Thursday, January 8, 2009

Pimp My Product

In the January issue of Archives of General Psychiatry, there is an article (1) titled "Influence of Cognitive Status, Age, and APOE-4 Genetic Risk on Brain FDDNP Positron-Emission Tomography Imaging in Persons Without Dementia." The purpose of this study was to determine if the above-mentioned variables are associated "with increased cerebral FDDNP-Pet binding." What is FDDNP? it stands for 2-(1-{6-[(2-[F-18]fluoroethyl)methyl)amino]-2-naphthyl}ethylidene)malononitrile. Kind of just roles off the toungue doesn't it.

The researchers of this article and this other article (2) are responsible for developing this molecule, which binds to both amyloid plaques and tau tangles, the neuropathological hallmarks of Alzheimer's disease (AD is actually more than just the presence of these two abnormalities, but I'll get into at a later date). In their most recent study, they demonstrated that cognitive status, age, and APOE status were all associated with increased cerebral FDDNP uptake, which means that the above-mentioned variables are associated with increased deposition of amyloid plaques and tau tangles. As the authors state, "the results are consistent with our hypothesis and with previous clinical and postmortem studies demonstrating a relationship between such risk factors and amyloid plaque and tau tangle formation in the brain." The objective of this study was not add to this specific literature (pathology), but to demonstrate that their molecule worked, which it apparently did.

If you read the piece over at (3), you would think the objective was something else. I know I piss on this site frequently, but it's a good barometer for how the media (mis)represents science news. Their piece is titled, "Scientists See Brain Aging Before Symptoms Appear." Sounds way cooler than the journal title. However, that was not the aim of study; determining if their tracer worked was the real aim. Remember, all of the findings regarding pathology were already known. The researchers even cite that research in their article.

So why the hyperbole? This stuff is only interesting to a select group of people (e.g., radiologists). Why try to make the uninteresting, interesting? Marketing, "UCLA scientists have used innovative brain-scan technology developed at UCLA, along with patient-specific information on Alzheimer's disease risk, to help diagnose brain aging, often before symptoms appear." I guess before this "innovative brain-scan technology," diagnosing presymptomatic brain ageing was difficult, right? Not really, (4, 5, 6, 7, 8, 9, 10). Again, the purpose of the study was to demonstrate the utility of the tracer.

In the journal article's financial disclosure section it says, "The University of California, Los Angeles, owns a US patent (6,274,119) titled 'Methods for Labeling B-Amyloid Plaques and Neurofibrillary Tangles...Drs Small, Huang, Cole, and Barrio reported that they are among the inventors, have received royalties, and will receive royalties on future sales." They're pimping their invention. Nothing wrong with that. But is all the BS necessary? Even the lead researcher joins in on the BS game, "Combining key patient information with a brain scan may give us better predictive power in targeting those who may benefit from early interventions, as well as help test how well treatments are working...this type of scan offers an opportunity to see what is really going on in the brain." The picture included with post is a FDDNP-PET image. Clear as mud, right? Not to be a nit-pick, but the study wasn't designed to determine if the stated variables can be utilized to predict onset, course, impairment, etc.

Here is more subtle advertising:

"Eventually, this imaging method, together with patient information like age, cognitive status and genetics, may help us better manage brain aging"

"PET, combined with the FDDNP probe, is the only imaging technology that offers a full profile of neurodegeneration that includes measures of both plaques and tangles"

This one is my favorite, "According to Small, in the future (cue music from Sagan's Cosmos), brain aging may be controlled similarly to high cholesterol or high blood pressure. Patients would receive a brain scan and perhaps a genetic test to predict their risk. Medications and other interventions could be prescribed, if necessary, to prevent or delay future neurodegeneration, allowing doctors to protect a healthy brain before extensive damage occurs. The brain scans may also prove helpful in tracking the effectiveness of treatments." What a prognosticator. Granted Dr. Small's utopia is a cliche and a bit hackneyed, but I still get this warm and fuzzy feeling inside the cockles of my heart.

Once again, the purpose of this study was "to determine if impaired cognitive status, older age, apolipoprotein E-4 (APOE-4) genetic risk for Alzheimer disease, family history of dementia, and less education are associated with increased regional cerebral FDDNP-PET binding." This is one of those study where the researchers knew the answer before going in (2, 11). The subjects involved were the same subjects involved in their previous study (2).

Hey, did any know that people want to revise the diagnostic criteria for Alzheimer's disease? These researchers sure did, "these criteria (referring to the revised criteria) include the presence of...1 or more abnormal biomarkers such as molecular neuroimaging with PET...FDDNP-PET might be a useful tool in applying such revised research diagnostic criteria."

I'm not faulting these people for pimping their product. That's expected. Just don't pretend that you're doing something otherwise.

Do You Hate Your Grandparents?

Are you tired of receiving birthday and Christmas cards with only five bucks inside? Do you wish that grandma and grandpa would die so you can get your share of the inheritance? If you answered "yes" to any of the above questions, then I have the product you're looking for. Antipsychotic medication. Yes, that's right folks, the same drugs you use to sedate your annoying children can be use to kill your grandparents. And the best part is, it's completely legal.

A new article published in the January 9th issue of the Lancet Neurology (1) gives the details. "The study involved 165 Alzheimer’s patients in care homes who were being prescribed antipsychotics. 83 continued treatment and the remaining 82 had it withdrawn and were instead given oral placebos. Findings showed a significant increase in risk of death for patients who continued taking antipsychotic medication. The difference between the two groups became more pronounced over time, with 24-month survival rates for antipsychotic-treated patients falling to 46% versus 71% on the placebo and at 36 months it was 30% versus 59%. It means that after three years, less than a third of people on antipsychotics were alive compared to nearly two thirds using the dummy drug."

Just imagine, in three short years you will no longer need to listen to your grandmother as she goes on and on about how lonely she is and how much she hates the nursing home you put her in. You can finally live a guilt free existence.

For whatever reason, these results came as a surprise to some people, "Rebecca Wood, Chief Executive of the Alzheimer’s Research Trust, said: 'The findings of this research are a real wake-up call and underline the danger of prescribing antipsychotics long-term for anything other than exceptional circumstances. We must avoid the use of these drugs as a potentially dangerous "chemical cosh" to patients who would be better off without it. The study also highlights the urgent need to develop better treatments as Alzheimer’s patients have few options available to them.'" "Wake-up call?" "Highlights the urgent need?" I guess she's not aware of all this research (2, 3, 4, 5, 6, 7).

However, if history is any indicator, this "new" research won't change a damn thing (8).

Wednesday, January 7, 2009

And the Award Goes To...

It's common practice on web logs to hand out specialized awards. Because I am both a narcissist and a conformist, I too have my own award to hand out: The Silver Douche Award. I chose the name in honor of comedian George Carlin, who frequently referred to Barbara Bush as a silver douche.

Since I am the only committee member on the board to nominate douche bags for excellence in douche baggery, the first Silver Douche Award (The Douchey) is awarded to Dr. Alan Schatzberg.

His credits include the following: 1, 2, 3, 4, 5, 6.

Congrats Dr. Alan Schatzberg! You're A Douche.

Neuropsychology Research is Lame

Admittedly, I'm biased. I've taken many cheap shots at psychiatry and, to a lesser extent, clinical psychology. However, my training is in neuropsychology, which is the study of the relations between brain function and behavior. I have yet to bite the hand that feeds me. Since it's a new year, I figured I'd begin by doing just that.

In the January 2009 issue Neuropsychology (1), an article titled "Exploring Effects of Type 2 Diabetes on Cognitive Functioning in Older Adults" was published. First, let's identify the assumption in this title: Type 2 diabetes affects cognitive functioning. The article is summarized over at (2). As usual, the article begins with hyperbole, "Adults with diabetes experience a slowdown in several types of mental processing, which appears early in the disease and persists into old age, according to new research." Now, when I looked up the definition for the word "several," the definition I found was this, "more than two but fewer than many." In the actual study, of all the administered neuropsychological tests, only two statistically significant differences were found. According to my own new research, the opening sentence of the Sciencedaily article is nonsense.

However, there's more. The Sciencedaily article incorrectly summarizes the results, "Healthy adults performed significantly better than adults with diabetes on two of the five domains tested: executive functioning, with significant differences across four different tests, and speed, with significant differences or trends across five different tests. There were no significant differences on tests of episodic and semantic memory, verbal fluency, reaction time and perceptual speed."

Actually, out of the four tests of executive functioning, healthy controls performed significantly better than the diabetes group on one test only. Also, heed attention to this phrase, "...and speed [referring to processing speed], with significant differences or trends across five different tests. " [my emphasis]. Buyer beware when you come across the word "trend" in research articles. The term is not interchangeable with statistical significance. To say "significant differences or trends" is misleading. When a difference is statistically significant, we believe that it's likely the result didn't happen by chance. When that the difference was "close" to being statistically significant (i.e., it could have occurred by chance), we use to term trend instead. Trends do have heuristic value. They can identify areas that need further research or closer scrutiny; however, to include the phrase in a popular article is sloppy. It makes the results seem more significant than they are. It's akin to reporting response rates as opposed to remission rates in antidepressant research (e.g., 70% response rate, 25% remission rate). It's semantics, not science. In the actual study, only one test yielded significant results, not five.

What we have is a study that found two significant results (and 19 negative results), and the conclusion is that people with type 2 diabetes experience a slowdown in executive functioning and processing speed. There are a few problems that the researchers don't address. First, the more neuropsychological tests an individual is administered, the probability of having an abnormal test result increases. Second, all this study shows is that there were differences between two groups, not that the scores obtained were abnormal.

In neuropsychology, we categorize performance based on standard scores and percentiles. The line between normal and abnormal varies depending on the cut off point (typically a cut off of one standard deviation is used). Nowhere in this study do the authors state that the type 2 diabetes group had abnormal scores (i.e., below one standard deviation). They're just different from the control group. Also, the diabetes group had 41 subjects while the control group had 424 subjects. Again, we have a problem with external validity (3).

I would have an impromptu visit from a proctologist if a patient performed poorly on a single test and then I concluded that they had an impairment. The reason we give multiple tests for each domain of functioning (e.g., executive, language, visual-spatial, memory, somatosensory, processing speed, and olfaction), is to look for patterns of deficits, not just deficits. It's the patterns of deficits that lead us to a diagnosis.

Getting back to the actual study, the following domains were assessed: verbal memory (they incorrectly called this episodic memory, which is different), semantic memory (i.e., crystallized intelligence to you CHC fans out there), verbal fluency, executive functioning, and processing speed (they used the fancy term neurocognitive speed).

They improperly assessed memory, and the data they reported makes no sense. The results they listed deal with proactive and retroactive interference, which is source memory, not the ability to learn, encode, and to retain information.

They used a form of verbal fluency that isn't widely used clinically.

The tests they used to assess so-called executive functioning, the Hayling Sentence Completion Test and the Brixton Spatial Anticipation Test, don't even crack the top 40 tests used by neuropsychologists (4). The tests have only been around since 1997, and they are poorly normed.

The tests used to assess processing speed (excuse me, neurocognitive speed) are not used clinically.

I question whether these researchers know what they are doing. I understand that the more widely used neuropsychological instruments are expensive, but they still could have used tests that have clinical relevance (at least ones that crack the top 40). Secondly, identifying group differences without indicating if results are abnormal (e.g., mild deficit or moderate deficit) is clinically meaningless (in this case). I can administer IQ tests to high school graduates and college graduates. Will there be group differences. Very likely. Does that mean those differences are abnormal and require clinical intervention? NO! They're just different. Somehow, that didn't stop one of the co-authors from suggesting public health policy, "...public health programs could check the cognitive status of people with more advanced or severe cases [of diabetes]; ensure that diet and medications are effectively employed in all early diagnosed cases; and enact possible cognitive monitoring or training programs for people with diabetes." If they are normal, what's the point?

At least the last paragraph in the Sciencedaily article has shades of rationalism (I'm being ironic here), "Diabetes is a known risk factor for late-life neurodegenerative diseases such as Alzheimer's [current research suggests it doubles the risk]. Although the deficits [when were these identified as deficits? How about differences] detected in the current sample were not clinically significant [duh!], they appear (according to subsequent research by the authors [where's the reference to this research?]) to foreshadow additional deficits [differences]. Only further study would reveal whether it's possible to "connect the dots" between mild early deficits [differences] in speed and executive function, and later signs of a progressive cognitive impairment." Based on this study, many (as opposed to several) additional studies are needed.

So, getting back to the assumption implied by the article's title, does type 2 diabetes affect cognitive functioning? If this was the only article I read on the matter, I would have no idea.