Primecuts – This Week In The Journals

November 25, 2013

By Ali Mendelson, MD

Faculty Peer Reviewed

With Thanksgiving quickly approaching, the holidays are on everybody’s mind. There are parades to watch, food to cook, thanks to give, and inevitably, diets to break. That doesn’t mean you can’t find time to exercise, and for those who are pregnant, fitting in a few trips to the gym might aid in the development of your unborn child’s brain.

Two studies presented at this month’s Society for Neuroscience’s annual meeting looked at the association between exercise and infant brain development. One study, by Robinson et al., reported that when pregnant rats were allowed to exercise throughout their pregnancies, their male offspring performed better on object recognition memory tests than male offspring from rats who did not have access to exercise wheels during pregnancy [1]. The offspring were placed in a plastic tub and given time to explore two identical objects. They were returned to the same tub 24 hours later, but this time there was one object identical to those from the initial session and one new, unfamiliar object. Infants from mothers who exercised during pregnancy spent significantly more time exploring the novel object (p<0.03). Offspring from mothers who did not exercise, on the other hand, spent an equal amount of time with the two objects (p>0.06), signifying that they did not recognize the object that should have appeared familiar. These effects lasted into adulthood, when the rats were retested two weeks later with different objects. While an interesting study, it was limited by its use of animals and the delay between birth and testing, increasing the risk of confounding environmental factors.

A randomized controlled trial led by Elise Labonte-LeMoyne, a Ph.D. candidate at the University of Montreal, took this one step further and studied people instead of animals [2]. They recruited women in their third trimester of pregnancy, all of whom were young, healthy adults who exercised regularly but were not athletes and did not exercise more than one to two days per week in the year prior to enrollment in the study. The women were then randomized to either an active or sedentary group. The active group was told to exercise at least 20 minutes, 3 times per week, at a minimal intensity of 55% of their maximal aerobic activity. The sedentary group, on the other hand, did not exercise. Eight to twelve days after birth the newborns’ brains were studied using mismatch negativity (MMN), in which their brains were monitored with EEGs while they listened to sounds loops of soft sounds interspersed with jarring noises. When babies hear these unfamiliar sounds, a spike is seen on the EEG, but the amplitude of these spikes decreases as the brain matures. In this study, the spikes were blunted in the EEGs of newborns of mothers who exercised, indicating neuronal maturity. It is still unclear if these effects will last into adulthood, as seen in the rat study, but the researchers planning on testing the infants again at one year. We look forward to seeing the results.

When we take a break from the gym to plan our Thanksgiving meals, we should take into consideration the results of a large cohort study in this week’s NEJM, which showed an association between nut consumption and total and cause specific mortality [3]. Since 2003, the FDA has recommended consuming 43g of nuts per day to help reduce the risk of heart disease [4]. In another NEJM article from this year, Estruch et al. reported the results of a randomized primary-prevention trial, which showed significantly fewer major cardiovascular events among people with high cardiovascular risk eating a Mediterranean diet, which included nuts, than those eating a control diet [5]. Bao et al, in this week’s NEJM utilized two large independent cohorts of nurses and health professionals. After excluding people with a history of cancer, heart disease and stroke, those who did not report anthropometric measures or physical activity, and those who did not complete the dietary questionnaire, their sample consisted of 76,464 nurses from one cohort and 42,498 male health professionals from a second cohort. The participants filled out the dietary survey every 2-4 years and reported how frequently they ate one serving of nuts. The primary end point was death from any cause. They found that those who consumed nuts more frequently had a lower BMI, were less likely to smoke and more likely to exercise, take multivitamins, consume more fruits and vegetables, and drink more alcohol. Pooled analysis of the two cohorts revealed a significant dose-dependent inverse association between nut intake and total mortality (HR 0.93, 95% CI, 0.90 to 0.96 for those who consumed nuts less than once per week; HR 0.89, 95% CI, 0.86 to 0.93 for once per week; HR 0.87, 95% CI, 0.83 to 0.90 for two to four times per week; HR 0.85, 95% CI, 0.79 to 0.91 for five to six times per week; and HR 0.80, 95% CI, 0.73 to 0.86 for seven or more times per week; P<0.001). The significant inverse association held even when controlling for confounders, such as smoking, diabetes, and other diet factors (olive oil, sodium intake, Mediterranean-diet score). There was also a significant inverse association between nut intake and cause specific mortality from cancer (HR 0.91, 95% CI, 0.85 to 0.97), heart disease (HR 0.74, 95% CI, 0.68 to 0.81), and respiratory disease (HR 0.81, 95% CI, 0.65 to 1.01). As with total mortality, the associations were dose dependent. Results were similar for peanuts and tree nuts [3].

While there were limitations to this study, for example nut intake was self-reported, increasing the risk of bias and measurement error, and the population of health care professionals may decrease generalizability, the prospective design, large sample size, long follow up (30 years and 24 years for the two cohorts), and multiple points of data collection strengthen the study. Just as pregnant women should fit in time to exercise while awaiting more data on the effects it may have on their children’s brains, we should all fit in a few servings of nuts a week. And if nothing else, maybe the bowl of nuts on the Thanksgiving table will stop us from eating that third helping of stuffing or pie.

We all hope to remember holidays from years past, and in an article that will appear in an upcoming issue of Neurology, Nation et al. report the association between pulse pressure and Alzheimer biomarkers in cognitively normal older adults [6]. While the association between blood pressure, cognitive decline, and Alzheimer dementia has been documented, and pulse pressure has been found to be associated with the risk of Alzheimer dementia, little is known about the underlying mechanism of this association. The authors report two possible theories: (1) pulse pressure may play a role in cerebral small-vessel disease because of its association with vascular aging and arterial stiffening, and (2) elevated pulse pressures may increase β-amyloid accumulation and tau phosphorylation. Therefore, the authors were interested in the association between pulse pressure and Alzheimer biomarkers. Their sample included 177 55- to 100-year-old cognitively normal older adults with no history of stroke, TIA, MI, diabetes, and BMI ≥ 30. They all had Mini-Mental State Examinations scores ≥ 26 and Clinical Dementia Rating Scale scores of 0. All participants had a lumbar puncture and CSF samples sent. Blood pressure measurements were taken two times from each arm and averaged. Multivariate analyses showed a significant association between elevated pulse pressure and increased P-tau levels (β = 0.15, p = 0.044) and increased P-tau to Aβ1-42 ratio (β = 0.0016, p<0.001). In post hoc analyses, the relationship was only observed in patients 55 to 70 years old, not in those greater than 70. There was no significant association between Aβ1-42 and elevated pulse pressure in the multivariate analysis, but there was an inverse association in the ad hoc analysis in those ages 55-70 (β = -0.87, p = 0.050). These results hint that the relationship between elevated pulse pressures and Alzheimer dementia might be related to P-tau. P-tau has a stronger association not only with pulse pressure, as observed in this study, but also with neurodegeneration and cognitive decline than amyloid. Furthermore, it is mid-life pulse pressure that is important and may play a role in neurodegeneration later in life.

This study does not mean that middle-age hypertension causes Alzheimer dementia, it simply hints at a possible underlying mechanism and serves as yet another reason to monitor and control blood pressure in our patients.

Some additional interesting articles:

1. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus Abacavir-Lamivudine for the treatment of HIV-1 infection. N Engl J Med. Nov 7 2013;369:1807-18.

Dolutegravir, a once-daily, unboosted integrase inhibitor, plus Abacavir-lamividune not only had a better safety profile and provides a simpler regimen than efavirenz-tenofovir DF-emtricitabine, it was more effective at 48 weeks.

2. Samierei C, Sun Q, Townsend MK, et al. The association between dietary patterns at midlife and health in aging. Annals of Internal Medicine. Nov 5 2013;159(9):584-91.

Greater adherence to the Alternative Healthy Eating Index-2010 and Alternate Mediterranean Diet was related to greater odds of healthy vs. usual aging and no major limitation in physical function and mental health.

3. Mack MJ, Brennan JM, Brindis R, et al. Outcomes following transcatheter aortic valve replacement in the United States. JAMA. Nov 20 2013;310(19):2069-77.

The authors collected data from all 7710 TAVR cases from 224 participating hospitals since the Edwards Sapien XT device was commercialized and found that the device was successfully implanted in 92% of cases, the overall in-hospital mortality rate was 5.5%, and the stroke rate was 2.0%.

Dr. Ali Mendelson is a  1st year resident at NYU Langone Medical Center

Peer reviewed by Brian Greet, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


1. Robinson AM and Bucci DJ. Maternal exercise during pregnancy improves object recognition memory in adult male offspring [Abstract]. Society for Neuroscience Annual Meeting, 2013 Nov 9-13; San Diego, CA. Program#/Poster# 578.13/KKK52.

2. Labonte-LeMoyne E, Curnier D, Ellemberg D. Foetal brain development is influenced by maternal exercise during pregnancy. Society for Neuroscience Annual Meeting, 2013 Nov 9-13; San Diego, CA. Program#/Poster# 217.08.{8D2A5BEC-4825-4CD6-9439-B42BB151D1CF}

3. Bao Y, Han J, Hu FB, et al. Association of nut consumption with total and cause-specific mortality. N Engl J Med. Nov 21 2013;369(21): 2001-11.

4. Qualified health claims: letter of enforcement discretion – nuts and coronary heart disease. Rockville, MD: Food and Drug Administration, July 14, 2003.

5. Estruch R, Ros E, Salas-Salvadó, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. Apr 4 2013;368:1279-90.

6. Nation DA, Edland SD, Bondi MW, et al. Pulse pressure is associated with Alzheimer biomarkers in cognitively normal older adults. Neurology. Dec 3 2013;81:1-4.