Skip Navigation LinksHome > ADCS > Alzheimer's Insights: an ADCS Blog  
 
    

Alzheimer's Insights:
an ADCS Blog


  Recent Post

Wednesday, February 29, 2012

Omega-3 Fatty Acids and Brain Health


Dear Readers,

Further evidence was published this week in the prestigious journal Neurology supporting the importance of omega-3 fatty acids, specifically DHA and EPA in maintaining brain health through aging. The main finding is that participants with low levels of omega-3 fatty acids in their blood had more brain atrophy and lower scores on memory and cognitive tests than people with higher blood levels of omega-3s. The study involved 1,575 people with an average age of 67 who were cognitively normal, and part of the larger Framingham Heart Study, which has been ongoing since 1948. It was from this study that we learned about the relationship between blood levels of cholesterol and heart disease.

Several studies have shown that diets that are rich in fish, such as the Mediterranean diet, lower people's risks of developing heart problems or having a stroke. And some intake of fatty fish like salmon and tuna can lower the risk of Alzheimer's disease.

The study, led by Dr. Zaldy Tan, measured the level of omega-3 fatty acids, specifically DHA, in red blood cells over three months. The study participants underwent an MRI scan of the brain and researchers measured total brain volume, as well as performance on a battery of cognitive tests.

The researchers then looked at and ranked the level of omega-3 fatty acids in the participants' blood. People who scored in the bottom 25% in omega-3 fatty acid levels were compared with the rest of the participants. Researchers found that those who had the lowest level of omega-3 fatty acid levels in their blood had lower brain volume compared with those with higher levels, and scored lower on multiple cognitive tests.

As readers of this blog will recall, to build brain cells you need fatty acids. Two kinds of fatty acids are considered "essential," which means you must get these essential fatty acids from the food you eat. Your body cannot manufacture them. The first essential fatty acid is Alpha-linolenic acid (ALA). ALA is the foundation of the "omega-3" family of fatty acids. Food sources of omega-3 ALA include flax seeds, walnuts, sea vegetables, green leafy vegetables, and cold water fish like salmon, sardines, and trout.The second essential fatty acid is Linoleic acid (LA). LA is the foundation of the "omega-6" family of fatty acids. Food sources of omega-6 LA include sunflower, safflower, corn, and sesame oils.

Essential fatty acid deficiency is common in the United States, particularly Omega-3 deficiency. An ideal intake ratio of Omega-6 to Omega-3 fatty acids is between 1:1 and 4:1, with most Americans only obtaining a ratio between 10:1 and 25:1. The minimum healthy intake for both linolenic (Omega-3) and linoleic (Omega-6) acid via diet, per adult per day, is 1.5 grams of each.

Cold-water oceanic fish oils are rich in DHA. Most of the DHA in fish originates from algae, and becomes increasingly concentrated in organisms the further they are up the food chain. Below-normal levels of DHA have been associated with Alzheimer's disease and DHA is the most abundant omega-3 fatty acid in the brain. In fact, DHA comprises 40% of the polyunsaturated fatty acids in the brain. Fish oil is widely sold in gelatin capsules containing a mixture of omega-3 fatty acids including EPA and smaller quantities of DHA. By consuming a diet rich in the essential fatty acids, over a period of years, one may in fact maintain a healthy brain throughout the aging process.



By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 3:48 PM 0 Comments

Wednesday, February 22, 2012

Electrical Brain Stimulation and Memory Enhancement


Readers,

A recent study published Feb. 9th in the New England Journal of Medicine reports on seven patients awaiting possible surgery for the treatment of epilepsy who had electrodes implanted in their brains to pinpoint the origin of their convulsions. In doing so, this technique also gave the researchers the chance to send a burst of electrical current to specific brain regions, known as deep-brain stimulation, and observe changes in memory.

By stimulating a specific area of the brain, the researchers found that the patients were better able to recognize landmarks and to navigate routes more quickly while playing a video game featuring a taxi cab, virtual passengers and a cyber city. Patients played the role of cab drivers who picked up passengers and delivered them to one of six requested shops in the city. Stimulation of the entorhinal cortex -- a region considered crucial to transforming daily experience into lasting memories -- produced the improvement. All patients, regardless of how good their memory was, saw improvement in their memory after stimulation in of this area. Stimulating areas just millimeters away showed no benefit to memory function.

During the video game task, participants learned their way around a virtual town with and without five-second periods of deep brain stimulation, and were tested for their ability to reach predetermined landmarks. Six patients showed a 64 percent reduction in "excess path length" -- the ideal path between destinations, which indicated better performance -- for locations that had been learned during periods of deep brain stimulation. Ongoing stimulation of the entorhinal cortex wasn't a necessary means to boost one's memory. Instead, it was found more effective when only trying to learn important information. This discovery provides evidence for a possible mechanism that could enhance memory.

The entorhinal cortex sits between the hippocampus and the cerebral cortex, and constitutes the major gateway between these two areas. The entorhinal cortex is known to be critical to memory functioning, and is also an area of the brain that is one of the first to be damaged by Alzheimer's disease.

The possibility of using electrical stimulation to improved cognition may sound far fetched, but in fact there are a few examples of electrical stimulation currently being used in patients with neurological disorders. The Food and Drug Administration (FDA) approved Deep Brain Stimulation as a treatment for essential tremor in 1997, for Parkinson's disease in 2002 and dystonia in 2003. In addition, Vagus Nerve Stimulation is approved for the treatment of certain forms of epilepsy.

Of course, the brain damage that occurs with epilepsy, which can produce memory problems, is quite different than that resulting from Alzheimer's disease, in which the formation of amyloid plaques and neurofibrillary tangles are believed to contribute to neuronal deterioration. So it's difficult to generalize this study's results to other diseases that affect memory. However, the across the board improvement seen with Deep Brain Stimulation, makes the possibility of improving memory with this technology tantalizing.

Suthana N, et al "Memory enhancement and deep-brain stimulation of the entorhinal area" N Engl J Med 2012; 366: 502-510.




By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 9:15 AM 0 Comments

Wednesday, February 15, 2012

Bexarotene and Rapid Amyloid Plaque Removal in Mice


Readers,
In a study published this week in the prestigious journal Science, researchers from Case Western Reserve University in Cleveland have found that an FDA-approved skin cancer drug rapidly removes beta-amyloid from the brains of animal models of Alzheimer’s disease, and even reverses some symptoms of dementia.

The Case Western team, led by Gary Landreth looked at the drug bexarotene (Targretin), approved in 1999 for cutaneous T cell lymphomas. Landreth and his colleagues fed bexarotene to demented mice, and with just a single dose it lowered the most toxic form of beta-amyloid in the brain by 25 percent within six hours, an effect that lasted for up to three days; after two weeks, there was a 75% decline in the amount of amyloid plaques. The drug did its job with unprecedented speed. Mice that were cognitively impaired resumed normal behaviors after 72 hours of treatment: They began to crinkle toilet paper placed nearby to make nests, a skill lost as amyloid increased in their brains. The drug also restored some of the animals' other normal behaviors. After treatment, the mice could identify a smell and perform better on water maze tests requiring them to remember how to find a submerged platform. They were also better able to remember a cage in which they had been shocked, all behaviors that are lost with the progression of the illness.

Bexarotene activates retinoid receptors on brain cells that increases the production of apolipoprotein E, which readers of this blog will recall, is known to remove excess beta-amyloid from the brain. It also appears to enhance another cleanup process, called phagocytosis. Bexarotene functions differently than the amyloid-clearance approach using monoclonal antibodies, which are further down the drug development pipeline. Those antibodies bind directly to amyloid and then remove it. Bexarotene activates the ApoE clearance mechanism of beta-amyloid.
One reason the field is buzzing about this finding is that bexarotene is an oral medication while monoclonal antibodies must be delivered intravenously. This makes Bexarotene appealing on many fronts; it is already FDA-approved, it can be taken orally, and it has an unprecedented speed by which it reduces beta-amyloid and improves cognition (in mice.

In humans, the gene for apolipoprotein E comes in three versions, one of which, the E4 variant, confers a significantly higher risk of getting Alzheimer’s disease--a roughly 60 percent chance at age 80 for those who carry a copy from both their mother and father, as against a less than 10 percent overall risk at that age in the general population. About 20 percent of the U.S. population has at least one copy. The E4 carriers are thought to be vulnerable to Alzheimer's because they have a diminished ability to clear beta-amyloid from the brain.
The science behind this set of experiments looks very good. That is, it is well designed and well controlled, but the results are still limited to the context of mouse models of Alzheimer’s disease, which are not exact replicas of the human form of the disease. Early-stage human clinical trials are set to begin within months to examine the possibility of any benefit in humans.

By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 1:27 PM 0 Comments

Thursday, February 09, 2012

Impact of New Criteria on MCI Diagnosis


An analysis of the recently revised definition of the syndrome called ‘Mild Cognitive Impairment’ (MCI) could mean that many people now considered to have mild or early Alzheimer’s disease would be re-classified has having MCI instead.

As readers of this blog will recall, MCI is already seen by physicians as the first hint of a future Alzheimer’s diagnosis in many cases. About half of all patients with MCI will progress to full blown dementia within five years. Determining which half progresses has been the subject of intense research efforts and can be made by the use of biomarkers such as volumetric MRI, spinal fluid levels of beta-amyloid and tau protein, as well as Amyloid PET scans. In fact, those patients who have a positive signal on such biomarkers, and are destined to progress to dementia, are said to have prodromal AD. However, until such tools are widely available outside of research centers, clinicians will have to rely on clinical history.

To assess what the impact of the new criteria would be on patients diagnosed with Alzheimer's disease, Dr. John Morris at Washington University examined data on more than 17,000 people evaluated for Alzheimer’s disease at 33 different centers between 2005 and 2011, including about 6,000 who were originally diagnosed with full-on Alzheimer’s or mild dementia related to Alzheimer’s. Participants were classified based on how well they could function performing a variety of activities, including preparing meals and taking medication. The results showed 99.8 percent of patients currently diagnosed with very mild Alzheimer's disease, and 92.7 percent of those diagnosed with mild Alzheimer's disease, would be reclassified as having MCI based on the revised criteria. Considering about 2.5 million people have very mild Alzheimer's disease, the findings suggest that, very roughly, about 2.2 million people could be reclassified as having MCI. In many states, the difference between a diagnosis of MCI and Mild Dementia can mean the difference between driving and not, for example. As such, this latest paper reminds us that a clinical history that includes loss of some cognitive functioning seems to be an imprecise measure. That is, Alzheimer's disease covers a spectrum of symptoms -- from none at all to MCI to advanced dementia -- that can't be neatly compartmentalized from a functional standpoint.

Where does all of this controversy leave us?

The revised criteria for MCI recommend an etiologic diagnosis, so that the patient is told he or she has “MCI due to AD,” when the clinical judgment is that underlying AD is responsible for the cognitive dysfunction. Since the diagnostic confidence for MCI due to AD is significantly enhanced by using biomarkers such as volumetric MRI, spinal fluid amyloid and tau levels, as well as amyloid imaging, clinicians will soon be able to make the most accurate diagnosis possible as these technologies become more widely available.




By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 10:50 AM 0 Comments

Friday, February 03, 2012

Alzheimer's Disease Analogies - Part One


So often patients and families ask about the how and why Alzheimer’s disease develops. As clinicians, we provide the best answers available based on the most current research. However, we will also use analogies to help explain things more clearly. In this blog, I want to talk about three of the most common analogies that we use in clinic to explain the ideas of 1) Symptomatic versus disease modifying treatments; 2) Prodromal Alzheimer’s disease versus Alzheimer’s disease dementia and 3) The idea that the most common forms of AD may be due to ‘underexcretion’ rather than ‘overproduction’ of beta-amyloid.

Symptomatic versus Disease Modifying Treatments

1. Symptomatic treatments simply relieve symptoms associate with a disease. They do not affect the underlying cause of the disease, and therefore do not affect the duration of the illness. Examples of symptomatic treatments include ‘cold remedies.’ If a patient is suffering from the common cold, and its associated symptoms such as sneezing, coughing, runny nose, and sore throat, physicians will often prescribe medications to reduce these symptoms. However, the patient still has the cold, and the cold will run its usual course. The medications will reduce some of the symptoms, but the patient still has the cold. The natural progression of the common cold is such that the body’s immune system usually clears the virus, and the patient recovers.

The medications that are currently FDA approved for AD, reduce the symptoms associated with AD, such as forgetfulness, confusion, and difficulty performing activities, but these medications do not affect the course of AD, which in time progresses to more severe deficits that do not respond to these medications. A disease modifying drug actually affects the course of the disease, and makes its duration less, or even stops its progression. Antibiotics are a good example of disease modifying medications. They stop an infection in its tracks. In the field of AD, we are actively testing drugs that are thought to be disease modifying, as they target the underlying cause of the disease, toxic beta-amyloid.

Prodromal AD versus AD dementia

2. Another analogy is used to convey the idea that, decades before Alzheimer’s disease dementia becomes apparent in a patient, there is an underlying pathological process that is affecting the brain. High cholesterol levels are associated with a higher incidence of heart attacks. However, a patient does not present to their doctor with any symptom associated with high cholesterol. In fact, until 25 years ago when cholesterol levels started to be routinely checked, many patients would present with a heart attack as the first symptom of their long standing high cholesterol levels. The same is thought to be true about AD.

The symptoms of dementia are to the brain much like a heart attack is to the heart. By the time the symptoms of dementia have developed, there have been years of an underlying pathological process affecting the brain, namely the accumulation of beta-amyloid and the loss of synapses and neurons. And, much the same way, if a patient presents to the emergency with a heart attack, prescribing a cholesterol lowering medication for the first time may be too late. Specifically, 15-20 years too late. Now that we can check cholesterol levels earlier in life with a simple blood test, in the absence of any symptoms, we can start patients on cholesterol lowering medications to reduce their risk of have the heart attack in the first place.

The same is believed to be true about treatment of Alzheimer’s disease dementia. By treating Alzheimer’s disease early, by lowering beta-amyloid levels, we may be able to prevent the dementia phase from ever developing. One of the biggest hurdles in the field has been how best to predict which individuals are ‘on their way’ to developing Alzheimer’s disease dementia. So far, measuring spinal fluid levels of beta-amyloid seems to be one of the most accurate methods. Other techniques being studied include amyloid PET scans, volumetric MRIs and cognitive testing.

To be continued......



By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 10:34 AM 0 Comments

Friday, February 03, 2012

Alzheimer's Disease Analogies - Part Two


Overproduction versus Underexcretion

3. Gout is a kind of arthritis that occurs when uric acid builds up in blood and causes joint inflammation. Gout is caused by having higher-than-normal levels of uric acid in the body. This may occur if a) the body makes too much uric acid or b) the body has a hard time getting rid of uric acid. The exact cause is unknown. And interestingly, not everyone with high uric acid levels in the blood has gout. The diagnosis is made when the disease becomes clinically apparent and the patient has symptoms, or by the visualization of the characteristic crystals in joint fluid. Some inherited causes of gout are solely due to overproduction of uric acids. Underexcretion of uric acid by the kidney is the primary cause of 90% of gout cases, while overproduction is the cause in less than 10% of cases.

There are some parallels with AD. Although it has been known for the past 20 years that all of the inherited forms of Alzheimer’s disease (5% of all cases) affect the processing of beta-amyloid in the brain, leading to its ‘overproduction’, it was not until last year that it was shown that the non-inherited forms of AD (95% of all cases) are due to ‘underexcretion’ of beta-amyloid from the brain. That is, most cases of AD seem to be due to an impaired ability of the body to remove beta-amyloid from the brain and into the blood stream, where it is rapidly cleared by the liver. The longer beta-amyloid stays within the confines of the brain, the more damage it causes to synapses and neurons, and eventually deposits into plaques. It is believed that different forms of the protein ApoE (2, 3 and 4) appear to regulate the removal of beta-amyloid from the brain, and they do so with different efficiencies. It has also been shown that ApoE4 seems to be the slowest in removing beta-amyloid from the brain, which may be why it confers the most genetic risk for the late-onset form of AD.




By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, Sa

 
Author: Michael Rafii MD, PhD at 10:33 AM 0 Comments

<< 1 >> 

Archive

Helpful Sites

About Us

The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.