Recently in Neurology Category

A remarkable, unprecedented development. Roche's anti-amyloid MAb, crenezumab (for which there are no entries at PubMed—!), will be given in an attempt to stave off familial Alzheimer disease. According to Reuters and the NYT, the experimental drug will be studied in members of an extended Colombian family who harbor mutations in a deterministic gene (presenilin 1*) for AD. The US DHHS and Banner Health are providing $16 million and $15 million, respectively, to fund the study. The US government's support is part of the new National Alzheimer's Project (announced yesterday), which has an advertised goal of finding an effective treatment for AD by 2025.

Also according to news coverage, crenezumab was chosen as a potential preemptive treatment for AD among "25 rivals," primarily because it does not cause vasogenic edema—for instance, like Pfizer/Janssen's bapineuzumab. This information is sourced in news write-ups to a Colombian neurologist. Although I have to say Roche's MAb has really come out of left field. As someone who has followed the investigational development of anti-amyloid drugs fairly closely, this molecule has flown way under my radar—partly because it has been registered heretofore under the unfriendly research name of MABT5102A. (Nevertheless, the oversight says something about my limitations.)

According to the NIH database, crenezumab/MABT5102A is currently being investigated in two phase 2 studies in the United States, Canada, and/or the United Kingdom (see here and here). Respective study completion dates are currently designated as June and August of 2014. Presumably the data regarding vasogenic edema (or lack thereof) were determined during phase 1 study and/or confirmed during the ongoing phase 2 trials.

Roche also has the investigational anti-amyloid MAb gantenerumab, which is also in phase 2 development.

As previously written, phase 3 data for the anti-amyloid MAbs bapineuzumab and solanezumab (in existing AD) are expected sometime this summer—which is drawing nigh.

DHHS = Department of Health and Human Services; MAb = monoclonal antibody.
* Presenilin 1 is a component of a metabolic enzyme that cleaves amyloid precursor protein to ultimately create beta amyloid--the stuff the aggregates and forms plaques in the brains of patients with AD.

Update: AC Immune, from which crenezumab was licensed by Roche/Genentech, reported last year that the "drug showed no signs of cerebral vasogenic edema in any of the [phase 1 trial] patients at any dose."

Another update: You have to wonder, though. If crenezumab doesn't cause (or isn't associated with) vascular edema, how effective is it at removing amyloid? If the cause of vasogenic edema with these anti-amyloid compounds is due to the immune-mediated vascular removal of amyloid and/or a direct attack on vascular amyloid (see, for instance, Figure 5 in Sperling et al. Lancet Neurol. 2012:11:241-249), then you would expect some kind of class effect given the putative mechanism of action. Consequently I wonder at the efficacy of an anti-amyloid MAb that doesn't cause some vasogenic edema in a percentage of patients. Certainly amyloid PET imaging in this Colombian study will allow researchers to visualize the removal or prevention of amyloid buildup with crenezumab. So...wait to see. Of course, the bigger question is whether the targeting of amyloid is associated with clinical improvement or, as in this study, the prevention of AD dementia.

The FDA has revised its recommendations for cardiovascular monitoring after the initiation of Gilenya (fingolimod), Novartis's oral drug for relapsing-remitting MS. The new recommendations, which extend the post-dosage monitoring for bradycardia from 6 to 24 hours, are based on the report of a woman who died within a day after starting the drug.

Although the cause of the woman's death was not determined, the agency reported that she was taking two antihypertensive medications, including the beta-blocker metoprolol. In addition, she had "extensive" MS lesions in her brainstem, which have been associated with sudden death.

On the basis of a post-hoc analysis of clinical-trial data, the FDA also concluded that the possible depressant effect of Gilenya on the heart rate is biphasic: There is an initial risk during the first 6 hours after the first dose and a second risk during hours 12-20. Therefore the agency believes that cardiac monitoring beyond 6 hours is warranted in patients whose heart rate falls below 45 bpm during the first 6 hours after the first dose.

Other reports of cardiovascular death in Gilenya-treated patients are being examined. However, the FDA cautions, "For each of these deaths, Gilenya’s contribution to the death was unclear. The number of deaths of apparent cardiovascular origin or of unknown origin does not appear to be higher than in MS patients not treated with Gilenya."

Regardless it seems prudent to consider the drug very carefully in MS patients with concomitant cardiovascular disease (especially arrhythmia) and particularly those patients taking beta-blockers or antiarrhythmics.

This morning, the FDA has finally stepped in and is warning healthcare professionals and MS patients alike about death and other injuries associated with the so-called "liberation procedure" (ugh), which amounts to either angioplasty or stenting of (typically) jugular veins. The procedure, which is ostensibly designed to promote the egress of blood flow from the brain, has no basis for use, because there is no confirmed link between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis. For background on this ever-vexing issue, start here.

The FDA has received reports of associated adverse events, which include "death, stroke, detachment and migration of the stents, damage to the treated vein, blood clots, cranial nerve damage and abdominal bleeding." In February, the agency sent a letter to a NY vascular surgeon, warning of "objectionable conditions" and the lack of regulatory protocol and oversight for what amounts to an investigational (ie, non-FDA-approved) procedure.

For the Internet's edification, the phase 3 trials of MAbs in AD are tabulated by drug (bapineuzumab, solanezumab) and expected completion date.

Although the phase 3 trial of bapineuzumab in APOE ε4 carriers (NCT00575055 or ELN115727-302) reached its estimated completion date last month, the online buzz indicates that Pfizer/Janssen won't publicly release these data until the phase 3 study in noncarriers is completed in August of this year. As readers may recall, the phase 2 data of bapineuzumab suggested that APOE ε4 noncarriers with AD (meaning generally those patients with a lower beta-amyloid burden) fared somewhat clinically better than APOE ε4 carriers and were specifically less likely to develop vasogenic brain edema.

The public release of phase 3 solanezumab data is also expected imminently or at least (I would think) this summer.

Bapineuzumab (Pfizer/Janssen) Phase 3 Trials*

Subjects	Clinical Trials Identifier	Approximate Duration	Estimated Completion Date
1121 APOE ε4 carriers	NCT00575055 (aka ELN115727-302)	1.5 years	April 2012
1300 APOE ε4 noncarriers	NCT00574132 (aka ELN115727-301)	1.5 years	August 2012
Subjects who participated in above studies	NCT00937352	2.5 years or marketing application	June 2012
1100 APOE ε4 carriers	NCT00676143 (aka 3133K1-3001)	1.5 years	June 2013
Subjects who participated in above study	NCT00998764	4 years (extension)	June 2017
1000 APOE ε4 noncarriers	NCT00667810 (aka 3133K1-3000)	1.5 years	June 2014
Subjects who participated in above study	NCT00996918	4 years (extension)	June 2018

Solanezumab (Eli Lilly) Phase 3 Trials**

Subjects	Clinical Trials Identifier	Approximate Duration	Estimated Completion Date
1000 AD patients	NCT00905372	~1.5 years	April 2012
1000 AD patients	NCT00904683	~1.5 years	June 2012
1250 AD patients	NCT01127633 (extension)	2 years	July 2014

In addition, there are several phase 3 studies evaluating IV Ig (eg, Baxter's Gammagard) in patients with AD. Clinical data from these trials aren't expected until 2013 and later.

MAb = monoclonal antibody.

* Owing to a dose-dependent effect on the risk of amyloid-related imaging abnormalities (aka vasogenic edema and microhemorrhages), particularly in APOE ε4 carriers, the dosage of bapineuzumab received by APOE ε4 carriers is now the lowest, tested dosage: 0.5 mg/kg. APOE ε4 noncarriers are receiving 2 dosages of bapineuzumab (0.5 or 1.0 mg/kg) in phase 3 clinical trials.

** Treated patients are receiving one, standard dosage of the MAb.

Chronic cerebrospinal venous insufficiency (CCSVI) is neither common, nor more common, in patients with multiple sclerosis, say investigators at the University of Texas Health Sciences Center in Houston. According to 2 preliminary reports presented at the recent annual meeting of the American Academy of Neurology, CCSVI—determined by blinded readers using "strict" ultrasound criteria*—was detected in only 8 of 206 (~4%) patients with MS** and 5 of 59 (~8%) patients with other neurologic disorders (eg, stroke).

In a companion MR venography study, only 9 of 63 (14%) patients with MS showed evidence of CCSVI. None of these patients met ultrasound criteria for CCSVI, but 2 patients with normal MR venography showed ultrasound evidence of CCSVI. Although MR venography appeared, therefore, to be more sensitive for detecting venous insufficiency than ultrasound, the investigators found that there was reasonable correlation between the 2 imaging techniques.

In 2009, Italian physician Paolo Zamboni proposed that the cause of MS was related to obstructed venous outflow from the brain and documented CCSVI by ultrasonography in an inordinately high number of MS subjects. His published findings led to unjustified zeal for venous stenting and other procedures that were intended to increase venous outflow from the brain. However, Zamboni's data have not been reliably replicated; more damning, in fact, is that his data have been refuted in numerous studies.

General consensus among MS specialists is that the condition is an autoimmune (not vascular) disorder, and the most effective, known treatments for delaying the progression of MS are immunomodulatory drugs.

MR = magnetic resonance.
* Consistent with those criteria outlined by Zamboni.
** Approximately two thirds of patients with MS had relapsing-remitting disease.

HT: MedPage Today.

The use of Avid/Lilly's newly approved amyloid tracer, Amyvid, hinges on the accuracy (or inaccuracy) of a clinical diagnosis of Alzheimer disease (AD) during life. If the historic accuracy of a clinical diagnosis of AD is generally high—meaning the correlation between a clinical diagnosis of AD during life and postmortem evidence of the disease is good—then use of the very expensive radiolabeled tracer (and the consequent ordering of associated PET scanning) is less well justified, if at all.

In Avid/Lilly's press release for the approval of Amyvid, Avid's President and CEO, radiologist Daniel Skovronsky, implicitly promotes the use of amyloid imaging by claiming, "It's estimated that one in five patients clinically diagnosed with probable Alzheimer's Disease during life do not end up having Alzheimer's Disease pathology upon autopsy." The references cited to support his statement are the following:

• Lim A, Tsuang D, Kukull W, et al. Clinico-neuropathological correlation of Alzheimer's disease in a community-based case series. J Am Geriatr Soc. 1999;47(5):564-569.
• Petrovitch H, White LR, Ross GW, et al. Accuracy of clinical criteria for AD in the Honolulu-Asia Aging Study, a population-based study. Neurology. 2001;57(2):226-234.

Let's examine these references to determine if they really do support Skovronsky's claim of diagnostic accuracy and, moreover, if they're representative of the literature at large.

The article by Lim et al, from 1999, is not available online. Therefore I'm currently limited to examining the PubMed abstract, which describes a "community-based case series" of 134 patients with "memory complaints" (who were presumably seen at the VA Puget Sound Health Care System in Seattle, Washington). The rationale for the study was to make a clinico-pathologic correlation for AD in non-research subjects. These community-based subjects, who were enrolled in the University of Washington/Group Health Cooperative Alzheimer's Disease Patient Registry, met a diagnosis of "probable AD" on the basis of NINCDS-ADRDA criteria (1984 guidelines). Among the 134 individuals, postmortem criteria for AD (CERAD criteria) were met in 95 patients (71%). The authors calculated the sensitivity of a clinical diagnosis of AD ("probable AD" during life) at 83% and an overall diagnostic accuracy of 75%. Of the 94 cases with postmortem evidence of AD, most of these patients demonstrated coexisting pathology—like vascular lesions and evidence of Parkinson disease. Neuropathologic diagnoses in the patients without postmortem evidence of AD are, unfortunately, not provided in the abstract. In other words, the Lim abstract doesn't reveal what was misdiagnosed as AD during life in this study.

The other cited article, by Petrovitch et al, describes a kind of a holy-smokes study, in which the clinico-pathologic correlation for a diagnosis of AD in Japanese-American men (who participated in the Honolulu-Asia Aging Study in the early-mid 90s) was a paltry 65%. (Again, the rationale for this study was to assess the diagnostic accuracy in a community-based sample [ie, outside of a referral center], as well as to examine a non-Caucasian population.) A closer look at the article reveals that, among the 20 men (ie, a small study) diagnosed with "pure AD" (as opposed to pure vascular dementia or AD plus something else) who came to autopsy, only 13 (65%) met CERAD criteria for "definite" or "probable" AD (which was partly based on the density of neuritic, amyloid-containing plaques*). Many of these patients also showed evidence of amyloid angiopathy and/or cerebrovascular disease. Among the patients with "possible" or no postmortem evidence of AD (ie, with minimal evidence of neuritic plaques), diagnoses for the most part were confined to vascular disease (which CT or MRI somehow missed). In one case, there was evidence of midbrain Lewy bodies (eg, Parkinson disease); in another, there was evidence of chronic subdural hematoma.

Petrovitch et al also cite several previous clinico-path studies (performed at referral centers in Western countries), in which the correlation of a diagnosis of "pure" AD during life and postmortem evidence varied between 80% and 90%. In cases of "probable" AD, the correlation rates were even higher: between 80% and 100%. The accuracy of the clinical diagnosis of "possible" AD, logically, has been historically lower: 60%-90%.

In a very recently published study, which draws on more recent NIA registry data (2005-2010), the sensitivity of a clinical diagnosis of "probable" or "possible" AD (when measured against neuropathologic data—which were based on amyloid-plaque density* and neurofibrillary tangles) was about 80%70%-90%. Meaning: Physicians correctly identified clinical AD as being neuropathologic AD about 85% 80% of the time (438/526 subjects). These data are consistent with the median values provided by the bulk of clinico-path studies in the literature. Conversely the specificity of clinical diagnosis was lower, from about 40%-70%. Meaning: Clinicians were not as good at correctly recognizing non-AD causes of dementia and often ascribed other causes of dementia to neuropathologic AD.

Among the most common primary neuropathologic diagnoses that were misidentified as AD during life were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration (aka Pick's disease), cerebrovascular disease, Lewy body disease, and hippocampal sclerosis. (Addendum: It's also curious to note that among the 88 patients who were diagnosed with probable AD but who didn't meet the minimum pathologic standards for AD at autopsy, 17 were still considered to have a "primary neuropathologic diagnosis of AD despite [the] low level of AD histopathology." So the rate of diagnostic accuracy for clinical AD was a slightly higher, at ~85%. But the authors note that the criteria for the histopathologic diagnosis of AD has been a bit of a moving target over the last few decades.)

So circling back to Dr. Skovronsky's quote, a 25% 20% rate of a misapplied diagnosis of AD during life is a bit of an overstatement reasonable—especially if the reference standard for clinical diagnosis is some type of AD referral center. (And I bet any primary care physician who might ever entertain an amyloid-imaging study would first refer his suspect patient to an AD referral center, or at least a neurologist.) A more accurate percentage of a misapplied diagnosis, on the basis of a totality of the literature, is closer to 15%. But despite the reasonable agreement with the literature at large, Skovronsky should have cited some other reference than the Honolulu-Asia Aging Study, which indicates a relatively high rate of misdiagnosis, at 35%.

Regardless, the crucial follow-up question is What are we missing when we mistakenly diagnose dementia as AD during life? And the answer is a number of related neurodegenerative, dementing illnesses and cerebrovascular disease—features of which may coexist. Moreover, evidence of some of these non-AD conditions (hippocampal sclerosis, vascular disease) should be detectable on standard MR imaging.

* What Amyvid is designed to detect.

NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association; CERAD = Consortium to Establish a Registry for Alzheimer's Disease.

Much to my disquiet, the FDA approved Amyvid (florbetapir), an amyloid imaging agent, late last Friday. The radiolabeled tag for amyloid-beta, which is intended to be used with PET scanning, latches onto the stuff of neuritic plaques in the brains of people with Alzheimer disease (AD) and shows up as bright red on color-coded images. Amyvid is the product of a Lilly subsidiary, Avid Radiopharmaceuticals. (In November 2010, Lilly bought Avid for $300 million, and will now fork over another $500 million to Avid with approval of the amyloid tracer.)

Last March (meaning 13 months ago), the agency all but rejected Amyvid, after an advisory panel gave its unanimous recommendation for conditional approval in January of 2011. The FDA said that it wanted Avid/Lilly to establish a reader training program, because of potential problems with inconsistent interpretations among readers of Amyvid-enhanced PET images. The lack of inter-reader reliability with the tracer-enhanced PET images has been a major concern of the pharma watchdog group Public Citizen. Presumably the FDA was satisfied with Avid/Lilly's response to this issue.

Amyvid's package insert (found here) stipulates that use of the amyloid-imaging agent is intended to...

...estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s Disease (AD) and other causes of cognitive decline. A negative Amyvid scan indicates sparse to no neuritic plaques, and is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition; a negative scan result reduces the likelihood that a patient’s cognitive impairment is due to AD. A positive Amyvid scan indicates moderate to frequent amyloid neuritic plaques; neuropathological examination has shown this amount of amyloid neuritic plaque is present in patients with AD, but may also be present in patients with other types of neurologic conditions as well as older people with normal cognition. Amyvid is an adjunct to other diagnostic evaluations.

In other words, clinical context is mandatory when using Amyvid-enhanced PET, particularly because of the high rate of brain amyloid in cognitively normal elderly (~30%). In some cases, the PET scans of elderly individuals with ostensibly normal cognition* are indistinguishable from those of patients with clinical AD. This fact and the associated caveat are stressed in a 2009 article by Rabinovici et al in the context of using a different, purely investigative amyloid tracer, 11C-Pittsburgh compound B (PIB).**

The high rate of PIB-positivity in normal controls underscores that a positive PIB scan cannot be interpreted without a careful clinical evaluation, and emphasizes that amyloid imaging alone must not serve as a surrogate for a clinical diagnosis of AD or dementia.

Clinical utility aside, physicians and their patients will have to decide if the staggering cost of PET imaging is worth the marginally useful information that may be provided. The possible clinical scenarios—dementia with brain amyloid, dementia without brain amyloid—may help establish the presumptive clinical diagnosis: Alzheimer dementia or some other dementia type (eg, Pick's disease), respectively. But if treatment is not substantively altered, what's the point of 1) exposing a patient to a radiolabeled tracer, 2) requiring that a cognitively impaired patient be transported to the nearest PET imaging center, and 3) leaving a patient to deal with the enormous cost of the study?

According to the WSJ, Amyvid will cost $1600 per dose, and various online sources indicate that the price of brain PET imaging ranges from $3000 to $6000. Moreover, there's no indication that Medicare will pay for or supplement the cost of new imaging agents for PET; although Lilly is reportedly hoping to change the relevant Medicare policy.

PET = positron emission tomography.
* Although more sophisticated neuropsychiatric tests may indicate small, but distinct, cognitive impairments in these people, according to a recent study.
** PIB has a substantially shorter half-life than Amyvid, and its use therefore requires an on-site PET-imaging facility. Amyvid, on the other hand, has a substantially longer half-life (~110 minutes), and can be administered at a site fairly remote from a PET scanner (to which the Amyvid-injected patient must be transported).

N.B.--Two other amyloid tracers are in late-phase clinical development: GE's flutemetamol and Bayer's florbetaben.

With an emphasis on "may." Newly published post-hoc data from bapineuzumab's phase 2 studies indicate that the anti-amyloid MAb reduces CSF levels of tau—a traditional downstream marker of neurodegeneration in AD (as well as in similar diseases). These data appear to have been originally presented at the AAIC in 2010, and the focus on tau, instead of amyloid, may be a way of maintaining investor interest in the ongoing investigation of bapineuzumab. The MAb provided underwhelming clinical benefit in the same phase 2 studies and, consequently, some have cooled toward the idea that attacking amyloid is the way to go when searching for a disease-modifying treatment in AD. Hence, the emphasis on tau.

According to the pooled data from a post-hoc analysis of the two placebo-controlled phase 2 studies of bapineuzumab (n = 46), the CSF level of tau (and particularly phosphorylated tau) declined with treatment* (from baseline to week 54), while the CSF levels of beta amyloid (Aβ) did not (see mocked-up table).

CSF Biomarker	Change From Baseline		P Value (Bapineuzumab vs Placebo)
	Bapineuzumab (n = 27)	Placebo (n = 19)
Total tau	–72.3 (P = .03)	–5.6 (P = .80)	.09
Phosphorylated tau	–9.9 (P = .001)	–2.6 (P = NS)	.03
Aβ1-42	–10.5 (P = .44)	–6.1 (P = .75)	.79
AβX-42	32.2 (P = .02)	13.8 (P = .06)	.89
Aβ1-40	–188.5 (P = .78)	–700.4 (P = .84)	.72

The table shows a treatment-related statistical difference only in the CSF levels of phosphorylated tau, but importantly (and curiously) not in any Aβ level. In addition, a figure in the article (Figure 2) demonstrates a substantial amount of overlap between all CSF measures for bapineuzumab- and placebo-treated patients. So, take these data (particularly with such a small sample size) cum grano salis. The lack of change in any CSF Aβ level by the anti-Aβ MAb is "attributed to clearance of cortical Aβ through other pathways than CSF or, alternatively, oligomerization of Aβ or binding of Aβ to chaperones or to the therapeutic antibody that masks a change in CSF Aβ with treatment. For these reasons, the Aβ results have to be interpreted with caution." Maybe. But one might otherwise expect a rise in CSF Aβ, if the MAb were truly disease modifying.

Of course, any changes in AD biomarkers are arguably irrelevant if there's no favorable clinical correlate. And here's where the authors (some of whom are employees of Janssen or Pfizer, the current codevelopers of bapineuzumab) make a considerable effort to defend a long-term clinical endpoint for a potentially disease-modifying drug in AD, particularly in contradistinction to comparatively shorter endpoints (eg, 6 months) for symptomatic treatments, like cholinesterase inhibitors.

They write upfront, "[T]herapies aiming to slow the progression of the disease may require clinical trials with longer duration to observe clinical improvement owing to downstream therapeutic effects on the underlying pathophysiological process." This statement is intended to justify the use of biomarkers as early endpoints (which it does), but it also seems to be a couched defense of anticipated phase 3 results, which may be disappointing at the studies' currently defined endpoint (18 months, I believe). Perhaps they're laying expectations for a longer period of clinical observation. Who knows? And clearly, I speculate.

The authors also imply that cholinesterase inhibitors, by distinction, are merely symptomatic therapies—which may be true; but there are published arguments to the contrary (see an article from an Eisai** employee here, for example).

AD = Alzheimer disease; CSF = cerebrospinal fluid; MAb = monoclonal antibody.
* Most patients received all 6 intended doses of bapineuzumab over the 52-week treatment period. Ten patients received 0.15 mg/kg; 5, 0.5 mg/kg; 6, 1.0 mg/kg, and 4, 2.0 mg/kg.
** Which comarkets the cholinesterase inhibitor Aricept (donepezil) with Pfizer.

Presumably powered on expectations about bapineuzumab and its phase 3 results—which are expected to be released later this year (possibly at the AAIC in mid-July). But see Adam Fuerstein's article of March 19th for an appropriate, cautionary reminder.

Bapineuzumab, an anti-amyloid MAb, has been codeveloped by Pfizer and JNJ (or really, Janssen), along with original co-owner Elan,* and the drug performed marginally (if at all) in earlier phase 2 studies of patients with AD. The bottom line: the MAb targets amyloid and removes it (or targets it for immune-mediated removal), but this mechanism doesn't appear to be associated with clinical improvement. Specifically enrollees who were APOE ε4 carriers (meaning those enrollees at greater risk of AD and who probably have a greater amyloid burden) didn't benefit as much (if at all) as APOE ε4 non-carriers—a finding that patently contradicts the rationale for targeting amyloid in the first place.

Last bapineuzumab has been associated with brain edema in about 17% of patients (a phenomenon that has been dubbed ARIA-E), and this edema was more likely in APOE ε4 carriers (again, those patients who probably have a greater amyloid burden) and when using the highest bapineuzumab dosage (which was discontinued for phase 3). The mechanism by which bapineuzumab—and other anti-amyloid compounds, for that matter—cause edema is unclear; however, one compelling explanation is through the removal of vascular amyloid, which results in leaky vessels.

And yet the seemingly mindless runup on Elan stock continues, just like it did (albeit less robustly) in 2008 before the disappointing phase 2 results were presented. The share price is now, in fact, at a 3-year high.

* The original co-developers of bapineuzumab were Elan and Wyeth, which were respectively bought up by Janssen and Pfizer. Janssen and Pfizer then formed the Alzheimer's Immunotherapy Program (AIP), the putative darling of which is bapineuzumab.

AAIC = Alzheimer's Association International Conference; AD = Alzheimer's disease; APOE = gene encoding apolipoprotein E; MAb = monoclonal antibody.

Toss one or two more potential biomarkers for dementia into the CSF soup.

European investigators found that the activity of the enzyme chitinase, a marker of telomere dysfunction and DNA damage, was significantly increased in the spinal fluid of patients with AD or non-AD dementia (when compared with similarly aged, nondemented controls).

The results of the study, published in the latest online issue of Neurology, indicate that elevated chitinase activity in the CSF has a nearly 86% accuracy for distinguishing between patients with dementia and those without. When combined with the more traditional CSF markers of AD—namely, decreased beta amyloid levels and increased tau—the accuracy of elevated chitinase activity for identifying dementia rose to 91%. Levels of a secondary biomarker, stathmin (also an indicator of telomere dysfunction and DNA damage), were likewise elevated in individuals with AD or non-AD dementia; but the distinction between nondemented controls was not as robust as that with chitinase activity.

Biomarker	AD Dementia (n = 94)	Non-AD Dementia (n = 30)	No Dementia (n = 40)	P Value
Tau, pg/mL	604 (399.75-1045.5)	309 (229-494)	327 (231.5-410.025)	6.462 x 10-11
Aβ42, pg/mL	494.5 (381.25-578.75)	734 (617-1001)	843 (588.7-1062.25)	1.020 x 10-8
Stathmin, ng/μL	0.76 (0.67-0.8975)	1.00 (0.94-1.14)	0.655 (0.56-0.7375)	1.590 x 10-13
Chitinase activity, ng/μL	0.665 (0.5525-1.09)	0.76 (0.61-0.94)	0.32 (0.19-0.5325)	8.442 x 10-8

Important caveats to the study are 1) there is a substantial overlap of these biomarker levels between demented and nondemented subjects (see Figure 1 in the article); and 2) chitinase activity in the CSF does not appear to aid a distinction between AD and non-AD dementia.

CSF = cerebrospinal fluid.