The relation among aging, dopamine-regulating genes, and neurocognition

When people are getting old, they often feel increasingly harder to concentrate, and become slower and more inflexible during tasks that involve focused attention, information maintenance in the face of distractions, and when fast switching according to changing goals is required. These cognitive functions are collectively referred to as working memory (WM). Both cross-sectional and longitudinal studies have reported WM impairment in aging. Moreover, aging is accompanied by alterations in brain structure, brain function, and dopaminergic neurotransmission. This thesis sought to link WM to brain structure, brain function, and dopamine (DA)-related genes in large samples of younger and older adults. The chief aims were to provide neural and genetic evidence to increase our understanding of the mechanisms of age-related deficits in WM.

The DRD2/ANKK1-Taq1A polymorphism has been associated with DA D2 receptor densities in caudate. In study I, we investigated the effects of this polymorphism on grey-matter (GM) volume in striatum in older adults, and examined whether the genetic effect interacts with age. Results showed that the A allele of the DRD2/ANKK1-Taq1A polymorphism was associated with smaller GM volume in caudate and this effect was only observed in older adults (>72 years).

The DRD2-C957T polymorphism has been linked to DA D2 receptor densities in both striatum and extrastriatal areas, such as in prefrontal cortex (PFC). In study II, we investigated the genetic effects of two DRD2 polymorphisms on WM functioning and examined how these effects may interact with adult age. In comparing younger and older adults, we found that the old had lower caudate activity in a highly demanding WM task. In addition, there were single and joint genetic effects of the two DRD2 polymorphisms on WM performance and frontostriatal brain activity. The genetic effects on brain function were observed in older, but not in younger adults, suggesting magnified genetic effects in aging.

In study III, we related white-matter integrity with WM performance in a large sample across a wide age range. Results demonstrated that WM was associated with white-matter integrity in multiple tracts, indicating that WM functioning relies on global structural connections among multiple brain regions. Moreover, white-matter integrity could partially account for the age-related difference in WM. The COMT-Val158Met polymorphism has been associated with PFC DA levels. In this study, we found genetic effects of COMT on white-matter microstructure, suggesting a relation between dopaminergic function and white-matter integrity.

In study IV, we investigated changes of white-matter integrity and WM performance using longitudinal data. We found that white-matter integrity declined across 10 years in the whole sample (25-80 years) and the decline was greater for older than for younger adults, reflecting a non-linear relation between age and white matter. More importantly, we found change – change associations of white-matter integrity and WM performance in several tracts including genu and body of corpus callosum and superior longitudinal fasciculus, suggesting that impaired WM performance in aging might reflect age-related decrease of white-matter integrity in these tracts. Collectively, these studies demonstrate age-related differences and changes in brain structure and brain function associated with impaired WM performance in aging.

The findings support and extend previous work on the roles of DA in WM functioning and brain integrity in aging, and contribute to our understanding of neural and genetic correlates of WM, and how these are affected in aging.

List of scientific papers

I. Li, X., Papenberg, G., Kalpouzos, G., Bäckman, L., and Persson, J. (2018). Influence of the DRD2/ANKK1 Taq1A polymorphism on caudate volume in older adults without dementia. Brain Structure and Function. 223(6), 2653-2662.
https://doi.org/10.1007/s00429-018-1650-0

II. Li, X., Bäckman, L., and Persson, J. (2019). The relationship of age and DRD2 polymorphisms to frontostriatal brain activity and working memory performance. Neurobiology of Aging. 84, 189-199.
https://doi.org/10.1016/j.neurobiolaging.2019.08.022

III. Li, X., Salami, A., Bäckman, L., and Persson, J. White-matter integrity and working memory: Relationships to aging and dopaminerelated genes. [Manuscript]

IV. Li, X., and Persson, J. Age-related changes in white-matter integrity and their associations with decline in working memory. [Manuscript]