Fluids and Barriers of the CNS最新文献

Background: Pharmacotherapy for brain diseases is severely compromised by the blood-brain barrier (BBB). ABCB1 and ABCG2 are drug transporters that restrict drug entry into the brain and their inhibition can be used as a strategy to boost drug delivery and pharmacotherapy for brain diseases.

Methods: We employed elacridar and tariquidar in mice to explore the conditions for effective inhibition at the BBB. Abcg2;Abcb1a/b knockout (KO), Abcb1a/b KO, Abcg2 KO and wild-type (WT) mice received a 3 h i.p. infusion of a cocktail of 8 typical substrate drugs in combination with elacridar or tariquidar at a range of doses. Abcg2;Abcb1a/b KO mice were used as the reference for complete inhibition, while single KO mice were used to assess the potency to inhibit the remaining transporter. Brain and plasma drug levels were measured by LC-MS/MS.

Results: Complete inhibition of ABCB1 at the BBB is achieved when the elacridar plasma level reaches 1200 nM, whereas tariquidar requires at least 4000 nM. Inhibition of ABCG2 is more difficult. Elacridar inhibits ABCG2-mediated efflux of weak but not strong ABCG2 substrates. Strikingly, tariquidar does not enhance the brain uptake of any ABCG2-subtrate drug. Similarly, elacridar, but not tariquidar, was able to inhibit its own brain efflux in ABCG2-proficient mice. The plasma protein binding of elacridar and tariquidar was very high but similar in mouse and human plasma, facilitating the translation of mouse data to humans.

Conclusions: This work shows that elacridar is an effective pharmacokinetic-enhancer for the brain delivery of ABCB1 and weaker ABCG2 substrate drugs when a plasma concentration of 1200 nM is exceeded.

Background: Achieving effective drug delivery to the central nervous system (CNS) remains a challenge for treating neurological disorders. Intrathecal (IT) delivery, which involves direct injection into the cerebrospinal fluid (CSF), presents a promising strategy. Large animal studies are important to assess the safety and efficacy of most drugs and treatments and translate the data to humans. An understanding of the influence of IT injection parameters on solute distribution within the CNS is essential to optimize preclinical research, which would potentially help design human clinical studies.

Methods: A three-dimensional (3D) in vitro model of a cynomolgus monkey, based on MRI data, was developed to evaluate the impact of lumbar injection parameters on intrathecal solute dispersion. The parameters evaluated were (a) injection location, (b) bolus volume, (c) flush volume, (d) bolus rate, and (e) flush rate. To simulate the CSF flow within the subarachnoid space (SAS), an idealized CSF flow waveform with both cardiac and respiratory-induced components was input into the model. A solution of fluorescein drug surrogate tracer was administered in the lumbar region of the 3D in vitro model filled with deionized water. After injection of the tracer, the CSF system wide-solute dispersion was imaged using high-resolution cameras every thirty seconds for a duration of three hours. To ensure repeatability each injection protocol was repeated three times. For each protocol, the average spatial-temporal distribution over three hours post-injection, the area under the curve (AUC), and the percent injected dose (%ID) to extra-axial CSF (eaCSF) at three hours were determined.

Results: The changes to the lumbar injection parameters led to variations in solute distribution along the neuro-axis. Specifically, injection location showed the most impact, enhancing the delivery to the eaCSF up to + 10.5%ID (p = 0.0282) at three hours post-injection. Adding a post-injection flush of 1.5 ml at 1 ml/min increased the solute delivery to the eaCSF by + 6.5%ID (p = 0.0218), while the larger bolus volume resulted in a + 2.3%ID (p = 0.1910) increase. The bolus and flush rates analyzed had minimal, statistically non-significant effects.

Conclusion: These results predict the effects of lumbar injection parameters on solute distribution in the intrathecal space in NHPs. Specifically, the choice of injection location, flush, and bolus volume significantly improved solute delivery to eaCSF. The in vitro NHP CSF model and results offer a system to help predict and optimize IT delivery protocols for pre-clinical NHP studies.

Background: Maintaining the structural and functional integrity of the blood-brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases.

Main body: Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions.

Conclusions: BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.

Background: Cerebrospinal fluid (CSF) circulation is essential in removing metabolic wastes from the brain and is an integral component of the glymphatic system. Abnormal CSF circulation is implicated in neurodegenerative diseases. Low b-value magnetic resonance imaging quantifies the variance of CSF motion, or pseudodiffusivity. However, few studies have investigated the relationship between the spatial patterns of CSF pseudodiffusivity and cognition.

Methods: We introduced a novel technique, CSF-based spatial statistics (CBSS), to automatically quantify CSF pseudodiffusivity in each sulcus, cistern and ventricle. Using cortical regions as landmarks, we segmented each CSF region. We retrospectively analyzed a cohort of 93 participants with varying degrees of cognitive impairment.

Results: We identified two groups of CSF regions whose pseudodiffusivity profiles were correlated with each other: one group displaying higher pseudodiffusivity and near large arteries and the other group displaying lower pseudodiffusivity and away from the large arteries. The pseudodiffusivity in the third ventricle positively correlated with short-term memory (standardized slope of linear regression = 0.38, adjusted p < 0.001) and long-term memory (slope = 0.37, adjusted p = 0.005). Fine mapping along the ventricles revealed that the pseudodiffusivity in the region closest to the start of the third ventricle demonstrated the highest correlation with cognitive performance.

Conclusions: CBSS enabled quantitative spatial analysis of CSF pseudodiffusivity and suggested the third ventricle pseudodiffusivity as a potential biomarker of cognitive impairment.

Background: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer's disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans.

Methods: We used an APP knock-in mouse model, APP^NL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD.

Results: ChP tissue proteome was dysregulated in APP^NL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways.

Conclusions: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.

The principles of cerebrospinal fluid (CSF) production, circulation and outflow and regulation of fluid volumes and pressures in the normal brain are summarised. Abnormalities in these aspects in intracranial hypertension, ventriculomegaly and hydrocephalus are discussed. The brain parenchyma has a cellular framework with interstitial fluid (ISF) in the intervening spaces. Framework stress and interstitial fluid pressure (ISFP) combined provide the total stress which, after allowing for gravity, normally equals intracerebral pressure (ICP) with gradients of total stress too small to measure. Fluid pressure may differ from ICP in the parenchyma and collapsed subarachnoid spaces when the parenchyma presses against the meninges. Fluid pressure gradients determine fluid movements. In adults, restricting CSF outflow from subarachnoid spaces produces intracranial hypertension which, when CSF volumes change very little, is called idiopathic intracranial hypertension (iIH). Raised ICP in iIH is accompanied by increased venous sinus pressure, though which is cause and which effect is unclear. In infants with growing skulls, restriction in outflow leads to increased head and CSF volumes. In adults, ventriculomegaly can arise due to cerebral atrophy or, in hydrocephalus, to obstructions to intracranial CSF flow. In non-communicating hydrocephalus, flow through or out of the ventricles is somehow obstructed, whereas in communicating hydrocephalus, the obstruction is somewhere between the cisterna magna and cranial sites of outflow. When normal outflow routes are obstructed, continued CSF production in the ventricles may be partially balanced by outflow through the parenchyma via an oedematous periventricular layer and perivascular spaces. In adults, secondary hydrocephalus with raised ICP results from obvious obstructions to flow. By contrast, with the more subtly obstructed flow seen in normal pressure hydrocephalus (NPH), fluid pressure must be reduced elsewhere, e.g. in some subarachnoid spaces. In idiopathic NPH, where ventriculomegaly is accompanied by gait disturbance, dementia and/or urinary incontinence, the functional deficits can sometimes be reversed by shunting or third ventriculostomy. Parenchymal shrinkage is irreversible in late stage hydrocephalus with cellular framework loss but may not occur in early stages, whether by exclusion of fluid or otherwise. Further studies that are needed to explain the development of hydrocephalus are outlined.

Background: The cerebrospinal fluid (CSF), primarily generated by the choroid plexus (ChP), is the major carrier of the glymphatic system. The alternations of CSF production and the ChP can be associated with the Alzheimer's disease (AD). The present work investigated the roles of the ChP in the AD based on a proposed ChP image segmentation pipeline.

Methods: A human-in-the-loop ChP image segmentation pipeline was implemented with intermediate and active learning datasets. The performance of the proposed pipeline was evaluated on manual contours by five radiologists, compared to the FreeSurfer and FastSurfer toolboxes. The ChP volume and blood flow were investigated among AD groups. The correlations between the ChP volume and AD CSF biomarkers including phosphorylated tau (p-tau), total tau (t-tau), amyloid-β42 (Aβ42), and amyloid-β40 (Aβ40) was investigated using three models (univariate, multiple variables, and stepwise regression) on two datasets with 806 and 320 subjects.

Results: The proposed ChP segmentation pipeline achieved superior performance with a Dice coefficient of 0.620 on the test dataset, compared to the FreeSurfer (0.342) and FastSurfer (0.371). Significantly larger volumes (p < 0.001) and higher perfusion (p = 0.032) at the ChP were found in AD compared to CN groups. Significant correlations were found between the tau and the relative ChP volume (the ChP volume and ChP/parenchyma ratio) in each patient groups and in the univariate regression analysis (p < 0.001), the multiple regression model (p < 0.05 except for the t-tau in the LMCI), and in the step-wise regression model (p < 0.021). In addition, the correlation coefficients changed from - 0.32 to - 0.21 along with the AD progression in the multiple regression model. In contrast, the Aβ42 and Aβ40 shows consistent and significant associations with the lateral ventricle related measures in the step-wise regression model (p < 0.027).

Conclusions: The proposed pipeline provided accurate ChP segmentation which revealed the associations between the ChP and tau level in the AD. The proposed pipeline is available on GitHub ( https://github.com/princeleeee/ChP-Seg ).

Background: Idiopathic Normal Pressure Hydrocephalus (iNPH) is a chronic condition affecting the elderly. It is characterized by a triad of symptoms and radiological findings. Glaucoma is the leading cause of irreversible blindness worldwide. Earlier studies have proposed that the rate of glaucoma is higher in iNPH patients, and of a possible link between ventriculoperitoneal shunt (VP) treatment and the development of glaucoma.

Objectives: This study aimed to determine the prevalence of glaucoma among iNPH patients and assess the impact of VPs on glaucoma prevalence.

Methods: A cohort study was conducted at Kuopio University Hospital (KUH), including 262 patients with a ventriculoperitoneal shunt. Clinical data were obtained from the Kuopio NPH Registry and medical records. Patients were grouped by iNPH status: iNPH (+) - probable/possible iNPH (n = 192), and iNPH (-) - other causes of hydrocephalus (congenital, secondary, obstructive) (n = 70). We conducted statistical analysis using the Independent Samples T-test, Fisher's exact test, and Pearson Chi-Square. We compared demographics, glaucoma prevalence, brain biopsies positive for Amyloid-β (Aβ) and hyperphosphorylated tau (HPτ) as well as comorbidities for hypertension and diabetes medication. Age stratification assessed glaucoma prevalence in the full cohort.

Results: Both iNPH (+) and iNPH (-) groups had comparable demographic and comorbidity profiles. The prevalence of glaucoma in the iNPH (+) group was 11.5% (n = 22) and 11.4% (n = 8) in the iNPH (-) group without a statistically significant difference (p = 1.000). Brain biopsies positive for Amyloid-β (Aβ) and hyperphosphorylated tau (HPτ) were similar.

Conclusions: Neither shunted iNPH patients nor those with a comorbid condition other than iNPH showed a markedly higher prevalence of glaucoma. Instead, both groups exhibited age-related increases in glaucoma prevalence, similar to the trends observed in population-based studies. Our data does not suggest a correlation between VP shunts and an elevated rate of glaucoma.

AQP4 is expressed in the endfeet membranes of subpial and perivascular astrocytes and in the ependymal cells that line the ventricular system. The sporadic appearance of obstructive congenital hydrocephalus (OCHC) has been observed in the offspring of AQP4^-/- mice (KO) due to stenosis of Silvio's aqueduct. Here, we explore whether the lack of AQP4 expression leads to abnormal development of ependymal cells in the aqueduct of mice. We compared periaqueductal samples from wild-type and KO mice. The microarray-based transcriptome analysis reflected a large number of genes with differential expression (809). Gene sets (GS) associated with ependymal development, ciliary function and the immune system were specially modified qPCR confirmed reduced expression in the KO mice genes: (i) coding for transcription factors for ependymal differentiation (Rfx4 and FoxJ1), (ii) involved in the constitution of the central apparatus of the axoneme (Spag16 and Hydin), (iii) associated with ciliary assembly (Cfap43, Cfap69 and Ccdc170), and (iv) involved in intercellular junction complexes of the ependyma (Cdhr4). By contrast, genes such as Spp1, Gpnmb, Itgax, and Cd68, associated with a Cd11c-positive microglial population, were overexpressed in the KO mice. Electron microscopy and Immunofluorescence of vimentin and γ-tubulin revealed a disorganized ependyma in the KO mice, with changes in the intercellular complex union, unevenly orientated cilia, and variations in the planar cell polarity of the apical membrane. These structural alterations translate into reduced cilia beat frequency, which might alter cerebrospinal fluid movement. The presence of CD11c + microglia cells in the periaqueductal zone of mice during the first postnatal week is a novel finding. In AQP4^-/- mice, these cells remain present around the aqueduct for an extended period, showing peak expression at P11. We propose that these cells play an important role in the normal development of the ependyma and that their overexpression in KO mice is crucial to reduce ependyma abnormalities that could otherwise contribute to the development of obstructive hydrocephalus.