Recently in Neuropsychiatry Category
Two articles in this week's Neurology consider the significance of biomarkers for Alzheimer disease in the cognitively normal elderly.Essentially confirming a recently published Mayo Clinic study, investigators from Texas reported the high prevalence of beta amyloid deposits (detected with Avid Pharmaceutical's PET tracer florbetapir) in the brains of a substantial portion (~20%) of healthy elderly subjects (aged 60 years or older). A high burden* of beta amyloid was associated with 1) the presence of the e4 allele of APOE, a genetic risk factor for AD and 2) poorer cognitive performance on more sophisticated** cognitive tests. The authors, two of whom receive financial support or have a financial interest in Avid Pharmaceuticals, suggest that "subtle cognitive changes accrue as amyloid progresses." The implication being that brain amyloid in the so-called healthy elderly may be more predictive than not about the risk of AD (an essential point or spin, if you will, which argues for the clinical utility of Avid's amyloid tracer). However, the authors also concede that "the relative contribution of amyloid vs other well-demonstrated predictors of cognitive aging (eg, regional atrophy, leukoaraiosis) is unclear." Among recommended follow-up studies is the assessment of the long-term consequences of amyloid deposition—ie, Are cognitively normal elderly with high amyloid burdens more like to development AD...that is, if they live long enough?. The question can only be answered with longitudinal follow-up study, which is planned.
Another multi-multi-authored international study assessed the effect of aging on the diagnostic value of CSF biomarkers for AD—specifically the triad of decreased amyloid and increased total and phosphorylated tau—in cognitively normal elderly. This study was distinctive in that, in addition to assessing individuals with AD and healthy elderly controls, a short (2-year) longitudinal assessment was made of subjects with mild cognitive impairment (MCI). The related conclusions (if I'm reading this article correctly and can recall anything useful about specificity, sensitivity, and positive and negative predictive values***) are 1) that there is substantial overlap in the biomarker distributions among these subgroups with advancing age and 2) that (therefore) the specificity of the biomarkers for ruling out AD decreases with age. Nevertheless, the sensitivity (85% cutoff) for the triad in MCI and AD, perhaps not too surprisingly, remained stable. In other words, the biomarker triad lost its strength to identify people with truly negative results as they aged (a decreased negative predictive value), but its ability to recognize truly AD-consistent findings (positive predictive value) remained stable—at least according to the authors and/or how I'm reading the study.
The overall conclusion, therefore, is that positive biomarkers for AD become less and less meaningful (as an indicator of AD) in the general elderly population—which is, ironically, the group in which these tests are most likely to be needed and used.
Addendum: Some would view these study results to mean that amyloid deposits and the triad of CSF changes are suggestive (or even indicative) of age-dependent cognitive dysfunction, albeit very subtle cognitive dysfunction. But the capacity of these tests to support or even confirm a diagnosis of clinical AD—depending on how we're defining the condition (there's the rub, isn't it?)—appears to be eroded in the older, general population (because they're more likely to demonstrate these findings, regardless of whether they demonstrate clinical meaningful cognitive dysfunction).
APOE = apolipoprotein E; SUVR = standardized uptake value ratio.
* At a mean SUVR cutoff of 1.22 or greater.
** Meaning more sophisticated than the Mini-Mental State Examination (MMSE).
*** Damn you, rudimentary biostatistics, when will you leave me alone!
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
Medivation and partner Pfizer will cease development of Dimebon (latrepirdine), a now thoroughly defunct antihistamine, "for all indications and will terminate the ongoing open label extension study in Alzheimer's disease." The small biopharm company announced the official end of Dimebon development yesterday in a press release, and the story was picked up by the WSJ. Dimebon's demise is based on flat results in the companies' CONCERT trial, a phase 3 study in which Dimebon was assessed as add-on treatment to symptomatic treatment donepezil (Aricept) in patients with mild-moderate AD.Previous news on Dimebon (March 2010) was that it failed to improve cognition or global functioning in a placebo-controlled phase 3 study of patients with AD, and Medivation's share price plummeted 30 points on the dated news. In 2008, Pfizer agreed to pay Medivation $225 million upfront and another $500 million when Dimebon was FDA approved. The agreement—which split development costs and potential profits on a 60-40 basis (Pfizer assumed the larger share)—also conferred licensing rights to Pfizer for use of the drug in Huntington's disease. But Dimebon also disappointed in this devastating condition.
Pfizer was evidently betting on the chance that Dimebon would sail through US clinical development, given very favorable phase 2 results published in The Lancet in July of 2008. In a randomized, double-blind, placebo-controlled, multicenter study (N = 183) that was conducted entirely within Russia and funded by Medivation, patients with mild-moderate AD who received Dimebon demonstrated significantly less cognitive decline at 6 months, as measured by the ADAS-cog (mean score difference, 4.0; P < .0001). Although some were scratching their heads as to why an antihistamine would have a disease-delaying or merely symptomatic effect in AD. The ultimate, tired lesson: promising phase 2 results are not a harbinger of anything, except chancy phase 3 study.
Medivation reminds us that it's also developing an investigational drug (MDV3100) with Astellas for the treatment of advanced prostate cancer. The compound is in the phase 3 stage, and Medivation got a huge bump in its stock price in late October just before news of very favorable survival data was publicly released.
About one-third of cognitively normal elderly demonstrate an elevated load of beta-amyloid,* a pathologic hallmark of Alzheimer disease, in the brain, according to a newly published study from the Mayo Clinic. These data support previous observations, in which the PET-imaged brains of about a third of elderly, nondemented subjects will exhibit an abnormal accumulation of the AD-associated protein.However, the Mayo investigators went a bit further by examining the potential association between the load of beta-amyloid, as measured with an established radiolabeled tracer (Pittsburgh compound B, or PiB) on PET images, and cognitive performance on various memory, language, attention, and visuospatial tests. As well, a relationship among brain amyloid, cognitive performance, and APOEe4 status (a well-known genetic marker for AD) was examined. What the researchers found was that poorer cognitive performance was associated with greater amyloid deposition, and that this relationship was more robust in APOEe4 carriers. Conversely the association between amyloid load and relative cognitive impairment was much weaker (ie, only "modest") in subjects who did not carry an APOEe4 allele, suggesting (the authors concluded) "that APOE isoforms modulate the harmful effects of [beta-amyloid] on cognitive function."
What any of this information means practically is very murky, however. Will some of these cognitively normal subjects with heavier amyloid burdens (and who perform less well on cognitive tests) develop AD—that is, if they live long enough? Is AD more likely in these subjects if they're APOE e4 carriers? We don't know, and obviously further longitudinal work is necessary. The Mayo authors do imply that follow-up is ongoing.
In an accompanying editorial, Buchman and Bennett commended the Mayo investigators for the size of the study (a highly respectable 408 subjects [with a median age of about 80 years]) and their "important contribution to our understanding of AD, illustrating that even among persons without dementia or [mild cognitive impairment], amyloid deposition is associated with very mild symptoms, especially among carriers of the APOE e4 allele." But "[w]hether...amyloid imaging agents will have clinical utility remains to be determined," the editorialists appropriately caution. They advise about the lack of data concerning the prognostic value of amyloid retention (presumably in any subjects, whether demented or not) and how amyloid retention may change over time. And they add that the utility of amyloid-imaging agents "will remain low in the absence of an effective amyloid modulating agent." In other words, what's the point of knowing the amyloid burden if you can't do anything to lighten the load?
A related issue, however, not explored by the editorial authors, is whether even removing amyloid in the context of cognitive impairment, is beneficial or, in fact, does more harm. Existing AD trials suggest that amyloid-modulating agents (eg, bapineuzumab) can cause brain edema—presumably due to the removal of vascular amyloid—and that they do so without improving cognition to any substantial degree overall.
Intervening earlier with anti-amyloid drugs in less cognitively impaired subjects, as proposed by some industry investigators, is a tricky move: obviously primum non nocere in persons with only mild cognitive impairment and certainly in individuals with no practical cognitive problems (regardless of their amyloid burden).
PET = positron emission tomography.
* Defined by a "global cortical PiB retention ratio" of greater than 1.50.
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
In its search (some might say crusade) to link repetitive head injury with chronic traumatic encephalopathy, or CTE, in professional sports, Boston University's Center for the Study of Traumatic Encephalopathy revealed that another NHL player, NY Rangers' enforcer Derek Boogaard, had the condition at a remarkably advanced stage. Boogaard died in May of this year, at the age of 28, as a result of an overdose of alcohol and prescription narcotics, and the Center solicited Boogaard's family to examine the athlete's brain. The results of the examination, which are convincingly described and displayed in a multipart NYT video piece, were reported by the paper on December 3rd. Boogaard is now the fourth NHL player with the condition in the Center's case series of this particular sport.*
Among the disturbing facets of the NYT coverage, NHL commissioner Gary Bettman downplays the risk of brain injury as a result of brawling in his league* and minimizes the Center's research as "preliminary" and "great for headlines." One is reminded of neurologist Ira Casson's essential denial of the association between repetitive head injury and CTE in January of 2010. Casson was co-chairman of the NFL's panel on brain injury until he resigned November of 2009, largely owing to his perceived insensitivity toward a possible link.
* The Center's case series of NFL players with CTE, 13 of 14, is substantially larger.
** Which he, inexplicably, denies is allowed.
Among the disturbing facets of the NYT coverage, NHL commissioner Gary Bettman downplays the risk of brain injury as a result of brawling in his league* and minimizes the Center's research as "preliminary" and "great for headlines." One is reminded of neurologist Ira Casson's essential denial of the association between repetitive head injury and CTE in January of 2010. Casson was co-chairman of the NFL's panel on brain injury until he resigned November of 2009, largely owing to his perceived insensitivity toward a possible link.
* The Center's case series of NFL players with CTE, 13 of 14, is substantially larger.
** Which he, inexplicably, denies is allowed.
For those who are following the XMRV-CFS-Mikovits story, science blogger John Timmer at ars technica provides a decent synopsis of the crazy soap opera/Greek tragedy.
Specifically Timmer outlines a complicated narrative in reasonably comprehensible (but not outstanding*) prose. The salient points:
CFS = chronic fatigue syndrome; DHHS = Department of Health and Human Services; XMRV = xenotropic murine leukemia virus-related virus.
Specifically Timmer outlines a complicated narrative in reasonably comprehensible (but not outstanding*) prose. The salient points:
- the rise and fall of data linking XMRV with the dubious CFS;
- researcher Judy Mikovits's refusal to abandon the idea that XMRV is associated with CFS, despite others' data indicating XMRV contamination;
- the symbiotic nexus between Mikovits and individuals with CFS, some of whom reportedly tried to undermine any investigation debunking the link between XMRV with CFS;
- Mikovits's subsequent unethical, and possibly criminal, behavior; and
- the overall integrity of the collective, collaborative scientific process (including nods to the DHHS and the "publishing system").
CFS = chronic fatigue syndrome; DHHS = Department of Health and Human Services; XMRV = xenotropic murine leukemia virus-related virus.
The Nature News Blog and Retraction Watch provide the ongoing, head-torquing narrative of Judy Mikovits, the dubious or embattled (depending on your viewpoint) XMRV-CFS researcher who was fired in September from the Whittemore Peterson Institute in Reno, Nevada. The latest news: Mikovits was arrested last Friday in California (as a fugitive from Nevada, from what I can tell) for allegedly stealing property—eg, laboratory notebooks—from the Institute.
And while the jig certainly appears to be up for Mikovits regarding the validity of her past scientific claims about XMRV and chronic fatigue syndrome or a future career in legitimate science, to hold her without bail (especially while, elsewhere, an alleged serial pedophile is allowed out on $100,000 and no monitoring) seems terribly draconian and patently unfair.
And while the jig certainly appears to be up for Mikovits regarding the validity of her past scientific claims about XMRV and chronic fatigue syndrome or a future career in legitimate science, to hold her without bail (especially while, elsewhere, an alleged serial pedophile is allowed out on $100,000 and no monitoring) seems terribly draconian and patently unfair.
From this week's issue of Neurology.Using MR venography and ultrasound* in 40 patients with MS, German investigators failed to replicate the 100% prevalence of chronic cerebrospinal venous insufficiency (CCSVI) defined famously (and notoriously) by Zamboni et al in 2009 (for background, start here or search Pathophilia for "Zamboni"). This newly published study, by the authors' account, is at least the 13th study** that has failed to validate Zamboni's theory of venous insufficiency in MS and his follow-up idea that the stenting of cerebral veins (ostensibly to improve the egress of iron) could be somehow objectively clinically beneficial.
Here's the parade of negative studies cited by the German authors (Doepp et al); 11 of these studies have been published in English-language peer-reviewed journals (all of which are reasonably well regarded).
Ultrasound studies
- Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol. 2010;68:173-183.
- Baracchini C, Perini P, Calabrese M, Causin F, Rinaldi F, Gallo P. No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. Ann Neurol. 2011;69:90-99.
- Krogias C, Schroeder A, Wiendl H, Hohlfeld R, Gold R. "Chronic cerebrospinal venous insufficiency" and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients. Nervenarzt.
- 2010;81:740-746. (article in German)
- Mayer CA, Pfeilschifter W, Lorenz MW, et al. The perfect crime? CCSVI not leaving a trace in MS. J Neurol Neurosurg Psychiatry. 2011;82:436-440.
- Centonze D, Floris R, Stefanini M, et al. Proposed CCSVI criteria do not predict MS risk nor MS severity. Ann Neurol. 2011;70:52-59.
- Sundstroem P, Wåhlin A, Ambarki K, Birgander R, Eklund A, Malm J. Venous and cerebrospinal fluid flow in multiple sclerosis: a case control study. Ann Neurol. 2010;68:255-259.
- Wattjes M, van Oosten BW, de Graaf WL, et al. No association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flow-quantification study. J Neurol Neurosurg Psychiatry. 2011;82:429-435.
- Zivadinov R, Lopez-Soriano A, Weinstock-Guttman B, et al. Use of MR venography for characterization of the extracranial venous system in patients with multiple sclerosis and healthy control subjects. Radiology. 2011;258-562-570.
Measurement of intraocular venous pressure
Measurement of CSF ferritin levels
* Specifically dynamic extracranial color-coded duplex sonography (ECCS).
** The cited studies do not include the essentially negative ultrasound study from the University of Buffalo, which was recently published in April in Neurology. Consequently the peer-reviewed tally comes to 14 negative studies.
Image of neck veins from Gray's Anatomy (1918).
Amyloid-related imaging abnormalities of edema/effusion, or ARIA-E.
[Insert snarky X-Files/Roswell quip here.]
It's what Alzheimer experts are now calling the brain edema associated with the administration of Pfizer/JNJ's bapineuzumab, and other investigational anti-amyloid compounds, according to an article in last week's Neurology Today. The write-up also highlighted that ARIA-E occurs more frequently than previously thought—in about 17% of bapineuzumab-treated patients (36/210). But about three quarters of these re-examined cases, detected via MRI, were asymptomatic. Risks for the potentially adverse phenomenon were APOE4 homozygosity, a known risk for Alzheimer disease, and a higher dosage of bapineuzumab (more amyloid, more drug).
The Neurology Today report also described the results of a bapineuzumab extension trial, in which the rate (or risk) of ARIA-E declined after the third dose of medication. The lead investigator, Stephen Salloway, presented an unusually cheery picture of the drug's safety (and, by association, brain edema): "The majority of cases of ARIA are asymptomatic and almost all resolve by holding the dose," he was quoted as saying, along with, "Overall, bapineuzumab was generally well tolerated and adverse effects tended to be mild to moderate. Importantly, there were no new safety signals with exposure over five years of treatment." But there were questions among interviewed experts about the high drop-out rate of patients in bapineuzumab trials—a fact suggesting that the drug is not easily tolerated (or is ineffective, or both).*
Image from alzforum.org (reproduced in Neurology Today) showing development and remission of brain edema, aka ARIA-E, on MR images in bapineuzumab-treated patients. Credit given to Stephen Salloway and Reisa Sperling.
The question of bapineuzumab's safety is irrelevant if the drug doesn't improve cognition—which it doesn't seem to, at least not across the board in established Alzheimer disease. Salloway suggested, in an end-quote, that bapineuzumab might have a niche in earlier stages of dementia. But the general subtext of the article (or that of any transmission attempting to mitigate safety concerns about a marginally beneficial compound) is THIS DRUG IS A DEAD DUCK. And the scary generalization from this all-caps inference (and see the N.B. for support) is that all anti-amyloid compounds for Alzheimer disease are in serious jeopardy.
* The results of both of these described studies were presented in July at the Alzheimer’s Association International Conference in Paris.
N.B.—The cause of ARIA-E is unknown but has been entertained frequently at this blog and elsewhere. In the NT article, Dr. Reisa Sperling, suggested that the phenomenon is caused by "transient increases in vascular permeability—leaky vessels—due to mobilization of amyloid from plaque and into vessels and clearance of vascular amyloid." She added further, "I do think the leaky vessel problem will affect the whole class [of amyloid-modifying drugs], but it's manageable." That's one helluva qualified endorsement.
[Insert snarky X-Files/Roswell quip here.]
It's what Alzheimer experts are now calling the brain edema associated with the administration of Pfizer/JNJ's bapineuzumab, and other investigational anti-amyloid compounds, according to an article in last week's Neurology Today. The write-up also highlighted that ARIA-E occurs more frequently than previously thought—in about 17% of bapineuzumab-treated patients (36/210). But about three quarters of these re-examined cases, detected via MRI, were asymptomatic. Risks for the potentially adverse phenomenon were APOE4 homozygosity, a known risk for Alzheimer disease, and a higher dosage of bapineuzumab (more amyloid, more drug).
The Neurology Today report also described the results of a bapineuzumab extension trial, in which the rate (or risk) of ARIA-E declined after the third dose of medication. The lead investigator, Stephen Salloway, presented an unusually cheery picture of the drug's safety (and, by association, brain edema): "The majority of cases of ARIA are asymptomatic and almost all resolve by holding the dose," he was quoted as saying, along with, "Overall, bapineuzumab was generally well tolerated and adverse effects tended to be mild to moderate. Importantly, there were no new safety signals with exposure over five years of treatment." But there were questions among interviewed experts about the high drop-out rate of patients in bapineuzumab trials—a fact suggesting that the drug is not easily tolerated (or is ineffective, or both).*
Image from alzforum.org (reproduced in Neurology Today) showing development and remission of brain edema, aka ARIA-E, on MR images in bapineuzumab-treated patients. Credit given to Stephen Salloway and Reisa Sperling.
The question of bapineuzumab's safety is irrelevant if the drug doesn't improve cognition—which it doesn't seem to, at least not across the board in established Alzheimer disease. Salloway suggested, in an end-quote, that bapineuzumab might have a niche in earlier stages of dementia. But the general subtext of the article (or that of any transmission attempting to mitigate safety concerns about a marginally beneficial compound) is THIS DRUG IS A DEAD DUCK. And the scary generalization from this all-caps inference (and see the N.B. for support) is that all anti-amyloid compounds for Alzheimer disease are in serious jeopardy.
* The results of both of these described studies were presented in July at the Alzheimer’s Association International Conference in Paris.
N.B.—The cause of ARIA-E is unknown but has been entertained frequently at this blog and elsewhere. In the NT article, Dr. Reisa Sperling, suggested that the phenomenon is caused by "transient increases in vascular permeability—leaky vessels—due to mobilization of amyloid from plaque and into vessels and clearance of vascular amyloid." She added further, "I do think the leaky vessel problem will affect the whole class [of amyloid-modifying drugs], but it's manageable." That's one helluva qualified endorsement.
A peculiar kind of living agony must be had by those who are diagnosed with psyche-robbing disorders, like Alzheimer's disease, while they remain aware that they're being robbed of whatever makes them them. A recent case in point is that of Pat Summitt, legendary coach of the UT women's basketball team, who was recently diagnosed with early-onset AD.In this Washington Post clip (along with a funny and moving write-up by the coach's friend and the coauthor of Summitt's 1999 autobiography), there are subtle, but definite, halts in Summitt's speech that hint at her early, mental disability—which troubled family (primarily her incredibly stalwart son), friends, and UT colleagues early on and ultimately brought Summitt to the attention of physicians at the Mayo Clinic—where she received her diagnosis 3 months ago.
Photo of Summitt on one of many of her days of basketball victory; from the UT website.
Today the WSJ provides a very high-level overview of the currently prevailing idea for meaningful Alzheimer's treatment: attack earlier. The conclusion is largely based on increasingly disappointing results of anti-amyloid drugs in development (from Pfizer/JNJ, Lilly, and BMS), which have been tested in established disease.
Some scientists speculate (and it's all speculation) that amyloid deposition in the brain may be most toxic before symptoms of clinical dementia appear, the WSJ notes. Others imply that follow-up tau-related deposits are the major instigator of brain damage. The WSJ cites one study, presented at the recent ICAD conference, in which there was little change in amyloid deposits among patients "progressing toward Alzheimer's" but "substantial changes in tau and brain volumes."
The quoted industry cheerleaders, who (understandably) remain tireless in their efforts to find uses for their companies' investigational anti-amyloid agents:
Howard Feldman, MD, BMS's vice president of global clinical research for neuroscience ("Earlier intervention will allow us to treat patients when they have much less disability and when it could still be possible to prevent or delay such [memory] losses");
Rachel Schindler, MD, Pfizer's executive director for Alzheimer's disease ("The growing evidence from biomarkers has led to a greater acceptance in the field of looking towards earlier treatment"); and
Eric Siemers, MD (right), senior medical director for Alzheimer's disease ("There's not quite a template,but there's a broad acknowledgment of how important [linking biomarkers to disease progression] is"). The Midwesterner—to his credit—has a very accessible, almost mild-mannered way of speaking, which is probably keeping some Lilly shareholders from running for the hills.
Some scientists speculate (and it's all speculation) that amyloid deposition in the brain may be most toxic before symptoms of clinical dementia appear, the WSJ notes. Others imply that follow-up tau-related deposits are the major instigator of brain damage. The WSJ cites one study, presented at the recent ICAD conference, in which there was little change in amyloid deposits among patients "progressing toward Alzheimer's" but "substantial changes in tau and brain volumes."
The quoted industry cheerleaders, who (understandably) remain tireless in their efforts to find uses for their companies' investigational anti-amyloid agents:
Howard Feldman, MD, BMS's vice president of global clinical research for neuroscience ("Earlier intervention will allow us to treat patients when they have much less disability and when it could still be possible to prevent or delay such [memory] losses");
Rachel Schindler, MD, Pfizer's executive director for Alzheimer's disease ("The growing evidence from biomarkers has led to a greater acceptance in the field of looking towards earlier treatment"); and
Eric Siemers, MD (right), senior medical director for Alzheimer's disease ("There's not quite a template,but there's a broad acknowledgment of how important [linking biomarkers to disease progression] is"). The Midwesterner—to his credit—has a very accessible, almost mild-mannered way of speaking, which is probably keeping some Lilly shareholders from running for the hills.
