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Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults

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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.

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Figure 1: A bilateral map of the hippocampal circuit generated from the high-resolution acquisitions of CBV-fMRI.
Figure 2: Mapping a differential pattern of age-related dysfunction in the hippocampal circuit.
Figure 3: Performance on the ModBent declines with age.
Figure 4: Performance on the ModBent overlaps with the anatomical site of hippocampal aging.
Figure 5: Flavanols enhance CBV-fMRI.

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Change history

  • 02 November 2014

    In the version of this article initially published online, the abstract referred to a high or low cocoa–containing diet. It should have read high or low cocoa flavanol–containing diet. The error has been corrected for the print, PDF and HTML versions of this article.

References

  1. Gazzaley, A., Cooney, J.W., Rissman, J. & D'Esposito, M. Top-down suppression deficit underlies working memory impairment in normal aging. Nat. Neurosci. 8, 1298–1300 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Small, S.A., Stern, Y., Tang, M. & Mayeux, R. Selective decline in memory function among healthy elderly. Neurology 52, 1392–1396 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Morrison, J.H. & Baxter, M.G. The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat. Rev. Neurosci. 13, 240–250 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Small, S.A., Schobel, S.A., Buxton, R.B., Witter, M.P. & Barnes, C.A. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat. Rev. Neurosci. 12, 585–601 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Small, S.A., Tsai, W.Y., DeLaPaz, R., Mayeux, R. & Stern, Y. Imaging hippocampal function across the human life span: is memory decline normal or not? Ann. Neurol. 51, 290–295 (2002).

    Article  PubMed  Google Scholar 

  6. Yassa, M.A., Mattfeld, A.T., Stark, S.M. & Stark, C.E. Age-related memory deficits linked to circuit-specific disruptions in the hippocampus. Proc. Natl. Acad. Sci. USA 108, 8873–8878 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Small, S.A., Chawla, M.K., Buonocore, M., Rapp, P.R. & Barnes, C.A. Imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging. Proc. Natl. Acad. Sci. USA 101, 7181–7186 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hara, Y. et al. Synaptic distributions of GluA2 and PKMzeta in the monkey dentate gyrus and their relationships with aging and memory. J. Neurosci. 32, 7336–7344 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Moreno, H. et al. Imaging the abeta-related neurotoxicity of Alzheimer disease. Arch. Neurol. 64, 1467–1477 (2007).

    Article  PubMed  Google Scholar 

  10. Pavlopoulos, E. et al. Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. Sci. Transl. Med. 5, 200ra115 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Villeda, S.A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. van Praag, H. et al. Plant-derived flavanol (−)epicatechin enhances angiogenesis and retention of spatial memory in mice. J. Neurosci. 27, 5869–5878 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Borowsky, I.W. & Collins, R.C. Metabolic anatomy of brain: a comparison of regional capillary density, glucose metabolism and enzyme activities. J. Comp. Neurol. 288, 401–413 (1989).

    Article  CAS  PubMed  Google Scholar 

  14. Fonta, C. & Imbert, M. Vascularization in the primate visual cortex during development. Cereb. Cortex 12, 199–211 (2002).

    Article  PubMed  Google Scholar 

  15. Lin, W., Celik, A. & Paczynski, R.P. Regional cerebral blood volume: a comparison of the dynamic imaging and the steady state methods. J. Magn. Reson. Imaging 9, 44–52 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Belliveau, J.W. et al. Functional mapping of the human visual cortex by magnetic resonance imaging. Science 254, 716–719 (1991).

    CAS  PubMed  Google Scholar 

  17. Pereira, A.C. et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc. Natl. Acad. Sci. USA 104, 5638–5643 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Erickson, K.I. et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl. Acad. Sci. USA 108, 3017–3022 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Volpe, J.J., Herscovitch, P., Perlman, J.M. & Raichle, M.E. Positron emission tomography in the newborn: extensive impairment of regional cerebral blood flow with intraventricular hemorrhage and hemorrhagic intracerebral involvement. Pediatrics 72, 589–601 (1983).

    CAS  PubMed  Google Scholar 

  20. Wu, W. et al. The brain in the age of old: the hippocampal formation is differentially affected by diseases of late life. Ann. Neurol. 64, 698–706 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Khan, U.A. et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nat. Neurosci. 17, 304–311 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Brickman, A.M., Stern, Y. & Small, S.A. Hippocampal subregions differentially associate with standardized memory tests. Hippocampus 21, 923–928 (2011).

    PubMed  Google Scholar 

  23. Strauss, E., Sherman, E.M.S. & Spreen, O. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary (Oxford University Press, 2006).

  24. Yassa, M.A. & Stark, C.E. Pattern separation in the hippocampus. Trends Neurosci. 34, 515–525 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Broadbent, N.J., Squire, L.R. & Clark, R.E. Spatial memory, recognition memory and the hippocampus. Proc. Natl. Acad. Sci. USA 101, 14515–14520 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schacter, D.L., Cooper, L.A. & Valdiserri, M. Implicit and explicit memory for novel visual objects in older and younger adults. Psychol. Aging 7, 299–308 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Grady, C.L. et al. Age-related reductions in human recognition memory due to impaired encoding. Science 269, 218–221 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Moss, M.B., Rosene, D.L. & Peters, A. Effects of aging on visual recognition memory in the rhesus monkey. Neurobiol. Aging 9, 495–502 (1988).

    Article  CAS  PubMed  Google Scholar 

  29. Erickson, C.A. & Barnes, C.A. The neurobiology of memory changes in normal aging. Exp. Gerontol. 38, 61–69 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Jessberger, S. et al. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn. Mem. 16, 147–154 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Khan, U.A. et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nat. Neurosci. 17, 304–311 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Van Leemput, K. et al. Automated segmentation of hippocampal subfields from ultra-high resolution in vivo MRI. Hippocampus 19, 549–557 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Avants, B.B., Epstein, C.L., Grossman, M. & Gee, J.C. Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med. Image Anal. 12, 26–41 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Anastasi, A. & Urbina, S. Psychological Testing (Prentice Hall, Upper Saddle River, New Jersey, 1997).

  35. New York State Psychiatric Institute & Mars, Inc. Mars flavanol exercise and cognitive function study. ClinicalTrials.Gov <http://clinicaltrials.gov/show/NCT01180127> (2014).

  36. Schroeter, H. et al. (−)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc. Natl. Acad. Sci. USA 103, 1024–1029 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sorond, F.A., Hollenberg, N.K., Panych, L.P. & Fisher, N.D. Brain blood flow and velocity: correlations between magnetic resonance imaging and transcranial Doppler sonography. J. Ultrasound Med. 29, 1017–1022 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Reuter, M., Rosas, H.D. & Fischl, B. Highly accurate inverse consistent registration: a robust approach. Neuroimage 53, 1181–1196 (2010).

    Article  PubMed  Google Scholar 

  39. Frangi, A., Niessen, W., Vincken, K. & Viergever, M. Multiscale vessel enhancement filtering. Med. Image Comput. Comput. Assist. Interv. 1496, 130–137 (1998).

    Google Scholar 

  40. Buchfuhrer, M.J. et al. Optimizing the exercise protocol for cardiopulmonary assessment. J. Appl. Physiol. 55, 1558–1564 (1983).

    Article  CAS  PubMed  Google Scholar 

  41. Yuan, Y.C. Multiple imputation for missing data: concepts and development (Version 9.0). SAS Support http://support.sas.com/rnd/app/stat/papers/multipleimputation.pdf (2012).

  42. Little, R.J.A. & Rubin, D.B. Statistical Analysis with Missing Data (Wiley, Hoboken, N.J., 2002).

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Acknowledgements

We thank F. Gage for previous discussions and A. Glass for helping with the statistical analysis. This investigation was supported by US National Institutes of Health grants AG034618, AG035015, AG025161 and AG08702, the James S. McDonnell Foundation, and an unrestricted grant by MARS, Inc.

Author information

Authors and Affiliations

Authors

Contributions

A.M.B. designed and implemented the ModBent task and help write the manuscript. U.A.K. and F.A.P. performed the imaging analyses and help write the manuscript. L.-K.Y. aided in designing the ModBent task. W.S. administered the ModBent task to college students. H.S. aided is establishing inclusionary/exclusionary criteria for the clinical trial. M.W. performed the statistical analysis on the cognitive variables. R.P.S. was responsible for subject recruitment and characterization and helped to write the manuscript. S.A.S. designed and evaluated all the studies and was the primary writer of the manuscript.

Corresponding author

Correspondence to Scott A Small.

Ethics declarations

Competing interests

H.S. is employed by MARS, Inc., a company with long-term research and commercial interests in flavanols and procyanidins.

Integrated supplementary information

Supplementary Figure 1 Stimulus generation

(a) Lissajous figures parameterized by the equations X = sin(at+d), Y = sin(bt). a and b determined the vertical and horizontal frequency of the Lissajous loop, respectively. a was selected from the integer set [1-8,11] and b was selected from [1-6]. Only those a and b values were chosen that generated a non-integer quotient when b was divided by a

(b) Lissajous figures belonging to a specific a/b pair were further modified by d=[1-5]. All figures were traced in the range t=[1-20pi] with a sampling step of pi/100.

Supplementary Figure 2 Study Protocol Flow Diagram

Supplementary Figure 3 Effect of flavanol and exercise on ModBent performance

a) Mean performance on the ModBent for the groups receiving the low (gray bars) and high (black bars) flavanol dietary supplements at baseline and follow up, analyzed with a between-group ANCOVA controlling for each individual’s baseline performance. The high dietary flavanol group improved cognitive performance by a mean time of 630ms.

b) Mean performance on the ModBent for the no exercise (gray bars) and exercise (black bars) groups at baseline and follow up.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1 and 2 (PDF 2077 kb)

Supplementary Methods Checklist

(PDF 428 kb)

3D surface rendering of the hippocampal formation.

The hippocampal formations of subjects were masked and coregistered into a groupwise template. The resulting grayscale template image was thresholded and rendered in 3DSlicer using an adaptive marching cubes algorithm. The hippocampal formation is displayed in the left-anterior-oblique view and rotated clockwise. (MOV 6363 kb)

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Brickman, A., Khan, U., Provenzano, F. et al. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci 17, 1798–1803 (2014). https://doi.org/10.1038/nn.3850

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