Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders

Hovd, Markus Herberg; Mariussen, Espen; Uggerud, Hilde Thelle; Lashkarivand, Aslan; Christensen, Hege; Ringstad, Geir; Eide, Per Kristian

doi:10.1186/s12987-022-00352-w

Cited by 21 publications

(50 citation statements)

References 78 publications

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“…The clearance pathways described by this parameter relate to minor leakage across the blood-brain-barrier, or very rapid transport along paravascular pathways at scales not detectable with MRI. As such, our clearance rate estimate could be compared to the half-life of gadobutrol to the blood (from the subarachnoid space) of 3.83 hours or 230 minutes as reported by Hovd et al 47 . Also note that the subject variation is similar when comparing the clinical data (ibid) and our estimation (150 versus 153 min).…”

Section: Discussionmentioning

confidence: 96%

Human brain solute transport quantified by glymphatic MRI-informed biophysics during sleep and sleep deprivation

Vinje¹,

Zapf

Ringstad

et al. 2023

Preprint

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Whether you are reading, running or sleeping, your brain and its fluid environment continuously interacts to distribute nutrients and clear metabolic waste. Yet, the precise mechanisms for solute transport within the human brain have remained hard to quantify using imaging techniques alone. From multi-modal human brain MRI data sets in sleeping and sleep-deprived subjects, we identify and quantify CSF tracer transport parameters using forward and inverse subject-specific computational modelling. Our findings support the notion that extracellular diffusion alone is not sufficient as a brain-wide tracer transport mechanism. Instead, we show that human MRI observations align well with transport by either substantially enhanced (3.5 times faster) extracellular diffusion in combination with local clearance rates corresponding to a tracer half-life of up to 5 hours, or by extracellular diffusion augmented by advection with brain-wide average flow speeds on the order of 1-9 micrometers/min. Reduced advection fully explains reduced tracer clearance after sleep-deprivation, supporting the role of sleep and sleep deprivation on human brain clearance.

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Section: Discussionmentioning

confidence: 96%

Human brain solute transport quantified by glymphatic MRI-informed biophysics during sleep and sleep deprivation

Vinje¹,

Zapf

Ringstad

et al. 2023

Preprint

Self Cite

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“…In line with this hypothesis, we previously demonstrated enrichment in the parasagittal dura of this intrathecal CSF tracer 16 . Furthermore, the CSF-to-blood clearance variables of the pharmacokinetic model showed large variation between individuals and across disease catgeories 14 . Therefore, the direction of the correlation might be expected to vary.…”

Section: Introductionmentioning

confidence: 99%

Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders

et al. 2023

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Clearance of neurotoxic brain proteins via cerebrospinal fluid (CSF) to blood has recently emerged to be crucial, and plasma biomarkers of neurodegeneration were newly introduced to predict neurological disease. This study examines in 106 individuals with neurological disorders associations between plasma biomarkers [40 and 42 amino acid-long amyloid-β (Aβ40 and Aβ42), total-tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL)] and magnetic resonance imaging measures of CSF-mediated clearance from brain via extra-vascular pathways (proxy of glymphatic function) and CSF-to-blood clearance variables from pharmacokinetic modeling (proxy of meningeal lymphatic egress). We also examine how biomarkers vary during daytime and associate with subjective sleep quality. Plasma concentrations of neurodegeneration markers associate with indices of glymphatic and meningeal lymphatic functions in individual- and disease-specific manners, vary during daytime, but are unaffected by sleep quality. The results suggest that plasma concentrations of neurodegeneration biomarkers associate with measures of glymphatic and meningeal lymphatic function.

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“…Given the importance of impaired molecular clearance from CSF to blood in the development of neurological diseases, the direct measurement of CSF to blood clearance on an individual basis has been studied for paving the way toward personalized intrathecal drug administration in CNS [ 135 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis

et al. 2022

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Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson’s disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative diseases has led to the hypothesis of new pathogenic mechanisms to target and design new potential therapeutic approaches. The recent observation that the glymphatic system is supposed to be responsible for the movement of cerebrospinal fluid into the brain and clearance of metabolic waste has led to study its involvement in the pathogenesis of these classic proteinopathies. Aquaporin-4 (AQP4), a water channel located in the endfeet of astrocyte membrane, is considered a primary driver of the glymphatic clearance system, and defective AQP4-mediated glymphatic drainage has been linked to proteinopathies. The objective of the present review is to present the recent body of knowledge that links the glymphatic system to the pathogenesis of AD and PD disease and other lifestyle factors such as sleep deprivation and exercise that may influence glymphatic system function. We will also focus on the potential neuroimaging approaches that could identify a neuroimaging marker to detect glymphatic system changes.

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Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders

Cited by 21 publications

References 78 publications

Human brain solute transport quantified by glymphatic MRI-informed biophysics during sleep and sleep deprivation

Human brain solute transport quantified by glymphatic MRI-informed biophysics during sleep and sleep deprivation

Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders

The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis

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