Brain Ischemia in Alzheimer's Disease May Partly Counteract the Disruption of the Blood-Brain Barrier

Background: In normal pressure hydrocephalus (NPH) there is blood-brain barrier (BBB) disruption, which should increase the CSF formation rate (CSFfr) and, therefore, also increase the intracranial pressure (ICP). However, the ICP is normal in NPH. A lumped parameter study was performed to look at the interrelation between the ICP, cerebral blood flow (CBF), and the degree of BBB disruption in NPH. The model 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 and a reduced CBF. In early Alzheimer's disease (AD), there is BBB disruption, reduced ICP, and global ischemia. This raises the possibility that the same physiology may occur in AD as occurs in NPH. 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 that the average 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 suggest a cause for the development of ischemic neuronal loss and amyloid accumulation secondary to glymphatic flow disruption as AD progresses.