29 Jul 2011

Human beings stand out from other species by having big brains, complex cognitive abilities, and long lifespans. Two new papers suggest we may pay for these blessings with increased vulnerability to age-related cognitive declines. Both studies used non-human primates that do not develop dementia to look at the effects of normal aging on the brain. Writing in the July 25 Proceedings of the National Academy of Sciences, researchers led by Chet Sherwood at The George Washington University, DC, report that human brains age differently from those of our closest relatives, the chimpanzees. Sherwood and colleagues used structural MRI to compare brain volumes of humans and chimps. Even healthy people who have no apparent cognitive problems lose both white and gray brain matter with age, but chimpanzees do not, the researchers found. The authors attribute this difference to the fact that people enjoy a lengthened old age relative to chimps. Microstructural changes in the aging brain, such as the loss of dendrites and synapses, are known to occur in both species. In humans, however, these losses accumulate over decades until they are visible at a gross anatomical level as shrinkage of total brain volume, the authors suggest.

Researchers led by Amy Arnsten at Yale University, New Haven, Connecticut, looked at the other end of the scale, examining subtle cellular changes that occur with age in rhesus monkey brains. Like humans, older rhesus monkeys develop deficits in working memory. In the July 27 Nature, Arnsten and colleagues show that these cognitive losses are tied to reduced firing of specific neurons in the prefrontal cortex of elderly monkeys. Importantly, drugs known to improve working memory in animals restored normal firing, demonstrating that at least some age-related synaptic deficits are reversible. One such drug, guanfacine, is now in a clinical trial for non-demented elderly with mild cognitive problems (see below).

It is not known whether aging-related changes such as reduced neuron firing and the loss of brain matter also make people more susceptible to dementia, but researchers are intrigued by the possibility. “If we can identify the biochemical differences that make humans vulnerable to late-life neurodegenerative diseases by doing these comparative studies, maybe we can identify pathways for intervention,” said Todd Preuss at Emory University, Atlanta, Georgia. He was not involved in the work.

The dramatic aging-related brain atrophy seen in humans (see, e.g., Kruggel, 2006) has not been shown in any other species, Sherwood told ARF. To find out if the phenomenon is unique to humans, Sherwood and colleagues compared MRI brain scans from 87 healthy people, aged from 22 to 88 years, to scans from 69 chimpanzees, who ranged from 10 to 45 years old (the maximum age of chimps in the wild). The scientists also included data from 30 postmortem chimp brains; the oldest animal had died at the age of 51. The researchers found that in humans, total gray matter and frontal lobe gray matter shrank throughout life in a linear fashion. Hippocampal volume, total white matter, and frontal lobe white matter in humans, on the other hand, stayed fairly constant for most of the lifespan, then dropped off rapidly in the elderly. By contrast, chimpanzees showed no age-related declines in any of these measures.

The researchers wondered if the differences could be explained simply by the fact that humans live longer than apes. Supporting this, when Sherwood and colleagues removed the oldest people from each analysis, all of whom were older than the maximum chimp lifespan, there was no longer a significant difference between chimp and human data. This suggests that age-related brain atrophy is an evolutionarily new phenomenon, and is the price humans pay for an extended lifespan, the authors propose. Sherwood noted, however, that his sample did not include the oldest apes, as some females live into their sixties in captivity. “I am open to the possibility that older chimps might show more human-like degeneration,” he told ARF. Importantly, the difference between chimp and human lifespans is not simply the result of modern medical care giving humans longer lives, Sherwood added, as even in hunter-gatherer societies, humans can live into their eighties, well beyond the maximum lifespan of chimps in the wild.

“The results are kind of surprising,” Preuss observed. He noted it is typically assumed that animals that live longer have the same pattern of change throughout life as shorter-lived animals, but stretch it out over more years. The finding by Sherwood and colleagues suggests this is not the case with humans. Instead of drawing out the lifespan of our great ape relatives, we have tacked decades onto its end. Preuss pointed out that both female chimps and human women stop ovulating in their mid-forties, but for chimpanzees, “the end of fertility means the end of life,” while humans follow an evolutionarily unique pattern. “We are unusually adapted for long life,” Preuss suggested.

The results do not explain what makes human brains shrink with age. One possibility, Sherwood said, is that humans’ longevity, in combination with the high metabolic needs of our neurons, allows oxidative damage to accumulate in the brain, overwhelming repair mechanisms and damaging connections. There may also be fundamental differences in brain biochemistry between the species. For example, apes and monkeys accumulate much more β amyloid than do non-demented people, Preuss said, but seem insensitive to it. Chimpanzees apparently do not get dementia, even in the rare case where an aged chimp shows some AD-like pathology (see ARF related news story).

In other ways, human and other primate brains seem to age similarly, a fact exploited by Arnsten and colleagues for their study. They used rhesus monkeys, because these animals develop a similar pattern of cognitive deficits with age as humans do, including problems with working memory, but do not get dementia. Working memory, or the ability to hold a thought in mind in the absence of external stimulation, depends on networks of neurons in the prefrontal cortex that can maintain persistent firing. Previous work in monkeys has shown that high levels of neuronal cyclic-AMP (cAMP) can disrupt this firing by opening potassium channels on dendritic spines. Drugs that inhibit cAMP signaling or block potassium channels, when given systemically, improve working memory in older monkeys (see, e.g., Arnsten et al., 1988; Franowicz and Arnsten, 1998; Ramos et al., 2006; and Wang et al., 2007). However, no one had shown exactly what alters in the brain during memory tasks as animals age.

To answer this, first author Min Wang recorded the activity of neurons in the prefrontal cortex of young, middle-aged, and old rhesus monkeys while they performed a spatial working memory task. For this, the monkeys had to remember a spatial cue for two and a half seconds before responding to receive a reward. Wang and colleagues found that some neurons fired only when the monkeys saw the cue; these cells did not change behavior in older monkeys. Most of the prefrontal neurons, however, fired persistently during the delay period. The firing rate of these “delay” neurons declined steeply with age.

Wang and colleagues then administered tiny amounts of drugs locally into the prefrontal cortex, using an electric current to push them through a glass pipette attached to the recording electrode. Drugs known to inhibit cAMP or block potassium channels restored neuron firing to youthful levels. Since the injections affected only a few neurons, researchers did not see improvements in performance in this experiment, but the results were consistent with past behavioral data showing that these drugs improve working memory. The data suggest that “at least some age-related, higher cognitive decline is due to changes in the neurochemical environment, which gives us hope we might be able to treat it,” Arnsten told ARF. One of the cAMP inhibitors they used, guanfacine, is an FDA-approved anti-hypertensive drug, which Christopher van Dyck, director of the Yale Alzheimer's Disease Research and Cognitive Disorders Unit, has taken to a clinical trial to see if it can improve working memory in non-demented elderly who have mild prefrontal deficits.

In future work, Arnsten would like to investigate what goes wrong in the aging brain to throw cAMP out of whack. One possibility, Arnsten said, is that it might be a faulty stress response. Psychological stress is known to generate high levels of cAMP and dampen prefrontal cortical firing, perhaps as a way of turning control over to more primitive brain regions when an organism needs to respond to an imminent threat, Arnsten said. She noted that highly stressed caregivers of people with Alzheimer’s disease often develop cognitive problems themselves. A number of caregivers are enrolled in the guanfacine trial, Arnsten added.

Intriguingly, work by John Morrison at Mount Sinai Medical Center, New York City, has shown that psychological stress can cause dendritic spines in rodent brains to shrink or disappear (see, e.g., Radley et al., 2006 and Radley et al., 2008). Arnsten believes that the dampening of neuronal firing in the prefrontal cortex might also lead over time to the loss of synaptic connections, spines, and eventually to the shrinkage of gray matter seen in aging human brains. She points out that neurons in the prefrontal cortex of humans have far more connections than do the same neurons in monkeys, and therefore humans might be vulnerable to greater brain volume losses than monkeys once these neurons start failing.

“The prefrontal cortex mediates probably the highest levels of cognitive function,” Morrison told ARF. That includes such things as planning, abstract thinking, and setting goals. Morrison finds it interesting that it is the neurons that fire during the “delay” part of a task that are affected by age, because it is during the delay period that abstract thinking occurs. Almost everything that people do involves a time delay between getting a stimulus and responding to it, Morrison said. “The demands on the prefrontal cortex in humans are extraordinary,” he noted. These demands are only increasing in the modern information age, Arnsten added, which highlights the importance of finding a way to maintain the function of this brain region throughout the lifespan.

Both Sherwood's and Arnsten’s studies raise the question of whether the deficits that develop during normal aging make people more vulnerable to dementia. More research, as well as more funding, is needed to answer this question, scientists contacted for this article agreed. If the synaptic changes seen by Arnsten are a precursor to dementia, Morrison said, researchers would want to target these effects for early intervention. Synaptic activity is known to affect neuronal health (for a review, see Bell and Hardingham, 2011), and scientists are increasingly focusing on these early changes. Sherwood sums up: “The ultimate goal [of this research] is to understand what sort of interventions people can take to undergo brain aging in a healthier way.”—Madolyn Bowman Rogers

Comments

1. • Lary Walker
     Emory University
   • Posted: 29 Jul 2011
   • Paper: Neuronal basis of age-related working memory decline.

   This paper by Wang et al. is well written and makes a strong case for potentially reversible declines in neuronal function with age. As the authors note, despite their relatively close biological proximity to humans, rhesus monkeys do not develop Alzheimer’s disease. Monkeys do, however, lose a step cognitively as they age. Hence, old monkeys are an attractive model of aging that is uncontaminated by AD-type dementia. Though it is worrisome that the authors recorded declines in persistent neuronal firing that commence rather early in life (by 12 years; the maximum lifespan of rhesus monkeys approaches 40 years), the ability of agents such as guanfacine to reverse this process is encouraging. It will be exciting to see whether these agents are effective in senescent humans, and whether their efficacy can withstand the neuronal ravages of AD.

   View all comments by Lary Walker

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References

News Citations

1. Chimpanzees Get AD Pathology—But Clock Is Ticking on Research 28 May 2008

Paper Citations

1. Kruggel F. MRI-based volumetry of head compartments: normative values of healthy adults. Neuroimage. 2006 Mar;30(1):1-11. PubMed.
2. Arnsten AF, Cai JX, Goldman-Rakic PS. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci. 1988 Nov;8(11):4287-98. PubMed.
3. Franowicz JS, Arnsten AF. The alpha-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology (Berl). 1998 Mar;136(1):8-14. PubMed.
4. Ramos BP, Stark D, Verduzco L, van Dyck CH, Arnsten AF. Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. Learn Mem. 2006 Nov-Dec;13(6):770-6. PubMed.
6. Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, McEwen BS, Morrison JH. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006 Mar;16(3):313-20. PubMed.
7. Radley JJ, Rocher AB, Rodriguez A, Ehlenberger DB, Dammann M, McEwen BS, Morrison JH, Wearne SL, Hof PR. Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J Comp Neurol. 2008 Mar 1;507(1):1141-50. PubMed.
8. Bell KF, Hardingham GE. The influence of synaptic activity on neuronal health. Curr Opin Neurobiol. 2011 Apr;21(2):299-305. PubMed.

External Citations

1. clinical trial

Further Reading

News

1. Chimpanzees Get AD Pathology—But Clock Is Ticking on Research 28 May 2008