December 2011 Archives

About one-third of cognitively normal elderly demonstrate an elevated load of beta-amyloid,* a pathologic hallmark of Alzheimer disease, in the brain, according to a newly published study from the Mayo Clinic. These data support previous observations, in which the PET-imaged brains of about a third of elderly, nondemented subjects will exhibit an abnormal accumulation of the AD-associated protein.

However, the Mayo investigators went a bit further by examining the potential association between the load of beta-amyloid, as measured with an established radiolabeled tracer (Pittsburgh compound B, or PiB) on PET images, and cognitive performance on various memory, language, attention, and visuospatial tests. As well, a relationship among brain amyloid, cognitive performance, and APOEe4 status (a well-known genetic marker for AD) was examined. What the researchers found was that poorer cognitive performance was associated with greater amyloid deposition, and that this relationship was more robust in APOEe4 carriers. Conversely the association between amyloid load and relative cognitive impairment was much weaker (ie, only "modest") in subjects who did not carry an APOEe4 allele, suggesting (the authors concluded) "that APOE isoforms modulate the harmful effects of [beta-amyloid] on cognitive function."

What any of this information means practically is very murky, however. Will some of these cognitively normal subjects with heavier amyloid burdens (and who perform less well on cognitive tests) develop AD—that is, if they live long enough? Is AD more likely in these subjects if they're APOE e4 carriers? We don't know, and obviously further longitudinal work is necessary. The Mayo authors do imply that follow-up is ongoing.

In an accompanying editorial, Buchman and Bennett commended the Mayo investigators for the size of the study (a highly respectable 408 subjects [with a median age of about 80 years]) and their "important contribution to our understanding of AD, illustrating that even among persons without dementia or [mild cognitive impairment], amyloid deposition is associated with very mild symptoms, especially among carriers of the APOE e4 allele." But "[w]hether...amyloid imaging agents will have clinical utility remains to be determined," the editorialists appropriately caution. They advise about the lack of data concerning the prognostic value of amyloid retention (presumably in any subjects, whether demented or not) and how amyloid retention may change over time. And they add that the utility of amyloid-imaging agents "will remain low in the absence of an effective amyloid modulating agent." In other words, what's the point of knowing the amyloid burden if you can't do anything to lighten the load?

A related issue, however, not explored by the editorial authors, is whether even removing amyloid in the context of cognitive impairment, is beneficial or, in fact, does more harm. Existing AD trials suggest that amyloid-modulating agents (eg, bapineuzumab) can cause brain edema—presumably due to the removal of vascular amyloid—and that they do so without improving cognition to any substantial degree overall.

Intervening earlier with anti-amyloid drugs in less cognitively impaired subjects, as proposed by some industry investigators, is a tricky move: obviously primum non nocere in persons with only mild cognitive impairment and certainly in individuals with no practical cognitive problems (regardless of their amyloid burden).

PET = positron emission tomography.

* Defined by a "global cortical PiB retention ratio" of greater than 1.50.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

My Foolish Heart (1949): A major weepie with Susan Hayward. As an alcoholic and terribly unhappy wife, Hayward recounts the lost love of her life to a visiting college chum. The movie, which is oh-so-loosely based on* J. D. Salinger's short story "Uncle Wiggly in Connecticut,"** was viewed with such scorn by the author (and critics) that he refused to sell the rights to his other, more famous works for film adaptation. Nevertheless, Hayward and especially Dana Andrews (as her former love) sustain the story and preserve an authentic glimpse of a bygone, melodramatic era.

* Really more, inspired by.
** Originally published in The New Yorker.

First Jeffrey Kindler, then Lipitor, and now this: Pfizer announced today that it's* its dependency on the FDA's approval is over.

* Bloody hell.

Tinker, Tailor, Soldier, Spy (1979): The faithfully adapted 7-part BBC mini-series of John Le Carre's titular novel—a story as much about of the banality of espionage during the Cold War, as it is about the treachery. Starring the (nearly) incomparable Alec Guinness as Le Carre's George Smiley, a British agent pulled out of retirement to flush out a Russian—oops, Soviet—mole in the upper ranks of the UK's secret service. Compare and contrast with the new and very well-received theatrical release of the same name, starring Gary Oldman as Smiley. To wit: "Guinness's turn is the Torah; Mr. Oldman's the Talmud." Uh, whatever the hell that means, Manohla Dargis.

Yesterday the FDA announced that it will evaluate postmarketing reports of "serious" bleeding in patients taking the anticoagulant Pradaxa (dabigatran); although the agency doesn't say how many reports of serious bleeding have been received since the drug was approved a little more than a year ago.* The FDA is basing its analysis on data from its own pilot program, the Mini-Sentinel system, as well as submitted information to its standard reporting system, AERS.

Currently Pradaxa is only available in the United States in the form of 150- and 75-mg pills, the latter approved for renally compromised patients (CrCL 15-30 mL/min) and solely on the basis of pharmacokinetic studies. The FDA has been criticized for failing to approve the 110-mg pill, which was shown to be comparable (ie, nonsuperior) to warfarin in the large RE-LY trial (for background, start here). According to SDI's proprietary national tracking services, cited by the FDA, about 1.1 million prescriptions for Pradaxa were dispensed in the United States between October 2010 and August 2011, and 371,000 patients received Pradaxa from outpatient retail pharmacies. Not a huge population, but not insignificant either.

The FDA also advises, wisely, that comparing postmarketing reports of bleeding with Pradaxa and those with warfarin is probably not helpful, because "warfarin has been marketed for over 50 years and is well known to cause bleeding, [consequently] patients and healthcare professionals are not likely to report bleeding in association with warfarin." The agency concludes, "Thus, a simple comparison between Pradaxa and warfarin...is of limited value." The FDA also says that it's working with Pradaxa's manufacturer, Boehringer Ingelheim, to assess a range of potentially adverse postmarketing events.

AERS = Adverse Events Reporting System.

* For the prevention of stroke and other cases of systemic embolism in patients with nonvalvular a-fib.

In its search (some might say crusade) to link repetitive head injury with chronic traumatic encephalopathy, or CTE, in professional sports, Boston University's Center for the Study of Traumatic Encephalopathy revealed that another NHL player, NY Rangers' enforcer Derek Boogaard, had the condition at a remarkably advanced stage. Boogaard died in May of this year, at the age of 28, as a result of an overdose of alcohol and prescription narcotics, and the Center solicited Boogaard's family to examine the athlete's brain. The results of the examination, which are convincingly described and displayed in a multipart NYT video piece, were reported by the paper on December 3rd. Boogaard is now the fourth NHL player with the condition in the Center's case series of this particular sport.*

Among the disturbing facets of the NYT coverage, NHL commissioner Gary Bettman downplays the risk of brain injury as a result of brawling in his league* and minimizes the Center's research as "preliminary" and "great for headlines." One is reminded of neurologist Ira Casson's essential denial of the association between repetitive head injury and CTE in January of 2010. Casson was co-chairman of the NFL's panel on brain injury until he resigned November of 2009, largely owing to his perceived insensitivity toward a possible link.

* The Center's case series of NFL players with CTE, 13 of 14, is substantially larger.
** Which he, inexplicably, denies is allowed.

For those who are following the XMRV-CFS-Mikovits story, science blogger John Timmer at ars technica provides a decent synopsis of the crazy soap opera/Greek tragedy.

Specifically Timmer outlines a complicated narrative in reasonably comprehensible (but not outstanding*) prose. The salient points:

• the rise and fall of data linking XMRV with the dubious CFS;
• researcher Judy Mikovits's refusal to abandon the idea that XMRV is associated with CFS, despite others' data indicating XMRV contamination;
• the symbiotic nexus between Mikovits and individuals with CFS, some of whom reportedly tried to undermine any investigation debunking the link between XMRV with CFS;
• Mikovits's subsequent unethical, and possibly criminal, behavior; and
• the overall integrity of the collective, collaborative scientific process (including nods to the DHHS and the "publishing system").

* One feels that Timmer's lengthy post could be a terrific short article with some professional editorial help.
CFS = chronic fatigue syndrome; DHHS = Department of Health and Human Services; XMRV = xenotropic murine leukemia virus-related virus.