Recently in Neurology Category
Two articles in this week's Neurology consider the significance of biomarkers for Alzheimer disease in the cognitively normal elderly.Essentially confirming a recently published Mayo Clinic study, investigators from Texas reported the high prevalence of beta amyloid deposits (detected with Avid Pharmaceutical's PET tracer florbetapir) in the brains of a substantial portion (~20%) of healthy elderly subjects (aged 60 years or older). A high burden* of beta amyloid was associated with 1) the presence of the e4 allele of APOE, a genetic risk factor for AD and 2) poorer cognitive performance on more sophisticated** cognitive tests. The authors, two of whom receive financial support or have a financial interest in Avid Pharmaceuticals, suggest that "subtle cognitive changes accrue as amyloid progresses." The implication being that brain amyloid in the so-called healthy elderly may be more predictive than not about the risk of AD (an essential point or spin, if you will, which argues for the clinical utility of Avid's amyloid tracer). However, the authors also concede that "the relative contribution of amyloid vs other well-demonstrated predictors of cognitive aging (eg, regional atrophy, leukoaraiosis) is unclear." Among recommended follow-up studies is the assessment of the long-term consequences of amyloid deposition—ie, Are cognitively normal elderly with high amyloid burdens more like to development AD...that is, if they live long enough?. The question can only be answered with longitudinal follow-up study, which is planned.
Another multi-multi-authored international study assessed the effect of aging on the diagnostic value of CSF biomarkers for AD—specifically the triad of decreased amyloid and increased total and phosphorylated tau—in cognitively normal elderly. This study was distinctive in that, in addition to assessing individuals with AD and healthy elderly controls, a short (2-year) longitudinal assessment was made of subjects with mild cognitive impairment (MCI). The related conclusions (if I'm reading this article correctly and can recall anything useful about specificity, sensitivity, and positive and negative predictive values***) are 1) that there is substantial overlap in the biomarker distributions among these subgroups with advancing age and 2) that (therefore) the specificity of the biomarkers for ruling out AD decreases with age. Nevertheless, the sensitivity (85% cutoff) for the triad in MCI and AD, perhaps not too surprisingly, remained stable. In other words, the biomarker triad lost its strength to identify people with truly negative results as they aged (a decreased negative predictive value), but its ability to recognize truly AD-consistent findings (positive predictive value) remained stable—at least according to the authors and/or how I'm reading the study.
The overall conclusion, therefore, is that positive biomarkers for AD become less and less meaningful (as an indicator of AD) in the general elderly population—which is, ironically, the group in which these tests are most likely to be needed and used.
Addendum: Some would view these study results to mean that amyloid deposits and the triad of CSF changes are suggestive (or even indicative) of age-dependent cognitive dysfunction, albeit very subtle cognitive dysfunction. But the capacity of these tests to support or even confirm a diagnosis of clinical AD—depending on how we're defining the condition (there's the rub, isn't it?)—appears to be eroded in the older, general population (because they're more likely to demonstrate these findings, regardless of whether they demonstrate clinical meaningful cognitive dysfunction).
APOE = apolipoprotein E; SUVR = standardized uptake value ratio.
* At a mean SUVR cutoff of 1.22 or greater.
** Meaning more sophisticated than the Mini-Mental State Examination (MMSE).
*** Damn you, rudimentary biostatistics, when will you leave me alone!
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
Medivation and partner Pfizer will cease development of Dimebon (latrepirdine), a now thoroughly defunct antihistamine, "for all indications and will terminate the ongoing open label extension study in Alzheimer's disease." The small biopharm company announced the official end of Dimebon development yesterday in a press release, and the story was picked up by the WSJ. Dimebon's demise is based on flat results in the companies' CONCERT trial, a phase 3 study in which Dimebon was assessed as add-on treatment to symptomatic treatment donepezil (Aricept) in patients with mild-moderate AD.Previous news on Dimebon (March 2010) was that it failed to improve cognition or global functioning in a placebo-controlled phase 3 study of patients with AD, and Medivation's share price plummeted 30 points on the dated news. In 2008, Pfizer agreed to pay Medivation $225 million upfront and another $500 million when Dimebon was FDA approved. The agreement—which split development costs and potential profits on a 60-40 basis (Pfizer assumed the larger share)—also conferred licensing rights to Pfizer for use of the drug in Huntington's disease. But Dimebon also disappointed in this devastating condition.
Pfizer was evidently betting on the chance that Dimebon would sail through US clinical development, given very favorable phase 2 results published in The Lancet in July of 2008. In a randomized, double-blind, placebo-controlled, multicenter study (N = 183) that was conducted entirely within Russia and funded by Medivation, patients with mild-moderate AD who received Dimebon demonstrated significantly less cognitive decline at 6 months, as measured by the ADAS-cog (mean score difference, 4.0; P < .0001). Although some were scratching their heads as to why an antihistamine would have a disease-delaying or merely symptomatic effect in AD. The ultimate, tired lesson: promising phase 2 results are not a harbinger of anything, except chancy phase 3 study.
Medivation reminds us that it's also developing an investigational drug (MDV3100) with Astellas for the treatment of advanced prostate cancer. The compound is in the phase 3 stage, and Medivation got a huge bump in its stock price in late October just before news of very favorable survival data was publicly released.
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.
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.
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.
Geron is dumping (or seeking a partnership for) its stem-cell development program, according to a company press release from November 14. The stated reason: Geron wants to focus on its "first-class" oncology programs, which are not beyond the phase 2 stage of development, in "the current environment of capital scarcity and uncertain economic condition." So Geron is closing its "GRNOPC1 trial for spinal cord injury to further enrollment, although it will continue to follow all enrolled patients, accruing data and updating [the] FDA and the medical community on their progress." As of July, only 4 patients had been enrolled in the landmark and highly publicized trial, in which "GRNOPC1 has been well tolerated with no serious adverse events," according to Geron.
Geron's exit from clinical hESC investigation leaves Advanced Cell Technology as the only company, to my knowledge, that is actively engaged in clinical trials of human embryonic stem cells (specifically in cases of Stardgardt's disease and dry age-related macular degeneration [AMD]).
Besides oligodendrocyte hESCs (GRNOPC1), Geron is/was developing cardiomyocyte, pancreatic islet cell, dendritic cell, and chrondrocyte hESCs.
Transverse section of the thoracic spinal cord from Gray's Anatomy (1918).
On Friday, the FDA approved Xarelto (generic name, rivaroxaban) for the prevention of stroke in patients with nonvalvular a-fib.* Approval of the direct factor Xa inhibitor, a product of Janssen Ortho (essentially JNJ) and Bayer Healthcare AG, was based on the mammoth-sized (N > 14,000) ROCKET-AF trial, in which Xarelto was found to be noninferior (ie, comparable) to warfarin for the prevention of stroke and other systemic embolic events in patients with nonvalvular a-fib and other stroke risks (mean CHADS2 score = 3.5).
Xarelto is the second anticoagulant to seriously compete with the old-as-dirt warfarin for the prevention of stroke in patients with a-fib. In October of last year, the FDA approved Boehringer Ingelheim's Pradaxa (dabigatran), a direct thrombin inhibitor. Neither medication requires the usually cumbersome protime monitoring, but Pradaxa, unlike Xarelto, was shown to be superior (at the 150-mg BID dosage) to warfarin for the prevention of stroke in a similar patient population.
Other important differences between Xarelto and Pradaxa are 1) the package insert for the former contains a so-called black-box warning (against the risks of thrombosis after drug discontinuation and spinal/epidural hematoma); and 2) Xarelto is taken once a day, unlike the twice-daily Pradaxa.
Beyond superior-versus-noninferiority claims, potential drug-related risks, and any convenience of dosing, a distinction between Xarelto and Pradaxa may emerge with respect to pricing. According to destinationrx, a month's supply of Xarelto costs $218.70 (~$7.30 per pill or day).** A month's supply of Pradaxa (60, 150-mg pills) will set you back $236.20 (~$7.87 per day). Much of the cost distinction between these 2 drugs, however, will probably depend on how formularies classify the drugs and exact prescription co-pays on health-plan members. Branded warfarin (ie, Coumadin) is, of course, a fraction of these costs, and the price of generic warfarin (which some cardiologists are loathe to prescribe owing to the unpredictability of protimes) is even lower still.
* As well as for the prevention of deep vein thrombosis (DVT).
** 10 mg daily is the dosage for DVT prophylaxis; for the prevention of stroke in patients without renal dysfunction, the recommended dosage is 20 mg per day.
Xarelto is the second anticoagulant to seriously compete with the old-as-dirt warfarin for the prevention of stroke in patients with a-fib. In October of last year, the FDA approved Boehringer Ingelheim's Pradaxa (dabigatran), a direct thrombin inhibitor. Neither medication requires the usually cumbersome protime monitoring, but Pradaxa, unlike Xarelto, was shown to be superior (at the 150-mg BID dosage) to warfarin for the prevention of stroke in a similar patient population.
Other important differences between Xarelto and Pradaxa are 1) the package insert for the former contains a so-called black-box warning (against the risks of thrombosis after drug discontinuation and spinal/epidural hematoma); and 2) Xarelto is taken once a day, unlike the twice-daily Pradaxa.
Beyond superior-versus-noninferiority claims, potential drug-related risks, and any convenience of dosing, a distinction between Xarelto and Pradaxa may emerge with respect to pricing. According to destinationrx, a month's supply of Xarelto costs $218.70 (~$7.30 per pill or day).** A month's supply of Pradaxa (60, 150-mg pills) will set you back $236.20 (~$7.87 per day). Much of the cost distinction between these 2 drugs, however, will probably depend on how formularies classify the drugs and exact prescription co-pays on health-plan members. Branded warfarin (ie, Coumadin) is, of course, a fraction of these costs, and the price of generic warfarin (which some cardiologists are loathe to prescribe owing to the unpredictability of protimes) is even lower still.
* As well as for the prevention of deep vein thrombosis (DVT).
** 10 mg daily is the dosage for DVT prophylaxis; for the prevention of stroke in patients without renal dysfunction, the recommended dosage is 20 mg per day.
From this week's issue of Neurology.Using MR venography and ultrasound* in 40 patients with MS, German investigators failed to replicate the 100% prevalence of chronic cerebrospinal venous insufficiency (CCSVI) defined famously (and notoriously) by Zamboni et al in 2009 (for background, start here or search Pathophilia for "Zamboni"). This newly published study, by the authors' account, is at least the 13th study** that has failed to validate Zamboni's theory of venous insufficiency in MS and his follow-up idea that the stenting of cerebral veins (ostensibly to improve the egress of iron) could be somehow objectively clinically beneficial.
Here's the parade of negative studies cited by the German authors (Doepp et al); 11 of these studies have been published in English-language peer-reviewed journals (all of which are reasonably well regarded).
Ultrasound studies
- Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol. 2010;68:173-183.
- Baracchini C, Perini P, Calabrese M, Causin F, Rinaldi F, Gallo P. No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. Ann Neurol. 2011;69:90-99.
- Krogias C, Schroeder A, Wiendl H, Hohlfeld R, Gold R. "Chronic cerebrospinal venous insufficiency" and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients. Nervenarzt.
- 2010;81:740-746. (article in German)
- Mayer CA, Pfeilschifter W, Lorenz MW, et al. The perfect crime? CCSVI not leaving a trace in MS. J Neurol Neurosurg Psychiatry. 2011;82:436-440.
- Centonze D, Floris R, Stefanini M, et al. Proposed CCSVI criteria do not predict MS risk nor MS severity. Ann Neurol. 2011;70:52-59.
- Sundstroem P, Wåhlin A, Ambarki K, Birgander R, Eklund A, Malm J. Venous and cerebrospinal fluid flow in multiple sclerosis: a case control study. Ann Neurol. 2010;68:255-259.
- Wattjes M, van Oosten BW, de Graaf WL, et al. No association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flow-quantification study. J Neurol Neurosurg Psychiatry. 2011;82:429-435.
- Zivadinov R, Lopez-Soriano A, Weinstock-Guttman B, et al. Use of MR venography for characterization of the extracranial venous system in patients with multiple sclerosis and healthy control subjects. Radiology. 2011;258-562-570.
Measurement of intraocular venous pressure
Measurement of CSF ferritin levels
* Specifically dynamic extracranial color-coded duplex sonography (ECCS).
** The cited studies do not include the essentially negative ultrasound study from the University of Buffalo, which was recently published in April in Neurology. Consequently the peer-reviewed tally comes to 14 negative studies.
Image of neck veins from Gray's Anatomy (1918).
By way of Nature Medicine's blog, A Spoonful of Medicine:Now 4 clinical trials with human embryonic stem cells (hESCs) have been launched; although 3 of these trials are from the same company (Advanced Cell Technology [ACT]) with the same hESCs (retinal pigment cells) for similar diseases (Stardgardt's disease, an inherited form of macular degeneration, and dry age-related macular degeneration [AMD]).
Here's the timeline (derived, in part, from a previous post):
1. In July 2010, the FDA lifted its regulatory hold* on Geron's clinical trial program for hESC-derived oligodendrocytes in subacute spinal-cord injury. The company announced this week that it has now enrolled 4 patients in the study. The "landmark" trial was featured in last week's SF Chronicle. The first unidentified enrollee was profiled by the Washington Post in April.
2. In November 2010, the FDA approved ACT's first trial of retinal pigment cells in patients with Stardgardt's disease (which affects only about 30,000 Americans but is an important disease model for dry AMD—which is much, much more prevalent). The first enrollee was treated in July at UCLA.
3. In January 2011, the FDA gave another nod to ACT to begin its hESC trial in patients with dry AMD. The first enrollee was treated in July at UCLA.
4. The UK Medicine and Healthcare products Regulatory Agency just gave approval to ACT to also conduct a trial of its retinal pigment cells in patients with Stargardt's disease at Moorfields Eye Hospital in London.
The Nature blog adds that ACT is in "late-stage talks" with other global regulators to conduct similar trials elsewhere around the world. News of these advances in clinical development of hESC treatment appears to have already been built into both companies' share prices—which are in the penny range.
* The hold was originally placed owing to preclinical concerns about the development of epithelial cysts at the site of injury.
Transverse section of the thoracic spinal cord from Gray's Anatomy (1918).
There's a lot of Facebook-generated schadenfreude in the aftermath of Michael Vick's concussion during yesterday's game between the Philadelphia Eagles (Vick's current team for you non-football fans) and the Atlanta Falcons (Vick's former football team). And while it's certainly nobody's duty to cheer for Vick or wish him well or even forgive him for his notorious animal cruelty, to celebrate his concussion as some kind of karmic payback is both inappropriate and nonsensical in a game where everyone (regardless of their off-the-field morals) is at risk. In a world of bizarre happenstance (of which American football is an important microcosm), narcissistic assholes can finish first,* and shit happens to decent people. Just ask Mike Utley.
As far as Vick returning to play, I suspect it will be soon, given a review of the videotape footage. It was a lateral helmet-on-helmet blow (with his own teammate!), followed by a bit of quick head torquing to the left—the latter of which is what probably rang Vick's bell.
* And given the bounty of narcissism in the NFL, it is probable that narcissistic assholes will finish first.
As far as Vick returning to play, I suspect it will be soon, given a review of the videotape footage. It was a lateral helmet-on-helmet blow (with his own teammate!), followed by a bit of quick head torquing to the left—the latter of which is what probably rang Vick's bell.
* And given the bounty of narcissism in the NFL, it is probable that narcissistic assholes will finish first.
