Fluids and Barriers of the CNS最新文献

Background: An increase in choroid plexus (CP) volume may be associated with cognitive decline in older individuals without dementia. In this study, we aimed to clarify whether CP volume can serve as an imaging marker of cognitive decline, determine how strongly CP volume is associated with cognitive decline, and explore factors associated with CP volume in older adults.

Methods: We measured CP volume, brain parenchyma, and cerebrospinal fluid (CSF) spaces associated with disproportionately enlarged subarachnoid space hydrocephalus (DESH), an imaging feature of normal-pressure hydrocephalus, in community-dwelling older adults aged ≥ 65 years without dementia.

Results: In 1,370 participants, lower Mini-Mental State Examination (MMSE) scores were significantly associated with higher CP volume, even after adjusting for DESH-related CSF space and brain parenchymal volume. CP volume was more strongly associated with MMSE scores than DESH-related CSF space and brain parenchymal volume. History of smoking, white matter hyperintensity, enlarged perivascular spaces, age, body mass index, and diabetes mellitus were also associated with increased CP volume.

Conclusions: CP volume may be a highly sensitive imaging marker of cognitive decline in community-dwelling older adults without dementia, as it is linked to cognitive decline independently of brain parenchyma and CSF volumes. Our findings emphasize the importance of investigating CP volume increase to maintain cognitive function in older individuals. Accordingly, further longitudinal studies are required.

The importance of optimizing intrathecal drug delivery is highlighted by its potential to improve patient health outcomes. Findings from previous computational studies, based on an individual or a small group, may not be applicable to the wider population due to substantial geometric variability. Our study aims to circumvent this problem by evaluating an individual's cycle-averaged Lagrangian velocity field based on the geometry of their spinal subarachnoid space. It has been shown by Lawrence et al. (J Fluid Mech 861:679-720, 2019) that dominant physical mechanisms, such as steady streaming and Stokes drift, are key to facilitating mass transport within the spinal canal. In this study, we computationally modeled pulsatile cerebrospinal fluid flow fields and Lagrangian velocity field within the spinal subarachnoid space. Our findings highlight the essential role of minor structures, such as nerve roots, denticulate ligaments, and the wavy arachnoid membrane, in modulating flow and transport dynamics within the spinal subarachnoid space. We found that these structures can enhance fluid transport. We also emphasized the need for particle tracking in computational studies of mass transport within the spinal subarachnoid space. Our research illuminates the relationship between the geometry of the spinal canal and transport dynamics, characterized by a large upward cycle-averaged Lagrangian velocity zone in the wider region of the geometry, as opposed to a downward zone in the narrower region and areas close to the wall. This highlights the potential for optimizing intrathecal injection protocols by harnessing natural flow dynamics within the spinal canal.

Background: Cerebral blood flow normally places a limit on the magnitude of brain vascular permeability (P) that can be measured in vivo. At normal cerebral blood flow, this limit falls at the lower end of lipophilicity for most FDA-approved CNS drugs. In this study, we report on two methods that can be used to overcome this limitation and measure brain vascular permeability values that are up to ~1000 times higher using the in situ brain perfusion technique.

Methods: Rat brain was perfused with physiological saline at increased flow rate and in the presence of various concentrations of plasma protein, serum albumin or alpha-acid glycoprotein. Plasma protein was added to the saline perfusion fluid to lower extraction into the measurable range using the Crone Renkin "diffusion-flow" equation to calculate brain P_oS.

Results: Cerebrovascular P_o was determined for 125 solutes, of which 78 showed little or no evidence of active efflux transport. Fifty of the solutes were in the lipophilicity zone (Log P_oct 1-5) of most FDA-approved CNS drugs. Care was taken to ensure the integrity of the brain vasculature during perfusion and to measure flow accurately using markers that had been verified for the flow rates. The results showed a linear relationship between Log P_o and Log P_oct over ~10 orders of magnitude with values for diazepam, estradiol, testosterone, and other agents that exceed prior published values by fivefold to 200-fold.

Conclusions: The results show that brain vascular permeability can be measured directly in vivo for highly lipophilic solutes and the PS values obtained match reasonably with that predicted by the Crone-Renkin flow diffusion equation with care taken to validate the accuracy for the component measurements and with no need to invoke "enhanced" or "induced" dissociation.

Background: The choroid plexus (ChP), a highly vascularized structure within the ventricles, is essential for cerebrospinal fluid (CSF) production and metabolic waste clearance, crucial for neurofluid homeostasis and cognitive function. ChP enlargement is seen in normal aging and neurodegenerative diseases like Alzheimer's disease (AD). Despite its key role of in the blood-CSF barrier (BCSFB), detailed studies on age-related changes in its perfusion and microstructure remain limited.

Methods: We analyzed data from 641 healthy individuals aged between 36 and 90, using the Human Connectome Project Aging (HCP-A) dataset. Volumetric, perfusion, and diffusion metrics of the ChP were derived from structural MRI, arterial spin labeling (ASL), and diffusion-weighted imaging (DWI), respectively. Partial correlations were used to explore age-related ChP changes, and independent t-tests to examine sex differences across age decades. One-way ANOVA was employed to compare perfusion characteristics among ChP, gray matter (GM), and white matter (WM). Relationships between volume, perfusion, and diffusion were investigated, adjusting for age and sex. Additionally, the distribution of cyst-like structures within the ChP and their diffusion/perfusion MRI characteristics were analyzed across different age groups.

Results: The ChP undergoes notable changes with age, including an increase in volume (r² = 0.2, P < 0.001), a decrease in blood flow (r² = 0.17, P < 0.001), and elevated mean diffusivity (MD) values (r² = 0.16, P < 0.001). Perfusion characteristics showed significant differences between the ChP, GM, and WM (P < 0.001). Both the ChP and GM exhibited age-related declines in CBF, with a more pronounced decline in the ChP. A negative correlation was observed between the age-related increase in ChP volume and the decrease in CBF, suggesting compensatory dystrophic hyperplasia in response to perfusion decline. Cyst-like structures in ChP, characterized by lower MD and reduced CBF, were found to be more prevalent in older individuals.

Conclusions: Our findings provide a detailed quantitative assessment of age-related changes in ChP perfusion and diffusion, which may affect CSF production and circulation, potentially leading to waste solute accumulation and cognitive impairment.

Grant support: This work was supported in part by the NIH U01AG052564, P30AG066512, P01AG060882, RF1 NS110041, R01 NS108491, U24 NS135568.

Background: Choroid plexus (CP) or blood-cerebrospinal fluid-barrier (BCSFB) is a unique functional tissue which lines the brain's fluid-filled ventricles, with a crucial role in CSF production and clearance. BCSFB dysfunction is thought to contribute to toxic protein build-up in neurodegenerative disorders, including Alzheimer's disease (AD). However, the dynamics of this process remain unknown, mainly due to the paucity of in-vivo methods for assessing CP function.

Methods: We harness recent developments in Arterial Spin Labelling MRI to measure water delivery across the BCSFB as a proxy for CP function, as well as cerebral blood flow (CBF), at different stages of AD in the widely used triple transgenic mouse model (3xTg), with ages between 8 and 32 weeks. We further compared the MRI results with Y-maze behaviour testing, and histologically validated the expected pathological changes, which recapitulate both amyloid and tau deposition.

Results: Total BCSFB-mediated water delivery is significantly higher in 3xTg mice (> 50%) from 8 weeks (preclinical stage), an increase which is not explained by differences in ventricular volumes, while tissue parameters such as CBF and T1 are not different between groups at all ages. Behaviour differences between the groups were observed starting at 20 weeks, especially in terms of locomotion, with 3xTg animals showing a significantly smaller number of arm entries in the Y-maze.

Conclusions: Our work strongly suggests the involvement of CP in the early stages of AD, before the onset of symptoms and behavioural changes, providing a potential biomarker of pathology.

Background: Oxycodone, a widely used opioid analgesic, has an unbound brain-to-plasma concentration ratio (K_p,uu) greater than unity, indicating active uptake across brain barriers associated with the putative proton-coupled organic cation (H⁺/OC) antiporter system. With this study, we aimed to elucidate oxycodone's CNS disposition during lipopolysaccharide (LPS)-induced systemic inflammation in Sprague-Dawley rats.

Methods: Using brain microdialysis, we dynamically and simultaneously monitored unbound oxycodone concentrations in blood, striatum, lateral ventricle, and cisterna magna following intravenous administration of oxycodone post-LPS challenge.

Results: Our results indicated a reduced, sex-independent brain net uptake of oxycodone across the blood-brain barrier (BBB) measured in the striatum. Notably, the LPS challenge has significantly altered the systemic pharmacokinetics (PK) of oxycodone, in a sex-specific manner, leading to lower clearance and higher blood concentrations in females compared to LPS-treated males and healthy rats of both sexes. Proteomic analysis using Olink Target 96 Mouse Exploratory assay confirmed the induction of systemic inflammation and neuroinflammation. The inflammation led to an increased paracellular transport, measured using 4 kDa dextran, while preserving net active uptake of oxycodone across both BBB and the blood-cerebrospinal fluid barrier (BCSFB), with K_p,uu values of 2.7 and 2.5, respectively. The extent of uptake was 1.6-fold lower (p < 0.0001) at the BBB and unchanged at the BCSFB after the LPS challenge compared to that in healthy rats. However, the mean exposure of unbound oxycodone in the brain following LPS was similar to that in healthy rats, primarily due to the LPS-induced changes in systemic exposure.

Conclusions: These findings highlight the dissimilar responses at blood-brain interfaces during LPS-induced inflammation. Advancing the knowledge of neuropharmacokinetic mechanisms, specifically those involving the H⁺/OC antiporter system, will enable the development of more effective therapeutic strategies during inflammation conditions.

Background: The choroid plexus (CP) plays a crucial role in cerebrospinal fluid (CSF) production and brain homeostasis. However, non-invasive imaging techniques to assess its function remain limited. This study was conducted to develop a novel, contrast-agent-free MRI technique, termed relaxation-exchange magnetic resonance imaging (REXI), for evaluating CP-CSF water transport, a potential biomarker of CP function.

Methods: REXI utilizes the inherent and large difference in magnetic resonance transverse relaxation times (T₂s) between CP tissue (e.g., blood vessels and epithelial cells) and CSF. It uses a filter block to remove most CP tissue magnetization (shorter T₂), a mixing block for CP-CSF water exchange with mixing time t_m, and a detection block with multi-echo acquisition to determine the CP/CSF component fraction after exchange. The REXI pulse sequence was implemented on a 9.4 T preclinical MRI scanner. For validation of REXI's ability to measure exchange, we conducted preliminary tests on urea-water proton-exchange phantoms with various pH levels. We measured the steady-state water efflux rate from CP to CSF in rats and tested the sensitivity of REXI in detecting CP dysfunction induced by the carbonic anhydrase inhibitor acetazolamide.

Results: REXI pulse sequence successfully captured changes in the proton exchange rate (from short-T₂ component to long-T₂ component [i.e., k_sl]) of urea-water phantoms at varying pH, demonstrating its sensitivity to exchange processes. In rat CP, REXI significantly suppressed the CP tissue signal, reducing the short-T₂ fraction (f_short) from 0.44 to 0.23 (p < 0.0001), with significant recovery to 0.28 after a mixing time of 400 ms (p = 0.014). The changes in f_short at various mixing times can be accurately described by a two-site exchange model, yielding a steady-state water efflux rate from CP to CSF (i.e., k_bc) of 0.49 s^-1. A scan-rescan experiment demonstrated that REXI had excellent reproducibility in measuring k_bc (intraclass correlation coefficient = 0.90). Notably, acetazolamide-induced CSF reduction resulted in a 66% decrease in k_bc within rat CP.

Conclusions: This proof-of-concept study demonstrates the feasibility of REXI for measuring trans-barrier water exchange in the CP, offering a promising biomarker for future assessments of CP function.

Background: The Blood-Brain Barrier (BBB) is a complex and dynamic interface that regulates the exchange of molecules and cells between the blood and the central nervous system. It undergoes structural and functional throughout oxidative stress and inflammation, which may compromise its integrity and contribute to the pathogenesis of neurodegenerative diseases.

Main body: Maintaining BBB integrity is of utmost importance in preventing a wide range of neurological disorders. NRF2 is the main transcription factor that regulates cellular redox balance and inflammation-related gene expression. It has also demonstrated a potential role in regulating tight junction integrity and contributing to the inhibition of ECM remodeling, by reducing the expression of several metalloprotease family members involved in maintaining BBB function. Overall, we review current insights on the role of NRF2 in addressing protection against the effects of BBB dysfunction, discuss its involvement in BBB maintenance in different neuropathological diseases, as well as, some of its potential activators that have been used in vitro and in vivo animal models for preventing barrier dysfunction.

Conclusions: Thus, emerging evidence suggests that upregulation of NRF2 and its target genes could suppress oxidative stress, and neuroinflammation, restore BBB integrity, and increase its protection.