Tom A. Saul

Amyloid and tau accumulation precede CSF production decline in normal aging

Background It has been shown that there is an age-related decrease in CSF production in the Fischer rat brain, and that this decrease follows the CNS deposition of amyloid rather than preceding it [1]. We have postulated that amyloid and Tau accumulation in normal aging is multi-factorial, combining early defects in the blood-brain barrier (BBB) efflux transport of amyloid beta-peptide (A-beta) with later changes in CSF production and turnover, as well as up-regulation of A-beta influx transport.

Shunting in AD slows progression of the dementia

Background The pathogenesis of Alzheimers disease (AD) may involve impaired clearance of toxic metabolites, e.g. amyloid-beta peptides (Aβ), from the brain via interstitial fluid (ISF) and cerebrospinal fluid (CSF) circulation, and the blood-brain barrier (BBB). If so, then increasing ISF and CSF circulation may improve CSF Aβ clearance and may slow the progression of AD. We tested this hypothesis in a prospective, randomized, double-blind, placebo-controlled trial of low-flow CSF shunting. Our previously reported analysis using the Generalised Estimating Equations showed no effect of CSF shunting. The present report provides post hoc analyses using linear mixedeffects models fit by maximum likelihood.

Shunting in AD increases ventricular CSF protein levels

Background Defects in CSF circulation may impair clearance of toxic metabolites (i.e. amyloid-beta peptides – Aβ), from the brain via interstitial fluid (ISF) and so contribute to pathology in Alzheimers disease (AD). On this view, constant drainage of CSF via a low-flow ventriculo-peritoneal shunt could facilitate clearance of toxic moieties from ISF and so slow disease progression. We tested this possibility in a prospective, randomized, double-blind controlled, multi-centre trial. We have reported elsewhere that patients with active shunts showed less cognitive decline than controls. Here, we analyse the effects of shunting on CSF protein concentrations in AD patients.