| 41. |
- Papenberg, Goran, et al.
(författare)
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Genetics and Functional Imaging : Effects of APOE, BDNF, COMT, and KIBRA in Aging
- 2015
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Ingår i: Neuropsychology Review. - : Springer. - 1040-7308 .- 1573-6660. ; 25:1, s. 47-62
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Forskningsöversikt (refereegranskat)abstract
- Increasing evidence from cross-sectional and longitudinal molecular-genetic studies suggests that effects of common genetic variations on cognitive functioning increase with aging. We review the influence of candidate genes on brain functioning in old age, focusing on four genetic variations that have been extensively investigated: APOE, BDNF, COMT, and KIBRA. Similar to the behavioral evidence, there are reports from age-comparative studies documenting stronger genetic effects on measures of brain functioning in older adults compared to younger adults. This pattern suggests disproportionate impairments of neural processing among older individuals carrying disadvantageous genotypes. We discuss various factors, including gene-gene interactions, study population characteristics, lifestyle factors, and diseases, that need to be considered in future studies and may help understand inconsistent findings in the extant literature.
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| 42. |
- Papenberg, Goran, et al.
(författare)
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Mapping the landscape of human dopamine D2/3 receptors with [11C]raclopride
- 2019
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Ingår i: Brain Structure and Function. - : Springer Science and Business Media LLC. - 1863-2653 .- 1863-2661. ; 224:8, s. 2871-2882
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Tidskriftsartikel (refereegranskat)abstract
- The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show high density of D2/3 dopamine receptors (D2/3DR) in striatum, but also demonstrate the existence of such receptors across cortical and limbic regions. Assessment of D2/3DR BPND in the extrastriatal regions with [C-11]raclopride has long been considered unreliable due to the relatively low density of D2/3DR outside the striatum. We describe the distribution and interregional links of D2/3DR availability measured with PET and [C-11]raclopride across the human brain in a large sample (N = 176; age range 64-68 years). Structural equation modeling revealed that D2/3DR availability can be organized according to anatomical (nigrostriatal, mesolimbic, mesocortical) and functional (limbic, associative, sensorimotor) dopamine pathways. D2/3DR availability in corticolimbic functional subdivisions showed differential associations to corresponding striatal subdivisions, extending animal and pharmacological work. Our findings provide evidence on the dimensionality and organization of [C-11]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways.
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| 43. |
- Papenberg, Goran, et al.
(författare)
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The Influence of Hippocampal Dopamine D2 Receptors on Episodic Memory Is Modulated by BDNF and KIBRA Polymorphisms
- 2019
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Ingår i: Journal of cognitive neuroscience. - : MIT Press - Journals. - 0898-929X .- 1530-8898. ; 31:9, s. 1422-1429
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Tidskriftsartikel (refereegranskat)abstract
- Episodic memory is a polygenic trait influenced by different molecular mechanisms. We used PET and a candidate gene approach to investigate how individual differences at the molecular level translate into between-person differences in episodic memory performance of elderly persons. Specifically, we examined the interactive effects between hippocampal dopamine D2 receptor (D2DR) availability and candidate genes relevant for hippocampus-related memory functioning. We show that the positive effects of high D2DR availability in the hippocampus on episodic memory are confined to carriers of advantageous genotypes of the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. By contrast, these polymorphisms did not modulate the positive relationship between caudate D2DR availability and episodic memory.
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| 44. |
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| 45. |
- Pedersen, Robin, et al.
(författare)
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Dopamine D1-receptor organization contributes to functional brain architecture
- 2024
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 44:11
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Tidskriftsartikel (refereegranskat)abstract
- Recent work has recognized a gradient-like organization in cortical function, spanning from primary sensory to transmodal cortices. It has been suggested that this axis is aligned with regional differences in neurotransmitter expression. Given the abundance of dopamine D1-receptors (D1DR), and its importance for modulation and neural gain, we tested the hypothesis that D1DR organization is aligned with functional architecture, and that inter-regional relationships in D1DR co-expression modulate functional cross talk. Using the world's largest dopamine D1DR-PET and MRI database (N = 180%, 50% female), we demonstrate that D1DR organization follows a unimodal–transmodal hierarchy, expressing a high spatial correspondence to the principal gradient of functional connectivity. We also demonstrate that individual differences in D1DR density between unimodal and transmodal regions are associated with functional differentiation of the apices in the cortical hierarchy. Finally, we show that spatial co-expression of D1DR primarily modulates couplings within, but not between, functional networks. Together, our results show that D1DR co-expression provides a biomolecular layer to the functional organization of the brain.
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| 46. |
- Pedersen, Robin, et al.
(författare)
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Dopamine D1-signaling modulates maintenance of functional network segregation in aging
- 2023
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Ingår i: Aging Brain. - : Elsevier. - 2589-9589. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Past research has shown that as individuals age, there are decreases in within-network connectivity and increases in between-network connectivity, a pattern known as functional dedifferentiation. While the mechanisms behind reduced network segregation are not fully understood, evidence suggests that age-related differences in the dopamine (DA) system may play a key role. The DA D1-receptor (D1DR) is the most abundant and age-sensitive receptor subtype in the dopaminergic system, known to modulate synaptic activity and enhance the specificity of the neuronal signals. In this study from the DyNAMiC project (N = 180, 20-79y), we set out to investigate the interplay among age, functional connectivity, and dopamine D1DR availability. Using a novel application of multivariate Partial Least squares (PLS), we found that older age, and lower D1DR availability, were simultaneously associated with a pattern of decreased within-network and increased between-network connectivity. Individuals who expressed greater distinctiveness of large-scale networks exhibited more efficient working memory. In line with the maintenance hypotheses, we found that older individuals with greater D1DR in caudate exhibited less dedifferentiation of the connectome, and greater working memory, compared to their age-matched counterparts with less D1DR. These findings suggest that dopaminergic neurotransmission plays an important role in functional dedifferentiation in aging with consequences for working memory function at older age.
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| 47. |
- Pedersen, Robin, 1989-
(författare)
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The architecture of the aging brain : functional reorganization, structural changes, and the role of dopamine receptors
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aging is associated with reorganization of functional brain architecture, potentially leading tocognitive decline in older age. However, the mechanisms responsible for alterations in functionalbrain architecture remain poorly understood. Using a combination of multimodal neuroimagingtechniques and advanced statistical analyses in four independent studies, this thesis aims tocontribute to our understanding of age-related alterations in functional brain architecture andcognitive decline. Study I demonstrated age-related decline in functional brain network segregationin a longitudinal setting. Age-related changes in network segregation were associated withconcomitant losses of white matter integrity and domain-general cognitive function. Study II testedthe hypothesis that older age and lower dopamine D1-receptor (D1DR) availability concomitantly arerelated to less segregated network structure in older age. The results supported the hypothesis,revealing that greater D1DR availability in older age is associated with a more youth-like functionalarchitecture and greater working memory performance compared to age-matched counterparts withless D1DR. Study III further assessed the relationship between D1DR organization and functionalarchitecture. Using a non-linear decomposition method, we demonstrate that the spatial coexpression and distribution of D1DRs are aligned with the principal organization of brain function.Individual differences in D1DR distribution were related to the degree of functional differentiationbetween unimodal and transmodal cortices. Study IV investigated age-related differences in thefunctional organization of the hippocampus, revealing three overlapping modes of organization. Amedial-to-anterior and posterior mode largely corresponded to macroscale cortical organization ofconnectivity, aligned with local D1DR topography. Older age was associated with less distinctorganization of cortico-hippocampal connectivity, and maintenance of youth-like hippocampalorganization in older age was related to superior episodic memory function. Collectively, this thesisoffers multiple lines of evidence for age-related alterations in functional brain organization,associations with white-matter integrity and cognitive function, in addition to a novel link betweenfunctional brain architecture and the D1DR system.
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| 48. |
- Pedersen, Robin, et al.
(författare)
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When functional blurring becomes deleterious : Reduced system segregation is associated with less white matter integrity and cognitive decline in aging
- 2021
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 242
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Tidskriftsartikel (refereegranskat)abstract
- Healthy aging is accompanied by progressive decline in cognitive performance and concomitant changes in brain structure and functional architecture. Age-accompanied alterations in brain function have been characterized on a network level as weaker functional connections within brain networks along with stronger interactions between networks. This phenomenon has been described as age-related differences in functional network segregation. It has been suggested that functional networks related to associative processes are particularly sensitive to age-related deterioration in segregation, possibly related to cognitive decline in aging. However, there have been only a few longitudinal studies with inconclusive results. Here, we used a large longitudinal sample of 284 participants between 25 to 80 years of age at baseline, with cognitive and neuroimaging data collected at up to three time points over a 10-year period. We investigated age-related changes in functional segregation among two large-scale systems comprising associative and sensorimotor-related resting-state networks. We found that functional segregation of associative systems declines in aging with exacerbated deterioration from the late fifties. Changes in associative segregation were positively associated with changes in global cognitive ability, suggesting that decreased segregation has negative consequences for domain-general cognitive functions. Age-related changes in system segregation were partly accounted for by changes in white matter integrity, but white matter integrity only weakly influenced the association between segregation and cognition. Together, these novel findings suggest a cascade where reduced white-matter integrity leads to less distinctive functional systems which in turn contributes to cognitive decline in aging.
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| 49. |
- Salami, Alireza, et al.
(författare)
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A Multivariate Analysis of Age-Related Differences in Functional Networks Supporting Conflict Resolution
- 2014
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Ingår i: NeuroImage. - San Diego : Academic Press. - 1053-8119 .- 1095-9572. ; 86, s. 150-163
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Tidskriftsartikel (refereegranskat)abstract
- Functional neuroimaging studies demonstrate age-related differences in recruitment of a large-scale attentional network during interference resolution, especially within dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). These alterations in functional responses have been frequently observed despite equivalent task performance, suggesting age-related reallocation of neural resources, although direct evidence for a facilitating effect in aging is sparse. We used the multi-source interference task and multivariate partial-least-squares to investigate age-related differences in the neuronal signature of conflict resolution, and their behavioral implications in younger and older adults. There were interference-related increases in activity, involving fronto-parietal and basal ganglia networks that generalized across age. In addition an age-by-task interaction was observed within a distributed network, including DLPFC and ACC, with greater activity during interference in the old. Next, we combined brain–behavior and functional connectivity analyses to investigate whether compensatory brain changes were present in older adults, using DLPFC and ACC as regions of interest (i.e. seed regions). This analysis revealed two networks differentially related to performance across age groups. A structural analysis revealed age-related gray-matter losses in regions facilitating performance in the young, suggesting that functional reorganization may partly reflect structural alterations in aging. Collectively, these findings suggest that age-related structural changes contribute to reductions in the efficient recruitment of a youth-like interference network, which cascades into instantiation of a different network facilitating conflict resolution in elderly people.
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| 50. |
- Salami, Alireza, et al.
(författare)
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Age-related white matter microstructural differences partly mediate age-related decline in processing speed but not cognition
- 2012
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Ingår i: Biochimica et Biophysica Acta - Molecular Basis of Disease. - : Elsevier. - 0925-4439 .- 1879-260X. ; 1822:3, s. 408-415
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Tidskriftsartikel (refereegranskat)abstract
- Aging is associated with declining cognitive performance as well as structural changes in brain gray and white matter (WM). The WM deterioration contributes to a disconnection among distributed brain networks and may thus mediate age-related cognitive decline. The present diffusion tensor imaging (DTI) study investigated age-related differences in WM microstructure and their relation to cognition (episodic memory, visuospatial processing, fluency, and speed) in a large group of healthy subjects (n = 287) covering 6 decades of the human life span. Age related decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) were observed across the entire WM skeleton as well as in specific WM tracts, supporting the WM degeneration hypothesis. The anterior section of the corpus callosum was more susceptible to aging compared to the posterior section, lending support to the anterior-posterior gradient of WM integrity in the corpus callosum. Finally, and of critical interest. WM integrity differences were found to mediate age-related reductions in processing speed but no significant mediation was found for episodic memory, visuospatial ability, or fluency. These findings suggest that compromised WM integrity is not a major contributing factor to declining cognitive performance in normal aging. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.
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