A Quick and Easy Biomarker for Alzheimer's?

Summary:  A new method of visually assessing shrinkage of certain areas of the brain using standard MRIs may improve the diagnosis and treatment of Alzheimer's.

ICAD was all about biomarkers.  Biomarkers are physical or biochemical characteristics that are signs of an ongoing disease process in a living person.  They include genetic variations, molecules in blood or spinal fluid, and patterns seen on imaging tests.  To be useful in screening for a disease or monitoring the progress of a disease, they should be easy to obtain.  This typically involves collecting blood, urine, stool or saliva samples, or performing a radiological test. The use of biomarkers for certain diseases is well-accepted - for example, blood tests are used to indicate the presence of certain cancers or the risk of heart disease.

But for Alzheimer's, diagnosis is currently based on neuropsychological tests and medical histories showing cognitive impairment.  Brain scans (MRI and CT scans) are not typically used to diagnose Alzheimer's, but instead are used to exclude other conditions that can cause cognitive problems.

Speaker after speaker at ICAD explained that we need biomarkers to:

• diagnose [and eventually treat] Alzheimer's in early stages, perhaps even before symptoms appear

• diagnose Alzheimer's more accurately, at any stage

• measure the effect of drugs on disease progression in clinical trials.

This concept sounds good, but there are practical problems:

• studies have not yet confirmed the accuracy of many of the biomarkers proposed; a high percentage of false positive results seems possible

• new technologies to measure potential biomarkers like amyloid protein in the brain are expensive and not yet available outside of research facilities

• some studies have shown that the levels of certain proteins in spinal fluid may be an accurate biomarker, but the required spinal tap is unappealing to many patients.

Ranjan Duara, MD

Dr. Ranjan Duara, Medical Director of the Wien Center for Alzheimer's Disease and Memory Disorders in Miami Beach, Florida and Associate Professor of Medicine, Neurology and Psychiatry at the University of Miami, thinks we already have a biomarker that is accurate, inexpensive and doesn't require drawing spinal fluid.  He has developed a system for visually measuring and rating the atrophy, or shrinkage, of three areas within the medial temporal lobe of the brain.  He and his colleagues recently completed a study showing that this method can help differentiate among people who are cognitively normal, those with Mild Cognitive Impairment and those with Alzheimer's.  The study also showed that this assessment can help predict which patients will progress from Mild Cognitive Impairment to Alzheimer's.

 

The system involves looking at an MRI scan in a way Dr. Duara says radiologists (and many neurologists) are not trained to do.  "It happens all the time," he says.  "Someone comes in for a neurological problem and gets a brain scan.  The scan can have findings typical of Alzheimer's disease, and it won't get reported." 

He has incorporated his visual assessment method into software that can operate on any computer.  The software is mostly educational, he says.  "We have installed it in our radiology suites, and our radiologists are starting to use it.  Once you understand the method, you don't really need the program.  However, the quantitative aspects of the program are useful in a research setting, so that measurements are done in exactly the same way."

Other studies have shown that visually assessing atrophy of the medial temporal lobe can improve the accuracy of diagnosis.  Dr. Duara's method rates three areas within the medial temporal lobe (the entorhinal cortex, the perirhinal cortex and the hippocampus) separately, and is more sensitive to atrophy.  "We need to look at the individual structures within the medial temporal lobe," he says.  "For example, in Alzheimer's, the entorhinal cortex is often affected earlier than the other structures." 

There are alternative (and more quantitative) ways to assess atrophy in various areas of the brain, but according to Dr. Duara, those methods may not work using many MRI scanners that are in common use.  In addition, MRI technicians need to receive specialized training and conduct scans in a standardized way.  His method requires only a standard MRI and a few minutes of a radiologist's or neurologist's time to read a scan.

The method could be useful right away in making sure people participating in clinical trials have been accurately diagnosed, he says.  "People who are recruited to participate in Alzheimer's research studies and clinical trials sometimes do not have Alzheimer's at all, but instead may have Frontotemporal Dementia, depression, Lewy Body Dementia or other conditions.  We may not be testing the effect of a study drug on a particular disease if the clinical diagnosis is inaccurate.  If we had a radiologic criterion based on something like this method, we'd have much greater accuracy in the clinical diagnosis, and in many cases we'd be able to diagnose Alzheimer's disease much earlier than we do now."

While this type of assessment could catch on quickly in research clinics, it's not likely to be adopted by radiologists and become a routine part of an Alzheimer's diagnosis anytime soon.  "What will drive this is when we have a medication that affects the course of the disease much more dramatically than we're able to do now," says Dr. Duara.  Without such a drug, many patients and doctors may not see the benefits of an accurate diagnosis, no matter which biomarker is used. 

He is confident that in the long run, we will be able to diagnose, treat, and perhaps prevent Alzheimer's the way we deal with heart disease now.  "The most remarkable medical success in the western world has been the improvement in our ability to treat vascular risk factors," he says.  "We don't die from heart disease and stroke the way we used to, and we delay the onset of those diseases by as much as twenty to thirty years.  Ultimately, we'll develop early markers of Alzheimer's disease, make better diagnoses, be able to delay the onset of the disease and treat it more effectively, just as we do for vascular disease."

Comments

[Gail Rae Hudson]

Astonishing, and promising. I beg to differ, though, with the idea that until there is a way to treat Alzheimer's it doesn't matter whether we know the cause of the dementia. I believe it matters a lot. My experience with other caregivers and with my mother tells me that when a caregiver, for instance, and, in other instances, medical personnel (including but not limited to doctors) think that someone has Alzheimer's they imagine, and treat (yes, that's right, TREAT, even though there are no really good treatments available at this time) the patient in a completely different way than if it is thought that the dementia is of another type. Recently, in the hospital, a Hospitization doctor, without my knowledge, assumed Alzheimer's in my mother, even though I was clear when she arrived that she had non-progressive vascular dementia, and began a course of Effexor (for the depression he assumes Alzheimer's patients have) and Aricept (to try to allay "further progression"). Both medications were wildly inappropriate for her for several reasons, not the least of which was her type of dementia. Several other medical professionals, having understood that my mother has dementia but not bothering to understand that vascular dementia is not Alzheimer's, made some riotously faulty judgments about her temporary dementia and other symptoms caused by her pneumonia, assuming they were indicative of Alzheimer's since "it looked like a duck and quacked like a duck", refused to listen to me until I was literally yelling that her speech difficulties were not typical of her, and delayed the pneumonia diagnosis for four days, through which my mother's pneumonia worsened.
Whether or not curative treatment for any dementia is available, there are several compelling reasons why medical personnel should be urged to consider using Dr. Duara's imaging analyses in order to determine an individual's dementia type. I believe that this will cause several outcomes, not the least of which will be:
1. Caregivers understanding better what they may and may not expect from their care recipients as time passes, which will make a difference in their ability to provide adequate and accurate care, and;
2. Medical personnel not making assumptions based on observed (and possibly temporary) behavior that allow for misjudgment of symptoms and mistreatment of patients.