Claims for the cognitive benefits of exercise enjoy increasing research support. Numerous observational studies link physical activity to a lower risk of age-related cognitive decline and dementia (see AlzRisk analysis and ARF related news story). Some trial data support the relationship—for example, seniors who followed a regular exercise program for six months did better than non-exercisers on cognitive tests a year later (see ARF related news story). Recently, studies using structural MRI revealed that exercise can pump up brain volume. Older people who walked six to nine miles per week over a nine-year period ended up with more gray matter in several brain regions, including the hippocampus, than those who were more sedentary. The walkers also had a lower risk of cognitive impairment (see ARF related news story). In another study, the anterior hippocampus grew in seniors who walked three times per week for a year, but shrank in their sedentary peers (see ARF related news story).

Speaking at SfN, Gene Alexander at the University of Arizona, Tucson, described a different approach to testing the benefits of exercise. Rather than measuring the amount of exercise per se, he looked at physical fitness. As described in his poster, first author Krista Hanson and colleagues examined about 120 healthy, cognitively normal adults between the ages of 50 and 90 by structural MRI. In general, older participants showed a consistent pattern of smaller volumes in the lateral and medial frontal cortices, parietal and lateral temporal cortices, and cerebellum. Hippocampal size was relatively preserved with age. The researchers then tested the aerobic conditioning of the volunteers on an inclined treadmill. Those who scored the highest on fitness measures such as endurance and breathing efficiency also showed the least age-related brain changes. In effect, the most aerobically fit participants boasted “younger” brains than their less fit peers. They also scored better on tests of memory, processing speed, and executive function.

“Regions that are affected by aging are modulated by fitness,” Alexander concluded. He said the mechanism is not yet known, but suggested it might involve better vascularization or more brain-derived neurotrophic factor (BDNF), which is stimulated by exercise and plays a role in learning and memory (see, e.g., ARF related news story, ARF news story, and ARF story). The data add to accumulating evidence that exercise and fitness can preserve brain health. By focusing on specific fitness measures and how they correlate with brain volume, researchers may be able to pinpoint the best exercise interventions, Alexander suggested.

In contrast to the consensus on exercise, the benefits of estrogen for aging women have been hotly debated. (For the most recent analysis of this issue, see AlzRisk.) Though clinical trials showed health risks from long-term hormone replacement therapy, other studies suggest that estrogen helps the brain learn. Few studies have looked at the effect of the hormone on brain structure. One cross-sectional study found that postmenopausal women on hormone replacement therapy had more gray matter in prefrontal, parietal, and temporal cortices, and more white matter in medial temporal lobe, than non-users (see Erickson et al., 2005). The women who took hormones longest had more pronounced effects, suggesting that estrogen stems brain volume loss. However, this study did not follow women over time, so it could not demonstrate a causal relationship.

At SfN, Paul Newhouse at Vanderbilt University, Nashville, Tennessee, described a longitudinal estrogen study done in collaboration with Julie Dumas at the University of Vermont, Burlington. The authors gave either placebo or standard doses of 17β-estradiol, the primary human estrogen, to 24 healthy women around 60 years of age for three months. Each volunteer got structural MRI scans before and after treatment. Baseline scans showed no difference between placebo and treatment groups, but after treatment, women who had taken estradiol had more gray matter in several regions of the parietal, temporal, and prefrontal cortices than controls. In particular, the treatment enhanced frontal and temporal gyri, which play a role in attention, decision-making, and memory, Newhouse noted. These areas involve the cholinergic system, which degenerates in AD.

Newhouse said his data fit with primate work by John Morrison and colleagues at Mount Sinai School of Medicine in New York City that also shows volume loss in aged brains. Morrison found that aged, ovariectomized female rhesus monkeys lose dendritic spines from pyramidal cells in the prefrontal cortex, but that cyclical estrogen treatment restores spine density to the level seen in young monkeys (see Bailey et al., 2011). Spine density is closely tied to cognitive ability, as spines contain synapses.

One implication of the human study is that estrogen-induced neuroplasticity remains after menopause, Newhouse said. The women in this study were, on average, a few years past menopause, and some were as old as 70. Many researchers have advanced the idea of a “critical window” for estrogen treatment, saying brains that have been without the hormone for many years no longer respond to it (see, e.g., ARF related news story). In support of this idea, previous research by Newhouse and Dumas found that short-term estradiol treatment strengthens the cholinergic system in women in their fifties, but worsens performance in women over 70 (see Dumas et al., 2008).

A crucial question is whether these estrogen-related brain changes last, Newhouse said. If so, then perhaps short-term estrogen treatment could protect cognition in older women while avoiding the risk of stroke, breast cancer, and other health problems seen with long-term hormone therapy. “That’s the $64 million question,” Newhouse said, and he intends to address it if he can get funding, he told the crowd.

Sleep is another factor that has more recently begun to be tied to cognition and even Alzheimer’s disease (see, e.g., ARF related news story and ARF news story), as it plays a crucial role in memory consolidation (see ARF related news story). In her SfN press conference, Rebecca Spencer at the University of Massachusetts, Amherst, suggested that one culprit in age-related memory decline could be poor quality of sleep. It is believed that during sleep, the brain replays the day’s experiences to code them into the memory banks, but that this process becomes choppy in older brains (see Gerrard et al., 2008). Previously, Spencer’s group showed that sleep fails to consolidate motor learning in older adults (see Spencer et al., 2007). However, other studies have shown that episodic memories can be consolidated during sleep in older people (see Aly and Moscovitch, 2010).

For her current study, Spencer wondered whether the coding of a non-motor, sequential task would be affected by age. To test this, first author Laura Kurdziel taught 24 young adults and about 30 adults older than 50 to perform a computer task that required memorization of a sequence of colored doors in order to navigate through 10 virtual rooms. Kurdziel retested the participants 12 hours later. For half of each group, this time included a sleep interval during normal sleeping hours, while for the other half it did not. Kurdziel saw sharply divergent results for the young and old participants. Young adults who had had a chance to sleep made fewer errors on the task than those who had stayed awake. Older adults, however, got no cognitive benefit from sleep, and also made more errors overall than did younger participants. Spencer attributed this difference to the fragmented nature of sleep in older people, noting that seniors with more regular sleep patterns do better on memory tasks. She suggested that improving sleep quality could boost memory in aging adults. One hitch, however, is that researchers do not have a good way to “defragment” disordered sleep. Spencer said one possibility would be to use cognitive behavioral therapy to change sleep habits, as seniors who stay awake during the day and go to bed more tired sleep better than those who nap.—Madolyn Bowman Rogers.