Linking cognitive aging to alterations in dopamine neurotransmitter functioning: Recent data and future avenues

Bäckman, Lars; Lindenberger, Ulman; Li, Shu-Chen; Nyberg, Lars

doi:10.1016/j.neubiorev.2009.12.008

Cited by 359 publications

(304 citation statements)

References 103 publications

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“…This pattern of results (and our subsequent statistical examination of this effect; Fig. S4) is consistent with the general notion of an inverted-U-shaped DA curve (10,13,14), now linking DA and SD BOLD . These AMPH-related effects were found within several brain regions typically associated with WM in mean BOLD activation studies (25, 26) and/or DA (13,14,27), including bilateral middle frontal gyri (DLPFC), left SMA, bilateral posterior parietal cortices, and striatum (left putamen/left caudate nucleus).…”

Section: Discussionsupporting

confidence: 88%

“…However, it is not yet known whether DA affects brain signal variability in relation to age and performance. DA is generally considered a neuromodulator supporting both system stability (e.g., signal "fidelity," "precision," and "signal-to-noise ratio") and flexibility/adaptability (8)(9)(10)(12)(13)(14). Single-unit and multiunit computational models demonstrate that simulated aging-related DA losses can yield more inefficient stimulus detection, lower average neuronal firing pattern, and dedifferentiation of neural responses in the face of varying stimuli (8).…”

mentioning

confidence: 99%

“…DA neuromodulation is a leading mechanistic candidate for age-related cognitive losses (8)(9)(10). Concurrent with substantia nigra and ventral tegmental DA neuron loss, D 1 and D 2 receptor densities reduce notably from early to late adulthood across various subcortical and cortical regions (9)(10)(11).…”

mentioning

confidence: 99%

“…Concurrent with substantia nigra and ventral tegmental DA neuron loss, D 1 and D 2 receptor densities reduce notably from early to late adulthood across various subcortical and cortical regions (9)(10)(11). However, it is not yet known whether DA affects brain signal variability in relation to age and performance.…”

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confidence: 99%

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Amphetamine modulates brain signal variability and working memory in younger and older adults

Garrett

Nagel

Preuschhof

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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106

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Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI-based blood oxygen level-dependent (BOLD) signal variability (SD BOLD ) in younger and older adults during a working memory task (letter n-back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SD BOLD levels in the presence of AMPH. Drug session order greatly moderated change-change relations between AMPH-driven SD BOLD and reaction time means (RT mean ) and SDs (RT SD ). Older adults who received AMPH in the first session tended to improve in RT mean and RT SD when SD BOLD was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SD BOLD decreased (for RT mean ) or no effect at all (for RT SD ). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state-and practice-dependent neurochemical basis of human brain dynamics.brain signal variability | dopamine | aging | working memory | fMRI H uman brain signals are characteristically variable and dynamic, at a variety of timescales and levels of analysis (1, 2). For decades, age-related cognitive deficits have been conceptualized as due to various forms of "noisy," inefficient neural processing (3, 4). However, the preponderance of available neuroimaging work on brain signal variability and aging indicates that healthy, higher performing, younger adults typically express more signal variability across trials and time in a variety of cortical regions relative to older, poorer performers (2, 5-7). Theoretical and computational explanations of this finding include notions such as flexibility/adaptability, dynamic range, Bayesian optimality, and multistability (2), but empirically supported mechanisms for age and performance-graded differences in human brain signal dynamics are not yet available. Dopamine (DA) neuromodulation may provide one such mechanism.DA neuromodulation is a leading mechanistic candidate for age-related cognitive losses (8-10). Concurrent with substantia nigra and ventral tegmental DA neuron loss, D 1 and D 2 receptor densities reduce notably from early to late adulthood acro...

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Amphetamine modulates brain signal variability and working memory in younger and older adults

Garrett

Nagel

Preuschhof

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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106

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“…This pattern of age differences provides further support for the resource modulation hypothesis, which posits that effects of common genetic polymorphisms on cognition are stronger in populations with reduced brain resources, such as older adults . Healthy aging is associated with marked decline in dopaminergic neuromodulation (Bäckman et al, 2006(Bäckman et al, , 2010. Similarly, NMDA receptor efficacy declines with advancing adult age, as documented in both animal and human studies (for a review, see Magnusson et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Dopamine and glutamate receptor genes interactively influence episodic memory in old age

Papenberg¹,

Li²,

Nagel³

et al. 2014

Neurobiology of Aging

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a b s t r a c tBoth the dopaminergic and glutamatergic systems modulate episodic memory consolidation. Evidence from animal studies suggests that these two neurotransmitters may interact in influencing memory performance. Given that individual differences in episodic memory are heritable, we investigated whether variations of the dopamine D2 receptor gene (rs6277, C957T) and the N-methyl-D-aspartate 3A (NR3A) gene, coding for the N-methyl-D-aspartate 3A subunit of the glutamate N-methyl-D-aspartate receptor (rs10989591, Val362Met), interactively modulate episodic memory in large samples of younger (20e31 years; n ¼ 670) and older (59e71 years; n ¼ 832) adults. We found a reliable gene-gene interaction, which was observed in older adults only: older individuals carrying genotypes associated with greater D2 and N-methyl-D-aspartate receptor efficacy showed better episodic performance. These results are in line with findings showing magnification of genetic effects on memory in old age, presumably as a consequence of reduced brain resources. Our findings underscore the need for investigating interactive effects of multiple genes to understand individual difference in episodic memory.

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Moderators of Remission in Patients With Late-Life Depression

Taylor

2016

JAMA Psychiatry

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Linking cognitive aging to alterations in dopamine neurotransmitter functioning: Recent data and future avenues

Cited by 359 publications

References 103 publications

Amphetamine modulates brain signal variability and working memory in younger and older adults

Amphetamine modulates brain signal variability and working memory in younger and older adults

Dopamine and glutamate receptor genes interactively influence episodic memory in old age

Moderators of Remission in Patients With Late-Life Depression

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