Cheikh Diack (1), Christophe Boetsch (1), Valerie Cosson (1), Nicolas Frey (1), Eric Worth (2)
(1) F. Hoffmann-La Roche Ltd, Switzerland, (2) Roche Products, UK
Objectives: The improving understanding of the brain pathology dementia has led to several clinical trials with focus upon the dominating theory known as the amyloid hypothesis [1]. The amyloid hypothesis suggests that increased production or reduced clearance of amyloid beta (Aβ) species (mainly Aβ-40 and Aβ-42) and their subsequent deposition as plaques in the brain play a critical role in the cascade of biological events involved in the pathogenesis of Alzheimer’s disease. Biomarkers of brain Aβ amyloidosis include reductions of the Aβ level in the cerebrospinal fluid.
A number of clinical trials have shown a high intra-individual variability of CSF Aβ level which also tended to rise when sampled repeatedly by means of an indwelling lumbar catheter over a number of hours [2]. Some recent findings have associated the rise of CSF Aβ to the sampling frequency or sampling volume or both [2] while others postulated a diurnal change [3] in CSF Aβ to explain the intra-individual variability observed.
It is therefore important to characterize the dynamic of Aβ in CSF when sampled in this manner.
Methods: Placebo (10 subjects) and baseline data (40 subjects including the placebo group) were collected from a clinical trial of healthy volunteers. CSF was sampled (2mL sample every 2 hours) for each subject at 19 time points over 36 hours. Based on these data three different turnover models were developed all with modulated production rate:
- Model 1: the input rate is function of the sampling frequency
- Model 2: the input rate is function of the sampling volume
- Model 3: the input rate is periodic (circadian variation)
All models were tested against published data on 21 healthy subjects from three different studies [2] with different sampling frequencies and volumes.
Results: This an on-going work. However first modeling results suggest that the observed rise of CSF Aβ 40 may not be due to sampling frequency or sampling volume but, at least in part, to its hypothesized diurnal variation.
Conclusions: The dynamic of CSF Aβ 40 was characterized using an indirect response model with modulated input rate. First results seem to indicate that the high intra-individual variability of Aβ 40 in CSF is due to its circadian variation, however further investigations are needed to validate this approach.
References:
[1] E. Karran, M. Mercken and B. De Strooper. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nature Reviews – Drug Discovery. Vol. 10. Sept. 2011
[2] J. Li et. al. Effect of human cerebrospinal fluid sampling frequency on amyloid-β levels. Alzheimer’s & Dementia. Vol. 8 (2012) 295-303
[3] Y. Huang et. al. Effect of age and amyloid deposition on Aβ dynamics in the human central nervous system. Arch Neurol. (2012) Jan: 69 (1) 51-8
Reference: PAGE 22 () Abstr 2929 [www.page-meeting.org/?abstract=2929]
Poster: New Modelling Approaches