Eat Fish
This is a bit more technical than my usual posts on memory testing. However this study was exceptionally well done and seems to have come to an important conservative conclusion.
Omega-3 Supplements Delay Cognitive Decline in Mild Alzheimer's Disease CME
News Author: Caroline Cassels
CME Author: Charles Vega, MD, FAAFP
Release Date: October 23, 2006; Valid for credit through October 23, 2007
October 23, 2006 — Omega-3 fatty acid supplements may slow cognitive decline in patients with very mild Alzheimer's disease (AD), a study published in the October 2006 issue of the Archives of Neurology suggests.
The randomized, double-blind, placebo-controlled trial of 174 AD patients found overall administration of omega-3 fatty acids made no difference to the rate of cognitive decline compared with placebo at 6-months follow-up. However, a small subgroup of 32 patients with mild AD experienced a significant reduction in their rate of cognitive decline compared with the placebo group.
"Notwithstanding the negative results in the entire group of patients, our study indicated that the omega-3 fatty acid preparation conferred a slower decline of cognition in those with the mildest impairment compared with placebo-treated control subjects with a similar degree of cognitive dysfunction at the start of the study," the authors write.
Led by Yvonne Freund-Levi, MD, from the Karolinska Institute in Stockholm, Sweden, the study was conducted between December 31, 2000, and March 24, 2004.
Inclusion criteria consisted of a diagnosis of AD and a Mini-Mental State Examination (MMSE) score between 15 and 30 points. In addition, patients had to receive a stable dose of acetylcholine esterase inhibitors for at least 3 months prior to the start of the study. All subjects lived in their own home and planned to continue acetylcholine esterase inhibitors for the duration of the study.
Patients were excluded if they were treated with nonsteroidal anti-inflammatory agents, omega-3 preparations, or anticoagulants. In addition, subjects who abused alcohol, had a concomitant serious illness, or who did not have a caregiver were also excluded from the trial.
Atypical Formulation
Routine blood and urine analyses, blood pressure assessment, global function using the Clinical Dementia Rating Scale, and cognitive function using the MMSE and the modified cognitive portion of the Alzheimer Disease Assessment Scale (ADAS-COG) were evaluated at baseline and again at 6 and 12 months.
Subjects were randomized to receive a daily dose of four 1-g tablets, containing a combination of 430 mg of docosahexaenoic acid (DHA) and 150 mg of eicosapentaenoic acid (EPA) or placebo. However, after 6 months, subjects in the placebo group were also given supplements.
According to the current authors, in many previous trials of supplementation with omega-3 fatty acids, EPA has been the predominant acid over DHA. However, in the current study, there was 2.8 times more DHA than EPA. The rationale for this, the current authors explain, is based on previous research that has shown AD-affected brains are deficient in DHA. Furthermore, studies in transgenic mouse models of AD have shown that dietary DHA reduced total amyloid in the brain in a dose-dependent way, particularly in the hippocampi and parietal cortices.
"These areas are also the earliest to be affected by AD in human beings, disturbing for example, verbal episodic memory. The neuropathologic findings in this mouse model of AD may mimic a very early stage of AD," the authors write.
The study's primary outcomes included cognitive function testing assessed by MMSE and ADAS-COG. Secondary outcomes were safety, tolerability, blood pressure, and global function as assessed by the Clinical Dementia Rating Scale.
Sooner May Be Better
At 6 months, there was no difference in the rate of cognitive decline between the 2 groups. However, among a subgroup of 32 patients with very mild cognitive impairment at the beginning of the study, those who took omega-3 supplements experienced less decline at 6 months vs the placebo group.
In addition, the authors note that at 12-month follow-up of patients who were initially in the placebo group also demonstrated a slowed rate of cognitive decline once they began taking omega-3 supplements.
According to the investigators, the mechanisms by which omega-3 fatty acids interfere in AD pathology are not clear. However, they speculate that fish oil's anti-inflammatory effects may play a role in the early, but not later, stages of the disease.
"It is possible that when the disease is clinically apparent, the neuropathologic involvement is too advanced to be substantially attenuated by anti-inflammatory treatment," the researchers write.
The authors caution that the study's finding should not serve as a basis for general recommendations for the treatment of AD with fish oil preparations. However, they note, such supplements should be tested in larger cohorts with mild cognitive impairment to determine whether omega-3 fatty acids could potentially halt initial progression of AD.
Arch Neurol. 2006;63:1402-1408.
The n-back
One of our tests, the second one of the 3 available to members, uses photographs in an unusual way. The images are presented one after the other and the user must decide if a particular image was seen before in the series. It is a fun and challenging experience. We also use different pictures each time the test is shown.
This particular design has a long history in memory testing and the design is known as "n-back" because the subject must remember back by a certain number of images. It is difficult to score and drives the psychometricians nuts. Psychometricians are the experts who use mathmatics and statistics to analyze psychological data.
Dr. Wesson Ashford, MD, Ph.D., a distinguished Alzheimer's Disease specialist, currently working at the Stanford VA in Palo Alto, has worked with us to develop this test in several different versions. He uses the basic n-back design in lectures and demonstrations all over the country. Everyone enjoys the 5-minute demonstration of this test - not just the Alzheimer's specialists. Dr. Ashford likes its simplicity and quickness. This is what is needed for an Alzheimer's screen. When I was in his office last week he and his assistant Emily Gere demonstrated it to me on Dr. Ashford's laptop using PowerPoint. For large audiences they distribute test sheets and have everyone check a box if they have seen a particular image before. It works very well.
So when you take the n-back test (number 2) you are in for a treat. You should also know that this test design is being used daily for memory testing.
Unintended Consequences
An article in the Monterey Herald last week brought some interesting connections to mind. Apparently there is some evidence that taking a common medication for an overactive bladder may have an unintended consequence: memory problems. Gary G. Kay, an associate professor of neurology at Georgetown University, has just completed a study of Ditropan XL. The results indicate that men taking this drug suffer memory loss equivalent to aging by ten years. Sixty year olds performed like 70 year olds.
The biologic connection has to do with how the drugs works on the cholinergic cells in the bladder and, unexpectedly, on cholinergic neurons in the brain. These brain cell are the main target in dementia since in the brain they are involved in memory and learning. Interestingly, the effect seems to be reversible: stop the drug and memory returns to normal.
The memory tests used in the study asked the subjects to remember named faces over a 30 minute period. Tests such as the Memory Migrations tests may have been equally appropriate.
It just makes sense to establish a baseline of memory performance with some form of memory testing. Given the unexpected results of some drugs (who would have thought a bladder medicine would affect the brain) memory testing should be a regular part of medical testing.
Hyperthymesmestic Syndrome
That wonderfully described condition occurs when a person remembers too much. It could describe many of my friends, but, seriously, it is a fascinating and unusual problem for some rare individuals.
University of California researchers, Jim McGaugh, Larry Cahill and Elizabeth Parker, have just discovered such a person and published their findings in the journal Neurocase.
The woman in question, code named AJ, can remember fantastically well: she has “nonstop, uncontrollable and automatic” memory of everything in her personal history. Given any date over the last 20 years she can remember the weather and events that happened on that day. On the other hand, she can not memorize numbers particularly well.
I don’t know how seriously to take all this, I have not read the article, but it is a reminder that we have incredible memory capability. The tests we promote cannot ever plumb the depths of human memory. Maybe we can help track the surface changes and help understand long term trends. But there is a lot to learn and remember.
Study Shows Importance of Testing
We have long advocated early testing as a way to detect Alzheimer’s Disease. There is no particular mystery here, the disease starts covertly somewhere in the brain by a process we have yet to understand, well maybe a little mystery. But, since Alzheimer's needs to be detected early for current treatment methods, longitudinal (long term) studies are very important.
As this article indicates, there is some good science being done by our friends at the University of California. They used a modified version of the Mini Mental State Exam to check memory performance and to compare with MRI results. Ultimately MRI testing may be the best way to detect brain changes, but we still need to check the old fashion way and build our own brain profile with actual memory testing.
WEDNESDAY, Feb. 8 (HealthDay News) -- Brain scans may one day help detect Alzheimer's disease and other forms of cognitive impairment before symptoms appear.
A new study has found a relationship between performance on certain cognitive and memory tests and certain differences in the brain. A new study has found a relationship between performance on certain cognitive and memory tests and certain differences in the brain.
"It's a very exiting study in the sense that it's probably the first time we've seen brain imaging evidence of this type from a normal population," said Maria Carrillo, director of medical and scientific affairs for the Alzheimer's Association.
"Clearly things are going on in the brain before people have symptoms of Alzheimer's," added study lead author Dr. William Jagust, professor of neuroscience and public health at the University of California, Berkeley. "The question is, how do we detect this?"
Finding a way to detect Alzheimer's disease early on, before symptoms start to appear, is one of the holy grails of Alzheimer's research.
"That's the goal, because we're hopeful that in the near future we'll be able to detect who's going to get it and have pharmaceutical drug interventions so we can stop them from getting it," Carrillo said.
Researchers have already used imaging to detect changes in the brains of people who have a genetic predisposition to Alzheimer's and in people with mild cognitive impairment, often a precursor to Alzheimer's. The problem is that many of these individuals already have symptoms, so the disease is not being picked up early enough.
Currently, there are only limited detection and treatment methods for Alzheimer's disease, which affects 4 million people in the United States -- a number that is expected to quadruple in the coming decades.
The new study, appearing in the Feb. 8 issue of the Annals of Neurology, looked at 60 cognitively normal older people. All the participants were part of SALSA, the first study of dementia and cognitive functioning in a Latino (mostly Mexican-American) population.
At the beginning of the study, the 60 participants underwent baseline PET and MRI brain scans along with a full battery of neuropsychological tests. They were followed for an average of 3.8 years, taking cognition and memory tests about once a year.
Over time, some people's performance declined on these cognition and memory tests, some stayed the same and some actually improved, Jagust said. Five people slipped from "normal older" to cognitive impairment, while one person developed Alzheimer's.
The researchers then cross-referenced these test scores with the PET and MRI results.
In the PET scans, people with lower blood sugar metabolism in the temporal and parietal cortex regions of the brain declined faster on the modified mini mental state examination (3MSE), a test that assesses global cognitive functions such as memory, language, spatial ability and judgment.
"This area is the same region that's involved in PET scans in people who have Alzheimer's, except this scan was done when they were normal," Jagust said. "What we're seeing is that the baseline PET scans in regions that we know are affected by Alzheimer's predict whether or not people are going to decline or how fast they are going to decline."
The story told by the MRI scans was similar: The smaller the entorhinal cortex and hippocampus regions of the brain in the scan, the more an individual's score declined on the delayed recall memory test. These regions appear to be the first affected as Alzheimer's develops. "What we're finding is a relationship between decline on the memory test and a brain region affected by Alzheimer's," Jagust said.
Although this study was done among Latinos, Carrillo saw "no reason why it can't be generalized."
Jagust is now involved in a study where scans are taken and then study participants are "tagged" as to how likely they appear to be to develop cognitive impairment and/or Alzheimer's. The researchers will then track these people over time to see if the scans have any predictive power.
"This leaves us with some optimism about predicting Alzheimer's in normal people," Jagust said. "There are a lot of different ways that people are trying to do this. We're working with brain imaging, others with memory testing, others with blood tests. We don't know which one will be the most effective, but the general sense is that something like this would be very helpful."
A Good Virus for Alzheimer's
Here is some good news on the Alzheimer's front. Scientists have developed a way to speed up the creation of Nerve Growth Factor "NGF" in the brain. More NGF means better memory performance. It can even, in theory, reverse some of the effects of Alzheimer's.
Here is how it works: A virus is redesigned with a specialized gene that generates NGF. This virus is then injected into the basal forebrain where memory cells are located. These virus particles then "infect" the memory cells and change their DNA to cause them to start producing more NGF. NGF then works its magic to maintain and protect memory cells.
Dr Roy A.E. Bakay at Rush University Medical Center is conducting trials of this technique and there is some evidence that it may be effective. Results could be available within one year.
Because this is a relatively simple technique, if it works, it could quickly become commonplace as a way to slow the progression of Alzheimer's. We can then thank the good doctors and the brave pioneers who volunteered for this study. We can thank them in any case.
One Word
Axiomnemoneuton - a Greek word meaning "that which is worthy of being remembered". Just a reminder that selective memory is a good thing. Of course we should do everything we can to maintain and measure memory performance but not everything needs to be rememembered. Relax and remember the best things in life, the best things you said, the best places you have been and the best people you have known. If you forget a few things along the way, that may be for the best.
