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News from the Society for Neuroscience Meeting: The Impact of Inflammation on the Unhealthy and Healthy Aging Brain

WASHINGTON, DC—Inflammation, an integral part of the aging process, hits the brain especially hard, contributing to white matter damage, amyloid accumulation, and a cascade of biochemical changes, according to new research described here at the Society for Neuroscience meeting in November.

“Genetic variants associated with pro-inflammatory activity are linked to increased volume of white matter hyperintensities independent of other factors,” said Naftali Raz, PhD, of Wayne State University's Institute of Gerontology, in a presentation of his recent research.

DR. TREY HEDDEN said his study supports the theory that attention, dependent on prefrontal and parietal regions, diminishes with age, and yet activity in those regions often increases with age.

“Vascular risk factors amplify these age-related alterations of the cerebral white matter, which are more prevalent in the frontal lobes, especially in people with hypertension. These findings weigh in favor of theories of aging that treat inflammation as one of the main contributors to brain aging.”

CALORIE RESTRICTION, BRAIN HEALTH

Moderate calorie restriction has been shown to slow aging in a variety of species, presumably by constraining inflammatory processes, and Aadhavi Sridharan, an MD-PhD student at the University of Wisconsin, Madison, reported on evidence supporting that hypothesis.

In an ongoing study of calorie restriction in rhesus macaques at the Wisconsin National Primate Research Center, autopsies on four monkeys on calorie restriction, and seven on normal diets, showed that the calorie-restricted monkeys expressed 20- to 40-percent less glial fibrillary acidic protein (GFAP) in the hippocampus.

“In trauma, ischemia, and neurodegeneration, astrocytes exhibit changes leading to reactive astrogliosis and an increased expression of GFAP,” Dr. Sridharan told Neurology Today. “Reactive astrogliosis is a response to any stress on the brain, but there is also increased expression of GFAP as a function of normal aging, presumably due to -cumulative oxidative, metabolic, and inflammatory stresses on the brain over time.” So less GFAP immunoreactivity in the hippocampus of monkeys on calorie restricted diets suggests they possessed healthier brains at the time of death.

Genes also exert an effect on hippocampal degeneration, according to Elias Pavlopoulos, PhD, associate research scientist in the laboratory of Eric R. Kandel, MD, at Columbia University. He pointed out that while the entorhinal cortex of the hippocampus is most affected in Alzheimer disease, the dentate gyrus is most affected in age-related memory loss, and that a gene, RbAp48, has been implicated in that process.

DR. NAFTALI RAZ: “Genetic variants associated with pro-inflammatory activity are linked to increased volume of white matter hyperintensities independent of other factors. Vascular risk factors amplify these age-related alterations of the cerebral white matter, which are more prevalent in the frontal lobes, especially in people with hypertension. These findings weigh in favor of theories of aging that treat inflammation as one of the main contributors to brain aging.”

According to Dr. Pavlopoulos, RbAp48, which encodes a histone binding protein that modifies histone acetylation, regulates the remodeling of the chromatin that binds DNA tightly in the nucleus, thereby controlling gene expression. In a transgenic mouse model that expresses an inhibitor of RbAp48, even young mice displayed hippocampal-dependent memory deficits similar to those observed in aging. Therefore, Dr. Pavlopoulos concludes, inhibition of RbAp48 expression may play a role in producing age-related memory problems.

IMMUNE-RELATED TRANSCRIPTS

Microglia are the resident immune cells in the CNS, and would be expected to play a significant role in coordinating immune-related responses evoked by aging, but that didn't prove to be the case in a study conducted by Stephen Bonasera, MD, assistant professor of internal medicine geriatrics at the University of Nebraska College of Medicine.

Reporting on his research involving neuroinflammation in two mouse strains, Dr. Bonasera found that immune defense dysfunctions were found to coincide with changes in mobility and energy regulation, suggesting an inflammatory process, but a study of microglia from the hypothalamus and cerebellum of the mice showed that most of the genes expressed were not expressed in microglia. This, according to Dr. Bonasera, suggests that “age-related changes in the expression of immune-related transcripts may represent a process distinct from neuroinflammation.”

Klotho, a transmembrane protein encoded by the KL gene, appears to combat the inflammatory effects of aging. Mice bred to overexpress Klotho live 19- to 31-percent longer than typical mice, and a recent paper in Nature Cell Biology reports that Klotho inhibits the expression of inflammatory proteins interleukin-6 and interleukin-8.

ROLE IN MYELINATION

Now researchers at the Boston University School of Medicine have shown that Klotho induces the maturation of oligodendrocytes, which contribute to the production and maintenance of myelin, the fatty white sheath that is attacked by the immune system in multiple sclerosis and other inflammatory disorders. Mice bred to be deficient in the gene for Klotho have a reduced lifespan, and exhibit many manifestations of human aging, including cognitive decline. In a poster presentation the researchers, led by Carmela Abraham, PhD, report that Klotho may play an important role in oligodendrocyte biology and myelination.

“We treated isolated oligodendrocyte precursor cells with Klotho protein and observed that these cells responded to Klotho by producing myelin basic protein, a marker of oligodendrocyte maturation and a necessary protein of myelin,” they reported in a summary of their findings. “Interestingly, when we examined the myelin in two myelin-rich regions of the brain of a mouse lacking Klotho, and compared it to a normal mouse, we observed a striking reduction in the percentage of myelinated nerve fibers in the absence of Klotho.

Ninety percent of fibers are myelinated in the control mouse while only 10 percent are in the Klotho-deficient mouse. This finding suggests that Klotho is a necessary ingredient in the formation of normal myelin by the oligodendrocytes, and in the differentiation of precursor to mature oligodendrocytes.

Brain atrophy in aging is believed to be caused, in part, by inflammatory processes that degrade myelin, and physical fitness correlates with less brain shrinkage and other age-related changes, according to researchers from the University of Arizona. They scanned the brains of 58 men and 65 women ages 50 to 89 years, and evaluated their fitness by having them walk on an inclined treadmill. The most fit — especially those who spent the longest times on the treadmill and showed good breathing efficiency — had fewer age-related brain changes and did better on tests of memory, executive function, and information processing.

“Identifying those fitness indices that are the best predictors of brain aging and cognitive performance may aid efforts in developing and evaluating exercise-based interventions for age-related cognitive decline,” the researchers stated in their poster presentation.

NEURAL SCAFFOLDING

Attention, dependent on prefrontal and parietal regions, diminishes with age, and yet activity in those regions often increases with age, according to a study in Cerebral Cortex led by Trey Hedden, PhD, a research associate at Harvard University's Martinos Center for Biomedical Imaging.

Dr. Hedden and colleagues propose that this increased activity may reflect a process of “neural scaffolding” — a concept introduced by Denise C. Park, PhD, of the University of Texas at Dallas, and Patricia Reuter-Lorenz, PhD, of the University of Michigan — to explain how the aging brain, in response to insults such as atrophy, white matter disruption, and amyloid deposition — all aggravated by inflammation — develops additional circuits in an effort to meet cognitive challenges.

Dr. Hedden's group found that the failure to display increased activity, which resulted in poorer cognitive performance, was associated with an increase in white matter hyperintensities, but not with an increase in amyloid burden. However, amyloid burden but not white matter hyperintensities was associated with impaired functioning of the default network, which is active when the brain is not occupied with a specific task.

A recent fMRI study of memory-related networks of 52 younger and 66 older adults, presented by Dr. Hedden and colleagues as a poster, found that age and amyloid burden disrupt functional connectivity in two memory-related networks identified by fMRI while the subjects were asked to remember previously learned word pairs. Amyloid burden was not associated with changes in one network, which included the hippocampal formation, posterior cingulate, and inferior parietal cortex; but it was associated with changes in another network, which included the lateral prefrontal cortex, superior parietal cortex, and the dorsal anterior cingulate. These changes may impair the brain's ability to modulate activity in response to a challenge.

WHAT'S THE SECRET BEHIND THE ‘SUPERAGERS’?

With the brain so sensitive to the insults inflicted by aging, why do some octogenarians retain the cognitive capacity of people a generation younger?

Researchers at Northwestern University's Feinberg School of Medicine, led by Emily Rogalski, PhD, are following 27 “SuperAgers,” as they call them, in an effort to find out.

Lifestyle offers almost no clues. “Some people come in using a walker and are not very active,” said Dr. Rogalski, an assistant professor of cognitive neurology. “Others lift weights five days a week. We have smokers, and some who never drink or smoke ever. They're not all wealthy and well educated. They come from all walks of life.”

But structural MRI scans of 12 SuperAgers, 10 typical octogenarians, and 14 adults in their late 50s and early 60s provided a tantalizing clue — they display none of the cortical thinning thought to be an inevitable byproduct of aging.

“You see significant atrophy in the brain of a normal 80-year-old, and you would expect to see some in SuperAgers too, but there was no significant difference in cortical thickness compared with people in their 50s,” said Dr. Rogalski, who presented the group's findings here. “And their anterior cingulates were thicker than the 50-year-olds', which was very surprising.

Cingulate hypometabolism as measured by PET is one of the earliest correlates of neuronal dysfunction in Alzheimer disease, and in vivo amyloid imaging with PET shows early accumulation of amyloid in the cingulate gyrus of Alzheimer disease patients, suggesting the cingulate is an important region in abnormal aging.”

Tom Valeo

REFERENCES:

• Liu F, Wu S, Ren H, Gu J. Klotho suppresses RIG-I-mediated senescence-associated inflammation. Nat Cell Biol 2011;13:254-262.
• Hedden T, Van Dijk KRA, Shire EH, Sperling RA, Johnson KA, Buckner RL. Failure to modulate attentional control in advanced aging linked to white matter pathology. Cerebral Cortex 2011; E-pub 2011 Jul 17.
    • Park DC, Reuter-Lorenz P. The adaptive brain: Aging and neurocognitive scaffolding. Annu Rev Psychol 2009;60:173-196.