Blood Brain Barrier Disruption Correlates with Worse Memory Function in Older People
Healthy, cognitively normal older people are called healthy and cognitively normal because their degeneration is not yet severe enough to be called disease. Whether or not one has an age-related disease isn't as binary as the regulators would like it to be, however. Loss of function is a progression, growing over time, and disease status is just a line in the sand drawn somewhere along that path. The average healthy older person is impaired to some measurable degree in comparison to their younger self, and that impairment derives from the accumulation of damage and dysfunction in cells and tissues throughout the body.
As an illustration of this point, today's open access paper provides data on cognitively normal older people. The researchers show that measurable dysfunction in the blood-brain barrier correlates with loss of memory function. When the blood-brain barrier leaks, it allows unwanted molecules and cells into the brain, where they can provoke chronic inflammation. This is harmful to brain function. This damage and cognitive decline definitively exist, and yet these people are considered healthy and cognitively normal in the present system of medicine. One might hope that this way of looking at things will change dramatically as the first rejuvenation therapies emerge into widespread use.
The deposition of amyloid-beta (Aβ) plaques and neurofibrillary tau tangles has been the focus of Alzheimer's disease (AD) research. Both Aβ and tau show relationships with cognition that are particularly malignant when the two proteins occur together. Recent research suggests that neurovascular factors including blood-brain barrier disruption (BBBd) may be an early biomarker of human cognitive dysfunction and possibly an underlying mechanism of age-related cognitive decline or AD. BBBd is implicated in both aging and AD, with BBBd observed in regions susceptible to neurodegeneration and important for cognitive function. Studies have also identified that BBBd is associated with cognitive deficits, independent of AD pathology and atrophy. However, there is also evidence that pathological protein aggregation may be related to BBBd. These findings highlight the need to further consider relationships between BBBd and pathological protein aggregation, and to examine in greater depth the likely complex processes that drive age related cognitive decline and perhaps AD.
The current model of AD is a sequential cascade: first Aβ deposition, then tau pathology, neurodegeneration, and eventually dementia. Some research points to BBBd as a potential early biomarker and underlying mechanism of cognitive decline. The BBB is essential for brain homeostasis, and its disruption has been implicated in AD pathogenesis. BBBd may facilitate the entry of neurotoxic substances into the brain and impair Aβ clearance, contributing to plaque accumulation. This raises critical questions about how BBBd fits into the current AD model and whether it acts as an early or parallel process that exacerbates neurodegeneration and cognitive decline.
We used dynamic contrast-enhanced MRI (DCE-MRI) and positron emission tomography (PET) imaging in cognitively normal older adults to explore how BBBd correlates with brain atrophy and cognitive function, and whether these relationships are influenced by Aβ or tau. We found that greater BBBd in the hippocampus (HC) and an averaged BBBd-susceptible region of interest (ROI) were linked to worse episodic memory, with interactions between BBBd and atrophy influencing this relationship, independent of Aβ and tau. However, there were no significant relationships between BBBd and non-memory cognitive performance. In participants with longitudinal AD biomarker and cognitive data acquired prior to DCE-MRI, faster longitudinal entorhinal cortex (EC) tau accumulation and episodic memory decline were associated with greater HC BBBd, independent of global Aβ changes and regional atrophy.
Taken together, both our cross-sectional and longitudinal findings suggest that BBBd may play a role in the early stages of cognitive decline, independent of the key biomarker of AD, Aβ. The significant relationships among HC BBBd, atrophy, and memory performance point to the potential of BBBd as an early indicator of cognitive decline.