Recently in Neurology Category

There are no optimistic forward-looking statements here.

Today, Myriad Genetics announced that its experimental agent tarenflurbil (Flurizan) failed to affect cognition or activities of daily living in early Alzheimer's disease, the primary endpoints of a large (N = 1600), 18-month, phase 3 trial. Tarenflurbil is an NSAID enantiomer of flurbiprofen. The company's CEO reported that, consequently, the development of the compound would be discontinued.

This news follows on the heels of the missed primary endpoints in a phase 2 trial of bapineuzumab in mild-to-moderate Alzheimer's disease, which were nevertheless spun as favorably as possible by developers Elan and Wyeth.

In patients with Parkinson's disease, first-time therapy with L-dopa (eg, Sinemet) provides modestly better motor function and health-related quality of life in the long term than the dopamine agonist bromocriptine (Parlodel). The final, 14-year results of the open, randomized, multicenter study of 3 initial treatments from the PD Research Group of the United Kingdom (PDRG-UK) were published yesterday in the online edition of Neurology.

Previous, interim results from the trial had shown a significantly higher mortality rate with initial L-dopa plus the MAO-B inhibitor selegiline (Eldepryl), leading to discontinuation of that treatment arm in 1995. Ten-year results showed no significant difference in mortality between L-dopa and bromocriptine; although patients who initially received bromocriptine demonstrated slightly worse disability scores but a lower rate of dyskinesias.

In the latest report, data from 166 surviving participants of the original 782 enrollees were assessed. Disability scores and physical functioning were statistically significantly better in patients who initially received L-dopa; however, there were no treatment differences in mortality, dyskinesias, motor fluctuations, or cognitive function.

On the basis of the cumulative data, the authors recommend dopamine agonists as initial treatment for mild PD, particularly in younger patients and when motor function is the chief concern. However, they conclude that initial L-dopa "remains the most efficacious therapy for motor improvement" and should be considered early for all PD patients.

MAO-B = monoamine oxidase B.

Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers at Wikimedia Commons.

For the first time, researchers showed that amyloid beta (Aβ) dimers from the brains of individuals with Alzheimer's disease induce several AD-like changes in normal rodents. The results of a series of related experiments were reported in the latest online edition of Nature Medicine.

AD-consistent pathophysiologic changes were observed in the normal rodent hippocampus after it was exposed to soluble (but not insoluble) Aβ. The investigators, from Boston and Ireland, discovered

1. the inhibition of long-term potentiation (LTP) of synaptic transmission (a cellular model for learning and memory) in a dose-dependent fashion;
2. enhanced long-term depression (LTD) (a marker of weakening synaptic transmission); and
3. reduced dendritic spine density (a marker of synaptic loss).*

The administration of the Aβ dimer also disrupted the learning of a standard avoidance task in rats. Antibodies to the N-terminus of Aβ prevented the dimer's effects on LTP and LTD (which requires metabotropic glutamate receptors); however, the effect of antibodies to other regions of Aβ was not as remarkable.

The fact that AD-like changes were not detected with insoluble Aβ or other oligomers of Aβ may explain the disconnect between relatively preserved cognitive function during life and a high burden of Aβ in some brains at autopsy—as Marcelle Morrison-Bogorad, director of the neuroscience division at the National Insititute on Aging (NIA), told the AP. The Nature Medicine study was funded, in part, by the NIA.

* The authors note that decreased synaptic density is the strongest neuropathologic correlate of dementia in AD.

Image of wild-type amyloid precursor protein (left) and amyloid fibril (right) by David S. Goodsell from Wikimedia Commons.

While the FDA considers whether to add suicide warnings to the labels of 11 epilepsy drugs,* the measure is unlikely to affect prescriptions—at least by neurologists. That's because the cost of nonadherence to anticonvulsant therapy among epileptic patients is known to be so high.

For example, in this week's print issue of Neurology, investigators report a 3-fold increased risk of death among nonadherent epileptic patients in a retrospective study of Medicaid claims from Florida, Iowa, and New Jersey (N = 33,658).** Nonadherence, determined by non-possession of medication, was also associated with significantly more ER visits (50% increased risk), hospital admissions (86%), car accidents (108%), and bone fractures (21%).

In the FDA's assessment of 199 placebo-controlled studies of patients with epilepsy, selected psychiatric illnesses, or pain conditions (N = 43,892), there were only 4 (0.009%) suicides in drug-treated patients and none in placebo-treated individuals. Suicidal behavior or ideation was reported in 0.37% of patients who received an anticonvulsant and in 0.22% of those who received placebo. While the risk of suicidality is almost 70% higher with anticonvulsant treatment, the absolute risk remains small at 0.15%. Not surprising, the risk of suicidality with either drug treatment or placebo was lower in epileptic patients than in psychiatric patients (see table).

Indication	Suicidality Risk, %		Relative Risk Increase, %	Absolute Risk Increase, %
	Placebo	Drug
Epilepsy	0.10	0.34	240	0.24
Psychiatric	0.57	0.85	49	0.28
Other	0.10	0.18	80	0.08
Total	0.22	0.37	68	0.15

The FDA is holding a public advisory meeting on the risk of suicide with anticonvulsant drugs on July 10.

Photo: iStockPhoto.

*The 11 drugs are carbamazepine (Carbatrol; Shire); felbamate (Felbatol; Meda); gabapentin (Neurontin; Pfizer), lamotrigine (Lamictal; GSK); levetiracetam (Keppra; UCB); oxcarbazepine (Trileptal; Novartis); pregabaline (Lyrica; Pfizer); tiagabine (Gabitril; Cephalon); topiramate (Topamax; Ortho-McNeil); valproate (Depakote; Abbott); and zonisamide (Zonegran; Eisai).

**The study was sponsored by GSK, maker of Lamictal (lamotrigine). One of the study authors is an employee of GSK, and the other authors report support from GSK, in the form of research grants and/or "other activities."

Elan and Wyeth announced "encouraging top-line results" from a randomized, dose-ranging phase 2 trial of bapineuzumab in 240 patients with mild-to-moderate Alzheimer's disease; although the monoclonal antibody was no better than placebo when assessing cognition or disability at 18 months, the primary endpoints. A press release from the companies contained the primary-endpoint data in the second paragraph.

Instead the companies chose to highlight results from the post-hoc analyses of subgroups, including patients who do not carry the high-risk apolipoprotein E4 allele (40%-70% of AD patients).* Data in this subgroup showed "statistically significant and clinically meaningful benefits" with bapineuzumab, per cognitive scales like the ADAS-cog. The treated subgroup also demonstrated relatively preserved brain volume on MRI, the press release reported.

Safety data in the phase 2 trial indicated that ApoE4 carriers may be especially prone to vasogenic edema with the agent. Consequently the dose of bapineuzumab, an anti-Aβ agent, is being modified for this subpopulation in phase 3 studies. According to ClinicalTrials.gov, two phase 3 studies of bapineuzumab in AD are currently recruiting subjects, and another two phase 3 studies are "active" but "not yet recruiting."

The Elan/Wyeth press release indicates that full details of the phase 2 study will be presented July 28 at the International Conference on Alzheimer's Disease in Chicago. Despite the mixed phase 2 results, the reaction of Wall Street was mostly optimistic, according to the WSJ Health Blog.

06/18/08 update: According to Forbes, analysts Leerink Swann and Davy Stockbrokers are talking up the study and the companies' prospects. For no particularly good reason, respective share prices of Elan and Wyeth shot up yesterday 10.6% and 4.8%.

Image: depiction of amyloid plaque from National Institute on Aging.

Aβ = amyloid beta.

*So, in this case, we may guess that approximately 12-20 patients per treatment group (4 for bapineuzumab; 4 for placebo) were noncarriers.

The aggregation of insoluble amyloid fibrils is an important pathologic hallmark of Alzheimer's disease (and a number of other conditions). The most fibrillogenic isoform of amyloid beta, Aβ42, is produced when the enzyme γ-secretase cleaves the transmembrane portion of amyloid precursor protein (APP). Therefore a potential strategy for the treatment of AD is the inhibition of γ-secretase with γ-secretase modulators (GSMs).

In this week's issue of Nature, Kukar and colleagues report the surprising finding that the target of their synthetic GSMs is the substrate APP and not the enzyme itself. Specifically the GSM binding site localizes to the 28-36 residue portion of amyloid beta, a region that is critical for amyloid aggregation. Therefore certain GSMs have the potential to suppress the production of Aβ42 and its aggregation. The authors propose that substrate-targeting GSMs for further investigation can be identified by their ability to bind Aβ and APP. One Aβ42-lowering GSM, tarenflurbil (Flurizan; Myriad), is in phase 3 clinical study in patients with mild AD.

The goal of suppressing Aβ42 formation, however, is at odds with recent population studies, which showed that the risk reduction of AD with NSAIDs is not dependent on the suppression of Aβ42. In an e-mail, Kukar acknowledged the disconnect but also stressed that epidemiologic studies cannot substitute for well-controlled clinical trials.

Image of wild-type APP (left) and amyloid fibril (right) by David S. Goodsell from Wikimedia Commons.

Today's NYT features a write-up of optical, or really perceptual, illusions ("Anticipating the Future to 'See' the Present" by Benedict Carey) and refers specifically to a Flash image of a spinning dancer* created by Nobuyuki Kayahara. The popular idea behind this fascinating (and infuriating) image is that it is a kind of left-brain-right-brain personality test, which depends on how you see the image spinning. Dancer rotating clockwise? You're right-brained. Counterclockwise? You're left-brained. Whatever that means in popular culture.

As Tara Parker-Hope explained in April at the NYT Health blog, the silhouetted image doesn't have any depth cues—such as lines to indicate how her legs should overlap. For instance, notice in the still-shot thumbnail (above) that the dancer could be facing toward you with her left leg extended or away from you with her right leg extended (a la the ambiguous Necker cube). How she spins depends on this split-second decision, which is perhaps based on how your brain is wired, past experience, or both. Parker-Hope indicated that most people will see the dancer flip her rotation, if they stare at her long enough.

Thinking I'd somehow be a better person for it, I spent an embarrassing amount of time trying to get the dancer to flip at will. It's tough, particularly because there's some weird desire to maintain her movement that interferes with the flip. It's easiest if you scroll your PC screen so that only the dancer's lower legs are visible. Then once the flip happens, scroll back to view the entire image. There are also Wikipedia cheat views (here and here), which fill in the overlap lines to define the rotation.

BTW, I'm one hardcore right-brainer.

*Kayahara's Web site features a faster-spinning image here.

Pathetic update: Turn your head away from the monitor (either left or right), so that the dancer is in your far peripheral vision. She should appear to be some undulating blob; her movements may even resemble those of a rollerblader. Then imagine her turning clockwise or counterclockwise. Then look back directly at the image. Repeat this exercise until you can reliably flip her rotation, and then tell your friends and family members that you can do this.

Mercury-containing dental fillings may harm pregnant women and young children.

That's the general, and not particularly useful, lede provided by most media outlets last week, while reporting on a settlement in the case of Moms Against Mercury et al v. Leavitt et al. As part of the settlement, the FDA will reopen a comment period, beginning July 28, 2008, to potentially reclassify dental amalgam and will issue a final ruling 1 year later. And that's really all that's news, if you call that news.

Essential background on the issue can be found from the American Dental Association, which states in a press release that the "FDA has different classifications for encapsulated amalgam and its component parts, dental mercury and amalgam alloy. The FDA's proposed reclassification, which the ADA has supported since 2002, would place encapsulated amalgam and its components under one classification." The organization also writes, "As far as the ADA is aware, the FDA has in no way changed its approach to, or position on, dental amalgam."

However, last week the media latched onto the following statements made at the FDA web site, in response to the settlement:

Dental amalgams contain mercury, which may have neurotoxic effects on the nervous systems of developing children and fetuses. When amalgam fillings are placed in teeth or removed from teeth, they release mercury vapor. Mercury vapor is also released during chewing. FDA’s rulemaking...will examine evidence concerning whether release of mercury vapor can cause health problems, including neurological disorders, in children and fetuses.

Pregnant women and persons who may have a health condition that makes them more sensitive to mercury exposure, including individuals with existing high levels of mercury bioburden, should not avoid seeking dental care, but should discuss options with their health practitioner.

This information is best couched in the FDA's statements indicating that there is not enough information to know whether dental amalgam—which is approximately 50% mercury and has been widely used for more than a century—is harmful to pregnant women or young children. Other countries (Canada, France, Sweden), follow a "precautionary principle" in these populations, given the lack of data. During the comment period, the FDA requests "empirical data and scientific evidence concerning this classification and special controls for dental amalgam."

The original cause of the brouhaha, the "Petition to Order Mercury Amalgam Withdrawn From Interstate Commerce," is, itself, a curious document. For one, the diverse group of petitioners (listed) shows how the ultra-right and ultra-left often come together in their own Bizarro World. They are the following:

• Moms Against Mercury, a nonprofit organization located in North Carolina and founded by Amy Carson, who believes that the ethylmercury-containing vaccine preservative Thimerosal causes autism—despite a wealth of medical data to the contrary.
• The Connecticut Coalition for Environmental Justice, an organization dedicated to eliminating environmental toxins in the state and their effects, particularly on low-income or minority populations. The coalition is led by president Mark A. Mitchell, MD. 
• Oregonians for Life, a pro-life/anti-abortion organization.
• California Citizens for Health Freedom, one of the more "out-there" health-related nonprofits. The CCHF is dedicated to a "toxic-free environment" and the right to access alternative medical treatments for cancer. The organization also opposes the fluoridation of public drinking water.
• Kevin J. Biggers, a candidate for the California state senate and a public member of the Dental Board of California.
• Karen Johnson, an Arizona state senator whose "issues of concern" include the "precious right to life of the unborn," "eradicating pornography," and "standing resolutely against the homosexual agenda."
• Linda Brocato, an Illinoisan who believes that mercury-containing dental fillings caused her multiple sclerosis, and that her symptoms improved substantially after the removal of these fillings.
• R. Andrew Landerman, DDS, a California dentist whose advertised "services" include acupuncture, ayurveda, homeopathy, and the use of the Cavitat device.
• Anita Vasquez Tibau, the California organizer of the Consumers for Dental Choice. Tibau believes that mercury in dental fillings caused her asthma.

The hapless respondents demonstrate, once again, that a visible government job is a gift that keeps on giving: Mike Leavitt, DHHS Secretary; Andrew von Eschenbach, MD, FDA Commissioner; and Dan Schultz, MD, and Mary S. Runner, DDS, both of the FDA's CDRH.

Generally the petitioners allege that the FDA has been negligent in its duty to classify dental amalgam and specifically imply that the FDA has taken a deliberate, passive stance to maintain a profitable status quo for the subversive, pro-amalgam ADA and amalgam manufacturers.

Among the more intriguing allegations in the petition is the following:

It should come as no surprise that all government literature reviews on amalgam's toxicity have been managed by groups composed mainly of dentists. For example, a multimillion dollar grant to study amalgam was given to a dentist sitting on the ADA's Council of Scientific Affairs; that person chose a defenseless group—institutionalized Portuguese orphans—on which to experiment with mercury, without disclosures of health risks. The study is now under investigation by the Secretary's Office of Human Research Protections, the watchdog charged with stopping unethical medical experimentation.

The petitioners are presumably referring to a 2006 study in JAMA by DeRouen et al from the University of Washington and the University of Lisbon. The prospective study was funded by the Cooperative Agreement U01 DE11894 for the National Institute of Dental and Craniofacial Research (NIDCR) of the NIH. According to a 2005 Business Wire story, the University of Washington School of Dentistry did receive $22 million from the NIDCR; however, it is highly unlikely that this chunk of change was consumed by the JAMA study. The story indicated that DeRouen was the designated principal investigator and chair of a research network among his institution, the Washington Dental Service, and the School of Dentistry at Oregon Health Sciences University.

In the JAMA study, more than 500 Portuguese children (aged 8-10 years) received either randomly assigned posterior dental amalgam or resin-based composite as required dental work. The children enrolled were students within the Casa Pia system. According to Wikipedia, Casa Pia is Portugal's largest educational institution for children at risk of "social exclusion or without parental support." Casa Pia has been described as an orphanage in the mainstream press and, parenthetically, is at the center of an ongoing sex-abuse scandal and trial—which should be neither here nor there as far as the DeRouen study is concerned.

It is noted within the JAMA article that the study protocol was approved by the institutional review boards at the University of Washington and the University of Lisbon, and that written, informed consent was obtained from parents or guardians. DeRouen et al reported no significant differences in urinary mercury levels or neurologic function between the 2 treatment groups over the course of 7 years. However, after 5 years, "the need for additional restorative treatment was approximately 50% higher in the composite group."

Regarding implied ethical violations by the study investigators (and presumably the petitioners are referring to the DHHS Office for Human Research Protections), a 2006 AP news report indicated that the counsel for Consumers for Dental Choice, Charlie Brown (who, by george, is one of the petition drafters) found the Casa Pia study unethical because "guardians were never told of the potential risks of the mercury fillings."

DeRouen shot back in the AP story, "We weren't doing anything experimental. We were giving standard dental treatment." A University of Washington review board evidently found the allegations to be unfounded; however, a spokesperson for the OHRP said that the DeRouen study was "under investigation."

According to letters at the OHRP web site, the office did find that the University of Washington's informed consent document "failed to adequately describe the reasonably foreseeable risks of amalgams and composite materials used in dental procedures," as required by DHHS regulations. In response, UW developed a new policy and guidance for its institutional review board concerning the risks of standard-of-care procedures and revised its informed-consent templates to reference this policy. These changes, which appear to be general changes regarding the risks of standard of care and not mercury-related risks specifically, satisfied the OHRP as of April 2007.

Photo: iStockPhoto.

A peptide vaccine, CDX-110 (Avant/Celldex, Pfizer), significantly prolonged survival in patients with newly diagnosed glioblastoma multiforme, when administered with temozolomide (Temodar; Schering). Results of a phase 2 study, conducted at Duke University and MD Anderson, were presented Monday at the annual meeting of ASCO. CDX-110 targets a tumor-specific mutation of epidermal growth factor receptor, EGFRvIII, which is present in one third to one half of glioblastoma tumors.

In the ACT II trial, 23 patients with resected glioblastoma underwent radiation and temozolomide therapy (75 mg/m2/d), followed by subsequent monthly cycles of temozolomide (200 mg/m2; n = 13) or continuous therapy (100 mg/m2; n = 8). Intradermal injections of CDX-110 were administered simultaneously. The overall median survival, 33.1 months, was significantly longer than that (15.2 months) in historical, temozolomide-treated matched controls. Time to progression,* 16.6 months, was also significantly longer (matched controls, 6 months).

The investigators reported 1 allergic reaction to the vaccine but no other serious adverse events. Temozolomide-induced grade 2 lymphopenia was experienced by more than half of the patients. Among the 11 patients who experienced tumor recurrence, only 3 exhibited EGFRvIII positivity—suggesting that tumor resistance occurs through an antigen-escape mechanism.

CDX-110 is under investigation in a phase 2/3, multicenter, randomized clinical trial and was granted fast-track status by the FDA in January. In an ASCO media briefing, MD Anderson oncologist Mark Gilbert said that Senator Ted Kennedy, who underwent glioma resection at Duke earlier this week, would qualify for the vaccine only if all of his tumor had been removed.

*Defined as a new, radiographically demonstrable lesion ≥1 cm in any 2 perpendicular planes.

Sagittal MRI demonstrating glioblastoma from Wikimedia Commons.

The Public Broadcasting System is known for its high-quality cultural and investigative programming, like "Masterpiece," "Nova," and "Frontline." However, the station has also developed a disconcerting record for airing self-improvement claptrap (eg, Gary Null's "Mind Power"; Wayne Dyer's "Power of Intention"). The latest example comes in the form of psychiatrist Daniel Amen, whose infomercial, "Change Your Brain, Change Your Life," promotes the routine use of SPECT imaging to identify behavioral problems. The program aired on my local PBS channel last evening.

I lasted about 20 minutes: in part, because of Amen's simplistic nonsense about "prefrontal," "cingulate," and "limbic" personalities; in part, because of his promotion of diet, exercise, and his dubious proprietary supplements to alter these personalities; and in part, because of his annoying habit of constantly referring to some backroom prompter, a la Orson Welles in a Paul Masson wine ad.

In May, neurologist Robert Burton lasted a whole lot longer than I did while watching another installment of Amen's program, which promoted the prevention (yes, the prevention) of Alzheimer's disease. He provides a thoughtful critique at Slate.

HT: Carlat Psychiatry Blog.