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, 85 (2), 296-302

Blood-brain Barrier Breakdown in the Aging Human Hippocampus

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Blood-brain Barrier Breakdown in the Aging Human Hippocampus

Axel Montagne et al. Neuron.

Abstract

The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.

Conflict of interest statement

Competing interests

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1. Blood-brain barrier breakdown in the hippocampus in the living human brain during normal aging
(A–B) A dynamic contrast enhanced magnetic resonance imaging was used to quantify the blood-brain barrier (BBB) regional permeability Ktrans constant in 12 regions-of-interest in the gray and white matter in the living human brain (A) including subdivisions of the hippocampus (B). (C) Representative BBB Ktrans maps of the whole brain (left) and the hippocampus (right) in a young participant with no cognitive impairment. (D–G) Age-dependent increase in the BBB permeability Ktrans constant in the entire hippocampus, its CA1 region and dentate gyrus, but not CA3 region. Single data points for the Ktrans constant from 24 individuals with no cognitive impairment (both genders, ages 23–91; see Table 1) were plotted against age; r = Pearson’s coefficient; P, significance; NS, non-significant. See also Supplementary Figure S1.
Fig. 2
Fig. 2. Blood-brain barrier breakdown in the hippocampus during normal aging and aging associated with mild cognitive impairment
(A) Representative Ktrans maps within the hippocampus in young and older individuals with no cognitive impairment (NCI) and mild cognitive impairment (MCI). MS, a multiple sclerosis case with no cognitive impairment. (B–E) A progressive significant increase in the BBB permeability constant Ktrans in older compared young NCI group and MCI compared to older NCI group in the entire hippocampus, CA1 region and dentate gyrus. MS group was compared with age-matched young NCI group. Boxplots represent the median (dark horizontal line), with the box representing the 25th and 75th percentiles, the whiskers the 5th and 95th percentiles. P, significance by ANOVA followed by Tukey’s post hoc tests; NS, non-significant. NCI, young (n=6, ages 23–47, both genders); NCI, older (n=18, ages 55–91, both genders); MCI (n=20, ages 55–85, both genders); MS (n=19, ages 26–53, both genders). See Table 1 and Supplementary Figure S2.
Fig. 3
Fig. 3. Hippocampus volume in the studied groups
Hippocampus volume was determined on T2-weighted images in individuals with no cognitive impairment (NCI), with mild cognitive impairment (MCI), and multiple sclerosis (MS) cases with no cognitive impairment. NS, non-significant by ANOVA followed by Tukey’s post hoc tests. NCI, young (n=6, ages 23–47, both genders); NCI older (n=18, ages 55–91, both genders); MCI (n=20, ages 55–85, both genders); MS (n=19, ages 26–53, both genders). See Table 1.
Fig. 4
Fig. 4. Soluble platelet-derived growth factor receptor β in the cerebrospinal fluid in humans and mice
(A) Elevated sPDGFRβ levels in the CSF in individuals with mild cognitive impairment (MCI; n=17) compared to age-matched group with no cognitive impairment (NCI, older; n=14). (B–D) Single data points for sPDGFRβ CSF levels from 31 individuals with NCI (n=14, black) or MCI (n=17, red) plotted against the Ktrans constant in the hippocampus (B), its CA1 region (C), and dentate gyrus (D); r = Pearson’s coefficient; P, significance. (E–F) sPDGFRβ CSF levels in 16-month-old Pdgfrβ+/− mice and Pdgfrβ+/+ controls (C) and 16-month-old Tg2576 mice compared to age-matched littermate controls (D). In C and D, n=5 mice per group. P, significance by a Student’s t-test. See also Supplementary Figures S3 and S4.

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