Temporal course of cerebrospinal fluid dynamics and amyloid accumulation in the aging rat brain from three to thirty months

Abstract

Background: Amyloid accumulation in the brain parenchyma is a hallmark of Alzheimer's disease (AD) and is seen in normal aging. Alterations in cerebrospinal fluid (CSF) dynamics are also associated with normal aging and AD. This study analyzed CSF volume, production and turnover rate in relation to amyloid-beta peptide (Aβ) accumulation in the aging rat brain.

Methods: Aging Fischer 344/Brown-Norway hybrid rats at 3, 12, 20, and 30 months were studied. CSF production was measured by ventriculo-cisternal perfusion with blue dextran in artificial CSF; CSF volume by MRI; and CSF turnover rate by dividing the CSF production rate by the volume of the CSF space. Aβ40 and Aβ42 concentrations in the cortex and hippocampus were measured by ELISA.

Results: There was a significant linear increase in total cranial CSF volume with age: 3-20 months (p < 0.01); 3-30 months (p < 0.001). CSF production rate increased from 3-12 months (p < 0.01) and decreased from 12-30 months (p < 0.05). CSF turnover showed an initial increase from 3 months (9.40 day-1) to 12 months (11.30 day-1) and then a decrease to 20 months (10.23 day-1) and 30 months (6.62 day-1). Aβ40 and Aβ42 concentrations in brain increased from 3-30 months (p < 0.001). Both Aβ42 and Aβ40 concentrations approached a steady state level by 30 months.

Conclusions: In young rats there is no correlation between CSF turnover and Aβ brain concentrations. After 12 months, CSF turnover decreases as brain Aβ continues to accumulate. This decrease in CSF turnover rate may be one of several clearance pathway alterations that influence age-related accumulation of brain amyloid.

Figure 1

Age-related increase in CSF volume. A) Graph of ventricular CSF volume plotted against age (n = 4 for all age groups). Error bars represent SEM. B) Graph of total cranial CSF volume plotted against age (n = 4 for all age groups). Error bars represent SEM. Note that both ventricular and total cranial CSF volumes appear to increase linearly with age.

Figure 2

Total CSF volume. A) CSF in the ventricles was measured by placing fiducial points (pink dots) on black pixels within the region of interest. FastMarching Segmentation in Slicer 3D generates a rough sketch of the region of interest (green areas), as well as a 3D model. Volume is calculated from this model. B) Similar steps were taken to measure CSF in the subarachnoid space. All measurements were done by one reader for consistency. C) T1-weighted MR images. Each row represents five coronal slices from one rat brain (top row = 3 month, second row = 12 month, third row = 20 month, bottom row = 30 month). Images were magnified and brightened for printing purposes.

Figure 3

CSF production and turnover rate as a function of age. A) Graph of CSF production plotted against age (3 months, n = 6; 12 months, n = 8, 20 months, n = 3; 30 months, n = 7). Error bars represent SEM. B) Graph of CSF turnover plotted against age. CSF turnover is calculated from the means of CSF production and volume measurements. Both production and turnover are non-linear and show an initial increase to 12 months with a subsequent decrease to 30 months. Note the marked decrease in CSF turnover between 20 and 30 months compared to the turnover rate prior to 20 months. The late turnover decrease is due, in large part, to the marked increase in CSF volume, whereas the initial increase is influenced more by the CSF production rate.

Figure 4

Graphs of the concentration of Aβ40 and Aβ42 in cerebral cortex plus hippocampus, and CSF turnover plotted against age. Aβ40 (dashed line, diamonds) and Aβ42 (solid line, squares) in pg/mg total protein concentrations are plotted on the left ordinate (3 months, n = 8; 12 months, n = 8; 20 months, n = 8; 30 months, n = 7). CSF turnover (dotted line, circles) is plotted on the right ordinate. Error bars for Aβ are SEM. CSF turnover is calculated from the means of CSF production and volume measurements. Note that Aβ40 and Aβ42 concentrations increase before there is a significant decrease in CSF turnover. Only later (after 12 months) in the lifespan of the F344/BN rat is there an inverse relationship between Aβ accumulation and the CSF turnover rate.