Study finds association between vascular factors and brain shrinkage

Tiny blood vessels carry life-sustaining nutrition to the deepest recesses of the brain. How early in life do these small, but essential, tributaries begin to lose their function?

This decline might start in middle age, and a subset of people may be more at risk for it than others, suggests a study published by faculty at three institutions, including the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio.

Vascular health is important for brain function. The brain consumes energy and requires a constant supply of blood and oxygen, as well as blood glucose. The research study correlated higher levels of three vascular growth factors with increased small-vessel disease and brain atrophy in middle-aged adults. The study was published in Stroke, the journal of the American Heart Association, in 2018.

Surprising association

Claudia Satizabal, Ph.D., Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health San Antonio

Given that these vascular growth factors participate in the formation of new small blood vessels and their repair, the association may seem a bit surprising, said Claudia L. Satizabal, Ph.D., assistant professor of epidemiology and biostatistics at UT Health San Antonio and faculty of the Biggs Institute. She is the study corresponding author.

Elevation of vascular growth factors may be a compensatory response to large-vessel ischemia (oxygen deprivation), but many possible explanations are yet to be explored, said paper co-author Sudha Seshadri, M.D., founding director of the Biggs Institute and senior investigator in the Massachusetts-based Framingham Heart Study. Indeed, previous studies have related these factors to cardiovascular disease.

Mekala R. Raman, Ph.D., former postdoctoral fellow at Boston University School of Medicine and lead author of the study, analyzed blood samples from healthy, middle-aged Framingham participants (average age 46) to measure vascular growth factors. The team then reviewed magnetic resonance imaging (MRI) to assess structural brain measures.

MRI and the brain

MRI measures of brain atrophy included the loss of brain volume, which tends to decrease as people age. Along with this shrinkage, the cavities holding cerebrospinal fluid in the brain enlarge. These cavities are called ventricles. MRI studies also reveal white matter hyperintensities, which are brain sections that show up as brighter on certain sequences of the MRI. White matter hyperintensities indicate damage in the white matter.

Risk factor APOE-4

The researchers also explored whether Framingham participants who have a copy of a gene called APOE-4 would show stronger associations between the vascular growth factors and MRI markers of brain aging. APOE-4 is a genetic risk factor for Alzheimer’s disease and cardiovascular disease. APOE is short for apolipoprotein E.

“Some of this is part of normal brain aging,” Dr. Satizabal said. “When it is more severe, it may be related to a neurological disease.”

The four vascular growth factors studied from blood samples were:

  • VEGF (vascular endothelial growth factor),
  • Ang2 (angiopoietin 2),
  • sTie2 (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2), and
  • HGF (hepatocyte growth factor)


Dr. Satizabal and collaborators designed the study to analyze associations of these four factors with brain atrophy and white matter hyperintensities. The team found no association between VEGF and the brain markers, either in APOE-4 carriers or other participants.

Higher sTie2 was associated with smaller brain volume and larger volume of white matter hyperintensities in the full study sample. Higher Ang2 and HGF, meanwhile, were associated with larger ventricular volumes in all groups.

The researchers employed a special MRI sequence called diffusion tensor imaging. One of the features that can be measured with this sequence is called fractional anisotropy, which looks at disruptions in the microstructure of white matter fibers, Dr. Satizabal said. A lower value indicates more disruption. In Framingham participants with the APOE-4 Alzheimer’s risk copy, higher Ang2 was associated with decreased fractional anisotropy.

“This is a finer level of vascular microstructural abnormalities, and these were found only in APOE-4 carriers,” Dr. Satizabal said.

Observed in younger people

“All of these are associations only, and we cannot say anything about causality,” she said. “But this opens up new possibilities for research. What is very interesting is that we observed these associations in young people, in middle age. It tells us that all of these processes potentially start many years before any diagnosis of a neurological disease.”

Several grants from the National Institutes of Health supported this research. Vascular growth factors were measured in the Framingham third-generation cohort participants by Vasan S. Ramachandran, M.D., currently principal investigator and director of the Framingham Heart Study, using funds from the National Heart, Lung and Blood Institute. MRI studies were funded by grants from the National Institute on Aging.

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