BACKGROUND:Although clinical evaluation, radiological findings, and supplementary tests are routinely used to diagnose idiopathic normal pressure hydrocephalus (INPH), the large variability in surgical outcomes raises the question of whether diagnostic radiological markers truly reflect the typical clinical gait impairment. Gait disorder (GD) and ventriculomegaly (VM) are both common in older adults and may coincide by chance, potentially contributing to this inconsistency in results. This study aimed to determine the prevalence of typical INPH-related higher-level gait disorder (HLGD), diagnosed independently of imaging, and assess its association with VM and other MRI features. METHODS:In this case-control study, 6467 individuals age 65-84 years were screened for GD per questionnaire. Physicians with experience of neurological GD identified cases with HLGD and matched controls without GD through clinical evaluation of 1047 of these individuals. Subsequently, brain MRI (n = 909) or CT (n = 98) was performed. After exclusions, 81 with HLGD and 192 controls remained. Radiological hydrocephalus features were compared between the groups. RESULTS:The prevalence of HLGD in the general older population was 5.8%. For HLGD combined with Evans Index (EI)>0.3, it was 3.7%, and 1.7% had HLGD with Disproportionately Enlarged Subarachnoid space Hydrocephalus (DESH). The estimated prevalence of asymptomatic VM, i.e. EI > 0.3 without GD, was 24%, and 4.1% had asymptomatic VM with DESH. Individuals with HLGD were older and performed worse on cognitive tests. Radiology revealed higher ventricular volumes and EI, and a more acute callosal angle in HLGD versus controls. DESH was also more frequent in HLGD (29% vs 7%, p < 0.001). Despite group-level differences, individual overlap was substantial. MRI markers showed poor to moderate ability to discriminate HLGD (AUC 0.614-0.765) from normal gait. CONCLUSIONS:In this population-based case-control study, both HLGD and EI > 0.3 were common. EI > 0.3 occurred more frequently with HLGD, but it was also common in asymptomatic individuals, indicating that ventriculomegaly is not specific to HLGD. Most MRI biomarkers showed limited ability to distinguish HLGD from normal gait, although lateral ventricular volume divided by total intracranial volume (relative ventricular volume) was the most informative. The frequent occurrence of EI > 0.3 and DESH in asymptomatic individuals highlights the need for longitudinal studies to clarify prognosis in these individuals.

Several aging-related brain changes have been associated with unsuccessful cognitive aging, including dopamine decline, increased astrocyte reactivity, and cerebral small-vessel disease (SVD). We hypothesized that dopamine decline is exacerbated in older adults with higher measures of astrocyte reactivity and cerebral SVD, and that reduced dopamine integrity would be the strongest predictor of lower cognitive performance. Healthy adults (n = 55, ages: 60-79 years) underwent positron emission tomography with ligands 18F-FE-PE2I to estimate levels of dopamine transporters (DAT) and 11C-L-deprenyl-D2 to estimate levels of monoamine oxidase B (MAO-B)-a protein expressed to some degree by neurons but mainly by astrocytes. Cerebral SVD was assessed by white matter lesion volumes from magnetic resonance images. General cognition was evaluated via tests of episodic memory, working memory, and perceptual speed. Contrary to expectations, increased MAO-B levels (indicative of astrocyte reactivity) were associated with higher DAT availability (r = 0.53, p < 0.001) and reduced white matter lesion volumes (r = -0.33, p = 0.021). Reduced DAT availability was more strongly related to reduced MAO-B (r = 0.47, p < 0.001) than white matter lesion volumes (r = -0.22, p > 0.05), and only DAT was a significant predictor of cognition (r = 0.36, p = 0.032). These findings underscore the critical role of dopamine for cognition and indicate reduced glial function to underlie dopaminergic losses.

PURPOSE:The aim was to estimate T1 relaxivity of gadobutrol and gadoteric acid in cerebrospinal fluid (CSF) at 3T, to support research on CSF-flow and the glymphatic system in humans utilizing T1 mapping after intrathecal injection. METHODS:Using a phantom, relaxivity was estimated for gadobutrol and gadoteric acid in lumbar CSF and an isotonic solution. All samples were scanned simultaneously using the variable flip angle method with B1 correction, repeated six times on one 3T scanner, and once on a second 3T scanner. Difference in relaxivity between CSF and the isotonic solution were evaluated from the repeated measurements. RESULTS:There was a significant difference in relaxivity between CSF and the isotonic solution for both gadobutrol and gadoteric acid. The relaxivity for gadobutrol for the respective scanners was estimated to 3.02 ± 0.09 vs. 3.63 L mmol-1 s-1 in CSF and 2.35 ± 0.05 vs. 2.74 L mmol-1 s-1 in isotonic solution. For gadoteric acid, corresponding results were 2.47 ± 0.02 vs. 2.91 L mmol-1 s-1 in CSF and 2.37 ± 0.03 vs. 2.8 L mmol-1 s-1 in isotonic solution. Between the scanners, there was a high correlation (R2 0.998) but an 18% scaling difference in the T1 relaxation rates and corresponding relaxivities. CONCLUSIONS:The relaxivity was higher in CSF than in the isotonic solution, particularly for gadobutrol. Systematic differences in relaxivity between scanners may potentially be corrected using a scaling factor derived from the T1 time of baseline CSF. For CSF studies using T1 mapping with a gadolinium-based contrast agent, we recommend using a CSF-specific relaxivity constant.

ABSTRACT Introduction Autism spectrum disorder, or autism, is a common neurodevelopmental condition characterized by socio-communicative problems together with restrictive and repetitive behaviors. Typically, the latter is manifested as deficits in behavioral flexibility, i.e. changing routine behaviors to adapt to environmental changes. Despite noticeable difficulties with flexible behavior in autism, there is to date not adequate knowledge about the intricacies of such challenges and neurobiological processes that may subserve them. This study aims to investigate both cognitive and motor flexibility in autistic compared with neurotypical adults using a novel combination of detailed methods for brain imaging and behavioral investigations in relation to probabilistic reversal learning (PRL) paradigms. In addition, the experiences of autistic adults on flexible behavior in education and everyday activities will be explored. Methods and analysis Differences in cognitive flexibility between autistic (n≥20) and neurotypical (n≥20) adults (18-35 years) will be investigated in terms of brain activations, measured by functional magnetic resonance imaging (fMRI), during two-choice PRL performance (cognitive task). In addition, group differences in microcirculation as measured by arterial spin labelling (ASL) will be evaluated. Group differences in motor flexibility will be investigated as expressed in movement planning and execution (spatio-temporal parameters), measured by a robotic manipulandum platform (KinArm End-Point Robot), during two-choice PRL performance (motor task). Semi-structured interviews will be conducted individually with autistic participants (n=15). Questions concern own experiences of cognitive and motor behavior, and strategies used to support flexibility in these behaviors. Data from this qualitative approach will be analyzed by thematic analysis. Ethics and dissemination Ethical approval has been obtained from the Swedish Ethical Review Authority (ref:2025-07939-01) and the study will be conducted in accordance with the Declaration of Helsinki, the European Union General Data Protection Regulation (GDPR) and national guidelines for the storing of personal data. The different investigations included are well-established, non-invasive and safe. Study outcomes will be published in peer-reviewed international scientific journals (open access), presented at national and international conferences, and to any interested audience/stakeholders. STRENGHTS AND LIMITATIONS OF THIS STUDY High-resolution measurements will be used to collect data on the nature of both cognitive and motor flexibility in autistic adults within a narrow age range. The study is expected to generate novel data revealing the links between brain activation, cerebral blood flow, and ability for flexible behavior in autism. Includes the voices of autistic adults themselves regarding experiences of flexible behavior in educational and leisure contexts. Flexible behavior in quantitative data collection is limited to performance on probabilistic reversal learning tasks.

According to glymphatic system theory, cerebrospinal fluid (CSF) perfuses the brain's interstitial space to support waste clearance, but the magnitude of this flow and the outflow pathway of interstitial fluid (ISF) in humans remain uncertain. To achieve flow quantification, we applied a compartment-model approach applied in conjunction with serial quantitative MRI data acquired after intrathecal gadolinium administration. Using the method, we estimated CSF-to-ISF inflow to 45 ± 20 mL/h, in patients with suspected idiopathic normal pressure hydrocephalus. Tissue-specific contributions were 34 ± 14 mL/h in cortical gray matter, 11±6 mL/h in white matter, and 0.4 ± 0.3 mL/h in subcortical gray matter, suggesting that CSF perfusion occurs primarily in superficial regions near the subarachnoid space. A lack of correlation between inflow and total craniospinal system outflow (r = 0.03, P = 0.91) suggested that ISF recirculates back into CSF rather than exiting the craniospinal system via a separate route. Independent experiments in healthy older individuals using intravenous gadolinium administration supported ISF-to-CSF recirculation, where contrast material that presumably crossed the blood-brain barrier subsequently appeared in the subarachnoid space, allowing ISF-to-CSF flow quantification. These findings provide a quantitative framework for studying brain clearance in humans and support subarachnoid space recirculation as an important efflux route.

BACKGROUND AND OBJECTIVES:Glymphatic function affects brain health and could be part of the pathophysiology in idiopathic normal-pressure hydrocephalus. Elevated intracranial pressure pulsatility and increased resistance to cerebrospinal fluid (CSF) outflow (Rout) are commonly observed in idiopathic normal-pressure hydrocephalus. Whether such alterations indicate impaired glymphatic function or affect ventricle volumetrics in ordinary elderly is unknown. We investigated the associations between CSF dynamics and changes in cognitive performance, gait, and brain MRI parameters over a 10-year period in a cohort of healthy older adults. METHODS:Twenty-nine subjects (mean age 79 ± 6, range 71-92 years) were investigated with brain MRI, clinical testing, and a CSF infusion test. MRI and clinical testing were repeated after 10 years. An automated software program was used to calculate ventricle volumes, and linear ventricle radiological indices were calculated (Evan's index, callosal angle, and z-Evan's index). CSF dynamic parameters were correlated with longitudinal changes in clinical and MRI parameters. RESULTS:In a multivariable regression model including age, sex, baseline cognitive performance, and CSF dynamic parameters, lower CSF outflow resistance was associated with better cognitive performance after 10 years (standardized β = 0.37, P = .047, n = 29). In a bivariate analysis, outflow resistance had a negative correlation to the difference in cognitive testing score between baseline and follow-up (r = -.44, 95% CI -0.701 to -0.08, P = .017, n = 29, Spearman's rho). CSF dynamic parameters were not associated with changes in gait performance or ventricle volume. Intracranial pressure pulsatility was associated with reduced callosal angle (standardized β = -0.35, P = .02, n = 29) and intracranial pressure with increased z-Evan's index (standardized β = 0.18, P = .003, n = 29). CONCLUSION:Our results provide insight into the complexity of CSF physiology and its possible role in longitudinal change in brain function and structure. Measurement of CSF outflow characteristics hold potential in furthering the understanding of glymphatic performance with regard to change in cognitive function and warrants further investigation.

PURPOSE:Cerebrospinal fluid (CSF) flow oscillations have emerged as a potentially important marker related to brain clearance, but their acquisition often relies on specialized imaging MRI sequences. The purpose of this work was to enable quantitative assessment of CSF flow associated with cardiac, respiratory, and low-frequency cycles using widely available functional magnetic resonance imaging (fMRI) acquisitions. METHODS:A method was developed to translate fMRI-derived CSF inflow signals into quantitative flow rates. This approach modeled the spin-history of an oscillating ensemble of molecules. Validation was performed using phantom experiments with cardiac-, respiratory-, and low-frequency-like oscillatory flow. The method was further applied to resting-state data from 48 older adults (68-82 years, 19 women) to characterize CSF flow at the foramen magnum. RESULTS:Phantom experiments demonstrated excellent correlations between estimated and true velocities for cardiac- and respiratory-like frequencies (r = 0.94 and 0.97, respectively) and moderate correlation for the low-frequency-like oscillation (r = 0.58). In the population cohort, median CSF stroke volumes were 0.77 [0.57, 1.09] mL for the cardiac cycle, 0.38 [0.26, 0.88] mL for the respiratory cycle, and 0.26 [0.14, 0.39] mL for the low-frequency cycle. CONCLUSION:The proposed spin-history modeling method enabled quantitative estimation of CSF flow components using a conventional fMRI dataset and showed that the cardiac cycle dominates CSF motion at the foramen magnum.

Normal aging is associated with decline in dopamine function. Factors associated with individual differences in dopamine decline rates remain unclear but are important to map to spare dopamine-related functions, such as cognition. Here we focused on manifestations of cerebral small-vessel disease from magnetic resonance imaging (white-matter lesions, lacunes, and perivascular space dilation) and vascular risk factors (e.g., hypertension, body mass index (BMI), and hyperlipidemia). We assessed striatal dopamine D2-like receptor (DRD2) reductions across five years in healthy, older adults (n = 129, ages: 64-68 years at baseline) using 11C-raclopride/positron emission tomography. Manifestations of confluent lesions and lacunes at baseline had additive effects on DRD2 decline. Individuals with both manifestations showed fastest DRD2 decline rates (∼ -4 %), followed by those with one manifestation (∼ -2 %), whereas individuals spared of confluent lesions and lacunes showed stable DRD2 levels over time (∼ 0 % change). Furthermore, individuals with confluent lesions or lacunes showed more marked decline in perceptual speed performance, as compared to individuals spared of these manifestations (p < 0.05). Higher systolic blood pressure and lower BMI at baseline were associated with faster 5-year DRD2 decline in the putamen (r = -0.17, p < 0.05) and caudate (r = 0.23, p < 0.05), respectively. Together, confluent lesions and lacunes explained up to 8 % of striatal DRD2 change, and up to 10 % when adding hypertension and BMI to the model. These findings suggest that hallmarks of SVD and certain vascular risk factors predispose faster DRD2 decline in aging and may thus serve as factors to consider in future interventions.

Disproportionately enlarged subarachnoid space hydrocephalus (DESH) is a radiological biomarker for idiopathic normal pressure hydrocephalus (iNPH). DESH is a subjective measure, based on visual assessments, which may limit its reliability. The aim of this study was to develop and validate a method for the objective quantification of DESH. By using a semiautomatic quantitative method, we calculated quantitative DESH (qDESH), defined as a ratio between CSF volumes at high convexities and Sylvian fissures. The analysis was based on three-dimensional T1-weighted images from 35 subjects with iNPH (mean age 74 yrs; 10 females) and 45 controls (mean age 72 yrs; 13 females). The interrater agreement for qDESH was evaluated by the intraclass correlation coefficient, and qDESH was compared with visual assessments performed by two neuroradiologists. All subjects with iNPH and 13

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.

A single, arterial-optimized 4D-flow MRI acquisition may enable fast assessment of both cerebral arterial and venous flow. However, arteries and veins require different velocity encoding (VENC) settings for optimal velocity-to-noise ratio (VNR). Consequently, venous measurements using arterial-optimized VENC settings are subject to reduced VNR and require further evaluation. This study compared cerebral venous flow and pulsatility assessments using a high-VENC (110 cm/s, adapted to the arterial system) and a low-VENC (40 cm/s, adapted to the venous system) 4D-flow MRI sequence at 3 Tesla. Flow and pulsatility index (PI) were calculated for cerebral veins, sinuses and internal jugular veins in 36 elderly volunteers (79 ± 5 years). The high-VENC acquisitions allowed visualization of nearly all venous structures. Mean flow differences were small and the correlation, strong, when comparing both acquisitions across sinuses (R = 0.90–0.99, difference = -8–7%) and cortical veins (R = 0.93, difference = − 6%). Inflow-outflow differences at the confluence of sinuses were similar between acquisitions. PI showed moderate to strong agreement except in the straight sinus. Both the vein of Galen and the jugular veins suffered from aliasing in the venous VENC acquisitions. In summary, this study demonstrated that a VENC setting adapted for the arterial cerebral circulation was feasible for studying cerebral venous flow and pulsatility.

Abstract 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.

White matter lesions (WML) and dilated perivascular spaces (PVS) are features of small vessel disease (SVD), commonly observed in aging and dementia, with unknown pathophysiology. Human studies have documented contrast accumulation within and in proximity of SVD-lesions. However, whether such observations mainly reflect excessive blood-brain barrier (BBB) leakage, or altered microvascular density in the investigated regions, remains unclear. To evaluate the roles of BBB leakage and vascular density in aging and SVD, dynamic contrast enhanced (DCE) MRI was used to estimate the permeability-surface area product (PS) and fractional plasma volume ( v_p ) in normal-appearing brain tissue and in proximity of and within WML and PVS in a population-based cohort (N = 56; 34/22 m/f; age 64 to 84 years). Analysis of variance (ANOVA) was used to assess regional differences in PS and v_p and analysis of covariance (ANCOVA) was used to assess regional differences in PS with v_p and vascular risk as covariates. Pronounced increases in PS and v_p were observed from normal-appearing white matter (NAWM) to WML peripheries to WMLs. Similar PS and v_p increases were observed from basal ganglia (BG) to BG-PVS. Further, PS in NAWM and white matter (WM) PVS were found to increase with cortex-to-ventricular depth. However, ANCOVA models with v_p as a covariate showed that variance in PS was mainly explained by vp (η2=0.17 to η2=0.35; all p < 10− 3), whereas the effect of region was only borderline-significant when comparing NAWM, WML peripheries and WML (p = 0.03) and non-significant for the other comparisons (p > 0.29). Our findings support the notion that contrast leakage across the BBB accumulates within and in proximity of SVD-related lesions. However, high contrast accumulation may mainly reflect high vascularization, and to a lesser degree than previously recognized BBB dysfunction.

BACKGROUND:Induced hypertension is used clinically to increase cerebral blood flow (CBF) in conditions such as vasospasm after subarachnoid hemorrhage. However, increased blood pressure also raises pulsatile force. Cerebrovascular compliance plays a key role in buffering flow dynamics and protecting the microcirculation, but whether it adapts to elevated pressure remains unclear. This study assessed the response of compliant cerebral arteries to induced hypertension in healthy adults using phase-contrast magnetic resonance imaging (PCMRI) and two compliance models: a two-element Windkessel (compliance estimated using the Windkessel model, C WK ) and a simplified model (compliance calculated as the ratio of pulsatile volume to pressure, C VP ), representing the extremes of pulsatility transmission at the capillary level. METHODS:Eighteen healthy adults (median age, 34 yr; nine women) underwent PCMRI at baseline and after increasing mean arterial pressure by 20% using norepinephrine infusion. PCMRI quantified CBF and cardiac output, while cerebrovascular resistance and systemic vascular resistance were derived. Flow waveforms were combined with blood pressure to assess C WK and C VP in CBF, ascending/descending aorta, and external carotid arteries, while corresponding regions of interest were used to calculate cross-sectional flow areas. Data are reported as median (interquartile range). RESULTS:Norepinephrine increased cerebrovascular compliance significantly: C WK by 110% (56 to 163%; P = 0.001) and C VP by 11% (-2 to 26%; P = 0.018). C WK increased in the external carotid artery by 12% (1 to 32%; P = 0.037) but did not change in the ascending or descending aorta. C VP decreased in the descending aorta by 5% (-11 to 2%; P = 0.028), with no changes in the ascending aorta or external carotid artery. Cross-sectional area of cerebral arteries contributing to CBF decreased by 5% (-17 to -3%; P = 0.033), while the ascending and descending aorta areas increased by 7% (4 to 11%; P = 0.012) and 8% (6 to 11%; P < 0.001), respectively. CONCLUSIONS:Cerebral arteries enhanced their compliance during norepinephrine-induced hypertension, unlike systemic arteries, regardless of the assumed degree of pulsatility transmission.

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.

Aging-related dopamine decline has been suggested as a key factor behind individual differences in cognitive decline at older ages. Thus far, the hypothesized age-dopamine-cognition triad has been extrapolated from cross-sectional studies, which cannot uncover change associations. Using data from the longitudinal Cognition, Brain, and Aging (COBRA) study, we examined whether dopamine D2-receptor availability changes are correlated with cognitive changes across individuals in old age. At the first wave, 181 healthy adults aged 64 to 68 years underwent positron emission tomography with 11C-raclopride, magnetic resonance imaging, multiple cognitive tests assessing episodic memory, working memory, and perceptual speed, and mapping of health-related factors. The returnees (n = 129 after 5 years; n = 93 after 10 years) were representative of the parent sample regarding gender composition, educational attainment, cognitive performance, and dopamine D2-receptor status at baseline. Bayesian structural equation modeling revealed mean decline and individual differences in decline for striatal dopamine D2-receptor availability (approximately -5% per decade) and for all three cognitive abilities. Changes in dopamine D2-receptor and a factor of general cognition were positively correlated (r = 0.31, P(r > 0.00) > 0.95). Taken together, these longitudinal findings support that striatal dopamine decline is associated with cognitive aging, possibly reflecting dopamine influences via striato-thalamo-cortical loops on general cognitive functions.

INTRODUCTION: INPH is diagnosed based on clinical criteria and physiological measurements, including brain imaging parameters. Increased aqueductal CSF flow dynamics, assessed with Phase-Contrast MRI (PC-MRI), is one of the supportive features in iNPH diagnostic guidelines. A predictive value has been suggested but remains largely debatable. This study aimed to clarify the role of aqueductal flow in supporting diagnosis and shunt selection for iNPH patients. METHODS We retrospectively included 92 iNPH patients with preoperative PC-MRI together with pre- and post-operative gait speed measurement. Aqueductal CSF flow dynamics were calculated and correlated with gait outcomes and baseline gait speed. Additionally, we compared our cohort with 42 age-matched healthy controls. RESULTS We found no significant differences in CSF flow parameters between shunt responders and non-responders: Stroke volume was 130 ± 90 and 150 ± 100 µl, p = 0.32 respectively, with net flows of 0.06 ± 1.71 and − 0.07 ± 1.51 ml/min, p = 0.563. There were no correlations of aqueduct CSF dynamics with baseline gait performance, nor with gait change (-0.15 < R < 0.1, p > 0.5 for all parameters). Furthermore, comparisons with healthy controls revealed differences in stroke volume (140 ± 100µl iNPH vs 80 ± 41 healthy, p < 0.001) but not in net flow (p > 0.05). CONCLUSIONS Our findings indicate no significant predictive value of aqueductal CSF dynamics for shunt efficacy in iNPH patients. The heterogeneity of iNPH and variability in CSF dynamics across its time course, may contribute to these negative results. From a clinical point of view, aqueductal flow measured by 2D PC-MRI appears to have very limited value for selecting patients for shunting.

Studying cerebrospinal fluid (CSF) flow can reveal physiological and neural drivers of potential importance in brain clearance. CSF flow may be acquired in functional magnetic resonance imaging (fMRI) scans by considering the inflow effect in an edge-slice. Such measurements have large potential considering the broad availability of fMRI, and the already extensive databases focusing on e.g. aging and dementia. However, limiting factors are that the measurements are not quantitative and can rarely separate contributions from different driving mechanisms due to insufficient sampling rate. Here, we present a method that translates fMRI CSF signals into quantitative flow rates associated with cardiac, respiratory and slow-vasomotion cycles, by modeling the spin-history of an oscillating ensemble of molecules. Phantom experiments showed excellent correlations between estimated and true velocities for cardiac- and respiratory-like frequencies, and moderate correlations for a slow vasomotion-like frequency (r = 0.94, 0.97, 0.58 respectively). We also applied the method in a cohort of 48 subjects from the population (68-82 years, 19 women) to characterize CSF flow at the foramen magnum at resting state. These measurements showed a CSF stroke volume of 0.86 [0.61, 1.17] mL for the cardiac, 0.44 [0.25, 0.94] mL for the respiratory, and 0.28 [0.14, 0.45] mL for the slow vasomotion cycle. In conclusion, the method presented here enabled quantitative assessments of CSF flow compatible with typical fMRI acquisitions and showed that the cardiac cycle is a dominant driver of CSF flow. ### Competing Interest Statement The authors have declared no competing interest. Swedish Research Council, 2022-04263 Swedish Heart-Lung Foundation, 20210653 Swedish Foundation for Strategic Research, RMX18-0152

BACKGROUND:Maintaining cerebral perfusion during anesthesia and intensive care is critical, yet the relationship between mean arterial pressure (MAP) and cerebral blood flow (CBF) remains poorly defined. In patients with aneurysmal subarachnoid hemorrhage (aSAH), pharmacologically induced hypertension is commonly applied to support cerebral perfusion, but its effects are uncertain. METHODS:This protocol describes two parallel clinical studies using identical methodology. The first study population includes adults undergoing elective general anesthesia (MAP-ANE), and the second comprises sedated intensive care patients with aSAH (MAP-SAH). In both study populations, MAP will be increased stepwise with norepinephrine (NE) infusion under continuous invasive blood pressure monitoring, and CBF measured with phase-contrast MRI (PCMRI) and arterial spin labeling (ASL), while near-infrared spectroscopy (NIRS) will be performed in parallel to evaluate its validity as a surrogate marker. The primary outcome is the change in total CBF between baseline and elevated MAP, directly testing whether induced hypertension increases CBF. Secondary outcomes include ASL perfusion changes, the slope of the MAP-CBF relationship, systemic-cerebral hemodynamic correlations, and NIRS responses. EXPECTED IMPACT:These studies test the hypothesis that pharmacological MAP augmentation does not predictably increase CBF. By combining quantitative MRI with invasive monitoring, it aims to clarify MAP-CBF interactions, define the physiological basis of induced hypertension, and assess whether NIRS can serve as a clinically useful proxy. Findings are expected to inform safer and more individualized blood pressure management in perioperative and neurocritical care. The studies are registered at ClinicalTrials.gov (MAP-ANE: NCT06855407; MAP-SAH: NCT06033378). TRIAL REGISTRATION:ClinicalTrials.gov, MAP-ANE NCT06855407, MAP-SAH NCT06033378.

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 ($${v}_{p}$$ v p ), 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 $${v}_{p}$$ v p 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.