The Tangled Neuron

Calcium Channel Blockers and Alzheimer's

Every day, in Alzheimer’s labs and clinics around the world, researchers conduct target practice. One of their targets is beta amyloid, the sticky protein many scientists think causes Alzheimer’s. This target practice is somewhat of a trial and error process, involving educated guesses about which weapons might work against beta amyloid and other substances and conditions implicated in Alzheimer’s.

One such target practice is directed from the Roskamp Institute, only thirty miles south of where I live. Working with the Trinity College Institute of Neuroscience in Dublin, Ireland, Dr. Michael Mullan and his colleagues are conducting a clinical trial of the calcium channel blocker Nilvadipine to see whether it reduces beta amyloid and improves memory in Alzheimer’s patients.

Calcium channel blockers are drugs used to treat high blood pressure and other diseases. Some studies have shown that these medications might be useful in preventing or treating dementia. A follow-up to the Systolic Hypertension in Europe trial showed that for people with high blood pressure, long term use of a calcium channel blocker may cut the risk of developing dementia by 55%. This makes sense, because scientists have observed toxic levels of calcium in Alzheimer’s brains. “Calcium overload in cells is lethal, says Dr. Mullan, “and this is the final pathway by which cells may die in Alzheimer’s.”

It’s not clear whether calcium channel blockers as a group help preserve memory. Results from the Canadian Study of Health and Aging showed that people taking these drugs were more likely to suffer from cognitive decline. Another study concluded that patients taking blood pressure medicines, including calcium channel blockers, performed worse on cognitive tests than did those taking other drugs. The conflicting results of these studies might be because each drug in this class has different effects.

The fact that Nilvadipine is a calcium channel blocker may be irrelevant anyway. “Nilvadipine's anti-amyloid effects do not seem to be due to the calcium channel blocking of drugs,” says Dr. Mullan. It’s not clear how Nilvadipine might reduce amyloid in Alzheimer’s brains, but it may be related to increased blood flow.

“This drug increases cerebral blood flow in rodents and humans, and we wonder whether there is a link between the two,” Dr. Mullan says. “It could be that there is increased clearance of amyloid from the brain due to increased blood flow. If that is the case, we don't know what the mechanism would be. However, the most likely reason that we see reduced amyloid in the brains of mice is that Nilvadipine directly reduces amyloid production. We've seen this effect in a number of cell types.”

The trial of Nilvadipine in 150 people diagnosed with mild to moderate Alzheimer’s is being carried out in Ireland, where the drug is available by prescription [it’s not currently approved for use in the US]. Doctors will measure the level of amyloid in these patients’ blood. If the levels of amyloid are higher in the blood of patients taking Nilvadipine compared with those not taking the drug, this may mean that it is clearing amyloid from the brain. Doctors will also monitor any changes in blood flow in the brains of trial participants, as well as blood pressure and performance on cognitive tests.

In the US, the Roskamp Institute is also looking for volunteers who have been diagnosed with Alzheimer’s. These volunteers won’t receive any medication, but will give blood to provide data to be used in the trial.

When my father had mild dementia, I wondered whether increased blood flow to his brain would help his memory. I asked Dr. Mullan if Dad would have been eligible for this trial, given that his pulse rate and blood pressure were low, not high. “It's possible (although there are many alternative reasons why your father may have had his cardiovascular signs) that increasing cerebral blood flow would have been beneficial. However, the blood pressure lowering effect of Nilvadipine would probably have precluded him from the study,” he says.

Dad also had cerebral amyloid angiopathy (CAA), and it’s not clear how Nilvadipine and other drugs thought to reduce amyloid would affect CAA patients. In CAA, beta amyloid similar to that in Alzheimer’s plaques is deposited on the walls of the blood vessels in the brain. The protein deposits cause the vessel walls to crack, allowing blood to leak out. Every hemorrhage, large or small, damages brain cells and can cause dementia as well as major hemorrhagic strokes like the one Dad had. “The vessel walls are weakened by amyloid and removing it (depending on how it is removed) might weaken them further,” says Dr. Mullan. “This is a very difficult area to predict, and clinically we will see when we have potent anti-amyloid drugs.”

Memory Pharmaceuticals is testing a similar drug called Mem 1003, and this trial is currently recruiting patients in the US. The company hasn’t responded to my request for information. [11/01/06 Note: Memory Pharmaceuticals says that Mem 1003 works by modulating the amount of calcium that enters neurons in the brain. This seems to be a different mechanism for treating dementia than the potential anti-amyloid action of Nilvadipine.]

It’s too late for my father, but I hope all this target practice means that multiple treatments for Alzheimer’s and dementia will be ready in time to help others who have dementia now. With its established safety record, Nilvadipine could be available fairly quickly. But first it must be proven effective in this study and in future trials.

Grand Rounds 3.5

Grand Rounds 3.5 is up at the Health Care Law Blog. Bob Coffield has added some thoughts about health care social networking sites to the usual rich selection of health-related posts.

Trial of Alzheimer's Drug Halted

The Raleigh (North Carolina) News & Observer is reporting that Voyager Pharmaceutical Corporation has put its trial of Memryte (leuprolide acetate) on hold because of “clinical and financial issues.” The trial was based on the hypothesis that midlife changes in reproductive hormones (in this case luteinizing hormone) are an underlying cause of Alzheimer’s. According to the article, the company hopes to find more funding and restart trials in eighteen months.

Looks like we’ll have to rely on other trials and studies to find out more about the relationship between reproductive hormones and Alzheimer’s…

Some Thoughts From A Person With Dementia

One of my goals for this blog is to help dementia patients, caregivers and concerned laypersons participate in and contribute to dementia research and treatment. DASN International (Dementia Support and Advocacy Network) is an organization working towards that goal. One of their members, Richard Taylor, gave a talk at the Alzheimer’s Disease International conference held in Berlin last week.

Richard Taylor, Ph.D.

A retired psychologist, Richard was diagnosed three years ago with dementia. As part of his advocacy work, he’s written a book called Alzheimer's from the Inside Out. With his permission, I’ve posted portions of the talk he gave at last week’s conference here:

Guten Tag

My name is Richard Taylor. Four years ago my daughter leaned over the back seat of our car and whispered to my wife, “there is something wrong with Dad.” One year later we all found out what that something was: I have dementia, probably of the Alzheimer’s type.

Since then I have become an advocate for the rights and responsibilities of people with dementia. Being a former psychologist I think about thinking a lot. Probably too much. I have developed my own views of Alzheimer’s from the Inside Out.

I don’t drive any more. I don’t handle the family finances any more. I go out only when someone will take me with them. I feel as if I am turning invisible quicker than my mind is turning away from me.

I would like to briefly speak to you today on what has happened and is happening with my communication with my family. How it has changed. How I think it changes in most of us who are living with Dr. Alzheimer’s and his stick footed supporters living between our respective ears. And finally what I would do different if I could, what you might consider doing different instead of simply trying harder.

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How does it happen? What did I miss? Why can’t we talk? Why can’t we resolve our differences, solve our problems: like we did before Dr. Alzheimer invited himself into my brain?

Couples invest themselves in each other. They trust each other with their feelings, their vulnerabilities, their fears, their secrets, their dreams….

Enter Dr. Alzheimer. “You are going to die. You are going to die sooner than either of you expected. You are going to become unpredictable, different, some one who will be different from the person you are now. You might even become violent. You will probably not recognize those you presently know and love.” announces the Doctor as the diagnosis is pronounced.

“Oh, oh. What have I gotten myself and you into?” ponder both of us. “Can I take care of you? Who will take care of me? Can we afford you? Can we afford me? Who will be my best friend? Will I ever have a best friend again? Who will listen to me when I am upset, angry, and afraid? Who will listen to me drone on and on about God knows what? Who will hold me as only you do? Who will ever want to make love to me again?” The questions pop up to our level of awareness only to quickly sink back down into a cave (somewhere between our respective ears) full of the fears for each other and ourselves.

Deep into the night, these fears morph into nightmares. In the bright light of day, these fears transform even simple conversations into arguments that in the end have little to do with where the conversation started or ended.

“I can’t trust you any more; you are leaving me emotionally naked, emotionally stranded. I can’t trust you any more, you are leaving me,” we say to each other, but never using these brutally accurate words.

“You have already changed. You have already changed.” we whisper to ourselves about the other one.

“I can never trust you; the disease has caused you to break your promise to me to take care of me forever. I can never trust you, and the disease and/or I have caused me to become untrustworthy. I know that and cannot seem to do anything about it in your eyes. You are still the person I love, and I so strongly (desperately) want that to be so forever or at least for as long as humanly possible.”

Who helps couples deal with these issues? Who spends the time with couples exploring their emotional entanglements? The sticky clumps of fear for ourselves, each other, and the future take up just as much room in our brains as do clumps of sticky dead cells. The only difference being one can be seen with a million dollar scanner and the other can only be felt through a human heart.

How can we and others improve our communication, given this fine mess, we and Dr. Alzheimer have created for each of us and both of us?

Surprise, surprise. I have no easy or simple answers. I am a participant and not an observer in the interpersonal quagmire created by the disease. I and my spouse are not alone. There are at least one million couples in the United States in the same stage and in the same boat as my spouse and I. There are millions and millions more around the world, many I am sure from each of your countries. We pretty much hid our fears from each other at the start. We pretty much convinced our selves there were no fears to hide at the start.

I am frankly suspicious of others who say the diagnosis has no current impact on them. Who can hear the words “you have dementia, probably of the Alzheimer’s type,” then turn around, and resume their lives as before. In my view, they are standing in their own self-constructed invisible closet, and will stay there until the odor of their disorder cannot be ignored.

We were wrong, and so are most of the other couples and even families I have spoken with who are confronted with the disease. We became silent partners, a silent family. “We can talk about it when we need to” we said to ourselves and each other.”

Professionals, especially physicians do not seem to want consider our presenting problem, we hurt emotionally. Our fears are consuming us. There is no pill of it. Counselors pass us off to each other because they claim they are “unfamiliar with the disease.”

Can’t we have a conference about us, with us, for us? About the real problems we all face from the day we hear the diagnosis. It’s great to talk about proteins, and nude mice, and pills and profits, but what about us: those of us living with the disease. Must you always squeeze us together in a program with no time to explore our issues. We have real problems, real to us. Problems which others could help us solve if they would take the time to understand each of us.

We are worth your time and effort to understand how the disease affects our emotions, our feelings. We need your help to develop better communication models that change as the disease changes our family dynamics and us. Do not give up on my mental health simply because eventually I will end up mute and bent over in a wheel chair, waiting to die.

Psychosocial research does not have the glitz or profit of pure research, but it sure is need. It will be needed more next year than this year, and so on and so on.

I better understand what has happened as a result of writing this presentation. Thus far, I am no better at changing it.

Help, Please. Help 500,000 souls in the U.S.A. and millions and millions of us around the world.

[Note: the 500,000 people Richard talks about are Americans with early onset dementia. There are an estimated 4.5 million Americans with Alzheimer's disease, and an estimated 24 million worldwide. Mona]

Should You Be Tested For Memory Problems?

When Dad started having trouble finding words, he went to see his family physician. The doctor dismissed his concerns. “I’d know it if you had problems,” he said. He was wrong about Dad, and studies published this year show he may have been wrong in general.

In the May issue of Archives of Neurology, Mayo Clinic researchers published the results of their analysis of the brains of 15 people who had died while they had a diagnosis of Mild Cognitive Impairment. The researchers compared the brains to those of 28 people who had had no memory problems and 23 who had been diagnosed with probable Alzheimer’s disease. The level of pathologies in the brains of the people with Mild Cognitive Impairment was in between that of patients diagnosed with probable Alzheimer’s disease and that of those with no memory problems. The study authors concluded that their findings suggest Mild Cognitive Impairment is “a transitional state of evolving AD [Alzheimer’s disease].”

In the September issue of Neurology, scientists at Dartmouth Medical School in Hanover, New Hampshire wrote about their study of brain volume in patients diagnosed with Mild Cognitive Impairment. They performed MRI scans on the brains of 40 people who had normal scores on neuropsychological tests, but complained about memory problems. The researchers compared these scans to those of two other groups: 40 people diagnosed with Mild Cognitive Impairment and 40 healthy volunteers with no memory complaints. In the group with normal test performances but memory complaints, the decrease in gray matter volume was similar to that in those diagnosed with Mild Cognitive Impairment. The greater the memory problems reported by participants, the more volume had been lost.
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The idea that abnormal brain degeneration starts long before people have clinical signs of dementia isn’t really new. Scientists at Vrije Universiteit in Amsterdam had previously found that brain volume in people diagnosed with Mild Cognitive Impairment seemed to be at an intermediate stage between that of healthy volunteers and those diagnosed with Alzheimer’s.

If my father’s doctor had ordered an MRI when Dad first mentioned memory problems, the scan might have shown signs of atrophy. But what good would that have done? There’s no drug to stop the progression of either Alzheimer’s or the cerebral amyloid angiopathy (CAA) Dad had. There’s not even agreement about what should be included in the criteria for diagnosis of Mild Cognitive Impairment.

This lack of understanding is exactly why I think you should be tested if your memory isn’t what it used to be. Whether or not your test results show a problem, you might be able to contribute to Alzheimer’s and dementia research. Try to have your testing done at a memory clinic, university or an Alzheimer’s Disease Research Center that will use your results in studies.

Especially if you’re in the US, don’t forget to ask how much you will be charged for any testing. You might be able to find programs you can participate in at no cost. We sent Dad’s MRI scans, other medical records and brain tissue to Dr. Steven Greenberg to get a second opinion on autopsy results and to try to help with his research on CAA and Alzheimer’s. This summer, I went through the testing for the Wisconsin Registry for Alzheimer’s Prevention. There was no charge for participating in either of these research efforts.

Someday doctors will be able to accurately diagnose and treat degeneration of the brain. Until then, participating in research programs is one way we can help.

Can Insulin-Degrading Enzyme Drain Beta Amyloid From Alzheimer's Brains?

Our roads flood all the time here in Tampa Bay. We’re close to sea level. When it rains, there’s just no place for the water to go, especially at high tide. Storm drains back up, the water level rises, cars stall and traffic stops. The problem isn’t just too much rain, it’s also too little drainage.

Some Alzheimer’s researchers think the same thing may be happening in the brains of people with dementia. According to this theory, the problem isn’t really just too much production of beta amyloid [the sticky protein that forms plaques and is thought to cause Alzheimer’s], it’s also too little “drainage” of that beta amyloid.

Most of the efforts to find a cure for Alzheimer’s have focused on preventing the over-production of beta amyloid. But over the last few years, some scientists have been exploring the idea that in Alzheimer’s brains, the balance between production and elimination of this protein has gone awry.

One of the researchers working to find treatments based on this “drainage” theory is Dr. Malcolm Leissring at The Scripps Research Institute. He is testing various proteases’ [enzymes that break down proteins] ability to destroy beta amyloid and unplug the drain. Much of his research is focused on one specific protease: Insulin-Degrading Enzyme (IDE).

Malcolm Leissring, Ph.D.

Insulin-Degrading Enzyme

“I am interested in all beta amyloid degrading proteases, but IDE is particularly attractive for a lot of reasons,” Dr. Leissring says. “It is one of the few to be linked genetically to Alzheimer’s disease. It appears to be the main protease involved in the degradation of (extracellular) beta amyloid in neurons, because when you delete IDE from cells, you also reduce the amount of beta amyloid degradation by over ninety percent. And there are a lot of tantalizing and unanswered questions about IDE, such as how it gets secreted from cells, which makes it very attractive for research.”

His research fits well with that of other scientists who have found that IDE levels are low in the hippocampus of the brains of people who have been diagnosed with Mild Cognitive Impairment, and even lower in those diagnosed with Alzheimer’s. Low levels of IDE are associated with high levels of beta amyloid.

Progress So Far

Dr. Leissring and his colleagues have shown that mice bred to have increased IDE (or another protease called neprilysin) have reduced levels of beta amyloid in their brains. The increased level of IDE appeared to slow plaque formation in the brains of these mice.

Focusing on the proteases that might increase beta amyloid drainage gives researchers a lot of new possible therapies to prevent dementia. “I don’t think we are anywhere near [human] trials involving IDE,” Dr. Leissring says, “ but there are some exciting results coming out.” One encouraging finding is that increasing the levels of IDE or other proteases (and thereby reducing beta amyloid levels in the brain) might be done via the bloodstream. This could be much safer than attempting to administer a therapy directly to the brain.

Raising levels of IDE will probably not involve adding the enzyme itself to the bloodstream or the brain. According to Dr. Leissring, logistical problems with purifying IDE make it more probable that potential treatments will take a slightly different approach. “All cells make IDE,” he says, “and we can engineer bacteria or other cells to produce it. So it’s easy to produce, but not so easy to purify. I don’t think it will ever be produced on a scale for use in humans. More likely, a drug will be found that affects IDE or influences its expression levels within cells.”

The Insulin Connection

The promise of IDE-related therapies seems to contradict studies that show increasing insulin levels may improve memory for some Alzheimer’s patients. IDE degrades insulin as well as beta amyloid, so increasing IDE levels would be expected to lower insulin levels.

While increasing insulin levels may help some patients in the short term, Dr. Leissring points out that “accumulating evidence suggests that chronically high levels of insulin are not good, neither for diabetes nor for AD. There is a growing body of evidence that suggests that chronically high levels of insulin cause the body to become desensitized to the hormone’s effects---which is exactly what Type 2 diabetes is.”

”Based on our understanding of the causes of Alzheimer’s disease, and the role of IDE in degrading beta amyloid,” he says, “increasing insulin levels would be predicted to increase beta amyloid levels. We actually know that this is true from human studies. But insulin is a potent hormone that has myriad effects on cells, and it just might work for some other reason.”

Some diabetes drugs work to increase insulin sensitivity, rather than raising insulin levels. Researchers at the University of Washington are studying whether these drugs can improve memory in patients diagnosed with Mild Cognitive Impairment.

So, Dr. Leissring thinks simply increasing insulin may not help Alzheimer’s patients. “The approach of using insulin enhancers, on the other hand, seems sound, and there is emerging evidence from animal studies that it might work,” he says.

The Cerebral Amyloid Angiopathy Challenge

Cerebral amyloid angiopathy (CAA) seems to have been the main cause of my father’s dementia and death. In people with CAA, beta amyloid similar to that in Alzheimer’s plaques is deposited on the walls of the blood vessels in the brain. The protein causes the vessel walls to crack, allowing blood to leak out. Every hemorrhage, large or small, damages brain cells and can cause dementia and major hemorrhagic strokes like the one Dad had.

Unfortunately, some therapies that decrease the beta amyloid in Alzheimer’s plaques seem to increase the beta amyloid deposits on blood vessels. In theory, Dr. Leissring says, increasing the elimination of beta amyloid would be predicted to prevent both Alzheimer’s and CAA. But in some studies, attempts to dissolve beta amyloid via vaccination have increased CAA and hemorrhages in animals.

A large percentage of Alzheimer’s patients also have CAA. For them, using drugs designed to dissolve amyloid may be risky. “I think we can definitely hope for a preventative treatment for CAA, but the chances of a cure are less certain and will require much more study,” he says.

The Funding Challenge

Dr. Leissring reports that his research is currently funded by “start-up” money from Scripps Florida, funds from the National Institute on Aging (NIA), and a grant from the Ellison Medical Foundation. But even with this funding, he says he’s only been able to start ten percent of his planned projects.

“We are living in an incredible age, where we can do things in a day that would have taken many months just a few short years ago,” he says. “But it really does simply boil down to money (and lab space, ultimately). The more money, the more scientists we can hire and the more experiments can get done.”

Other Alzheimer’s researchers are experiencing the same problems - government and large organization funding seems totally inadequate. It may be that the only way to fill the gap is with private donations. The McNally family, whose father Richard died of Alzheimer’s six weeks after my dad’s death, has started a non-profit fund to support the research of Dr. Leissring and his colleagues. If you’d like to help, please go to The Unforgettable Fund, read the McNally family’s blog, and click on How to Donate.

Change of Shift

Change of Shift is up at Emergiblog - this carnival gets bigger and better with each edition!