Indiana University Bloomington Health Sciences News

A study by Indiana University researchers has identified 24 compounds – including caffeine – with the potential to boost an enzyme in the brain shown to protect against dementia.

The protective effect of the enzyme, called NMNAT2, was discovered last year through research conducted at IU Bloomington.

The new study appeared in the journal Scientific Reports.

“This work could help advance efforts to develop drugs that increase levels of this enzyme in the brain, creating a chemical ‘blockade’ against the debilitating effects of neurodegenerative disorders,” said Hui–Chen Lu, who led the study. Lu is a Gill Professor in the Linda and Jack Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, a part of the IU Bloomington College of Arts and Sciences.

Previously, Lu and colleagues found that NMNAT2 plays two roles in the brain: a protective function to guard neurons from stress and a “chaperone function” to combat misfolded proteins called tau, which accumulate in the brain as “plaques” due to aging. The study was the first to reveal the “chaperone function” in the enzyme.

Misfolded proteins have been linked to neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig’s disease. Alzheimer’s disease, the most common form of these disorders, affects over 5.4 million Americans, with numbers expected to rise as the population ages.

To identify substances with the potential to affect the production of the NMNAT2 enzyme in the brain, Lu’s team screened over 1,280 compounds, including existing drugs, using a method developed in her lab. A total of 24 compounds were identified as having potential to increase the production of NMNAT2 in the brain.

One of the substances shown to increase production of the enzyme was caffeine, which also has been shown to improve memory function in mice genetically modified to produce high levels of misfolded tau proteins.

Lu’s earlier research found that mice altered to produce misfolded tau also produced lower levels of NMNAT2.

To confirm the effect of caffeine, IU researchers administered caffeine to mice modified to produce lower levels of NMNAT2. As a result, the mice began to produce the same levels of the enzyme as normal mice.

Another compound found to strongly boost NMNAT2 production in the brain was rolipram, an “orphaned drug” whose development as an antidepressant was discontinued in the mid–1990s. The compound remains of interest to brain researchers due to several other studies also showing evidence it could reduce the impact of tangled proteins in the brain.

Other compounds shown by the study to increase the production of NMNAT2 in the brain – although not as strongly as caffeine or rolipram – were ziprasidone, cantharidin, wortmannin and retinoic acid. The effect of retinoic acid could be significant since the compound derives from vitamin A, Lu said.

An additional 13 compounds were identified as having potential to lower the production of NMNAT2. Lu said these compounds are also important because understanding their role in the body could lead to new insights into how they may contribute to dementia.

“Increasing our knowledge about the pathways in the brain that appear to naturally cause the decline of this necessary protein is equally as important as identifying compounds that could play a role in future treatment of these debilitating mental disorders,” she said.

METHODS: A group of Atahualpa residents, aged ≥60 years, were interviewed with a validated Spanish version of the Pittsburgh Sleep Quality Index, and underwent magnetic resonance imaging (MRI) for identification of silent markers of SVD. Using multinomial logistic regression analysis, after adjusting for demographics and cardiovascular health status, it was evaluated whether sleep quality is associated with the severity of white matter hyperintensity (WMH), lacunar infarcts, and deep microbleeds.

RESULTS: Out of 311 people aged ≥60 years, 237 (76%) were enrolled into the study. Mean age was 70 ± 8 years, 59% were women, 83% had primary school education only, and 73% had a poor cardiovascular health status. Seventy-eight (33%) had poor sleep quality. The MRI showed: WMH in 154 (65%) participants (moderate-to-severe in 52); silent lacunar infarcts in 28 (12%); and deep microbleeds in 17 (7%). Poor sleep quality was associated with WMH presence (OR 2.44, 95% CI 1.26 to 4.71, p = 0.008) and severity (β coefficient 0.77, SE 0.37, p = 0.037), but not with silent lacunar infarcts or deep microbleeds.

CONCLUSIONS:
The present study showed an association between poor sleep quality and WMH severity. Further longitudinal studies would help to elucidate the cause and effect of this relationship.

“Our findings contradict many but not all previous studies and is currently controversial” Nawab Qizilbash, MBChB, MRCP (UK), head of OXON Epidemiology Ltd, and honorary senior lecturer in epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom, told Medscape Medical News.

The study was published online April 9 in The Lancet Diabetes & Endocrinology.

Using the UK Clinical Practice Research Datalink (CPRD), the researchers analyzed the medical records of nearly 2 million (1,958,191) people with an average age of 55 years at the outset and an average BMI of 26.5 kg/m². During an average follow-up of 9 years (range, 6.3 to 12.6 years), nearly 45,507 were diagnosed with dementia, at a rate of 2.4 cases per 1000 person-years.

Compared with middle-aged adults with a normal weight (BMI, 20 to 24.9 kg/m²), those who were underweight were roughly a third more likely to develop dementia during follow-up. And the incidence of dementia fell with increasing BMI.

Table. Risk for Dementia by BMI Category

The pattern persisted throughout follow-up, after adjustment for potential confounders and allowance for the J-shape association of BMI with mortality, the researchers say.

“The jury is out” on why higher BMI in mid-life might help protect against dementia, Dr Qizilbash told Medscape Medical News. Factors postulated to explain the previously observed protective effect of increased BMI on late-life dementia include low late-life blood pressure; high late-life cholesterol levels; higher leptin levels; age-related regulatory changes in carbohydrate, lipid, or protein metabolism; and increased intake of vitamin E antioxidant and vitamin D. “Clearly more investigation is required,” Dr Qizilbash said.

In a statement, study investigator Stuart Pocock, PhD, from the London School of Hygiene & Tropical Medicine, said the findings “open up an intriguing new avenue in the search for protective factors for dementia — if we can understand why people with a high BMI have a reduced risk of dementia, it’s possible that further down the line, researchers might be able to use these insights to develop new treatments for dementia.”

Not the Final Word

In a linked Comment, Deborah Gustafson, PhD, from SUNY Downstate Medical Center in New York, urges caution in interpreting the findings. “There are some key issues with the study design that influence the validity of the results presented. I hope the Commentary sheds light on this,” she told Medscape Medical News.

She notes that the published literature on BMI and dementia is “equivocal. Some studies report a positive association between high mid-life BMI and dementia, whereas others do not.”

“Many considerations are needed in the assessment of the epidemiology of the association between BMI and late-onset dementia, as is the case for many recorded associations involving late-life disorders,” Dr Gustafson writes. For example, BMI trajectory throughout life, baseline BMI, competing causes of death, and adiposity measurement (total vs central) are “important considerations.”

“To understand the association between BMI and late-onset dementia should sober us as to the complexity of identifying risk and protective factors for dementia. The report by Qizilbash and colleagues is not the final word on this controversial topic,” Dr Gustafson concludes.

“Our results highlight the importance of maintaining high levels of cognitive and social stimulation throughout work and retiree life and emphasize the need for interventions and policies to help older individuals achieve such cognitive and social engagement,” stated Dr. Dufouil, Director of Research in Neuroepidemiology at INSERM in Paris.

Even after adjustment for white matter changes seen on MRI and history of stroke, those who met criteria for physical activity had significantly lower risks of developing any cognitive impairment, any dementia, and vascular dementia over a 3-year period, according to Ana Verdelho, MD, of the University of Lisbon in Portugal, and colleagues.

The relationship between physical activity and vascular dementia remained significant after further adjustment for baseline cognitive function (HR 0.49, 95% CI 0.26 to 0.94), the researchers reported online in Stroke: Journal of the American Heart Association.

“Our data support the conviction that older subjects with vascular risk factors and evidence for vascular cerebral damage benefit from regular physical activity,” Verdelho and colleagues wrote. “We think that [the] relation between physical activity and cognitive impairment should be further studied by interventional studies.”

Previous analyses have identified associations between physical activity and lower risks of cognitive decline and progression to dementia, with possible explanations including mental and social stimulation from exercise, improved cerebral blood flow, reduced vascular risk factors, decreased stress hormone levels, stimulation of brain plasticity, enhanced endothelial function, and decreased progression of intima-media thickness.

Verdelho and colleagues turned to the European LADIS (Leukoaraiosis and Disability) study to explore the issue in nondisabled individuals ages 65 to 84 who were living on their own, presented with minor neurological, cognitive, mood, or motor complaints that did not affect daily activities, and who had white matter changes seen on MRI.

The participants were evaluated at baseline and annually for 3 years. At each assessment, they underwent a battery of neuropsychological tests. MRI was performed at baseline and at the end of the study to assess the severity of the white matter changes.

The study included 638 people. The average age was 74.1 and 55% were female.

At baseline, 64% of the participants were considered physically active, defined as performing at least 30 minutes of activity at least 3 days a week.

The initial MRI revealed a severity of white matter changes that was mild in 44%, moderate in 31%, and severe in 25%.

At the end of follow-up, 90 patients had dementia, including 54 with vascular dementia, 34 with Alzheimer’s disease with a vascular component, and two with frontotemporal dementia. Another 147 had cognitive impairment that was not dementia.

After adjustment for age, education, the severity of white matter changes, medial temporal atrophy, previous and incident stroke, and diabetes, being physically active was associated with significantly lower risks of the following outcomes:

• Any cognitive impairment, including dementia (HR 0.64, 95% CI 0.48 to 0.85)
• Any dementia (HR 0.61, 95% CI 0.38 to 0.98)
• Vascular dementia (HR 0.42, 95% CI 0.22 to 0.80)

Physical activity was not, however, related to Alzheimer’s disease risk.

After further adjustment for baseline cognitive function, the results remained significant for any cognitive impairment and vascular dementia, but not for any dementia.

The authors said that the main limitation of the study was related to the selection of the participants. The study included those who had minor complaints and, thus, probably catches nondisabled patients with white matter changes when they are first seeking medical attention.

Primary source: Stroke: Journal of the American Heart Association
Source reference:
Verdelho A, et al “Physical activity prevents progression for cognitive impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study” Stroke 2012; DOI: 10.1161/STROKEAHA.112.661793.

By Todd Neale, Senior Staff Writer, MedPage Today
Published: November 01, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner

The study showed that patients with MCI who have a plasma caffeine level of 1200 ng/mL avoided progression to dementia over the following 2 to 4 years.

These patients exhibited a plasma cytokine profile that was exactly the same as that of Alzheimer’s disease (AD) transgenic mice that were given caffeinated coffee and didn’t progress to dementia. It’s therefore very likely that it’s caffeine from coffee, and not from other sources, that affords the cognitive protection, said study senior author Gary W. Arendash, PhD, research scientist, Bay Pines Veterans Affairs Hospital, St. Petersburg, Florida.

The research also suggests that certain cytokine patterns could signal for impending conversion to dementia among those with MCI, said Dr. Arendash.

Lower Caffeine Levels

The new case-control study included 2 cohorts of 124 participants in a Florida Alzheimer’s Disease Research Center study of persons aged 65 years and older. All participants had undergone a battery of baseline neurologic assessments and cognitive tests and were categorized as normal, MCI, or dementia. As well, researchers had access to fasting blood samples taken at baseline.

Over the next 2 to 4 years, researchers annually reassessed the cognition of the participants. They separated the participants into 5 groups: (1) initially normal and remained normal, (2) initially normal but converted to MCI, (3) initially MCI and remained so, (4) initially MCI but converted to dementia, and (5) initially dementia and remained so.

Analysis of plasma caffeine levels from the initial visit showed significantly lower caffeine levels in participants with MCI relative to the normal group (P < .03). Caffeine levels were also lower in participants with dementia than in those with normal cognition, but this association did not reach statistical significance (P < .07).

There was a 26% lower plasma level of caffeine in normal persons who converted to MCI over the course of the study compared with those who remained normal, but this was not significant because of considerable variability in caffeine levels among individuals in both of these subgroups.

However, 11 patients with MCI who progressed to dementia had plasma caffeine levels that were 51% below levels at study initiation vs those with MCI who remained MCI (P < .02).

None of the MCI participants who converted to dementia had initial caffeine levels above 1200 ng/mL while half of those with stable MCI had higher levels. Baseline plasma caffeine levels greater than 1200 ng/mL in MCI patients were associated with a 100% chance of avoiding progression to dementia during the 2- to 4-year follow-up.

Patients with MCI in both the Miami (n = 81) and the Tampa (n = 43) study cohorts independently showed the same relationship between blood caffeine levels and later risk for dementia progression.

Critical Level

That 1200-ng/mL level appears to be an important threshold, said Dr. Arendash. The amount of coffee needed to reach this critical level appears to be 3 to 5 cups of daily, with a target of 5 cups or 500 mg of caffeine. Those previous AD mouse studies showed that 1 to 2 cups, or between 100 and 200 mg of caffeine (which is what typical Americans drink daily), was not enough to ward off dementia, he said. It’s not known whether it’s necessary to spread those 5 cups throughout the day, he added.

It’s important to remember, though, that half of the patients with stable MCI in the study who had caffeine levels below 1200 ng/mL also didn’t progress to dementia. Clearly, other factors play a role. Such factors probably include the level of cognitive and physical activity, the presence of hypertension, and antioxidant intake, especially from fruits and vegetables, said Dr. Arendash.

The study also found that 3 cytokines — granulocyte colony-stimulating factors (G-CSF), interleukin-10, and interleukin-6 — were lower in the plasma of patients with MCI who were destined for AD conversion than in both the nonconverting MCI participants and the participants with dementia. None of the 8 other plasma cytokines that were measured showed any such profile when the same 2 MCI subgroups were compared.

“When that initial blood sample was taken, MCI patients that went on to convert to AD had low levels of all those cytokines,” said Dr. Arendash. “That could be diagnostic; it could be a very important plasma indicator of impending AD.”

The studies of AD transgenic mice, which produce the same abnormal human protein as the human brain, amyloid-beta, demonstrated that long-term oral administration of caffeinated coffee prevents cognitive impairment.

The cytokine profile of the participants in this current study was the same as that in these AD mice. “Their profiles matched identically to the mice given coffee but not other sources of caffeine;” said Dr. Arendash. “That’s why we strongly believe that most, if not all, of those MCI patients who did not convert were on habitual coffee intake.”

The mouse research allowed investigators to identify disease-modifying mechanisms for caffeine. The studies showed that caffeine alone suppresses brain levels of enzymes required for amyloid-beta production via targeting of specific signal transduction mechanisms. This research also suggested that something in coffee increases plasma levels of those 3 key cytokines: G-CSF, interleukin-10, and interleukin-6. G-CSF, in particular, has beneficial cognitive actions in AD mice that involve synaptogenesis and neurogenesis.

Aside from caffeine, coffee is rich in antioxidants and anti-inflammatory compounds that may also contribute to reduced risk for AD.

This study was a retrospective analysis, so a definitive relationship will have to be derived through a clinical trial in which participants consume caffeinated coffee, other caffeinated products, or decaffeinated coffee, over a period several years, said Dr. Arendash. He suggested that residents of China, where coffee consumption is very rare, would make an ideal control population for such research.

Accumulating Evidence

Reached for a comment, Karen Ritchie, PhD, Faculty of Medicine, Imperial College, London, United Kingdom and Directeur de Recherche, Institut National de la Santé et de la Recherche Médicale, Montpellier, France, said the study, which involved a direct measure of caffeine in plasma rather than just reports of caffeine consumption, adds to accumulating evidence of a beneficial effect of caffeine.

However, she told Medscape Medical News, the study’s “weak point” is that, unlike the epidemiologic studies, such as the ones she and her colleagues have carried out, alternative explanations of this observation were not taken into account.

“For example, persons drinking less coffee may also have more hypertension, more depression, more heart disease, less social activity than those with higher levels, and these factors are in themselves related to onset of dementia.”

Still, one of Dr. Ritchie’s own previous studies, published in Neurology , concluded that the psychostimulant properties of caffeine appear to reduce cognitive decline in women without dementia, especially at higher ages.

The question of whether some people are protected against dementia because they drink coffee or because they do or have something else that non–coffee drinkers don’t, remains unanswered, she said.

In a group of more than 700 elderly individuals free of dementia at baseline, a higher level of total daily physical activity, determined objectively via 24-hour actigraphy, was associated with a lower risk for the subsequent development of AD, as well as a slower rate of cognitive decline.

The association remained “robust” after accounting for a wide variety of potentially confounding factors, and supports efforts to encourage physical activity even in the very old, conclude Aron S. Buchman, MD, from the Rush Alzheimer’s Disease Center, Rush University Medical Center in Chicago, Illinois, and colleagues.

Their findings were published in the April 24 issue of Neurology.

Objective Activity Data

The authors of a linked editorial point out that this is the first study to report prospective associations of physical activity with AD and cognitive decline using an objective measurement of physical activity, which “importantly eliminates recall bias, and includes an all-encompassing measure of daily physical activity.”

Most prior studies have consistently associated physical activity with decreased risk for cognitive decline and dementia but have relied on self-report measures of physical activity without objective validation.

During the study, 716 dementia-free individuals (mean age, 82 years) wore an actigraph on the nondominant wrist 24 hours a day for up to 10 days. The device records total daily exercise and nonexercise physical activity. As part of the ongoing prospective observational Rush Memory and Aging Project, participants underwent structured annual clinical exams, including a battery of 19 cognitive tests.

Over an average of 3.5 years, 71 participants (9.9%) developed AD. According to a Cox proportional hazards model adjusted for age, sex, and education, level of total daily physical activity was associated with incident AD (hazard ratio, 0.477; 95% confidence interval, 0.273 – 0.832).

The association remained after further adjustment for self-report physical, social, and cognitive activities, as well as current level of motor function, depressive symptoms, chronic health conditions, and APOE allele status.

According to the investigators, an individual with low total daily physical activity (10th percentile) had a more than 2-fold higher risk of developing AD as compared with a participant with high total daily physical activity (90th percentile).

In a linear mixed-effect model, the level of total daily physical activity was also associated with a slower rate of global cognitive decline (estimate, 0.033 [standard error, 0.012]; P = .007), particularly for episodic memory, working memory, perceptual speed, and visuospatial abilities.

Pragmatic Implications

Dr. Buchman and colleagues say the finding that not only exercise but also higher levels of nonexercise activity are associated with cognition in old age has “important implications not only for observational studies but also for the design of physical activity intervention studies and cognition in old age. Older individuals, for whom participation in formal exercise may be constrained because of underlying health problems, may nonetheless benefit from a more active lifestyle through increases in the full spectrum of routine activities,” they explain.

Michal Schnaider Beeri, PhD, from the Department of Psychiatry, Mount Sinai School of Medicine in New York City, and Laura Middleton, PhD, from the Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel, agree.

“These results may have substantial pragmatic implications for public health,” they write in their editorial. “Motivating the elderly to be physically active, even if mobility is limited, may decrease their risk of developing AD. Since in the Buchman et al. study the actigraph was attached to the wrist, cooking, washing dishes, playing cards, and even activity in the setting of reduced mobility, such as moving a wheelchair with one’s arms, constitute nonexercise physical activity from which elderly may benefit,” they note.

As for the research implications, Dr. Buchman and colleagues say, going forward, it may be particularly important to measure exercise and nonexercise activities in older adults.

“It is likely that with falling cost and technologic advances,” the study authors conclude, the use of actigraphs and other devices that provide objective data “will become more commonplace, increasing the precision and specificity of physical activity measures and facilitating efforts to explicate the link between physical activity and cognition in old age.”

The study was supported by the National Institutes of Health and the National Institute on Aging, the Illinois Department of Public Health, and the Robert C. Borwell Endowment Fund. The study and editorial authors have disclosed no relevant financial relationships.

May 1, 2012 — Increased consumption of blueberries and strawberries appears to slow cognitive decline in older women, according to an analysis of data from the Nurses’ Health Study (NHS).

“Increasing berry intake appears to slow memory decline by up to 2.5 years,” lead author, Elizabeth E. Devore, ScD, from the Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News. “By this, we mean that women eating the most berries vs. little to no berries had memory differences equivalent to women 2.5 years apart in age.”

The news study was published online April 25 in the Annals of Neurology.

Berries and Flavonoids

In their prospective, observational study, which was funded by the National Cancer Institute and the California Strawberry Commission, Dr. Devore and her team evaluated long-term intake of berries and flavonoids in relation to memory decline in 16,010 older women who were participants in the NHS.

The NHS encompasses a large population cohort of 121,700 female registered nurses aged 30 to 55 years who completed health and lifestyle questionnaires starting in 1976.

Between 1995 and 2001, cognitive function was measured every 2 years in study participants aged 70 and older. The mean age of the women in the current analysis was 74, and their mean body mass index was 26 kg/m².

“Experimental data show that berry supplementation enhances neuronal function and survival and ameliorates age-related cognitive impairment in rodents,” Dr. Devore noted.

Berries are particularly high in a subclass of flavonoids called anthocyanidins, which can cross the blood-brain barrier and localize in the hippocampus, known to be an area of the brain involved in learning and memory, she said.

“Flavonoids have powerful antioxidant and anti-inflammatory properties, and both oxidative stress and inflammation are thought to be important contributors to cognitive impairment. So increased flavonoid consumption could be a potential strategy for reducing cognitive decline in older adults,” she said.

The researchers found that greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline.

After adjustment for age and education, greater consumption of blueberries was highly associated with slower decline in the global score (P trend = .010), the verbal score (P trend = .016), and the Telephone Interview of Cognitive Status (P trend = .027).

The mean difference in rate of global decline was 0.04 standard unit over the study period (95% confidence interval [CI], 0.01 – 0.07) in women who had 1 or more servings of blueberries per week vs those who ate less than 1 serving per week.

They also found that a greater intake of strawberries was related to slower decline in the global and verbal scores after adjustment for age (P trend for global score = .021) and education (P trend for verbal score = .014).

Women who ate 2 or more servings of strawberries per week had an average decline in the global score that was 0.03 standard unit less over the study follow-up period compared with women who had less than 1 serving per week (95% CI, 0.00 – 0.06).

Overall in the study population, the researchers found that 1 year of age was associated with a mean decline of 0.02 standard unit on the global score over the follow-up period.

“Thus, the mean differences that we observed comparing extreme categories of blueberry and strawberry intakes were equivalent to approximately 1.5 to 2.5 years of cognitive aging,” Dr. Devore explained. “Women with higher berry intake appeared to have delayed their cognitive aging by up to 2.5 years.”

However, she cautioned that although the study controlled for other health factors, the possibility that the preserved cognition in those who ate more berries may be also influenced by other lifestyle choices, such as exercising more, cannot be ruled out.

The study does, however, have strengths, she said. “It is the first large epidemiologic study of long-term berry and flavonoid intake in relation to memory decline, utilizing information from over 16,000 older women. In addition, we collected information on berry intake over 20 years prior to initial memory testing, which enabled us to analyze long-term patterns of berry intake.”

For now, however, doctors can tell their patients that eating berries may delay memory decline. “Specifically, eating 1 or more servings per week of blueberries or 2 or more servings per week of strawberries appears to be associated with memory benefits,” Dr. Devore said.

Remain Skeptical

Commenting on this study for Medscape Medical News, David Knopman, MD, from the Mayo Clinic, Rochester, Minnesota, and a spokesperson for the American Academy of Neurology, agreed that the study did have its strengths, including the fact that mid-life dietary practices were assessed at the time, not retrospectively, and its inclusion of a very large number of women who had had 3 cognitive assessments.

However, he said he still has concerns about the study.

“The concerns that I have about the report stem primarily from the fact that studies of associations between dietary habits and health outcomes are notoriously difficult to replicate,” Dr. Knopman said. “Second, the possibility of residual confounding by general health behavior, levels of physical activity, socioeconomic status is a possibility that cannot be discounted. The authors acknowledge this.

I would note that inclusion of physical activity and household annual income in the statistical models that they used attenuated the associations to the point that they were no longer significant.

“Further, I would note that inclusion of physical activity and household annual income in the statistical models that they used attenuated the associations to the point that they were no long significant at the p < 0.05 level for 2 of 3 of the cognitive outcomes,” he said.

“The authors presented the results but did not comment on these analyses in the text of their article or in the abstract. I think that the authors should have said: ‘When controlling for other health-related variables, the associations were attenuated and raise questions about the specificity of our findings.’ Therefore, I remain skeptical that these results reflect what the authors say they do,” Dr. Knopman said.

The study was funded by the National Cancer Institute and the California Strawberry Commission. Dr. Devore and Dr. Knopman have disclosed no relevant financial relationships.

May 2, 2012 — Six months of twice-weekly resistance training (RT) improved executive function, associative memory, and regional patterns of functional brain plasticity in a group of older women with probable mild cognitive impairment (MCI).

“We provide novel evidence that RT can benefit multiple domains in those at risk for dementia,” the researchers report.

“We found improvement in both cognitive and brain function with resistance training — not just maintenance — over the 6 months. Thus, our results imply that resistance training can delay the onset of dementia in older adults,” first author Teresa Liu-Ambrose, PhD, PT, from the Aging, Mobility, and Cognitive Neuroscience Laboratory, University of British Columbia, Vancouver, Canada, told Medscape Medical News.

In a previous study reported by Medscape Medical News, she and her colleagues found that 12 months of twice-weekly RT significantly improved executive function in cognitively healthy older women. Their latest study found improvement after only 6 months and in women with MCI. Thus, the benefits of RT on executive function “may be more potent among those at greater risk for dementia,” the researchers say.

“Among individuals with MCI, over half will develop dementia in the next 5 years,” Dr. Liu-Ambrose noted. “Our finding is new and greatly extends our current knowledge about the potential benefit of exercise in reducing the risk of dementia in older adults.”

Their findings were published April 23 in the Archives of Internal Medicine.

The EXCEL Study

The Exercise for Cognition and Everyday Living (EXCEL) study enrolled 86 community-dwelling women aged 70 to 80 years with probable MCI (defined as a score < 26 [of 30] on the Montreal Cognitive Assessment) and subjective memory symptoms. They were randomly allocated to twice-weekly, instructor-led classes (60 minutes each) of RT (28 women), aerobic training (AT; 28 women) or balance and tone training (BAT; 30 women, control group) for 6 months.

For RT, both a Keiser Pressurized Air system and free weights were used. Participants performed 2 sets of 6 to 8 repetitions, and loading was increased when sets were completed with proper form. The AT program involved walking outdoors at 40% of a participant’s age-specific target heart rate and progressed to 70% to 80% of target heart rate. The BAT program comprised stretching, range of motion, balance exercises, and relaxation techniques.

Seventy-seven (89.5%) of the 86 participants completed the trial (26 in the RT group, 24 in the AT group, and 27 in the BAT group). Twenty-two participants were included in a functional magnetic resonance imaging analysis (7 each in the RT and AT groups and 8 in the BAT group).

After 6 months, compared with the BAT group, the RT group showed significantly improved performance on the Stroop test (P = .04), an executive cognitive test of selective attention/conflict resolution, which was the primary outcome. The RT group also performed significantly better on an associative memory task (P = .03).

Compared with BAT, RT also led to functional changes in 3 regions of the cortex — the right lingual (P = .03) and occipital-fusiform (P = .02) gyri and the right frontal pole (P = .03) — during the associative memory task.

The researchers also found a significant positive correlation between change in hemodynamic activity in the right lingual gyrus and change in behavioral associative memory performance (P = .02).

Twice-weekly AT significantly improved general balance (P = .03) and cardiovascular capacity (P = .04) compared with BAT.

Findings “Timely and Relevant”

“This small study provides evidence that weekly resistance and aerobic training programs can improve brain blood flow and in so doing increase performance on memory tests,” Cyrus A. Raji, MD, PhD, University of Pittsburgh Medical Center Mercy Hospital, Pennsylvania, who was not involved in the study, told Medscape Medical News.

“While the study was limited to elderly females, women as a group are at a higher risk for Alzheimer’s, making the findings of the study timely and relevant. Larger studies need to be done looking at combinations of different physical activity regimens across gender and wider age ranges,” Dr. Raji added.

Dr. Liu-Ambrose cautioned that although RT was “more beneficial” than AT in promoting both cognitive and brain function, “more research is needed to refine exercise prescription for optimal benefit.”

Dr. Raji agrees. While this study “seems to suggest that [RT] is more beneficial that [AT], caution must be exercised in interpreting the results because more people dropped out of the [AT] group,” he said.

A study published in 2010 in Archives of Neurology and reported by Medscape Medical News at that time did find that a 6-month high-intensity aerobic exercise program improved cognitive performance on multiple tests of executive function in older adults with MCI.

Differences in both the frequency and intensity of AT regimens between the 2 studies may underlie the differing results, Dr. Liu-Ambrose and colleagues note in their report. In addition, the women in their study were older and had lower baseline Mini-Mental State Examination scores.

The study was supported by the Pacific Alzheimer’s Research Foundation. The authors and Dr. Raji have disclosed no relevant financial relationships.

Arch Intern Med. 2012;172:666-668. Abstract