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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.

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.

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.

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.

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.

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.

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.