Delayed clearance of cerebrospinal fluid tracer from choroid plexus in idiopathic normal pressure hydrocephalus.
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ABSTRACT:
SUBMITTER: Eide PK
PROVIDER: S-EPMC7446558 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The glymphatic system plays a key role for clearance of waste solutes from the rodent brain. We recently found evidence of glymphatic circulation in the human brain when using magnetic resonance imaging (MRI) contrast agent as cerebrospinal fluid (CSF) tracer in conjunction with multiple MRI acquisitions (gMRI). The present study explored the hypothesis that reduced glymphatic clearance in entorhinal cortex (ERC) may be instrumental in idiopathic normal pressure hydrocephalus (iNPH) dementia. gMRI acquisitions were obtained over a 24-48?h time span in cognitively affected iNPH patients and non-cognitively affected patients with suspected CSF leaks. The CSF tracer enrichment was determined as changes in normalized MRI T1 signal units. The study included 30 patients with iNPH and 8 individuals with suspected CSF leaks (i.e. reference individuals). Compared to reference individuals, iNPH patients presented with higher medial temporal lobe atrophy score and Evan's index and inferior ERC thickness. We found delayed clearance of the intrathecal CSF tracer gadobutrol from CSF, the ERC and adjacent white matter, suggesting impaired glymphatic circulation. Reduced clearance and accumulation of toxic waste product such as amyloid-? may be a mechanism behind dementia in iNPH. Glymphatic MRI (gMRI) may become a tool for assessment of early dementia.
| S-EPMC6668515 | biostudies-literature
Project description:Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation, such as hydrocephalus, can negatively affect perinatal neurodevelopment. The mechanisms regulating CSF clearance during the postnatal critical period are unclear. Here, we show that CSF K+, accompanied by water, is cleared through the choroid plexus (ChP) during mouse early postnatal development. We report that, at this developmental stage, the ChP showed increased ATP production and increased expression of ATP-dependent K+ transporters, particularly the Na+, K+, Cl-, and water cotransporter NKCC1. Overexpression of NKCC1 in the ChP resulted in increased CSF K+ clearance, increased cerebral compliance, and reduced circulating CSF in the brain without changes in intracranial pressure in mice. Moreover, ChP-specific NKCC1 overexpression in an obstructive hydrocephalus mouse model resulted in reduced ventriculomegaly. Collectively, our results implicate NKCC1 in regulating CSF K+ clearance through the ChP in the critical period during postnatal neurodevelopment in mice.
| S-EPMC7815709 | biostudies-literature
Project description:Disturbed clearance of toxic metabolites from the brain via cerebrospinal fluid is emerging as an important mechanism behind dementia and neurodegeneration. To this end, magnetic resonance imaging work-up of dementia diseases is largely focused on anatomical derangements of the brain. This study explores magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in patients with the dementia subtype idiopathic normal pressure hydrocephalus and a cohort of reference subjects. All study participants underwent multi-phase magnetic resonance imaging up to 48 h after intrathecal administration of the contrast agent gadobutrol (0.5 ml, 1 mmol/ml), serving as cerebrospinal fluid tracer. Imaging biomarkers of cerebrospinal fluid tracer dynamics (i.e. ventricular reflux grades 0-4 and clearance) were compared with anatomical magnetic resonance imaging biomarkers of cerebrospinal fluid space anatomy (Evans' index, callosal angle and disproportional enlargement of subarachnoid spaces hydrocephalus) and neurodegeneration (Schelten's medial temporal atrophy scores, Fazeka's scores and entorhinal cortex thickness). The imaging scores were also related to a pulsatile intracranial pressure score indicative of intracranial compliance. In shunt-responsive idiopathic normal pressure hydrocephalus, the imaging biomarkers demonstrated significantly altered cerebrospinal fluid tracer dynamics (ventricular reflux grades 3-4 and reduced clearance of tracer), deranged cerebrospinal fluid space anatomy and pronounced neurodegeneration. The altered MRI biomarkers were accompanied by pressure indices of impaired intracranial compliance. In conclusion, we present novel magnetic resonance imaging biomarkers characterizing idiopathic normal pressure hydrocephalus pathophysiology, namely measures of cerebrospinal fluid molecular redistribution and clearance, which add information to traditional imaging scores of cerebrospinal fluid space anatomy and neurodegeneration.
| S-EPMC7753057 | biostudies-literature
Project description:BackgroundThe significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown.ObjectiveTo investigate the role of soluble APP (sAPP) and amyloid beta (A?) isoforms, proinflammatory cytokines, and biomarkers of neuronal damage in the cerebrospinal fluid (CSF) in relation to brain biopsy A? and hyperphosphorylated tau (HP?) findings.MethodsThe study population comprised 102 patients with possible NPH with cortical brain biopsies, ventricular and lumbar CSF samples, and DNA available. The final clinical diagnoses were: 53 iNPH (91% shunt-responders), 26 AD (10 mixed iNPH+AD), and 23 others. Biopsy samples were immunostained against A? and HP?. CSF levels of AD-related biomarkers (A?42, p-tau, total tau), non-AD-related A? isoforms (A?38, A?40), sAPP isoforms (sAPP?, sAPP?), proinflammatory cytokines (several interleukins (IL), interferon-gamma, monocyte chemoattractant protein-1, tumor necrosis factor-alpha) and biomarkers of neuronal damage (neurofilament light and myelin basic protein) were measured. All patients were genotyped for APOE.ResultsLumbar CSF levels of sAPP? were lower (p<0.05) in patients with shunt-responsive iNPH compared to non-iNPH patients. sAPP? showed a similar trend (p?=?0.06). CSF sAPP isoform levels showed no association to A? or HP? in the brain biopsy. Quantified A? load in the brain biopsy showed a negative correlation with CSF levels of A?42 in ventricular (r?=?-0.295, p?=?0.003) and lumbar (r?=?-0.356, p?=?0.01) samples, while the levels of A?38 and A?40 showed no correlation. CSF levels of proinflammatory cytokines and biomarkers of neuronal damage did not associate to the brain biopsy findings, diagnosis, or shunt response. Higher lumbar/ventricular CSF IL-8 ratios (p<0.001) were seen in lumbar samples collected after ventriculostomy compared to the samples collected before the procedure.ConclusionsThe role of sAPP isoforms in iNPH seems to be independent from the amyloid cascade. No neuroinflammatory background was observed in iNPH or AD.
| S-EPMC3956805 | biostudies-literature
Project description:BackgroundThe amyloid-β oligomers, consisting of 10-20 monomers (AβO10-20), have strong neurotoxicity and are associated with cognitive impairment in Alzheimer's disease (AD). However, their role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood.ObjectiveWe hypothesized that cerebrospinal fluid (CSF) AβO10-20 accumulates in patients with iNPH, and its clearance after CSF shunting contributes to neurological improvement. We measured CSF AβO10-20 levels before and after CSF shunting in iNPH patients evaluating their diagnostic and prognostic role.MethodsWe evaluated two iNPH cohorts: "evaluation" (cohort-1) with 32 patients and "validation" (cohort-2) with 13 patients. Comparison cohorts included: 27 neurologically healthy controls (HCs), and 16 AD, 15 Parkinson's disease (PD), and 14 progressive supranuclear palsy (PSP) patients. We assessed for all cohorts CSF AβO10-20 levels and their comprehensive clinical data. iNPH cohort-1 pre-shunting data were compared with those of comparison cohorts, using cohort-2 for validation. Next, we compared cohort-1's clinical and CSF data: 1) before and after CSF shunting, and 2) increased versus decreased AβO10-20 levels at baseline, 1 and 3 years after shunting.ResultsCohort-1 had higher CSF AβO10-20 levels than the HCs, PD, and PSP cohorts. This result was validated with data from cohort-2. CSF AβO10-20 levels differentiated cohort-1 from the PD and PSP groups, with an area under receiver operating characteristic curve of 0.94. AβO10-20 levels in cohort-1 decreased after CSF shunting. Patients with AβO10-20 decrease showed better cognitive outcome than those without.ConclusionAβO10-20 accumulates in patients with iNPH and is eliminated by CSF shunting. AβO10-20 can be an applicable diagnostic and prognostic biomarker.
| S-EPMC8461658 | biostudies-literature
Project description:BackgroundLongitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.ObjectiveTo examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.MethodsL-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.ResultsAll biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.ConclusionLongitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.
| S-EPMC8150674 | biostudies-literature
Project description:The aim of the present study was to examine cerebrospinal fluid (CSF) volumetric net flow rate and direction at the cranio-cervical junction (CCJ) and cerebral aqueduct in individuals with idiopathic normal pressure hydrocephalus (iNPH) using cardiac-gated phase-contrast magnetic resonance imaging (PC-MRI). An in-depth, pixel-by-pixel analysis of regions of interest from the CCJ and cerebral aqueduct, respectively, was done in 26 iNPH individuals, and in 4 healthy subjects for validation purposes. Results from patients were compared with over-night measurements of static and pulsatile intracranial pressure (ICP). In iNPH, CSF net flow at CCJ was cranially directed in 17/22 as well as in 4/4 healthy subjects. Estimated daily CSF volumetric net flow rate at CCJ was 6.9 ± 9.9 L/24 h in iNPH patients and 4.5 ± 5.0 L/24 h in healthy individuals. Within the cerebral aqueduct, the CSF net flow was antegrade in 7/21 iNPH patients and in 4/4 healthy subjects, while it was retrograde (i.e. towards ventricles) in 14/21 iNPH patients. Estimated daily CSF volumetric net flow rate in cerebral aqueduct was 1.1 ± 2.2 L/24 h in iNPH while 295 ± 53 mL/24 h in healthy individuals. Magnitude of cranially directed CSF net flow in cerebral aqueduct was highest in iNPH individuals with signs of impaired intracranial compliance. The study results indicate CSF flow volumes and direction that are profoundly different from previously assumed. We hypothesize that spinal CSF formation may serve to buffer increased demand for CSF flow through the glymphatic system during sleep and during deep inspiration to compensate for venous outflow.
| S-EPMC6154456 | biostudies-literature
Project description:The choroid plexus (CP) forming the blood-cerebrospinal fluid (B-CSF) barrier is among the least studied structures of the central nervous system (CNS) despite its clinical importance. The CP is an epithelio-endothelial convolute comprising a highly vascularized stroma with fenestrated capillaries and a continuous lining of epithelial cells joined by apical tight junctions (TJs) that are crucial in forming the B-CSF barrier. Integrity of the CP is critical for maintaining brain homeostasis and B-CSF barrier permeability. Recent experimental and clinical research has uncovered the significance of the CP in the pathophysiology of various diseases affecting the CNS. The CP is involved in penetration of various pathogens into the CNS, as well as the development of neurodegenerative (e.g., Alzheimer´s disease) and autoimmune diseases (e.g., multiple sclerosis). Moreover, the CP was shown to be important for restoring brain homeostasis following stroke and trauma. In addition, new diagnostic methods and treatment of CP papilloma and carcinoma have recently been developed. This review describes and summarizes the current state of knowledge with regard to the roles of the CP and B-CSF barrier in the pathophysiology of various types of CNS diseases and sets up the foundation for further avenues of research.
| S-EPMC7201396 | biostudies-literature
Project description:The aim of this study was to determine whether the improvement of cerebrospinal fluid (CSF) flow dynamics by CSF shunting, can suppress the oligomerization of amyloid ?-peptide (A?), by measuring the levels of Alzheimer's disease (AD)-related proteins in the CSF before and after lumboperitoneal shunting. Lumbar CSF from 32 patients with idiopathic normal pressure hydrocephalus (iNPH) (samples were obtained before and 1 year after shunting), 15 patients with AD, and 12 normal controls was analyzed for AD-related proteins and APLP1-derived A?-like peptides (APL1?) (a surrogate marker for A?). We found that before shunting, individuals with iNPH had significantly lower levels of soluble amyloid precursor proteins (sAPP) and A?38 compared to patients with AD and normal controls. We divided the patients with iNPH into patients with favorable (improvement ? 1 on the modified Rankin Scale) and unfavorable (no improvement on the modified Rankin Scale) outcomes. Compared to the unfavorable outcome group, the favorable outcome group showed significant increases in A?38, 40, 42, and phosphorylated-tau levels after shunting. In contrast, there were no significant changes in the levels of APL1?25, 27, and 28 after shunting. After shunting, we observed positive correlations between sAPP? and sAPP?, A?38 and 42, and APL1?25 and 28, with shifts from sAPP? to sAPP?, from APL1?28 to 25, and from A?42 to 38 in all patients with iNPH. Our results suggest that A? production remained unchanged by the shunt procedure because the levels of sAPP and APL1? were unchanged. Moreover, the shift of A? from oligomer to monomer due to the shift of A?42 (easy to aggregate) to A?38 (difficult to aggregate), and the improvement of interstitial-fluid flow, could lead to increased A? levels in the CSF. Our findings suggest that the shunting procedure can delay intracerebral deposition of A? in patients with iNPH.
| S-EPMC4379026 | biostudies-other
Project description:BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological condition of unresolved etiology characterized by a clinical triad of symptoms; gait disturbances, urinary incontinence, and cognitive deterioration. In the present study, we aimed to elucidate the molecular coupling between inflammatory markers and development of iNPH and determine whether inflammation-induced hyperactivity of the choroidal Na+/K+/2Cl- cotransporter (NKCC1) that is involved in cerebrospinal fluid (CSF) secretion could contribute to the iNPH pathogenesis.MethodsLumbar CSF samples from 20 iNPH patients (10 with clinical improvement upon CSF shunting, 10 without clinical improvement) and 20 elderly control subjects were analyzed with the novel proximity extension assay technique for presence of 92 different inflammatory markers. RNA-sequencing was employed to delineate choroidal abundance of the receptors for the inflammatory markers found elevated in the CSF from iNPH patients. The ability of the elevated inflammatory markers to modulate choroidal NKCC1 activity was determined by addition of combinations of rat version of these in ex vivo experiments on rat choroid plexus.Results11 inflammatory markers were significantly elevated in the CSF from iNPH patients compared to elderly control subjects: CCL28, CCL23, CCL3, OPG, CXCL1, IL-18, IL-8, OSM, 4E-BP1, CXCL6, and Flt3L. One inflammatory marker, CDCP1, was significantly decreased in iNPH patients compared to control subjects. None of the inflammatory markers differed significantly when comparing iNPH patients with and without clinical improvement upon CSF shunting. All receptors for the elevated inflammatory markers were expressed in the rat and human choroid plexus, except CCR4 and CXCR1, which were absent from the rat choroid plexus. None of the elevated inflammatory markers found in the CSF from iNPH patients modulated the choroidal NKCC1 activity in ex vivo experiments on rat choroid plexus.ConclusionThe CSF from iNPH patients contains elevated levels of a subset of inflammatory markers. Although the corresponding inflammatory receptors are, in general, expressed in the choroid plexus of rats and humans, their activation did not modulate the NKCC1-mediated fraction of choroidal CSF secretion ex vivo. The molecular mechanisms underlying ventriculomegaly in iNPH, and the possible connection to inflammation, therefore remains to be elucidated.
| S-EPMC8645122 | biostudies-literature