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

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.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.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.The cerebrospinal fluid (CSF) circulation is critical to maintaining a healthy environment for the brain, and its functional decline with normal aging and the age-related dementias remains of particular interest and concern. For example, there is decreased CSF production and turnover, diminished clearance of proteins, peptides and other potentially toxic metabolites, altered ion and solute transport, and decreased resistance to oxidative stress [1-3]. CSF is secreted mainly by the choroid plexus (CP) as an ultrafiltrate of blood. It circulates through the cerebral ventricles, leptomeninges, and along central nervous system (CNS) surfaces, reentering the bloodstream, in humans, at the arachnoid villi [4]. In rodents there appears to be a significant am