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5 - Cognitive Aging: The Role of Neurotransmitter Systems

from Part I - Models of Cognitive Aging

Published online by Cambridge University Press:  28 May 2020

Ayanna K. Thomas
Affiliation:
Tufts University, Massachusetts
Angela Gutchess
Affiliation:
Brandeis University, Massachusetts
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Summary

Much of the extant work in the cognitive neurosciences of aging has focused on identifying the neural correlates of age-related declines in episodic memory and working memory. This chapter reviews evidence from human studies that speaks to the hypothesis that age-related dysfunctions in specific neurotransmitter systems play a critical role in cognitive decline. Based in large part on results from functional neuroimaging studies including positron emission tomography (PET) and pharmacological functional magnetic resonance imaging (fMRI), we conclude that there is emerging evidence that dysfunctions in the dopamine, noradrenaline, and cholinergic systems play a critical role in age-related cognitive decline of working memory and episodic memory. These conclusions are important and encourage further study in order to tailor interventions that preserve cognitive functions in older age via augmentation of neurotransmitter functions.

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The Cambridge Handbook of Cognitive Aging
A Life Course Perspective
, pp. 82 - 100
Publisher: Cambridge University Press
Print publication year: 2020

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References

Aalto, S., Brück, A., Laine, M., Någren, K., & Rinne, J. O. (2005). Frontal and temporal dopamine release during working memory and attention tasks in healthy humans: A positron emission tomography study using the high-affinity dopamine D2 receptor ligand [11C]FLB 457. Journal of Neuroscience, 25(10), 24712477. https://doi.org/10.1523/JNEUROSCI.2097-04.2005CrossRefGoogle Scholar
Atri, A., Sherman, S., Norman, K. A., et al. (2004). Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task. Behavioral Neuroscience, 118(1), 223236. http://dx.doi.org/10.1037/0735-7044.118.1.223CrossRefGoogle Scholar
Bäckman, L., Ginovart, N., Dixon, R. A., et al. (2000). Age-related cognitive deficits mediated by changes in the striatal dopamine system. American Journal of Psychiatry, 157(4), 635637. https://doi.org/10.1176/ajp.157.4.635Google Scholar
Bäckman, L., Karlsson, S., Fischer, H., et al. (2011). Dopamine D(1) receptors and age differences in brain activation during working memory. Neurobiology of Aging, 32(10), 18491856. https://doi.org/10.1016/j.neurobiolaging.2009.10.018Google Scholar
Bäckman, L., Lindenberger, U., Li, S. C., & Nyberg, L. (2010). Linking cognitive aging to alterations in dopamine neurotransmitter functioning: Recent data and future avenues. Neuroscience and Biobehavioral Reviews, 34(5), 670677. https://doi.org/10.1016/j.neubiorev.2009.12.008CrossRefGoogle ScholarPubMed
Bäckman, L., Nyberg, L., Lindenberger, U., Li, S. C., & Farde, L. (2006). The correlative triad among aging, dopamine, and cognition: Current status and future prospects. Neuroscience and Biobehavioral Reviews, 30(6), 791807. https://doi.org/10.1016/j.neubiorev.2006.06.005Google Scholar
Bartus, R. T., Dean, R. L. 3rd, Beer, B., & Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science, 217(4558), 408414. https://doi.org/10.1126/science.7046051CrossRefGoogle ScholarPubMed
Bentley, P., Driver, J., & Dolan, R. J. (2011). Cholinergic modulation of cognition: Insights from human pharmacological functional neuroimaging. Progress in Neurobiology, 94(4), 360388. https://doi.org/10.1016/j.pneurobio.2011.06.002CrossRefGoogle ScholarPubMed
Berry, A. S., Shah, V. D., Furman, D. J., et al. (2018a). Dopamine synthesis capacity is associated with D2/3 receptor binding but not dopamine release. Neuropsychopharmacology, 43(6), 12011211. https://doi.org/10.1038/npp.2017Google Scholar
Berry, A. S., Shah, V. D., & Jagust, W. J. (2018b). The influence of dopamine on cognitive flexibility is mediated by functional connectivity in young but not older adults. Journal of Cognitive Neuroscience, 30(9), 115. https://doi.org/10.1162/jocn_a_01286Google Scholar
Björklund, A., & Dunnett, S. B. (2007). Dopamine neuron systems in the brain: An update. Trends in Neurosciences, 30(5), 194202. https://doi.org/10.1016/j.tins.2007.03.006CrossRefGoogle ScholarPubMed
Bolam, J. P., Hanley, J. J., Booth, P. A. C., & Bevan, M. D. (2000). Synaptic organisation of the basal ganglia. Journal of Anatomy, 196(4), 527542. https://doi.org/10.1046/j.1469-7580.2000.19640527.xGoogle Scholar
Braak, H., Thal, D. R., Ghebremedhin, E., & Del Tredici, K. (2011). Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years. Journal of Neuropathology and Experimental Neurology, 70(11), 960969. https://doi.org/10.1097/NEN.0b013e318232a379Google Scholar
Brozoski, T. J., Brown, R. M., Rosvold, H. E., & Goldman, P. S. (1979). Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science, 205(4409), 929932. https://doi.org/10.1126/science.112679CrossRefGoogle ScholarPubMed
Carlsson, A., & Winblad, B. (1976). Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia. Journal of Neural Transmission, 38(3–4), 271276. https://doi.org/10.1007/BF01249444Google Scholar
Chandler, D. J. (2016). Evidence for a specialized role of the locus coeruleus noradrenergic system in cortical circuitries and behavioral operations. Brain Research, 1641(Pt. B), 197206. https://doi.org/10.1016/j.brainres.2015.11.022Google Scholar
Chowdhury, R., Guitart-Masip, M., Bunzeck, N., Dolan, R. J., & Düzel, E. (2012). Dopamine modulates episodic memory persistence in old age. Journal of Neuroscience, 32(41), 1419314204. https://doi.org/10.1523/JNEUROSCI.1278-12.2012CrossRefGoogle ScholarPubMed
Clewett, D. V., Lee, T. H., Greening, S., et al. (2016). Neuromelanin marks the spot: Identifying a locus coeruleus biomarker of cognitive reserve in healthy aging. Neurobiology of Aging, 37, 117126. https://doi.org/10.1016/j.neurobiolaging.2015.09.019Google Scholar
Cools, R., & D’Esposito, M. (2011). Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biological Psychiatry, 69(12), 113125. https://doi.org/10.1016/j.biopsych.2011.03.028Google Scholar
Decker, M. W. (1987). The effects of aging on hippocampal and cortical projections of the forebrain cholinergic system. Brain Research Reviews, 12(4), 423438. https://doi.org/10.1016/0165-0173(87)90007-5Google Scholar
Dewey, S. L., Volkow, N. D., Logan, J., et al. (1990). Age-related decreases in muscarinic cholinergic receptor binding in the human brain measured with positron emission tomography (PET). Journal of Neuroscience Research, 27(4), 569575. https://doi.org/10.1002/jnr.490270418Google Scholar
Drachman, D. A., & Leavitt, J. (1974). Human memory and the cholinergic system: A relationship to aging? Archives of Neurology, 30(2), 113121. https://doi.org/10.1001/archneur.1974.00490320001001CrossRefGoogle ScholarPubMed
Dumas, J. A., Saykin, A. J., McDonald, B. C., et al. (2008). Nicotinic versus muscarinic blockade alters verbal working memory-related brain activity in older women. American Journal of Geriatric Psychiatry, 16(4), 272282. https://doi.org/10.1097/JGP.0b013e3181602a2bCrossRefGoogle ScholarPubMed
Durstewitz, D., Seamans, J. K., & Sejnowski, T. J. (2000). Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex. Journal of Neurophysiology, 83(3), 17331750. https://doi.org/10.1152/jn.2000.83.3.1733Google Scholar
Eriksson, J., Vogel, E. K., Lansner, A., Bergström, F., & Nyberg, L. (2015). Neurocognitive architecture of working memory. Neuron, 88(1), 3346. https://doi.org/10.1016/j.neuron.2015.09.020Google Scholar
Fearnley, J. M., & Lees, A. J. (1991). Ageing and Parkinson’s disease: Substantia nigra regional selectivity. Brain, 114(5), 22832301. https://doi.org/10.1093/brain/114.5.2283Google Scholar
Fischer, H., Nyberg, L., Karlsson, S., et al. (2010). Simulating neurocognitive aging: Effects of a dopaminergic antagonist on brain activity during working memory. Biological Psychiatry, 67(6), 575580. https://doi.org/10.1016/j.biopsych.2009.12.013Google Scholar
Floel, A., Garraux, G., Xu, B., et al. (2008). Levodopa increases memory encoding and dopamine release in the striatum in the elderly. Neurobiology of Aging, 29, 267279. https://doi.org/10.1016/j.neurobiolaging.2006.10.009Google Scholar
Garrett, D. D., Nagel, I. E., Preuschhof, C., et al. (2015). Amphetamine modulates brain signal variability and working memory in younger and older adults. Proceedings of the National Academy of Sciences USA, 112(24), 75937598. https://doi.org/10.1073/pnas.1504090112CrossRefGoogle ScholarPubMed
Hall, H., Sedvall, G., Magnusson, O., et al. (1994). Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain. Neuropsychopharmacology, 11(4), 245256. https://doi.org/10.1038/sj.npp.1380111CrossRefGoogle ScholarPubMed
Hämmerer, D., Callaghan, M. F., Hopkins, A., et al. (2018). Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events. Proceedings of the National Academy of Sciences USA, 115(9), 22282233. https://doi.org/10.1073/pnas.1712268115CrossRefGoogle ScholarPubMed
Hasselmo, M. E. (2006). The role of acetylcholine in learning and memory. Current Opinion in Neurobiology, 16(6), 710715. https://doi.org/10.1016/j.conb.2006.09.002Google Scholar
Hasselmo, M. E., & Sarter, M. (2011). Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology, 36(1), 5273. https://doi.org/10.1038/npp.2010.104CrossRefGoogle ScholarPubMed
Karlsson, S., Nyberg, L., Karlsson, P., et al. (2009). Modulation of striatal dopamine D1 binding by cognitive processing. NeuroImage, 48(2), 398404. https://doi.org/10.1016/j.neuroimage.2009.06.030CrossRefGoogle ScholarPubMed
Karrer, T. M., Josef, A. K., Mata, R., Morris, E. D., & Samanez-Larkin, G. R. (2017). Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: A meta-analysis. Neurobiology of Aging, 57, 3646. https://doi.org/10.1016/j.neurobiolaging.2017.05.006CrossRefGoogle Scholar
Koepp, M. J., Gunn, R. N., Lawrence, A. D., et al. (1998). Evidence for striatal dopamine release during a video game. Nature, 393(6682), 266268. https://doi.org/10.1038/30498Google Scholar
Kuhl, D. E., Minoshima, S., Fessler, J. A., et al. (1996). In vivo mapping of cholinergic terminals in normal aging, Alzheimer’s disease, and Parkinson’s disease. Annals of Neurology, 40(3), 399410. https://doi.org/10.1002/ana.410400309Google Scholar
Landau, S. M., Lal, R., O’Neil, J. P., Baker, S., & Jagust, W. J. (2009). Striatal dopamine and working memory. Cerebral Cortex, 19(2), 445454. https://doi.org/10.1093/cercor/bhn095Google Scholar
Laruelle, M. (2000). Imaging synaptic neurotransmission with in vivo binding competition techniques: A critical review. Journal of Cerebral Blood Flow and Metabolism, 20(3), 423451. https://doi.org/10.1097/00004647-200003000-00001Google Scholar
Lee, T. H., Greening, S. G., Ueno, T., et al. (2018). Arousal increases neural gain via the locus coeruleus–noradrenaline system in younger adults but not in older adults. Nature Human Behaviour, 2(5), 356366. https://doi.org/10.1038/s41562-018-0344-1Google Scholar
Lisman, J., Grace, A. A., & Düzel, E. (2011). A neoHebbian framework for episodic memory; role of dopamine-dependent late LTP. Trends in Neurosciences, 34(10), 536547. https://doi.org/10.1016/j.tins.2011.07.006CrossRefGoogle ScholarPubMed
Mather, M., & Carstensen, L. L. (2005). Aging and motivated cognition: The positivity effect in attention and memory. Trends in Cognitive Sciences, 9(10), 496502. https://doi.org/10.1016/j.tics.2005.08.005Google Scholar
Mather, M., & Harley, C. W. (2016). The locus coeruleus: Essential for maintaining cognitive function and the aging brain. Trends in Cognitive Sciences, 20(3), 214226. https://doi.org/10.1016/j.tics.2016.01.001Google Scholar
Mattay, V. S., Fera, F., Tessitore, A., et al. (2006). Neurophysiological correlates of age-related changes in working memory capacity. Neuroscience Letters, 392(1–2), 3237. https://doi.org/10.1016/j.neulet.2005.09.025Google Scholar
McNamara, C. G., & Dupret, D. (2017). Two sources of dopamine for the hippocampus. Trends in Neurosciences, 40(7), 383384. https://doi.org/10.1016/j.tins.2017.05.005Google Scholar
Mitsis, E. M., Cosgrove, K. P., Staley, J. K., et al. (2009). Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT. Neurobiology of Aging, 30(9), 14901497. https://doi.org/10.1016/j.neurobiolaging.2007.12.008Google Scholar
Monchi, O., Hyun Ko, J., & Strafella, A. P. (2006). Striatal dopamine release during performance of executive functions: A [11C] raclopride PET study. NeuroImage, 33(3), 907912. https://doi.org/10.1016/j.neuroimage.2006.06.058Google Scholar
Morcom, A. M., Bullmore, E. T., Huppert, F. A., et al. (2009). Memory encoding and dopamine in the aging brain: A psychopharmacological neuroimaging study. Cerebral Cortex, 20(3), 743757. https://doi.org/10.1093/cercor/bhp139Google Scholar
Moriguchi, S., Yamada, M., Takano, H., et al. (2017). Norepinephrine transporter in major depressive disorder: A PET study. American Journal of Psychiatry, 174(1), 3641. https://doi.org/10.1176/appi.ajp.2016.15101334Google Scholar
Nordberg, A. (1999). PET studies and cholinergic therapy in Alzheimer’s disease. Revue Neurologique, 155(Suppl. 4), 5363. https://doi.org/10.1016/S0338-9898(99)80366-7Google Scholar
Nyberg, L., Andersson, M., Kauppi, K., et al. (2014). Age-related and genetic modulation of frontal cortex efficiency. Journal of Cognitive Neuroscience, 26(4), 746754. https://doi.org/10.1162/jocn_a_00521Google Scholar
Nyberg, L., Karalija, N., Salami, A., et al. (2016). Dopamine D2 receptor availability is linked to hippocampal-caudate functional connectivity and episodic memory. Proceedings of the National Academy of Sciences USA, 113(28), 79187923. https://doi.org/10.1073/pnas.1606309113Google Scholar
Onur, Ö. A., Piefke, M., Lie, C. H., et al. (2011). Modulatory effects of levodopa on cognitive control in young but not in older subjects: A pharmacological fMRI study. Journal of Cognitive Neuroscience, 23(10), 27972810. https://doi.org/10.1162/jocn.2011.21603CrossRefGoogle Scholar
O’Reilly, R. C., & Frank, M. J. (2006). Making working memory work: A computational model of learning in the prefrontal cortex and basal ganglia. Neural Computation, 18(2), 283328. https://doi.org/10.1162/089976606775093909Google Scholar
Persson, J., Kalpouzos, G., Nilsson, L. G., Ryberg, M., & Nyberg, L. (2011). Preserved hippocampus activation in normal aging as revealed by fMRI. Hippocampus, 21(7), 753766. https://doi.org/10.1002/hipo.20794Google Scholar
Picciotto, M. R., Higley, M. J., & Mineur, Y. S. (2012). Acetylcholine as a neuromodulator: Cholinergic signaling shapes nervous system function and behavior. Neuron, 76(1), 116129. https://doi.org/10.1016/j.neuron.2012.08.036CrossRefGoogle ScholarPubMed
Reeves, S., Bench, C., & Howard, R. (2002). Ageing and the nigrostriatal dopaminergic system. International Journal of Geriatric Psychiatry, 17(4), 359370. https://doi.org/10.1002/gps.606CrossRefGoogle ScholarPubMed
Reuter-Lorenz, P. A., & Cappell, K. A. (2008). Neurocognitive aging and the compensation hypothesis. Current Directions in Psychological Science, 17(3), 177182. https://doi.org/10.1111/j.1467-8721.2008.00570.xCrossRefGoogle Scholar
Rieckmann, A., Buckner, R. L., & Hedden, T. (2016). Molecular imaging of aging and neurodegenerative disease. In Cabeza, R., Nyberg, L., & Park, D. C. (Eds.), Cognitive neuroscience of aging (2nd ed., pp. 3569). New York: Oxford University Press.Google Scholar
Rieckmann, A., Karlsson, S., Karlsson, P., et al. (2011). Dopamine D1 receptor associations within and between dopaminergic pathways in younger and elderly adults: Links to cognitive performance. Cerebral Cortex, 21(9), 20232032. https://doi.org/10.1093/cercor/bhq266Google Scholar
Robertson, I. H. (2013). A noradrenergic theory of cognitive reserve: Implications for Alzheimer’s disease. Neurobiology of Aging, 34(1), 298308. https://doi.org/10.1016/j.neurobiolaging.2012.05.019Google Scholar
Sara, S. J., & Bouret, S. (2012). Orienting and reorienting: The locus coeruleus mediates cognition through arousal. Neuron, 76(1), 130141. https://doi.org/10.1016/j.neuron.2012.09.011Google Scholar
Sawaguchi, T., & Goldman-Rakic, P. (1991). D1 dopamine receptors in prefrontal cortex: Involvement in working memory. Science, 251(4996), 947950. https://doi.org/10.1126/science.1825731Google Scholar
Schliebs, R., & Arendt, T. (2011). The cholinergic system in aging and neuronal degeneration. Behavioural Brain Research, 221(2), 555563. https://doi.org/10.1016/j.bbr.2010.11.058Google Scholar
Schwarz, L. A., & Luo, L. (2015). Organization of the locus coeruleus-norepinephrine system. Current Biology, 25(21), R1051R1056. https://doi.org/10.1016/j.cub.2015.09.039Google Scholar
Segal, S. K., Stark, S. M., Kattan, D., Stark, C. E., & Yassa, M. A. (2012). Norepinephrine-mediated emotional arousal facilitates subsequent pattern separation. Neurobiology of Learning and Memory, 97(4), 465469. https://doi.org/10.1016/j.nlm.2012.03.010CrossRefGoogle ScholarPubMed
Servan-Schreiber, D., Printz, H., & Cohen, J. (1990). A network model of catecholamine effects: Gain, signal-to-noise ratio, and behavior. Science, 249(4971), 892895. https://doi.org/10.1126/science.2392679Google Scholar
Shibata, E., Sasaki, M., Tohyama, K., et al. (2006). Age-related changes in locus ceruleus on neuromelanin magnetic resonance imaging at 3 Tesla. Magnetic Resonance in Medical Sciences, 5(4), 197200. https://doi.org/10.2463/mrms.5.197Google Scholar
Shohamy, D., & Adcock, R. A. (2010). Dopamine and adaptive memory. Trends in Cognitive Sciences, 14(10), 464472. https://doi.org/10.1016/j.tics.2010.08.002CrossRefGoogle ScholarPubMed
Sperling, R. A., Bates, J. F., Chua, E. F., et al. (2003). fMRI studies of associative encoding in young and elderly controls and mild Alzheimer’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 74(1), 4450. http://dx.doi.org/10.1136/jnnp.74.1.44Google Scholar
Sperling, R. A., Greve, D., Dale, A., et al. (2002). Functional MRI detection of pharmacologically induced memory impairment. Proceedings of the National Academy of Sciences USA, 99(1), 455460. https://doi.org/10.1073/pnas.012467899Google Scholar
Strange, B. A., & Dolan, R. J. (2004). Beta-adrenergic modulation of emotional memory-evoked human amygdala and hippocampal responses. Proceedings of the National Academy of Sciences USA, 101(31), 1145411458. https://doi.org/10.1073/pnas.0404282101CrossRefGoogle ScholarPubMed
Takahashi, H., Kato, M., Takano, H., et al. (2008). Differential contributions of prefrontal and hippocampal dopamine D(1) and D(2) receptors in human cognitive functions. Journal of Neuroscience, 28(46), 1203212038. https://doi.org/10.1523/JNEUROSCI.3446-08.2008Google Scholar
Tully, K., & Bolshakov, V. Y. (2010). Emotional enhancement of memory: How norepinephrine enables synaptic plasticity. Molecular Brain, 3(1), p. 15. https://doi.org/10.1186/1756-6606-3-15Google Scholar
Vijayashankar, N., & Brody, H. (1979). A quantitative study of the pigmented neurons in the nuclei locus coeruleus and subcoeruleus in man as related to aging. Journal of Neuropathology and Experimental Neurology, 38(5), 490497. https://doi.org/10.1097/00005072-197909000-00004Google Scholar
Voss, B., Thienel, R., Reske, M., et al. (2012). Cholinergic blockade under working memory demands encountered by increased rehearsal strategies: Evidence from fMRI in healthy subjects. European Archives of Psychiatry and Clinical Neuroscience, 262(4), 329339. https://doi.org/10.1007/s00406-011-0267-6Google Scholar
Whitehouse, P. J., Price, D. L., Struble, R. G., et al. (1982). Alzheimer’s disease and senile dementia: Loss of neurons in the basal forebrain. Science, 215(4537), 12371239. https://doi.org/10.1126/science.7058341Google Scholar
Wilson, R. S., Nag, S., Boyle, P. A., et al. (2013). Neural reserve, neuronal density in the locus ceruleus, and cognitive decline. Neurology, 80(13), 12021208. https://doi.org/10.1212/WNL.0b013e3182897103Google Scholar
Wittmann, B. C., Schott, B. H., Guderian, S., et al. (2005). Reward-related FMRI activation of dopaminergic midbrain is associated with enhanced hippocampus-dependent long-term memory formation. Neuron, 45(3), 459467. https://doi.org/10.1016/j.neuron.2005.01.010Google Scholar
Yassa, M. A., & Stark, C. E. L. (2011). Pattern separation in the hippocampus. Trends in Neurosciences, 34(10), 515525. https://doi.org/10.1016/j.tins.2011.06.006CrossRefGoogle ScholarPubMed

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