Meghann McKale, Junior Committee President and
Christina Cohen, Junior Committee Vice-President interview

Dr. Lisa Mosconi

MEGHANN MCKALE (MM): We are pleased to talk to someone in our own generation. How did you become interested in Alzheimer’s?

DR. LISA MOSCONI (LM): I’ve always been interested in the brain. At sixteen I wanted to be a psychiatrist, but in college I became more interested in biology and in doing research. I come from a family of very professional scientists, both my parents are professors of nuclear physics at the University of Florence in Italy and I learned so much from them. I decided to study experimental psychology and neuroscience and became involved with brain imaging. I ended up working in the Department of Nuclear Medicine at the University of Florence, doing positron emission tomography (PET) and magnetic resonance imaging (MRI). At that time the University was one of the centers working with Alzheimer’s patients. I saw patients and worked on image analysis. It’s hard not to be affected by what you see and feel. I’ve seen and spoken to families whose lives have been severely affected by this disease. It became more and more the main focus of my work because there’s so much that’s not known yet — really shocking because Alzheimer’s was discovered in 1906. We’re in 2008 and still not capable of making a precise diagnosis.

CHRISTINA COHEN (CC): Is that when you came to New York to work with Dr. Mony de Leon?

LM: Yes. Mony is a pioneer in the early detection of Alzheimer’s. In 2001, Mony published papers on early detection of Alzheimer’s showing that it was possible to use a PET scan of glucose metabolism to predict decline from normal cognition to cognitive impairment. If you examine the metabolic rates of glucose with PET, it represents brain activity. Our working hypothesis is that reduced brain activity is a very early sign of Alzheimer’s disease. In fact, individuals at risk for Alzheimer’s have significantly reduced brain activity as compared to subjects who are not at risk.

In Italy, we were not even allowed to scan normal subjects unless there’s a medical reason. I thought maybe he would let me come over and work with him. He said yes, and we’ve been working together ever since. There are some people in my field that are like icons, and Mony is certainly one of them. He’s been a great mentor for me. Working with him and Susan De Santi, an Associate Professor at the lab, is a great privilege.

MM: What are some of your research goals?

LM: My goals are specific: early detection and prediction; accurate diagnosis; treatment and prevention. With early detection and prediction, the point is to determine who will get the disease and when. We’re working on prediction models that give probability of decline and a timeline. Two years ago, we published the first PET paper that showed we can predict in normal subjects who will develop Alzheimer’s with over 80% accuracy, at least 7 years in advance of symptoms. We can also predict who will develop another form of dementia with 80% accuracy and who will remain normal with 90% accuracy. Early identification of individuals at risk for developing Alzheimer’s may enable earlier intervention, when treatment effects are thought to be most effective, and empower people to plan for their health and future sooner.

CC: When did this research begin?

LM: Mony started scanning people 25 years ago. Most of those subjects are still in our study. When I arrived, he had followed over 90 normal subjects using PET over an average of 15 years. We decided to analyze the PET images of 77 of these longitudinally followed normal subjects who received multiple clinical evaluations, MRI and PET examinations every year for up to 14 years. Then we retrospectively divided them into groups; those who declined to Alzheimer’s, those who declined to Mild Cognitive Impairment (MCI) or another form of dementia, and those who were still normal at the end of the study. When we went back to look at the earlier PET scans we found that the scans of subjects who later on developed Alzheimer’s were different in terms of brain activity as compared to the subjects who remained normal. In particular, brain activity in the hippocampus, the memory center of the brain, was significantly reduced in the future Alzheimer’s patients when they were still cognitively normal, and this reduction was detectable several years before clinical decline.

We could see that even when all of the subjects appeared to be normal on clinical grounds, the brain activity of subjects who went on to develop Alzheimer’s was already reduced by 25%; those who developed MCI 13%; and those who developed another dementia were 15% percent reduced.

MM: Why is the metabolic rate of glucose in the hippocampus important?

LM: The brain doesn’t contain fat, relying on glucose and sugar for energy. The brain neurons are active because they burn glucose to function properly. If you burn a lot of sugar, it means that your brain is very active. Normal people who stay normal over time have a brain metabolic rate of about 40 micromoles per 100 grams per minute. The future Alzheimer’s patient, 7 years before the onset of the disease, the metabolic rates were down to 24. That’s a big difference.

CC: Does diet affect a person’s metabolic rate?

LM: It’s extremely important. Without glucose and oxygen your body shifts from an aerobic to an anaerobic metabolism. You don’t want to deprive yourself of anything that is good for your brain, and you don’t want to overindulge on sweets because that’s not good either.

MM: Is there a relationship between diet and the prevention of Alzheimer’s?

LM: Having a healthy lifestyle is extremely important for prevention. So many scientists are working together to be finally able to prevent cognitive impairment and to delay its progression in people who are mildly impaired. We are in pretty good shape to treat cognitive impairment as related to vascular problems. You know how we hear that you should take care of your cardiovascular health because that’s good for your brain? If you improve your vascular system, that’s good for the brain, but why is it good to prevent Alzheimer’s? It seems very nonspecific, but it actually makes sense. Vascular problems affect neuronal activity, and therefore create cognitive impairment. There is a vascular component in Alzheimer’s that is in part due to amyloid deposition. How do we keep brain cells healthy? We provide them with nutrients, oxygen and glucose through blood circulation. If your vascular system is impaired and you have amyloid deposits in the vessels of the brain, that slows blood flow to the brain. If blood doesn’t get there, the brain doesn’t get glucose or oxygen and neurons become sick. By improving our cardiovascular system we provide neurons with good oxygen and good sugars.

However, even though we can treat vascular risk factors (high blood pressure, high cholesterol levels, diabetes, etc), the main problem in Alzheimer’s seems to be amyloid. When amyloid is not processed effectively, it tends to form deposits in the brain, called amyloid plaques. There are toxic forms of amyloid that damage neurons. If the neurons are not healthy to begin with, they will definitely be more affected when the toxic amyloid attacks them. Furthermore, amyloid is associated with increased free radical production. These are very dangerous because they produce brain inflammation, which further damages neurons. If neurons are already vulnerable, then it’s easier for them to be affected, and they will deteriorate and then die faster.

Many people have amyloid in their brains and never develop dementia. Some people have amyloid and dementia. What distinguishes normal subjects with amyloid and the demented patients with amyloid is the number of neurons they actually lose. If you have amyloid and you lose a lot of neurons, you have Alzheimer’s pathology and you’re cognitively impaired. If you have a lot of amyloid but your neurons don’t die because they’re healthy and resistant and plastic, then you’ll never develop symptoms. So in my opinion, the thing that really makes a difference is how much pathology your neurons can tolerate before they die.

We want to understand who is at risk for future cognitive impairment and try to keep them healthy as long as possible. If an individual finds out that they are at risk for developing AD and are not taking much care of their health, that’s already a good reason to start immediately.

Another question is why focus on brain activity in Alzheimer’s? It’s hard to differentiate Alzheimer’s from other dementias on clinical examinations alone, especially in the early stages. But while other dementias have common symptoms and clinical presentation, the brains look different from Alzheimer’s. We think it’s possible to differentiate future types of dementia using PET imaging so we can say, “You are at 70% risk for Alzheimer’s, 20% for fronto-temporal dementia, 10% for vascular dementia.” That’s important for successful therapeutic interventions.

And our last goal is treatment. It’s extremely important to know what the real problem is in order to treat it. Every patient has a different brain, a different body, different needs and different neurotransmitter issues that have to be addressed separately. We’re trying to do early and accurate diagnosis, especially to plan effective therapeutic interventions. For example, if I know that there’s no amyloid in your brain, I won’t suggest you undergo a treatment to remove amyloid, for example, immunotherapy. This is important because some people who are diagnosed with possible AD might end up being immunized against amyloid, based on the assumption that they must have amyloid. However, the clinical diagnosis may be wrong. The patient may not have AD or may not have amyloid in the brain. If there is no amyloid to remove, the treatment will not be successful. It is very important to make sure there is amyloid to remove before starting an anti-amyloid therapy. PET imaging allows one to see if there is amyloid in the brain. Another example would be cholinesterase inhibitors, which work for memory problems in AD patients and hallucinations in patients with Lewy Body dementia, but they don’t work in subjects with fronto-temporal dementia (FTD), because the pathology is different. Therefore, if a patient is diagnosed as Alzheimer’s but in reality has FTD pathology, the treatment will not work and may even do damage.

Many scientists believe that amyloid is the main problem in AD. At present, there are two ways to remove amyloid from the brain. One is active immunization, which means injecting a little bit of amyloid into the patient, so the body develops antibodies against it. When real amyloid is produced, the antibody is already there, so the body gets rid of it faster. This approach turned out to be a little aggressive, and works on the assumption that your immune system works properly, which is generally not the case in Alzheimer’s patients because they’re older and they have immune system deficiencies.

The other option is passive immunization, which is gentler because you are given antibodies directly from donors. Everybody produces antibodies against amyloid, which underlies the fact that amyloid is bad for you. By donating antibodies, people get infusions, like in dialysis. These studies are still undergoing, and it will take a few years before we find out the best approach to treat Alzheimer’s.

CC: Has your work benefited from advances in technology and other research innovations?

LM: Absolutely. For example, tracers for amyloid are very new. It was unthinkable to be able to see amyloid in people who were alive until 4 years ago. And it’s not just amyloid, there are new ways of measuring neuro-inflammation that were developed just a few years ago.

MM: When new technology is developed, can you use it in existing studies?

LM: No. You have to start from scratch with the new technology.

MM: When something new comes out, who puts it to use?

LM: We certainly do! We keep adding work, which pays off, because in the end you have the largest amount of data. For example, one of our major accomplishments of the last 5 years has been to develop software to analyze brain activity in the hippocampus. I should emphasize that over the years, MRI studies and pathology studies have shown that the hippocampus is one of the very first brain regions to get damaged and affected in AD. This has been known for around 20 years, since the first CAT scan. Mony showed that the hippocampus in AD patients is very small as compared to normal subjects. It’s one of the very first regions to show substantial neuronal loss.

In the past, when we did PET scans, the hippocampus was not clearly visible and people concluded that the activity in the hippocampus was not affected in AD. But the resolution on the image was not good enough, and most importantly, people were not sampling the hippocampus correctly and therefore did not measure its activity correctly. That’s a technical issue. We were the first to show it experimentally in 2005, just 3 years ago. PET imaging in Alzheimer’s started 20 years ago. It took 17 years to publish the first paper showing that the negative findings were just due to a technical problem. We were using the wrong methods to analyze the scans. We were not precise enough. We were not in the hippocampus. So we developed a method to measure hippocampus activity precisely. Now a lot of collaborators are using our method, and most people agree that there are reductions in hippocampal activity in AD and also in MCI patients.

CC: How realistic is it for us to talk about preventing the disease, delaying the onset, and even a cure in our lifetime?

LM: It’s unbelievable how many things have changed in the 5 years that I’ve been in New York. Five years is not much, right? But everybody was sort of stuck on the amyloid cascade hypothesis, which was not consistent with the data. Now the whole thing has been totally changed, because so many people are working on it and showing that we should be going about the problem differently.

Just think about the huge number of Phase I and Phase II trials getting underway for immunization and new compounds. I would say there is definitely potential for a cure in our lifetime.

MM: Our Junior Committee members wonder whether this will happen in our parents’ lifetimes.

LM: Maybe. That may be a little too optimistic. But I don’t really know, because I don’t work in pharmaceutical development. I find it disappointing that it takes so long to plan and carry out a pharmaceutical study.

The main problem with AD is that there are so many things that are not working. It’s not just one gene that is responsible for the disease. There are several different phenotypes involved in what we call Alzheimer’s disease. There seems to be a strong genetic component. There are some early-onset forms. We know the genes that are responsible for these forms. These are very rare, probably less than 5% of the total AD population. But the majority of AD cases are sporadic and have a late onset, after age 65. We don’t really know which genes are involved in this form of AD. We know the ApoE gene and the SORL 1 gene are susceptibility genes, which increase the chances of developing AD, but they’re not the reason for getting the disease. They’re just sort of pathological chaperones. There are also late-onset cases that are transmitted from the mother, the father, the grandparents to their children and we don’t really know what genes are involved.

CC: Can we develop drugs without understanding what’s happening?

LM: No. Drugs need to be targeting a specific issue, like cholinesterase inhibitors. The problem is that in the Alzheimer’s brain there is not enough acetylcholine. These drugs stop the enzyme that is degrading the neurotransmitter. Now, if that is not the main problem, you can degrade everything you like but you’re not treating the patient. You get symptomatic benefit. Current drugs can give some relief for 6 months, 8 months, 1 year, in some people. What we really need to understand is what the real problem is. It seems to be clear that some people are more vulnerable to dementia. We need to study these people and figure out what’s happening in their bodies and in their genes that predisposes them to develop AD. We may end up developing different treatments for different subtypes of AD patients.

For example, we just published a paper showing for the first time that children of Alzheimer’s affected mothers appear to be at higher risk for developing AD as compared to children of Alzheimer’s fathers. What we found is that, if your mother has AD, there is a negative impact on the way your brain uses glucose to perform activities. It looks like there is a maternally inherited metabolic deficit. We found that children of mothers with AD showed reduced brain function as compared to subjects with the father affected and those with no parent affected. The metabolic deficits were located in the same brain regions that are typically affected in clinical AD patients, and that are responsible for memory, attention, and language. Over time, the metabolic reductions worsened in the subjects with maternal AD. We found that individuals with an Alzheimer’s affected mother lost metabolism in their brains almost 6 times faster than the rest of the subjects. These results are published in two papers, one in the Proceedings of National Academy of Sciences USA (2007) and one in Neurology (2008).

Our findings show that children of Alzheimer’s mothers may have an oxidative stress problem, as reflected in the brain metabolic reductions. So maybe giving them antioxidants will work for them. But antioxidant trials did not succeed in AD patients. The point is, why would we expect a person with no oxidative damage to benefit from antioxidants? First we have to make sure that their brains are under oxidative stress, and then treat it. The therapeutic interventions have to target the real problem.

The reason we’re so excited about the finding that having an Alzheimer’s mother confers more brain risk than having an Alzheimer’s father is that it gives some direction toward the genes that are involved. The place in the body where glucose is metabolized is the mitochondria, little structures that are within cells. The peculiar thing about mitochondria is that they have their own DNA. When we think about DNA we usually think about chromosomes. We have 23 pair. We get half from our mother, half from our father. But mitochondrial DNA comes completely from your mother and is responsible for glucose metabolism. Put those two ideas together and you can guess that it’s probably a mitochondrial DNA related deficit.

The good thing about mitochondria DNA is that it’s very small. So looking for genes is a lot easier than in the whole genome. There are only 37 possible spots vs. more than 10,000. One star compared to the galaxy. Much easier to work with! Of course, we may find that this is not the case, and that other genes are involved. There is a lot of work to do and so much to understand. We are also trying to link what we saw on PET scans with something that we can measure in blood. I just received a grant from the NIH to do that. We want to see if metabolic deficits in the brain are related to metabolic deficits in the rest of the body. This means it’s a systemic disorder — inherited, genetic. If it’s systemic, you have it all over your body, and you may really have gotten it entirely from your mother’s genes.

CC: We’re struck by how you and your colleagues maintain an optimistic view of the future in the face of decades of not finding the answer.

LM: The reason we’re optimistic is because we’re good at what we’re doing. Smart people work in this field. The papers that are produced and the way people go about the work is extremely creative. And it’s impressive how fast things are developing. There’s a lot of competition, so you really have to be good at what you’re doing. You’re here, you struggle and you become better every day. You have to feel confident that you can help. I feel a lot of responsibility and it is very important to me that I do my job well. We’re doing the best we can.

MM: Lisa, thank you so much for enlightening us in ways that we didn’t know we needed to be enlightened!

LM: My pleasure!

Lisa Mosconi is a research assistant professor of Psychiatry at the Center for Brain Health at New York University School of Medicine. Specifically, Dr. Mosconi’s research is focused on the early diagnosis and development of therapies for patients with Alzheimer’s disease as well as in individuals at risk for developing dementia. Major research interests include positron emission tomography (PET) and magnetic resonance imaging (MRI) in early Alzheimer’s disease. Dr. Mosconi uses PET imaging to study brain glucose metabolism in normal aging and Alzheimer’s disease brains, as well as brain amyloid deposition, neuroinflammation, and neuroreceptor abnormalities in patients with early Alzheimer’s disease.

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