Publications by authors named "Anders Wahlin"

99 Publications

Assessing cerebral arterial pulse wave velocity using 4D flow MRI.

J Cereb Blood Flow Metab 2021 Apr 14:271678X211008744. Epub 2021 Apr 14.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Intracranial arterial stiffening is a potential early marker of emerging cerebrovascular dysfunction and could be mechanistically involved in disease processes detrimental to brain function via several pathways. A prominent consequence of arterial wall stiffening is the increased velocity at which the systolic pressure pulse wave propagates through the vasculature. Previous non-invasive measurements of the pulse wave propagation have been performed on the aorta or extracranial arteries with results linking increased pulse wave velocity to brain pathology. However, there is a lack of intracranial "target-organ" measurements. Here we present a 4D flow MRI method to estimate pulse wave velocity in the intracranial vascular tree. The method utilizes the full detectable branching structure of the cerebral vascular tree in an optimization framework that exploits small temporal shifts that exists between waveforms sampled at varying depths in the vasculature. The method is shown to be stable in an internal consistency test, and of sufficient sensitivity to robustly detect age-related increases in intracranial pulse wave velocity.
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http://dx.doi.org/10.1177/0271678X211008744DOI Listing
April 2021

Quantification and mapping of cerebral hemodynamics before and after carotid endarterectomy, using 4D flow MRI.

J Vasc Surg 2021 Mar 31. Epub 2021 Mar 31.

Department of Clinical Sciences, Neuroscience, Umeå University, Umeå, SWEDEN.

Background And Purpose: Carotid stenosis can profoundly impact cerebral hemodynamics that cannot simply be inferred from the degree of stenosis. We quantified and mapped the distribution of blood flow rate in cerebral arteries before and after carotid endarterectomy using four-dimensional phase-contrast magnetic resonance imaging (4D flow MRI).

Methods: Nineteen patients (71 ± 6 years, 2 women) with symptomatic carotid stenosis (≥ 50%) undergoing carotid endarterectomy (CEA) were investigated using 4D flow MRI before and after surgery. BFR was measured in 17 cerebral arteries and in the ophthalmic arteries (OA). Collateral recruitment through the anterior and posterior communicating arteries, the OA and the leptomeningeal arteries was quantified. BFR laterality was significantly different in paired contralateral vs. ipsilateral arteries. Subgroups were defined as with or without collateral recruitment.

Results: Total cerebral blood flow increased by 15% (P < .01) after CEA. Before CEA, laterality was seen in internal carotid artery (ICA), anterior cerebral artery (ACA) and middle cerebral artery (MCA). On the ipsilateral side, increased BFR was found after CEA in ICA (246 ± 62 mL/min vs. 135 ± 80 mL/min; P < .001), ACA (87 ± mL/min vs. 38 ± 58 mL/min; P < .01) and MCA (149 ± 43 mL/min vs. 119 ± 34 mL/min; P < .01), resulting in a postoperative BFR distribution without signs of laterality. In patients with preoperatively recruited collaterals (n = 9), BFR laterality was found in MCA before, but not after, CEA (P < .01). This laterality was not found in patients without collateral recruitment (n = 10) (P = .2). The degree of stenosis did not differ between the groups with vs. without collateral recruitment (P = .85).

Conclusion: Using 4D flow MRI we have presented a comprehensive and non-invasive way to evaluate cerebral hemodynamics due to carotid stenosis prior to and after CEA. MCA laterality, seen in patients with collateral recruitment before CEA, pointed towards a hemodynamic disturbance in MCA territory for those patients. This methodological advancement provides an insight into the pathophysiology in cerebral hemodynamics in patients with carotid stenosis.
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http://dx.doi.org/10.1016/j.jvs.2021.01.074DOI Listing
March 2021

Multimodal Image Analysis of Apparent Brain Age Identifies Physical Fitness as Predictor of Brain Maintenance.

Cereb Cortex 2021 Mar 5. Epub 2021 Mar 5.

Umeå Center for Functional Brain Imaging (UFBI), Umeå University, S-901 87 Umeå, Sweden.

Maintaining a youthful brain structure and function throughout life may be the single most important determinant of successful cognitive aging. In this study, we addressed heterogeneity in brain aging by making image-based brain age predictions and relating the brain age prediction gap (BAPG) to cognitive change in aging. Structural, functional, and diffusion MRI scans from 351 participants were used to train and evaluate 5 single-modal and 4 multimodal prediction models, based on 7 regression methods. The models were compared on mean absolute error and whether they were related to physical fitness and cognitive ability, measured both currently and longitudinally, as well as study attrition and years of education. Multimodal prediction models performed at a similar level as single-modal models, and the choice of regression method did not significantly affect the results. Correlation with the BAPG was found for current physical fitness, current cognitive ability, and study attrition. Correlations were also found for retrospective physical fitness, measured 10 years prior to imaging, and slope for cognitive ability during a period of 15 years. The results suggest that maintaining a high physical fitness throughout life contributes to brain maintenance and preserved cognitive ability.
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http://dx.doi.org/10.1093/cercor/bhab019DOI Listing
March 2021

Reply.

Ophthalmology 2021 Feb 4. Epub 2021 Feb 4.

Department of Radiation Sciences, Umeå University, Umeå, Sweden; Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2021.01.004DOI Listing
February 2021

Cerebral arterial pulsatility is linked to hippocampal microvascular function and episodic memory in healthy older adults.

J Cereb Blood Flow Metab 2021 Jan 14:271678X20980652. Epub 2021 Jan 14.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

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.
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http://dx.doi.org/10.1177/0271678X20980652DOI Listing
January 2021

Middle cerebral artery pressure laterality in patients with symptomatic ICA stenosis.

PLoS One 2021 8;16(1):e0245337. Epub 2021 Jan 8.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

An internal carotid artery (ICA) stenosis can potentially decrease the perfusion pressure to the brain. In this study, computational fluid dynamics (CFD) was used to study if there was a hemispheric pressure laterality between the contra- and ipsilateral middle cerebral artery (MCA) in patients with a symptomatic ICA stenosis. We further investigated if this MCA pressure laterality (ΔPMCA) was related to the hemispheric flow laterality (ΔQ) in the anterior circulation, i.e., ICA, proximal MCA and the proximal anterior cerebral artery (ACA). Twenty-eight patients (73±6 years, range 59-80 years, 21 men) with symptomatic ICA stenosis were included. Flow rates were measured using 4D flow MRI data (PC-VIPR) and vessel geometries were obtained from computed tomography angiography. The ΔPMCA was calculated from CFD, where patient-specific flow rates were applied at all input- and output boundaries. The ΔPMCA between the contra- and ipsilateral side was 6.4±8.3 mmHg (p<0.001) (median 3.9 mmHg, range -1.3 to 31.9 mmHg). There was a linear correlation between the ΔPMCA and ΔQICA (r = 0.85, p<0.001) and ΔQACA (r = 0.71, p<0.001), respectively. The correlation to ΔQMCA was weaker (r = 0.47, p = 0.011). In conclusion, the MCA pressure laterality obtained with CFD, is a promising physiological biomarker that can grade the hemodynamic disturbance in patients with a symptomatic ICA stenosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245337PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793245PMC
January 2021

Feasibility of MRI to assess differences in ophthalmic artery blood flow rate in normal tension glaucoma and healthy controls.

Acta Ophthalmol 2020 Nov 19. Epub 2020 Nov 19.

Department of Clinical Sciences, Ophthalmology, Umeå University, Umeå, Sweden.

Purpose: To examine feasibility of phase-contrast magnetic resonance imaging (PCMRI) and to assess blood flow rate in the ophthalmic artery (OA) in patients with normal tension glaucoma (NTG) compared with healthy controls.

Methods: Sixteen patients with treated NTG and 16 age- and sex-matched healthy controls underwent PCMRI using a 3-Tesla scanner and ophthalmological examinations. OA blood flow rate was measured using a 2D PCMRI sequence with a spatial resolution of 0.35 mm .

Results: The blood flow rate in the NTG group was 9.6 ± 3.9 ml/min [mean ± SD] compared with 11.9 ± 4.8 ml/min in the control group. Resistance Index (RI) and Pulsatility Index (PI) were 0.73 ± 0.08 and 1.36 ± 0.29, respectively, in the NTG group and 0.68 ± 0.13 and 1.22 ± 0.40, respectively, in the healthy group. The mean visual field index (VFI) was 46% ± 25 for the worse NTG eyes. The measured differences observed between the NTG group and the control group in blood flow rate (p = 0.12), RI (p = 0.18) and PI (p = 0.27) were non-significant.

Conclusions: This case-control study, using PCMRI, showed a slight, but non-significant, reduction in OA blood flow rate in the NTG patients compared with the healthy controls. These results indicate that blood flow may be of importance in the pathogenesis of NTG. Considering that only a limited portion of the total OA blood flow supplies the ocular system and the large inter-individual differences, a larger study or more advanced PCMRI technique might give the answer.
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http://dx.doi.org/10.1111/aos.14673DOI Listing
November 2020

Immediate effects of a single session of physical exercise on cognition and cerebral blood flow: A randomized controlled study of older adults.

Neuroimage 2021 01 24;225:117500. Epub 2020 Oct 24.

Aging Research Center (ARC), Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Tomtebodavägen 18A, 171 65 Stockholm, Sweden; Department of Psychology, University of Gothenburg, Gothenburg, Sweden.

Background: Regular physical activity is beneficial for cognitive performance in older age. A single bout of aerobic physical exercise can transiently improve cognitive performance. Researchers have advanced improvements in cerebral circulation as a mediator of long-term effects of aerobic physical exercise on cognition, but the immediate effects of exercise on cognition and cerebral perfusion are not well characterized and the effects in older adults are largely unknown.

Methods: Forty-nine older adults were randomized to a 30-min aerobic exercise at moderate intensity or relaxation. Groups were matched on age and cardiovascular fitness (VO2 max). Average Grey Matter Blood Flow (GMBF), measured by a pulsed arterial-spin labeling (pASL) magnetic resonance imaging (MRI) acquisition, and working memory performance, measured by figurative n-back tasks with increasing loads were assessed before and 7 min after exercising/resting.

Results: Accuracy on the n-back task increased from before to after exercising/resting regardless of the type of activity. GMBF decreased after exercise, relative to the control (resting) group. In the exercise group, higher n-back performance after exercise was associated with lower GMBF in the right hippocampus, left medial frontal cortex and right orbitofrontal cortex, and higher cardiovascular fitness was associated with lower GMBF.

Conclusion: The decrease of GMBF reported in younger adults shortly after exercise also occurs in older adults and relates to cardiovascular fitness, potentially supporting the link between cardiovascular fitness and cerebrovascular reactivity in older age.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117500DOI Listing
January 2021

Intraocular Pressure Decrease Does Not Affect Blood Flow Rate of Ophthalmic Artery in Ocular Hypertension.

Invest Ophthalmol Vis Sci 2020 Oct;61(12):17

Department of Clinical Sciences, Ophthalmology, Umeå University, Umeå, Sweden.

Purpose: To investigate if decrease of IOP affects the volumetric blood flow rate in the ophthalmic artery (OA) in patients with previously untreated ocular hypertension.

Methods: Subjects with untreated ocular hypertension (n = 30; mean age 67 ± 8 years; 14 females) underwent ophthalmologic examination and a 3-Tesla magnetic resonance imaging investigation. The magnetic resonance imaging included three-dimensional high-resolution phase-contrast magnetic resonance imaging to measure the OA blood flow rate. The subjects received latanoprost once daily in the eye with higher pressure, the untreated eye served as control. The same measurements were repeated approximately 1 week later.

Results: The mean OA blood flow rate before and after treatment was 12.4 ± 4.4 and 12.4 ± 4.6 mL/min in the treated eye (mean ± SD; P = 0.92) and 13.5 ± 5.2 and 13.4 ± 4.1 mL/min in the control eye (P = 0.92). There was no significant difference between the treated and control eye regarding blood flow rate before (P = 0.13) or after treatment (P = 0.18), or change in blood flow rate after treatment (0.1 ± 3.1 vs. -0.1 ± 4.0 mL/min, P = 0.84). Latanoprost decreased the IOP by 7.2 ± 3.1 mm Hg in the treated eye (P < 0.01).

Conclusions: The results indicate that a significant lowering of IOP does not affect the blood flow rate of the OA in ocular hypertension subjects. The ability to maintain blood supply to the eye independent of the IOP could be a protective mechanism in preserving vision in subjects with ocular hypertension.
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http://dx.doi.org/10.1167/iovs.61.12.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585392PMC
October 2020

Increased functional homotopy of the prefrontal cortex is associated with corpus callosum degeneration and working memory decline.

Neurobiol Aging 2020 12 25;96:68-78. Epub 2020 Aug 25.

Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden; Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden; Department of Radiation Sciences, Umeå University, Umeå, Sweden; Department of Integrative Medical Biology, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.

Functional homotopy reflects the link between spontaneous activity in a voxel and its counterpart in the opposite hemisphere. Alterations in homotopic functional connectivity (FC) are seen in normal aging, with highest and lowest homotopy being present in sensory-motor and higher-order regions, respectively. Homotopic FC relates to underlying structural connections, but its neurobiological underpinnings remain unclear. The genu of the corpus callosum joins symmetrical parts of the prefrontal cortex (PFC) and is susceptible to age-related degeneration, suggesting that PFC homotopic connectivity is linked to changes in white-matter integrity. We investigated homotopic connectivity changes and whether these were associated with white-matter integrity in 338 individuals. In addition, we examined whether PFC homotopic FC was related to changes in the genu over 10 years and working memory over 5 years. There were increases and decreases in functional homotopy, with the former being prevalent in subcortical and frontal regions. Increased PFC homotopic FC was partially driven by structural degeneration and negatively associated with working memory, suggesting that it reflects detrimental age-related changes.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.08.008DOI Listing
December 2020

Optic Nerve Length before and after Spaceflight.

Ophthalmology 2021 Feb 10;128(2):309-316. Epub 2020 Jul 10.

Department of Radiation Sciences, Umeå University, Umeå, Sweden; Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden. Electronic address:

Purpose: The spaceflight-associated neuro-ocular syndrome (SANS) affects astronauts on missions to the International Space Station (ISS). The SANS has blurred vision and ocular changes as typical features. The objective of this study was to investigate if microgravity can create deformations or movements of the eye or optic nerve, and if such changes could be linked to SANS.

Design: Cohort study.

Participants: Twenty-two astronauts (age 48 ± 4 years).

Methods: The intervention consisted of time in microgravity at the ISS. We co-registered pre- and postspaceflight magnetic resonance imaging (MRI) scans and generated centerline representations of the optic nerve. The coordinates for the optic nerve head (ONH) and optic chiasm (OC) ends of the optic nerve were recorded along with the entire centerline path.

Main Outcome Measures: Optic nerve length, ONH movement, and OC movement after time in microgravity.

Results: Optic nerve length increased (0.80 ± 0.74 mm, P < 0.001), primarily reflecting forward ONH displacement (0.63 ± 0.53 mm, P < 0.001). The forward displacement was positively related to mission duration, preflight body weight, and clinical manifestations of SANS. We also detected upward displacement of the OC (0.39 ± 0.50 mm, P = 0.002), indicative of brain movement, but this observation could not be linked to SANS.

Conclusions: The spaceflight-induced optic nerve lengthening and anterior movement of the ONH support that SANS is caused by an altered pressure difference between the brain and the eye, leading to a forward push on the posterior of the eye. Body weight is a potential contributing risk factor. Direct assessment of intracranial pressure in space is required to verify the implicated mechanism behind the ocular findings in SANS.
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http://dx.doi.org/10.1016/j.ophtha.2020.07.007DOI Listing
February 2021

The many facets of brain aging.

Elife 2020 04 16;9. Epub 2020 Apr 16.

Umeå center for Functional Brain Imaging, Umeå University, Umeå, Sweden.

Applying big-data analytic techniques to brain images from 18,707 individuals is shedding light on the influence of aging on the brain.
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http://dx.doi.org/10.7554/eLife.56640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162651PMC
April 2020

Longitudinal evidence that reduced hemispheric encoding/retrieval asymmetry predicts episodic-memory impairment in aging.

Neuropsychologia 2020 02 27;137:107329. Epub 2019 Dec 27.

Department of Radiation Sciences, Umeå University, S90187, Umeå, Sweden; Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Sweden; Department of Integrative Medical Biology, Umeå University, S90187, Umeå, Sweden.

The HERA (Hemispheric Encoding/Retrieval Asymmetry) model captures hemispheric lateralization of prefrontal cortex (PFC) brain activity during memory encoding and retrieval. Reduced HERA has been observed in cross-sectional aging studies, but there is no longitudinal evidence, to our knowledge, on age-related changes in HERA and whether maintained or reduced HERA relates to well-preserved memory functioning. In the present study we set out to explore HERA in a longitudinal neuroimaging sample from the Betula study [3 Waves over 10 years; Wave-1: n = 363, W2: n = 227, W3: n = 101]. We used fMRI data from a face-name paired-associates task to derive a HERA index. In support of the HERA model, the mean HERA index was positive across the three imaging waves. The longitudinal age-HERA relationship was highly significant (p < 10), with a HERA decline occurring after age 60. The age-related HERA decline was associated with episodic memory decline (p < 0.05). Taken together, the findings provide large-scale support for the HERA model, and suggest that reduced HERA in the PFC reflects pathological memory aging possibly related to impaired ability to bias mnemonic processing according to the appropriate encoding or retrieval state.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.107329DOI Listing
February 2020

Cerebral arterial pulsatility is associated with features of small vessel disease in patients with acute stroke and TIA: a 4D flow MRI study.

J Neurol 2020 Mar 14;267(3):721-730. Epub 2019 Nov 14.

Department of Pharmacology and Clinical Neuroscience, Umeå University, 90187, Umeå, Sweden.

Cerebral small vessel disease (SVD) is a major cause of stroke and cognitive impairment. However, the underlying mechanisms behind SVD are still poorly understood. High cerebral arterial pulsatility has been suggested as a possible cause of SVD. In population studies, arterial pulsatility has been linked to white matter hyperintensities (WMH), cerebral atrophy, and cognitive impairment, all features of SVD. In stroke, pulsatility data are scarce and contradictory. The aim of this study was to investigate the relationship between arterial pulsatility and SVD in stroke patients. With a cross-sectional design, 89 patients with acute ischemic stroke or TIA were examined with MRI. A neuropsychological assessment was performed 1 year later. Using 4D flow MRI, pulsatile indices (PI) were calculated for the internal carotid artery (ICA) and middle cerebral artery (M1, M3). Flow volume pulsatility (FVP), a measure corresponding to the cyclic expansion of the arterial tree, was calculated for the same locations. These parameters were assessed for associations with WMH volume, brain volume and cognitive function. ICA-FVP was associated with WMH volume (β = 1.67, 95% CI: [0.1, 3.24], p = 0.037). M1-PI and M1-FVP were associated with decreasing cognitive function (β = - 4.4, 95% CI: [- 7.7, - 1.1], p = 0.009 and β = - 13.15, 95% CI: [- 24.26, - 2.04], p = 0.02 respectively). In summary, this supports an association between arterial pulsatility and SVD in stroke patients, and provides a potential target for further research and preventative treatment. FVP may become a useful biomarker for assessing pulsatile stress with PCMRI and 4D flow MRI.
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http://dx.doi.org/10.1007/s00415-019-09620-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035303PMC
March 2020

Characterizing pulsatility in distal cerebral arteries using 4D flow MRI.

J Cereb Blood Flow Metab 2020 12 13;40(12):2429-2440. Epub 2019 Nov 13.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Recent reports have suggested that age-related arterial stiffening and excessive cerebral arterial pulsatility cause blood-brain barrier breakdown, brain atrophy and cognitive decline. This has spurred interest in developing non-invasive methods to measure pulsatility in distal vessels, closer to the cerebral microcirculation. Here, we report a method based on four-dimensional (4D) flow MRI to estimate a global composite flow waveform of distal cerebral arteries. The method is based on finding and sampling arterial waveforms from thousands of cross sections in numerous small vessels of the brain, originating from cerebral cortical arteries. We demonstrate agreement with internal and external reference methods and show the ability to capture significant increases in distal cerebral arterial pulsatility as a function of age. The proposed approach can be used to advance our understanding regarding excessive arterial pulsatility as a potential trigger of cognitive decline and dementia.
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http://dx.doi.org/10.1177/0271678X19886667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820688PMC
December 2020

Assessment of Cerebral Blood Flow Pulsatility and Cerebral Arterial Compliance With 4D Flow MRI.

J Magn Reson Imaging 2020 05 12;51(5):1516-1525. Epub 2019 Nov 12.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Background: Four-dimensional flow magnetic resonance imaging (4D flow MRI) enables efficient investigation of cerebral blood flow pulsatility in the cerebral arteries. This is important for exploring hemodynamic mechanisms behind vascular diseases associated with arterial pulsations.

Purpose: To investigate the feasibility of pulsatility assessments with 4D flow MRI, its agreement with reference two-dimensional phase-contrast MRI (2D PC-MRI) measurements, and to demonstrate how 4D flow MRI can be used to assess cerebral arterial compliance and cerebrovascular resistance in major cerebral arteries.

Study Type: Prospective.

Subjects: Thirty-five subjects (20 women, 79 ± 5 years, range 70-91 years).

Field Strength/sequence: 4D flow MRI (PC-VIPR) and 2D PC-MRI acquired with a 3T scanner.

Assessment: Time-resolved flow was assessed in nine cerebral arteries. From the pulsatile flow waveform in each artery, amplitude (ΔQ), volume load (ΔV), and pulsatility index (PI) were calculated. To reduce high-frequency noise in the 4D flow MRI data, the flow waveforms were low-pass filtered. From the total cerebral blood flow, total PI (PI ), total volume load (ΔV ), cerebral arterial compliance (C), and cerebrovascular resistance (R) were calculated.

Statistical Tests: Two-tailed paired t-test, intraclass correlation (ICC).

Results: There was no difference in ΔQ between 4D flow MRI and the reference (0.00 ± 0.022 ml/s, mean ± SEM, P = 0.97, ICC = 0.95, n = 310) with a cutoff frequency of 1.9 Hz and 15 cut plane long arterial segments. For ΔV, the difference was -0.006 ± 0.003 ml (mean ± SEM, P = 0.07, ICC = 0.93, n = 310) without filtering. Total R was 11.4 ± 2.41 mmHg/(ml/s) (mean ± SD) and C was 0.021 ± 0.009 ml/mmHg (mean ± SD). ΔV was 1.21 ± 0.29 ml (mean ± SD) with an ICC of 0.82 compared with the reference. PI was 1.08 ± 0.21 (mean ± SD).

Data Conclusion: We successfully assessed 4D flow MRI cerebral arterial pulsatility, cerebral arterial compliance, and cerebrovascular resistance. Averaging of multiple cut planes and low-pass filtering was necessary to assess accurate peak-to-peak features in the flow rate waveforms.

Level Of Evidence: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1516-1525.
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http://dx.doi.org/10.1002/jmri.26978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216927PMC
May 2020

Frontal Contribution to Hippocampal Hyperactivity During Memory Encoding in Aging.

Front Mol Neurosci 2019 25;12:229. Epub 2019 Sep 25.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Hippocampal - as well as -activation have been reported during memory encoding in older individuals. Prefrontal cortex (PFC) provides top-down state signals to the hippocampus that bias its computation during memory encoding and retrieval, and disturbed top-down signals could contribute to hippocampal hyper-activation. Here, we used >500 cross-sectional and longitudinal observations from a face-name encoding-retrieval fMRI task to examine hippocampal hypo- and hyper-activation in aging. Age-related anterior hippocampal hypo-activation was observed during memory encoding. Next, older individuals who longitudinally dropped-out were compared with those who remained in the study. Older dropouts had lower memory performance and higher dementia risk, and hyper-activated right anterior and posterior hippocampus during memory encoding. During encoding, the dropouts also activated right prefrontal regions that instead were active during retrieval in younger and older remainers. Moreover, the dropouts showed altered frontal-hippocampal functional connectivity, notably elevated right PFC to anterior hippocampus (aHC) connectivity during encoding. In the context of a general pattern of age-related anterior hippocampal hypo-activation during encoding, these findings support a top-down contribution to paradoxically high anterior hippocampal activity in older dropouts who were at elevated risk of pathology.
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http://dx.doi.org/10.3389/fnmol.2019.00229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798051PMC
September 2019

Cardiovascular factors are related to dopamine integrity and cognition in aging.

Ann Clin Transl Neurol 2019 11 30;6(11):2291-2303. Epub 2019 Oct 30.

Department of Radiation Sciences, Diagnostic Radiology, Umeå University, S-90187, Umeå, Sweden.

Objective: The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with age-related cognitive deficits. However, their relative importance, interrelations, and links to risk factors remain elusive.

Methods: The present work used magnetic resonance imaging and positron emission tomography with C-raclopride to jointly examine vascular parameters (white-matter lesions and perfusion), DA D2-receptor availability, brain structure, and cognitive performance in healthy older adults (n = 181, age: 64-68 years) from the Cognition, Brain, and Aging (COBRA) study.

Results: Covariance was found among several brain indicators, where top predictors of cognitive performance included caudate and hippocampal integrity (D2DR availability and volumes), and cortical blood flow and regional volumes. White-matter lesion burden was negatively correlated with caudate DA D2-receptor availability and white-matter microstructure. Compared to individuals with smaller lesions, individuals with confluent lesions (exceeding 20 mm in diameter) had reductions in cortical and hippocampal perfusion, striatal and hippocampal D2-receptor availability, white-matter microstructure, and reduced performance on tests of episodic memory, sequence learning, and processing speed. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey-matter volumes, a larger number of white-matter lesions, and lower episodic memory performance.

Interpretation: Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age-sensitive cognitive functions, with emphasis on DA integrity.
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http://dx.doi.org/10.1002/acn3.50927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856613PMC
November 2019

Mapping the landscape of human dopamine D2/3 receptors with [C]raclopride.

Brain Struct Funct 2019 Nov 23;224(8):2871-2882. Epub 2019 Aug 23.

Aging Research Center, Karolinska Institutet and Stockholm University, Tomtebodavägen 18A, 171 65, Solna, Sweden.

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 BP in the extrastriatal regions with [C]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]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]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways.
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http://dx.doi.org/10.1007/s00429-019-01938-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778542PMC
November 2019

At the Heart of Cognitive Functioning in Aging.

Trends Cogn Sci 2019 09 11;23(9):717-720. Epub 2019 Jul 11.

Department of Radiation Sciences, Umeå University, Umeå, Sweden; Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden; Department of Integrative Medical Biology, Umeå University, Umeå, Sweden. Electronic address:

Several neural and non-neural factors contribute to individual differences in cognitive performance. Here we outline a sequence of vascular events where excessive transfer of arterial-pressure pulsatility damages hippocampal capillaries. We argue that the vascular alterations decrease the ability to sustain neural activity and thereby contribute to episodic-memory impairment in aging.
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http://dx.doi.org/10.1016/j.tics.2019.06.004DOI Listing
September 2019

Secondary Acute Myeloid Leukemia and the Role of Allogeneic Stem Cell Transplantation in a Population-Based Setting.

Biol Blood Marrow Transplant 2019 09 6;25(9):1770-1778. Epub 2019 Jun 6.

Division of Hematology, Department of Medicine, Karolinska Institute, Stockholm, Sweden; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Secondary AML (s-AML), including AML with an antecedent hematologic disorder (AHD-AML) and therapy-related AML (t-AML), constitutes a large proportion of patients with AML and is considered to confer a dismal prognosis. The role of allogeneic hematopoietic cell transplantation (HCT) in patients with s-AML and the extent to which HCT is performed in these patients has been little studied to date. We used the population-based Swedish AML Registry comprising 3337 intensively treated adult patients over a 17-year period to study the role of HCT within the group of patients with s-AML as well as compared with patients with de novo AML. HCT was performed in 576 patients (22%) with de novo AML, in 74 patients (17%) with AHD-AML, and in 57 patients (20%) with t-AML. At 5 years after diagnosis, there were no survivors among patients with previous myeloproliferative neoplasms who did not undergo HCT, and corresponding survival for patients with antecedent myelodysplastic syndromes and t-AML was and 2% and 4%, respectively. HCT was compared with chemotherapy consolidation in s-AML using 3 models: (1) a 200-day landmark analysis, in which HCT was favorable compared with conventional consolidation (P = .04, log-rank test); (2) a multivariable Cox regression with HCT as a time-dependent variable, in which the hazard ratio for mortality was 0.73 (95% confidence interval, 0.64 to 0.83) for HCT and favored HCT in all subgroups; and (3) a propensity score matching analysis, in which the 5-year overall survival (OS) and relapse-free survival in patients with s-AML in first complete remission (CR1) was 48% and 43%, respectively, for patients undergoing HCT versus 20% and 21%, respectively, for those receiving chemotherapy consolidation (P = .01 and .02, respectively, log-rank test). Our observational data suggest that HCT improves survival and offers the only realistic curative treatment option in patients with s-AML.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.038DOI Listing
September 2019

Blood Flow Lateralization and Collateral Compensatory Mechanisms in Patients With Carotid Artery Stenosis.

Stroke 2019 05;50(5):1081-1088

From the Department of Pharmacology and Clinical Neuroscience, Umeå, Sweden (L.Z., J.M.).

Background and Purpose- Four-dimensional phase-contrast magnetic resonance imaging enables quantification of blood flow rate (BFR; mL/min) in multiple cerebral arteries simultaneously, making it a promising technique for hemodynamic investigation in patients with stroke. The aim of this study was to quantify the hemodynamic disturbance and the compensatory pattern of collateral flow in patients with symptomatic carotid stenosis. Methods- Thirty-eight patients (mean, 72 years; 27 men) with symptomatic carotid stenosis (≥50%) or occlusion were investigated using 4-dimensional phase-contrast magnetic resonance imaging. For each patient, BFR was measured in 19 arteries/locations. The ipsilateral side to the symptomatic carotid stenosis was compared with the contralateral side. Results- Internal carotid artery BFR was lower on the ipsilateral side (134±87 versus 261±95 mL/min; P<0.001). BFR in anterior cerebral artery (A1 segment) was lower on ipsilateral side (35±58 versus 119±72 mL/min; P<0.001). Anterior cerebral artery territory bilaterally was primarily supplied by contralateral internal carotid artery. The ipsilateral internal carotid artery mainly supplied the ipsilateral middle cerebral artery (MCA) territory. MCA was also supplied by a reversed BFR found in the ophthalmic and the posterior communicating artery routes on the ipsilateral side (-5±28 versus 10±28 mL/min, P=0.001, and -2±12 versus 6±6 mL/min, P=0.03, respectively). Despite these compensations, BFR in MCA was lower on the ipsilateral side, and this laterality was more pronounced in patients with severe carotid stenosis (≥70%). Although comparing ipsilateral MCA BFR between stenosis groups (<70% and ≥70%), there was no difference ( P=0.95). Conclusions- With a novel approach using 4-dimensional phase-contrast magnetic resonance imaging, we could simultaneously quantify and rank the importance of collateral routes in patients with carotid stenosis. An important observation was that contralateral internal carotid artery mainly secured the bilateral anterior cerebral artery territory. Because of the collateral recruitment, compromised BFR in MCA is not necessarily related to the degree of carotid stenosis. These findings highlight the importance of simultaneous investigation of the hemodynamics of the entire cerebral arterial tree.
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http://dx.doi.org/10.1161/STROKEAHA.119.024757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485302PMC
May 2019

Accuracy of blood flow assessment in cerebral arteries with 4D flow MRI: Evaluation with three segmentation methods.

J Magn Reson Imaging 2019 08 14;50(2):511-518. Epub 2019 Jan 14.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Background: Accelerated 4D flow MRI allows for high-resolution velocity measurements with whole-brain coverage. Such scans are increasingly used to calculate flow rates of individual arteries in the vascular tree, but detailed information about the accuracy and precision in relation to different postprocessing options is lacking.

Purpose: To evaluate and optimize three proposed segmentation methods and determine the accuracy of in vivo 4D flow MRI blood flow rate assessments in major cerebral arteries, with high-resolution 2D PCMRI as a reference.

Study Type: Prospective.

Subjects: Thirty-five subjects (20 women, 79 ± 5 years, range 70-91 years).

Field Strength/sequence: 4D flow MRI with PC-VIPR and 2D PCMRI acquired with a 3 T scanner.

Assessment: We compared blood flow rates measured with 4D flow MRI, to the reference, in nine main cerebral arteries. Lumen segmentation in the 4D flow MRI was performed with k-means clustering using four different input datasets, and with two types of thresholding methods. The threshold was defined as a percentage of the maximum intensity value in the complex difference image. Local and global thresholding approaches were used, with evaluated thresholds from 6-26%.

Statistical Tests: Paired t-test, F-test, linear correlation (P < 0.05 was considered significant) along with intraclass correlation (ICC).

Results: With the thresholding methods, the lowest average flow difference was obtained for 20% local (0.02 ± 15.0 ml/min, ICC = 0.97, n = 310) or 10% global (0.08 ± 17.3 ml/min, ICC = 0.97, n = 310) thresholding with a significant lower standard deviation for local (F-test, P = 0.01). For all clustering methods, we found a large systematic underestimation of flow compared with 2D PCMRI (16.1-22.3 ml/min).

Data Conclusion: A locally adapted threshold value gives a more stable result compared with a globally fixed threshold. 4D flow with the proposed segmentation method has the potential to become a useful reliable clinical tool for assessment of blood flow in the major cerebral arteries.

Level Of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:511-518.
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http://dx.doi.org/10.1002/jmri.26641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767555PMC
August 2019

Dopamine D Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.

J Neurosci 2019 01 26;39(3):537-547. Epub 2018 Nov 26.

Umeå Center for Functional Brain Imaging.

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA-BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) -back task along with DA D PET assessment using [C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D receptors to BOLD response in the thalamo-striatal-cortical circuit, which supports WM functioning. Critically, the DA-BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA-BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA-BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks. Dopamine (DA) is a major neuromodulator in the CNS and plays a key role in several cognitive processes via modulating the blood oxygenation level-dependent (BOLD) signal. Some studies have shown a link between DA and BOLD, whereas others have failed to observe such a relationship. A possible reason for the discrepancy is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. We examined the relationship of DA to BOLD response during working memory under three load conditions and found that the DA-BOLD association is expressed in a load-dependent fashion. These findings may help explain the disproportionate impairment evident in more effortful cognitive tasks in normal aging and in those suffering dopamine-dependent neurodegenerative diseases (e.g., Parkinson's disease).
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http://dx.doi.org/10.1523/JNEUROSCI.1493-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335744PMC
January 2019

Rehabilitation in chronic spatial neglect strengthens resting-state connectivity.

Acta Neurol Scand 2019 Mar 3;139(3):254-259. Epub 2018 Dec 3.

Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.

Objectives: Rehabilitation of patients with chronic visuospatial neglect is underexplored, and little is known about neural mechanisms that can be exploited to promote recovery. In this study, we present data on resting-state functional connectivity within the dorsal attention network (DAN) in chronic neglect patients as they underwent training in a virtual reality (VR) environment that improved left-side awareness.

Methods: The study included 13 patients with visuospatial neglect persisting more than six months after a right-sided stroke. The patients underwent resting-state functional magnetic resonance imaging (fMRI). Scans were collected at baseline and after five weeks of intense training. We specifically examined resting-state functional connectivity within the DAN. In addition, using spatial concordance correlation, we compared changes in the spatial topology of the DAN with that of other networks.

Results: We found a longitudinal increase in interhemispheric functional connectivity between the right frontal eye field and the left intraparietal sulcus following training (before: 0.33 ± 0.17 [mean ± SD]; after: 0.45 ± 0.13; P = 0.004). The spatial concordance analyses indicated that training influenced the DAN connectivity more than any of the other networks.

Conclusion: Intense VR training that improved left-sided awareness in chronic stroke patients also increased sporadic interhemispheric functional connectivity within the DAN. Specifically, a region responsible for saccadic eye movement to the left became more integrated with the left posterior parietal cortex. These results highlight a mechanism that should be exploited in the training of patients with chronic visuospatial neglect.
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http://dx.doi.org/10.1111/ane.13048DOI Listing
March 2019

C957T-mediated Variation in Ligand Affinity Affects the Association between C-raclopride Binding Potential and Cognition.

J Cogn Neurosci 2019 02 8;31(2):314-325. Epub 2018 Nov 8.

Umeå University.

The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with C-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64-68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of C-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that C-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between C-raclopride BP and cognitive performance. In accordance with previous findings, we show that C-raclopride BP was increased in T-homozygotes. Importantly, C-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest C-raclopride BP-cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and C-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.
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http://dx.doi.org/10.1162/jocn_a_01354DOI Listing
February 2019

Assessment of Neutrophil Chemotaxis Upon G-CSF Treatment of Healthy Stem Cell Donors and in Allogeneic Transplant Recipients.

Front Immunol 2018 11;9:1968. Epub 2018 Sep 11.

Department of Clinical Microbiology & Laboratory of Molecular Infection Medicine Sweden, Umeå University, Umeå, Sweden.

Neutrophils are crucial for the human innate immunity and constitute the majority of leukocytes in circulation. Thus, blood neutrophil counts serve as a measure for the immune system's functionality. Hematological patients often have low neutrophil counts due to disease or chemotherapy. To increase neutrophil counts and thereby preventing infections in high-risk patients, recombinant G-CSF is widely used as adjunct therapy to stimulate the maturation of neutrophils. In addition, G-CSF is utilized to recruit stem cells (SCs) into the peripheral blood of SC donors. Still, the actual functionality of neutrophils resulting from G-CSF treatment remains insufficiently understood. We tested the functionality of neutrophils isolated from blood of G-CSF-treated healthy SC donors. We quantified chemotaxis, oxidative burst, and phagocytosis before and after treatment and detected significantly reduced chemotactic activity upon G-CSF treatment. Similarly, treatment of previously untreated neutrophils with G-CSF led to reduced chemotactic activity. In addition, we revealed that this effect persists in the allogeneic SC recipients up to 4 weeks after neutrophil engraftment. Our data indicates that neutrophil quantity, as a sole measure of immunocompetence in high-risk patients should be considered cautiously as neutrophil functionality might be affected by the primary treatment.
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http://dx.doi.org/10.3389/fimmu.2018.01968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141688PMC
September 2019

Self-rated intensity of habitual physical activities is positively associated with dopamine D receptor availability and cognition.

Neuroimage 2018 11 21;181:605-616. Epub 2018 Jul 21.

Aging Research Center, Karolinska Institutet and Stockholm University, S-11330, Stockholm, Sweden.

Between-person differences in cognitive performance in older age are associated with variations in physical activity. The neurotransmitter dopamine (DA) contributes to cognitive performance, and the DA system deteriorates with advancing age. Animal data and a patient study suggest that physical activity modulates DA receptor availability, but data from healthy humans are lacking. In a cross-sectional study with 178 adults aged 64-68 years, we investigated links among self-reported physical activity, D2/D3 DA receptor (DDR) availability, and cognitive performance. DDR availability was measured with [C]raclopride positron emission tomography at rest. We used structural equation modeling to obtain latent factors for processing speed, episodic memory, working memory, physical activity, and DDR availability in caudate, putamen, and hippocampus. Physical activity intensity was positively associated with DDR availability in caudate, but not putamen and hippocampus. Frequency of physical activity was not related to DDR availability. Physical activity intensity was positively related to episodic memory and working memory. DDR availability in caudate and hippocampus was positively related to episodic memory. Taken together, our results suggest that striatal DA availability might be a neurochemical correlate of episodic memory that is also associated with physical activity.
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http://dx.doi.org/10.1016/j.neuroimage.2018.07.036DOI Listing
November 2018