Hippocampal blood–brain barrier permeability is related to the APOE4 mutation status of elderly individuals without dementia

Abstract

Blood–brain barrier (BBB) disruption, modulated by APOE4 mutation, is implicated in the pathogenesis of cognitive decline. We determined whether BBB permeability differed according to cognitive functioning and APOE4 status in elderly subjects without dementia. In this prospective study, 33 subjects with mild cognitive impairment (MCI) and 33 age-matched controls (normal cognition [NC]) underwent 3 T brain magnetic resonance imaging. The Patlak model was used to calculate tissue permeability (Ktrans). A region-of interest analysis of Ktrans was performed to compare relevant brain regions. Effects of Ktrans on cognitive functioning were evaluated with linear regression analysis adjusted for confounding factors. NC and MCI groups did not differ in terms of vascular risk factors or hippocampal Ktrans, except for hippocampal volume. Hippocampal Ktrans was significantly higher in APOE4 carriers than in non-carriers ( p = 0.007). Factors which predicted cognitive functioning included hippocampal volume (beta=−0.445, standard error [SE]=0.137, p = 0.003) and hippocampal BBB permeability (beta = 0.142, SE = 0.050, p = 0.008) after correcting for age, education, and APOE4 status. This suggests that hippocampal BBB permeability is associated with APOE4 mutation, and may predict cognitive functioning. BBB permeability imaging represents a distinct imaging biomarker for APOE4 mutations in NC and MCI subjects and for determining the degree of APOE4-related pathology.

Regional Differences in Blood-Brain Barrier Permeability in Cognitively Normal Elderly Subjects: A Dynamic Contrast-Enhanced MRI-Based Study

“…All participants underwent MRI that included protocols for BBB permeability assessment. Out of the 35 subjects, 27 were included as a part of a previous publication [ 15 ].…”

Sex-Related Differences in Regional Blood–Brain Barrier Integrity in Non-Demented Elderly Subjects

“…The specific parameters and protocols used for the structural MRI and DCE-MRI are provided in Table S2 . Our DCE-MRI protocol was based on previously recommend parameters [ 27 ] and validated by revealing reliable and reasonable clinical results [ 9 ].…”

“…However, this method also has limitations in that the lumbar puncture used to obtain the samples is very intrusive and ultimately this method cannot be used to determine the location of the BBB leakage. Moreover, as albumin is a protein molecule with a fairly large molecular weight of 66.5 kDa, it can only be measured in cases of significantly advanced BBB damage and does not reflect early changes in BBB permeability [ 9 , 14 , 15 ].…”

“…Moreover, by using neuroimaging analysis, it is possible to reveal discrete regional changes [ 3 , 6 , 8 , 9 , 16 ]. A few DCE-MRI studies of mild cognitive impairment (MCI) and AD have reported increased BBB permeability in the hippocampus and several gray and white matter regions, before the onset of brain atrophy or dementia [ 8 ], and have made associations between BBB permeability and cognitive decline [ 6 , 7 , 8 , 9 ]. MCI corresponds to an intermediate stage in the extension line of cognitive function that connects normal and dementia, and the basic concept is “a state where cognitive decline is more severe than expected, but not dementia”.…”

Lipocalin 2 regulates iron homeostasis, neuroinflammation, and insulin resistance in the brains of patients with dementia: Evidence from the current literature

“…Alzheimer's disease, the most common type of dementia, is characterized by the excessive accumulation of amyloid beta, neuronal damage, BBB disruption, tau hyperphosphorylation, and neurofibrillary tangles in several brain regions, including the hippocampus and the entorhinal cortex. 27 , 28 , 29 Patients with AD show atrophy and degeneration of the cortex, as well as limbic and hippocampal regions, compared to healthy controls, which leads to memory loss. 30 , 31 …”