Can reduced dopamine availability and disrupted functional brain connectome serve as biomarkers for cognitive decline in aging?
Cognitive impairments impede the functioning of older people and create major individual and societal costs. Developing ways to preserve functioning in old age is thus of great importance. However, knowledge about brain mechanisms that underlie cognitive decline is insufficient to enable effective intervention programs. Changes in functional neural connectivity—the cross-talk between distant brain regions that collectively constitutes the human connectome—measured by functional MRI across different mental states, may be a potential mechanism underlying cognitive decline in aging. However, evidence relating age-related cognitive impairment to disruptions in functional connectome is sparse. In addition, the molecular underpinnings of age-related alterations in functional connectome are largely unknown. This stems from a lack of comprehensive integration of age-related changes in neurotransmitters measured by different dopaminergic markers (D1- and D2-like receptors), in relation to changes in connectome and cognitive deficits. Due to this omission, many scientific questions remain inconclusive: To what extent do age-related neurochemical deficits cause functional alterations? Do dopaminergic deficits and concomitant disruptive alterations in connectome mediate cognitive decline in aging, and how do these changes interrelate? Answering such questions will pave the road for design and implementation of novel intervention programs that improve cognitive abilities in older age.
Final report
I am writing a report concerning the project entitled “Kan minskad tillgänglighet av dopamin och störningar i funktionella nätverk i hjärnan fungera som biomarkörer för kognitiv nedgång i åldrandet?”, funded by RJ (P20-0515).
The project has progressed according to the initial plan, without any significant scientific or financial deviations. Several scientific publications have already been produced, addressing the research questions originally outlined in the proposal.
• Using the world’s largest combined dopamine PET and MRI dataset, we presented for the first time three lines of converging evidence to prove distinct phases of age-related D1-like dopamine receptors (D1DR) reductions in adults (20 – 80 years), likely attributed to development and degeneration. A bi-phasic pattern of age-related D1DR differences was revealed, with an inflection point at approximately 40 years of age. Notably, D1DR levels before and after the inflection showed opposing relations to neurocognitive functions, in concordance with distinct consequences of D1DR differences during development and in old age. Furthermore, D1DR reductions in later life were linked to age-related cerebrovascular consequences. Our results support a distinction between D1DR reductions in early adulthood from those later in life and suggest less dramatic and more malleable DA losses in aging than previously suggested. The paper is published in Cell Reports (Johansson et al., 2023)
These results address the question number 2-3 outlined in the project proposal where we aimed to characterize age-related trajectories of dopamine D1DRs and their contribution to neurocognitive function across the adult lifespan.
• We demonstrated the consequences of declining D1DR on brain function, including the dedifferentiation of striato-cortical functional connectivity (Korkki et al., 2025), and reduced segregation of cortico-cortical connectivity (Pedersen et al., 2023b), both contributing to impaired cognitive abilities in older age. Furthermore, we made an intriguing discovered that individual differences in the primary functional organization of the brain, which differentiate the default mode network from the sensory networks, contribute to differences in memory function and that D1DR shares organizational principles with brain functional architecture, thus adding an additional molecular layer of DA to the organization of the brain (Pedersen et al., 2023a).
• We explored hippocampal functional organization in aging and its impact on episodic memory. In addition to a primary gradient we reported previously (Nordin et al., 2021), our research uncovered two longitudinal axis gradients in hippocampal connectivity, revealing a unique link between the second gradient and the dopaminergic system. Age-related changes in these gradients were associated with memory decline, challenging prevailing theories and highlighting the need for a more comprehensive understanding of hippocampal function (Nordin et al., 2024). More specifically, older age was associated with less distinct transitions in functional connectivity along gradients, and a youth-like gradient profile, i.e. maintained distinctiveness, was linked to superior memory – highlighting age-related gradient dedifferentiation as a potential marker of cognitive decline. This finding, extends our previous collaborative efforts, indicating that preserving a youth-like functional organization contributes to superior intelligence in successful agers, now to the level of hippocampus and memory function(Zuo et al., 2019).
These results address the question number 1 & 3 outlined in the project proposal where we aimed to characterize age-related differences of brain function and contribution of molecular pathways and implication for cognitive decline.
• Finally addressing the last research question about the distinct roles of D1DR and D2-like dopamine receptors (D2DR), we found that D1DR in the anterior cingulate is significantly associated with working memory outside the scanner. In contrast D2DR in the hippocampus was associated with episodic memory. We prepared the manuscript that hasn’t been submitted yet (Stiernman et al. )
These results address the question number 3 where distinct contribution of D1DR and D2DR to neurocognitive function is specified.
We have successfully addressed the three research questions detailed in our original proposal, resulting in eight published papers and one manuscript currently under preparation.
(1) Korkki, S.M., Johansson, J., Nordin, K., Pedersen, R., Bäckman, L., Rieckmann, A., Salami, A., 2025. Dedifferentiation of caudate functional organization is linked to reduced D1 dopamine receptor availability and poorer memory function in aging. Imaging Neuroscience
(2) Nordin, K., Pedersen, R., Falahati, F., Johansson, J., Grill, F., Andersson, M., Korkki, S.M., Bäckman, L., Zalesky, A., Rieckmann, A., Nyberg, L., Salami, A. (2025). Two long-axis dimensions of hippocampal-cortical integration support memory function across the adult lifespan. eLife, 97658.1.
(3) Pedersen R, Johansson J, Nordin K, Rieckmann A, Wåhlin A, Nyberg L, Bäckman L, Salami A. (2024) Dopamine D1-receptor Organization Contributes to Functional Brain Architecture. The Journal of Neuroscience; e0621232024.
(4) Johansson, J., Nordin, K., Pedersen, R., Karalija, N., Papenberg, G., Andersson, M., Korkki, S.M., Riklund, K., Guitart-Masip, M., Rieckmann, A., Bäckman, L., Nyberg, L., Salami, A. (2023). Bi-phasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan. Cell Reports 42, 113107
(5) Johansson, J., Karalija, N., L., Salami, A. (2023). Cerebrovascular integrity affects gradients of age-related dopamine D1 differences in the striatum. Aging brain, 4, 100094
(6) Gustavsson, J., Johansson, J., Falahati, F., Andersson, M., Papenberg, G., Avelar-Pereira, B., Bäckman, L., Kalpouzos, G., Salami, A. (2023). The iron-dopamine D1 coupling modulates neural signatures of working memory across adult lifespan. NeuroImage (23) 00474-3
(7) Pedersen R., Johansson J., Salami A. (2023) Dopamine D1-signaling modulates maintenance of functional network segregation in aging. Aging brain, 3, 100079
(8) Nordin K., Gorbach T., Pedersen R., Panes Lundmark V., Johansson J., Andersson M., McNulty C., Riklund K., Wahlin A., Papenberg G., Kalpouzos G., Backman L., Salami A. (2022) DyNAMiC: A prospective longitudinal study of dopamine and brain connectomes: A new window into cognitive aging. J Neurosci Res.
Moreover, results from all three projects were presented in scientist conferences. These include:
• Invited talk at UTokyo Stockholm Trio Workshop
October 2024
Functional and molecular signatures of cognitive decline in aging: Evidence from large-scale longitudinal imaging studies
Alireza Salami
• Invited talk at Resting State Conference
September 2023
Dopamine Organization contributes to functional brain architecture and network segregation
Alireza Salami
• Symposium at Learning and Memory Conference
April 2023
Two long-axis dimensions of hippocampal cortical integration informs memory function across the adult lifespan
Alireza Salami
• Symposium at Dopamine Conference 2022
May 2022
Dopamine in relation to neural integrity across different cognitive state
Alireza Salami
• Oral session at Dopamine Conference 2022
May 2022
Dopamine D1 receptor density across the adult lifespan
Jarkko Johansson
• Poster at Dopamine Conference 2022
May 2022
Dopamine D1 Receptor Organization Reflects Functional Brain Architecture
Robin Pedersen, Jarkko Johansson, Alireza Salami
• Poster at Society for Neuroscience (SFN) 2022
November 2022
Human Dopamine D1 Organization Contributes to Functional Brain Architecture
Robin Pedersen, Jarkko Johansson, Alireza Salami
• Poster at Conference of Cognitive Neuroscience in Helsinki
May 2022
Effects of age and dopamine D1 receptor availability on the differentiation of striato-cortical functional connectivity
Saana Korkki, Kristin Nordin, Robin Pedersen, Jarkko Johansson, Anna Rieckmann, Alireza Salami
• Poster at Dopamine conference 2022
May 2022
Topographic organization of hippocampal functional connectivity is linked to the dopamine D1 receptor across the adult lifespan
Kristin Nordin, Jarkko Johansson, Filip Grill, Farshad Falahati, Robin Pedersen, Micael Andersson, Anna Rieckmann, Alireza Salami
• Poster at OHBM 2022
June 2022
Multiple hippocampal connectivity topographies across the adult lifespan
Kristin Nordin, Filip Grill, Farshad Falahati, Robin Pedersen, Jarkko Johansson, Micael Andersson, Anna Rieckmann, Alireza Salami
• Poster at OHBM 2022
June 2022
Connectome-based individualized prediction of behavior and cognition by an AI-based approach
Morteza Esmaeili, Alireza Salami
Johansson, J., Nordin, K., Pedersen, R., Karalija, N., Papenberg, G., Andersson, M., Korkki, S.M., Riklund, K., Guitart-Masip, M., Rieckmann, A., Backman, L., Nyberg, L., Salami, A., 2023. Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan. Cell Rep 42, 113107.
Korkki, S.M., Johansson, J., Nordin, K., Pedersen, R., Bäckman, L., Rieckmann, A., Salami, A., 2025. Dedifferentiation of caudate functional organization is linked to reduced D1 dopamine receptor availability and poorer memory function in aging. Imaging Neuroscience.
Nordin, K., Nyberg, L., Andersson, M., Karalija, N., Riklund, K., Backman, L., Salami, A., 2021. Distinct and Common Large-Scale Networks of the Hippocampal Long Axis in Older Age: Links to Episodic Memory and Dopamine D2 Receptor Availability. Cerebral cortex 31, 3435-3450.
Nordin, K., Pedersen, R., Falahati, F., Johansson, J., Grill, F., Andersson, M., Korkki, S.M., Bäckman, L., Zalesky, A., Rieckmann, A., Nyberg, L., Salami, A., 2024. Two long-axis dimensions of hippocampal-cortical integration support memory function across the adult lifespan. eLIFE https://doi.org/10.7554/eLife.97658.1.
Pedersen, R., Johansson, J., Nordin, K., Rieckmann, A., Wåhlin, A., Nyberg, L., Bäckman, L., Salami, A., 2023a. Dopamine D1-receptor Organization Contributes to Functional Brain Architecture. bioRxiv (accepted for publication in the Journal of Neuroscience).
Pedersen, R., Johansson, J., Salami, A., 2023b. Dopamine D1-signaling modulates maintenance of functional network segregation in aging. Aging Brain 3, 100079.
Zuo, N., Salami, A., Liu, H., Yang, Z., Jiang, T., 2019. Functional maintenance in the multiple demand network characterizes superior fluid intelligence in aging. Neurobiology of aging.
The project has progressed according to the initial plan, without any significant scientific or financial deviations. Several scientific publications have already been produced, addressing the research questions originally outlined in the proposal.
• Using the world’s largest combined dopamine PET and MRI dataset, we presented for the first time three lines of converging evidence to prove distinct phases of age-related D1-like dopamine receptors (D1DR) reductions in adults (20 – 80 years), likely attributed to development and degeneration. A bi-phasic pattern of age-related D1DR differences was revealed, with an inflection point at approximately 40 years of age. Notably, D1DR levels before and after the inflection showed opposing relations to neurocognitive functions, in concordance with distinct consequences of D1DR differences during development and in old age. Furthermore, D1DR reductions in later life were linked to age-related cerebrovascular consequences. Our results support a distinction between D1DR reductions in early adulthood from those later in life and suggest less dramatic and more malleable DA losses in aging than previously suggested. The paper is published in Cell Reports (Johansson et al., 2023)
These results address the question number 2-3 outlined in the project proposal where we aimed to characterize age-related trajectories of dopamine D1DRs and their contribution to neurocognitive function across the adult lifespan.
• We demonstrated the consequences of declining D1DR on brain function, including the dedifferentiation of striato-cortical functional connectivity (Korkki et al., 2025), and reduced segregation of cortico-cortical connectivity (Pedersen et al., 2023b), both contributing to impaired cognitive abilities in older age. Furthermore, we made an intriguing discovered that individual differences in the primary functional organization of the brain, which differentiate the default mode network from the sensory networks, contribute to differences in memory function and that D1DR shares organizational principles with brain functional architecture, thus adding an additional molecular layer of DA to the organization of the brain (Pedersen et al., 2023a).
• We explored hippocampal functional organization in aging and its impact on episodic memory. In addition to a primary gradient we reported previously (Nordin et al., 2021), our research uncovered two longitudinal axis gradients in hippocampal connectivity, revealing a unique link between the second gradient and the dopaminergic system. Age-related changes in these gradients were associated with memory decline, challenging prevailing theories and highlighting the need for a more comprehensive understanding of hippocampal function (Nordin et al., 2024). More specifically, older age was associated with less distinct transitions in functional connectivity along gradients, and a youth-like gradient profile, i.e. maintained distinctiveness, was linked to superior memory – highlighting age-related gradient dedifferentiation as a potential marker of cognitive decline. This finding, extends our previous collaborative efforts, indicating that preserving a youth-like functional organization contributes to superior intelligence in successful agers, now to the level of hippocampus and memory function(Zuo et al., 2019).
These results address the question number 1 & 3 outlined in the project proposal where we aimed to characterize age-related differences of brain function and contribution of molecular pathways and implication for cognitive decline.
• Finally addressing the last research question about the distinct roles of D1DR and D2-like dopamine receptors (D2DR), we found that D1DR in the anterior cingulate is significantly associated with working memory outside the scanner. In contrast D2DR in the hippocampus was associated with episodic memory. We prepared the manuscript that hasn’t been submitted yet (Stiernman et al. )
These results address the question number 3 where distinct contribution of D1DR and D2DR to neurocognitive function is specified.
We have successfully addressed the three research questions detailed in our original proposal, resulting in eight published papers and one manuscript currently under preparation.
(1) Korkki, S.M., Johansson, J., Nordin, K., Pedersen, R., Bäckman, L., Rieckmann, A., Salami, A., 2025. Dedifferentiation of caudate functional organization is linked to reduced D1 dopamine receptor availability and poorer memory function in aging. Imaging Neuroscience
(2) Nordin, K., Pedersen, R., Falahati, F., Johansson, J., Grill, F., Andersson, M., Korkki, S.M., Bäckman, L., Zalesky, A., Rieckmann, A., Nyberg, L., Salami, A. (2025). Two long-axis dimensions of hippocampal-cortical integration support memory function across the adult lifespan. eLife, 97658.1.
(3) Pedersen R, Johansson J, Nordin K, Rieckmann A, Wåhlin A, Nyberg L, Bäckman L, Salami A. (2024) Dopamine D1-receptor Organization Contributes to Functional Brain Architecture. The Journal of Neuroscience; e0621232024.
(4) Johansson, J., Nordin, K., Pedersen, R., Karalija, N., Papenberg, G., Andersson, M., Korkki, S.M., Riklund, K., Guitart-Masip, M., Rieckmann, A., Bäckman, L., Nyberg, L., Salami, A. (2023). Bi-phasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan. Cell Reports 42, 113107
(5) Johansson, J., Karalija, N., L., Salami, A. (2023). Cerebrovascular integrity affects gradients of age-related dopamine D1 differences in the striatum. Aging brain, 4, 100094
(6) Gustavsson, J., Johansson, J., Falahati, F., Andersson, M., Papenberg, G., Avelar-Pereira, B., Bäckman, L., Kalpouzos, G., Salami, A. (2023). The iron-dopamine D1 coupling modulates neural signatures of working memory across adult lifespan. NeuroImage (23) 00474-3
(7) Pedersen R., Johansson J., Salami A. (2023) Dopamine D1-signaling modulates maintenance of functional network segregation in aging. Aging brain, 3, 100079
(8) Nordin K., Gorbach T., Pedersen R., Panes Lundmark V., Johansson J., Andersson M., McNulty C., Riklund K., Wahlin A., Papenberg G., Kalpouzos G., Backman L., Salami A. (2022) DyNAMiC: A prospective longitudinal study of dopamine and brain connectomes: A new window into cognitive aging. J Neurosci Res.
Moreover, results from all three projects were presented in scientist conferences. These include:
• Invited talk at UTokyo Stockholm Trio Workshop
October 2024
Functional and molecular signatures of cognitive decline in aging: Evidence from large-scale longitudinal imaging studies
Alireza Salami
• Invited talk at Resting State Conference
September 2023
Dopamine Organization contributes to functional brain architecture and network segregation
Alireza Salami
• Symposium at Learning and Memory Conference
April 2023
Two long-axis dimensions of hippocampal cortical integration informs memory function across the adult lifespan
Alireza Salami
• Symposium at Dopamine Conference 2022
May 2022
Dopamine in relation to neural integrity across different cognitive state
Alireza Salami
• Oral session at Dopamine Conference 2022
May 2022
Dopamine D1 receptor density across the adult lifespan
Jarkko Johansson
• Poster at Dopamine Conference 2022
May 2022
Dopamine D1 Receptor Organization Reflects Functional Brain Architecture
Robin Pedersen, Jarkko Johansson, Alireza Salami
• Poster at Society for Neuroscience (SFN) 2022
November 2022
Human Dopamine D1 Organization Contributes to Functional Brain Architecture
Robin Pedersen, Jarkko Johansson, Alireza Salami
• Poster at Conference of Cognitive Neuroscience in Helsinki
May 2022
Effects of age and dopamine D1 receptor availability on the differentiation of striato-cortical functional connectivity
Saana Korkki, Kristin Nordin, Robin Pedersen, Jarkko Johansson, Anna Rieckmann, Alireza Salami
• Poster at Dopamine conference 2022
May 2022
Topographic organization of hippocampal functional connectivity is linked to the dopamine D1 receptor across the adult lifespan
Kristin Nordin, Jarkko Johansson, Filip Grill, Farshad Falahati, Robin Pedersen, Micael Andersson, Anna Rieckmann, Alireza Salami
• Poster at OHBM 2022
June 2022
Multiple hippocampal connectivity topographies across the adult lifespan
Kristin Nordin, Filip Grill, Farshad Falahati, Robin Pedersen, Jarkko Johansson, Micael Andersson, Anna Rieckmann, Alireza Salami
• Poster at OHBM 2022
June 2022
Connectome-based individualized prediction of behavior and cognition by an AI-based approach
Morteza Esmaeili, Alireza Salami
Johansson, J., Nordin, K., Pedersen, R., Karalija, N., Papenberg, G., Andersson, M., Korkki, S.M., Riklund, K., Guitart-Masip, M., Rieckmann, A., Backman, L., Nyberg, L., Salami, A., 2023. Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan. Cell Rep 42, 113107.
Korkki, S.M., Johansson, J., Nordin, K., Pedersen, R., Bäckman, L., Rieckmann, A., Salami, A., 2025. Dedifferentiation of caudate functional organization is linked to reduced D1 dopamine receptor availability and poorer memory function in aging. Imaging Neuroscience.
Nordin, K., Nyberg, L., Andersson, M., Karalija, N., Riklund, K., Backman, L., Salami, A., 2021. Distinct and Common Large-Scale Networks of the Hippocampal Long Axis in Older Age: Links to Episodic Memory and Dopamine D2 Receptor Availability. Cerebral cortex 31, 3435-3450.
Nordin, K., Pedersen, R., Falahati, F., Johansson, J., Grill, F., Andersson, M., Korkki, S.M., Bäckman, L., Zalesky, A., Rieckmann, A., Nyberg, L., Salami, A., 2024. Two long-axis dimensions of hippocampal-cortical integration support memory function across the adult lifespan. eLIFE https://doi.org/10.7554/eLife.97658.1.
Pedersen, R., Johansson, J., Nordin, K., Rieckmann, A., Wåhlin, A., Nyberg, L., Bäckman, L., Salami, A., 2023a. Dopamine D1-receptor Organization Contributes to Functional Brain Architecture. bioRxiv (accepted for publication in the Journal of Neuroscience).
Pedersen, R., Johansson, J., Salami, A., 2023b. Dopamine D1-signaling modulates maintenance of functional network segregation in aging. Aging Brain 3, 100079.
Zuo, N., Salami, A., Liu, H., Yang, Z., Jiang, T., 2019. Functional maintenance in the multiple demand network characterizes superior fluid intelligence in aging. Neurobiology of aging.