BETHESDA, MD—While Alzheimer’s disease and other forms of dementia may seem like an accelerated or extreme example of the cognitive decline experienced in normal aging, studies show the neural pathology can be significantly different. “The ultimate goal of my research over the last several decades has been to help reveal the causes of memory decline that is generalizable over all mammals,” explained Carol Barnes, PhD, director of the Evelyn McKnight Brain Institute, at a talk on the campuses of NIH last month. Understanding the process that happens naturally due to aging will be key to better isolating and understanding the pathology of AD and dementia.

Changes in Circuit Connectivity, Plasticity

The normal cognitive decline due to aging is not due to a fewer number of brain cells, as was once thought. Looking at the hippocampus—one of the first regions of the brain to suffer damage due to AD—in humans, monkeys, mice, rats and other mammals, researchers have found that there is no change in principle cell numbers due to regular aging. “Hippocampal preservation during aging is more the rule. But there are anatomical and electrophysiological changes that do occur.”

An electrophysiologist by training, Barnes explained that there are two ways that the aging brain in studied mammals begins to deteriorate. The first is in granule cells—tiny neurons located in the dentate gyrus, part of the hippocampus thought to be important in the formation of new memories. “There are fewer synaptic contacts from the temporal lobe onto these granule cells in old animals. Synapses that remain in old animals are more powerful, [and ] stronger, as though a compensatory process were happening.”

Something similar is seen in CA1 pyramidal cells—another type of neuron found in one division of the hippocampus. “There is no loss of anatomical synapses, but a reduced postsynaptic density size in the older animals. Physiology shows no change in the number of axons, but a substantial loss of synaptic contacts along a given branch of axons in the older animals.”

She noted that there was no change in synaptic strength here. “Perhaps these synapses with the reduced post-synaptic density size are silent. This might be a good therapeutic target.”

The difference between how the aging process affects specific types of neurons is proof that aging is not a general effect, but something much more varied. “The changes that do occur in the aging brain are exquisitely specific. They are not wide-spread in general, but happen differently in different regions.”

Also, she added, “In AD, granule cells do not show changes until very late in the progression. So I think this favors the idea that, while normal aging and AD can co-occur, they have an independent neural pattern.”

The other effect of normal aging noted in animal studies is a loss of plasticity, known as long-term potentiation (LTP). In her research, Barnes has seen faster decay of LTP in older animals, which correlates with spatial memory. LTP decay rate also correlated with how accurate animals were in solving memory challenges. The reason for this decay is still unknown. “Is this an adaptive response to a lifetime of storing information? Or could it be a breakdown in synaptic strength?”

Expanding Research to Primates

Barnes has continued the work she began with mice and other small mammals in nonhuman primates. Looking at a population of rhesus monkeys (six young adult and six aged subjects), Barnes is making closer examinations of the aging brain of mammals.

MRI scans measuring hippocampal volume have been made, comparing the results over an age range. The results showed the volume differed by less than 6%, confirming that brain mass was no predictor of cognitive decline. “Not surprisingly, there was no relationship between hippocampal volume and the memory deficits we observed in these monkeys.”

The same animals were imaged again using an fMRI method designed to map cerebral blood volume. This way, researchers were able to segment out specific areas of the brain for examination. In particular, researchers looked for correlations between metabolic activity and cognitive processes. “Across [all the monkeys], there was no correlation between age and amount of metabolic activity in the adrenal cortex. But there was a significant negative correlation between activity levels and age in the region of granule cells, with older monkeys showing lower activity levels. Most importantly there was also significant correlation between how much metabolic activity there was and how well the animal did in memory tests. The more metabolic activity, the better the animal did on the tests.”

One of the big questions that remains is how to explain the difference in cognitive deficit severity between animals. Why are some more affected than others? Barnes believes the answer likely lies in the interaction between the animal’s experience and environment and their genes.

“Alterations in epigenetic mechanisms will be front and center among the important contributing factors that may explain some of the individual differences that are observed between different animals.”

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