Recently in Neurology Category

Raising a host of questions, from practical to philosophical, English and Belgian investigators showed that some patients with profound disorders of consciousness may be able to communicate—albeit in rudimentary fashion and with the aid of a million-dollar machine. Their functional MRI study of patients in persistent vegetative or "minimally conscious" state is available online today at the NEJM web site.

Among 54 severely disabled patients, investigators found that 5 could "willfully modulate their brain activity," as seen on fMRI pictures, in response to suggested motor imagery. Specifically when these patients were asked to imagine playing tennis, parts of the supplementary motor area reliably lit up. Four of the 5 patients could also respond to suggested spatial imagery, like navigating through a familiar city, by activating the parahippocampal gyrus. Follow-up bedside testing showed "some sign of awareness" in 3 of the 5 patients—suggesting that voluntary behavioral cues were missed before the fMRI assessment or that fMRI training primed these patients to respond behaviorally at the bedside (the former seems more likely).

The investigators then selected 1 patient with reliable fMRI responses to undergo training that correlated the motor imagery with "yes" and the spatial imagery with "no." The patient was then able to use the technique during fMRI to accurately answer yes-no questions, like Is your father's name Alexander? However, back at the bedside, no form of communication could be established with this patient.

All 5 responsive patients had traumatic brain injury without anoxic damage (among 32 in the study population). It is important to note that none of the 16 patients with anoxic brain injury responded (a fact that editorialist Allan Ropper also stresses).* Before fMRI testing, 4 of the responsive patients were diagnosed with vegetative state, including the patient who underwent communication training.

The American Academy of Neurology, the flagship organization for practicing US neurologists, provides the following criteria for the diagnosis of vegetative state:

• No evidence of awareness of self or environment and an inability to interact with others
• No evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli
• No evidence of language comprehension or expression
• Intermittent wakefulness manifested by the presence of sleep-wake cycles
• Sufficiently preserved hypothalamic and brainstem autonomic functions to permit survival with medical and nursing care
• Bowel and bladder incontinence
• Variably preserved cranial nerve and spinal reflexes

Minimally conscious state, which acknowledges the intermediate stage between no and some awareness in the severely brain damaged, is defined as follows:

A condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated.

Diagnosis: limited but clearly discernible self or environmental awareness on a reproducible or sustained basis by demonstrating one or more behaviors, including, following simple commands, gesturing yes/no answers to questions, intelligible verbalizations, purposeful behavior, appropriate smiling or crying, reaching for and touching objects, and pursuit eye movements.

Course: may be a transient stage in the recovery after severe head injury or other brain insult or a permanent condition.

Medicolegal cases of Jobes (1987) and Wendland (2002).

Results of this fMRI study suggest that the imaging technique might be useful for distinguishing the 2 conditions (and that, perhaps, the definition of minimally conscious state should include fMRI-dependent findings) and for establishing communication in patients with reproducible fMRI responses.

* Ropper also concludes his NEJM editorial with a groan-inducing pun that should not be reproduced.

Image of Berkeley's fMRI machine from Wikipedia.

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.

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). 

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.

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.