The relationship between blood-brain barrier permeability and cerebral blood flow in cognitive impairment

Giuseppe Barisano, Axel Montagne, Daniel A. Nation, Elizabeth Joe, Abhay P. Sagare, Lina M. D’Orazio, David P. Buennagel, Michael G. Harrington, John M. Ringman, Lon S Schneider, Helena C Chui, Judy Pa, Meng Law, Arthur W Toga, Berislav V. Zlokovic

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The contribution of cerebral microvascular dysfunction to early cognitive impairment and dementia is increasingly recognized. Here we investigated cerebral blood flow (CBF) and blood–brain barrier (BBB) permeability in relation to early cognitive decline in APOE3-homozygotes (ε3/ε3) and APOE4-carriers (ε3/ε4; ε4/ε4).

A total of 237 participants underwent neuropsychological evaluations, venipuncture, and magnetic resonance imaging (MRI). The global Clinical Dementia Rating (CDR) was used to classify participants in cognitively unimpaired (CU, CDR=0) and mild cognitive impairment (CDR=0.5). APOE genotyping was performed via polymerase chain reaction-based retention fragment length polymorphism analysis on DNA extracted from buffy coat. BBB permeability and CBF were estimated from dynamic contrast-enhanced and 3D pseudo-continuous arterial spin labeling (pCASL) MRI data, respectively, using in-house pipelines. After excluding APOE2-carriers and participants with CDR>0.5, 143 participants (86 females [60.1%]) were included in the analysis. (Table 1)

Standardized CBF levels in grey matter (GM), hippocampus (HC), and parahippocampal gyrus (PHG) were not significantly different in APOE3-homozygotes and APOE4-carriers, after controlling for age and sex. (Figure 1) Our results of BBB permeability in 52 CU participants (27 APOE3-homozygotes and 25 APOE4-carriers) confirm a significantly higher BBB permeability in the HC of APOE4-carriers compared with APOE3-homozygotes (p<0.001), as previously reported (Montagne et al., Nature, 2020), and show no relationship between BBB permeability and CBF. (Figure 2) In a subgroup of 46 participants (21 CU APOE3-homozygotes, 18 CU APOE4-carriers, and 7 APOE4-carriers with CDR=0.5) who underwent a second MRI approximately 2 years after the first MRI, we observed a significant reduction (p=0.008) of CBF in APOE4-carriers with mild cognitive impairment, but not in CU individuals.

APOE4 is associated with higher BBB permeability in CU participants compared with APOE3-homozygotes, but CBF is not different between the two genotypes. In the future, longitudinal data will be collected to confirm whether BBB breakdown precedes CBF alterations and to assess their relationship with cognitive decline, amyloid-β and tau pathology.
Original languageEnglish
Article numbere056255
Number of pages3
JournalAlzheimer's & Dementia
Issue numberS5
Publication statusPublished - Dec 2021

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