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The architecture of the aging brain: functional reorganization, structural changes, and the role of dopamine receptors
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2023. , p. 104
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2254
Keywords [en]
brain architecture, functional connectivity, dopamine, aging, cognition, memory, functional magnetic resonance imaging, positron emission tomography, graph theory, Laplacian eigenmapping, gradient
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-212692ISBN: 978-91-8070-136-5 (print)ISBN: 978-91-8070-137-2 (electronic)OAI: oai:DiVA.org:umu-212692DiVA, id: diva2:1786376
Public defence
2023-09-01, Aula Biologica, Biologihuset, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2023-08-15 Created: 2023-08-08 Last updated: 2023-08-09Bibliographically approved
List of papers
1. When functional blurring becomes deleterious: Reduced system segregation is associated with less white matter integrity and cognitive decline in aging
Open this publication in new window or tab >>When functional blurring becomes deleterious: Reduced system segregation is associated with less white matter integrity and cognitive decline in aging
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2021 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 242, article id 118449Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Academic Press, 2021
Keywords
Cognitive aging, Functional segregation, Graph theory, Longitudinal study, Resting-state fMRI, White matter integrity
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-186591 (URN)10.1016/j.neuroimage.2021.118449 (DOI)000693220400018 ()34358662 (PubMedID)2-s2.0-85111920792 (Scopus ID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2021-08-13 Created: 2021-08-13 Last updated: 2023-08-08Bibliographically approved
2. Dopamine D1-signaling modulates maintenance of functional network segregation in aging
Open this publication in new window or tab >>Dopamine D1-signaling modulates maintenance of functional network segregation in aging
2023 (English)In: Aging Brain, ISSN 2589-9589, Vol. 3, article id 100079Article in journal (Refereed) Published
Abstract [en]

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. 

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Aging, D1DR, Dedifferentiation, Dopamine, Functional connectivity, Working memory
National Category
Neurosciences
Research subject
molecular medicine (medical sciences)
Identifiers
urn:nbn:se:umu:diva-212688 (URN)10.1016/j.nbas.2023.100079 (DOI)
Funder
Swedish Research Council, 2016–01936Knut and Alice Wallenberg FoundationRiksbankens Jubileumsfond, P20-0515
Available from: 2023-08-08 Created: 2023-08-08 Last updated: 2023-08-08Bibliographically approved
3. Dopamine D1-receptor organization contributes to functional brain architecture
Open this publication in new window or tab >>Dopamine D1-receptor organization contributes to functional brain architecture
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-212690 (URN)
Available from: 2023-08-08 Created: 2023-08-08 Last updated: 2023-08-09
4. Two long-axis dimensions of hippocampal cortical integration support memory functionacross the adult lifespan
Open this publication in new window or tab >>Two long-axis dimensions of hippocampal cortical integration support memory functionacross the adult lifespan
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-212691 (URN)
Available from: 2023-08-08 Created: 2023-08-08 Last updated: 2023-08-09

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Pedersen, Robin

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Department of Integrative Medical Biology (IMB)Umeå Centre for Functional Brain Imaging (UFBI)Wallenberg Centre for Molecular Medicine at Umeå University (WCMM)
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