1. • The aging population is rapidly expanding- the number of individuals 65 years and
older will increase from 35 million in 2000 to an estimated 72 million in 2030 [1].
• The brain is particularly vulnerable to the effects of aging, and age-related
deterioration of membrane phospholipids results in cortical thinning [2,3].
• The extent of thinning varies across the cortex, with pronounced structural
degeneration in regions of the prefrontal cortex, which results in selective declines
in cognition [4,5].
• Executive functions (i.e. cognitive flexibility) decline early in normal aging, and
may reflect changes in prefrontal cortex integrity [6, 7].
• Plasma phosphatidylcholine is a marker of age-related membrane degeneration
and is highly predictive of cognitive decline. Thus, phosphatidylcholine shows
promise as a target for nutritional interventions in healthy aging [3,8,9,10,11,12].
1. Decision Neuroscience Laboratory, Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL
2. Abbott Nutrition, Columbus, OH
Hypothesis
Methods
Plasma phosphatidylcholine status will positively associate with cognitive
performance on a measure of executive function (cognitive flexibility), and this
relationship will be mediated by structural integrity of regions within the prefrontal
cortex.
• Subjects: Healthy adults
N = 70, 65-75 years old, average age= 69.05 (SD: 2.84) years
• Biomarker assessment:
Plasma phosphatidylcholine [13]
• Cognitive assessment:
Delis-Kaplin Executive Function System Trail Making Test: Cognitive flexibility [14]
• Structural magnetic resonance imaging
Freesurfer Image Analysis Package: Cortical thickness of prefrontal regions [15]
• Mediation analysis:
1. Multivariate linear regressions
a. Phosphatidylcholine levels à cognitive flexibility
Covariates: age, gender, education, income, BMI, depression
b. Phosphatidylcholine levels à cortical thickness
Covariates: age, gender, education, income, BMI, depression, frontal thickness
2. Sobel z-test [16,17]
Phosphatidylcholine levels + cortical thickness à cognitive flexibility
1. Projections for 2010 through 2050 are from: Table 12. Projections of the Population by Age and Sex for the United States: 2010 to 2050 (NP2008-T12), Population Division, U.S. Census
Bureau; Release Date: August 14, 2008
2. Kosicek, M., and Hecimovic, S. (2013). Phospholipids and Alzheimer’s Disease: Alterations, Mechanisms and Potential Biomarkers. Int. J. Mol. Sci. 14, 1310–1322.
3. Whiley, L., Sen, A., Heaton, J., Proitsi, P., Garcia-Gomez, D., Leung, R., et al. (2014). Evidence of altered phosphatidylcholine metabolism in Alzheimer’s disease. Neurobiol. Aging 35,
271–278.
4. Claassen, D. O., Dobolyi, D. G., Isaacs, D. A., Roman, O. C., Herb, J., Wylie, S. A., et al. (2016). Linear and Curvilinear Trajectories of Cortical Loss with Advancing Age and Disease
Duration in Parkinson’s Disease. Aging Dis. 7, 1–10.
5. Lockhart, S. N., and DeCarli, C. (2014). Structural Imaging Measures of Brain Aging. Neuropsychol. Rev. 24, 271–289.
6. Johnson, J., Lui, L., and Yaffe, K. (2007). Executive function, more than global cognition, predicts functional decline and mortality in elderly women. J. Gerontol. 62, 1134–1141.
7. Yuan, P., and Raz, N. (2014). Neuroscience and Biobehavioral Reviews Prefrontal cortex and executive functions in healthy adults : A meta-analysis of structural neuroimaging studies.
Neurosci. Biobehav. Rev. 42, 180–192.
8. Mapstone, M., Cheema, A. K., Fiandaca, M. S., Zhong, X., Mhyre, T. R., MacArthur, L. H., et al. (2014). Plasma phospholipids identify antecedent memory impairment in older adults.
Nat. Med. 20, 415–8.
9. Norris, S. E., Friedrich, M. G., Mitchell, T. W., Truscott, R. J. W., and Else, P. L. (2015). Human prefrontal cortex phospholipids containing docosahexaenoic acid increase during normal
adult aging, whereas those containing arachidonic acid decrease. Neurobiol. Aging 36, 1659–69.
10. Zeisel, S. H. (2008). Choline: critical role during fetal development and dietary requirements in adults. Annu. Rev. Nutr. 26, 229–250.
11. Frisardi, V., Panza, F., Seripa, D., Farooqui, T., and Farooqui, A. A. (2011). Glycerophospholipids and glycerophospholipid-derived lipid mediators: A complex meshwork in Alzheimer’s
disease pathology. Prog. Lipid Res. 50, 313–330.
12. Wurtman, R. (2015). Biomarkers in the diagnosis and management of Alzheimer’s disease. Metab. Clin. Exp. 4, 547–550.
13. Koc, H., Mar, M. H., Ranasinghe, A., Swenberg, J. A., and Zeisel, S. H. (2002). Quantitation of choline and its metabolites in tissues and foods by liquid chromatography/electrospray
ionization-isotope dilution mass spectrometry. Anal. Chem. 74, 4734–4740.
14. Delis, D. C., Kaplan, E., and Kramer, J. H. (2006). TEST REVIEW: Delis Kaplan Executive Function System (D-KEFS). Appl. Neuropsychol. 13.
15. http://surfer.nmr.mgh.harvard.edu/
16. Baron, R. M., and Kenny, D. A. (1986). The moderator–mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations. J. Pers. Soc.
Psychol. 51, 1173–1182.
17. Zhao, X., Lynch Jr., J. G., and Chen, Q. (2010). Reconsidering Baron and Kenny: Myths and Truths about Mediation Analysis. J. Consum. Res. 37, 197–206.
18. Jerneren, F., Elshorbagy, A. K., Oulhaj, A., Smith, S. M., Refsum, H., and Smith, A. D. (2015). Brain atrophy in cognitively impaired elderly : the importance of long-chain w-3 fatty acids
and B vitamin status in a randomized. Am. J. Clin. Nutr., 215–21.
19. Cole, G.M. & Frautschy, S.A. (2010). DHA may prevent age-related dementia. J. Nutr. 140, 869-874.
20. Blusztajn, J. K., Liscovitch, M., and Richardson, U. I. (1987). Synthesis of acetylcholine from choline derived from phosphatidylcholine in a human neuronal cell line. Proc. Natl. Acad.
Sci. U. S. A. 84, 5474–5477.
21. Cohen, B. M., Renshaw, P. F., Stoll, A. L., Wurtman, R. J., Yurgelun-todd, D., and Babb, S. M. (1995). Decreased Brain Choline in Older Adults. Jama 274, 902–907.
FUNDING:
Center for Nutrition, Learning, and Memory
UIUC Neuroscience Program
CONTACT: mzamro2@illinois.edu
Results & Discussion
Objective:
Investigate the neural mechanisms that mediate the relationship
between phosphatidylcholine and cognitive decline in normal aging
Conclusions:
Phosphatidylcholine may slow age-related decline in cognitive
flexibility by preserving structural integrity of inferior prefrontal cortex
Multivariate linear regressions
Future directions
• What mechanisms allow for specific nutrients to target particular brain
regions and therefore selectively influence cognitive decline?
• How can we further characterize such specific and sensitive relationships
between nutrition, cognition, and brain health to inform targeted treatment
of cognitive and neurological impairments of the aging brain?
Results:
Inferior prefrontal cortex thickness mediates the relationship
between phosphatidylcholine levels and cognitive flexibility
References
Phosphatidylcholine Cognitive flexibility
Prefrontal cortex
thickness
2.00!
2.10!
2.20!
2.30!
2.40!
2.50!
2.60!
2.70!
1000! 1500! 2000! 2500! 3000! 3500!
InferiorPrefrontalCortexThickness(mm)!
Phosphatidylcholine (uM)!
0!
2!
4!
6!
8!
10!
12!
14!
1000! 1500! 2000! 2500! 3000! 3500!
CognitiveFlexibilityScore!
Phosphatidylcholine (uM)!
Sobel Z-test
Mediating variable
(Left inferior prefrontal cortex thickness)
Independent variable
(Phosphatidylcholine)
Dependent variable
(Cognitive flexibility)
t = 1.953
p = 0.025
β = 0.672
p = 0.232
β = 7.047
p = 0.003
β = 0.672
p = 0.035
β = 0.043
p = 0.015
Phosphatidylcholine
Cognitive flexibility
Phosphatidylcholine
Inferior prefrontal
cortex thickness
Phosphatidylcholine
Potential mechanisms
2
1
4
3
6
5
2
1
A
B
3
C
Long-chain
polyunsaturated fats
Choline
Membrane integrity
[2]
Anti-inflammatory
effects [19]
Acetylcholine
projections [20,21]