The choroid plexus (ChP) comprises a collection of modified ependymal cells that play an important role in the production of brain cerebrospinal fluid (CSF), and ChP perfusion aberrations have been implicated in a range of cerebrovascular and neurodegenerative disorders. To provide an exemplar for the growing interest in ChP activity, we evaluated ChP perfusion and bulk CSF flow cross-sectionally across the healthy adult lifespan. Participants (n = 77; age range = 21–86 years) were scanned at 3T using T1-weighted, T2-weighted-FLAIR, perfusion-weighted pCASL, and phase contrast MRI to calculate ChP anatomy, perfusion, and aqueductal CSF flow, respectively. Regression models were applied to evaluate aging effects on ChP volume and ChP perfusion in the lateral ventricles, as well as CSF flow. ChP volume (mean ± std = 2.81 ± 1.1 cm3) increased (p < 0.001), ChP perfusion (36.3 ± 8.6 mL/100 g/min) decreased (p = 0.0078), and ChP total blood flow (1.13 ± 0.34 mL/min) increased (p < 0.001) with age. Cranial-to-caudal net CSF flow (0.245 ± 0.20 mL/min) decreased, absolute CSF flow (4.86 ± 2.96 mL/min) increased, and CSF regurgitant fraction (0.87 ± 0.126) increased with age (all: p < 0.001). ChP perfusion was directly related to net cranial-to-caudal CSF flow through the aqueduct (p = 0.033). The implications of these findings are discussed in the context of the growing literature on CSF circulatory dysfunction in neurodegeneration and cerebrovascular disease.

Background Recent studies have suggested alternative cerebrospinal fluid (CSF) clearance pathways for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of these pathways is the anatomic region surrounding the superior sagittal sinus, which has been shown to have relevance to trans-arachnoid molecular passage. This so-called parasagittal dural (PSD) space may play a physiologically significant role as a distal intracranial component of the human glymphatic circuit, yet fundamental gaps persist in our knowledge of how this space changes with normal aging and intracranial bulk fluid transport. Methods We re-parameterized MRI methods to assess CSF circulation in humans using high resolution imaging of the PSD space and phase contrast measures of flow through the cerebral aqueduct to test the hypotheses that volumetric measures of PSD space (1) are directly related to CSF flow (mL/s) through the cerebral aqueduct, and (2) increase with age. Multi-modal 3-Tesla MRI was applied in healthy participants (n = 62; age range = 20–83 years) across the adult lifespan whereby phase contrast assessments of CSF flow through the aqueduct were paired with non-contrasted T1-weighted and T2-weighted MRI for PSD volumetry. PSD volume was extracted using a recently validated neural networks algorithm. Non-parametric regression models were applied to evaluate how PSD volume related to tissue volume and age cross-sectionally, and separately how PSD volume related to CSF flow (significance criteria: two-sided p < 0.05). Results A significant PSD volume enlargement in relation to normal aging (p < 0.001, Spearman’s-$$\rho$$ ρ  = 0.6), CSF volume (p < 0.001, Spearman’s-$$\rho$$ ρ  = 0.6) and maximum CSF flow through the aqueduct of Sylvius (anterograde and retrograde, p < 0.001) were observed. The elevation in PSD volume was not significantly related to gray or white matter tissue volumes. Findings are consistent with PSD volume increasing with age and bulk CSF flow. Conclusions Findings highlight the feasibility of quantifying PSD volume non-invasively in vivo in humans using machine learning and non-contrast MRI. Additionally, findings demonstrate that PSD volume increases with age and relates to CSF volume and bi-directional flow. Values reported should provide useful normative ranges for how PSD volume adjusts with age, which will serve as a necessary pre-requisite for comparisons to persons with neurodegenerative disorders.

Cognitive control processes encompass many distinct components, including response inhibition (stopping a prepotent response), proactive control (using prior information to enact control), reactive control (last-minute changing of a prepotent response), and conflict monitoring (choosing between two competing responses). While frontal midline theta activity is theorized to be a general marker of the need for cognitive control, a stringent test of this hypothesis would require a quantitative, within-subject comparison of the neural activation patterns indexing many different cognitive control strategies, an experiment lacking in the current literature. We recorded EEG from 176 participants as they performed tasks that tested inhibitory control (Go/Nogo Task), proactive and reactive control (AX-Continuous Performance Task), and resolving response conflict (Global/Local Task-modified Flanker Task). As activity in the theta (4–8 Hz) frequency band is thought to be a common signature of cognitive control, we assessed frontal midline theta activation underlying each cognitive control strategy. In all strategies, we found higher frontal midline theta power for trials that required more cognitive control (target conditions) versus control conditions. Additionally, reactive control and inhibitory control had higher theta power than proactive control and response conflict, and proactive control had higher theta power than response conflict. Using decoding analyses, we were able to successfully decode control from target trials using classifiers trained exclusively on each of the other strategies, thus firmly demonstrating that theta representations of cognitive control generalize across multiple cognitive control strategies. Our results confirm that frontal midline theta-band activity is a common mechanism for initiating and executing cognitive control, but theta power also differentiates between cognitive control mechanisms. As theta activation reliably differs depending on the cognitive control strategy employed, future work will need to focus on the differential role of theta in differing cognitive control strategies.

Background: Recent studies have suggested the importance of a glymphatic clearance pathway for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of this pathway is the anatomic region surrounding the superior sagittal sinus, which has been hypothesized to encompass lymphatic vessels. This so-called parasagittal dural (PSD) space likely plays a physiologically significant role at the distal intracranial component of the human glymphatic circuit, yet owing to the relative novelty of this discovery, fundamental gaps persist in our knowledge of how this space changes with normal aging and intracranial bulk fluid transport. Methods: We tested the hypotheses that volumetric magnetic resonance imaging (MRI) measures of the PSD space (i) are directly related to cerebrospinal fluid (CSF) flow at the cerebral aqueduct, and (ii) increase with age. Healthy participants (n=62; age range = 20-83 years) provided informed, written consent and multi-modal 3 Tesla MRI was performed including phase contrast assessment of the CSF flow through the aqueduct of Sylvius, T1-weighted and T2-weighted MRI for tissue volume and PSD assessment. Standard anatomical and cognitive testing were applied to confirm inclusion criteria. PSD volume was extracted using a recently validated neural networks algorithm. Non-parametric regression models were applied to evaluate how PSD volume related to tissue volume and age cross-sectionally, and separately how PSD volume related to CSF flux (significance criteria: two-sided p<0.05). Results: A significant enlargement of PSD volume in relation to normal aging (p<0.001, Spearman’s- =0.6), CSF volume (p<0.001, Spearman’s- =0.6) and bulk CSF flux through the aqueduct of Sylvius (anterograde and retrograde, p<0.001) were observed. The elevation in PSD volume was not significantly related to changes in tissue volume (p=0.11 and p=0.24 for gray and white matter, respectively). Findings are consistent with PSD volume increasing with age and bulk CSF flux.Conclusions: The findings of this study are two folds, first they highlight the feasibility of quantifying PSD volume non-invasively in vivo in humans using machine learning and non-contrast MRI. Second, that PSD volume increases with age, and relates to bulk CSF volume and flux. Values reported should provide useful normative ranges for how PSD volume adjusts with age, which will serve as a necessary pre-requisite for comparisons to persons with neurodegenerative disorders.

One of the pathological hallmarks of Alzheimer’s and related diseases is the increased accumulation of protein amyloid-β in the brain parenchyma. As such, recent studies have focused on characterizing protein and related clearance pathways involving perivascular flow of neurofluids, but human studies of these pathways are limited owing to limited methods for evaluating neurofluid circulation non-invasively in vivo. Here, we utilize non-invasive MRI methods to explore surrogate measures of CSF production, bulk flow, and egress in the context of independent PET measures of amyloid-β accumulation in older adults. Participants (N = 23) were scanned at 3.0T with 3D T2-weighted turbo spin echo, 2D perfusion-weighted pseudo-continuous arterial spin labeling, and phase contrast angiography to quantify parasagittal dural space volume, choroid plexus perfusion, and net CSF flow through the aqueduct of Sylvius respectively. All participants also underwent dynamic PET imaging with amyloid-β tracer 11C-Pittsburgh Compound B to quantify global cerebral amyloid-β accumulation. Spearman’s correlation analyses revealed a significant relationship between global amyloid-β accumulation and parasagittal dural space volume (rho = 0.529, p = 0.010), specifically in the frontal (rho = 0.527, p = 0.010), and parietal (rho = 0.616, p = 0.002) subsegments. No relationships were observed between amyloid-β and choroid plexus perfusion nor net CSF flow. Findings suggest that parasagittal dural space hypertrophy, and its possible role in CSF-mediated clearance, may be closely related to global amyloid-β accumulation. These findings are discussed in the context of our growing understanding of the physiological mechanisms of amyloid-β aggregation and clearance via neurofluids.