Mechanisms behind changes of neurodegeneration biomarkers in plasma induced by sleep deprivation.

Acute sleep deprivation has been shown to affect cerebrospinal fluid and plasma concentrations of biomarkers associated with neurodegeneration, though the mechanistic underpinnings remain unknown. This study compared individuals who, for one night, were either subject to total sleep deprivation or free sleep, (i) examining plasma concentrations of neurodegeneration biomarkers the morning after sleep deprivation or free sleep and (ii) determining how overnight changes in biomarkers plasma concentrations correlate with indices of meningeal lymphatic and glymphatic clearance functions. Plasma concentrations of amyloid-ß 40 and 42, phosphorylated tau peptide 181, glial fibrillary acid protein and neurofilament light were measured longitudinally in subjects who from Day 1 to Day 2 either underwent total sleep deprivation (n = 7) or were allowed free sleep (n = 21). The magnetic resonance imaging contrast agent gadobutrol was injected intrathecally, serving as a cerebrospinal fluid tracer. Population pharmacokinetic model parameters of gadobutrol cerebrospinal fluid-to-blood clearance were utilized as a proxy of meningeal lymphatic clearance capacity and intrathecal contrast-enhanced magnetic resonance imaging as a proxy of glymphatic function. After one night of acute sleep deprivation, the plasma concentrations of amyloid-ß 40 and 42 were reduced, but not the ratio, and concentrations of the other biomarkers were unchanged. The overnight change in amyloid-ß 40 and 42 plasma concentrations in the sleep group correlated significantly with indices of meningeal lymphatic clearance capacity, while this was not seen for the other neurodegeneration biomarkers. However, overnight change in plasma concentrations of amyloid-ß 40 and 42 did not correlate with the glymphatic marker. On the other hand, the overnight change in plasma concentration of phosphorylated tau peptide 181 correlated significantly with the marker of glymphatic function in the sleep deprivation group but not in the sleep group. The present data add to the evidence of the role of sleep and sleep deprivation on plasma neurodegeneration concentrations; however, the various neurodegeneration biomarkers respond differently with different mechanisms behind sleep-induced alterations in amyloid-ß and tau plasma concentrations. Clearance capacity of meningeal lymphatics seems more important for sleep-induced changes in amyloid-ß 40 and 42 plasma concentrations, while glymphatic function seems most important for change in plasma concentration of phosphorylated tau peptide 181 during sleep deprivation. Altogether, the present data highlight diverse mechanisms behind sleep-induced effects on concentrations of plasma neurodegeneration biomarkers.

Physiological alterations of pineal recess crowding in symptomatic non-hydrocephalic pineal cysts.

Pineal cysts are prevalent in the population. Due to more widespread use of magnetic resonance imaging, an increasing number of symptomatic patients with non-hydrocephalic pineal cysts are referred to neurologists and neurosurgeons. Currently, there is no generally accepted theoretical framework for linking symptoms to a pineal cyst. We have previously suggested that cyst-induced crowding of the pineal recess may affect venous runoff from the deep cerebral veins crossing the cyst. However, evidence underpinning this hypothesis is sparse. In the present study, we asked whether crowding of the pineal recess without imaging signs of hydrocephalus may be accompanied with alterations in blood flow of the internal cerebral veins, cerebrospinal fluid flow in the Sylvian aqueduct and cerebrospinal fluid-mediated tracer clearance from the brain along extravascular pathways (referred to as glymphatic function). This prospective, observational study included symptomatic individuals with non-hydrocephalic pineal cysts who underwent a standardized magnetic resonance imaging protocol (n = 25): Eleven patients were treated surgically with craniotomy and cyst extirpation and 14 individuals were managed conservatively without surgery. Our findings suggest that cyst-induced crowding of the pineal recess may have brain-wide effects: (i) There was a significant negative correlation between degree of crowding within the pineal recess and change in maximum venous flow velocity at the cyst, and a significant positive correlation between maximum venous flow velocity change at the cyst and net cerebrospinal fluid flow in the Sylvian aqueduct; (ii) increased degree of crowding in the pineal recess was accompanied by significantly impaired glymphatic enrichment in the cerebral cortex and subcortical white matter, indicative of a brain-wide effect in this cohort who also reported markedly impaired subjective sleep quality; (iii) there was a significant negative correlation between the apparent diffusion coefficient (suggestive of interstitial water content) within the thalamus and glymphatic enrichment of tracer and (iv) pineal recess crowding associated with symptoms. Comparison of the surgical cases [in whom 10/11 (91%) reported marked clinical improvement at follow-up] and the conservatively managed cases [in whom 1/14 (7%) reported marked clinical improvement at follow-up] showed differences in pre-treatment glymphatic tracer enrichment as well as differences in tracer enrichment in subarachnoid cerebrospinal fluid spaces. Taken together, we interpret these observations to support the hypothesis that cyst-induced crowding of the pineal recess without hydrocephalus may alter blood flow of the internal cerebral veins and cerebrospinal fluid flow and even cause brain-wide impairment of glymphatic transport with possible implications for cerebrospinal fluid transport of trophic factors such as melatonin.

Prospective T1 mapping to assess gadolinium retention in brain after intrathecal gadobutrol.

PURPOSE: A possible pathway behind gadolinium retention in brain is leakage of contrast agents from blood to cerebrospinal fluid and entry into brain along perivascular (glymphatic) pathways. The object of this study was to assess for signs of gadolinium retention in brain 4 weeks after intrathecal contrast enhanced MRI. METHODS: We prospectively applied standardized T1 mapping of the brain before and 4 weeks after intrathecal administration of 0.5 mmol gadobutrol in patients under work-up of cerebrospinal fluid circulation disorders. Due to methodological limitations, a safety margin for percentage change in T1 time was set to 3%. Region-wise differences were assessed by pairwise comparison using t-tests and forest plots, and statistical significance was accepted at .05 level (two-tailed). RESULTS: In a cohort of 76 participants (mean age 47.2 years ± 17.9 [standard deviation], 47 women), T1 relaxation times remained unchanged in cerebral cortex and basal ganglia 4 weeks after intrathecal gadobutrol. T1 was reduced from 1082 ± 46.7 ms to 1070.6 ± 36.5 ms (0.98 ±2.9%) (mean [standard deviation]) (p=0.001) in white matter, thus within the pre-defined 3% safety margin. The brain stem and cerebellum could not be assessed due to poor alignment of posterior fossa structures at scans from different time points. CONCLUSION: Gadolinium retention was not detected in the cerebral hemispheres 4 weeks after an intrathecal dose of 0.5 mmol gadobutrol, implying that presence of contrast agents in cerebrospinal fluid is of minor importance for gadolinium retention in brain.

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

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-ß (Aß40 and Aß42), 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.

Human parasagittal dura is a potential neuroimmune interface.

Parasagittal dura (PSD) is located on both sides of the superior sagittal sinus and harbours arachnoid granulations and lymphatic vessels. Efflux of cerebrospinal fluid (CSF) to human PSD has recently been shown in vivo. Here we obtain PSD volumes from magnetic resonance images in 76 patients under evaluation for CSF disorders and correlate them to age, sex, intracranial volumes, disease category, sleep quality, and intracranial pressure. In two subgroups, we also analyze tracer dynamics and time to peak tracer level in PSD and blood. PSD volume is not explained by any single assessed variable, but tracer level in PSD is strongly associated with tracer in CSF and brain. Furthermore, peak tracer in PSD occurs far later than peak tracer in blood, implying that PSD is no major efflux route for CSF. These observations may indicate that PSD is more relevant as a neuroimmune interface than as a CSF efflux route.

CSF circulation and dispersion yield rapid clearance from intracranial compartments.

In this paper, we used a computational model to estimate the clearance of a tracer driven by the circulation of cerebrospinal fluid (CSF) produced in the choroid plexus (CP) located within the lateral ventricles. CSF was assumed to exit the subarachnoid space (SAS) via different outflow routes such as the parasagittal dura, cribriform plate, and/or meningeal lymphatics. We also modelled a reverse case where fluid was produced within the spinal canal and absorbed in the choroid plexus in line with observations on certain iNPH patients. No directional interstitial fluid flow was assumed within the brain parenchyma. Tracers were injected into the foramen magnum. The models demonstrate that convection in the subarachnoid space yields rapid clearance from both the SAS and the brain interstitial fluid and can speed up intracranial clearance from years, as would be the case for purely diffusive transport, to days.

Intrathecal Contrast-Enhanced Magnetic Resonance Imaging of Cerebrospinal Fluid Dynamics and Glymphatic Enhancement in Idiopathic Normal Pressure Hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease, characterized by cerebrospinal fluid (CSF) flow disturbance. Today, the only available treatment is CSF diversion surgery (shunt surgery). While traditional imaging biomarkers typically assess CSF space anatomy, recently introduced imaging biomarkers of CSF dynamics and glymphatic enhancement, provide imaging of CSF dynamics and thereby more specifically reveal elements of the underlying pathophysiology. The biomarkers address CSF ventricular reflux grade as well as glymphatic enhancement and derive from intrathecal contrast-enhanced MRI. However, the contrast agent serving as CSF tracer is administered off-label. In medicine, the introduction of new diagnostic or therapeutic methods must consider the balance between risk and benefit. To this end, we performed a prospective observational study of 95 patients with iNPH, comparing different intrathecal doses of the MRI contrast agent gadobutrol (0.10, 0.25, and 0.50 mmol, respectively), aiming at the lowest reasonable dose needed to retrieve diagnostic information about the novel MRI biomarkers. The present observations disclosed a dose-dependent enrichment of subarachnoid CSF spaces (cisterna magna, vertex, and velum interpositum) with dose-dependent ventricular reflux of tracer in iNPH, as well as dose-dependent glymphatic tracer enrichment. The association between tracer enrichment in CSF and parenchymal compartments were as well dose-related. Intrathecal gadobutrol in a dose of 0.25 mmol, but not 0.10 mmol, was at 1.5T MRI considered sufficient for imaging altered CSF dynamics and glymphatic enhancement in iNPH, even though 3T MRI provided better sensitivity. Tracer enrichment in CSF at the vertex and within the cerebral cortex and subcortical white matter was deemed too low for maintaining diagnostic information from a dose of 0.10 mmol. We conclude that reducing the intrathecal dose of gadobutrol from 0.50 to 0.25 mmol gadobutrol improves the safety margin while maintaining the necessary diagnostic information about disturbed CSF homeostasis and glymphatic failure in iNPH.

Altered glymphatic enhancement of cerebrospinal fluid tracer in individuals with chronic poor sleep quality.

Chronic sleep disturbance is a risk factor for dementia disease, possibly due to impaired sleep-dependent clearance of toxic metabolic by-products. We compared enrichment of a cerebrospinal fluid (CSF) tracer within brain of patients reporting good or poor sleep quality, assessed by the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Tracer enrichment in a selection of brain regions was assessed using multiphase magnetic resonance imaging up to 48 hours after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml) serving as tracer. Tracer enrichment differed between patients with good (PSQI ≤5) and poor (PSQI >5) sleep quality in a cohort of non-dementia individuals (n = 44; age 42.3 ± 14.5 years), and in patients with the dementia subtype idiopathic normal pressure hydrocephalus (n = 24; age 71.0 ± 4.9 years). Sleep impairment was associated with increased CSF tracer enrichment in several brain regions. Cortical brain volume as well as entorhinal cortex thickness was reduced in the oldest cohort and was correlated with the severity of sleep disturbance and the degree of cortical tracer enrichment. We suggest chronic sleep disturbance is accompanied by altered glymphatic function along enlarged perivascular spaces.

Impaired glymphatic function in idiopathic intracranial hypertension.

Idiopathic intracranial hypertension is a brain disease incorporating cerebrospinal fluid disturbance, increased intracranial pressure and visual failure, but with unknown cause. This study examined a hypothesis that glymphatic function is impaired in idiopathic intracranial hypertension patients. The MRI contrast agent gadobutrol was utilized as a cerebrospinal fluid tracer following intrathecal administration. Consecutive standardized T1 MRI acquisitions over 48 h were done to assess tracer distribution within brain of 15 idiopathic intracranial hypertension patients and 15 reference individuals who were comparable in age and gender distribution. Using FreeSurfer software, we semi-quantified tracer level in multiple brain regions as T1 MRI signal change. The tracer enriched the entire brain of idiopathic intracranial hypertension and reference subjects. In idiopathic intracranial hypertension, tracer enrichment was increased and clearance of tracer delayed from a wide range of brain regions, including both grey and white matter. Differences were most evident in frontal and temporal regions. The pulsatile intracranial pressure was measured overnight and tracer propagation in brain compared between individuals with pathological and normal pulsatile intracranial pressure. In individuals with pathological pulsatile intracranial pressure, tracer enrichment was stronger and clearance from brain delayed, particularly in regions nearby large artery trunks at the brain surface. The present in vivo observations provide evidence for impaired glymphatic function in several brain regions of idiopathic intracranial hypertension patients. Glymphatic failure may imply altered clearance of metabolic byproducts, which may precede neurodegeneration. Further studies are needed to characterize glymphatic failure in idiopathic intracranial hypertension.

Direction and magnitude of cerebrospinal fluid flow vary substantially across central nervous system diseases.

BACKGROUND: Several central nervous system diseases are associated with disturbed cerebrospinal fluid (CSF) flow patterns and have typically been characterized in vivo by phase-contrast magnetic resonance imaging (MRI). This technique is, however, limited by its applicability in space and time. Phase-contrast MRI has yet to be compared directly with CSF tracer enhanced imaging, which can be considered gold standard for assessing long-term CSF flow dynamics within the intracranial compartment. METHODS: Here, we studied patients with various CSF disorders and compared MRI biomarkers of CSF space anatomy and phase-contrast MRI at level of the aqueduct and cranio-cervical junction with dynamic intrathecal contrast-enhanced MRI using the contrast agent gadobutrol as CSF tracer. Tracer enrichment of cerebral ventricles was graded 0-4 by visual assessment. An intracranial pressure (ICP) score was used as surrogate marker of intracranial compliance. RESULTS: The study included 94 patients and disclosed marked variation of CSF flow measures across disease categories. The grade of supra-aqueductal reflux of tracer varied, with strong reflux (grades 3-4) in half of patients. Ventricular tracer reflux correlated with stroke volume and aqueductal CSF pressure gradient. CSF flow in the cerebral aqueduct was retrograde (from 4th to 3rd ventricle) in one third of patients, with estimated CSF net flow volume about 1.0 L/24 h. In the cranio-cervical junction, net flow was cranially directed in 78% patients, with estimated CSF net flow volume about 4.7 L/24 h. CONCLUSIONS: The present observations provide in vivo quantitative evidence for substantial variation in direction and magnitude of CSF flow, with re-direction of aqueductal flow in communicating hydrocephalus, and significant extra-cranial CSF production. The grading of ventricular reflux of tracer shows promise as a clinical useful method to assess CSF flow pattern disturbances in patients.

Apparent diffusion coefficient estimates based on 24 hours tracer movement support glymphatic transport in human cerebral cortex.

The recently proposed glymphatic system suggests that bulk flow is important for clearing waste from the brain, and as such may underlie the development of e.g. Alzheimer's disease. The glymphatic hypothesis is still controversial and several biomechanical modeling studies at the micro-level have questioned the system and its assumptions. In contrast, at the macro-level, there are many experimental findings in support of bulk flow. Here, we will investigate to what extent the CSF tracer distributions seen in novel magnetic resonance imaging (MRI) investigations over hours and days are suggestive of bulk flow as an additional component to diffusion. In order to include the complex geometry of the brain, the heterogeneous CSF flow around the brain, and the transport over the time-scale of days, we employed the methods of partial differential constrained optimization to identify the apparent diffusion coefficient (ADC) that would correspond best to the MRI findings. We found that the computed ADC in the cortical grey matter was 5-26% larger than the ADC estimated with DTI, which suggests that diffusion may not be the only mechanism governing transport.

Delayed clearance of cerebrospinal fluid tracer from choroid plexus in idiopathic normal pressure hydrocephalus.

Impaired clearance of amyloid-ß from choroid plexus is one proposed mechanism behind amyloid deposition in Alzheimer's disease. The present study examined whether clearance from choroid plexus of a cerebrospinal fluid tracer, serving as a surrogate marker of a metabolic waste product, is altered in idiopathic normal pressure hydrocephalus (iNPH), one sub-type of dementia. In a prospective observational study of close to healthy individuals (reference cohort; REF) and individuals with iNPH, we performed standardized T1-weighted magnetic resonance imaging scans before and through 24 h after intrathecal administration of a cerebrospinal fluid tracer (the magnetic resonance imaging contrast agent gadobutrol). Changes in normalized T1 signal within the choroid plexus and cerebrospinal fluid of lateral ventricles were quantified using FreeSurfer. The normalized T1 signal increased to maximum within choroid plexus and cerebrospinal fluid of lateral ventricles 6-9 h after intrathecal gadobutrol in both the REF and iNPH cohorts (enrichment phase). Peak difference in normalized T1 signals between REF and iNPH individuals occurred after 24 h (clearance phase). The results gave evidence for gadobutrol resorption from cerebrospinal fluid by choroid plexus, but with delay in iNPH patients. Whether choroid plexus has a role in iNPH pathogenesis in terms of delayed clearance of amyloid-ß remains to be shown.

Respiratory influence on cerebrospinal fluid flow - a computational study based on long-term intracranial pressure measurements.

Current theories suggest that waste solutes are cleared from the brain via cerebrospinal fluid (CSF) flow, driven by pressure pulsations of possibly both cardiac and respiratory origin. In this study, we explored the importance of respiratory versus cardiac pressure gradients for CSF flow within one of the main conduits of the brain, the cerebral aqueduct. We obtained overnight intracranial pressure measurements from two different locations in 10 idiopathic normal pressure hydrocephalus (iNPH) patients. The resulting pressure gradients were analyzed with respect to cardiac and respiratory frequencies and amplitudes (182,000 cardiac and 48,000 respiratory cycles). Pressure gradients were used to compute CSF flow in simplified and patient-specific models of the aqueduct. The average ratio between cardiac over respiratory flow volume was 0.21 ± 0.09, even though the corresponding ratio between the pressure gradient amplitudes was 2.85 ± 1.06. The cardiac cycle was 0.25 ± 0.04 times the length of the respiratory cycle, allowing the respiratory pressure gradient to build considerable momentum despite its small magnitude. No significant differences in pressure gradient pulsations were found in the sleeping versus awake state. Pressure gradients underlying CSF flow in the cerebral aqueduct are dominated by cardiac pulsations, but induce CSF flow volumes dominated by respiration.

A preliminary study of cortical morphology in schizophrenia patients with a history of violence.

Clinical studies of patients with schizophrenia and a history of violence are challenging both from an ethical and practical perspective, and the neurobiological underpinnings remain largely unknown. We here present a comprehensive account of the brain cortical characteristics associated with violence in schizophrenia. We obtained 3T MRI scans and thorough clinical characterization of schizophrenia patients with a history of violence (murder, attempted murder, criminal assault, SCZ-V, n = 11), schizophrenia patients with no history of violence (SCZ-NV, n = 17), and healthy controls (HC, n = 19). Cortical thickness, area, and folding were analyzed vertex-wise across the cortical mantle (FreeSurfer). SCZ-V had significantly increased cortical folding in the visual and orbitofrontal cortex, and reduced cortical thickness within the precentral-, parietal-, temporal-, and fusiform cortex compared to SCZ-NV, as well as widespread regional thinning and increased folding compared to HC. There were no group differences in cortical area. A major limitation is the small subject sample. If replicated, the results from this pilot study suggest cortical abnormalities in areas involved in sensory processing, emotion recognition, and reward to be of importance to the neurobiology of violence in schizophrenia.