Microscopic blood vessel disease in the brain’s white matter linked to poorer cognition in Alzheimer’s – ScienceDaily

Scientists report that a disease of the microscopic blood vessels that supply the white matter in our brain is linked to poorer cognitive function and memory deficits in people with Alzheimer’s.

“The main takeaway from this paper is that mixed pathology, as we call it – microvascular disease and Alzheimer’s – is associated with more brain damage, more white matter damage, and more inflammation,” says Dr. Zsolt Bagi, a vascular biologist in the Department of Physiology at Augusta University Medical College of Georgia.

Their and other recent findings suggest that some people with Alzheimer’s who have brain changes broadly associated with the disease, such as amyloid plaques, may not develop dementia without this underlying vascular dysfunction, the researchers write in the magazine geoscience.

“We propose that if you prevent the development of the microvascular component, you may give people with Alzheimer’s at least a few more years of normal functioning,” says Bagi.

he and dr Stephen Back, pediatric neurologist, Clyde and Elda Munson Professor of Pediatric Research and an expert in white matter injury and repair in the developing and adult brain at Oregon Health & Science University, are co-corresponding authors on the new study.

The good news is that vascular disease is potentially modifiable, Bagi says, by reducing root causes like high blood pressure, obesity, diabetes and inactivity.

The scientists examined the brains of 28 people who took part in the Adult Changes in Thought Study (ACT), a joint initiative of the Kaiser Permanente Washington Research Institute and the University of Washington, whose scientists also collaborated on the new study.

ACT is a longitudinal study of the cognitive health of volunteers in the Seattle, Washington area with the goal of finding ways to delay or prevent memory loss. Participants who are 65 years of age or older and have no cognitive problems at enrollment are followed until their death, and approximately 25% consent to an autopsy and the provision of genomic DNA from their blood and/or brain tissue to researchers.

The people who served as controls for the study had no evidence of Alzheimer’s or vascular disease in their brains. Other groups had Alzheimer’s without vascular disease, vascular disease without evidence of Alzheimer’s, or both Alzheimer’s and vascular disease.

Their focus in the studies was on the white matter, which makes up about 50% of the brain mass, allows communication between different regions of the brain and is full of long arms called axons, which connect neurons to each other and to other cells throughout the body like muscle cells; and the microscopic arterioles, which supply blood, oxygen, and nutrients directly to the white matter.

They wanted to test their theory that when these hair-thin arterioles struggled to dilate and support that part of the brain, it led to white matter changes that were evident on sophisticated MRIs, particularly when microvascular issues coexisted with the more classic brain Alterations of Alzheimer’s.

They found that the arterioles of those diagnosed with Alzheimer’s and dysfunction in these tiny arteries had an impaired ability to dilate in response to the powerful blood vessel dilator bradykinin compared to those with no apparent microvascular dysfunction. Dilation problems were associated with white matter injuries and changes in white matter structure that were visible on MRI.

Expression of the precursor to the equally potent blood vessel dilator nitric oxide was also reduced in these individuals with both diseases, while expression of superoxide, which produces NOX1, which damages blood vessels, was increased.

Arteriolar dysfunction was also linked to more white matter injury based on what was visible on those sophisticated MRI scans and the increased number of brain cells called astrocytes that support neurons.

The researchers previously reported an increase in these astrocytes in brains with the microvascular changes. This time they saw that when both Alzheimer’s and the microvascular changes were present, the astrocytes became more reactive, inflammatory and damaging.

Colleagues at Oregon Health & Science University, led by Back, examined the same brain tissue using a sophisticated MRI technique called diffusion tensor imaging, which uses water diffusion between cells to study white matter microstructure and its connectivity.

They couldn’t visualize individual arterioles because they’re too small — about 30 microns, or 0.0011811 inches — to see without a microscope. But they could see the white matter damage resulting from the arteriolar disease and again found the correlation between vascular impairment and tissue damage, which Bagi described through direct visualization of the tissue. This type of blood vessel disease was present in 50% of the brains they examined, and other autopsy studies have shown a similarly high rate.

In those with fewer signs of brain changes, they found that arterioles were able to dilate better, that area of ​​the brain had better connectivity, and less damage visible on postmortem MRI.

It is known that a reduced ability of these small white matter vessels to dilate is associated with white matter injury as seen on the specialized MRI scans. And there is evidence, both in laboratory studies and in humans, that this vascular dysfunction not only worsens, but plays a role in the development of cognitive decline and dementia in people with Alzheimer’s, the researchers write.

In fact, vascular dysfunction may be present before brain tissue damage and cognitive dysfunction are apparent. For example, in experimental animals bred to develop Alzheimer’s, there is evidence of microvascular problems in areas of the brain associated with Alzheimer’s, such as the hippocampus, a center for learning and memory, at a very young age.

The new work confirms the growing concept that small blood vessel disease can help predict the severity of dementia and/or the use of DTI-MRI can help identify patients with disease early enough that strategies to mitigate it Reducing or slowing down the small blood vessel disease can help delay the disease or reduce your cognitive loss. The technique could also help assess the potential benefit of an intervention.

“These individuals could particularly benefit from exercising, controlling blood sugar levels, and controlling their blood pressure,” says Bagi.

Some patients with Alzheimer’s disease are known to have white matter hyperintensity on MRI scans, essentially areas of damage that appear particularly bright on the scan and have been linked to problems such as dementia. A significant proportion of people with Alzheimer’s also suffer from conditions such as high blood lipid levels and high blood pressure, which are known to impair the functioning of blood vessels, including the smallest ones, Bagi notes. A disease of the small blood vessels in the brain is also common in old age and can indicate an increased risk of problems such as stroke or dementia. Sophisticated brain scans also often show microinfarcts, essentially microscopic strokes, which also tend to increase with age and are associated with memory impairment.

Age and family history are major risk factors for Alzheimer’s, and there are two categories of genes associated with increased risk, including risk genes, such as APOE-e4, the first gene identified and the one that has the strongest impact on risk in Alzheimer’s Organization. Then there are those genes that can directly cause Alzheimer’s, so-called deterministic genes, which affect the production or processing of beta-amyloid, the main component of the plaque associated with Alzheimer’s, but even the presence of these rare genes is no guarantee of disease.

“They have some genetic predisposition, but people realize that not everyone will develop memory loss or cognitive deficits unless there’s something else involved,” says Bagi. He notes that they haven’t analyzed the genes for this study yet.

Next steps include examining the associations they found in more human brains and further studies to better understand how exactly the small blood vessel disease works, which could point to new targets.

The research was supported by the National Institutes of Health, the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, and the Nancy and Buster Alvord Endowment. The scientists also thanked the participants in the ACT study, “whose dedication to supporting critical human research” made the published work possible.

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