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Publications (10 of 35) Show all publications
Johansson, J., Ericsson, M., Axelsson, J., af Bjerkén, S., Virel, A. & Karalija, N. (2024). Amphetamine-induced dopamine release in rat: Whole-brain spatiotemporal analysis with [11C]raclopride and positron emission tomography. Journal of Cerebral Blood Flow and Metabolism, 44(3), 434-445
Open this publication in new window or tab >>Amphetamine-induced dopamine release in rat: Whole-brain spatiotemporal analysis with [11C]raclopride and positron emission tomography
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2024 (English)In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 44, no 3, p. 434-445Article in journal (Refereed) Epub ahead of print
Abstract [en]

Whole-brain mapping of drug effects are needed to understand the neural underpinnings of drug-related behaviors. Amphetamine administration is associated with robust increases in striatal dopamine (DA) release. Dopaminergic terminals are, however, present across several associative brain regions, which may contribute to behavioral effects of amphetamine. Yet the assessment of DA release has been restricted to a few brain regions of interest. The present work employed positron emission tomography (PET) with [11C]raclopride to investigate regional and temporal characteristics of amphetamine-induced DA release across twenty sessions in adult female Sprague Dawley rats. Amphetamine was injected intravenously (2 mg/kg) to cause displacement of [11C]raclopride binding from DA D2-like receptors, assessed using temporally sensitive pharmacokinetic PET model (lp-ntPET). We show amphetamine-induced [11C]raclopride displacement in the basal ganglia, and no changes following saline injections. Peak occupancy was highest in nucleus accumbens, followed by caudate-putamen and globus pallidus. Importantly, significant amphetamine-induced displacement was also observed in several extrastriatal regions, and specifically in thalamus, insula, orbitofrontal cortex, and secondary somatosensory area. For these, peak occupancy occurred later and was lower as compared to the striatum. Collectively, these findings demonstrate distinct amphetamine-induced DA responses across the brain, and that [11C]raclopride-PET can be employed to detect such spatiotemporal differences.

Place, publisher, year, edition, pages
Sage Publications, 2024
Keywords
Amphetamine, displacement, dopamine, imaging, receptor
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-216126 (URN)10.1177/0271678X231210128 (DOI)001089209600001 ()37882727 (PubMedID)2-s2.0-85174906502 (Scopus ID)
Funder
Swedish Research Council
Available from: 2023-11-06 Created: 2023-11-06 Last updated: 2024-04-26Bibliographically approved
Karalija, N., Papenberg, G., Johansson, J., Wåhlin, A., Salami, A., Andersson, M., . . . Nyberg, L. (2024). Longitudinal support for the correlative triad among aging, dopamine D2-like receptor loss, and memory decline. Neurobiology of Aging, 136, 125-132
Open this publication in new window or tab >>Longitudinal support for the correlative triad among aging, dopamine D2-like receptor loss, and memory decline
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2024 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 136, p. 125-132Article in journal (Refereed) Published
Abstract [en]

Dopamine decline is suggested to underlie aging-related cognitive decline, but longitudinal examinations of this link are currently missing. We analyzed 5-year longitudinal data for a sample of healthy, older adults (baseline: n = 181, age: 64–68 years; 5-year follow-up: n = 129) who underwent positron emission tomography with 11C-raclopride to assess dopamine D2-like receptor (DRD2) availability, magnetic resonance imaging to evaluate structural brain measures, and cognitive tests. Health, lifestyle, and genetic data were also collected. A data-driven approach (k-means cluster analysis) identified groups that differed maximally in DRD2 decline rates in age-sensitive brain regions. One group (n = 47) had DRD2 decline exclusively in the caudate and no cognitive decline. A second group (n = 72) had more wide-ranged DRD2 decline in putamen and nucleus accumbens and also in extrastriatal regions. The latter group showed significant 5-year working memory decline that correlated with putamen DRD2 decline, along with higher dementia and cardiovascular risk and a faster biological pace of aging. Taken together, for individuals with more extensive DRD2 decline, dopamine decline is associated with memory decline in aging.

Keywords
11C-raclopride, Aging, Dopamine D2-like receptor, Longitudinal, Magnetic resonance imaging, Positron emission tomography, Working memory
National Category
Geriatrics
Identifiers
urn:nbn:se:umu:diva-221540 (URN)10.1016/j.neurobiolaging.2024.02.001 (DOI)38359585 (PubMedID)2-s2.0-85185304249 (Scopus ID)
Funder
Swedish Research Council, 421-2012-648Swedish Research Council, 2017-02217Swedish Research Council, 2022-01804Umeå UniversityKnut and Alice Wallenberg Foundation, 2015.0277Jonas and Christina af Jochnick FoundationAlzheimerfonden, AF-967710Riksbankens Jubileumsfond, P20-0779Region Västerbotten
Available from: 2024-03-15 Created: 2024-03-15 Last updated: 2024-03-15Bibliographically approved
Johansson, J., Nordin, K., Pedersen, R., Karalija, N., Papenberg, G., Andersson, M., . . . Salami, A. (2023). Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan. Cell Reports, 42(9), Article ID 113107.
Open this publication in new window or tab >>Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan
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2023 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 9, article id 113107Article in journal (Refereed) Published
Abstract [en]

Age-related alterations in D1-like dopamine receptor (D1DR) have distinct implications for human cognition and behavior during development and aging, but the timing of these periods remains undefined. Enabled by a large sample of in vivo assessments (n = 180, age 20 to 80 years of age, 50% female), we discover that age-related D1DR differences pivot at approximately 40 years of age in several brain regions. Focusing on the most age-sensitive dopamine-rich region, we observe opposing pre- and post-forties interrelations among caudate D1DR, cortico-striatal functional connectivity, and memory. Finally, particularly caudate D1DR differences in midlife and beyond, but not in early adulthood, associate with manifestation of white matter lesions. The present results support a model by which excessive dopamine modulation in early adulthood and insufficient modulation in aging are deleterious to brain function and cognition, thus challenging a prevailing view of monotonic D1DR function across the adult lifespan.

Keywords
aging, cognition, CP: Neuroscience, dopamine D1, functional connectivity, neuromodulation, protracted development
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-214414 (URN)10.1016/j.celrep.2023.113107 (DOI)2-s2.0-85169884676 (Scopus ID)
Funder
Swedish Research Council, 2016-01936Knut and Alice Wallenberg FoundationRiksbankens Jubileumsfond
Available from: 2023-09-18 Created: 2023-09-18 Last updated: 2024-01-17Bibliographically approved
Farnsworth von Cederwald, B., Johansson, J., Riklund, K., Karalija, N. & Boraxbekk, C.-J. (2023). White matter lesion load determines exercise-induced dopaminergic plasticity and working memory gains in aging. Translational Psychiatry, 13(1), Article ID 28.
Open this publication in new window or tab >>White matter lesion load determines exercise-induced dopaminergic plasticity and working memory gains in aging
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2023 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 28Article in journal (Refereed) Published
Abstract [en]

Age-related dopamine reductions have been suggested to contribute to maladaptive working memory (WM) function in older ages. One promising intervention approach is to increase physical activity, as this has been associated with plasticity of the striatal dopamine system and WM improvements, however with individual differences in efficacy. The present work focused on the impact of individual differences in white-matter lesion burden upon dopamine D2-like receptor (DRD2) availability and WM changes in response to a 6 months physical activity intervention. While the intervention altered striatal DRD2 availability and WM performance in individuals with no or only mild lesions (p < 0.05), no such effects were found in individuals with moderate-to-severe lesion severity (p > 0.05). Follow-up analyses revealed a similar pattern for processing speed, but not for episodic memory performance. Linear analyses further revealed that lesion volume (ml) at baseline was associated with reduced DRD2 availability (r = −0.41, p < 0.05), and level of DRD2 change (r = 0.40, p < 0.05). Taken together, this study underlines the necessity to consider cerebrovascular health in interventions with neurocognitive targets. Future work should assess whether these findings extend beyond measures of DRD2 availability and WM.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Neurosciences Psychiatry
Identifiers
urn:nbn:se:umu:diva-204468 (URN)10.1038/s41398-022-02270-9 (DOI)000924365700002 ()36720847 (PubMedID)2-s2.0-85147098951 (Scopus ID)
Funder
Swedish Research Council, 2012-00530Region VästerbottenUmeå UniversityThe Kamprad Family FoundationThe Swedish Brain Foundation
Available from: 2023-02-17 Created: 2023-02-17 Last updated: 2024-01-17Bibliographically approved
Vikner, T., Karalija, N., Eklund, A., Malm, J., Lundquist, A., Gallewicz, N., . . . Wåhlin, A. (2022). 5-year associations among cerebral arterial pulsatility, perivascular space dilation, and white matter lesions. Annals of Neurology, 92(5), 871-881
Open this publication in new window or tab >>5-year associations among cerebral arterial pulsatility, perivascular space dilation, and white matter lesions
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2022 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 92, no 5, p. 871-881Article in journal (Refereed) Published
Abstract [en]

Objective: High cerebral arterial pulsatility index (PI), white matter lesions (WMLs), enlarged perivascular spaces (PVSs), and lacunar infarcts are common findings in the elderly population, and considered indicators of small vessel disease (SVD). Here, we investigate the potential temporal ordering among these variables, with emphasis on determining whether high PI is an early or delayed manifestation of SVD.

Methods: In a population-based cohort, 4D flow MRI data for cerebral arterial pulsatility was collected for 159 participants at baseline (age 64–68), and for 122 participants at follow-up 5 years later. Structural MRI was used for WML and PVS segmentation, and lacune identification. Linear mixed-effects (LME) models were used to model longitudinal changes testing for pairwise associations, and latent change score (LCS) models to model multiple relationships among variables simultaneously.

Results: Longitudinal 5-year increases were found for WML, PVS, and PI. Cerebral arterial PI at baseline did not predict changes in WML or PVS volume. However, WML and PVS volume at baseline predicted 5-year increases in PI. This was shown for PI increases in relation to baseline WML and PVS volumes using LME models (R (Formula presented.) 0.24; p < 0.02 and R (Formula presented.) 0.23; p < 0.03, respectively) and LCS models ((Formula presented.) = 0.28; p = 0.015 and (Formula presented.) = 0.28; p = 0.009, respectively). Lacunes at baseline were unrelated to PI.

Interpretation: In healthy older adults, indicators of SVD are related in a lead–lag fashion, in which the expression of WML and PVS precedes increases in cerebral arterial PI. Hence, we propose that elevated PI is a relatively late manifestation, rather than a risk factor, for cerebral SVD. 

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-199208 (URN)10.1002/ana.26475 (DOI)000843724700001 ()36054261 (PubMedID)2-s2.0-85136905097 (Scopus ID)
Funder
Swedish Foundation for Strategic ResearchRegion Västerbotten, 2017‐04949Knut and Alice Wallenberg Foundation, 2017‐04949Max Planck SocietySwedish Research Council, 2017‐02217Swedish Research Council, 421‐2012‐648
Available from: 2022-09-08 Created: 2022-09-08 Last updated: 2023-05-04Bibliographically approved
Farnsworth von Cederwald, B., Josefsson, M., Wåhlin, A., Nyberg, L. & Karalija, N. (2022). Association of cardiovascular risk trajectory with cognitive decline and incident dementia. Neurology, 98(20), e2013-e2022
Open this publication in new window or tab >>Association of cardiovascular risk trajectory with cognitive decline and incident dementia
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2022 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 98, no 20, p. e2013-e2022Article in journal (Refereed) Published
Abstract [en]

Background and Objectives: Cardiovascular risk factors have a recently established association with cognitive decline and dementia, yet most studies examine this association through cross-sectional data, precluding an understanding of the longitudinal dynamics of such risk. The current study aims to explore how the ongoing trajectory of cardiovascular risk affects subsequent dementia and memory decline risk. We hypothesize that an accelerated, long-term accumulation of cardiovascular risk, as determined by the Framingham Risk Score (FRS), will be more detrimental to cognitive and dementia state outcomes than a stable cardiovascular risk.

Methods: We assessed an initially healthy, community-dwelling sample recruited from the prospective cohort Betula study. Cardiovascular disease risk, as assessed by the FRS, episodic memory performance, and dementia status were measured at each 5-year time point (T) across 20 to 25 years. Analysis was performed with bayesian additive regression tree, a semiparametric machine-learning method, applied herein as a multistate survival analysis method.

Results: Of the 1,244 participants, cardiovascular risk increased moderately over time in 60% of sample, with observations of an accelerated increase in 18% of individuals and minimal change in 22% of individuals. An accelerated, as opposed to a stable, cardiovascular risk trajectory predicted an increased risk of developing Alzheimer disease dementia (average risk ratio [RR] 3.3–5.7, 95% CI 2.6–17.5 at T2, 1.9–6.7 at T5) or vascular dementia (average RR 3.3–4.1, 95% CI 1.1–16.6 at T2, 1.5–7.6 at T5) and was associated with an increased risk of memory decline (average RR 1.4–1.2, 95% CI 1–1.9 at T2, 1–1.5 at T5). A stable cardiovascular risk trajectory appeared to partially mitigate Alzheimer disease dementia risk for APOE ε4 carriers.

Discussion: The findings of the current study show that the longitudinal, cumulative trajectory of cardiovascular risk is predictive of dementia risk and associated with the emergence of memory decline. As a result, clinical practice may benefit from directing interventions at individuals with accelerating cardiovascular risk.

Place, publisher, year, edition, pages
Wolters Kluwer, 2022
National Category
Psychology
Identifiers
urn:nbn:se:umu:diva-202461 (URN)10.1212/wnl.0000000000200255 (DOI)000796369700021 ()35444051 (PubMedID)2-s2.0-85130635509 (Scopus ID)
Funder
The Swedish Brain FoundationKnut and Alice Wallenberg FoundationRiksbankens Jubileumsfond, P17-0196:1
Available from: 2023-01-10 Created: 2023-01-10 Last updated: 2023-05-04Bibliographically approved
Karalija, N., Johansson, J., Papenberg, G., Wåhlin, A., Salami, A., Köhncke, Y., . . . Nyberg, L. (2022). Longitudinal Dopamine D2 Receptor Changes and Cerebrovascular Health in Aging. Neurology, 99(12), e1278-e1289
Open this publication in new window or tab >>Longitudinal Dopamine D2 Receptor Changes and Cerebrovascular Health in Aging
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2022 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 99, no 12, p. e1278-e1289Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND OBJECTIVES: Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline rates for DA D2-like receptors (DRD2) in aging and examine factors that may contribute to individual differences in DRD2 decline rates.

METHODS: We investigated 5-year within-person changes in DRD2 availability in a sample of older adults. At both occasions, PET with 11C-raclopride and MRI were used to measure DRD2 availability in conjunction with structural and vascular brain integrity.

RESULTS: Longitudinal analyses of the sample (baseline: n = 181, ages: 64-68 years, 100 men and 81 women; 5-year follow-up: n = 129, 69 men and 60 women) revealed aging-related striatal and extrastriatal DRD2 decline, along with marked individual differences in rates of change. Notably, the magnitude of striatal DRD2 decline was ∼50% of past cross-sectional estimates, suggesting that the DRD2 decline rate has been overestimated in past cross-sectional studies. Significant DRD2 reductions were also observed in select extrastriatal regions, including hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Distinct profiles of correlated DRD2 changes were found across several associative regions (ACC, dorsal striatum, and hippocampus) and in the reward circuit (nucleus accumbens and OFC). DRD2 losses in associative regions were associated with white matter lesion progression, whereas DRD2 losses in limbic regions were related to reduced cortical perfusion.

DISCUSSION: These findings provide the first longitudinal evidence for individual and region-specific differences of DRD2 decline in older age and support the hypothesis that cerebrovascular factors are linked to age-related dopaminergic decline.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-200514 (URN)10.1212/WNL.0000000000200891 (DOI)000862021800023 ()35790424 (PubMedID)2-s2.0-85139739013 (Scopus ID)
Funder
Swedish Research Council, 421-2012-648Swedish Research Council, 2017-02217Torsten Söderbergs stiftelseVästerbotten County CouncilThe Swedish Brain FoundationKnut and Alice Wallenberg Foundation, 2015.0277Umeå University
Available from: 2023-01-12 Created: 2023-01-12 Last updated: 2023-01-17Bibliographically approved
Nyberg, L., Karalija, N., Papenberg, G., Salami, A., Andersson, M., Pedersen, R., . . . Bäckman, L. (2022). Longitudinal stability in working memory and frontal activity in relation to general brain maintenance. Scientific Reports, 12(1), Article ID 20957.
Open this publication in new window or tab >>Longitudinal stability in working memory and frontal activity in relation to general brain maintenance
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2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 20957Article in journal (Refereed) Published
Abstract [en]

Cognitive functions are well-preserved for some older individuals, but the underlying brain mechanisms remain disputed. Here, 5-year longitudinal 3-back in-scanner and offline data classified individuals in a healthy older sample (baseline age = 64–68 years) into having stable or declining working-memory (WM). Consistent with a vital role of the prefrontal cortex (PFC), WM stability or decline was related to maintained or reduced longitudinal PFC functional responses. Subsequent analyses of imaging markers of general brain maintenance revealed higher levels in the stable WM group on measures of neurotransmission and vascular health. Also, categorical and continuous analyses showed that rate of WM decline was related to global (ventricles) and local (hippocampus) measures of neuronal integrity. Thus, our findings support a role of the PFC as well as general brain maintenance in explaining heterogeneity in longitudinal WM trajectories in aging.

Place, publisher, year, edition, pages
Springer Nature, 2022
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-201756 (URN)10.1038/s41598-022-25503-9 (DOI)000984275000060 ()36470934 (PubMedID)2-s2.0-85143310050 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 2018-05973Umeå UniversityRegion VästerbottenThe Swedish Brain Foundation
Note

The freesurfer-analyses were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at HPC2N, Umeå University

Available from: 2022-12-21 Created: 2022-12-21 Last updated: 2023-09-05Bibliographically approved
Karalija, N., Köhncke, Y., Düzel, S., Bertram, L., Papenberg, G., Demuth, I., . . . Brandmaier, A. M. (2021). A common polymorphism in the dopamine transporter gene predicts working memory performance and in vivo dopamine integrity in aging. NeuroImage, 245, Article ID 118707.
Open this publication in new window or tab >>A common polymorphism in the dopamine transporter gene predicts working memory performance and in vivo dopamine integrity in aging
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2021 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 245, article id 118707Article in journal (Refereed) Published
Abstract [en]

Dopamine (DA) integrity is suggested as a potential cause of individual differences in working memory (WM) performance among older adults. Still, the principal dopaminergic mechanisms giving rise to WM differences remain unspecified. Here, 61 single-nucleotide polymorphisms, located in or adjacent to various dopamine-related genes, were assessed for their links to WM performance in a sample of 1313 adults aged 61–80 years from the Berlin Aging Study II. Least Absolute Shrinkage and Selection Operator (LASSO) regression was conducted to estimate associations between polymorphisms and WM. Rs40184 in the DA transporter gene, SLC6A3, showed allelic group differences in WM, with T-carriers performing better than C homozygotes (p<0.01). This finding was replicated in an independent sample from the Cognition, Brain, and Aging study (COBRA; baseline: n = 181, ages: 64–68 years; 5-year follow up: n = 129). In COBRA, in vivo DA integrity was measured with 11C-raclopride and positron emission tomography. Notably, WM as well as in vivo DA integrity was higher for rs40184 T-carriers at baseline (p<0.05 for WM and caudate and hippocampal D2-receptor availability) and at the 5-year follow-up (p<0.05 for WM and hippocampal D2 availability). Our findings indicate that individual differences in DA transporter function contribute to differences in WM performance in old age, presumably by regulating DA availability.

Place, publisher, year, edition, pages
Academic Press, 2021
Keywords
11C-raclopride, Dopamine D2 receptor, Dopamine transporter, Single-nucleotide polymorphisms, Working memory
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-189575 (URN)10.1016/j.neuroimage.2021.118707 (DOI)2-s2.0-85118554159 (Scopus ID)
Available from: 2021-11-18 Created: 2021-11-18 Last updated: 2023-03-23Bibliographically approved
Vikner, T., Eklund, A., Karalija, N., Malm, J., Riklund, K., Lindenberger, U., . . . Wåhlin, A. (2021). Cerebral arterial pulsatility is linked to hippocampal microvascular function and episodic memory in healthy older adults. Journal of Cerebral Blood Flow and Metabolism, 41(7), 1778-1790
Open this publication in new window or tab >>Cerebral arterial pulsatility is linked to hippocampal microvascular function and episodic memory in healthy older adults
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2021 (English)In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 41, no 7, p. 1778-1790Article in journal (Refereed) Published
Abstract [en]

Microvascular damage in the hippocampus is emerging as a central cause of cognitive decline and dementia in aging. This could be a consequence of age-related decreases in vascular elasticity, exposing hippocampal capillaries to excessive cardiac-related pulsatile flow that disrupts the blood-brain barrier and the neurovascular unit. Previous studies have found altered intracranial hemodynamics in cognitive impairment and dementia, as well as negative associations between pulsatility and hippocampal volume. However, evidence linking features of the cerebral arterial flow waveform to hippocampal function is lacking. We used a high-resolution 4D flow MRI approach to estimate global representations of the time-resolved flow waveform in distal cortical arteries and in proximal arteries feeding the brain in healthy older adults. Waveform-based clustering revealed a group of individuals featuring steep systolic onset and high amplitude that had poorer hippocampus-sensitive episodic memory (p = 0.003), lower whole-brain perfusion (p = 0.001), and weaker microvascular low-frequency oscillations in the hippocampus (p = 0.035) and parahippocampal gyrus (p = 0.005), potentially indicating compromised neurovascular unit integrity. Our findings suggest that aberrant hemodynamic forces contribute to cerebral microvascular and hippocampal dysfunction in aging.

Place, publisher, year, edition, pages
Sage Publications, 2021
Keywords
4D flow MRI, arterial stiffness, hippocampus, cognition, vasomotion
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-184408 (URN)10.1177/0271678X20980652 (DOI)000664214100024 ()33444091 (PubMedID)2-s2.0-85099415705 (Scopus ID)
Available from: 2021-06-14 Created: 2021-06-14 Last updated: 2023-03-07Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-8603-9453

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