Every 67 seconds, someone in the United States develops Alzheimer's disease. Scientists aren't sure what causes it, but there's growing evidence that cognitive problems are linked to the development of brain plaques, abnormal buildups of protein. Now, new research indicates that a commonly used antidepressant may reduce production of Alzheimer's brain plaques.
Claire Anderson is an avid photographer. She focuses on nature, and portraits.
"There is that beauty of the face," Clair Anderson told Ivanhoe, "It is lovely to capture."
With three kids and nine grandchildren, Claire has plenty of potential subjects. Faces she hopes time doesn't erase.
"My parents both had the diagnosis of Alzheimer's," said Anderson.
Now, Claire is also showing early signs of the disease.
Anderson explained, "I wanted to see that something could be found that could alter that."
Researchers looking at the protein build-up in the Alzheimer's brain have discovered a commonly prescribed drug may make an impact.
"We know that people with a history of antidepressant use have less plaque in the brain than people who don't have a history of antidepressant use," explained John Cirrito, Ph.D., Assistant Professor of Neurology specializing in Alzheimer's disease at Washington University, St. Louis.
In the recent study, researchers gave a single dose of the antidepressant Citalopram to 23 adults under age 50. Samples of spinal fluids over the next 24 hours showed a 37% drop in the protein that forms brain plaques.
"This is promising," said Dr. Cirrito, "but it's early."
Claire knows that a cure for Alzheimer's may not come quickly, but it's crucial to her nonetheless.
"I can be optimistic that my grandchildren will benefit from these studies," Anderson said.
Cirrito says while most patients tolerate antidepressants well, the risks outweigh the benefits of using the drugs until a strong connection is established. He says that will take additional research. Researchers plan to study older adults and treat them for two weeks with the antidepressants to see if there is continued reduction in the proteins that cause brain plaque.
Contributors to this news report include: Cyndy McGrath, Supervising Producer/Field Producer; Kim Coley, News Assistant; Jamie Koczan, Videographer/Editor.
ANTIDEPRESSANTS: Antidepressants are used to normalize the primary neurotransmitters that are involved in regulating a person's mood: serotonin, norepinephrine, and dopamine. Each classification of antidepressants affects different neurotransmitters in different ways. Monoamine Oxidase Inhibitors (MAOI's) block monoamine oxidase, which breaks down neurotransmitters. By doing so, neurotransmitters remain active in the brain. Selective Serotonin Reuptake Inhibitors (SSRI's) are one of the most common types of antidepressants prescribed. SSRIs increase the serotonin in the brain.
(Source: http://www.fda.gov/forconsumers/consumerupdates/ucm095980.htm)
CURRENT ALZHEIMER'S TREATMENT: There are four main drugs approved by the FDA to prescribe to Alzheimer's patients. Three of them are cholinesterase inhibitors, which bind to cholinesterase resulting in increased acetylcholine in the synapses, causing increased parasympathetic activity. These four drugs mainly focus on helping the patient to maintain certain skills, such as thinking, speaking, and memory. Currently, none of these drugs are guaranteed to help every patient, but a patient may respond better to one drug over the others.
(Source: http://www.nia.nih.gov/alzheimers/topics/treatment)
ALZHEIMER'S AND ANTIDEPRESSANTS: Your risk of Alzheimer's doubles every five years after age 65. Two proteins involved in the disease's progression are amyloid beta and tau. Both types of protein build- ups are bad because they cause cell damage and cell death, causing the symptoms of Alzheimer's. Amyloid beta (a-beta) peptide accumulation in the brain is believed to be the primary cause of Alzheimer's disease. When a-beta concentrations are high, more plaques form. In an experimental study by John Cirrito, Ph.D. of the Department of Neurology at Washington University School of Medicine, St. Louis conducted an experimental study to see if a-beta levels can be lowered, similar to earlier results in mice. Cirrito told Ivanhoe, "We've found that a single dose of SSRI, both in mice and people can lower a-beta levels by 20% over the course of a day." Based on the mouse model, lowering a-beta even by that percentage, can block plaque growth. Although Cirrito says it is still too early to take SSRI's to treat Alzheimer's, he says the research is compelling enough to study on a larger scale.
(Source: https://hopecenter.wustl.edu/?faculty=john-cirrito-phd)
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John Cirrito, Ph.D., Assistant Professor of Neurology specializing in Alzheimer's disease at Washington University, St. Louis, discusses the effect of using antidepressants to treat Alzheimer's.
Interview conducted by Ivanhoe Broadcast News in September 2014.
By now most people have heard of Alzheimer's disease, and they know it's linked to dementia and cognitive deficit. Describe a little bit about Alzheimer's disease? What essentially are people doing about it?
J. Cirrito: It is an older person's disease and particularly people over age of 65 get it. Your risks of Alzheimer's doubles every five years after age 65. It's a problem with memory and cognitive function. It's generally the things that people think about when you think of Alzheimer's. That people have a hard time remembering things and it's gradual. It will start out forgetting keys, forgetting very basic things and it progresses so that in the late stages, forget who people are, they forget who they are and it's a progressive disease it takes 10 the 20 years in some cases to run its course.
Do we know what causes Alzheimer's at this point?
J. Cirrito: We know proteins that are involved in Alzheimer's disease. There are two, amyloid beta and Tau. Amyloid beta or A-beta, builds up in plaques in the brain I think it's why we believe that's the precipitating event that causes Alzheimer's disease. And that initiates Tau aggregation, this other protein Tau that aggregates as tangles. Both are incredibly bad in Alzheimer's disease. They both cause cell dysfunction, they cause cell death and both of those things then cause the symptoms of the disease.
Now your research centers on those amyloid plaques?
J. Cirrito: Correct.
Tell me a little bit about your latest research.
J. Cirrito: We're interested in what regulates this amyloid beta peptide. Why is it made, how is it made, how is it cleared from the brain; the idea that the plaques form when A-beta concentrations get high. If you keep A-beta concentrations low the goal is you can either stop or prevent these plaques from forming at all. What our lab has been studying for the last seven years is how brain activity, just the cells of the brain being active, causes this protein to be formed. We've done a lot of research around how that works, what are the cellular processes that do to regulate that. What we've looked at most recently is how serotonin, a neurotransmitter in the brain, regulates amyloid beta.
In terms of the most recent study in both mouse models and in humans, antidepressants?
J. Cirrito: We use antidepressants, selective serotonin reuptake inhibitors. What they do is they increase the levels of this molecule called serotonin; this neurotransmitter. By doing that we found you can lower Amyloid beta levels both in mice and in people. How SSRI's work is they prevent the serotonin that's normally in your brain from being degraded. By taking them you increase serotonin levels in brain. It's been used for depression for years.
Tell me a little bit about testing this in people; is that a second phase clinical trial?
J. Cirrito: I wouldn't consider it a clinical trial; it's an experimental study at this point. To see can we lower A-beta levels in people very similar to what we've done in mice.
What have you found?
J. Cirrito: We found that a single dose of an SSRI both in mice and in people can lower brain A-beta levels by about 20 to 25 percent over of the course of a day. And we've done that in young mice and in old mice, these are mouse models of Alzheimer's disease. We give mice the amyloid beta protein that the humans have, mice don't usually don't get Alzheimer's disease; we give it to them which seems a little mean. But they get plaques in their brain that are very similar to what you would find in Alzheimer's disease. They are not perfect models because they don't get cell death but they're very good at modeling what happens to amyloid beta in many instances.
In the humans that have tested this you said in one day it decreases by twenty percent?
J. Cirrito: Yes in their cerebral spinal fluid (CSF).
What periods of time are you testing it over? Is it just one day?
J. Cirrito: So far in humans it's been a one day of measurement. What we did is we actually admitted people in to the hospital. We put a catheter in their lower back so we could take cerebral spinal fluid every hour for 24 to 36 hours. And then we gave people one dose of an SSRI, it's citalopram in this case, and then started measuring A-beta levels in the CSF every hour starting eight hours after that first dose of that drug.
When you find that kind of a reduction what does that imply, what does that say to you?
J. Cirrito: In people we don't know yet. We know that in mice if you lower A-beta levels even by twenty percent you can completely block plaque growth, and you can lower plaques in mice. Whether the same thing happens in people or not, we don't know. We know that people with a history of antidepressant use have less plaque in their brain than people that haven't had a history of antidepressant use. This is a study that Yvette Sheline did when she was here; she's recently moved to the University of Pennsylvania. She was in the Department of Psychiatry and she was studying people with depression with the hypothesis that people that were depressed would have more plaques in their brain because they're stressed and there's a lot of things that they would have that could increase risk of Alzheimer's disease. She found the complete opposite; that people that were depressed actually had less plaques in the brain. And it turns out the link wasn't if they were depressed or not, it is if they had been treated with antidepressants they had less plaque in the brain, not if they were depressed.
This sounds like it's just the tip of the iceberg. What are the implications?
J. Cirrito: The study we've done in people so far was in young people, these are people between 20 to 50 years old, people that are not at risk of Alzheimer's disease yet and we can lower cerebral spinal fluid A-beta levels. What we don't know is what happens to people that are at risk of Alzheimer's disease, people that are 65 or older. That's the study we're doing now.
What are the implications from this finding?
J. Cirrito: We wanted to show in people that we can lower amyloid beta levels with the SSRI's but in young people we know if we can do that, we don't know if we can do that in older individuals yet and that's the people that really matter. We're not going to give people that are in their 20s to 40s an SSRI to treat Alzheimer's disease so it would be people that are hopefully right before they get disease, the disease symptoms, but they're going to be in their 50s or early 60s or even older than that. That's the next step. The implication would be if we want to lower A-beta levels here's a series of drugs that are clinically reasonable and safe. There are side effects of SSRI's but there are millions of people on these that are reasonably well tolerated, that there's a drug that could lower A-beta levels twenty percent and potentially lower plaque load.
What kind of the time frame would you be able to test that at the next level? Or tested in older people had a longer period of time?
J. Cirrito: We started the study already, to test older people with a one month treatment of an SSRI and see if we could affect amyloid beta levels. What we haven't done is study if it will actually affect clinical symptoms or not. That's really what people care about. People with Alzheimer's don't really care much if they have plaques in their brain; they care if they can remember things. The first step is to show that in people that are at risk of disease we can affect A-beta levels and then use that to then to compel a bigger study which will be years; it will take years and millions of dollars to do to see if it even affects symptoms or not.
If the amyloid is high then that's a good indication or a good predictor of Alzheimer's and if you bring it down then you lower your risk?
J. Cirrito: We think that if levels are high it's more likely to aggregate, and more likely to form these plaques. It turns out that people that have Alzheimer's disease that have plaques in the brain, their A-Beta levels actually go down. That's because it's going into the plaques. But right before the plaques form the levels are likely high.
But the link has been pretty well established?
J. Cirrito: Pretty well established.
Not a hundred percent?
J. Cirrito: Nothing is ever a hundred percent in this field.
How important is a finding like this in terms of what you do?
J. Cirrito: A finding like this? The whole field is working towards finding a way to prevent Alzheimer's disease. And are potentially a lot of drugs that are trying to do this. Secretase inhibitors, antibodies or immunization against A-beta are things that are being tested and clinical trials now to impacts disease. I think those are very promising, they're targeting A-beta and I think there's a variety of different ways and they're all drugs that so far are untested. They're being tested in people but there are going to be side effects and we don't know exactly what those are going to be yet. SSRI's are a tested class of drugs that have promising ability to lower A-beta levels. There's a lot of work to do now. I think it's premature to start taking SSRI's to treat Alzheimer's. We have a lot to still do to understand whether they could be effective. We're hopeful at this point but we don't know yet.
In the study how many people did you test it in, and which antidepressant was it?
J. Cirrito: We used the SSRI brand, its Celexa made by Forest Labs. It was 10 to 12 people per group that got the drug and then 10 to 12 that got the vehicle or placebo. Which seems like a small number of people for a study like this, our advantage is that we measured A-beta over time between them. We were able to reduce numbers we needed to see what we wanted to see.
In the study that's ongoing right now in the older set of people, can you tell me a little bit about that?
J. Cirrito: The set we just published was giving a single dose of citalopram and measuring over the course of a day cerebral spinal fluid A-beta levels. This study was getting a single dose for 30 days, 28 days and they had taken CSF beforehand and then the CSF at the end to see if A-beta levels changed or not.
Do you have any findings back on that?
J. Cirrito: No, it's just a few weeks old. And that's taking place both here and at University of Pennsylvania.
Is there anything I didn't ask you about the current research that you're doing that you think people need to know?
J. Cirrito: In humans we've tested one SSRI, in mice we've tested six. They all lowered A-beta levels by a similar amount so we don't see a big difference between them so far. They all seem to be effective. I guess the one thing that I would try to stress in all these that people shouldn't start taking SSRIs immediately. That there's a lot of work to do, this is promising it's early; I would say it's premature to start taking SSRIs for Alzheimer's.
Do you think there are people with the disease and families that are looking desperately at this point for something?
J. Cirrito: I think desperate is a good word for this. I think people with disease that are earlier than late really want to find a cure, something that can help and rightfully so, this is a terrible disease in a lot of ways. So I don't blame them at all for that, but we're not quite ready to use this as a treatment.
Are you optimistic that you will get there? And if you had to give a time frame are you able to?
J. Cirrito: I'm not even going to guess on time frame. I'd say very optimistic, I'm a little biased but I'm very optimistic.
I did have one other question about the adult/children's study. Can you tell me a little bit about that study, when it ran how many people were involved?
J. Cirrito: The adult studies are ongoing; it's been going on for I think ten years. It's been going on for a very long time and the idea is it will go on for many more years. It's taking parents that either had Alzheimer's disease or did not have Alzheimer's disease and then monitoring their children from before they had symptoms to when they develop symptoms. Because Alzheimer's disease takes place over such a long period you want to know what's going on in the brain and for the behavior, for their proteins, what's going on in their plaques before symptoms and after symptoms. You monitor these people every year in most cases, some have been going on for ten years, and it will hopefully continue going on to understand how the disease changes over time. A single snapshot in time doesn't tell us nearly as much.
The whole spectrum.
J. Cirrito: You want to see the whole spectrum. And the power of the totality of the study is you can get that whole spectrum, in a lot cases, in one person. You can see how each person is changing.
Do you find that you don't have any trouble enrolling participants? Do you find people are really anxious to help or to fund a cure or something that will help them or the next generation?
J. Cirrito: Some people are more anxious than others is my impression. Some people want to help, some people are desperate and want to know they're doing something about this, and some people don't want to think about it; all are respectable.
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