Dopamine D1-Receptor Organization Contributes to Functional Brain Architecture.

Recent work has recognized a gradient-like organization in cortical function, spanning from primary sensory to transmodal cortices. It has been suggested that this axis is aligned with regional differences in neurotransmitter expression. Given the abundance of dopamine D1-receptors (D1DR), and its importance for modulation and neural gain, we tested the hypothesis that D1DR organization is aligned with functional architecture, and that inter-regional relationships in D1DR co-expression modulate functional cross talk. Using the world's largest dopamine D1DR-PET and MRI database (N = 180%, 50% female), we demonstrate that D1DR organization follows a unimodal-transmodal hierarchy, expressing a high spatial correspondence to the principal gradient of functional connectivity. We also demonstrate that individual differences in D1DR density between unimodal and transmodal regions are associated with functional differentiation of the apices in the cortical hierarchy. Finally, we show that spatial co-expression of D1DR primarily modulates couplings within, but not between, functional networks. Together, our results show that D1DR co-expression provides a biomolecular layer to the functional organization of the brain.

Human brain clearance imaging: Pathways taken by magnetic resonance imaging contrast agents after administration in cerebrospinal fluid and blood.

Over the last decade, it has become evident that cerebrospinal fluid (CSF) plays a pivotal role in brain solute clearance through perivascular pathways and interactions between the brain and meningeal lymphatic vessels. Whereas most of this fundamental knowledge was gained from rodent models, human brain clearance imaging has provided important insights into the human system and highlighted the existence of important interspecies differences. Current gold standard techniques for human brain clearance imaging involve the injection of gadolinium-based contrast agents and monitoring their distribution and clearance over a period from a few hours up to 2 days. With both intrathecal and intravenous injections being used, which each have their own specific routes of distribution and thus clearance of contrast agent, a clear understanding of the kinetics associated with both approaches, and especially the differences between them, is needed to properly interpret the results. Because it is known that intrathecally injected contrast agent reaches the blood, albeit in small concentrations, and that similarly some of the intravenously injected agent can be detected in CSF, both pathways are connected and will, in theory, reach the same compartments. However, because of clear differences in relative enhancement patterns, both injection approaches will result in varying sensitivities for assessment of different subparts of the brain clearance system. In this opinion review article, the "EU Joint Programme - Neurodegenerative Disease Research (JPND)" consortium on human brain clearance imaging provides an overview of contrast agent pharmacokinetics in vivo following intrathecal and intravenous injections and what typical concentrations and concentration-time curves should be expected. This can be the basis for optimizing and interpreting contrast-enhanced MRI for brain clearance imaging. Furthermore, this can shed light on how molecules may exchange between blood, brain, and CSF.

Cerebral Blood Flow Patterns in Patients With Low-Flow Carotid Artery Stenosis, a 4D-PCMRI Assessment.

BACKGROUND: Compromised cerebral blood flow can contribute to future ischemic events in patients with symptomatic carotid artery disease. However, there is limited knowledge of the effects on cerebral hemodynamics resulting from a reduced internal carotid artery (ICA) blood flow rate (BFR). PURPOSE: Investigate how reduced ICA-BFR, relates to BFR in the cerebral arteries. STUDY TYPE: Prospective. SUBJECTS: Thirty-eight patients, age 72 ± 6 years (11 female). FIELD STRENGTH/SEQUENCE: 3-Tesla, four-dimensional phase-contrast magnetic resonance imaging (4D-PCMRI). ASSESSMENT: Patients with ischemic stroke or transient ischemic attack were evaluated regarding the degree of stenosis. 4D-PCMRI was used to measure cerebral BFR in 38 patients with symptomatic carotid stenosis (≥50%). BFR in the cerebral arteries was assessed in two subgroups based on symptomatic ICA-BFR: reduced ICA-flow (<160 mL/minutes) and preserved ICA-flow (≥160 mL/minutes). BFR laterality was defined as a difference in the paired ipsilateral-contralateral arteries. STATISTICAL TESTS: Patients were grouped based on ICA-BFR (reduced vs. preserved). Statistical tests (independent sample t-test/paired t-test) were used to compare groups and hemispheres. Significance was determined at P < 0.05. RESULTS: The degree of stenosis was not significantly different, 80% (95% confidence interval [CI] = 73%-87%) in the reduced ICA-flow vs. 72% (CI = 66%-76%) in the preserved ICA-flow; P = 0.09. In the reduced ICA-flow group, a significantly reduced BFR was found in the ipsilateral middle cerebral artery and anterior cerebral artery (A1), while significantly increased in the contralateral A1. Retrograde BFR was found in the posterior communicating artery and ophthalmic artery. Significant BFR laterality was present in all paired arteries in the reduced ICA-flow group, contrasting the preserved ICA-flow group (P = 0.14-0.93). DATA CONCLUSIONS: 4D-PCMRI revealed compromised cerebral BFR due to carotid stenosis, not possible to detect by solely analyzing the degree of stenosis. In patients with reduced ICA-flow, collaterals were not sufficient to maintain symmetrical BFR distribution to the two hemispheres. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Cerebral Blood Flow Assessed with Phase-contrast Magnetic Resonance Imaging during Blood Pressure Changes with Noradrenaline and Labetalol: A Trial in Healthy Volunteers.

BACKGROUND: Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on mean arterial pressure (MAP) as a surrogate, even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase-contrast magnetic resonance imaging to characterize blood flow responses in healthy volunteers to commonly used pharmacologic agents that increase or decrease arterial blood pressure. METHODS: Eighteen healthy volunteers aged 30 to 50 yr were investigated with phase-contrast magnetic resonance imaging. Intra-arterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase-contrast magnetic resonance imaging and defined as the sum of flow in the internal carotid arteries and vertebral arteries. Cardiac output (CO) was defined as the flow in the ascending aorta. RESULTS: Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg-1 · h-1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03). CONCLUSIONS: In healthy, awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. These data do not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

Phase-contrast magnetic resonance imaging of intracranial and extracranial blood flow in carotid near-occlusion.

PURPOSE: Compare extracranial internal carotid artery flow rates and intracranial collateral use between conventional ≥ 50% carotid stenosis and carotid near-occlusion, and between symptomatic and asymptomatic carotid near-occlusion. METHODS: We included patients with ≥ 50% carotid stenosis. Degree of stenosis was diagnosed on CTA. Mean blood flow rates were assessed with four-dimensional phase-contrast MRI. RESULTS: We included 110 patients of which 83% were symptomatic, and 38% had near-occlusion. Near-occlusions had lower mean internal carotid artery flow (70 ml/min) than conventional ≥ 50% stenoses (203 ml/min, P < .001). Definite use of ≥ 1 collateral was found in 83% (35/42) of near-occlusions and 10% (7/68) of conventional stenoses (P < .001). However, there were no differences in total cerebral blood flow (514 ml/min vs. 519 ml/min, P = .78) or ipsilateral hemispheric blood flow (234 vs. 227 ml/min, P = .52), between near-occlusions and conventional ≥ 50% stenoses, based on phase-contrast MRI flow rates. There were no differences in total cerebral or hemispheric blood flow, or collateral use, between symptomatic and asymptomatic near-occlusions. CONCLUSION: Near-occlusions have lower internal carotid artery flow rates and more collateral use, but similar total cerebral blood flow and hemispheric blood flow, compared to conventional ≥ 50% carotid stenosis.

5-Year Associations among Cerebral Arterial Pulsatility, Perivascular Space Dilation, and White Matter Lesions.

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  ≥  0.24; p < 0.02 and R  ≥  0.23; p < 0.03, respectively) and LCS models ( ß  = 0.28; p = 0.015 and ß  = 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. ANN NEUROL 2022;92:871-881.

4D flow MRI hemodynamic biomarkers for cerebrovascular diseases.

Alterations in cerebral blood flow are common in several neurological diseases among the elderly including stroke, cerebral small vessel disease, vascular dementia, and Alzheimer's disease. 4D flow magnetic resonance imaging (MRI) is a relatively new technique to investigate cerebrovascular disease, and makes it possible to obtain time-resolved blood flow measurements of the entire cerebral arterial venous vasculature and can be used to derive a repertoire of hemodynamic biomarkers indicative of cerebrovascular health. The information that can be obtained from one single 4D flow MRI scan allows both the investigation of aberrant flow patterns at a focal location in the vasculature as well as estimations of brain-wide disturbances in blood flow. Such focal and global hemodynamic biomarkers show the potential of being sensitive to impending cerebrovascular disease and disease progression and can also become useful during planning and follow-up of interventions aiming to restore a normal cerebral circulation. Here, we describe 4D flow MRI approaches for analyzing the cerebral vasculature. We then survey key hemodynamic biomarkers that can be reliably assessed using the technique. Finally, we highlight cerebrovascular diseases where one or multiple hemodynamic biomarkers are of central interest.

DyNAMiC: A prospective longitudinal study of dopamine and brain connectomes: A new window into cognitive aging.

Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age-related cognitive decline is crucial in promoting healthy aging. Here, we present the DopamiNe, Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5-year longitudinal study spanning the adult human lifespan. DyNAMiC examines age-related changes in the brain's structural and functional connectome in relation to changes in dopamine D1 receptor availability (D1DR), and their associations to cognitive decline. Critically, due to the complete lack of longitudinal D1DR data, the true trajectory of one of the most age-sensitive dopamine systems remains unknown. The first DyNAMiC wave included 180 healthy participants (20-80 years). Brain imaging included magnetic resonance imaging assessing brain structure (white matter, gray matter, iron), perfusion, and function (during rest and task), and positron emission tomography (PET) with the [11 C]SCH23390 radioligand. A subsample (n = 20, >65 years) was additionally scanned with [11 C]raclopride PET measuring D2DR. Age-related variation was evident for multiple modalities, such as D1DR; D2DR, and performance across the domains of episodic memory, working memory, and perceptual speed. Initial analyses demonstrated an inverted u-shaped association between D1DR and resting-state functional connectivity across cortical network nodes, such that regions with intermediate D1DR levels showed the highest levels of nodal strength. Evident within each age group, this is the first observation of such an association across the adult lifespan, suggesting that emergent functional architecture depends on underlying D1DR systems. Taken together, DyNAMiC is the largest D1DR study worldwide, and will enable a comprehensive examination of brain mechanisms underlying age-related cognitive decline.

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

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.

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

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.

When functional blurring becomes deleterious: Reduced system segregation is associated with less white matter integrity and cognitive decline in aging.

Healthy aging is accompanied by progressive decline in cognitive performance and concomitant changes in brain structure and functional architecture. Age-accompanied alterations in brain function have been characterized on a network level as weaker functional connections within brain networks along with stronger interactions between networks. This phenomenon has been described as age-related differences in functional network segregation. It has been suggested that functional networks related to associative processes are particularly sensitive to age-related deterioration in segregation, possibly related to cognitive decline in aging. However, there have been only a few longitudinal studies with inconclusive results. Here, we used a large longitudinal sample of 284 participants between 25 to 80 years of age at baseline, with cognitive and neuroimaging data collected at up to three time points over a 10-year period. We investigated age-related changes in functional segregation among two large-scale systems comprising associative and sensorimotor-related resting-state networks. We found that functional segregation of associative systems declines in aging with exacerbated deterioration from the late fifties. Changes in associative segregation were positively associated with changes in global cognitive ability, suggesting that decreased segregation has negative consequences for domain-general cognitive functions. Age-related changes in system segregation were partly accounted for by changes in white matter integrity, but white matter integrity only weakly influenced the association between segregation and cognition. Together, these novel findings suggest a cascade where reduced white-matter integrity leads to less distinctive functional systems which in turn contributes to cognitive decline in aging.

Optic Nerve Length before and after Spaceflight.

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.

Quantification and mapping of cerebral hemodynamics before and after carotid endarterectomy, using four-dimensional flow magnetic resonance imaging.

BACKGROUND: Carotid stenosis can profoundly affect cerebral hemodynamics, which cannot simply be inferred from the degree of stenosis. We quantified and mapped the distribution of the blood flow rate (BFR) in the cerebral arteries before and after carotid endarterectomy using four-dimensional (4D) phase-contrast (PC) magnetic resonance imaging (MRI). METHODS: Nineteen patients (age, 71 ± 6 years; 2 women) with symptomatic carotid stenosis (≥50%) undergoing carotid endarterectomy (CEA) were investigated using 4D PC-MRI before and after surgery. The BFR was measured in 17 cerebral arteries and the ophthalmic arteries. Collateral recruitment through the anterior and posterior communicating arteries, ophthalmic arteries, and leptomeningeal arteries was quantified. BFR laterality was significantly different between the paired contralateral and ipsilateral arteries. Subgroups were defined according to the presence of collateral recruitment. RESULTS: The total cerebral blood flow had increased by 15% (P < .01) after CEA. Before CEA, laterality was seen in the internal carotid artery, anterior cerebral artery, and middle cerebral artery (MCA). On the ipsilateral side, an increased BFR was found after CEA in the internal carotid artery (246 ± 62 mL/min vs 135 ± 80 mL/min; P < .001), anterior cerebral artery (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 the nine patients with preoperatively recruited collaterals, BFR laterality was found in the MCA before, but not after, CEA (P < .01). This laterality was not found in the 10 patients without collateral recruitment (P = .2). The degree of stenosis did not differ between the groups with and without collateral recruitment (P = .85). CONCLUSIONS: Using 4D PC-MRI, we have presented a comprehensive and noninvasive method to evaluate the cerebral hemodynamics due to carotid stenosis before and after CEA. MCA laterality, seen in the patients with collateral recruitment before CEA, pointed toward a hemodynamic disturbance in MCA territory for those patients. This methodologic advancement provides an insight into the pathophysiology of cerebral hemodynamics in patients with carotid stenosis.

Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.

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) n-back task along with DA D2/3 PET assessment using [11C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D2/3 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.SIGNIFICANCE STATEMENT 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).

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

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 (PItot ), total volume load (ΔVtot ), 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). ΔVtot was 1.21 ± 0.29 ml (mean ± SD) with an ICC of 0.82 compared with the reference. PItot 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.

C957T-mediated Variation in Ligand Affinity Affects the Association between 11C-raclopride Binding Potential and Cognition.

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 11C-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 11C-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that 11C-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 11C-raclopride BP and cognitive performance. In accordance with previous findings, we show that 11C-raclopride BP was increased in T-homozygotes. Importantly, 11C-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 11C-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 11C-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.

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

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.

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

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.

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

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.

Rehabilitation in chronic spatial neglect strengthens resting-state connectivity.

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.