http://answers.yahoo.com/question/index?qid=20060610231907AA3RN00
How Long Do Dogs Remember Things?
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Best Answer - Chosen by Voters
It all depends on how much the memory impacts them. Pups that I have sold, still remember me 9 or 10 years later. Adult dogs can't seem to remember to stay out of the trash! The rule of thumb for training, is to repeat each tast 14 times before you can expect the dog to remember. I think they remember about as well as I remembered what Mom told me to do.
Source(s): dog breeder since 1968
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If you get an intelligant dog they will remember for ever
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Im pretty sure they remember about 10 minutes but faces hey never forget
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It depends on how important something was. If a dog hears a car backfire while he's walking past a fire hydrant, he may be afraid of fire hydrants for the rest of his life - I knew one that was. If he just pooped on your expensive oriental rug - he may forget all about it in fifteen seconds. When your training a dog to obey commands, you have to practice every day until he knows them, and then give him a refresher course from time to time if you see him back-sliding.
Source(s): 28 years experience
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Forever probably
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FOREVER! Our Westie never forgets anything. When he had his cancer surgery we would ask him where his bo-bo was? To this day he rolls over to show us!
Soccer! He also watches the World Soccer matches with his older brother(my son). We are amazed at how he brings us the soccer ball when the matches are on. We don't even ask. PS he has three balls to choose from and it is always the right one... it's amazing! He goes to the vet every 27 days for his DOCP injection. Before we turn into the road he is scratching on me to go home........how he hates going for his injection! A dog can remember as much as you can teach them! Yes, that's why it is so important to love your pet. They never forget!
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It really depends on how much something impacts them. If they mess on the rug they don't remember doing it however they do remember the spanking and think that you are somebody who they should be afraid of. That's why it's very important NOT to hit your dog for any reason. Positive reinforcement. If something impacts a dog strongly such as a broom falling on them when they went into the closet they may become immortally afraid of that particular closet. Things like teaching a dog tricks and stuff takes a while for them to associate a certain word with a certain action because we speak totally different languages and have that barrier between us. Once they learn the trick though it isn't hard for them to remember but if you don't refresh their memory from time to time they will forget just like us humans. Aren't dogs great?
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Forever. Dogs are very intelligent. This is why they remember the things you train them to do. I have an 11 year old beagle that I purchased from a farmer for $20.00 and he is the smartest dog I have ever had. When we first got him at 9 weeks old, I watched him pull up the covers over him and my husband. I couldn't believe it. To this day, he still lays down, rolls over, speaks, sits, gets his leash if I ask if he wants to go for a walk and he also gets the car keys when I ask if he wants to go for a drive. I almost think he is smarter than some people. So all in all, I feel that dogs do remember forever.
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http://home.xtra.co.nz/hosts/Wingmakers/Telepathy.html
Telepathy in the Animal Kingdom
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During World War 2, a watchmaker near Hamburg had his German Shepherd confiscated for the war effort (to work as a watchdog). A year and a half later, the man was put into a concentration camp when it was learned he was 1/4 Jewish. One night he and three others escaped, which was discovered 30 minutes later by the guards, who immediately released the dogs. In one of those strange occurrences of life, the dog that reached the escaped prisoners first was the watchmaker's dog that had been forcibly taken away. After all the training to attack prisoners, what would the dog do? Would it even recognize his old master, who was physically depleted and looked like a totally different person? Later, after crossing the allied lines, the man describes what had happened. He said his eyes meet those of his dog, and that he felt a warmth in the back off his eyeballs. The dog suddenly turned around and began attacking the other dogs which were behind him starting to approach. The men made their escape during the dogfight, the result of which no one knows. The watchmaker never saw, or heard from his German Shepherd again. As said last week, there is usually a warm feeling in the eyes when the process of sight telepathy occurs. While the previous example shows that between an animal and human, this feeling also happens when this form of telepathy happens between humans. (Also, this sensation has been often described by those who reported having telepathy when abducted by aliens). It is the ganglion cells in the back of the eyes that take an image and convert it into electronic impulses which are then sent to the brain. It is this part of the body then, that is the first "processor" in function of mental telepathy. When trying to develop your mental telepathic talents, it is important to know what part of your body 'regulates' it, so you can then develop this physical part as well. It is the same logic why runners develop their legs, or a swimmer would want to develop their breathing.
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Discover- July 2003
Saving Private Squeaky
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By David Berreby
When laboratory biologists aren't forced to close ranks against the animal rights lobby, most will admit there's irony at the heart of their careers: Love of life make them curious, but curiorsity makes them kill. They can tell you how appealing and interesting a catepillar is at one moment and dissect it in the next. The tension isn't found only in the lab. Plenty of farmers love their animals, but their goal is producing food.
Zookeepers are close to their charges, but they know the zoo is there to bring in the crowds whether the animals like it or not. Some scientists get around this by denying their emotions: Rene' Descartes, for example, held that animals were unfeeling machines. But most biologists are more likely to agree with neuroscientist Charles Sherrington, who wondered whether Descartes ever had a dog.
A mother mouse struggling to pull her baby back to its cage can make even the most focused researcher's thoughts stray from the protocol. Experience teaches lab workers to defend against such upheavals. (One piece of good advice: Never name animals you'll have to euthanize.) As a layperson who has spent time among biologists, I've seen scientists give it to attacks of compassion for their fellow creatures.
A lab keeps feeding an elderly rodent for too long after they have run their last maze; a campus pond is mysteriously abundant in the amphibians that the local lab works with. Sometimes people even take an animals out of the system. I should know-I did it myself.
Once I was involved in a set of experiments with look-alike young rats who had to run a maze and make a lady-or-the-tiger choice at the end. If they make the right pick, they got to leave the maze; the wrong pick left them wandering about anxiously. We were interested in how well they could remember their choices over time.
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I had expected that all six rats would learned the game in a look-alike way, at a look-alike pace. On paper they were identical-same colony, same sex, same age. The only way I could tell them apart was by numbers inked on their tails. But they turned out to be not alike at all. Two of them never did figure out the game. Two others couldn't get beyond the basics.
Only two were abled to do the work we expected. But one of the latter-subject B-was something else altogether. He need far fewer demonstrations to see the point of the game. By the fourth test of nine, he was noticably calmer, while his colleagues were still panicking. He seemed to get it and to know that he was getting it. He was in the magic zone of "one trial" learning, the rodent equivalent of being able to drive in a country you've never visited before.
Thanks to him, our experiment was a success. And that had some interesting effects on the experimenters. Human beings are very good at making distinctions among look-alike individuals. We are also very keen at noticing when someone else has done us a good turn. And we tend to feel close to those who have shared a stressful situation with us-teammates, fellow soldiers, rescue workers. I was always happy to see Subject B.
He was hardworking, living proof that our team wasn't wasting its time. I was less happy as I thought about the reward he would get for his effort. Our protocol required that the animals be euthanized at the end of the task-not because we needed to dissect them to learn anything, just because they were surplus once we were done. As I put subject B in his clear plastic cage for the last time, I watched the rats scurry around their enclosure calmly, sniffing corners, checking in with one another, apparently deciding that nothing much had changed after another day at the office. Only I knew that tomorrow they were scheduled to die.
The protocol is designed to be as quick and painless as possible. Besides, in a few days, I would be traveling. And I owned a cat. Still, science, as I pointed out, is no stranger to contradictory feelings about animals. And as the playwright Frank McGuinness once put it, "A man who is alone may at times feel mercy, mercy towards himself." Death came for Subject B on schedule, but Subject B was not there. Months later, I noticed those indelible marks on his tail turned out to be not so indelible after all. Eventually, they faded to nothing.
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ttp://gizmodo.com/gadgets/awww/microchip-renuites-dog-with-owner-after-7-years-the-system-works-323939.php
If There Was Ever a Case For Embedding Your Dog With a Microchip, This Is It. In 2001 Lyn O'Byrne's dog Rhia was stolen from the vets office where she worked as a nurse. Amazingly enough, last week she received a call from a lost animals line informing her that a dog was found with her contact info stored in a microchip embedded in its neck. Dog and owner were reunited, hugs and kisses all around, technology rules, and all is right with the world. [Wimbeldon Guardian via Spluch]
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Comments
I dunno about seven years, but I remember whenever I'd go to visit my dad (I only got to do so maybe once every 1-2 years, since he was in a different part of the state) his dog would instantly recognize my footsteps before I had even gotten within viewing distance. He died a while back. :( Long live Pepe, the chihuahua!
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Poor thing. Looks like it's had a few too many nights without a meal. Seeing lost dogs on the street always brings a tear to my eye.
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Well, this breed of dog always looks like this and these chips are just RFID and require someone taking it to be scanned. So, if the person that stole it had it for seven years, that might explain why it took that long.
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That is one funny looking dog, I think he has Stockholm syndrome.
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Yeah most animals recognize on sound and smell rather than sight. My parents own two cats and when I come home to visit they can hear my truck before I get to the driveway. They'll wait at the stairs for me, and this is a behavior they only exhibit for our vehicles. Also my friend's dog hadn't seen me in two years yet seemed to recognize me the last time I saw it. It's one of those dogs who will bark at strangers, but last time I saw it, it ran up and waited for attention.
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"Stolen from the vets office"? WTF?? I'd definitely not go back to that vet. Uh.. unless I worked there, I guess...
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Anyone ever stole my dog I would get completely Bourne on their asses. But more so.Spaying and neutering their relatives for seven generations in both directions. Blood feud. As far as spaying and neutering pets, I never fixed my bitch and woah howdy, she never reproduced. Fixing pets is great if you are an irresponsible bastard. But get off the backs of people who train their dogs and treat them well. Bob Barker wanna-bes!
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I know if you love your four legged kid, they will never forget you. I know when I went overseas and came back our Huskie Zack knew I was home before anyone else did and was so happy to see me, he truly missed me while I was gone. I believe if you give them the love and attention they deserve, they'll never turn their back on you.
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As YARDAMEUS pointed out, the chips implanted in dogs (and cats, parrots, ferrets, etc...) are just RFID chips. They have to be scanned by a handheld scanner in order to give up their info, which is just the manufacturer of the chip (AVID, HomeAgain, ...) and a number. The person scanning the chip would then call the manufacturer, who would look up that number and contact the owner. Many vets, and most shelters, routinely scan new client animals or new arrivals. If the person who stole the dog went to such a vet after 7 years, this might be how the dog was scanned. The dog in the photo appears, to me, to be a Whippet. A lot like a Greyhound, but smaller. Though it certainly could be a Greyhound. They are supposed to be skinny. Even obese sighthounds tend to look "starving" to the general public, but they are just built for pure speed = MUCH muscle, very little fat stores. There are now GPS tracking collars available, and the handheld scanner IIRC can locate them for about 5 miles, intended for hunting dogs. Someday it would be awesome if the little chips could also include a "Locate me!" feature. Tracy, whose pack of dogs has been assimilated (chipped)
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http://egyptianchronicles.spaces.live.com/blog/cns!333930840EEA2F90!1649.entry
Alexander the Great or Alexander the Gay?
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Was Alexander the great really as they are saying now gay? Sorry to be specific in the description was he really bisexual person? Since the 70s of the last century and there are claims that were turned as historical facts that the great young leader who invaded the world was a gay and he preferred men over women and the rest of this talk you can find in Oliver Stone's Alexander movie!! Greeks refuse these claims and if you remember when Alexander the movie was released and even they sued Stone for spreading these claims.
Anyway I was watching today a documentary in Discovery channel in Showtime Arabia, this documentary was Battle ground: Ancient wars, it was about the famous historical war between the Persian army and Alexander the great army. That ancient war is not only historical but legendary 45 thousand Greek solider in front of 1/2 million Persian solider in Persia "Iran now" and yet Alexander made a miracle and won.
The tactics used in the war are great, the plan, the whole design of the Greek army, also the personality and intelligence of Alexander as a commander, an excellent documentary. This documentary made me think a lot about the claims about Alexander's sexuality is he or is he not? I felt from the documentary that he is straight man; the kind of a commander to achieve this victory must be a man on all levels if you understand what I am saying.
Also I remember I saw another documentary on Discovery civilization called lost civilizations: Persia and I remember them saying that Alexander warned his officers and soldiers from imitating the Persian lifestyle as it is homosexual life style no suitable for a man, as Alexander who came from Harsh country compared to Persia finds the Persians were not men enough as they had so comfortable lifestyle, this is recorded in historical records, as you see Homosexuality was something bad from his point of view ,something he warned his officers and soldiers from , so how come he became a gay!?
Another thing and this historical proof, according to the Egyptian Egyptologists and historians and also Greek literature and history professors there is no single Greek record or document saying that he was a gay. Also it was well known that he had many wives and the most famous one of them was Roxanna. So what is the story?
It started in the Novel "The Persian slave or boy" as I read some where from sometime after that Alexander the great joined Leonardo Da Vinci in the ancient gay club!! I don't believe that for one good reason, historians always change history as they are humans; already the western Historians portrayed Cleopatra as whore who stole roman men from their wives while she was an intelligent woman who worked very hard to preserve the independence and dignity of her own country!!
This reminds me with stupid claims by some western historians I saw it on either the National geographic channel "Asia" or on the history channel saying that Akhenaton, the famous pharaoh and the first person in Egypt to call for One God, was a gay!!!! Despite all the historical proofs that he was a straight man who adored both his wife and his mistress "he had one who gave birth to son!!"
What about you folks? Do you think that Alexander was gay?
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Comments
@anonymous Greek , I think you are greek , I agree with you 100% and I already from few days I had watched the film in te TV of course a censored version , to tell you the truth I found the film not so interesting whether from acting or from direction , Stone this time failed in his film on levels. The relation between Alexander and his friend I see it more as friendship ,I mean when his pal was dying he kept saying to him that he would live and that both will see their children from their wivesplay with each other , not to mention according to the film Alexander married another three women beside Roxanne ,so how can he be gay if he is so much in women !!??
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The underlying fact is that there is no proof. No proof without assuming, or twisting, NONE. If Greece was so openly gay backing those days, then wouldn’t it have been easy to find proof of him rodgering everyone with a penis. Instead they cling to one sentence where he wrote he loves his “male” friend of whom he has grown up with. I have male friends that I grew up with that I love dearly. Could this msg then become evidence in 700 years to prove to people reading it that I am gay?? A smart film producer for the "Shock" value of making him gay tried to cash in on this as a Marketing tool. He failed because once the courts realized they’re no proof to portray him as gay without defaming his character “illegally”. The producer couldn’t promote the movie as he wanted to and it was too late for him to change the script and the movie was SHIT because he couldn’t use the gay angle which im sure although being incorrect would have made the movie a success.
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http://community.livejournal.com/wtf_nature/tag/crustacean
Cymothoa Exigua
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Cymothoa exigua is a parasitic crustacean of the family Cymothoidae. This parasite attaches itself at the base of the tongue of the spotted rose snapper, Lutjanus guttatus, with the claws on its front three pairs of legs, and extracts blood. As the parasite grows, less and less blood is able to reach the tongue, and eventually the organ atrophies from lack of blood. The parasite then replaces the fish's tongue with its own body, by attaching to the muscles of the tongue stub. The fish is able to use the parasite just like a normal tongue, except that it has to share its food with the parasite.
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By Regina Nuzzo, PhD
http://reginanuzzo.com/?p=43
Using Algorithms to Tackle Alzheimer’s Disease
Computing the Ravages of Time
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In 1906, at a small medical meeting in Tabingen, Germany, physician Alois Alzheimer gave a now-famous presentation about a puzzling patient. At age 51, Auguste D.’s memory was failing rapidly. Confused and helpless, she was growing inarticulate and fearful of her family, Alzheimer reported. Auguste died four years later. During the autopsy Alzheimer found dramatic shrinkage in Auguste’s brain, with cells that were already dead and dying at the time of her death — plus two kinds of microscopic deposits that Alzheimer had never seen before. He summed it up in his presentation abstract: "All in all, we are faced obviously with a peculiar disease process."
Now, a century later, about 5 million people in the United States have Alzheimer’s disease, at a cost of more than $100 billion annually. About one in every eight people 65 years and older has been diagnosed with the disease. With lifespans continuing to lengthen and waves of babyboomers hitting prime-risk ages, the number of Alzheimer’s patients could triple by the time today’s college students enter retirement. Thus far, no clinical treatment has been shown to stop Alzheimer’s neurodegeneration.
In addition to searching for new pharmaceutical targets, however, researchers are grappling with other disease fundamentals: how plaques and tangles form on the brain, how best to detect early onset of the disease before cognitive decline starts, and how to predict a person’s genetic risk. The stage is set for computational approaches to Alzheimer’s, says Arthur Toga, PhD, a professor of neurology at the University of California, Los Angeles.
The slippery, highly variable nature of the disease demands sensitive tools, an aging population creates the urgency, and new technology provides the power to meet those demands. "In some sense," he says, "we’re now set for a perfect storm for Alzheimer’s disease research." Computational tools are extending researchers’ reach at all scales.
Molecular dynamics simulations visualize the protein clumps in the brain that experiments can’t capture. With unprecedented ease, data-mining methods sift through the rapidly accumulating information about the proteome and genome. And sophisticated imaging analyses reveal changes in the structure and functioning of the entire brain.
PROTEIN DYNAMICS: GETTING AT THE CAUSE OF ALZHEIMER’S
In the 1960s, researchers were finally able to use new electron microscope technology to see the molecular structure of the two types of mysterious lesions that Alzheimer first noticed in his patient’s cerebral cortex — the so-called senile plaques and neurofibrillary tangles. The plaques, it turns out, consist mainly of amyloid beta peptides, while the tangles consist of abnormal forms of the tau protein. How these two proteins influence each other is not well known.
Some researchers postulate, however, that aggregates of amyloid beta "seen as senile plaques in their final form "are the proximal cause behind Alzheimer's disease, and the tangles and other neuropathological changes are a side effect of the gone-haywire amyloid beta assembly. Known as the amyloid cascade hypothesis, this suggests that understanding amyloid self-assembly could help crack open the puzzle of how Alzheimer's disease starts in the first place.
Researchers trying to study amyloid beta through experimental approaches run into problems, however, because many amyloid beta aggregates are unstable and short-lived. Computer simulations, on the other hand, provide the chance to study small amyloid beta aggregates in full atomic-resolution glory. Over the past two decades computational power has increased, allowing for better "all-atom" molecular dynamics simulations of short time-frames.
And for longer simulation dynamics, coarse-grained protein models have been developed that can boil down a large number of degrees of freedom to a more manageable few, for instance by representing amino acids by a less complex structure of "beads." H. Eugene Stanley, PhD, professor of physics and physiology at Boston University and director of the university’s Center for Polymer Studies, models the folding and aggregation of amyloid beta peptides with a variety of approaches.
In recent work, Stanley, Brigita Urbanc, PhD, senior research associate in physics at Boston University, and their students simulated these peptides using a coarse, four-bead protein model, in which amino acids are represented by three backbone beads and one side chain bead. Urbanc, Stanley and colleagues have been especially interested in investigating differences between the two most common protein forms seen in senile plaques: amyloid beta 40 and amyloid beta 42.
Their results, published in the Proceedings of the National Academy of Sciences in 2004, showed that the amyloid beta 40 and amyloid beta 42 peptides first folded into collapsed coil structures, then assembled into chains of different lengths. During the simulation, Stanley says, "amyloid beta 42 tended to form longer chains, and the amyloid beta 40 shorter ones" in proportions consistent with laboratory results. More recently, Stanley and his colleagues refined their simulation model to include the presence of electrostatic interactions between pairs of charged amino acids.
Published in Biophysical Journal in June 2007, their results point to a specific spot on the amyloid beta 42 chains "the C-terminal region" that may be crucial for the molecule to aggregate. This suggests that inhibitors targeting this region could prevent chain formation or change the structure of the assemblies to reduce their toxicity, Stanley says.
These in silico analyses are useful, Stanley points out, because they lead to predictions that lab researchers can test in vitro. And because computer simulations can reveal crucial, three-dimensional details of amyloid beta molecules, they can also aid in designing and testing drug molecules specifically for this target. "It's easier to design a key if you know the exact, three-dimensional contours of the lock," he says.
PROTEOMICS: SEEKING BIOMARKERS TO HELP DIAGNOSE ALZHEIMER'S
Before Alzheimer's disease can be treated, of course, it needs to be spotted and the sooner the better. Evidence suggests that molecular mechanisms of the disease are at work early, perhaps even several years before neurons start dying and cognition starts to decline. Yet tests that can accurately and reliably detect the disease at early stages have been hard to come by.
As researchers understand more about the proteins involved in the disease process, they are also starting to investigate whether any of these molecules could serve as an Alzheimer's biomarker. The answer isn't likely to be found in a single protein, however. The obvious candidates for biochemical markers "amyloid beta 40, amyloid beta 42, and the hyperphosphorylated tau protein" are indeed found at elevated levels in Alzheimer's patients, but they are also found in other neurological disease patients as well as in some normal controls.
Some researchers are therefore taking a bigpicture, proteomic approach. They're looking for a combination of proteins whose expression levels in blood plasma serum or cerebrospinal fluid might yield a biochemical signature of Alzheimer's disease in early stages. The lab of Tony Wyss-Coray, PhD, associate research professor of neurology at Stanford University, recently collaborated with Satoris, Inc., a biotechnology company Wyss-Coray cofounded, on such a project. Their focus: signaling proteins in plasma.
Sandip Ray, chief scientific officer and cofounder of Satoris, came up with the idea. Using supervised learning software called Predictive Analysis of Microarrays (PAM), the researchers studied plasma expression levels for 120 immune response factors and other signaling proteins from an initial set of 43 Alzheimer's disease subjects and 40 age-matched unaffected controls.
The algorithm honed in on a subset of 18 proteins that seemed to be characteristic and predictive for Alzheimer's disease. Individually, each protein could not accurately classify the subjects as either a case or a control. But taken all together, the proteins "expression signature appeared to be good at predicting disease status," Ray says.
The researchers tested the 18-protein predictor on an independent test set of 92 subjects, which, like the training set, was drawn from seven different patient centers to minimize possible center biases, Ray says. The predictor reached a total accuracy of 89 percent. The group went on to evaluate the expression signature's predictive abilities for a set of 47 patients with mild cognitive impairment, a condition which sometimes precedes Alzheimer's disease.
The expression signature predicted that 27 of these patients would later develop Alzheimer's disease, and indeed, 20 of the 27 were diagnosed with the disease within six years. Overall, the predictor achieved an estimated 91 percent sensitivity and 72 percent specificity.
Biologically, the 18 proteins seem to point to a systemic, not isolated, dysregulation in neuronal support, immune response, cell growth and cell death in Alzheimer's disease patients several years before clinical symptoms appear, says Markus Britschgi, PhD, a postdoctoral fellow in Wyss-Coray's lab and presenting author of a poster on the work in June at the Alzheimer's Biomarkers Meeting in Washington, D.C.
The work has recently been accepted for publication in Nature Medicine. "But what we don't know at this time is whether these dysregulations are due to processes in the brain or processes only in the periphery, he says.
GENOME-WIDE ASSOCIATIONS: TYING GENES TO ALZHEIMER'S
Studies of twins hint that up to 80 percent of Alzheimer's cases are due to genetic causes. Yet only three genes have been found on which mutations likely cause the disease through simple Mendelian inheritance: APP, which encodes the amyloid beta precursor protein, and PSEN1 and PSEN2, which encode presenilin 1 and 2. Mutations on these genes cause familial earlyonset forms of the disease. Most people, however, develop Alzheimer's disease after the age of 65 and do not have such a strong history in the immediate family.
For this form, the most important known gene is ApoE, which encodes apolipoprotein E. Yet ApoE doesn’t convey the whole picture: only about half of late-onset cases have a copy of the high-risk allele. The search is on for other Alzheimer's susceptibility genes, but hard results have been elusive so far. It has been suggested that the survey of at least 300,000 single nucleotide polymorphisms (SNPs) from the whole human genome might be necessary for studies of genetically complex phenotypes. Until recently, however, published studies had not looked at more than 100,000 SNPs at a time. Technology is changing that.
"We're entering the era of high-density genome-wide association studies," says Eric Reiman, MD, executive director of Banner Alzheimer's Institute in Phoenix, Arizona. Thanks to advances over the past decade "in computing power, microarray technology and analysis tools, and human genome maps, for instance" genome-wide association studies are suddenly becoming feasible and successful (see the other feature story in this issue of BCR).
Their benefits extend beyond simple efficiency. The methods, which use high-throughput processes to examine about half a million genomic markers, can test many SNPs independent of any biases related to a researcher's favorite gene. "What's exciting about hypothesis-free genomewide studies is that they can help uncover new mechanisms that people haven't thought about before," Reiman says. The first high-density genome-wide association study of Alzheimer's disease was published in Neuron in June 2007 by a 15-institution international team led by Reiman and Dietrich Stephan, PhD, associate director at the Translational Genomics Research Institute in Phoenix.
That research was supported by 20 of the National Institute on Aging's Alzheimer's Disease Centers. Using samples from 861 subjects with late-onset Alzheimer's disease and 550 elderly unaffected controls, they genotyped about 500,000 SNPs. These classifications were verified in more than 1,000 Alzheimer's cases and controls at autopsy. In three rounds of analyses, the researchers found six promising SNPs from a single gene that were significantly associated with the disease in subjects with the high-risk ApoE epsilon 4 allele.
The SNPs all lay within the GRB-associated binding protein 2 (GAB2) gene. In this particular study, the most significant SNP on GAB2 was associated with an overall four-fold increased risk for Alzheimer's disease, Reiman says. And people who carried both the epsilon 4 allele and the GAB2 high-risk allele had a 24-fold increase in risk for Alzheimer's disease.
The study's results need to be replicated with independent data, Reiman cautions. But for now they allow for possible mechanisms to be tested "investigating, for instance, whether the normal form of the GAB2 protein protects vulnerable neurons from tangles," he says. The researchers have deposited all of their data into the public domain. "We have just begun to have enough letters in the genetic book of life to understand the genetic story of Alzheimer's disease and other common phenotypes," Reiman says.
LETTING INTERMEDIATE PHENOTYPES STAND IN FOR ALZHEIMER'S IN GENOMIC STUDIES
One problem that genetic studies of complex diseases can run into is simply finding the right people to study. Clinical diagnoses of Alzheimer's disease in particular are not always accurate, and small errors in identifying the cases and controls in a study can mask or skew real genetic associations in the results. One way to overcome this is to work with endophenotypes: intermediate quantitative traits that stand in for a more complex disease phenotype.
Finding a good endophenotype for Alzheimer's isn't simple, however. It must be a trait that is heritable, associated with the causes and risks of Alzheimer's disease" which itself is still a mystery" and ideally be normally distributed within the population, says Alison Goate, PhD, professor of psychiatry, genetics and neurology at Washington University Medical School in St. Louis. With the right endophenotype, however, the power of a genetic study can jump dramatically, Goate says.
"If your quantitative trait represents something that is highly correlated with the disease but controlled by a small number of genes, then it should be easier to find those genes with the quantitative trait," she says. Amyloid beta peptide levels are a natural endophenotype candidate, Goate says, because they are highly correlated with the presence of Alzheimer's disease and also with high-risk alleles in APP, ApoE, PSEN1 and PSEN2. Goate and her colleagues are working with cerebrospinal fluid levels of two of the most common forms of the protein, amyloid beta 40, amyloid beta 42, plus the ratio of amyloid beta 42 to amyloid beta 40.
As part of an ongoing study, they recently looked at a set of 300 subjects in which two-thirds had a family history of Alzheimer's disease but were themselves unaffected and one-third had a diagnosis of mild Alzheimer's disease. From a list of 19 candidate SNPs selected from the AlzGene database's meta-analysis, nine were significantly associated with the amyloid beta endophenotoype, with eight showing directions of association that were consistent with existing meta-analyses.
"This is promising, because it suggests that these associations are likely to be real," Goate says. The group is still collecting more samples, Goate says, and they hope to reach the point where they have a large enough sample to try out the amyloid beta endophenotypes in a broader set of SNPs across the entire genome.
IMAGING: CAPTURING THE BRAIN ON SCREEN TO DIAGNOSE AND TRACK ALZHEIMER'S
Brain imaging has long played a role in the diagnosis of Alzheimer's disease by helping physicians exclude the possibility of brain tumors or other ailments. More recently, however, researchers have become interested in using imaging tools for broader purposes: understanding the disease, detecting it at early stages, and tracking its progress over time.
As the tangles and plaques of Alzheimer's disease creep across a brain, its structure changes in subtle ways. With a skilled eye, radiologists examining brain magnetic resonance images one by one can quickly categorize the spread and degree of atrophy in the brain. But researchers would like to use assessments that rely less on subjective evaluations of skilled experts.
VOXEL-BASED METHODS TO CATCH EARLY SIGNS OF DISEASE
Some researchers are developing machine learning approaches that focus on individual voxels. Clifford Jack, MD, a professor of radiology at Mayo Clinic and postdoctoral fellow Prashanthi Vemuri, PhD, are investigating one such pattern classification method. The technique uses a support vector machine algorithm, which aims to find a combination of brain image voxels that can best distinguish images of Alzheimer's patients from unaffected controls, Vemuri says.
Their results, from a set of images of 380 Alzheimer's disease subjects and unaffected controls, were presented at the Human Brain Mapping meeting in June 2007. The researchers first narrowed their attention to those brain regions that showed evidence of atrophy in Alzheimer's disease subjects. Within these regions, their tool found a subset of voxels that best classified the subjects into cases and controls.
Altogether, the algorithm winnowed 10,000 voxels down to an essential set of 300, Vemuri says. And these voxels, it turns out, form regional clusters that mirror the typical spread of neurofibrillary tangles. This provides an extra intuitive affirmation, Jack says.
But the quantitative validation is what really counts: the method achieved 85 percent sensitivity and 85 percent specificity. Adding information about age, gender, and ApoE genotype further boosted both scores to 90 percent. The process takes less than 15 minutes per case to run on a desktop computer. "Ten years ago, it might have required a supercomputer to do it," Jack says. "People in medical imaging are just now taking advantage of improved software available to the public."
MODELING BRAIN CONTOURS TO FIND ALZHEIMER
Another approach to analyzing structural brain images is to take a step back from the trees and look at the forest. Rather than analzying data on individual voxels, some methods model overall contours of brain regions, an approach that characterizes the shape of subcortical and cortical structures.
John Csernansky, MD, a professor of psychiatry and neurobiology, and Lei Wang, PhD, a research assistant professor, both at the Washington University School of Medicine in St. Louis, along with Michael I. Miller, PhD, a professor of biomedical engineering and electrical and computer engineering at Johns Hopkins University, are working with surface-based methods that stem from classical mechanics. When brain regions of Alzheimer's patients atrophy over time, they change shape in complicated ways.
Miller has pioneered methods based on the principles of computational anatomy "which include tools such as large-deformation high-dimensional brain mapping"to model these variations. The techniques assume that differences in brain contours can be captured by "morphing" one brain anatomy into another through highdimensional diffeomorphic transformations that smoothly change one shape into another. Essentially, Miller says, brain matter is modeled as if it had the physical properties of a viscous liquid.
Since sets of differential equations describe the transformation, group differences can be efficiently characterized. The group has applied their methods in a variety of settings. In a longitudinal study of 44 subjects published in 2003 in Neuroimage, the researchers used patterns of change in hippocampal shape over two years of follow-up to distinguish subjects with mild Alzheimer's disease from unaffected elderly controls.
And in a study of 49 subjects published in 2005 in Neuroimage, variation in the shape of a particular part of the hippocampus surface could predict "whether a subject would go on to develop mild Alzheimer's during five years of follow-up"and if so, how long it took for cognitive effects to show up. With thousands of data points collected on each hippocampal surface and only a relatively small number of subjects, these methods demand some form of data reduction, Csernansky says.
Early studies used principal components analysis to hone in on the most informative areas of the brain surface. More recently, however, the group has been working to make their results more interpretable to clinicians by using a simplified anatomical template of the hippocampus. In a study of 135 subjects published in 2006 in Neuroimage, patterns of surface variation in particular hippocampal substructures could distinguish subjects with very mild Alzheimer's disease from elderly controls.
In particular, changes in two specific areas of the hippocampus surface, one in the CA1 subfield and the other near the subiculum, significantly increased the odds that a subject had very mild Alzheimer's disease. The group is looking now at how particular substructures change over time in Alzheimer's patients as compared to the normal aging population.
And they hope to combine their own measures of surface deformations with other types of data, such as functional images or PIB-PET scans, Wang says. "With this type of metadata, we can understand how the disease progresses and also do a better job of prediction," he says.
FUNCTIONAL IMAGING TO SEE THE ALZHEIMER'S BRAIN IN ACTION
With functional brain imaging, researchers can investigate the clinical aspects of Alzheimer's disease: how does the brain behave differently when it's affected by the disease? Functional magnetic resonance imaging provides some of the most detailed clues to this question. Many fMRI studies have pointed out particular brain areas that show damaged functioning in Alzheimer's disease patients. But some researchers are now interested in how the entire brain might also change and adapt as the disease progresses.
Michael Greicius, MD, an assistant professor of neurology at Stanford University, is particularly interested in how brain regions connect and communicate among themselves. Recently, he and Kaustubh Supekar, a biomedical informatics graduate student also at Stanford, turned to analyzing a large network of brain regions for mathematical characteristics that were first used to describe social networks. Their approach uses small-world measures, which have also been used to analyze a variety of other networks, including the Internet, global airline routes, and "six-degrees-of-separation" human networks.
In social groups, a network node would be a person; in functional brain networks, a node represents a particular region of the brain. Previous work has suggested that normal brains, like human social networks, exhibit smallworld characteristics. This means that they encompass many tight clusters of nodes, and that information shared between any two nodes must likely pass through a large number of short-range connections. Greicius and his colleagues wanted to see if there were any small-world differences between Alzheimer's disease brains and unaffected brains.
The group recorded resting-state fMRI brain activity in 36 Alzheimer's disease patients and unaffected elderly controls every two seconds for six minutes. They then looked at activity in 90 separate regions of the brain "tens of thousands of voxels for each brain region" and created a time series of activity for each. They could then calculate the connectivity, or the amount of mutual information, between each of the 90 nodes.
The Alzheimer's disease patients, they discovered, had significantly less regional connectivity and displayed more impaired small-world functioning than did healthy controls. The results were presented at the Human Brain Mapping meeting in June, 2007. It's not yet clear what the results mean biologically, Greicius says, but for now that's fine.
"Intellectually it's less satisfying if there's not a clear biological interpretation, but from a practical, clinical standpoint we're agnostic as to what's driving the results, as long as they're reproducible and accurate," he says. A measure based on regional connectivity was able to distinguish Alzheimer's disease patients from healthy controls with 73 percent sensitivity and 80 percent specificity.
The next step is to see if data reduction tools could construct a more simplified global network "based on 20 or 30 regions, say, rather than 90" that could better classify individual subjects as having Alzheimer's disease or not, Greicius says.
CHALLENGES FOR THE FUTURE:
Future challenges for computational work in Alzheimer's disease research will likely center around the usual suspects, researchers say: data, people, and money. "From the computational standpoint, researchers need more powerful ways to glean information from an increasing array of complex datasets," says Eric Reiman of the Banner Alzheimer's Institute, "and they need new ways to characterize the relationships among these potentially complementary datasets." Indeed, simply using study subjects recruited in different ways from different clinical centers poses a real problem for the integrity of results, says Clifford Jack, MD of the Mayo Clinic.
"The incompatibility of these patient groups is a huge confounder in our field that's not well recognized," he says. What's more, the old, single-lab approaches to research likely won't survive in today's cyber-connected environment. "Increasingly, researchers from different scientific teams must work together to address their problems in a more fundamental way than any one team could do by iself," Reiman says.
"That is both the challenge and opportunity now at hand." Researchers might need to be jacks-of-all-trades, or at least forge connections with colleagues across campus. “We need computational researchers to enrich our information, but then that information needs to be transformed back into something that biologists and clinicians can comprehend," says John Csernansky of Washington University.
"It takes time and a willingness to struggle together for a common understanding." But real stumbling blocks to success in Alzheimer's disease research may lurk from sources beyond control. "It won't be from a lack of smart people, a lack of insights, a lack of new and useful things to do," says Jack. "The number one problem will be money."
Nevertheless, the field is a trendsetter of sorts, bringing together an unprecedented diversity of disciplines, data and people. Alzheimer's disease is one of the gold standards of this research trend, says Arthur Toga of University of California Los Angeles. "It's motivated lots of people to try to do science in this way. That's very exciting."
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www.alzheimer.sk.ca/english/Just4Kids/alz_disease-brainpics.shtml
Pictures of Normal and Diseased Brains
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The Alzheimer's disease brain is on the left. It’s much smaller than the normal brain (on the right) and the gaps between the folds of brain tissue are wider.
A cross-section of a normal brain and one with Alzheimer's disease. The normal brain segment is on top. Check out how much larger the ventricles of the brain are in the brain with Alzheimer's disease. The ventricles are the cavities or spaces in the brain that contain a special clear, colourless fluid (cerebrospinal fluid) which acts as a cushion to protect the brain from damage if there is a blow to the head.
The bottom three pictures show how the brain shrinks as Alzheimer's disease continues to do damage. The arrows show shrinkage in the region of the brain that stores short term memories. Some people refer to the three stages of Alzheimer's disease as early, middle, and late stage. Over time, people with the disease will have problems relating to time, place, and person. My Grammy is in the early stage of the disease and she knows that her memory is failing. She often asks, "What’s wrong with me? I get all mixed up in my thinking." Grammy needs help from us especially in planning for the future, looking after her money and paying her bills, keeping appointments, and making sure her day to day needs are met. She’ll need a lot more assistance when she’s in the middle stage of the disease. Her short term memory will become worse and it’ll be hard for her to make good decisions. She will probably need a lot more care and supervision when it comes to daily activities like eating, dressing, bathing, etc. I don’t like to think about the late stage of the disease. Mama says that there may come a time when Gram needs more care than what our family can give her. She might have to live in a special care home where there are workers to look after her needs round the clock. She might get to the point where she isn’t able to speak and has trouble swallowing or holding her head up. Grammy’s feet and hands might not work as well either and she could end up spending lots of time in bed. Her memory for us may disappear altogether. I’ll be very sad should that day come. But even if Gram doesn’t recognize me when she looks my way, I know that she still loves me in her heart and I feel the same way about her.
