The blood-brain barrier is a layer of specialized cells that only very selectively allow passage of molecules and cells to and from blood vessels that pass through the brain. The barrier separates the biochemistry of the brain from that of the rest of the body. Unfortunately, the blood-brain barrier becomes dysfunctional with age, allowing leakage of unwanted molecules and cells into the brain, where they can, for example, provoke chronic inflammatory behavior in innate immune cells and other supporting cell populations responsible for maintaining brain tissue. It is presently thought that blood-brain barrier dysfunction is important in the development of neurodegenerative conditions, and may be an early contributing cause, preceding many of the other biomarkers and pathological mechanisms.

In today’s open access paper, researchers report on their use of MRI to produce regional maps of blood-brain barrier leakage in the brains of old and young volunteers. The researchers then compared these maps with PET imaging of amyloid-β and tau protein, both of which misfold and aggregate in old age, and particularly in the context of Alzheimer’s disease, in search of correlations. The researchers found a tendency for blood-brain barrier dysfunction to follow the regional pattern of neurodegenerative pathology that is associated with Alzheimer’s disease. This is another data point to add to the evidence for the importance of the blood-brain barrier in neurodegenerative conditions. More effort should be directed towards approaches that might reverse age-related blood-brain barrier dysfunction.

Associations between regional blood-brain barrier permeability, aging, and Alzheimer’s disease biomarkers in cognitively normal older adults

Brain aging is accompanied by the aggregation of pathological proteins and the increasing prevalence of cerebrovascular disease. Recent research has shown that blood-brain barrier dysfunction is an important feature of both brain aging and Alzheimer’s disease (AD). Blood-brain barrier permeability (BBBp) alteration in human aging and Alzheimer’s disease (AD) has been documented through the detection of blood-derived proteins in the hippocampus (HC) and cortex of AD patients and increases in the cerebrospinal fluid (CSF) of the plasma albumin protein ratio (Qalb) in both aging and AD. More recent evidence of BBBp in humans comes from studies using the high spatial and temporal resolution imaging technique, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which allows measurement of subtle BBB changes. A number of studies using DCE MRI have shown increased BBBp in both aging and AD with particular vulnerability of the hippocampus to this process. Major questions remain, however, regarding the overall spatial distribution of BBBp, whether abnormalities are limited to the medial temporal lobe (MTL) and most importantly, whether or how BBBp is related to the development of AD.

In this study, we investigated the relationship between BBBp and AD through two lines of evidence. First, we examined the full spatial distribution of BBBp which offers an ability to draw inferences about causal mechanisms and to help establish the role of BBBp in dementia. To do this, we compared BBB function in a group of cognitively normal older adults (OA) to young adults (YA) and mapped the whole brain distribution of BBBp. Second, we investigated whether BBBp in OA was associated with APOE4 genotype and regional Aβ and tau, measured using PET imaging.

Using DCE-MRI in cognitively normal OA and YA, we showed that increased BBBp in aging does not occur globally, but rather occurred predominately in the temporal lobe, with involvement of the parietal, and less involvement of occipital and frontal lobes. In these regions we also found that APOE4 carriers had greater BBBp than non-carriers. The regional BBBp we found strikingly reflects the pattern of brain vulnerability to AD pathology, particularly in regions that are affected early. Tau accumulation in normal aging begins in the medial temporal lobe and spreads to neighboring regions in the inferolateral temporal and medial parietal lobes in the presence of Aβ. The pattern of brain Aβ accumulation overlaps with the spatial location of tau best in later disease stages, covering regions in prefrontal, parietal, lateral temporal, and cingulate cortices.

In line with previous studies, we saw greater BBBp in the MTL, particularly regions which accumulate tau pathology and undergo atrophy in normal aging, but do not typically accumulate Aβ at early stages of AD. We also saw that in our sample the frontal lobe is relatively spared from increased BBBp, which is interesting because this brain region is associated with early Aβ accumulation but late tau accumulation. These differences suggest that increased BBBp follows a distribution pattern more like tau accumulation than Ab, with involvement of the MTL, temporal, parietal, and occipital lobes. The degree of BBBp alteration varied considerably in older individuals and increases were also seen in young adults, so it is difficult to say with certainty that these changes are pathological from these data alone. However, their associations with brain regions affected by AD and the suggestion of relationships with abnormal protein accumulation, raise concerns.

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