Summary: Functional brain networks and brain shrinkage are affected in different ways by age, sex, and blood immune factors.
Source: Buck Institute
Humans lose brain volume as they age, at an estimated rate of 5% per decade after age 40. But this estimate obscures the role that individual physiology plays in the functional aging of the brain.
Using sophisticated analytical tools, researchers from the Buck Institute and the University of California, San Francisco analyzed 554 patients using volumetric MRIs and immune blood samples taken over a decade .
The results of the study, published in Proceedings of the National Academy of Sciencesshow that functional brain networks are affected in different ways by aging, gender and blood immune factors.
The researchers, led by bioinformatics scientist Nikola Markov, Ph.D., first looked at circulating blood proteins, identifying patterns of inflammatory protein concentrations that increase with age, a process called “inflammatory aging.”
The correlation with aging was so clear that scientists were able to predict a person’s chronological age with startling accuracy simply by analyzing the concentration profile of these proteins. This measurement is called CyClo or “cytokine clock”.
The researchers found that the cytokine clock and brain shrinkage follow different trajectories by gender, with women having faster cytokine clocks even though they were more protected against brain shrinkage overall.
“This work opens the black box between aging and neurodegeneration,” says David Furman, Ph.D., lead author and associate professor at the Buck Institute.
“We are now able to tell the difference between brain shrinkage caused by aging and shrinkage caused by chronic inflammation.
“Basically, if we remove the causality of time and someone has high inflammation, they’re on track to have a smaller brain in certain areas. Additionally, by identifying inflammatory biomarkers of brain aging, we have potential targets for the early diagnosis and prevention of age-related neurodegeneration.
The results are based on a canonical correlation analysis. This technique allows researchers to take two sets of variables collected from the same individual and decouple the effects of those variables on a particular outcome, in this case, functionally connected brain regions. It also allows scientists to see in the same individual how parameters correlate with each other.
The researchers in this study analyzed three parameters – age, sex and CyClo – as well as volume measurements of seven functional brain networks in the same dataset. Markov says the correlation functions revealed some interesting observations.
The variability of chronological age measured in the population constructs the strongest correlation function with the volume of brain networks dedicated to motor control and body sensing. The subject’s gender was correlated with the visual system, ventral attention, and fronto-parietal networks.
The biological age represented by the cytokine clock, CyClo, was most correlated with the limbic, default, and dorsal attention network that deals with directing one’s focus on a particular task.
“The significance is not just that we mapped the cytokine clock onto gray matter, but that we did it by looking at the functional networks, the areas in which neurons fire together, work together, connect and interact together,” Markov said. .
“We also found that although the networks are distributed throughout the brain, they share common vulnerabilities to the aging process.”
Markov says the next challenge is understanding how these circulating immune proteins directly impact the aging brain and why some parts of the brain are more susceptible to peripheral inflammation than others.
He says the most impactful immune proteins, or cytokines/chemokines, that have emerged in blood samples include IL-6 and TNF alpha which are associated with chronic inflammation that increases with age, as well as VEGF and PLGF, which appear to be critical for the health of the vascular system, especially the small capillaries.
The researchers also identified MCP-1, Vcam-1 and Eotaxin-1 which are chemokines that change with age and attract immune cells from the blood to cross the blood-brain barrier. Markov says that when these chemokines cross the blood-brain barrier, they cause the activation of microglia, a potential initiator of the neurodegenerative process.
Going forward, Furman sees two potential uses for the science: “Once we identify that the most affected networks are also mapped with cognitive impairment in people diagnosed with Alzheimer’s disease or mild cognitive impairment, then we have a diagnostic test.
“The next opportunity involves the question of whether we can modify this cocktail of cytokines to help individuals be more resilient and avoid decline in these different areas of the brain where we have seen decline in function.”
About this neuroscience research news
Author: Press office
Source: Buck Institute
Contact: Press Office – Buck Institute
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Original research: Free access.
“Age-related brain atrophy is not a homogeneous process: Different functional brain networks associate differently with aging and blood factors” by Nikola T. Markov et al. PNAS
Age-related brain atrophy is not a homogeneous process: different functional brain networks associate differently with aging and blood factors
Aging is characterized by a progressive loss of cerebral volume at a rate estimated at 5% per decade after 40 years. If these morphometric changes, including those affecting gray matter and temporal lobe atrophy, are predictors of cognitive performance, the strong association with aging obscures the parallel, but more specific, potential role of individual subject physiology.
Here, we studied a cohort of 554 human subjects who were monitored using structural MRIs and blood immune protein concentrations.
Using machine learning, we derived a cytokine clock (CyClo), which predicted age with good accuracy (mean absolute error = 6 years) based on the expression of a sub- set of immune proteins.
These proteins included, among others, placental growth factor (PLGF) and vascular endothelial growth factor (VEGF), both involved in angiogenesis, chemoattractant vascular cell adhesion molecule 1 (VCAM-1), canonical inflammatory proteins interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), chemoattractant IP-10 (CXCL10) and eotaxin-1 (CCL11), previously implicated in brain disorders.
Age, sex and CyClo were independently associated with different functionally defined cortical networks in the brain. While age was primarily correlated with changes in the somatomotor system, sex was associated with variability in the frontoparietal, ventral attention, and visual networks.
A significant canonical correlation was observed for CyClo and the default, limbic and dorsal mode attention networks, indicating that circulating immune proteins preferentially affect brain processes such as focused attention, emotion, memory, social stress response, internal evaluation and access to consciousness. .
Thus, we have identified immune biomarkers of brain aging that could be potential therapeutic targets for the prevention of age-related cognitive decline.
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