January 2010 Archives

The Conversation

(1974): Come on. It's been how many years since you've seen this movie? Rediscover what a national treasure Gene Hackman is. It's also one of Coppola's best, and I'm including The Godfather and The Godfather: Part II.

For my part, I've watched this film, about a wiretapper with a Catholic conscience, more times than I care to admit outside a group of drooling cinephiles: There's the pulling of focus to complement audio lapses; the showing of character (Hackman picking up sidewalk trash to emphasize his character's fastidiousness); the best dream sequence on film; the confession (play close attention to the developing mismatch between the audio and Hackman's lips*); tech geeks cutting loose; the wry nod to Psycho in the hotel bathroom; John Cazale (fer Christ's sake!); a fetal Harrison Ford; the surveillance camera-like closing. Yes. YES. YES!

* This guy's so wound up he can't even tell his deepest secret to a priest in a confessional.

In an apparent effort to atone for every Microsoft error message, the Gateses are committing $10 billion USD over the next 10 years for the research, development, and delivery of mortality-reducing vaccines to "the world's poorest countries." Some details of the financial pledge are available in today's press release from the couple's philanthropic foundation. The donated money is in addition to the foundation's already committed $4.5 billion for vaccine R&D.

The foundation's new support is motivated by recent data from the Johns Hopkins Bloomberg School of Public Health, which showed that a 90% vaccination-coverage level* in developing countries would prevent the deaths of about 7.6 million young children during the next decade. The number of lives saved could be ramped up to 8.7 million, if a malaria vaccine is introduced in the year 2014.

Another inspiration for the Gateses' pledge is the success of the rotavirus vaccine. In this week's NEJM, pooled results of a randomized, multicenter trial in South Africa (n = 3166 infants) and Malawi (n = 1733 infants) showed that a live, oral rotavirus vaccine (Rotarix; GSK) reduced cases of severe gastroenteritis due to the organism by 61% (4.9% vs 1.9%).** 

Also reported in this week's issue, the recent introduction of rotavirus vaccines in Mexico reduced diarrhea-related deaths by 35% among children younger than 5 years of age (18.1 vs 11.8 deaths per 100,000 children). The life-saving benefit of vaccination was even more apparent among infants younger than 11 months (41% mortality reduction).

Vaccine researchers looking for a chunk of the Gateses' big money can start here. But the foundation only accepts letters of inquiry (LOIs) from 501(c)(3) organizations and other nonprofits. Individuals need not apply.

* Which would include new vaccines for diarrheal illnesses and pneumonia.

** Although there was no significant difference in mortality, 2.5% vs 2.6%.

In Orange County, California, opening statements began yesterday in a multi-plaintiff civil case against Allergan, maker of Botox. The plaintiffs, including the mother of a deceased 7-year-old Texas girl with cerebral palsy, argue that off-label use of the company's drug caused severe adverse reactions including death. Trial coverage is provided in frustratingly nonlinear stories from ABC News and the LA Times.

Piecing together the information, the case against Allergan appears to rest on these issues:

1. Can injected botulinum toxin migrate sufficiently, especially when used for spasticity, to cause paralysis of respiratory muscles?
2. Can injected botulinum toxin cause seizures?
3. Did Allergan promote the off-label use of Botox for pediatric spasticity?

Related to the third issue is whether Allergan promoted the off-label use of Botox a) at particularly high doses and b) despite being aware of the related dangers.

For its part, Allergan is claiming that Botox did not cause the death of the 7-year-old girl, Kristen Spears, who received a series of 7 Botox treatments, beginning at the age of 6 years, for muscle spasticity in her legs, groin, and chest. Spears's mother alleges that these treatments led to the girl's clinical deterioration. Already underweight and with a baseline seizure disorder, Kristen allegedly experienced more severe seizures and swallowing difficulties after her treatments began. The latter problem, along with breathing problems, led to 10 hospitalizations. Kristen died of respiratory failure and pneumonia in November 2007, reports the LA Times. 

Apparently on the basis of Kristen's case and others, the FDA announced last year that it had received postmarketing reports of toxin spread, when the drug was used to treat spasticity in children or adults. The reported symptoms were essentially those of botulism: dysphagia and respiratory compromise. Consequently the agency required makers of botulinum toxin products to add a black-box warning to their drug labels, advising of the risk of toxin spread.

But in its very recent review of published trials, the American Academy of Neurology (AAN) did not find evidence of drug-associated hospitalization or death when botulinum toxin was used to treat limb spasticity in children. All trial-based adverse events—the most common being localized pain, excessive weakness, unsteadiness, increased falls, and fatigue—were transient. Dysphagia was observed in 2 patients among more than 500 children. Seizures or the increased severity of seizures were not reported.*

The plaintiffs also argue that Allergan, in violation of federal law, promoted the off-label use of Botox for pediatric spasticity and specifically in the case of Kristen Spears. The company allegedly paid for the girl's pediatrician, Rolf Habersang, and his nurse practitioner wife to attend sponsored training seminars in 2000 and 2001 and arranged for Dr. Habersang to receive instruction from an Arkansas pediatric neurologist. In depositions, Habersang testified that he learned to use Botox at a dosage of 15 units/kg—a high, but not-unheard-of, dose in the case of CP-related spasticity in kids. The suit also alleges that Allergan sales reps discussed the off-label use of Botox repeatedly with the Habersangs and provided the dosage range of 10-15 units/kg for juvenile spasticity.

While the off-label promotion reportedly took place, the company knew of mounting Botox-related adverse events, the plaintiffs claim. Beginning in 2005, Allergan became aware of European reports of toxin spread that led to aspiration and death, and the company accumulated its own safety database, at least some of which it shared with the FDA. Also according to the plaintiffs, Allergan knew of reports of Botox-related seizures.*

The plaintiffs' allegations of off-label promotion, if true, are at complete odds with Allergan's current stance against the FDA, which requested last year that the company disseminate safety information about the off-label use of Botox. The agency's request led to Allergan's pending federal suit against the government, which seeks "declaratory relief" from the FDA's long-time restrictions against the discussion of off-label uses of prescription drugs.

To confuse matters even further, Allergan's supplemental biologics license application (sBLA) for the use of Botox in upper-limb spasticity after stroke is currently being considered by the FDA. The goal date for the agency's decision is April 1st.

Currently Botox is approved to treat spasticity associated with pediatric CP in more than 60 countries, according to news reports. In the United States, the drug's off-label use for CP-related spasticity is, by and large, considered standard practice.

* Because the effects of botulinum toxin are strictly confined to the neuromuscular junction, it seems highly unlikely that a direct mechanism exists for the drug to cause or exacerbate seizures. However, it is conceivable that the drug, through respiratory compromise, could indirectly precipitate or exacerbate seizures through hypoxic brain damage. The case of Kristen Spears, as reported, is unusual in that she received injections of botulinum toxin in her chest, which could have paralyzed her intercostal muscles.

02/01/10 addendum: The total doses used in the pediatric Botox studies that were assessed by the AAN ranged from 2 to no more than 13 U/kg for upper-extremity spasticity (n = 193; age range, 2.5-10 years) and from 4 to 30 U/kg for lower-extremity spasticity (n = 286; age range, 2-16 years). Ranges of respective per-muscle doses, when provided, were 0.3-4 U/kg and 4-6 U/kg (only 1 lower-extremity study provided these data).

While plowing through Novartis's newly released financial report for 2009, I found this quiet gem: the "dossier" for Gilenia, the proposed trade name for fingolimod or FTY720, was submitted to the FDA and the European Medicines Agency in December. Now by "dossier," I assume that the company means its new drug application for the investigational compound; certainly the media are reasonably interpreting dossier as NDA.

This under-the-radar news of the NDA submission comes as a surprise—not because the fingolimod NDA was submitted (that was actually expected back in December), but because the news was provided so sotto voce.* I merely stumbled across the information while I was looking for more dirt on the company's recent Trileptal plea agreement.

And just in case I missed news of the NDA submission back in December (despite blogging semi-feverishly about the race between Novartis and Merck Serono to market the first-ever disease-modifying pill for multiple sclerosis), I rechecked the Google news archives. Nope, nothing.**

So the question is: Why no big announcement of the Gilenia NDA submission, Novartis? In typical fashion, Merck Serono trumpeted the submission of its NDA for the fast-track approval of oral cladribine in September.

Perhaps the answer has something to do with the FDA's December announcement that it refused to file Merck Serono's cladribine NDA. But I have to admit: I'm kind of flummoxed.

* Not to mention, a month after it happened.

** Although, last week, both Dow Jones and Reuters reported Novartis's NDA submission of fingolimod. I am mentally flaggellating myself for missing these reports.

While the FDA and Allergan remain at an impasse on how to disseminate off-label safety information for Botox, the American Academy of Neurology (AAN) just published its recommendations for use of the toxin in children with spasticity due to cerebral palsy (CP).*

On the basis of 14 20 controlled studies (N = 573) in which botulinum toxin A was assessed in children with CP-related limb spasticity, the AAN recommends injections for localized arm or leg spasticity "that warrants treatment." Although, the Academy writes, "There is insufficient evidence to support or refute the use of [botulinum toxin A] to improve motor function in this population."

In its safety assessment, the AAN found the most common treatment-related adverse events to be localized pain, excessive weakness, unsteadiness, increased falls, and fatigue. A few patients experienced urinary incontinence (n = 5) or dysphagia (n = 2). All adverse events were transient and did not require hospitalization or cause death—despite the fact that, last year, the FDA announced postmarketing reports of toxin spread, which compromised breathing and possibly led to death. The agency continues to investigate these cases.

According to lead author of the AAN guidelines, Mauricio Delgado, CP is the most common cause of spasticity in children, and most children with CP have spasticity. In Western nations, the prevalence of CP among 8-year-olds is 0.36%.

* An unapproved use.

Once again: I'll attempt to clarify the difference between participating in speakers' bureaus and delivering continuing medical education (CME).

The repeat effort to distinguish the two is prompted by today's newspaper and blog reports of physician Lawrence DuBuske, who decided to give up his academic gig at Harvard when the institution required him to make a choice between speaking for pharma and working at the Brigham and Women's Hospital.

Evidently DuBuske earned nearly $100,000 during April, May, and June of last year for giving Glaxo-paid talks to physicians and decided that the pharma gigs were just too lucrative.* In GSK's second-quarter report, "Fees Paid to US Based Healthcare Professionals for Consulting & Speaking Services," DuBuske's services are described as "speaker" and are apparently distinct from any CME honoraria that he might have received through GSK's educational grants (see, for example, "Grants & Charitable Contributions to US Based Healthcare Organizations").

A quick Google search shows that DuBuske did, in fact, also deliver certified CME programs last year (see here and here). Published disclosures through one of these CME programs reveal that DuBuske participated in the speakers' bureaus of 10 drug companies (including GSK) and received honoraria (assumed to be CME honoraria) through grants from 11 drug companies during the last 12 months (at least).

Distinction Between Speakers' Bureaus and CME

Participation in speakers' bureaus consists of giving talks that are based on slides and talking points created by the drug or medical-device company. The content of these talks must be reviewed by the company's medical-legal department and must adhere to FDA guidelines—for example, they must contain so-called fair-balance information. In essence, a healthcare professional who participates in speakers' bureaus becomes a glorified sales representative (like Daniel Carlat during his speakers' gigs for Wyeth).

Participation in CME requires either the development of educational content or its delivery to other healthcare professionals. In the case of industry-funded CME, funds are procured by an organization that is accredited to produce CME.** This organization—which can be a university-based CME department, a medical professional organization, or a for-profit medical education communications company (MECC)—then recruits faculty and assists them with the development of the educational content. The organization is also instrumental in deciding the format of the CME program (eg, Internet-based activity, dinner meeting) and enforcing recognized guidelines to ensure the independence of the program. Honoraria to faculty that develop or deliver content are paid by the accredited organization from the industry-supplied educational grant. Critics of industry-funded CME (eg, Daniel Carlat) argue that companies unduly influence the content of these CME programs through their indirect or direct pressure on grant recipients.

Policies of Partners Healthcare Regarding Speakers' Bureaus and CME

The newly enforced policies of Partners Healthcare, comprising Harvard's Mass General and Brigham and Women's Hospitals, "ban faculty participation in industry speakers bureaus." However, policies relating to industry funding for CME only address involvement at the institutional level; they do not explicitly prohibit Partners physicians from receiving honoraria for developing or presenting certified industry-funded CME programs.

Industry funding for "educational programs" (whether certified or not) may only be accepted after approval from Partners' newly created Educational Review Board, which requires that support for a specific CME program come from more than one company. Also Partners faculty who earn so much per year from a potential industry sponsor (eg, ≥$20,000) might be prohibited from participating in the creation or delivery of a Partners-produced CME program.

* Whether industry will still want to pay DuBuske to speak after his separation from Harvard is debated.

** In the United States, accreditation is most often bestowed by the Accreditation Council for CME.

Friday the FDA announced its approval of dalfampridine* (Ampyra; Acorda/Elan) to improve walking in all patients with multiple sclerosis. The drug, in the form of a sustained-release 10-mg tablet, has been assessed in at least 4 well-controlled MS trials; but a non-sustained-release version of the drug, which is believed to enhance nerve conduction by blocking potassium (or possibly, calcium) channels, has been clinically studied in MS since at least 1990.**

The overriding theme of these earlier trials was that the compound has a narrow therapeutic window—meaning that it improves mobility, but drug toxicity (ie, seizures, acute confusion) is associated with fickle serum-concentration spikes. This observation was the rationale for developing a sustained-release formulation, which is intended to produce adequate drug concentrations while averting the toxicity-inducing peak levels.

According to Ampyra's prescribing information, approval is based on 2, 14-week, multicenter, randomized placebo-controlled trials conducted in North America: a double-blind phase 3 study (N = 301) and a sequential single-/double-blind study (N = 239). Efficacy is supported by significantly improved speeds of a timed 25-foot walk in about one quarter to one third of treated patients (the percentage differences between dalfampridine- and placebo-treated patients). Positive effects on ambulation were seen in all forms of MS.

Although the Ampyra label does not carry a so-called black-box warning, the FDA advises of the risk of seizures, particularly in patients taking higher-than-recommended doses and in individuals with renal dysfunction. (Last time I checked, the baseline risk of seizure in MS patients was about 5%.) The maximum recommended dosage of the drug is 10 mg (1 tablet) every 12 hours. The label also states that a routine injection of interferon beta-1b (ie, Betaseron or Extavia) does not interfere with the pharmacokinetics of Ampyra.

Share prices of Acorda spiked at end-of-day trading on Friday, after momentarily plunging in mid-October when the FDA questioned the drug's safety and the meaningfulness of the trials' outcomes.

* Aka pyridine-4-amine, 4-aminopyridine, 4-pyridinamine, 4-pyridylamine, and fampridine.

** A directed PubMed search reveals that the first well-controlled trial of 4-aminopyridine was published in 1990 (Polman CH et al. 4-Aminopyridine in multiple sclerosis. Ann Neurol. 1990;28:589). 

Pickup on South Street

(1953): Cops trailing a va-voom courier of government microfilm (Jean Peters) are diverted to a subway pickpocket (Richard Widmark), who unknowingly steals it. The pickpocket then has to contend with prying visits from the courier, the cops, and loathsome pinko sympathizers at his waterfront shack.

Other than asking, "What's the moral compass of a petty thief?" the movie raises this question: "Where exactly was there a waterfront shack in Manhattan?"

N.B.--The movie also features the incomparable Thelma Ritter as a tie peddler and professional CI. Her pre-demise monologue is something, bitches.

The latest in potentially cloying medical movies, which I avoid like they're pandemic H1N1, is the newly released Extraordinary Measures, starring the dramatically limited Harrison Ford* and the doughy, but generally likeable, Brendan Fraser. The story, at least on its surface, is reminiscent of 1992's Lorenzo's Oil, in which parents labor valiantly against the rigid medical community (or in the case of EM, the pharmaceutical industry) to find a cure for their children's very rare afflictions.**

Because I'm as likely to see this movie as I am the what-they-show-in-hell Patch Adams, there will be no review based on actual viewing. Instead I rely on the consumer services of critics from major US newspapers.

The reviews, like the movie itself, are more or less predictable. The overarching theme: EM is cable TV, but just with Harrison Ford.

From Michael Phillips of the Chicago Tribune: "[Y]ou can find more provocative medical crises on TV every week of the year, albeit without this film's headliners." "The big confrontations between Fraser and Ford...feel strangely rote...they are, in fact, written and performed at Emmy-highlights-reel pitch." Two stars.

James Verniere of the Boston Herald: "If I had a nickel for every time Ford's craggy-faced, grumpy old man growls 'Get out of my lab' at someone in the film I'd have a dollar." But Verniere calls the cast, especially the supporting actors, "Extraordinary."

Carrie Rickey, Philadelphia Inquirer: "[S]lack, well-meaning disease-of-the-week drama of the sort one might encounter on the Hallmark Channel." Rickey likes Ford (he's "a gas") but finds Fraser "stiff and visibly uncomfortable."

Robert Butler, Miami Herald: "'Measures' is competent enough. However, it's not the least bit inspired...[I]t feels as if it has been carefully assembled not to reveal some truth so much as to push certain dramatic buttons for its audience."

Betsy Sharkey, Los Angeles Times: "[A] sort of uplifting drama that neither touches the heart nor tests the brain—a film that wouldn't make the Showtime...or HBO quality cut." Sharkey says that Ford does a "credible job" but implies that Fraser is out of his league. (And if the league standard is Harrison Ford, for God's sake, change careers.)

A. O. Scott of The New York Times is, perhaps, the most gracious: While he finds a paradox in a "movie about a medical breakthrough" that "is not especially eager to break new ground of its own," Scott says the film delivers an education about the process of medical research. "This is the main reason that 'Extraordinary Measures'...rises above some of its made-for-TV trappings."  

* The last and only time I found Harrison Ford interesting in a dramatic role (and it was a bit part) was in The Conversation.

** In Lorenzo's Oil, the disease was adrenoleukodystrophy; in Extraordinary Measures, Pompe disease. The major difference between these 2 stories is that the treatment developed in EM, Myozyme (alglucosidase alfa; Genzyme), is FDA approved.

An earnest-looking Brendan Fraser and a gruff-looking Harrison Ford in a still from Extraordinary Measures.

In the neck-and-neck race to market the first-ever disease-modifying pill for multiple sclerosis, both Novartis and Merck Serono scored by getting their respective pivotal trials of fingolimod and cladribine published in the venerable NEJM this week. (For background, start at last year's No. 8 story.)

And because I like to make comparative tables, here's another one providing the salient features of the 3 studies—all of which enrolled patients with relapsing-remitting MS.

Study Features	FREEDOMS	TRANSFORMS	CLARITY
Phase	3	2	3
Drug	Fingolimod 0.5 or 1.25 mg/d	Fingolimod 0.5 or 1.25 mg/d	Cladribine 3.5 or 5.25 mg/kg*
Comparator drug	Placebo	IM interferon-beta 1a 30 µg/wk	Placebo
Duration	24 months	12 months	96 weeks
Enrollees	1272	1292	1326
Completers	1033 (81%)	1153 (89%)	1184 (89%)
Annualized relapse rate (primary outcome)	55% or 60% ↓	39% or 51% ↓	54% or 58% ↓
Major secondary outcomes	26% or 31% ↓ disability progression; significant ↓ MRI lesions	No difference in disability progression	~30% higher relapse-free rate; significantly ↓ 3-month disability progression and MRI lesion burden
Notable drug-related adverse events	Bradycardia, AV block, macular edema, high liver enzymes, mild HTN	Fatal infections,** nonfatal herpes, bradycardia, AV block, HTN, macular edema, skin cancer, high liver enzymes	Lymphocytopenia, herpes zoster

* 2-4 "short" courses for the first 48 weeks, then 2 short courses starting at weeks 48 and 52 (total treatment, 8-20 days/year).
** Two in high-dose group: disseminated primary varicella zoster and herpes encephalitis.

What's the take-home?

Although trial-to-trial comparisons are problematic, both drugs appear to have comparable and significant efficacy. Novartis, developer of fingolimod, has an edge owing to its phase 2 study with the standard MS treatment of interferon beta.

But the uptake of these drugs, once they are approved (and I predict they will be...eventually), will likely depend on their safety profiles. Fingolimod, in particular, is associated with some wicked side effects.

AV = atrioventricular; CLARITY = Cladribine Tablets Treating Multiple Sclerosis Orally; FREEDOMS = FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; HTN = hypertension; TRANSFORMS = Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis.

This is the final post in which randomized, clinical trials of the potentially active ingredients in the branded drink Souvenaid are reviewed. (For background on Souvenaid's development, go here, here, here, and here.) 

The remaining components to be examined in the nutritional supplement are phospholipids, choline, and uridine monophosphate (UMP).

In the case of UMP, a directed PubMed search reveals no randomized, controlled trial of the RNA nucleotide in Alzheimer disease. Therefore the rationale for assessing UMP in cognitive dysfunction appears to extend solely from animal studies (for instance, see a 2008 rat study by anchor author Wurtman, who is also coauthor of the recently published Souvenaid study).

The rationales for giving phospholipids or choline to AD patients are either 1) to bolster the integrity of neuronal membranes by providing the necessary building blocks, or b) in the case of choline, to supply a precursor for the neurotransmitter acetylcholine, which is deficient in AD. 

Barring the negative studies of lecithin,* a potential source of both phospholipids and choline, there are at least 9 randomized, controlled trials (published from 1986 to 2003) of these substances in dementia. Six studies, from the 80s and 90s, assessed the specific phospholipid phosphatidylserine; 3 studies assessed choline alfoscerate or citicoline. Most of these studies enrolled outpatients with mild-to-moderate AD. General study features are tabulated here:

Intervention	N	Duration	Outcome in a Nutshell
Phosphatidylserine
1986	42	6 wk	Trend toward improvement or significantly improved
1986	No abstract	—	—
1992	51	3 mo	Improvement observed in milder disease
1992	33	2 mo	Mixed improvement
1992**	40	6 mo	PET-correlated cognitive improvement
1994**	70	6 mo	Temporary improvement
Acetylcholine precursors
1993	126	?	Significant improvements with choline alfoscerate
1999	30	3 mo	Citicoline associated with improvements in APOE ε4 carriers; effect more pronounced in mild disease and associated with physiologic changes
2003	261	6 mo	Choline alfoscerate improved cognition or delayed cognitive decline

Cumulative data from the relatively small, controlled studies of phosphatidylserine in AD suggest that whatever cognitive improvements exist, they are short lived.

The most compelling support for the use of choline (ie, choline alfoscerate) comes from a sizeable, randomized, placebo-controlled, 6-month study performed at the Instituto Nacional de la Senectud in Mexico City. Cognitive assessments, performed with the ADAS-cog and other well-recognized tests, showed either a significant delay in cognitive decline or actual cognitive improvement. 

Nevertheless, these impressive results must be replicated. 

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; PET = positron emission tomography.

* A directed PubMed search reveals at least 5 studies of lecithin in AD, published from 1981 to 1987. Among the 3 small placebo-controlled studies in which an abstract is provided, none showed clinical improvement with supplementation (treatment duration, from 10 weeks to 6 months), despite a rise in plasma choline levels. These search results omit at least 8 trials of the defunct cholinesterase inhibitor tacrine, in which lecithin was provided as standard treatment.

** Treatment options were phosphatidylserine or pyritinol, a vitamin B6 analog.

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

Vitamin E and other antioxidants are included in the branded, nutritional drink Souvenaid, which is being developed as a treatment for Alzheimer disease. However, well-controlled clinical data to justify their use in AD or mild cognitive impairment (MCI) are scarce, and positive trial data require qualification.

The most prominent (and confounding) trial in which vitamin E was assessed in AD was the Alzheimer Disease Cooperative Study, published in 1997 in the NEJM. In this multicenter US study, 341 patients with moderately severe AD received randomized selegiline (10 mg/d), vitamin E (2000 IU/d), both, or placebo in a double-blind fashion.

In the unadjusted analysis, there were no significant differences among the 4 treatment arms with respect to the combined primary outcome of death, institutionalization, loss of the ability to perform basic ADLs, or severe dementia at 2 years. However, the trial results had to be statistically accommodated, because the mean baseline MMSE score of placebo-treated patients, despite randomization, was significantly higher than those of other enrollees. "[A]nd this variable," the authors predictably concluded, "was highly predictive of the primary outcome."

And so an adjusted analysis was performed, in which the investigators observed significant delays in the combined primary outcome with all 3 randomized treatments—selegiline, vitamin E, and both—when compared with placebo.

But these data are at odds with results from a 3-part Italian study of vitamin E and donepezil (Aricept; Eisai/Pfizer), published sequentially in 2001, 2002, and 2003. Among 40 patients with moderately severe AD who received randomized vitamin E (2000 IU/d), latencies of P300 recordings (a very rough, electrophysiologic indicator of cognition*), and cognitive scores declined significantly at 26 weeks (when compared with donepezil treatment [5-10 mg/d]).

These findings are supported by follow-up results, in which P300 latencies and cognitive test scores deteriorated with vitamin E supplementation at 3 months in patients with mild AD (n = 30). Cognition also significantly declined in subjects with moderate-to-severe AD (n = 30) who received vitamin E. Other electrophysiologic indicators of cognition worsened in a smaller and much briefer (ie, 30-day) study of vitamin E and donepezil in patients with "mild dementia."

To assess the potential benefit of vitamin E supplementation to prevent AD, investigators at the Mayo Clinic conducted a randomized, double-blind, placebo-controlled study of 769 patients with amnestic MCI. The results, published in a 2005 issue of the NEJM, showed no significant delay in the development of AD at 3 years with vitamin E (2000 IU/d) or donepezil (10 mg/d).** The annual rate of progression from MCI to AD was 16%, a rate that has been subsequently confirmed. 

The most recent trial assessing vitamin E in AD was published last year. In this small Spanish study, 57 patients with AD were assigned to placebo or vitamin E (800 IU/d) for 6 months. Among the 33 study completers, investigators correlated a controversial measure of oxidative stress (reduced glutathione) with maintained cognition in vitamin E-treated subjects. The authors concluded that "supplementation of AD patients with vitamin E cannot be recommended without determination of its antioxidant effect in each patient."

The American Psychiatric Association, as of 2007, no longer recommends vitamin E for the treatment of dementia because of limited efficacy data and potential safety concerns. The latter relate to reports of increased cardiovascular and cerebrovascular mortality. However, these risks may not be relevant in AD patients, according to a recent, longitudinal survival study.

So these clinical data for vitamin E in AD or MCI leave us firmly nowhere.

But there are other potential antioxidants in Souvenaid: namely, selenium and vitamin C. What are the clinical data to support their use in dementing disorders?

There is one semi-controlled Polish study (1999) in which selenium (100 µg every other day) was compared with placebo and some proline-rich substance isolated from sheep colostrum [yeesh] in patients with mild or moderate AD (N = 46). Psychiatrists blinded to treatment determined that cognition stabilized in 13 of 15 selenium-treated patients at 1 year, vs 8 of 16 placebo-treated patients. (The sheep colostrum product reportedly improved or stabilized cognition in all 15 treated patients.)

Controlled assessments of vitamin C, aka ascorbic acid, in AD are virtually absent, at least by my search. An Italian AD study, published in 1995, used ascorbic acid as a reference standard. In a later Czech study, 50 mg of ascorbic acid was given daily to all AD enrollees. 

* Increased latencies suggest delays in neuronal transmission.

** However, the rate of progression to AD at 12 months was reduced with donepezil treatment, and the AChEI prevented full-blown dementia at all time points in carriers of 1 or more APOE e4 alleles--a known genetic risk factor for late-onset AD. More recent, controlled studies of donepezil in patients with amnestic MCI suggest that the drug delays the progression to AD among depressed individuals but has only a modest effect on cognition in a more inclusive population with MCI.

AChEI = acetylcholinesterase inhibitor; ADLs = activities of daily living; MMSE = Mini-Mental State Examination; APOE = apolipoprotein E.

Ingredients in the proprietary nutritional drink Souvenaid, which its developers claim work synergistically to rejuvenate neuronal synapses in Alzheimer disease, include several B vitamins. (For necessary background on Souvenaid development and negative trials of omega-3 fatty acids [another ingredient in Souvenaid] in AD, go here and here.)

The rationale for using vitamins B6,* B9 (folic acid), and B12 specifically in AD is to reduce levels of homocysteine, an independent risk factor for AD. However, a directed PubMed search provides little evidence of the benefit of oral B-vitamin supplementation in dementing disorders. A total of 4 randomized, double-blind, placebo-controlled trials were discovered, in which 1 or more of these vitamins were assessed in patients with AD.

Published in 2007, a Thai study enrolled 89 AChEI-treated individuals with mild-to-moderate AD, all of whom had normal folic acid and vitamin B12 levels. The daily, oral administration of B12 500 mg and a multivitamin containing B6 (5 mg) and folic acid (1 mg) provided no statistically significant cognitive benefits at 26 weeks (measured by using the 11-item ADAS-cog); nor was the ability to perform activities of daily living (ADLs) affected. Negative clinical benefits were observed despite the reduction of homocysteine levels in treated AD patients.

A smaller UK pilot study, reported in 2008, revealed that folic-acid supplementation in 57 AChEI-treated AD outpatients improved the ability to perform instrumental ADLs and social behavior (a combined outcome) at 6 months; but daily folic acid did not significantly alter cognition (measured with the MMSE).

The same year, JAMA published results of an 18-month multicenter US study of 409 individuals with mild-to-moderate AD and normal folic-acid, B12, and homocysteine levels. Randomized, oral supplementation with B6 (25 mg/d), folic acid (5 mg/d), and B12 (1 mg/d) reduced homocysteine levels but had no effect on cognitive decline (measured with the ADAS-cog) in 340 "completers." Curiously depression was more likely to occur in supplemented patients.

Finally last year a multicenter Dutch study was printed, in which "vascular care" was assessed in 130 outpatients with AD and evidence of cerebrovascular disease on brain images. The combined, randomized treatment of aspirin, folic acid, and B6 provided no statistical benefits with respect to measures of cognition, dementia-related disabilities, or behavioral problems at 2 years. Rates of institutionalization were also comparable between patients who received vascular care and those who didn't. 

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; AChEI = acetylcholinesterase inhibitor (eg, Aricept [donepezil]); MMSE = Mini-Mental State Examination.

* It should be noted the B6 supplementation is associated with a dose-dependent peripheral neuropathy (for instance see Berger et al and Parry and Bredesen). The Food and Nutrition Board of the Institute of Medicine recommends that daily B6 intake should not exceed 100 mg.

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

Blast of Silence (1961): The stylized voiceover makes it noir; the on-location filming makes it neorealism. This coarse, low-budget hybrid from and starring Allen Baron follows an itinerant hit man, who develops second thoughts about his latest job in Manhattan over the Christmas holidays.

The short answer: it really isn't a mandate.

Yale law professor Jack Balkin explains further in his "Perspective" piece in this week's NEJM.

Balkin's overarching argument is that the requirement to purchase health insurance, described in both the House and Senate forms of the healthcare reform bill, is really a tax* on those persons** who fail to purchase health insurance. And, according to the Constitution, Congress has the power to legislate taxes that serve the general welfare. End of story.

Balkin predicts that the Supreme Court won't even touch the health-insurance mandate/tax issue, unless a federal court of appeals knocks it down. And in that case, the high court will uphold it.

* In the House version of the bill, the income of the uninsured is taxed; in the Senate version, an uninsured individual is taxed on an event basis--meaning, he is taxed each month that he doesn't purchase health insurance.

** Meaning individuals who don't already have employer-provided health insurance. The "mandate" also does not apply to dependents, Medicare or Medicaid recipients, military families, overseas ex-pats, or religious objectors.

Off-topic addendum: In the Age of Transparency, the NEJM has evidently found a way to avoid the multiple columns of small type that are sometimes necessary to print all of the disclosures of its published authors. Provide an online link instead to the author's filled-out disclosure form.

Yesterday, James Beck over at the Drug and Device Law blog provided an update on Allergan v the United States of America et al—last year's No. 5 story at this-here Pathophilia blog. I completely missed it, but 4 days ago the government responded to Allergan's "free-speech" complaint of last year with its own "45-page whopper" (Beck's words) of a motion to dismiss or for summary judgment.

Plowing through the document, my non-legal mind distills the government's 2 basic counterarguments to Allergan "free-speech" complaint to the following.

1. The argument for dismissal: The case isn't "ripe"—meaning, Allergan hasn't said anything yet to potentially violate the law. Of course, this argument highlights the double bind in which the FDA has put the company. Allergan has been asked by the agency to publish safety information about the off-label use of Botox for spasticity; but Allergan logically fears that if it does so, it will run afoul of federal law that prohibits drug promotion for off-label purposes. Allergan's fear is justified by text in the government's own motion, which reads, "advertisements for prescription drugs may not 'recommend or suggest' the drug for unapproved uses."

But the government allows itself a little wiggle room, by also stating, "It is critical to understand, however, that not all speech or actions by a manufacturer regarding an unapproved use is taken by the FDA to be evidence of intended use." However, I find the government's extended argument confusing: "Absent promotion, the dissemination of safety information relating to an unapproved use would not establish that the use is an intended use, and therefore would not trigger either the new drug approval process or the misbranding provisions of the FDCA [Food, Drug, and Cosmetics Act]."

The crux of the issue seems to be whether safety information regarding the off-label use of a drug, on its face, promotes a drug for that off-label use. The government says not necessarily. (In other words, "Hey, trust us. We won't prosecute you for something we ask you to do...unless we decide you've gone too far."). But again, how can a company know when off-label safety information constitutes illegal promotion before it potentially breaks the law?

2. The argument for summary judgment: Allergan's suit is a "frontal assault" (not a full-frontal assault?) on the 1962 Harris-Kefauver Amendment to the FDCA, which requires that a company prove the efficacy of a prescription drug for a particular indication before it can be promoted and sold in interstate commerce. The government lays out a series of contradictory (at least to me) arguments, while invoking a couple of metaphors from Greek mythology (to Beck's amusement).

Essentially the government claims a) current regulatory laws restricting commercial speech are Constitutional, and 2) if it prevailed, Allergan's complaint would allow the promotion of drugs for unapproved uses, thus placing the public health in jeopardy. Beck parses out the government's arguments in reader-friendly bulleted fashion and provides pointed commentary (like a parsimonious "Wow").

But what gets me (again) are the government's incongruous or ambiguous statements, which (as Beck points out) emphasize the vagueness of regulations that restrict the speech of a drug company—and specifically, 21 § CFR 201.128 regarding intended uses. The government writes stuff like...

The Act and regulations leave ample room for Allergan to disseminate truthful, non-promotional information about dangers associated with unapproved uses of Botox, above and beyond the information that FDA has already directed Allergan to provide. [emphasis added]

Okay, the issue again: How do we distinguish between promotional and nonpromotional information?

Well, try this head-spinner on intended uses:

When a manufacturer engages in speech such as advertising or promotional labeling that expressly or implicitly promotes a particular use, FDA treats such speech as evidence that the use is intended. [emphasis added]

Oy.

Beck's even more impressed with the vagueness of this statement.

In practice, FDA usually does not treat an unapproved use as an intended use solely because the manufacturer knows that the unapproved use is taking place.

Usually. [shudder] 

But all of this legal maneuvering between Allergan and the FDA may be moot (or "moo," as Joey on "Friends" would say*), according to the government's motion. In August 2008, Allergan submitted a supplemental biologics license application (sBLA) for the use of Botox in upper-limb spasticity after stroke—one of the off-label indications at issue. However, in May 2009, the FDA declined to approve the drug for the new indication, citing application deficiencies. Then 4 months later, Allergan resubmitted its sBLA. The "goal date" for the FDA's decision, per the motion, is April Fool's Day.

So is the government saying, "Wait. Give us time to approve Botox for spasticity, and this whole free-speech mess we've created will go away"?

N.B. A motion hearing in Allergan v the United States of America et al (09-cv-1879) is still scheduled for March 2nd, in the US District Court for the District of Columbia.

* Which is just about the only funny thing that was said on "Friends."

Developers of the proprietary drink, Souvenaid, claim its ingredients work synergistically to restore neuronal synapses in diseases like Alzheimer disease (for necessary background on Souvenaid clinical development, see yesterday's post). However, many of the individual components in the formula have been shown to be ineffective, or only marginally effective, in AD. Among these ingredients are omega-3 fatty acids—specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). One rationale for using DHA and EPA supplementation in AD is based on their potential to reduce disease-associated inflammation.

A directed PubMed search reveals exactly 1 randomized, double-blind, placebo-controlled study of DHA and EPA in AD. The 6-month study, with a 6-month open-label extension, was performed at the Karolinska Institute between 2001 and 2004 in 174 patients with mild-to-moderate disease who were receiving acetylcholinesterase-inhibitor therapy (eg, Aricept). Data were collected on cognitive decline, neuropsychiatric symptoms, weight gain, and plasma markers of inflammation and were parsed into 4 articles, published from 2006 to 2009.

Daily DHA (1.6 g) and EPA (0.6 g) supplementation did not affect cognitive decline (measured with the MMSE and ADAS-cog scales) at 6 months; however, in the subgroup with very mild AD (n = 32), supplementation was associated with a statistically significant reduction in the decline of the MMSE score. (This observation likely informed the enrollment of patients with very mild AD in the Souvenaid trial.)

Nor did DHA/EPA supplementation affect neuropsychiatric symptoms, the ability to perform activities of daily living (ADL), or caregiver burden at 6 months. In detailed subgroup analyses, however, supplementation reduced agitation in APOE ε4 carriers* (n = 125) and depression in APOE ε4 noncarriers (n = 49). Make of that what you can; I don't make much of it.

On the other hand, weight increased significantly with supplementation at 6 months and continued to increase for both treatment groups in the open-label extension phase. APOE ε4 noncarriers and high DHA plasma levels were independently associated with weight gain, reported the authors.

As expected, plasma levels of DHA and EPA increased with supplementation (n = 23). In addition, they were associated with reduced levels of some inflammatory cytokines (eg, interleukin-6).

* A genetic risk factor for late-onset AD.

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; APOE = apolipoprotein E; MMSE = Mini-Mental State Examination.

Image of cod liver oil capsules from Wikipedia.

Last week, various mainstream news sources reported the positive results of a randomized, double-blind, placebo-controlled, multicenter study of Souvenaid, a proprietary nutritional drink, in people with mild Alzheimer disease. The objective of the trial, printed in the latest issue of Alzheimer's and Dementia, was to restore neuronal synapses by providing "rate-limiting precursors for membrane phosphatide synthesis, such as...uridine, omega-3 polyunsaturated fatty acids, and choline," which Souvenaid contains. Citing rodent studies, the authors claimed, "These nutrients synergistically increase brain levels of phosphatide molecules that comprise the bulk of synaptic membranes, and brain levels of specific synaptic proteins, suggesting that they also increase synapse formation" [emphasis added].

Yes, it'd be nice to have a boosted smoothie that wards off cognitive decline, but...

To the credit of at least one news source, mainstream coverage of the Souvenaid study was tempered by reports of AD experts' "disdain" for the trial and its results.

Among the criticism:

• The relatively short length of the study, 12 weeks. The generally accepted minimum duration of an AD trial is 26 weeks; most extend to 1 year or longer.*
• The lack of benefit when measuring cognition with standard tests, like the ADAS-cog.
• The potential conflicts of interest among the authors, given their intimate connections to the company that makes Souvenaid. Notably coauthor Richard J. Wurtman, of MIT, owns patents on "uridine, omega-3 fatty acids, and choline to treat brain diseases by enhancing synapses," according to the study disclosures.

A review of the study article reveals additional problems.

• Because one unnamed study site failed to comply with ICH-GCP guidelines, data from 13 individuals (~6% of the study population) were excluded from the efficacy analysis.
• At baseline, approximately 40% of enrollees scored 0, the lowest score, on the delayed verbal-recall test (Wechsler Memory Scale-revised), one of the 2 primary outcome measures. This skew in the study population required the authors to use a nonparametric analysis (eg, use general categories of better, worse, and unchanged), instead of the planned parametric assessment (that is, use mean score changes in the study arms). Furthermore it's not clarified that the percentages of 0 scorers at baseline were similar in the 2 treatment groups. If they were not, then the potential for enrollees to decline on the basis of assigned treatment would certainly be affected.

Finally, although the authors claim synergistic effects of Souvenaid's active ingredients on synapse restoration, many of the individual ingredients in the formula have been shown to be ineffective (or only marginally effective) in AD. Watch for upcoming posts at the Pathophilia blog that review these AD studies.

* A 12-week blinded extension phase was conducted (n = 161). No benefit was seen with respect to the 2 primary outcome measures, but immediate verbal recall was significantly better in the group receiving Souvenaid.

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; GCP = good clinical practice; ICH = International Conference on Harmonisation; MMSE = Mini-Mental State Examination.

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

Addendum: On the basis of the 12-week proof-of-concept study, the makers of Souvenaid are recruiting enrollees for a multicenter US study, called S-Connect. The trial, however, is not registered in the NIH database. The 40 US trial sites, 3 of which appear to be university affiliated, are listed here.

In an apparent effort to suppress criticism of industry bias in continuing medical education (CME), Pfizer is giving Stanford $3 million to produce such programs without condition. Specifically the grant will not stipulate therapeutic areas of interest for the educational activities—a major departure from current, recognized standards for US-based CME. A full report, with soup-to-nuts opinions from physicians on Pfizer's new type of pooled CME grant to the university, is available in today's NYT.

However...however.

Decisions have apparently been made that Stanford's Pfizer-funded CME will concentrate on diabetes, cardiovascular disease, smoking cessation, and infections, reports the paper. All of these therapeutic areas are of potential interest to the monolithic company.* For example, Pfizer makes Chantix, a smoking-cessation drug; the blockbuster statin Lipitor; and Caduet, a combo calcium-channel blocker/statin.

Now whether bias is inherent in a CME grant that merely specifies a therapeutic area is up for debate. For instance, see the comments here.

And for the historical record:

1. Last year, Pfizer announced that it would no longer directly provide CME grants to medical education communications companies (MECCs), presumably because of the perception of bias in MECC-produced CME.
2. In 2004, Pfizer agreed to pay the government $430 million to settle allegations of promoting Neurontin (gabapentin) off-label. One alleged off-label outlet: Pfizer-funded CME.**

* Implying here that it might be hard to find a therapeutic area that is not of interest to Pfizer.

** Also 2 months ago, it was revealed that the protocol-defined primary endpoints in company-funded trials of Neurontin were often changed.

Green for Danger (1946): Interesting title for a black-and-white whodunit.

An off-beat inspector from Scotland Yard (Alistair Sim)* investigates the surgical death of a postman and the murder of an OR nurse at a remote English hospital. The suspects are soon limited to 5 overdramatic medical personnel—2 of whom deliver a priceless over-the-top sequence of mad laughter, followed by face slap, followed by hysterical sobbing.

* Think precursor to Columbo.

The usual HT to KTG.

Among the major differences between the House and Senate healthcare reform bills is this issue: Who will oversee the newly created competitive insurance "exchange"—a sort of Expedia.com equivalent for the 30 million people without job-provided health insurance? The House bill proposes national regulation of the exchange; the Senate wants state-level oversight. Both Congressional bodies have their points, according to today's WSJ.

House Democrats want federal regulation to promote consistency and thwart insurers who would try to create and exploit loopholes at the state level. House legislators believe they're owed this concession in exchange for eliminating a new government public insurance plan in the final bill.

The Senate and the insurance industry, on the other hand, want states to regulate the exchange—arguing that state administrators have a better understanding of the local markets and their consumers. Proponents of state regulation also cite the substandard federal regulation and abuse of Medicare Advantage plans.

Another bone of contention for the insurance industry is the Senate's proposed tax on high-premium group-health plans—a tax that is intended, in part, to finance healthcare reform. Insurers want the tax reduced and phased in. Otherwise the industry will have to pay up to $224 billion during the next decade, estimates a top insurance lobbyist.

For the record, President Obama wants the tax on high-premium group-health plans in the final bill.

Pandemic influenza may "notably increase" the overall death rate for pregnant American women in 2009. The prediction is based on data from pregnant or postpartum women who died of infection with the 2009 H1N1 virus in California during a 4-month period. An assessment of flu-related hospitalizations and deaths in this population is available in the latest issue of the NEJM.

Investigators from the California Pandemic (H1N1) Working Group collected data from 239 pregnant, postpartum, or nonpregnant women of reproductive age who were hospitalized with or died of probable or confirmed* pandemic flu between April 23 and August 11, 2009. Most (~78%) acquired infection in June or July.

Underlying chronic conditions, specifically asthma, were observed in substantial percentages of all women and particularly nonpregnant women—confirming that pregnancy itself is a risk factor for severe infection with the 2009 H1N1 virus.

Patient Feature	Pregnant (n = 94)[a]	Postpartum (n = 8)	Not Pregnant (n = 137)	P Value [b]
Chronic illness, %	34	25	60	<.001
Asthma, %	16	0	28	.04
Nongestational diabetes, %	2	0	15	.002
Immunosuppression, % [c]	3	0	15	.006
Neurologic disorder, %	1	12	10	.009
Hypertension, %	5	12	17	.009
Gastrointestinal disease, %	2	0	14	.006

a. Percentages based on pregnant women for whom data were available.
b. Pregnant women vs nonpregnant women.
c. Related to cancer or transplantation.

Notable among pregnant women was a rapid clinical deterioration that looked qualitatively different from typical seasonal influenza. About 25% of pregnant women who required mechanical ventilation were intubated at the time of hospitalization, and several deliveries were made in intensive care units. ICU admission and death were about 4 times more likely in pregnant women who received antiviral treatment after 48 hours of symptom onset. Delay of antiviral treatment appeared to be associated with false-negative rapid-antigen test results.

During the 4-month period, the mortality ratio for pandemic flu in pregnant women was estimated at 4.3. Previous mortality ratios for all-cause death among pregnant women in California (2005) and in the United States (2006) were 19.3 and 13.3, respectively.

The authors urge pregnant women to be vaccinated against pandemic flu on the basis of their findings and preliminary vaccine-trial results.

RT-PCT = reverse-transcriptase polymerase chain reaction.

* Probable disease was defined as a positive result by real-time RT-PCR for influenza A that could not be subtyped H1 or H3. Confirmed disease was defined as a positive result by real-time RT-PCR that was specific of 2009 H1N1 influenza.

Depiction of H1N1 virus from Wikipedia.

Ira Casson—neurologist, former co-chairman of the NFL's panel on brain injury, and target of yesterday's House Judiciary Committee hearing on football-related concussion—is technically correct: Data linking repeated head injuries in American football to lasting brain damage are limited.

But as they say, absence of evidence is not evidence of absence. Moreover, a link is highly plausible, given the well-described association between repetitive brain injuries in boxing and neurologic deterioration—aka dementia pugilistica.

To remedy the shortage of evidence on sports-related head injury, the nonprofit Sports Legacy Institute partnered with the Boston University School of Medicine in 2008 to create the Center for Traumatic Encephalopathy. The Center's raison d'etre is to assess neuropsychiatric symptoms in athletes and to examine their donated brains for pathologic signs.

The Center's most recent publication, printed in July of 2009, provides a review of 48 cases of neuropathologically verified chronic traumatic encephalopathy, or CTE, in the medical literature and adds data from 1 professional football player and 2 boxers. The clinical picture of CTE features memory loss, behavior and personality changes, speech problems, parkinsonism, and other gait or movement disorders.

Pathologically CTE is typified by nearly global brain atrophy and the accumulation of tau protein in neurofibrillary tangles. Consequently CTE is classified a tauopathy, like other neurodegenerative disorders (including Alzheimer disease); however, CTE can be distinguished from other tauopathies, the authors claim, by its predilection for certain brain areas (eg, the superficial layers of the cerebral cortex). Deposits of amyloid beta, typically in the form of plaques and characteristic of AD, are evidently not as common in CTE.

In December, the Center also described postmortem CTE in an NHL player. In an effort to accumulate more data, the Sports Legacy Institute encourages athletes to donate their brains to the Center. Current Legacy donors are listed at the Institute's website, along with links to their stories. Several of these cases were discovered by pathologist Bennet Omalu* and colleagues, who recently reported microscopic evidence of CTE in 5 professional athletes who attempted or committed suicide at relatively young ages.

* Omalu is the author of Play Hard, Die Young: Football Dementia, Depression and Death.

01/06/10 addendum: While the effects of performance-enhancing drugs (eg, anabolic steroids) on mood and personality are well known, their role in the development of CTE is debated—largely because data in that area are lacking as well. The NFL case report described recently by the Center (former linebacker John Grimsley) indicated no reported use of performance-enhacing drugs (if you believe that a linebacker can escape the NFL without having used them).

The role of the apolipoprotein E (ApoE) genotype in CTE appears to be more significant, however. Of the 10 CTE case reports in which ApoE genotyping was performed, half carried at least one APOE ε4 allele—a known genetic risk factor for Alzheimer disease. The authors suggest that ApoE ε4 carriers may be more susceptible to CTE.

About 16% of people with mild cognitive impairment (MCI) progress to Alzheimer disease during the course of a year, according to new data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Progression from MCI to AD, which correlated with baseline CSF levels of amyloid beta-42, occurred despite the prevalent use of available antidementia therapies (~50% of subjects).

ADNI investigators followed up more than 800 elderly subjects (mean age, ~75 years) with normal cognition, MCI, or AD. Baseline data were notable for remarkably high mean verbal IQ scores and education levels among all 3 groups and relatively high percentages of APOEε4 carriers among individuals with MCI or AD.

Baseline Feature	Normal   (n = 229)	MCI (n = 398)	AD (n = 192)	P Value
Mean education, y	16 ± 2.9	15.7 ± 3.0	14.7 ± 3.1	<.001*
Estimated mean premorbid verbal IQ	120	116	114	—
APOEε4 carriers, %	26.6	53.3	66.1	<.001*
Mean MMSE score	29.1 ± 1.0	27.0 ± 1.8	23.3 ± 2.1	<.001**
Mean ADAS-cog score	6.2 ± 2.9	11.5 ± 4.4	18.6 ± 6.3	<.001**
AChEI, %	0	43.7	84.9	—
Memantine, %	0	10.8	47.4	—
Combined therapy, %	0	8.8	40.6	—
Mean CSF Aβ-42 level, pg/mL	206 ± 5	164 ± 4	143 ± 4	<.001**

* Control vs MCI amd MCI vs AD.
** Control vs MCI; control vs AD; and MCI vs AD.

On the basis of a battery of cognitive and neuropsychological tests, the estimated rate of conversion from normal cognition to MCI was 1.4% during 12 months, and that from MCI to AD was 16.5%. Eight individuals with MCI reverted to normal cognition, and 2 subjects with AD reverted to MCI at 1 year. 

Among individuals with MCI, scores on a range of assessments (eg, MMSE, ADAS-cog, clock drawing) could be used to predict progression to AD. Lower CSF levels of amyloid beta-42, which did (and are known to) correlate with higher ADAS-cog scores, were also associated with cognitive decline in normal people and those with MCI. 

In July, the ADNI reported that structural abnormalities on MR images are more useful than known CSF biomarkers for discriminating among people with AD, amnestic MCI, or normal cognition, but that the use of MR imaging and CSF analysis is more diagnostically helpful than each measure individually.

AChEI = acetylcholinesterase inhbitor; ADAS-cog = Alzheimer's Disease Assessment Scale, Cognitive Subscale; APOE = apolipoprotein E; CSF = cerebrospinal fluid; MMSE = Mini-Mental State Examination; MR = magnetic resonance.

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

An Enemy of the People

(1966): Oh, the days when television tried to deliver serious drama to the masses. One example is the NET Playhouse production of Henrik Ibsen's "En Folkefiende," as adapted by Arthur Miller and forever captured on charming black-and-white videotape.

In the Victorian-era play, fraternal conflict escalates to extremes over the purity of the local spring baths, a major attraction of a small Norwegian town. One brother, a physician, tries to warn the citizens of bacterial contamination; the other brother, the town's mayor, uses his political influence to convince the villagers otherwise—at the expense of his brother's reputation and safety.

With Philip Bosco and James Daly as the brothers. Other, potentially recognizable actors include Kate Reid and James Olson (both of The Andromeda Strain) and James Daly's son, Timothy (of "Wings" and "Private Practice").