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Although age differences in the dopamine system have been suggested to contribute to age-related cognitive decline based on cross-sectional data, recent large-scale cross-sectional studies reported only weak evidence for a correlation among aging, dopamine receptor availability, and cognition. Regardless, longitudinal data remain essential to make robust statements about dopamine losses as a basis for cognitive aging. We present correlations between changes in D2/3 dopamine receptor availability and changes in working memory measured over 5 yr in healthy, older adults (n = 128, ages 64 to 68 yr at baseline). Greater decline in D2/3 dopamine receptor availability in working memory-relevant regions (caudate, middle frontal cortex, hippocampus) was related to greater decline in working memory performance in individuals who exhibited working memory reductions across time (n = 43; caudate: rs = 0.494; middle frontal cortex: rs = 0.506; hippocampus; rs = 0.423), but not in individuals who maintained performance (n = 41; caudate: rs = 0.052; middle frontal cortex: rs = 0.198; hippocampus; rs = 0.076). The dopamine–working memory link in decliners was not observed in the orbitofrontal cortex, which does not belong to the core working memory network. Our longitudinal analyses support the notion that aging-related changes in the dopamine system contribute to working memory decline in aging.

Higher-Level Gait Disorder (HLGD) is a type of gait disorder estimated to affect up to 6% of the older population. By definition, its symptoms originate from the higher-level nervous system, yet its association with brain morphology remains unclear. This study hypothesizes that there are patterns in brain morphology linked to HLGD. For the first time in the literature, this work investigates whether deep learning, in the form of convolutional neural networks, can capture patterns in magnetic resonance images to identify individuals affected by HLGD. To handle this new classification task, we propose setting up an ensemble of models. This leverages the benefits of combining classifiers instead of determining which network is the most suitable, developing a new architecture, or customizing an existing one. We introduce a computationally cost-effective search algorithm to find the optimal ensemble by leveraging a cost function of both traditional performance scores and the diversity among the models. Using a unique dataset from a large population-based cohort (VESPR), the ensemble identified by our algorithm demonstrated superior performance compared to single networks, other ensemble fusion techniques, and the best linear radiological measure. This emphasizes the importance of implementing diversity into the cost function. Furthermore, the results indicate significant morphological differences in brain structure between HLGD-affected individuals and controls, motivating research about which areas the networks base their classifications on, to get a better understanding of the pathophysiology of HLGD.

Background: Normal brain aging is associated with dopamine decline, which has been linked to age-related cognitive decline. Factors underlying individual differences in dopamine integrity at older ages remain, however, unclear. Here we aimed at investigating: (i) whether inflammation is associated with levels and 5-year changes of in vivo dopamine D2-receptor (DRD2) availability, (ii) if DRD2-inflammation associations differ between men and women, and (iii) whether inflammation and cerebral small-vessel disease (white-matter lesions) serve as two independent predictors of DRD2 availability.

Methods: Analyses were performed in a sample of healthy adults > 60 years assessed at two measurement occasions separated by 5 years. At both occasions, DRD2 availability was estimated by ¹¹C-raclopride PET, and white-matter lesions by MRI. Inflammation was assessed by two C-reactive protein-associated DNA methylation scores at study baseline.

Results: Individuals with higher DNA methylation scores at baseline showed reduced striatal DRD2 availability. An interaction was found between DNA methylation scores and sex in relation to striatal DRD2 availability, such that associations were found in men but not in women. DNA methylation scores at study entrance were not significantly associated with 5-year striatal DRD2 decline rates. No significant association was found between DNA methylation scores and white-matter lesions, but higher scores as well as higher lesion burden were independently associated with reduced striatal DRD2 availability in men.

Conclusions: These findings suggest negative associations between one proxy of inflammation and DRD2 availability in older adults, selectively for men who had higher DNA methylation scores. Future studies should investigate other inflammatory markers in relation to dopamine integrity.

Selective antegrade cerebral perfusion (SACP) is a protective procedure to ascertain adequate brain perfusion during aortic arch surgeries requiring moderate hypothermic circulatory arrest. SACP entails catheterization of arteries feeding the brain, which can be done bilaterally (bSACP) or unilaterally (uSACP), but there is no consensus on when to use each approach. bSACP may increase the risk of embolization, while uSACP risks hypoperfusion due to insufficient perfusion pressure in the contralateral hemisphere, since a single catheter must perfuse both hemispheres. We developed and tested the feasibility of a new method for predicting cerebral perfusion pressures (CPP) during SACP, which could potentially aid clinicians in preoperatively identifying which SACP approach to use. Feasibility of the method was evaluated in five patients eligible for aortic arch surgery (65 ± 7 years, 3 men). Patients were investigated preoperatively with computed tomography angiography (CTA) and 4D flow magnetic resonance imaging (MRI) to assess patient-specific arterial anatomy and blood flows. From the imaging, computational fluid dynamics (CFD) simulations estimated the patients' vascular resistances. Applying these resistances and intraoperative SACP pressure/flow settings to the model's boundary conditions allowed for predictions of contralateral CPP during SACP. Predicted pressures were compared to corresponding intraoperative pressure measurements. The method showed promise for predicting contralateral CPP during both uSACP (median error (range): 2.4 (−0.2–18.0) mmHg) and bSACP (0.8 (−3.3–5.4) mmHg). Predictions were most sensitive to collateral artery size. This study showed the feasibility of CPP predictions of SACP, and presents key features needed for accurate modelling.

Variations in cerebral blood flow and blood volume interact with intracranial pressure and cerebrospinal fluid dynamics, all of which play a crucial role in brain homeostasis. A key physiological modulator is respiration, but its impact on cerebral blood flow and volume has not been thoroughly investigated. Here we used 4D flow MRI in a population-based sample of 65 participants (mean age = 75 ± 1) to quantify these effects. Two gating approaches were considered, one using respiratory-phase and the other using respiratory-time (i.e. raw time in the cycle). For both gating methods, the arterial inflow was significantly larger during exhalation compared to inhalation, whereas the venous outflow was significantly larger during inhalation compared to exhalation. The cerebral blood volume variation per respiratory cycle was 0.83 [0.62, 1.13] ml for respiratory-phase gating and 0.78 [0.59, 1.02] ml for respiratory-time gating. For comparison, the volume variation of the cardiac cycle was 1.01 [0.80, 1.30] ml. Taken together, our results clearly demonstrate respiratory influences on cerebral blood flow. The corresponding vascular volume variations appear to be of the same order of magnitude as those of the cardiac cycle, highlighting respiration as an important modulator of cerebral blood flow and blood volume.

Blood-brain barrier (BBB) disruption may contribute to cognitive decline, but questions remain whether this association is more pronounced for certain brain regions, such as the hippocampus, or represents a whole-brain mechanism. Further, whether human BBB leakage is triggered by excessive vascular pulsatility, as suggested by animal studies, remains unknown. In a prospective cohort (N = 50; 68-84 years), we used contrast-enhanced MRI to estimate the permeability-surface area product (PS) and fractional plasma volume ( formula presented ), and 4D flow MRI to assess cerebral arterial pulsatility. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) score. We hypothesized that high PS would be associated with high arterial pulsatility, and that links to cognition would be specific to hippocampal PS. For 15 brain regions, PS ranged from 0.38 to 0.85 (·10-3 min-1) and formula presented from 0.79 to 1.78%. Cognition was related to PS (·10-3 min-1) in hippocampus (β = - 2.9; p = 0.006), basal ganglia (β = - 2.3; p = 0.04), white matter (β = - 2.6; p = 0.04), whole-brain (β = - 2.7; p = 0.04) and borderline-related for cortex (β = - 2.7; p = 0.076). Pulsatility was unrelated to PS for all regions (p > 0.19). Our findings suggest PS-cognition links mainly reflect a whole-brain phenomenon with only slightly more pronounced links for the hippocampus, and provide no evidence of excessive pulsatility as a trigger of BBB disruption.

White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66–85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV’s stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.

Background: Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on 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 MRI to characterize blood flow responses in healthy volunteers to commonly used pharmacological agents that increase or decrease arterial blood pressure.

Methods: Eighteen healthy volunteers aged 30-50 years were investigated with phase contrast MRI. Intraarterial 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 MRI and defined as the sum of flow in the internal carotid arteries and vertebral arteries. CO was defined as the flow in the ascending aorta.

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).

Conclusion: In healthy awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. This data does not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

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.

Introduction: The aim of this study was to assess sensitivity, specificity and interrater reliability of phase-contrast MRI (PC-MRI) for diagnosing carotid near-occlusion.

Patients and methods: Prospective cross-sectional study conducted between 2018 and 2021. We included participants with suspected 50%–100% carotid stenosis on at least one side, all were examined with CT angiography (CTA) and PC-MRI and both ICAs were analyzed. Degree of stenosis on CTA was the reference test. PC-MRI-based blood flow rates in extracranial ICA and intracranial cerebral arteries were assessed. ICA-cerebral blood flow (CBF) ratio was defined as ICA divided by sum of both ICAs and Basilar artery.

Results: We included 136 participants. The ICAs were 102 < 50% stenosis, 88 conventional ⩾50% stenosis (31 with ⩾70%), 49 near-occlusion, 12 occlusions, 20 unclear cause of small distal ICA on CTA and one excluded. For separation of near-occlusion and conventional stenoses, ICA flow rate and ICA-CBF ratio had the highest area under the curve (AUC; 0.98–0.99) for near-occlusion. ICA-CBF ratio ⩽0.225 was 90% (45/49) sensitive and 99% (188/190) specific for near-occlusion. Inter-rater reliability for this threshold was excellent (kappa 0.98). Specificity was 94% (29/31) for cases with ⩾70% stenosis. PC-MRI had modest performance for separating <50% and conventional ⩾50% stenosis (highest AUC 0.74), and eight (16%) of near-occlusions were not distinguishable from occlusion (no visible flow).

Conclusion: ICA-CBF ratio ⩽0.225 on PC-MRI is an accurate and reliable method to separate conventional ⩾50% stenosis and near-occlusion that is feasible for routine use. PC-MRI should be considered further as a potential standard method for near-occlusion detection, to be used side-by-side with established modalities as PC-MRI cannot separate other degrees of stenosis.