Leaky blood-brain barrier identified as potential early-warning sign for Alzheimer's
vrijdag, 25 januari 2019 - Categorie: Onderzoeken
16 jan. 2019
New research published in the journal Nature Medicine has described the results of a five-year study into the association between a breakdown of the blood-brain barrier and the onset of cognitive impairment. The study suggests leaky capillaries in the brain can act as an early biomarker of cognitive decline, and a new drug being developed for stroke patients may be an effective treatment.
The new study, led by researchers from the University of Southern California, follows on from prior work revealing potential connections between blood-brain barrier dysfunction and a number of neurodegenerative diseases, including Alzheimer's and Parkinson's. In the latest study, 161 subjects over the age of 45 were recruited, all with either no identifiable cognitive dysfunction or with very early signs of mild cognitive impairment.
Cognitive functions were assessed using a variety of clinical tests, while brain capillary damage was measured through neuroimaging and biomarkers tracked from cerebral spinal fluid. The results of the study revealed a strong association between blood-brain barrier leakage and cognitive impairment.
Perhaps the most striking result from the study, however, was the discovery that this correlation between leakage and cognitive impairment was irrespective of any identifiable amyloid or tau pathology. It is generally hypothesized that the onset of Alzheimer's symptoms are the result of the accumulation of toxic protein clusters in the brain. These toxic proteins, amyloid and tau, are currently the best biomarkers we have to understand human cognitive dysfunction.
''The fact that we're seeing the blood vessels leaking, independent of tau and independent of amyloid, when people have cognitive impairment on a mild level, suggests it could be a totally separate process or a very early process,'' explains Berislav Zlokovic, senior author on the new study. ''That was surprising that this blood-brain barrier breakdown is occurring independently.''
As Zlokovic notes, it is unclear at this stage whether this blood vessel leakage is just the earliest stages of what will ultimately manifest as Alzheimer's, or if this is an entirely independent neurodegenerative process. There have been hypotheses put forward in the past suggesting an increasingly permeable blood-brain barrier may allow more toxic amyloid and tau proteins to enter the brain, kicking off the pathological process that leads to Alzheimer's.
''If the blood-brain barrier is not working properly, then there is the potential for damage,'' says Arthur Toga, co-author on the new study. ''It suggests the vessels aren't properly providing the nutrients and blood flow that the neurons need. And you have the possibility of toxic proteins getting in.''
More work needs to be done to better understand the temporal link between blood vessel damage and cognitive problems. For example, it is unknown how much time passes between any initial vascular damage in the brain and the onset of cognitive impairment. Nevertheless, the researchers are investigating whether drugs that help protect the brain from blood-brain degeneration can be deployed as early Alzheimer's preventative treatments.
A concurrent new study from the USC team has revealed a drug being developed to treat stroke patients may fit this exact purpose. The drug is called 3K3A-APC, and it has been designed to reduce brain inflammation and intracerebral bleeding.
''Because of its neuroprotective, vasculoprotective, and anti-inflammatory activities in multiple models of neurological disorders, we investigated whether 3K3A-APC can also protect the brain from the toxic effects of amyloid-beta toxin in a mouse model of Alzheimer's disease,'' says Zlokovic.
Early mouse studies have revealed the drug to be incredibly promising in reducing the development of amyloid deposits in the brain. In a mouse model engineered to mimic the development of Alzheimer's, treatment with the drug was found to reduce amyloid accumulations by up to 50 percent.
It is still early days for the research, and although the 3K3A-APC drug is advancing through human trials as a new stroke treatment, it still hasn't officially been approved for clinical use by the FDA. The clear takeaway suggested by the USC team at this point is that vascular biomarkers should potentially be utilized to track the early stages of Alzheimer's and dementia.
The new research was published in the journal Nature Medicine:
Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction
Daniel A. Nation, Melanie D. Sweeney, Axel Montagne, Abhay P. Sagare, Lina M. D’Orazio, Maricarmen Pachicano, Farshid Sepehrband, Amy R. Nelson, David P. Buennagel, Michael G. Harrington, Tammie L. S. Benzinger, Anne M. Fagan, John M. Ringman, Lon S. Schneider, John C. Morris, Helena C. Chui, Meng Law, Arthur W. Toga & Berislav V. Zlokovic
Nature Medicine (2019)
Vascular contributions to cognitive impairment are increasingly recognized1,2,3,4,5 as shown by neuropathological6,7, neuroimaging4,8,9,10,11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer’s disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)3,11,14, and more recently tau15. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood–brain barrier (BBB) breakdown14,15,16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8,9,10,12,13, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging8,9,10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer’s Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau.
Leaky blood vessels may trigger Alzheimer's
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