Neurology -- Correspondence for Bateman et al., 68 (9) 666-669

HOME

HELP

FEEDBACK

SUBSCRIPTIONS

Correspondence published:

Fluctuations of CSF amyloid-ß levels: Implications for a diagnostic and therapeutic biomarker: Jiong Shi (23 May 2007)

Reply from the Authors: Randall J. Bateman (23 May 2007)

Fluctuations of CSF amyloid-ß levels: Implications for a diagnostic and therapeutic biomarker 23 May 2007

Jiong Shi,
Barrow Neurological Institute
500 W Thomas Road, Phoenix, AZ 85013
Send Correspondence to journal:
Re: Fluctuations of CSF amyloid-ß levels: Implications for a diagnostic and therapeutic biomarker

jiong.shi{at}chw.edu Jiong Shi

Bateman et al should be commended for this study which measures the fluctuations of amyloid-beta (A-beta) levels in human cerebrospinal fluid (CSF). [1] Most studies investigating the use of CSF A-beta level as a biomarker for Alzheimer's disease (AD) focused on the longitudinal changes or lack of change.[2, 3].
Bateman et al implied a steady baseline of CSF A-beta level upon which disease progression and therapeutic efficacy could be monitored. However, this study reveals a marked fluctuation within a 36-hour period. This hour-to-hour variability has broad implications in diagnostic and therapeutic biomarker studies.
There are several issues that need to be addressed. The authors suggest that the fluctuations could be attributable to the time of day or activity or, based on animal studies, synaptic activity or exocytosis. [4] Though it would be ideal to have a proteinomic study identifying the various changes in proteins which occur and their role in the fluctuations of CSF A-beta, a simple measurement of the total protein level in CSF might be used as an internal control or means of normalization as in numerous previous CSF A-beta studies. [3]
Secondly, the cerebrospinal fluid tau/ A-beta 42 ratio is recognized as a predictive biomarker in AD as shown in a later publication by the same group. [5] Did the authors in preliminary or unpublished data find that the concentration of tau fluctuated to a similar degree as the CSF A-beta preserving the importance of the ratio?
Finally, the author suggested that patients with AD might not be able to clear A-beta as efficiently as normal subjects. Since AD patients are the target population, a validation of this fluctuation in AD subjects will shed new light on future studies.
These considerations illustrate the difficult of using a biomarker for AD that represents its pathophysiology. This paper has laid a solid foundation to validate future biomarker studies.
References
1. Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology 2007;68:666-669.
2. Andreasen N, Hesse C, Davidsson P, et al. Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch Neurol 1999;56:673-680.
3. Van Nostrand WE, Wagner SL, Shankle WR, et al. Decreased levels of soluble amyloid beta-protein precursor in cerebrospinal fluid of live Alzheimer disease patients. Proc Natl Acad Sci U S A 1992;89:2551-2555.
4. Kamenetz F, Tomita T, Hsieh H, et al. APP processing and synaptic function. Neuron 2003;37:925-937.
5. Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal Fluid tau/beta-Amyloid42 Ratio as a Prediction of Cognitive Decline in Nondemented Older Adults. Arch Neurol 2007;64:343-349.
Disclosure: The author reports no conflict of interest.

Reply from the Authors 23 May 2007

Randall J. Bateman,
Washington University School of Medicine
660 South Euclid Ave, Box 8111, St. Louis, MO 63110
Send Correspondence to journal:
Re: Reply from the Authors

batemanr{at}neuro.wustl.edu Randall J. Bateman

We thank Dr. Shi for his interest in our results of A-beta fluctuations in CSF. We agree that using an internal control for normalization may be useful as a method to control for non-specific changes in protein levels, as was done for APP. [3] However, most A-beta studies do not use total protein or albumin as controls, [2,6,7,8] although some do use a ratio of A-beta 42 to A-beta 40, or A-beta 42 to Tau.
To determine general protein fluctuations, we measured hourly total protein levels in four participants. The correlation of A-beta to total protein was -0.09, 0.16, -0.09, and -0.33; none of which were statistically significant. This indicates that total protein may not be useful to normalize Aâ values, given that the variability seen in A-beta levels over a 24- to 36-hour period is not secondary to fluctuating total protein levels. Figure 1 represents a typical time course of total protein compared to A-beta.
We have not measured tau in these serially collected samples. However, the ratio of A-beta 42 to A-beta 40 was measured and demonstrated a tight correlation, indicating the potential use as a normalizing ratio.
We agree that studying these fluctuations of A-beta levels is important in AD and control participants and are currently investigating A-beta clearance and fluctuation levels in AD participants and controls.
Figure
In the assay for total protein in CSF (Figure 1A), the avalues do not vary significantly compared to the amyloid-beta variability as demonstrated in the published figure 1B.
References
6. Sunderland T, Linker G, Mirza N, et al. Decreased b-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer's disease. JAMA 2003;289:2094-2103.
7. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurology 2006;5:228-234.
8. Fagan AM, Mintun MA, Mach RH, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid A beta(42) in humans. Ann Neurol 2006;59:512-519.
Disclosure: The author reports no conflicts of interest