Alzheimer's Diagnostic Test, Misleading the Reader?

Contributed by: Dennis Fortier, President, Medical Care Corporation

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The popular press carries more stories like this in a given week than we could possibly highlight in this blog.

I am referring to this article describing a diagnostic test for Alzheimer's disease.  The test measures proteins in the spinal fluid and, according to the company with hopes of one day commercializing the test, it can diagnose Alzheimer's disease with 90% accuracy.  I believe that is a scientifically plausible claim and I suspect that careful measures of various biomarkers will achieve such accuracy in the very near future.

The potentially misleading element of this story comes from the following quote:

"Right now, diagnostic accuracy for Alzheimer's disease can be as low as 70 percent, meaning three out of 10 people who are diagnosed with this disease might not actually have Alzheimer's disease, but rather some other kind of dementia".

It is true that diagnostic accuracy for AD "can be" as low as 70 percent, if a physician does not follow published guidelines for working up a memory complaint.  However, when published guidelines are followed, then diagnostic accuracy is already better than the 90% target for which this new test is striving.

I think this test, and others, may pan out, but let's not mischaracterize the problem.  We need to help physicians update their knowledge to keep pace with the constant advances in medicine.  A new test, with inferior accuracy to the already achievable standard, is not a breakthrough, and the word "promising" probably does not belong in the story's headline.

2 Steps Toward Better Alzheimer's Diagnosis

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego. ______________________________________

While we sometimes note that the press over-emphasizes the difficulty in diagnosing Alzheimer's disease, there is no doubt that new tests could make the process faster and more accurate.  Two recent news stories have converged on this theme.

First, regarding efforts to diagnose Alzheimer's using PET scans to view amyloid plaques in brain, the U.S. Food and Drug Administration’s (FDA) Advisory Committee decided that it could not recommend approval of Amyvid™ (florbetapir) at this time based on the currently available data (13-3); but, voted unanimously (16-0) to recommend approval of Amyvid conditional on specialized training being instituted for the medical professionals who would administer it.  It is expected that this training will be formalized, and FDA approval granted by the end of this year.

Second, Kristine Yaffe and colleagues at UCSF published an article in JAMA this week in which they report on a new blood test that predicts subsequent cognitive decline. In the study, they took baseline plasma samples from nearly 1,000 elderly normal volunteers and then followed the participants for nine years, regularly measuring their cognitive performance.

Unlike similar previous studies, Yaffe and colleagues looked at cognitive decline rather than conversion to Alzheimer's disease (AD). They found that a low ratio of two forms of beta-amyloid at baseline correlated with a greater drop in cognition over the duration of the study. Intriguingly, this association was strongest in participants with low levels of education, and much weaker in subjects with more education. This is in accord with the long-standing view that a person’s cognitive reserve can protect against cognitive decline. If the result proves robust in future studies, it may lead to further development of blood tests to monitor for AD.

Yaffe K, Weston A, Graff-Radford NR, Satterfield S, Simonsick EM, Younkin SG, Younkin LH, Kuller L, Ayonayon HN, Ding J, Harris TB. Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA. 2011 Jan 19;305(3):261-6.

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Blood Test for Diagnosing Alzheimer's: A Major Leap Forward?

Contributed by: Dennis Fortier, President, Medical Care Corporation

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With so many of the news stories I summarize here, I include caveats about the long and arduous path that basic science must travel before a clinically beneficial advance becomes available to the public. The same caveat applies to the heavy coverage of a new, blood-based diagnostic test recently developed by the Scripps Research Institute and published in the January 7 issue of Cell.

Having said that, this scientific approach strikes me as one worthy of the frothy press it has already spawned.

The approach is exciting in its novelty. Rather than identifying the specific antigens that cause an immune response (production of antibodies) at early stages of a particular disease, and then screening the blood for the presence of those antibodies, the Scripps researchers took another path. They skipped the step at which conventional science is currently focused. That is, they did not bother with the daunting challenge of identifying which specific antigens might stimulate an immune response to fight in early stage Alzheimer's disease.

Rather, in their study, they loaded the blood with thousands of synthetic molecules designed to bind to antibodies of all sorts. By then analyzing the results from patients with Alzheimer's compared to those with Parkinson's and those deemed "healthy", they detected clear evidence that Alzheimer's patients had a much higher concentration of two particular antibodies in their blood. The conclusion, which must be validated with more data, is that these two antibodies are bio-markers for early-stage Alzheimer's disease.

This may prove to be extremely valuable in detecting early stage disease presence, but may pay other dividends as well. If these antibodies do indeed indicate a response to Alzheimer's pathology, then this study may also shed important, new light on the actual disease process which, in turn, could accelerate research on new treatments

Obviously, there is much science to conduct before the world can benefit from this research. But the prospect of leap-frogging one nagging problem in the process, the identification of specific antigens that indicate Alzheimer's, is an exciting proposition.

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Top 3 AD Research Trends

Contributed by: Dennis Fortier, President, Medical Care Corporation
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One site I follow for news in this field is the Alzheimer's Research Forum. The postings there can be quite technical as they target medical researchers as an audience. Nonetheless, the content they cover is often the same content as that which gets translated into lay terms (accurately or otherwise) by journalists in the general press.

They recently summarized their opinion of the top research trends in the AD field and I found it to be an excellent summary with a rich set of links to ongoing research stories. From a public impact perspective, I have selected the three from their list that I think are most likely to make a real-world difference, or at least be worthy news stories, in the coming year.

1. Revised Diagnostic Criteria
We posted this news followed by our perspective on this change when it was first discussed last summer. I think the new criteria, which define AD based on pathological evidence as opposed to severity of symptoms, provide a great step forward and will enable earlier intervention in a clinical setting.

2. Biomarkers
The ongoing effort to better understand AD pathology brings bio-markers to the forefront of importance. This year will likely see the first FDA approval for an agent that binds to amyloid in the brain and enables visibility on a PET scan. This along with ongoing research on proteins in the blood and spinal fluid, brain volumes, cognitive measures, and a host of other bio-markers portends a year of advance for the field.

3. The Amyloid Hypothesis (or hypotheses)
As described by the editors at Alzheimer's Forum, last year saw advances in understanding of amyloid's "...production, aggregation, function, and toxicity". All of this new knowledge must be assimilated into the evolving hypotheses about the role of beta-amyloid in Alzheimer's disease.

While there is much work underway in this field and many facets to the complex problems caused by Alzheimer's disease, the three noted trends above will certainly be central themes in the news during the coming year. Follow along with our posts at this blog to stay abreast of all developments and to understand the likely effects of each.

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Alzheimer's Drug Fails Phase III Trial

Contributed by: Dennis Fortier, President, Medical Care Corporation
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One of Eli Lilly's late-stage Alzheimer's drugs, the gamma-secretase inhibitor Semagacestat, has failed its Phase III FDA trial and the company has halted its development. This announcement today was somewhat expected by the research community as other gamma-secretase inhibitors, namely Flurizan (Myriad Genetics), had also been deemed ineffective in a large trial.

While this is disappointing news, the overall trend of scientific progress in the field of Alzheimer's is clearly positive. New guidelines have been proposed that will facilitate earlier intervention and better treatment results. New diagnostic tests are showing greater accuracy and bode well for more certainty in clinical practice. And perhaps most importantly, the pipeline of treatments under development is full of promising agents.

An updated summary of the current FDA pipeline for Alzheimer's treatments will be posted here later in the week.

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Brain Scans for Diagnosing AD

Contributed by: Dennis Fortier, President, Medical Care Corporation
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In this cleverly written, but wantonly provocative article in the Forbes blog “The Science of Business”, it takes the author only 53 words to completely mislead his audience.

In his attempt to find controversy in a straight forward advance, there are two areas where the author has blurred the truth. First, the guidelines he references, which define a very early stage of Alzheimer’s, are not intended for physicians seeing patients but for researchers doing scientific work in a laboratory. Second, adoption of a new definition by the research community has nothing to do with approval of a diagnostic process, like brain scans, that physicians would use in diagnosing patients.

Here is a more sensible summary of the situation than the one Robert Langreth has thrust upon his readership:

An expert panel, convened by the NIH and the National Alzheimer’s Association, has drafted new guidelines for defining Alzheimer’s disease. These new guidelines are intended to correct a major deficiency in the existing guidelines that were established in 1984.

Original Guidelines
The original guidelines suggest that Alzheimer’s disease is not present until the subject has dementia. Recall that the term “dementia” defines a state of impaired thinking that is so severe that subjects can no longer care for themselves without human assistance. This means that, under the old definition of Alzheimer’s disease, a subject with accumulating amyloid in their brain, and clear symptoms of memory loss, does not have Alzheimer’s disease until their impairment progresses to the point where they become dependent on others.

Obviously, this makes no sense. We wouldn’t set some late stage criteria, like blindness, before diagnosing diabetes, and we shouldn’t do so for Alzheimer’s disease. It is this old and problematic definition that has primary care physicians around the world, watching patients with memory loss, and doing nothing to treat the problem until the patient becomes demented. Only then can they consider diagnosing Alzheimer’s disease and prescribing a very late and predictably ineffective treatment regimen.

Proposed Guidelines
The new guidelines cover 3 stages of the disease:
1) AD Dementia – the definition of this progressed state is largely consistent with the original language used to describe the entire disease continuum.
2) Mild Cognitive Impairment due to AD - an earlier stage of the disease. This definition will facilitate timely intervention for patients with memory loss who are not yet demented.
3) Pre-Clinical AD - the earliest and least certain stage. It includes the period when pathological changes are underway but there are no outward symptoms of disease. These guidelines, which are the ones cited by Langreth, are clearly and expressly intended for researchers, not physicians.

Adoption into Clinical Practice
Finally, there is really no need for alarm that adoption of new definitions in the research community will unleash massive, premature change in clinical practice. Langreth makes a dangerous, conceptual leap based on the word “approved”. He states “…once a plaque brain scans gets approved the next step will be that aggressive doctors will start using it in patients with the slightest sign of fleeting memory or cognitive problems”. Lets be clear about this; adoption of new language by an expert panel has absolutely nothing to do with the FDA’s possible, eventual approval of a diagnostic test that can be used in clinical practice. The author implies a close association between these discrete events that is not justified. It is pure artistic license and sensationalism.

These are the kinds of articles that perpetrate the public’s nihilistic attitudes toward Alzheimer’s disease and prevent the kind of constructive discourse that will help us tackle the problem in a meaningful way. It is really a shame that the credibility of the Forbes imprimatur was lent to this misleading report on such a clear step forward for AD research.

The Role of Alzheimer's Diagnostic Tests

Contributed by: Dennis Fortier, President, Medical Care Corporation
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There has been a lot of press recently about diagnostic tests for Alzheimer's disease including this piece from Examiner.com that has garnered a lot of attention today. Digesting this news requires a broad perspective on the problem.

Physicians will tell you that solving a medical problem involves three distinct steps:

First you need to recognize that a problem exists. This is often a simple task when clear symptoms are present. Other times however, symptoms are vague and a physician must take steps to determine whether or not a legitimate health concern is at hand.

Second, you must diagnose the problem. If the symptom is blurry vision, for example, the physician must diagnose the root cause of the problem because a care plan for diabetes is much different then a care plan for a scratched cornea.

Third, the physician must select the appropriate care plan and oversee its administration.

When all three steps have clear guidelines that lead to successful clinical outcomes, physicians generally deliver fantastic medical care. When one or more of these three steps is uncertain, standards of care tend to vary from good to less good. In the case of Alzheimer's disease, it turns out that all three steps have some uncertainty.

Early stage Alzheimer's disease has generally vague symptoms usually including subtle memory loss. This is challenging for physicians because many adults, a large percentage of whom are perfectly healthy, sense that their memory is not as sharp as it may have been in the past. The difficulty in sorting the healthy from the unhealthy leads to a delay in meaningful intervention.

Once a physician decides a problem is present, the diagnostic process for AD is perceived as uncertain based on the over-emphasized fact that autopsy is the only certain approach. Importantly, any physician following the NINDS-ADRDA diagnostic guidelines can accurately diagnose AD and other problems on a consistent basis (but this is not well understood by most primary care physicians). Finally, current treatment options are considered uncertain given the variability with which patients respond. Some patients seem to respond while others do not. Overall, there is a lot of uncertainty around this disease.

The primary point of this post is that stories like the one referenced above can only be appreciated in the context of the full continuum of clinical steps to identify, diagnose, and treat Alzheimer's disease. While an accurate diagnostic test will be a welcomed advance, the problem is quite complex and such a test will have limited impact until we can sure up all three steps in the care process.

Stale Dogma about Detecting Alzheimer's Disease

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Earlier today, Forbes.com published an article titled "Do You Really Want That Alzheimer's Test?". I see pessimistic articles like this with alarming frequency where some "expert" laments the lack of effective treatment for this disease while entirely ignoring a solid decade of evidence that early intervention and appropriate treatment can be tremendously beneficial. Here is the comment I posted at Forbes.com:

From daily, first-hand experience, I can tell you that articles of this nature do an unintended disservice to humanity. While it is clear that treatments must get better, physicians, researchers, and the general public must all begin to divorce themselves from the stale dogma that "there is nothing you can do about Alzheimer's disease".

The biggest, and most immediately solvable, problem in treating this terrible disease is that up to 95% of patients are diagnosed in years 8, 9, and 10 of a typical 14-year disease course. This means that the patients have end-stage pathology with severe brain damage when they are first diagnosed and put on treatment. While the currently approved drugs will not reverse the progression of the disease at this late stage, they can slow its advance and afford a higher quality of life for a meaningful period of time. In those fortunate instances when patients have been diagnosed earlier, when less damage has occurred in the brain, the progression of the disease has been slowed by about 50% on average. In the best cases (but clearly not all), this can delay nursing home placement by up to several years and allow the luckier patients to live out their lives in their own home.

Although this clinical benefit (delaying progression) is not as appealing as a cure, it is still significant for patients facing end-of-life decisions. Additionally, better treatment efficacy based on more timely intervention is not the only reason why patients might "like to know" if they had Alzheimer's disease. Knowing early on gives them time to plan for the difficult period ahead and to participate in their care decisions prior to losing the ability to do so. There are also legal and financial plans to attend and, in some cases, the spiritual and philosophical preparation some choose to pursue when facing their mortality.

No one wants to see such diagnostic tests forced upon people who would prefer to remain ignorant but for the growing number who choose a proactive approach to their health, such medical clarity will be greatly beneficial. Nihilistic articles (of which there are many on this topic) tend to perpetrate the nation's sense that there is nothing we can do and no reason to know when Alzheimer's disease is present. I hope you and Dr. Smith will join the campaign to highlight the growing body of evidence that we can already help Alzheimer's patients in many ways. Acknowledging as much will not slow the research effort for a cure nor will it derail the scientific community's conviction that a better approach is needed. It may, however, begin to spur more patients and more primary care physicians to engage in the dialogue that will help us begin detecting and treating this disease at an earlier and more manageable stage.

A better understanding and more awareness of Alzheimer's related issues can impact personal health decisions and generate significant impact across a population of aging individuals. Please use the share button below to spread this educational message as widely as possible.

Alzheimer's Dianostic Test

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Researchers at the University of Pennsylvania have published in the Annals of Neurology the development and standardization of a test to accurately diagnose Alzheimer's Disease (AD) by measuring the levels of beta-amyloid and tau protein in the spinal fluid. While many news stories are forwarded to me on a daily basis, this one has come to me in extraordinary abundance. My primary take on this news story is two-fold.

First of all, it is tremendously positive in the following sense. We are currently detecting patients with AD, on average, when they have end-stage pathology (up to 95% of patients are detected 8-10 years after the onset of symptoms according to published data). One of the reasons we intervene so late is that many physicians believe (erroneously) that a brain biopsy is the only reliable method of establishing a certain AD diagnosis. While it is true that a brain biopsy is one certain diagnostic method, following the published NINDS-ADRDA diagnostic criteria yields a very acceptable diagnostic accuracy rate of about 95%. Nonetheless, the presence of a lab test with high accuracy would increase physician comfort with the diagnostic process and hopefully lead to a more proactive attitude toward early intervention.

My second reaction is rooted in 20 years of experience commercializing health care technologies. The discovery of a scientific means to diagnose a given condition is a very early step on the long and often arduous path to making a product available. This scientific advance is absolutely positive but the practical implications of the discovery are many years away from helping real patients.