Pauline Anderson

July 24, 2015

WASHINGTON, DC — New research shows that being physically active not only reduces cognitive decline and improves neuropsychiatric symptoms in patients with dementia but may actually reduce Alzheimer's disease (AD) biomarkers, including amyloid and tau protein in the brain.

Exercise could also benefit patients with types of dementia other than AD, another study suggests.

Some of this promising new research on exercise was presented at the Alzheimer's Association International Conference (AAIC) 2015.

Danish researchers had already presented cognition-related results of the multicenter ADEX study at the recent first Congress of the European Academy of Neurology. That analysis, reported at that time by Medscape Medical News, showed that older adults with mild to moderate AD who had at least 80% adherence to an aerobic exercise program and maintained at least 70% of their maximum heart rate (the "high exercise" group) had a statistically significant (P = .03) advantage on the Symbol Digit Modalities Test (SDMT) over a control group.

The intervention consisted of 1 hour of aerobic exercise three times a week for 16 weeks. The control group received usual care.

Here at the AAIC, researchers presented further results, including those of neuropsychiatric testing. The analysis found that these symptoms improved in the 66 patients in the "high exercise" group; there was a 3.4-point difference on the Neuropsychiatric Inventory (NI) (95% confidence interval [CI], 0.9 - 6.0; P =.01) compared with controls.

The NI is a 12-item questionnaire that rates, among other things, depression, apathy, agitation, hallucinations, irritability, weight loss, and sleep.

"We saw that the control group got worse; there was a small decline in this group, which you would expect because this is progressive disease," said Steen Hasselbalch, MD, Danish Dementia Research Centre, Copenhagen, Denmark. "But the intervention group remained at the same level and even got a little better, so at end of the intervention there was a significant difference."

This type of effect, said Dr Hasselbalch, is "comparable to what you would get in a pharmaceutical trial."

And, unlike with the cognitive measurement, the improvement in the neuropsychiatric symptoms was significant even in those who were less adherent and didn't consistently get their heart rate up. There was a 3.5-point between-group difference on the NI in the intention-to-treat (ITT) population of 102 participants (95% CI, 1.3 - 5.8; P = .002).

This suggests that just getting together in small groups might be enough to have a positive effect on depression, apathy, and other symptoms. "These subjects had an Alzheimer's diagnosis recently and maybe they were stressed and a bit depressed," said Dr Hasselbalch. "They really liked getting together with other people, and they made friends and some even went out for a beer."

Preventing neuropsychiatric symptoms is an important aspect of dementia management, noted Dr Hasselbalch. "Behavioral changes and psychiatric symptoms are very distressing for caregivers. One of the reasons patients go into a nursing home is that their caregiver can't take it anymore."

Change Pathology

The question arises of whether exercise could not just delay worsening of symptoms but actually change brain pathology.

The answer, suggests other research, is yes. In a separate study presented at the AAIC 2015, researchers found decreased phosphorylated tau (P tau) in older, previously sedentary persons completing a 6-month regimen of moderate- to high-intensity aerobic exercise.

The study enrolled 70 patients aged 55 to 89 years with prediabetes as well as amnestic mild cognitive impairment (MCI). These were "double hit" patients, Laura Baker, PhD, associate professor, internal medicine, at Wake Forest School of Medicine, Winston-Salem, North Carolina, told Medscape Medical News. "They had both prediabetes and MCI. We think they are at high, high risk for developing dementia of the Alzheimer's type."

These patients were randomly assigned to the aerobic exercise group or to the stretching group. Those in the aerobic group started slowly — 10 minutes of exercise a week — and gradually built the time and intensity up over 6 weeks to the point where they were exercising 45 minutes a day, 4 days a week, at 75% to 85% of their maximum heart rate.

"Starting slowly is the key," said Dr Baker. "For the average 70-year-old, we were getting the heart rate above 130 or 132 beats per minute for at least 30 of those 45 minutes, with the rest of the exercise period being a warm-up and cool-down."

This group had a choice of exercises: treadmill, stationary cycling, elliptical trainer, or preapproved group classes.

The stretching group, whose members could do balance exercises, gentle yoga, and other approved classes in addition to stretching, maintained a maximum heart rate of below 35%.

All exercises were adapted to the needs and limitations of individual patients and were done at a local YMCA.

Dr Baker pointed out that unlike other studies that compare exercise with usual care, in this study the control group "had all the same demands: they had to come out of their house, they had to go to the YMCA, they got the same contact with staff and a trainer."

The only difference, she said, was that they did only stretching and balance exercises and their heart rate was not significantly and consistently elevated.

The researchers looked at biomarkers in cerebrospinal fluid (CSF), including P tau protein and amyloid β 42.

The analysis showed a statistically significant (group-by-age: P = .0037) reduction in P tau levels as measured by pg/mL in CSF among those older than age 70 years in the exercise group. According to Dr Baker, P tau decreased 14% from baseline in this group.

Most intervention trials don't show such changes in P tau. "But we saw it with exercise and no medications," said Dr. Baker. "Exercise was enough to move a biomarker that indicates the severity of the disease."

It wasn't surprising, she added, that this was true only for older patients. "It may be that before age 70, you have a lot of compensatory mechanisms that help to maintain brain health, and after 70, those start breaking down."

She also pointed out that younger people have less tau to begin with. "So there's more room for improvement in older ones."

The study also showed that the aerobic activity increased blood flow to the brain (P < .05; means adjusted for age and baseline body mass index). The researchers demonstrated that the increased blood flow was in regions characteristically affected by aging and AD (ie, memory and processing).

Cognitive benefits were particularly noteworthy for executive function, measured with the Trails B, Word Fluency, and Digit Symbol Substitution tests (P < .05). According to Dr Baker, there was a 15% increase from baseline in the exercise group for all three tests. The improvement relative to the stretching group, which includes expected further decline in cognition, was 80%, she said.

"Our brain imaging results are just fantastic; they show some really nice increases in blood flow in the areas of brain that support executive function and areas of the brain that normally show decreased flow for people with MCI, so it's reversing the blood flow detriment in MCI."

It might sound "undo-able" for older people to "get that ticker moving" to the point where they're breathing hard and sweating, but the key, said Dr Baker, is to start slowly and use, "lots of TLC and confidence building."

Exercise, she stressed, "may be the fertilizer for pharmacological effects." She hopes hers and other similar trials will encourage those running drug trials to look at exercise as possibly being a mediating factor.

Dr Baker and her colleagues are now planning a multisite National Institute on Aging–funded 18-month phase 3 randomized controlled trial that should get off the ground later this year.

Vascular Dementia

AD may not be the only dementia potentially treatable through exercise. Another study discussed at the meeting showed that this intervention may help those with vascular cognitive impairment (VCI).

It's the first intervention trial to suggest that exercise can improve cognition in patients with confirmed VCI, said Teresa Liu- Ambrose, PhD, Canada Research Chair, University of British Columbia, Vancouver, Canada, who reported the results.

The 6-month study included 71 patients aged 56 to 96 years with mild VCI of varying physical capacities. They were assigned to usual care that included a nutrition component or to an intervention of moderate-intensity walking, 3 times a week for an hour.

Patients walked outside in small groups, starting in short time blocks, with an option to rest. Over time, they increased the walking period to 40 minutes without rest, in addition to a warm-up and cool-down.

The study found that the intervention group had a significant (P < .05) improvement on the ADAS-cog test compared with controls.

In a subset of patients who had neuroimaging, there was "evidence of efficiency" in the brain of those who exercised, Dr Liu-Ambrose told Medscape Medical News.

The general feeling among dementia experts is that while awaiting the pharmaceutical "cure" for AD, it's important to come up with better ways to control the disease — including exercise.

Offering a comment on this research, Maria Carrillo, PhD, chief science officer, medical and scientific relations, Alzheimer's Association, said this new work is important because it's on people who already have MCI or dementia, whether vascular or AD.

It means, she said, that people who already have dementia can improve with lifestyle changes. "That's really the key — living better with the disease."

Alzheimer's Association International Conference (AAIC) 2015. Oral presentations 05-0406, 0504-05, and 05-04-04. Presented July 23, 2015.

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