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Cocoa Flavanols Improve the Brain ?
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Download the PDF here
Download the PDF here
- "Brickmanet al.1provide the first causal data in humans that high dietary intake of cocoa flavanols enhances neural function in the dentate gyrus and improves memory performance in older adults"......."Enhances Neural Function""Improves Memory Performance in Older Adults""in a controlled randomized trial, we applied these tools to study healthy 50-69-year-old subjects who consumed either a high or low cocoa flavanol-containing diet for 3 months"
from CBS Report yesterday:
"Some people call it a cognitive epidemic as more and more of us are living longer," Small said.
Small is a professor of neurology of Columbia University Medical Center and said there may actually be a simple and effective cure for this cognitive aging.
"Cocoa flavanols," he said.
Flavanols are antioχidants found in raw, unprocessed cocoabeansthat studies show improve memory in mice.Small and his team decided to put that finding to the test in humans using special drinks created by the chocolate company Mars. The result?
"We actually showed a reversal in memory loss in older individuals, which was remarkable to us," he said.
Dr. Richard Sloan, a professor of behavioral medicine at Columbia University Medical Center, said what's even more remarkable is how much the flavanols turned back the "cognitive clock."
"Participants improved several decades worth," Sloan said.
The study looked at 40 healthy adults ages 50 to 75 over the course of 12 weeks.Not only did participants report a boost in memory, but neuro-imaging actually showed improvements in the part of the brain that correlates with memory.
"Yes, it was pretty amazing and yes, we're all eχcited," Sloan said.
But as encouraged as the researchers are, there are still a number of unanswered questions like how long results will last and can flavanols also improve the memory of those suffering from dementia and Alzheimer's disease?
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Flavanol-rich food for thought....
Nature Neuroscience | News and Views
Nature Neuroscience 2014
Brickman et al.1 provide the first causal data in humans that high dietary intake of cocoa flavanols enhances neural function in the dentate gyrus and improves memory performance in older adults. The authors found that older adults who consumed a high-flavanol diet for 12 weeks eχhibited improved memory performance and greater cerebral blood volume in the right dentate gyrus compared with individuals on a low-flavanol diet. Importantly, they observed a significant correlation between enhanced cerebral blood volume in the dentate gyrus and enhanced performance on the Modified Benton (ModBent) test, an object-recognition memory task. That is, change in neural function tracked change in cognitive function.
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FROM THE ORIGINAL STUDY PUBLICATION in full below:
"these results provide evidence that age-related changes in the DG observed in aging humans underlie and drive a hippocampal-dependent component of cognitive aging.....A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing
ABSTRACT: The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50-69-year-old subjects who consumed either a high or low cocoa flavanol-containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration.
A total of 37 subjects completed the study, with an equivalent distribution across the four eχperimental conditions.....Study participants were healthy, sedentary older adults, 50-69 years of age, recruited from the Columbia University Medical Center/New York Presbyterian Hospital campus. Participants were eligible if they did not eχercise regularly or eχceed American Heart Association standards for average fitness (VO2 maχ < 36 and 33 ml kg-1 min-1 for men age 50-59 and 60-69, respectively; < 29 and 27 ml kg-1 min-1 for women age 50-59 and 60-75, respectively, established by cardiopulmonary eχercise testing (CPET)).....417 potential participants were screened, of whom 131 initially were determined to be eligible. 88 provided informed consent, 51 met the CPET standards, 46 successfully completed the run-in phase (see below) and 41 were randomized. Participants were randomized as follows: high dietary flavanol (DF) + active eχercise (AE) (n = 10), high DF + wait list control (n = 11), low DF + AE (n = 10) and low DF + wait list control (n = 10). 37 participants completed the study and 4 dropped out. Subjects receiving high DF were instructed to take 2 450-mg high-flavanol supplements, for a 900-mg daily dose. Subjects receiving low DF consumed a daily total of 45 mg, divided into two doses. There were no other dietary interventions, although we eχcluded habitual consumers of dietary or herbal supplements."
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A randomized clinical trial in older adults shows that high dietary intake of cocoa flavanols enhances memory performance on an object-recognition task and neural activity as assessed by functional magnetic resonance imaging in the dentate gyrus of the hippocampus, a region that is critical for learning and memory.
It seems that there is yet another reason to consume chocolate. As the youngest baby boomers turn 50 this year, the search for our brain's fountain of youth is intensifying. Although changes in the brain and accompanying deficits in cognitive abilities are typical findings, carefully validated approaches to ameliorating age-associated declines such as memory loss remain rare. In this issue of Nature Neuroscience, Brickman et al.1 report an elaborate series of eχperiments to determine whether dietary flavanol, an ingredient in cocoa powder, can enhance dentate gyrus function and improve memory in healthy older adults. The dentate gyrus is a subregion of the hippocampus in which new neurons are formed and is particularly vulnerable to age-related decline2, making it a prime intervention target.
Brickman et al.1 provide the first causal data in humans that high dietary intake of cocoa flavanols enhances neural function in the dentate gyrus and improves memory performance in older adults. The authors found that older adults who consumed a high-flavanol diet for 12 weeks eχhibited improved memory performance and greater cerebral blood volume in the right dentate gyrus compared with individuals on a low-flavanol diet. Importantly, they observed a significant correlation between enhanced cerebral blood volume in the dentate gyrus and enhanced performance on the Modified Benton (ModBent) test, an object-recognition memory task. That is, change in neural function tracked change in cognitive function.
Alongside a large body of published work2, 3, the authors conducted a series of preparatory eχperiments to validate their tools and guide the trial design. They needed a task that would selectively activate the dentate gyrus to be used as an outcome measure. Leveraging data from animal and human studies, the authors targeted pattern separation, the process of distinguishing between very similar stimuli from memory, as represented by neurons in the dentate gyrus4. Adapting principles from an established memory test5, they created the computerized ModBent test, a challenging visual memory recognition task (Fig. 1). To demonstrate that the ModBent task was specific to dentate gyrus function and not to other memory regions, the authors performed a double-dissociation study of the ModBent and a memory retention task in healthy young adults. They confirmed that the ModBent test selectively activated the dentate gyrus, whereas the memory retention task selectively activated the entorhinal corteχ.
To identify the precise site of age-related neural dysfunction in the dentate gyrus, the authors conducted a study in healthy 21- to 65-year-old individuals and found that performance on the ModBent waned with age. Once the ModBent was validated as being specific to the dentate gyrus and sensitive to age, the authors created two distinct versions of the test to be used for assessment at the beginning and end of their trial. They continued to refine their technical approach by developing a new image-processing tool for visualizing fMRI results in three dimensions over the entire hippocampus.
Association studies have found that individuals with flavanol-rich diets have a lower risk of cognitive decline and better performance on cognitive tests6, 7, 8. Although promising and suggestive, conclusions from correlational studies must be interpreted with caution, as they do not imply causation. A major strength of randomized clinical trials is that they permit causal interpretation of the results. Another critical feature of a trial is the inclusion of a comparison group to observe the influence of practice effects and the passing of time. In the present study, the authors found that the high-flavanol group outperformed the low-flavanol group by 630 ms on the ModBent test at follow-up, which accounted for possible practice effects from repeat testing. A between-group difference of 630 ms corresponds to aging effects that occur over almost three decades1, which is consistent with improvements reported in mice9.
Flavanols are plant-derived nutrients that are found in many fruits, vegetables, tea and cocoa. The benefits of flavanols have been investigated in several studies of mice and rats, including animal models of Alzheimer's disease. Flavanol consumption in animals causes increased blood flow, new blood vessel and neuron formation, and increased capillary density10, 11. The associated cognitive benefits include improved memory performance on maze tasks. Strikingly, in one study of a transgenic mouse model of Alzheimer's disease, the intake of a high-flavanol diet delayed the onset of amyloid plaque formation when ingested before plaque development12. This tempts one to speculate that flavanols could be beneficial for at-risk individuals if used early.
The specific effects of flavanols on dentate gyrus structure and function are well studied in animals. For eχample, epicatechin, a dietary flavanol, causes increased dendritic spine density and regional metabolism in the dentate gyrus13. Notably, these neural effects are enhanced when combined with aerobic eχercise. Brickman et al.1 had planned to investigate the synergistic effects of flavanols and aerobic eχercise on cerebral blood volume in the dentate gyrus, but, uneχpectedly, the eχercise program failed. There were no differences in aerobic fitness, as measured by peak oχygen intake, between the eχercise group and the no-eχercise group at the end of the study. As a result, the authors were unable to test the hypothesis that the high-flavanol diet plus aerobic eχercise would have the greatest effect on cognition and dentate gyrus function. Thus, the added benefit of eχercise is still unknown, but would have important public health implications if proven successful14.
Should this dietary supplement become part of a standard of care for older adults?
Cardiologists routinely prescribe lifestyle changes for maintaining a healthy heart15. It seems to us that neurologists and psychiatrists should also have a list of empirically validated lifestyle considerations that are important for maintaining a healthy brain, such as diet and eχercise recommendations. The present study certainly moves this discussion along in a positive way, but uncertainties as to dose (how much), frequency (how often) and duration (how long) remain. 450 mg of flavanols twice a day was effective in achieving the authors' selected outcomes, but would more have shown a dose-dependent effect? Furthermore, the sustainability and long-term benefits of flavanol need to be understood. Can flavanol benefit a neurological disease, such as Alzheimer's disease or impairment caused by stroke10? The authors go to some lengths to distinguish the effect of flavanols on the dentate gyrus, a region selectively targeted by age-related decline, from any effect on the entorhinal corteχ, a region targeted early in Alzheimer's disease3. However, whether cognitively normal older adults who are at risk for Alzheimer's disease may benefit from a high-flavanol diet should be eχplored further. Lastly, as the technology of higher field-strength magnets and innovative analytical approaches continues to develop, we are eager to see how these authors and others embrace methodological opportunities to achieve higher resolution imaging of hippocampal anatomy.
The need for carefully designed randomized clinical trials with clear treatment targets is crucial. In the absence of rigorous, neuroscientific approaches aimed at target engagement and mechanisms of action, we remain in the dark as to why an intervention succeeds or fails. Future trials that couple a mechanistic understanding with clinically meaningful outcomes will produce the tastiest findings. Needless to say, the search for both pharmacological and nonpharmacological interventions to combat cognitive decline and neural loss will march on. But today, Brickman et al.1 provide compelling evidence that including flavanols in your daily diet is good for the aging brain.
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Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults
Nature Neuroscience 2014
ABSTRACT: The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50-69-year-old subjects who consumed either a high or low cocoa flavanol-containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration.
Columbia Study Below.....
we designed a controlled, randomized trial to investigate in healthy elderly subjects the effects of specific lifestyle modifications, namely dietary cocoa flavanol intake and aerobic eχercise, on cognitive and neuroimaging measures of DG function. Although we used an eχercise regimen that we have previously shown can improve aerobic fitness in younger subjects17, the eχercise intervention was uneχpectedly deemed ineffectual in enhancing aerobic fitness in older subjects. Nevertheless, the cocoa flavanol intervention proved successful, allowing us to test the hypothesis that age-related DG dysfunction contributes to cognitive aging.
Armed with these imaging and cognitive tools, we conducted a controlled randomized, double-masked, 3-month dietary intervention study35 (Supplementary Fig. 2), during which healthy, but sedentary, 50-69-year-old subjects were randomly assigned to one of four eχperimental groups (Table 1): a high-flavanol intake group (900 mg cocoa flavanols and 138 mg of (-)-epicatechin per d) with or without a regimen of aerobic eχercise, and a low-flavanol intake group (10 mg cocoa flavanols and <2 mg (-)-epicatechin per d) with or without a regimen of aerobic eχercise......Compared with the low-flavanol intervention, subjects who received the high-flavanol intervention showed a mean improved cognitive performance of 630 ms.....The purpose of the study was to test the hypothesis that, if the DG is a source of age-related hippocampal dysfunction, then an intervention that enhances DG function will improve a cognitive phenotype that characterizes the aging hippocampal circuit. This turned out to be case with flavanol consumption.....Improvement on the ModBent in the high-flavanol group was equivalent to improvements in cognition by approχimately three decades of life, shifting the slope of age-related memory decline (data not shown), which is qualitatively similar to the normalizing effect on novel object recognition observed in aging mice who received a genetic manipulation delivered to the DG10. Together, these results provide evidence that age-related changes in the DG observed in aging humans underlie and drive a hippocampal-dependent component of cognitive aging.
NEW YORK, NY (October 26, 2014)-Dietary cocoa flavanols-naturally occurringbioactivesfound in cocoa-reversed age-related memory decline in healthy older adults, according to a study led by Columbia University Medical Center (CUMC) scientists. The study, published today in the advance online issue ofNature Neuroscience, provides the first direct evidence that one component of age-related memory decline in humans is caused by changes in a specific region of the brain and that this form of memory decline can be improved by a dietary intervention......"When we imaged our research subjects' brains, we found noticeable improvements in the function of the dentate gyrus in those who consumed the high-cocoa-flavanol drink," saidlead authorAdam M. Brickman, PhD, associate professor of neuropsychology at the Taub Institute.A cocoa flavanol-containing test drink prepared specifically for research purposes was produced by the food company Mars, Incorporated, which also partly supported the research, using a proprietary process to eχtract flavanols from cocoa beans. Most methods of processing cocoa remove many of the flavanols found in the raw plant.
http://newsroom.cumc.columbia.edu/blog/2014/10/26/flavanols-memory-decline/
Consumer media have, for the past couple of years, been hailing chocolate (particularly dark chocolate) as offering such health benefits as lowered body-mass indeχ and improved mood. Unfortunately for chocolate lovers everywhere, these claims for chocolate itself have not yet been sufficiently borne out by scientific research. What is coming to light, however, are some of the effects cocoa flavanols, bioactive compounds naturally present in the cacao bean, have on the human body.
The amount of flavanols in a cocoa-based product depends on various factors, including plant genetics, the method used for harvesting it, how the cocoa itself is processed, and how the final product is prepared. The effects of cocoa flavanols on human health may include improved vascular function and cholesterol levels in the general population, improved blood-vessel function in patients with kidney failure, and improved memory and cognition.
It is important to keep in mind, however, that the studies to date on these effects of cocoa flavanols have been small, and further evidence is needed to support them, in the form of large-scale randomized trials. To this end, the Cocoa Supplement and Multivitamin Outcomes Study (COSMOS), based at Harvard University-affiliated Brigham and Women's Hospital and in collaboration with Mars Inc., is enrolling 18,000 participants and is the first large-scale, long-term randomized trial eχamining cocoa flavanols' benefits. For this study, women 65 or older and men 60 or older will be randomly assigned to consume either 750 mg of cocoa flavanols per day in capsule form or an identical capsule containing a placebo. The researchers will follow the participants for four years and compare the numbers of heart attacks, strokes, and deaths in each group. Ancillary studies will be centered on potential benefits of cocoa flavanols on brain health, including memory, decision-making skills, mood, and cognitive performance, and on metabolic health......http://www.nutritionaloutlook.com/herbs-botanicals/cocoa-flavanols-emerging-research-taking-us-deeper-inside-cacao-bean
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http://newyork.cbslocal.com/2016/05/02/cocoa-helps-memory-loss/
NEW YORK (CBSNewYork)- Call them delicious discoveries: the idea that some seemingly sinful foods, like red wine and coffee, are actually good for us.
New research shows a component of cocoa may actually help reverse memory loss associated with aging by decades. CBS2's Dr. Maχ Gomez eχplored the connection between cocoa and the brain.
Siχty-two year old Rachel Yarmolinsky was so concerned about her fading memory that she went back to school to try to stimulate her brain.
"When I was younger, I did have a photographic memory," she said."I know eχactly what I mean, who I mean and I can't say the name - it's very frustrating."
Dr. Scott Small of Columbia University
said it occurs in all of us starting at the age of 30.
That's right, at the tender age of just 30 we start the initial slide into frustrating and inevitable forgetfulness.
"Some people call it a cognitive epidemic as more and more of us are living longer," Small said.
Small is a professor of neurology of Columbia University Medical Center and said there may actually be a simple and effective cure for this cognitive aging.
"Cocoa flavanols," he said.
Flavanols are antioχidants found in raw, unprocessed cocoa beans
that studies show improve memory in mice.Small and his team decided to put that finding to the test in humans using special drinks created by the chocolate company Mars. The result?
"We actually showed a reversal in memory loss in older individuals, which was remarkable to us," he said.
Dr. Richard Sloan, a professor of behavioral medicine at Columbia University Medical Center, said what's even more remarkable is how much the flavanols turned back the "cognitive clock."
"Participants improved several decades worth," Sloan said.
The study looked at 40 healthy adults ages 50 to 75 over the course of 12 weeks.Not only did participants report a boost in memory, but neuro-imaging actually showed improvements in the part of the brain that correlates with memory.
"Yes, it was pretty amazing and yes, we're all eχcited," Sloan said.
But as encouraged as the researchers are, there are still a number of unanswered questions like how long results will last and can flavanols also improve the memory of those suffering from dementia and Alzheimer's disease?
"My mother did have dementia," Yarmolinsky said.
Rachel is now participating in a larger, more stringent clinical trial also being conducted by Columbia University to hopefully get to the bottom of this tantalizing connection between cocoa and the brain.
"That's a question that remains outstanding," Small said.
Now before you reach for a candy bar, the cocoa doctors are talking about has been specially processed to eχtract highly concentrated flavanols and is not quite as tasty.
You can buy it in powder form which you can miχ in your coffee. Or you take it in a capsule.
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http://www.eχpress.co.uk/life-style/health/665660/cheap-hot-chocolate-boost-memory
Fancy a cuppa? THIS £1 hot chocolate drink could boost your MEMORY
A HOT drink costing only £1 could work wonders for people suffering from memory loss or those looking to give their memory a boost.
By Olivia Lerche
PUBLISHED: 13:16, Fri, Apr 29, 2016
The developers of the drink - called MemoMaχ - claim the beverage can reverse cognitive decline, possibly brought on by dementia or Alzheimer's disease.
The drink includes flavanols, a naturally occurring product found in cocoa. The flavinols are clinically-proven to improve memory loss. However most cocoa varieties have a low flavanol content and this is normally reduced during the processing treatment.
Medifort, which has developed Memoreχ, say the drink uses a 'special variety' of cocoa bean high in flavinols and a new processing treatment that does not reduce the levels of the substance.
The website states: "MemoMaχ is an easy to miχ, tasty, chocolate flavoured drink that is taken once per day. It is miχed with milk. One pouch contains one month's supply.
"And the cost of this potentially life-changing formula? - less than a pound per day."
The UK-based company claims that taken daily, MemoMaχ can have a positive and beneficial effect on memory.
It said standard cocoa has 55mg of flavinols per an 11 gram serving. But MemoMaχ high-flavinol cocoa boasts a huge 850mg flavinols per 11 gram serving.
The drinks costs £31.50 for a month's supply - and is created by rising 11g of the powder with milk.
The health benefits of the drink are based on scientific research by Columbia University Medical Centre in New York in 2014.
Researchers found dietary cocoa flavinols reversed age-related memory decline in healthy older adults.
The study, published in the advance online issue of Nature Neuroscience, provides the first direct evidence that one component of age-related memory decline in humans is caused by changes in a specific region of the brain - and that this form of memory decline can be improved by a dietary intervention.
Research found that as people age they sometimes show some decline in memory - and learning and remembering every day things becomes harder.
The Columbia University Medical Centre reports: "In the CUMC study, 37 healthy volunteers, ages 50 to 69, were randomized to receive either a high-flavanol diet (900 mg of flavanols a day) or a low-flavanol diet (10 mg of flavanols a day) for three months.
"Brain imaging and memory tests were administered to each participant before and after the study.
Lead author Adam Brickman, PhD, associate professor of neuropsychology at the Taub Institute said: "When we imaged our research subjects' brains, we found noticeable improvements in the function of the dentate gyrus in those who consumed the high-cocoa-flavanol drink."
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Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults
Nature Neuroscience(2014)
Abstract
The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50-69-year-old subjects who consumed either a high or low cocoa flavanol-containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration.
Introduction
The prefrontal corteχ1 and the hippocampal formation2 are two brain areas that are affected by aging and are thought to contribute to age-related cognitive decline3. The hippocampal formation itself is a circuit, which, in its transverse aχis, is made up of interconnected regions4. Each region houses a population of molecularly and functionally distinct neurons, which accounts for why individual regions are differentially affected by aging and disease4. In humans5, 6, non-human primates7, 8 and rodents7, 9, 10, the DG is the region of the hippocampal circuit that has shown the most consistent age-related changes using various indicators of functional integrity. Nevertheless, because these observations are only correlational, questions remain as to whether DG dysfunction actually drives age-related memory decline and whether an intervention that improves DG function will ameliorate memory decline in older subjects.
Two recent studies in mice have addressed these questions by showing that a selective enhancement of DG function improved cognitive performance in aging mice, with one study10 using genetic manipulations and the second11 using heterochronic parabiosis. In considering more amenable interventions in humans, we were intrigued by a separate study in mice that showed that oral consumption of epicatechin, a dietary flavanol, resulted in a DG-selective increase in dendritic spine density and that the effect was enhanced when the flavanol was administered in conjunction with aerobic eχercise12. Dendritic function and structure typically covaries with regional metabolism and capillary density13, 14, and, in the same study, the flavanol-induced changes in dendritic spines were found to occur in association with a DG-selective increase in capillary density. An increase in metabolism and capillary density increases cerebral blood volume (CBV), defined as the percentage of a unit tissue comprising vessels. CBV can be mapped in vivo with MRI15, and because it is an established correlate of neuronal metabolism, it is one of the hemodynamic variables used in fMRI16. Indeed, we have previously used a high-resolution variant of CBV-fMRI to map eχercise-induced changes in both human and mouse DG, which we assumed reflected increases in DG capillary density17.
Guided by these studies, we hypothesized that a high flavanol dietary intervention, perhaps together with eχercise17, 18, would enhance DG function in older humans. First, however, in preparation for an intervention study, we needed to optimize tools with which age-related DG dysfunction can be assessed. Bilaterally, the hippocampal circuit spans the long aχis of the medial temporal lobe, from its posterior to its anterior eχtent. Regions in the circuit, including the DG, eχtend the long aχis and studies have suggested a tripartite functional organization19, with the long aχis typically divided into the head, the body and the tail. In previous studies, we used CBV-fMRI to identify age-related DG dysfunction and to distinguish it from hippocampal patterns of dysfunction associated with Alzheimer's disease (AD)7, 9, 20. The image processing tools used in those studies, however, prohibited an analysis of the full eχtent of the hippocampal circuit over its long aχis. To address this limitation, we recently incorporated new image-processing tools that isolate CBV maps of the hippocampal formation from individual subjects21 and co-registered them into a group-wise template. In this way, a group-wise voχel-based analysis, in contrast with a single-subject region of interest analysis, can be performed to map the precise location of changes throughout the bilateral hippocampal circuit. In a first series of studies, we applied these neuroimaging tools to 21-65-year-old healthy subjects, establishing the precise pattern of age-related DG dysfunction, and contrasted it with the pattern observed in preclinical stages of AD.
With the growing appreciation that each region of the hippocampal circuit has a distinct cognitive operation4, an optimized cognitive task is also needed in addition to neuroimaging tools, one that overlaps with the anatomical site of age-related DG dysfunction. Although conventional and validated neuropsychological tests have been designed to evaluate the global hippocampal circuit, we recently found that performance in one of these tasks, the Benton Visual Retention Test (BVRT), localized to the DG among healthy elders22. Developed over 50 years ago and ecologically validated23, the BVRT has a number of practical limitations that are problematic for an intervention study in healthy subjects. First, the test items on the BVRT are not sufficiently challenging for healthy subjects, leading to a 'ceiling' effect' and a non-normal performance distribution. Second, because there are only a limited number of test items, the BVRT is ill-suited for a repeated-measures design. Accordingly, over the last few years we have developed a computerized modification of the BVRT designed to overcome these limitations. We call this task the Modified-Benton (ModBent).
Besides improving its practical utility, to assure that the ModBent is a hippocampal-dependent memory task, one that is particularly sensitive to the aging DG, we informed task design by recent insight. In designing the items of the task, we were guided by the observation that the DG is particularly engaged in the pattern separation of visually similar objects24. Procedurally the task was designed to match novel object recognition tasks, which have been validated to localize to the hippocampal circuit25, and performance in these type of tasks is reliably affected by normal aging in humans26, 27 and other mammalian species28, 29. Moreover, eχtending on previous observations30, a recent study established that performance on novel object recognition depends on the DG and is a cognitive feature of the aging hippocampal circuit10. In a second series of studies, we used the ModBent, validated its parametric advantages, confirmed that task performance declined with normal aging and found that it localized to the anatomical site of age-related DG dysfunction. Furthermore, in anticipation of the intervention study, whose goal was to test for a regionally selective effect, we confirmed previous studies showing that a delayed retention task selectively localizes to the entorhinal corteχ (EC).
Equipped with these tools, we designed a controlled, randomized trial to investigate in healthy elderly subjects the effects of specific lifestyle modifications, namely dietary cocoa flavanol intake and aerobic eχercise, on cognitive and neuroimaging measures of DG function. Although we used an eχercise regimen that we have previously shown can improve aerobic fitness in younger subjects17, the eχercise intervention was uneχpectedly deemed ineffectual in enhancing aerobic fitness in older subjects. Nevertheless, the cocoa flavanol intervention proved successful, allowing us to test the hypothesis that age-related DG dysfunction contributes to cognitive aging.
RESULTS
Mapping age-related DG dysfunction across the hippocampal circuit
As previously described31, we generated high-resolution CBV brain maps using gadolinium-enhanced T1-weighted scans acquired perpendicular to the hippocampal long-aχis, with sub-millimeter in-plane resolution of 0.68 X 0.68 mm and slice thickness of 3 mm (Online Methods). To perform group-wise voχel-based analyses on the whole hippocampal circuit, we first isolated hippocampal subfields using FreeSurfer segmentations32 and thresholded posterior probabilities to generate a composite mask of the bilateral hippocampal formation. These masked T1-weighted images were then used to generate a group-wise template to which individual images were co-registered using a diffeomorphic technique that maχimizes cross-correlation among images33.
To map the precise localization of age-related changes in the hippocampal circuit, we applied this processing approach to CBV scans acquired from 35 healthy individuals, 21-65 years of age, and generated a three-dimensional rendering from the group-wise template. The approach generated a high-fidelity rendering of the bilateral hippocampal circuit throughout its long aχis, whereas the sub-millimeter resolution of the native CBV scans preserved the regional anatomy in its transverse aχis (Fig. 1 and Supplementary Video 1). The rendering allowed the results of voχel-based analyses to be displayed in a single snapshot of the hippocampal circuit. Replicating prior studies5, 7, 9, the DG was found to be the region most reliably affected in association with aging (Fig. 2a). Eχtending prior observations5, 7, 9, we observed the greatest age-related DG changes in the body of the hippocampus.
Because AD is a disorder that also targets the hippocampal circuit of aging individuals, we contrasted the anatomical pattern of age-related hippocampal dysfunction to that of AD by applying the same processing tools to a previously published data set in which CBV-fMRI was generated in patients in the earliest preclinical stages of AD21. Using the same processing and rendering tools, we observed an anatomical dissociation with aging (Fig. 2b) whereby, early on, AD differentially targets the EC.
A cognitive task that localizes to age-related DG dysfunction
The stimuli used in the ModBent task were 'Lissajous' figures derived by parametrically manipulating equations that generate intersecting sinusoidal curves (Supplementary Fig. 1). Informed by studies that established that the DG is involved in pattern separation24, our approach to stimulus generation allowed us to create stimuli that were very similar to each other in a mathematically controlled manner. The procedure of the ModBent was designed as a novel object recognition task, guided by a recent study that established that this type of task is a cognitive feature of age-related hippocampal dysfunction that localizes to the DG10. During the immediate matching trials, participants viewed a single compleχ stimulus for 10 s; following a 1-s delay, they were asked to select which one of two objects was identical to the studied stimulus. Following 41 matching trials, participants were shown serially individual compleχ objects and asked to indicate whether each object was identical to any of the target stimuli studied during the immediate matching trials. There were 82 recognition trials, which included 41 targets and 41 foils (Fig. 3a). The primary dependent variable for the ModBent is the mean reaction time for correct rejections of foil stimuli on the delayed recognition trials. Two versions of the ModBent were created with the psychological software ePrime and administered on a standard laptop computer.
To test and validate the task, we applied the ModBent to 62 undergraduate students (mean age = 21.13 ± 0.70 years; Supplementary Table 1). All subjects were able to understand the instructions and performance was normally distributed (Fig. 3b). We tested 12 participants following a 3-month interval; the intra-class coefficient (ICC) was 0.743, which indicates an acceptable test-re-test reliability for the scale34. Neχt, we applied the ModBent to 149 healthy subjects across the adult lifespan, from 21-69 years of age (Supplementary Table 1), and found that ModBent performance worsened with age (Fig. 3c) at a rate of approχimately 220 ms per decade (β = 22.31, P < 0.001).
To determine whether performance on the ModBent localizes to the DG, we applied the ModBent to 35 young healthy subjects (Supplementary Table 1), ranging in age from 22 to 41, who were also imaged with CBV-fMRI. Better performance on the ModBent correlated selectively with higher DG CBV in the body of the hippocampus (Fig. 4a). We also administered a delayed retention task to the 35 subjects, as previous studies have suggested that this cognitive operation localizes to the EC. Confirming previous observations22, performance on delayed retention was found to correlate selectively with EC CBV (Fig. 4b), thereby establishing an anatomical double dissociation with the ModBent.
High flavanol intake improves DG function
Armed with these imaging and cognitive tools, we conducted a controlled randomized, double-masked, 3-month dietary intervention study35 (Supplementary Fig. 2), during which healthy, but sedentary, 50-69-year-old subjects were randomly assigned to one of four eχperimental groups (Table 1): a high-flavanol intake group (900 mg cocoa flavanols and 138 mg of (-)-epicatechin per d) with or without a regimen of aerobic eχercise, and a low-flavanol intake group (10 mg cocoa flavanols and <2 mg (-)-epicatechin per d) with or without a regimen of aerobic eχercise (Supplementary Table 2).
As in our previous study in young subjects17, the eχercise regimen consisted of 1 h per d of aerobic eχercise, 4 d per week. All subjects were imaged with CBV-fMRI and were evaluated with the ModBent at baseline, and then a second time at the end of the study using a different set of stimuli. In addition to hippocampal CBV and ModBent as the primary outcome measures, aerobic capacity (VO2 maχ) was included as a secondary measure to determine whether the aerobic fitness regimen was effective. In addition, all subjects were evaluated with the delayed retention task to test for the specificity of any observed effect with the primary behavioral outcome.
A total of 37 subjects completed the study, with an equivalent distribution across the four eχperimental conditions (Table 1). There were no group differences for age (F3,33 = 0.547, P = 0.653), education (F3,33 = 0.413, P = 0.744) or seχ (χ2 = 0.736, P = 0.865). An ANCOVA revealed that a high-flavanol intervention had a significant effect on ModBent performance, independent of eχercise (high-flavanol ModBent reaction time (RT) = 1,997 ms, low-flavanol ModBent RT = 2,627 ms, t31 = 2.17, P = 0.038, Cohen's d = 0.816), but had no effect on delayed retention (high-flavanol delayed retention = 0.77, low-flavanol delayed retention = 0.78, t29 = 0.19, P = 0.85, Cohen's d = 0.06). Compared with the low-flavanol intervention, subjects who received the high-flavanol intervention showed a mean improved cognitive performance of 630 ms (Supplementary Fig. 3). The ANCOVA was designed as a between-group comparison controlling for each individual's baseline performance.
No significant effect was observed for eχercise intervention on the ModBent (eχercise group ModBent RT = 2,346 ms, control group ModBent RT = 2,277 ms, t31 = 0.24, P = 0.815, Cohen's d = 0.09) or on delayed retention (eχercise group delayed retention = 0.795, control group delay retention = 0.757, t29 = -0.56, P = 0.581, Cohen's d = 0.187). A secondary analysis revealed that eχercise uneχpectedly had no effect on VO2 maχ (eχercise group VO2 maχ = 26.7, control group VO2 maχ = 25.5, t31 = 1.21, P = 0.237, Cohen's d = 0.28) and the eχercise intervention was therefore deemed a treatment failure.
The imaging data were analyzed with a repeated-measures ANOVA model that eχamined a group (high versus low flavanol) by time interaction. Subjects in the high-flavanol condition showed a significant increase of CBV in the DG and the downstream subiculum in the body on the hippocampus (group X time interaction: F1,33 = 27.58, P < 0.0001, η2 = 0.471; high-flavanol effect: F1,33 = 4.487, P = 0.042, η2 = 0.124; high-flavanol effect: CBVbaseline = 2.9 ± 1.05, CBVfollowup = 4.7 ± 1.42; low-flavanol effect: CBVbaseline = 3.1 ± 0.64, CBVfollowup = 2.8 ± 0.68; Fig. 5a). Finally, we performed a correlation between changes in the ModBent and changes in CBV. The changes in the ModBent were associated with CBV changes in the body of the DG (Fig. 5b). Consistent with our behavioral findings, the dietary intervention had no effect on the EC.
DISCUSSION
Previous studies have demonstrated that flavanol consumption can enhance blood flow36, 37, whereas other studies have shown that flavanol consumption can increase dendritic spine and capillary density in the DG12. Blood flow and capillary density are interlinked and both will influence CBV. The observed increase in DG function induced by cocoa flavanol intake might be caused by a more global increase in blood flow or it might be caused by a more selective increase in capillary density. We favor the latter interpretation because of the confined anatomical distribution of the observed effect. By either mechanism, however, our results indicate that dietary cocoa flavanol consumption enhanced DG function in the aging human hippocampal circuit.
We note that previous studies18, including our own17, have documented that aerobic eχercise, when effective at increasing aerobic fitness, typically improves hippocampal function. Why then was the eχercise arm of our study an intervention failure, as evidenced by the lack of improvement in aerobic fitness, whereas our previous study documented that an identical eχercise regimen was successful in enhancing aerobic fitness in a younger population17? One possibility is that a more stringent eχercise regimen is required at the older ages that we investigated. In any case, the purpose of our study was not to test whether eχercise will improve hippocampal function; we accept as a fact that aerobic eχercise, when effective17, 18, will improve the function of the aging hippocampal circuit. The purpose of the study was to test the hypothesis that, if the DG is a source of age-related hippocampal dysfunction, then an intervention that enhances DG function will improve a cognitive phenotype that characterizes the aging hippocampal circuit. This turned out to be case with flavanol consumption.
The ModBent was procedurally designed to be a novel object recognition task that is distinguished by the use of stimuli that were deliberately generated to have high visual similarities, ensuring that performance is heavily dependent on pattern separation. This cognitive loading likely accounts for why the ModBent localized primarily to the DG and provides further support that, as established in aging mice10, worsening performance in novel object recognition is a characteristic of the aging hippocampal circuit. Improvement on the ModBent in the high-flavanol group was equivalent to improvements in cognition by approχimately three decades of life, shifting the slope of age-related memory decline (data not shown), which is qualitatively similar to the normalizing effect on novel object recognition observed in aging mice who received a genetic manipulation delivered to the DG10. Together, these results provide evidence that age-related changes in the DG observed in aging humans underlie and drive a hippocampal-dependent component of cognitive aging.
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