Aging Affects Dopaminergic Neural Mechanisms of Cognitive Flexibility.
Aging is accompanied by profound changes in the brain's dopamine system that affect cognitive function. Evidence of powerful individual differences in cognitive aging has sharpened focus on identifying biological factors underlying relative preservation versus vulnerability to decline. Dopamine represents a key target in these efforts. Alterations of dopamine receptors and dopamine synthesis are seen in aging, with receptors generally showing reduction and synthesis demonstrating increases. Using the PET tracer 6-[18F]fluoro-l-m-tyrosine, we found strong support for upregulated striatal dopamine synthesis capacity in healthy older adult humans free of amyloid pathology, relative to young people. We next used fMRI to define the functional impact of elevated synthesis capacity on cognitive flexibility, a core component of executive function. We found clear evidence in young adults that low levels of synthesis capacity were suboptimal, associated with diminished cognitive flexibility and altered frontoparietal activation relative to young adults with highest synthesis values. Critically, these relationships between dopamine, performance, and activation were transformed in older adults with higher synthesis capacity. Variability in synthesis capacity was related to intrinsic frontoparietal functional connectivity across groups, suggesting that striatal dopamine synthesis influences the tuning of networks underlying cognitive flexibility. Together, these findings define striatal dopamine's association with cognitive flexibility and its neural underpinnings in young adults, and reveal the alteration in dopamine-related neural processes in aging.



Few studies have combined measurement of brain dopamine with examination of the neural basis of cognition in youth and aging to delineate the underlying mechanisms of these associations. Combining in vivo PET imaging of dopamine synthesis capacity, fMRI, and a sensitive measure of cognitive flexibility, we reveal three core findings. First, we find evidence supporting older adults' capacity to upregulate dopamine synthesis. Second, we define relationships between dopamine, cognition, and frontoparietal activity in young adults indicating high levels of synthesis capacity are optimal. Third, we demonstrate alteration of these relationships in older adults, suggesting neurochemical modulation of cognitive flexibility changes with age.
Lawrence Berkeley National Laboratory, Berkeley, California 94720, and aberry@lbl.gov.|Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California 94720.
Anne S
0000-0002-5086-3643
AS
Berry
Lawrence Berkeley National Laboratory, Berkeley, California 94720, and.|Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California 94720.
Vyoma D
0000-0001-7322-0766
VD
Shah
Lawrence Berkeley National Laboratory, Berkeley, California 94720, and.
Suzanne L
0000-0003-0209-3127
SL
Baker
Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California 94720.
Jacob W
0000-0001-6394-9940
JW
Vogel
Lawrence Berkeley National Laboratory, Berkeley, California 94720, and.
James P
0000-0002-4980-4240
JP
O'Neil
Lawrence Berkeley National Laboratory, Berkeley, California 94720, and.
Mustafa
0000-0003-0134-0317
M
Janabi
Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California 94720.
Henry D
0000-0002-6055-6401
HD
Schwimmer
Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California 94720.
Shawn M
0000-0001-9884-8461
SM
Marks
Lawrence Berkeley National Laboratory, Berkeley, California 94720, and.|Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California 94720.
William J
0000-0002-4458-113X
WJ
Jagust
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging; D003071:Cognition / Q000502:physiology*; D004298:Dopamine / Q000096:biosynthesis / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000502:physiology*; D056344:Executive Function / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000502:physiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D017072:Neostriatum / Q000378:metabolism; D009483:Neuropsychological Tests; D010296:Parietal Lobe / Q000000981:diagnostic imaging / Q000502:physiology; D049268:Positron-Emission Tomography; D011930:Reaction Time / Q000502:physiology; D055815:Young Adult
D004298:Dopamine
PET; aging; cognitive flexibility; dopamine; fMRI; task switching