroke causes disability as a result of impaired cognition that interferes with long-term independence.  The exact clinical manifestation depends upon the size, location, and type of damage caused by the stroke.  Early impairment is more typically manifested as alterations of attention and executive functions rather than memory.  There are often greater deficits proximal in time to the stroke with recovery over the course of months if there is no new event.

Stroke is very pervasive and may either be the source of cognitive decline or contribute added disability to conditions like Alzheimer’s disease, head injury, Parkinson’s disease, or Lewy body disease.  Signs of stroke include sudden weakness or numbness of face, arm or leg especially on one side of the body; sudden confusion, trouble talking, or understanding; sudden trouble seeing; or sudden trouble walking, dizziness, or sudden loss of balance.  Women sometimes have unique symptoms stoke not found in men such as sudden onset of face and limb pain, hiccups, nausea, general weakness, chest pain, shortness of breath, or palpitations.  If you have any of these sudden symptoms or signs, call 911 and act quickly as early diagnosis and treatment are essential for better outcome.

 

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Benzodiazepines are widely used to treat anxiety and/or insomnia. They include medications like Valium (diazepam), Xanax (alprazolam), Ativan (lorazepam), and Klonopin (clonazepam) that are used for anxiety and Restoril (temazepam) and Halcion (triazolam) that are used to help induce sleep.

Benzodiazepines may also be separated into those that are long acting (e.g., Valium and Klonopin) and those that are short acting (e.g., Xanax and Halcion). Long acting medications tend to remain in the body for extended periods of time (e.g., days) whereas short acting medications remain in the body for hours – hence you need to take the medication more than once a day to maintain effects.

Benzodiazepines are probably most effectively used as short-term management of anxiety and insomnia. As with any medication, there are trade offs that must be considered by both prescribers and consumers. First, there are withdrawal effects such as rebound anxiety after chronic use that makes discontinuation a problem. Second, these medications may have a deleterious effect on memory, cognition, and balance. Finally, the long-term efficacy of these medications is unproven for insomnia and questioned for anxiety.

The results of a recent study suggest a correlation between use of benzodiazepines and Alzheimer’s disease (Benzodiazepines may be linked to Alzheimer’s disease, Z. Kimietowicz, 2014, British Medical Journal, 349, g5555, PMID: 25208536). The findings were based on a retrospective population study of about 39,000 insured residents of Quebec over 66 years of age based on claims between 2000-2009.

Any use of benzodiazepines was associated with a greater risk of Alzheimer’s disease. Long-term use of benzodiazepines was more common in those with a diagnosis Alzheimer’s disease (32.9%) than for those without this diagnosis (21.8%) regardless of whether the medication was short or long acting. The association was stronger for long acting medications – possibly because of cumulative actions. The risk appeared to be associated with use for greater than three months. There was no association between Alzheimer’s disease and anxiety, depression, or insomnia.

Of course these findings do not suggest that benzodiazepine use causes Alzheimer’s disease. Unlike chronic use of drugs like alcohol or cocaine, there is no pathophysiologic mechanism for these medications to cause a decline in memory or degeneration of the brain. Instead these findings remind us that benzodiazepines are still commonly used to try to manage difficult behaviors in demented elderly despite warnings of adverse effects with chronic use and no clear demonstration of efficacy.

Benzodiazepines are best utilized as targeted medications for short-term management of anxiety. They may be effective for getting through a particularly bad day or a stressful event like going to the dentist or flying. They are not long-tem solutions for behavioral disturbances.

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Alzheimer’s disease was first described as a case study of Auguste Deter, 51 year old, in a paper by Dr. Alois Alzheimer in 1907. He visually inspected her brain after her death and described “tangled bundles of fibrils” in her cortex that we now identify as plaques and tangles. Despite having over 100 years of study, we still have more questions than answers regarding etiology and biological processes underlying this progressive neurological disease (“Alzheimer’s disease: still a perplexing problem, Krishma Chinthapelli, British Medical Journal, 2014, 349, Q4433, PMID: 25005430).

Prime Minister David Cameron announced support for the world’s most extensive population study in saying “dementia now stands alongside cancer as one of the greatest enemies of humanity.” Despite launching a study with quadruple the funding of previous work, there are huge challenges to be overcome. For example he stated that we still don’t know how the brain becomes diseased and only 3 of 101 dementia drugs developed since 1998 have made it to market.

There are three major hypotheses directing most of the medical research. The most popular hypothesis is that Alzheimer’s disease is the result of dense accumulation of amyloids (a brain protein responsible for plaques). The major problem with this theory is that amyloids do not correlate well with atrophy (brain shrinkage) and are not always present in persons with the symptoms of Alzheimer’s disease.

The second hypothesis is technically named hyperphorylated tau (the brain protein responsible for tangles). Tangles correlate better with both neuronal loss and cognitive symptoms than amyloids. However, this is a much more difficult to measure with current technology and therefore less well studied.

Last is the acetylcholine hypothesis (a neurotransmitter believed by some to be necessary to form memories). Indeed, reduced levels of acetylcholine have been found in the brains of those with Alzheimer’s disease. This has lead to the development of medications like Aricept and Exelon that are modestly helpful in some but clearly do not cure or stop the progression of the disease.

One obstacle to advancement is the fact that not all with dementia have Alzheimer’s disease (the most prevalent diagnosis of dementia). Also, not everyone with Alzheimer’s pathology as currently defined becomes demented. Therefore, accurate diagnosis is difficult. Early identification of Alzheimer’s disease remains uncertain as up to 25% of those in a recent clinical trail were misdiagnosed. Even tissue analysis is not accurate. For example, more than 50% of those with probable Alzheimer’s disease also have brain infarcts and 25% or more of those with a heavy burden of amyloids have normal cognition. So it appears that the current definition used for diagnosis of Alzheimer’s disease is arbitrary.
Finally, plaques and tangles are common in the aged but do not correlate well with clinical symptoms. There are no biomarkers that reliably identify Alzheimer’s disease. And, imaging by means of PET and MRI has poor sensitivity and specificity.

We clearly have a long way to go. Dementia including Alzheimer’s disease is not a part of normal aging. My hope is that these enhanced initiatives do not myopically stay focused on amyloids. Maybe it is time to give up the concept of Alzheimer’s disease in favor of understanding better the concept of dementia and the multiple pathways leading to functional decline that is associated with aging for some.

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