The paper and publicity materials I'll point out today are one example of a range of recent investigations of blood-brain barrier dysfunction in Alzheimer's disease patients. The interior of the brain is its own strange domain, shut off from the rest of the body by the blood-brain barrier. Every system fails over the course of aging, however, and this barrier is no exception. There is a good amount of evidence linking increased leakage of the blood-brain barrier with the progression of neurodegenerative conditions such as Alzheimer's disease. Though, as in all such things, we must remember that aging is a global phenomenon, based on the accumulation of forms of cell and tissue damage that occur throughout the body, and thus correlations between many diverse aspects of aging can be found even when there are no direct links between them. Good research must include additional evidence beyond mere association.
What is the blood-brain barrier? The brain is laced with an intricate network of blood vessels large and small, pumping in oxygenated blood, nutrients, and an enormous range of proteins and other materials from the rest of the body. The blood-brain barrier is made up of cells that line every last millimeter of those blood vessels, each joined membrane to membrane with its neighbors in what are called tight junctions. These cells act as gatekeepers, allowing only a specific range of molecules to pass either to or from the brain tissue beyond the blood vessels. If the wrong materials leak or spill into the brain, the result is inflammation and damage - and all of the important neurodegenerative conditions are accelerated by higher levels of inflammation in brain tissues. Equally problematic is failure in the opposite direction, in which a faulty blood-brain barrier traps metabolic waste and other problem molecules in the brain rather than allowing their removal.
What to do about all of this? There is some evidence to suggest that exercise slows blood-brain barrier degeneration, but then exercise modestly slows aging across the board. Calorie restriction is much the same. Beyond these methods of slightly putting off the inevitable, one of the few plausible approaches to addressing blood-brain barrier failure is implementation of the SENS repair-based approaches to aging. Fix all of the fundamental cell and tissue damage known to cause aging, and see how things go from there. Accurately mapping the many, many intermediary steps of cause and consequence between initial damage and end result of blood-brain barrier failure is a massive project for the research community, far harder than fixing damage, even for this one small slice of aging - so why prioritize that path? The faster approach is to repair damage and observe results; if we are truly concerned about treating aging as a medical condition, alleviating suffering and rejuvenating the old rather than merely gathering data, then speed of action is a primary concern.
Researchers using contrast-enhanced MRI have identified leakages in the blood-brain barrier (BBB) of people with early Alzheimer's disease (AD). The results suggest that increased BBB permeability may represent a key mechanism in the early stages of the disease. For the study, researchers used contrast-enhanced MRI to compare 16 early AD patients with 17 healthy age-matched controls. They measured BBB leakage rates and generated a map called a histogram to help determine the amount of the leaking brain tissue.
The BBB leakage rate was significantly higher in AD patients compared with controls and the leakage was distributed throughout the cerebrum - the largest part of the brain. AD patients had a significantly higher percentage of leaking brain tissue in the gray matter, including the cortex, the brain's outer layer. The researchers also found very subtle BBB impairment in the brain's white matter. Indeed, the researchers found a relationship between the extent of BBB impairment and decline in cognitive performance, suggesting that a compromised BBB is part of the early pathology of AD and might be part of a cascade of events eventually leading to cognitive decline and dementia. The connection between BBB impairment and AD pathology was strengthened by the fact that the addition of diabetes and other non-cerebral vascular diseases to the analysis model did not change the results.
For this pilot study, 16 patients with early AD and 17 healthy age-matched control subjects underwent dynamic contrast material-enhanced magnetic resonance (MR) imaging sequence with dual time resolution for 25 minutes. The Patlak graphical approach was used to quantify the BBB leakage rate and local blood plasma volume. Subsequent histogram analysis was used to determine the volume fraction of the leaking brain tissue. The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total gray matter and cortex. Patients had a significantly higher volume fraction of the leaking brain tissue in the gray matter, normal-appearing white matter, deep gray matter, and cortex. When all subjects were considered, scores on the Mini-Mental State Examination decreased significantly with increasing leakage in the deep gray matter and cortex.
Not only did this show that the differences between patients with early AD and healthy control subjects were in the extent of the BBB leakage rather than the rate (ie, strength), but it also showed that the leakage was widespread rather than localized to a single tissue class. In addition, the BBB impairment did not fully originate from vascular abnormality, because adding diabetes and other noncerebral vascular diseases to the analysis model did not change the results. This suggested that the BBB impairment stemmed from the AD abnormality instead of from vascular comorbidities.
The leakage observed in this study can be explained as a breakdown of the BBB tight junctions. It has been shown in rodents that tight junction damage allows gadolinium leakage through the BBB. The regions with high BBB leakage were diffusely distributed throughout the brain, showing that BBB tight junctions were globally impaired. This could have allowed the passage of small and lipophilic molecules that could not cross a healthy BBB. The loss of tight junctions also changes cell polarity, which influences the expression of transporter complexes and thus indirectly affects active transport across the BBB. Therefore, both passive and active transport mechanisms may be impaired in patients with early AD, possibly disturbing homeostasis. We found that cognitive decline was associated with stronger BBB leakage, and both the patients with MCI and those with early AD showed increased BBB leakage. These observations suggest that BBB impairment may be a contributing factor in the early pathophysiology of AD. A possible mechanism is that loss of tight junctions impairs the filter function of the BBB, leading to a toxic accumulation of substances in the brain. This, combined with the altered active transport systems, might add up to a substantial effect on neuronal function that eventually leads to dementia.