Brain Ischemia in Alzheimer’s disease counteracts the Disruption of the Blood Brain Barrier: A Hypothesis Investigated with a Lumped Parameter Model

Abstract

Background: In normal pressure hydrocephalus (NPH) there is blood brain barrier (BBB) disruption, which should increase the CSF formation rate (CSFfr) and therefore the intracranial pressure (ICP). However, the ICP is normal in NPH. A lumped parameter study suggested that the CSFfr could be reduced in this condition if the BBB disruption was moderated by a reduction in the capillary transmural pressure (TMP) secondary to arteriolar constriction. In early Alzheimer's disease (AD), there is BBB disruption, reduced ICP and global ischemia. This raises the possibility that the same physiology may be occurring in AD as occurs in NPH. Objective: This hypothesis can be analyzed further using a lumped parameter hydrodynamic model we have developed. Methods: A lumped parameter model previously used to describe the hydrodynamics of NPH was modified to investigate the effects of changes in CSF pressure and blood flow in patients with mild cognitive impairment (MCI) and AD. Results: The model indicates the capillary TMP is normal in MCI but decreases as AD progresses. Removing CSF in AD patients during a tap test initially increases the capillary TMP. The brain in AD responds to a tap test by increasing its level of ischemia and this reduces the capillary TMP. Conclusions: A hypothesis is put forward that the BBB disruption in AD is partially mitigated by the brain making itself ischemic. Modelling gives support to this hypothesis. The model can explain the development of ischemic neuronal loss and amyloid accumulation secondary to glymphatic flow disruption as AD progresses.