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 Your highly cited research focuses on early diagnosis and the mild cognitive impairment stage of Alzheimer's disease. Why is that?

The field in general is moving toward earlier and earlier diagnosis. We've realized that by the time the patient reaches the current criteria for dementia, there is very substantial brain injury present. For our drugs to work and to preserve the patients' function at the highest possible level, we need to diagnose them at earlier phases in the disease.

That's why there's so much emphasis on mild cognitive impairment and what's called prodromal Alzheimer's disease. This means the patient does not meet the clinical criteria for Alzheimer's dementia, which is how we currently diagnose Alzheimer's disease, but we believe the disease is already present in the brain. Then the question is, how do we show that?

 What are best ways to do that now? And how reliable are they?

This is a year of great excitement for us, because it looks like an amyloid-imaging scan is likely to be approved by the FDA for widespread use. This is essentially a diagnostic test for Alzheimer's disease. And it's a game-changer in terms of identifying patients and allowing us to develop more specific patient populations for intervention studies.

 Is this the Pittsburgh compound B that has been mentioned by many of the researchers we've interviewed?

No. It is the nephew, I guess, of Pittsburgh compound B. That is a carbon 11-based imaging modality, and you have to have a cyclotron on site to use it, which means it's really not practical for widespread use. But after the experience with Pittsburgh compound B, another company called Avid developed a fluorine-based molecule that is practical for use in any existing PET scanner, and it also labels amyloid in the brain. So this is the compound, called AV45, that is likely to be approved later this year by the FDA. There's already been a preliminary review by the FDA and things look positive, with some additional adjustments for how they will present this compound.

 Can you quantify how accurate this is at establishing the presence of amyloid in subject's brains?

Well we believe it's very accurate. Almost every patient with Alzheimer's disease will have amyloid visible on this scan. Patients in the mild cognitive impairment phase who have Alzheimer's disease as a cause of their mild cognitive impairment also have positive scans. So the scan has high predictive value for saying which patients with mild cognitive impairment are going to progress to Alzheimer's-type dementia.

A somewhat unresolved part of this imaging is that we can see protein accumulating in people who do not yet have any symptoms, and we haven't followed enough people, long enough, to know that every single one of them is going to progress into a progressive cognitive impairment state. That needs clarification. So we don't know yet what we will tell a normal person who has a positive scan.

 Where do you see these scans being most useful? And, speaking personally, will individuals who are not cognitively impaired want to know if they're in a pre-Alzheimer's state?

"What we're learning as a field is that these trials are very hard to conduct, and so far the drugs themselves have either been unacceptably toxic or have not the entered brain in significant concentrations to provide therapeutic benefit."

That's a very important part of this dialogue. In people who have a dementia syndrome, it will confirm that Alzheimer's is the cause of the dementia. That will be very important. We know, for example, that general practitioners often don't pursue a diagnosis or even provide current therapies to patients, because it's very hard to do a mental status exam and have a lot of confidence that the abnormalities identified are diagnostic of Alzheimer's disease. It requires a high personal skill level. So GPs often don't do that, and people often go undiagnosed for a long period of time.

These scans will be very useful in that population, in patients who have dementia. It will be diagnostic for clarification of the cause. It will also be useful in patients with memory changes, who don't meet the criteria for dementia but might be in the earliest stages of Alzheimer's. We don't have a therapy for that group, but we're already conducting clinical trials for people who have positive imaging but don't meet the criteria for dementia.

 What interventions are using in these trials?

Right now, we're using a compound, for example, from Bristol Myers Squibb that is an inhibitor of amyloid formation. That's one of the trials we're doing in this prodromal Alzheimer's disease phase.

 The trials of amyloid inhibitors that have been published so far, have all failed., the most notable being the Lilly drug, semagacestat, last August. Why do you think those trials failed and what does that say about drugs like the one you're testing now?

There are several reasons for these failures and we're still learning from them. Some of these failures seem to have been the result of poorly conducted trials. In one trial of a drug called Alzhamed—another name for it is tramiprosate—there was so much site-to-site variability that you could not see if there was any drug-placebo difference. That suggests a poorly conducted trial.

The Lilly trial seems to have been well-conducted, but the drug itself had unacceptable toxicity. That is something one discovers when you start exposing larger number of patients to drugs. In the tarenflurbil trial—this was a drug from Myriad—the drug did not appear to have entered the brain in significant concentrations to alter the amyloid content of the brain.

What we're learning as a field is that these trials are very hard to conduct, and so far the drugs themselves have either been unacceptably toxic or have not the entered brain in significant concentrations to provide therapeutic benefit. So we're in the process of continually improving both the drugs and the trial process.

 What is your preferred hypothesis for the cause of Alzheimer's disease circa 2011?

I continue to believe that amyloid has a central role in the disease, but it may not itself be the most toxic component of the illness. There is increasing evidence that there's a linkage between amyloid and tau, with tau being the responsible neuronal assassin. So that the tau protein appears to be much more centrally related to cell death, but accumulation of tau seems to be related to presence of amyloid.

 As you see it, where does oxidative stress enter into the disease process?

I think oxidative stress is very important in several ways. It looks, for example, like the places where amyloid is laid down in the brain are areas of lifelong, high oxidative stress. There's always been a mystery why amyloid accumulates preferentially in some regions of the brain and not in others. Oxidative stress may be a part of the answer to that. Once amyloid begins to exert toxicity on tau and other mechanisms kick in, further oxidative injury occurs. So there are several levels of oxidative interplay with the amyloid hypothesis.

 You recently moved your center of operation from UCLA to the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. What do you hope to accomplish in your new position?

My primary goal is to develop a network of clinical trial sites within the Cleveland Clinic to more rapidly advance therapeutics and diagnostics for Alzheimer's disease. We have a robust clinical trial operation here in Las Vegas and I am in the process of recruiting a great clinical trials team to Cleveland, and I've been getting together a great clinical trial team at a Florida site.

I hope that by the end of 2011 we'll have a fully-functional network of these clinical trial sites well-staffed and seeing patients, all sharing a common institutional review board, common electronic medical records, and able to bring to bear these sites on important problems in Alzheimer's drug development.

 What do you consider the most significant findings to come out of Alzheimer's research in the past few years? The work that will have the most influence on future research?

There are several. The identification of the amyloid ligand for PET scanning is going to prove to be a very important advance. I think the resting-state MRI studies are very important, where they've identified this default resting-state network, and shown how active the brain is at rest and how this appears to relate to the deposition of amyloid. I think that's going to be a very important observation in the long run.

 Can you tell us more about the resting-state MRI studies and the implications of that research?

If you look at the brain at rest, it turns out there are certain areas in the brain that are in high-activity states. Then when you ask a person to perform a task, other areas are activated and the resting-state areas are deactivated. That turns out to be characteristic of all our brains through all our lives, and that is altered in Alzheimer's disease in a fascinating way. The areas of high activity at rest are areas where amyloid is deposited first in Alzheimer's disease, and those are likely areas of high-oxidative metabolism. That's why I said earlier that the oxidative state may determine areas of amyloid deposition in the brain.

I also think immunotherapy has significantly affected research in Alzheimer's disease, starting with AN1792, which never actually got a name, but is the very first vaccine tested in humans for Alzheimer's disease.

 By immunotherapy, do you mean the use of vaccines and antibodies against amyloid formation?

Yes. Although we do not have success there yet, there's tremendous activity in that area, and I think those observations have transformed the field and will be informative even if they turn out not to be therapeutic.

 If you were granted a quick answer to one outstanding question about Alzheimer's disease—other than how to cure or prevent it—what would that question be?

"The field in general is moving toward earlier and earlier diagnosis."

I'd like to know the relationship between a biomarker—say atrophy on MRI—and the change in the clinical status of the patient. If we knew that linkage, then we could do trials based on MRI rather than waiting for a clinical response, and we could accelerate drug development very substantially.

 Do you have a viable scheme for answering that question and are you attempting to do so?

Yes, but it's going to be a long, iterative process. We have to look at multiple trials and agents and gradually reach a consensus, and that consensus will then be highly informative for the trials that follow. But it's going to take us a while to get to that place.

 Has the research in the past five years induced you to change your opinion radically on something that you used to believe about this disease? And, if so, what is it?

Well, progress has been so incremental that it's hard to put yourself back in that place. I could say that the ability to identify very mild patients with accuracy is something that we did not envision five years ago we could do, and it now seems with amyloid-imaging and spinal fluid studies and other approaches to be highly realistic.

 If you lived in an ideal world and had unlimited funding for your research what one experiment would you do that you can't do now?

There's probably not a single experiment that I can think of that would be a game changer, but what we desperately need is something like a blood test for Alzheimer's. So I would invest in a program to develop a peripheral marker for the presence of Alzheimer's. That kind of marker would open the door to very important diagnostic and therapeutic advances. So the group of experiments I would perform would be about the presence of biochemical markers in the blood that are diagnostic of the presence of disease in the brain.

 Why hasn't that happened yet?

That work is expensive. The technology has to advance in order for us to detect very, very tiny amounts of these substances that leak out across the blood-brain barrier. Then, of course, we need enough longitudinal observations to know that the substances are not present in normal aging. It's the nature of research with a chronic disease. Just as the disease progresses slowly, so research tied to that slow progression has to move in concert with the evolution of the illness.

 What is the most challenging aspect of doing clinical trials on Alzheimer's disease?

Getting enough patients, enough well-qualified patients, into the trials quickly. The slowest aspect of any clinical trial is patient recruitment, and the aspect that subverts clinical trials is getting patients into the trial who do not actually have the target disorder—in our case, either Alzheimer's or prodromal Alzheimer's.

If I could do a few things to greatly improve the clinical trial process, it would be to get more patients to understand they have the power to help find the treatments for this disease and they employ that power by participating in clinical trials. Then I'd have clinicians who can make sure that the diagnosis is accurate.

Jeffrey L. Cummings, M.D.
Cleveland Clinic
Lou Ruvo Center for Brain Health
Las Vegas, NV, USA

JEFFREY L. CUMMINGS'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:

Petersen RC, et al., "Practice parameter: Early detection of dementia: Mild cognitive impairment (and evidence-based review) – Report of the Quality Standards Subcommittee of the American Academy of Neurology," Neurology 56(9): 1133-42, 8 May 2001 with 738 cites. Source: Essential Science Indicators from Clarivate.

KEYWORDS: ALZHEIMER’S DISEASE, EARLY DIAGNOSIS, MILD COGNITIVE IMPAIRMENT, BRAIN INJURY, DEMENTIA, PRODROMAL ALZHEIMER’S DISEASE, AMYLOID-IMAGING SCAN, DIAGNOSIS, CARBON-11-BASED IMAGING MODALITY, PITTSBURGH COMPOUND B, AV45, HIGH PREDICTIVE VALUE, DRUG TRIALS, TRAMIPROSATE, ALZHAMED, TARENFLURBIL, TOXICITY, TRIAL CONDUCTANCE, TAU, OXIDATIVE STRESS, RESTING STATE MRI STUDIES, IMMUNOTHERAPY, VACCINES, BIOMARKER, CLINICAL STATUS.

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