Neuropsychiatry: February 2012 Archives
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.
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.
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 |
Non-AD Dementia |
No Dementia |
P Value |
|
Tau, pg/mL |
604 |
309 |
327 |
6.462 x 10-11 |
|
Aβ42, pg/mL |
494.5 |
734 |
843 |
1.020 x 10-8 |
|
Stathmin, ng/μL |
0.76 |
1.00 |
0.655 |
1.590 x 10-13 |
|
Chitinase activity, ng/μL |
0.665 |
0.76 |
0.32 |
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.
At least one physician thinks so and that we should label the condition accordingly.A reassessment of patients classified with early Alzheimer disease indicates that almost all of them have mild cognitive impairment (MCI) instead—that is, if the reassessment is based on the newly revised diagnostic criteria for AD and MCI, which were released last April by the National Institute on Aging and the Alzheimer's Association. The results of the reclassification study are published in the latest online version of the Archives of Neurology and raise questions about the changing and admittedly arbitrary distinction between the two conditions.
John C. Morris, MD, a neurologist at Wash U (St. Louis), reassessed the functional scores of more than 17,000 individuals enrolled at federally funded Alzheimer's Disease Centers, including nearly 5000 people with MCI and about 6200 with probable AD. When the new diagnostic criteria, which now allow for some degree of functional impairment (eg, mild impairment of daily activities, like paying bills, shopping, etc) in MCI, were applied, more than 90% of patients originally classified with mild AD could be reclassified as having MCI. Morris concluded that the "categorical distinction between MCI and milder stages of AD dementia has been compromised by the revised criteria." But rather than advocate a renewed distinction between MCI and AD on the basis of functional impairment, he proposed, perhaps controversially, that MCI should really be called what it is, early AD, or at the very least, MCI due to AD.
However, physicians may be reluctant to label MCI as AD in clinical practice, possibly because of the distressing and stigmatizing effect of the latter condition, Morris conceded. Nevertheless, he argued, "many individuals with MCI are treated with pharmacological agents approved for symptomatic AD, indicating that clinicians often do not distinguish the 2 conditions when faced with issues of medical management." Moreover, the renaming will allow patients with milder dementia to be enrolled in bona fide AD studies of investigational agents (eg, anti-amyloid agents) that may show benefit in earlier stages of illness.
Morris's renaming argument has some merit and support, specifically in the form of a longitudinal study published in 2010 by the Alzheimer's Disease Neuroimaging Initiative. In a follow-up of 800 elderly subjects, including nearly 400 with MCI, the estimated annual rate of conversion from MCI to AD was 16.5%. However, a few individuals with MCI (8/398) also reverted to normal cognition—suggesting that the diagnosis of early cognitive impairment remains somewhat fluid and/or is misapplied in a small minority of cases.
Some may attempt to apply the same kind of spectrum-of-disease argument to the accumulation of beta amyloid in the brain (as observed on PET images with radioactive amyloid tracers): meaning that the age-related accumulation of beta amyloid is a harbinger of clinical AD (provided that the patient lives sufficiently long). However, I would counter that these potential biomarkers of age-related disease become increasingly imperfect indicators of anything meaningful during advancing life and more and more irrelevant without clinical manifestations of age-related disease. A correlate of similar imperfection would be something like the PSA test for prostate cancer in elderly men.
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
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.
