Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17.

Recent understanding of how the systemic environment shapes the brain throughout life has led to numerous intervention strategies to slow brain ageing1-3. Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds4,5. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures. Using SLAMseq to metabolically label nascent mRNA, we identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.

The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex.

Neural stem and progenitor cells have a central role in the development and evolution of the mammalian neocortex. In this review, we first provide a set of criteria to classify the various types of cortical stem and progenitor cells. We then discuss the issue of cell polarity, as well as specific subcellular features of these cells that are relevant for their modes of division and daughter cell fate. In addition, cortical stem and progenitor cell behavior is placed into a tissue context, with consideration of extracellular signals and cell-cell interactions. Finally, the differences across species regarding cortical stem and progenitor cells are dissected to gain insight into key developmental and evolutionary mechanisms underlying neocortex expansion.

Evidence for Two Subpopulations of Cerebrospinal Fluid-Contacting Neurons with Opposite GABAergic Signaling in Adult Mouse Spinal Cord.

Spinal cerebrospinal fluid-contacting neurons (CSF-cNs) form an evolutionary conserved bipolar cell population localized around the central canal of all vertebrates. CSF-cNs were shown to express molecular markers of neuronal immaturity into adulthood; however, the impact of their incomplete maturation on the chloride (Cl-) homeostasis as well as GABAergic signaling remains unknown. Using adult mice from both sexes, in situ hybridization revealed that a proportion of spinal CSF-cNs (18.3%) express the Na+-K+-Cl- cotransporter 1 (NKCC1) allowing intracellular Cl- accumulation. However, we did not find expression of the K+-Cl- cotransporter 2 (KCC2) responsible for Cl- efflux in any CSF-cNs. The lack of KCC2 expression results in low Cl- extrusion capacity in CSF-cNs under high Cl- load in whole-cell patch clamp. Using cell-attached patch clamp allowing recordings with intact intracellular Cl- concentration, we found that the activation of ionotropic GABAA receptors (GABAA-Rs) induced both depolarizing and hyperpolarizing responses in CSF-cNs. Moreover, depolarizing GABA responses can drive action potentials as well as intracellular calcium elevations by activating voltage-gated calcium channels. Blocking NKCC1 with bumetanide inhibited the GABA-induced calcium transients in CSF-cNs. Finally, we show that metabotropic GABAB receptors have no hyperpolarizing action on spinal CSF-cNs as their activation with baclofen did not mediate outward K+ currents, presumably due to the lack of expression of G-protein-coupled inwardly rectifying potassium (GIRK) channels. Together, these findings outline subpopulations of spinal CSF-cNs expressing inhibitory or excitatory GABAA-R signaling. Excitatory GABA may promote the maturation and integration of young CSF-cNs into the existing spinal circuit.

Measuring CSF shunt flow with MRI using flow enhancement of signal intensity (FENSI).

PURPOSE: To develop and validate a noninvasive imaging technique for accurately assessing very slow CSF flow within shunt tubes in pediatric patients with hydrocephalus, aiming to identify obstructions that might impede CSF drainage. THEORY AND METHODS: A simulation of shunt flow enhancement of signal intensity (shunt-FENSI) signal is used to establish the relationship between signal change and flow rate. The quantification of flow enhancement of signal intensity data involves normalization, curve fitting, and calibration to match simulated data. Additionally, a phase sweep method is introduced to accommodate the impact of magnetic field inhomogeneity on the flow measurement. The method is tested in flow phantoms, healthy adults, intensive care unit patients with external ventricular drains (EVD), and shunt patients. EVDs enable shunt-flow measurements to be acquired with a ground truth measure of CSF drainage. RESULTS: The flow-rate-to-signal simulation establishes signal-flow relationships and takes into account the T1 of draining fluid. The phase sweep method accurately accounts for phase accumulation due to frequency offsets at the shunt. Results in phantom and healthy human participants reveal reliable quantification of flow rates using controlled flows and agreement with the flow simulation. EVD patients display reliable measures of flow rates. Shunt patient results demonstrate feasibility of the method and consistent flow rates for functional shunts. CONCLUSION: The results demonstrate the technique's applicability, accuracy, and potential for diagnosing and noninvasively monitoring hydrocephalus. Limitations of the current approach include a high sensitivity to motion and strict requirement of imaging slice prescription.

Measurement of changes in cerebrospinal fluid pulsation after traumatic brain injury using echo-planar imaging-based functional MRI.

Traumatic brain injury (TBI) is a major public health concern worldwide, with a high incidence and a significant impact on morbidity and mortality. The alteration of cerebrospinal fluid (CSF) dynamics after TBI is a well-known phenomenon; however, the underlying mechanisms and their implications for cognitive function are not fully understood. In this study, we propose a new approach to studying the alteration of CSF dynamics in TBI patients. Our approach involves using conventional echo-planar imaging-based functional MRI with no additional scan, allowing for simultaneous assessment of functional CSF dynamics and blood oxygen level-dependent-based functional brain activities. We utilized two previously suggested indices of (i) CSFpulse, and (ii) correlation between global brain activity and CSF inflow. Using CSFpulse, we demonstrated a significant decrease in CSF pulsation following TBI (p < 0.05), which was consistent with previous studies. Furthermore, we confirmed that the decrease in CSF pulsation was most prominent in the early months after TBI, which could be explained by ependymal ciliary loss, intracranial pressure increment, or aquaporin-4 dysregulation. We also observed a decreasing trend in the correlation between global brain activity and CSF inflow in TBI patients (p < 0.05). Our findings suggest that the decreased CSF pulsation after TBI could lead to the accumulation of toxic substances in the brain and an adverse effect on brain function. Further longitudinal studies with larger sample sizes, TBI biomarker data, and various demographic information are needed to investigate the association between cognitive decline and CSF dynamics after TBI. Overall, this study sheds light on the potential role of altered CSF dynamics in TBI-induced neurologic symptoms and may contribute to the development of novel therapeutic interventions.

Four-dimensional flow MRI for quantitative assessment of cerebrospinal fluid dynamics: Status and opportunities.

Neurological disorders can manifest with altered neurofluid dynamics in different compartments of the central nervous system. These include alterations in cerebral blood flow, cerebrospinal fluid (CSF) flow, and tissue biomechanics. Noninvasive quantitative assessment of neurofluid flow and tissue motion is feasible with phase contrast magnetic resonance imaging (PC MRI). While two-dimensional (2D) PC MRI is routinely utilized in research and clinical settings to assess flow dynamics through a single imaging slice, comprehensive neurofluid dynamic assessment can be limited or impractical. Recently, four-dimensional (4D) flow MRI (or time-resolved three-dimensional PC with three-directional velocity encoding) has emerged as a powerful extension of 2D PC, allowing for large volumetric coverage of fluid velocities at high spatiotemporal resolution within clinically reasonable scan times. Yet, most 4D flow studies have focused on blood flow imaging. Characterizing CSF flow dynamics with 4D flow (i.e., 4D CSF flow) is of high interest to understand normal brain and spine physiology, but also to study neurological disorders such as dysfunctional brain metabolite waste clearance, where CSF dynamics appear to play an important role. However, 4D CSF flow imaging is challenged by the long T1 time of CSF and slower velocities compared with blood flow, which can result in longer scan times from low flip angles and extended motion-sensitive gradients, hindering clinical adoption. In this work, we review the state of 4D CSF flow MRI including challenges, novel solutions from current research and ongoing needs, examples of clinical and research applications, and discuss an outlook on the future of 4D CSF flow.

CSF and venous blood flow from childhood to adulthood studied by real-time phase-contrast MRI.

PURPOSE: In vivo measurements of CSF and venous flow using real-time phase-contrast (RT-PC) MRI facilitate new insights into the dynamics and physiology of both fluid systems. In clinical practice, however, use of RT-PC MRI is still limited. Because many forms of hydrocephalus manifest in infancy and childhood, it is a prerequisite to investigate normal flow parameters during this period to assess pathologies of CSF circulation. This study aims to establish reference values of CSF and venous flow in healthy subjects using RT-PC MRI and to determine their age dependency. METHODS: RT-PC MRI was performed in 44 healthy volunteers (20 females, age 5-40 years). CSF flow was quantified at the aqueduct (Aqd), cervical (C3) and lumbar (L3) spinal levels. Venous flow measurements comprised epidural veins, internal jugular veins and inferior vena cava. Parameters analyzed were peak velocity, net flow, pulsatility, and area of region of interest (ROI). STATISTICAL TESTS: linear regression, student's t-test and analysis of variance (ANOVA). RESULTS: In adults volunteers, no significant changes in flow parameters were observed. In contrast, pediatric subjects exhibited a significant age-dependent decrease of CSF net flow and pulsatility in Aqd, C3 and L3. Several venous flow parameters decreased significantly over age at C3 and changed more variably at L3. CONCLUSION: Flow parameters varies depending on anatomical location and age. We established changes of brain and spinal fluid dynamics over an age range from 5-40 years. The application of RT-PC MRI in clinical care may improve our understanding of CSF flow pathology in individual patients.

Development of the brain ventricular system from a comparative perspective.

The brain ventricular system (BVS) consists of brain ventricles and channels filled with cerebrospinal fluid (CSF). Disturbance of CSF flow has been linked to scoliosis and neurodegenerative diseases, including hydrocephalus. This could be due to defects of CSF production by the choroid plexus or impaired CSF movement over the ependyma dependent on motile cilia. Most vertebrates have horizontal body posture. They retain additional evolutionary innovations assisting CSF flow, such as the Reissner fiber. The causes of hydrocephalus have been studied using animal models including rodents (mice, rats, hamsters) and zebrafish. However, the horizontal body posture reduces the effect of gravity on CSF flow, which limits the use of mammalian models for scoliosis. In contrast, fish swim against the current and experience a forward-to-backward mechanical force akin to that caused by gravity in humans. This explains the increased popularity of the zebrafish model for studies of scoliosis. "Slit-ventricle" syndrome is another side of the spectrum of BVS anomalies. It develops because of insufficient inflation of the BVS. Recent advances in zebrafish functional genetics have revealed genes that could regulate the development of the BVS and CSF circulation. This review will describe the BVS of zebrafish, a typical teleost, and vertebrates in general, in comparative perspective. It will illustrate the usefulness of the zebrafish model for developmental studies of the choroid plexus (CP), CSF flow and the BVS.

Cerebrovascular activity is a major factor in the cerebrospinal fluid flow dynamics.

Cerebrospinal fluid (CSF) provides physical protection to the central nervous system as well as an essential homeostatic environment for the normal functioning of neurons. Additionally, it has been proposed that the pulsatile movement of CSF may assist in glymphatic clearance of brain metabolic waste products implicated in neurodegeneration. In awake humans, CSF flow dynamics are thought to be driven primarily by cerebral blood volume fluctuations resulting from a number of mechanisms, including a passive vascular response to blood pressure variations associated with cardiac and respiratory cycles. Recent research has shown that mechanisms that rely on the action of vascular smooth muscle cells ("cerebrovascular activity") such as neuronal activity, changes in intravascular CO2, and autonomic activation from the brainstem, may lead to CSF pulsations as well. Nevertheless, the relative contribution of these mechanisms to CSF flow remains unclear. To investigate this further, we developed an MRI approach capable of disentangling and quantifying CSF flow components of different time scales associated with these mechanisms. This approach was evaluated on human control subjects (n = 12) performing intermittent voluntary deep inspirations, by determining peak flow velocities and displaced volumes between these mechanisms in the fourth ventricle. We found that peak flow velocities were similar between the different mechanisms, while displaced volumes per cycle were about a magnitude larger for deep inspirations. CSF flow velocity peaked at around 10.4 s (range 7.1-14.8 s, n = 12) following deep inspiration, consistent with known cerebrovascular activation delays for this autonomic challenge. These findings point to an important role of cerebrovascular activity in the genesis of CSF pulsations. Other regulatory triggers for cerebral blood flow such as autonomic arousal and orthostatic challenges may create major CSF pulsatile movement as well. Future quantitative comparison of these and possibly additional types of CSF pulsations with the proposed approach may help clarify the conditions that affect CSF flow dynamics.

Autonomic arousals contribute to brain fluid pulsations during sleep.

During sleep, slow waves of neuro-electrical activity engulf the human brain and aid in the consolidation of memories. Recent research suggests that these slow waves may also promote brain health by facilitating the removal of metabolic waste, possibly by orchestrating the pulsatile flow of cerebrospinal fluid (CSF) through local neural control over vascular tone. To investigate the role of slow waves in the generation of CSF pulsations, we analyzed functional MRI data obtained across the full sleep-wake cycle and during a waking respiratory task. This revealed a novel generating mechanism that relies on the autonomic regulation of cerebral vascular tone without requiring slow electrocortical activity or even sleep. Therefore, the role of CSF pulsations in brain waste clearance may, in part, depend on proper autoregulatory control of cerebral blood flow.

Assessing pulsatile waveforms of paravascular cerebrospinal fluid dynamics within the glymphatic pathways using dynamic diffusion-weighted imaging (dDWI)

Cerebrospinal fluid (CSF) in the paravascular spaces of the surface arteries (sPVS) is a vital pathway in brain waste clearance. Arterial pulsations may be the driving force of the paravascular flow, but its pulsatile pattern remains poorly characterized, and no clinically practical method for measuring its dynamics in the human brain is available. In this work, we introduce an imaging and quantification framework for in-vivo non-invasive assessment of pulsatile fluid dynamics in the sPVS. It used dynamic Diffusion-Weighted Imaging (dDWI) at a lower b-values of 150s/mm2 and retrospective gating to detect the slow flow of CSF while suppressing the fast flow of adjacent arterial blood. The waveform of CSF flow over a cardiac cycle was revealed by synchronizing the measurements with the heartbeat. A data-driven approach was developed to identify sPVS and allow automatic quantification of the whole-brain fluid waveforms. We applied dDWI to twenty-five participants aged 18-82 y/o. Results demonstrated that the fluid waveforms across the brain showed an explicit cardiac-cycle dependency, in good agreement with the vascular pumping hypothesis. Furthermore, the shape of the CSF waveforms closely resembled the pressure waveforms of the artery wall, suggesting that CSF dynamics is tightly related to artery wall mechanics. Finally, the CSF waveforms in aging participants revealed a strong age effect, with a significantly wider systolic peak observed in the older relative to younger participants. The peak widening may be associated with compromised vascular compliance and vessel wall stiffening in the older brain. Overall, the results demonstrate the feasibility, reproducibility, and sensitivity of dDWI for detecting sPVS fluid dynamics of the human brain. Our preliminary data suggest age-related alterations of the paravascular pumping. With an acquisition time of under six minutes, dDWI can be readily applied to study fluid dynamics in normal physiological conditions and cerebrovascular/neurodegenerative diseases.

Real-time imaging of respiratory effects on cerebrospinal fluid flow in small diameter passageways.

PURPOSE: Respiration-related CSF flow through the cerebral aqueduct may be useful for elucidating physiology and pathophysiology of the glymphatic system, which has been proposed as a mechanism of brain waste clearance. Therefore, we aimed to (1) develop a real-time (CSF) flow imaging method with high spatial and sufficient temporal resolution to capture respiratory effects, (2) validate the method in a phantom setup and numerical simulations, and (3) apply the method in vivo and quantify its repeatability and correlation with different respiratory conditions. METHODS: A golden-angle radial flow sequence (reconstructed temporal resolution 168 ms, spatial resolution 0.6 mm) was implemented on a 7T MRI scanner and reconstructed using compressed sensing. A phantom setup mimicked simultaneous cardiac and respiratory flow oscillations. The effect of temporal resolution and vessel diameter was investigated numerically. Healthy volunteers (n = 10) were scanned at four different respiratory conditions, including repeat scans. RESULTS: Phantom data show that the developed sequence accurately quantifies respiratory oscillations (ratio real-time/reference QR  = 0.96 ± 0.02), but underestimates the rapid cardiac oscillations (ratio QC  = 0.46 ± 0.14). Simulations suggest that QC can be improved by increasing temporal resolution. In vivo repeatability was moderate to very strong for cranial and caudal flow (intraclass correlation coefficient range: 0.55-0.99) and weak to strong for net flow (intraclass correlation coefficient range: 0.48-0.90). Net flow was influenced by respiratory condition (p < 0.01). CONCLUSIONS: The presented real-time flow MRI method can quantify respiratory-related variations of CSF flow in the cerebral aqueduct, but it underestimates rapid cardiac oscillations. In vivo, the method showed good repeatability and a relationship between flow and respiration.

Does cerebrospinal fluid pulsation affect diffusion-weighted imaging thermometry? A study in healthy volunteers.

Diffusion-weighted imaging (DWI)-based thermometry offers potential as a noninvasive method for measuring temperatures deep inside the human brain. However, DWI might be influenced by the pulsatile flow of cerebrospinal fluid (CSF). This study aimed to investigate the influence of such pulsations on DWI thermometry in healthy individuals. A total of 104 participants (50 men, 54 women; mean [± standard deviation] age, 44.2 ± 14.3 years; range 21-69 years) were investigated. DWI-based brain temperature (TDWI ) was acquired at three speeds (maximum and minimum speeds of ascending flow and random timing at the cerebral aqueduct) of CSF pulsation using a 3-T magnetic resonance imaging scanner. Magnetic resonance spectroscopy (MRS)-based temperature (TMRS ) at the thalamus was also obtained as a reference standard for brain temperature. The three different CSF pulsatile flows were monitored by heart rate during the scan. The difference between reference temperature and brain temperature (ΔT = TDWI - TMRS ) along with the three CSF speeds were statistically compared using Student's matched pair t-test. No significant difference in ΔT was evident among CSF speeds (p > 0.05). No significant linear correlation between ΔT and CSF flow speed at the cerebral aqueduct was observed. Using DWI thermometry with clinical acquisition settings, which utilizes mean values within thresholds, no effect of CSF pulsation speed was observed in the estimation of ΔT.

Regulation of the apical extension morphogenesis tunes the mechanosensory response of microvilliated neurons.

Multiple types of microvilliated sensory cells exhibit an apical extension thought to be instrumental in the detection of sensory cues. The investigation of the mechanisms underlying morphogenesis of sensory apparatus is critical to understand the biology of sensation. Most of what we currently know comes from the study of the hair bundle of the inner ear sensory cells, but morphogenesis and function of other sensory microvilliated apical extensions remain poorly understood. We focused on spinal sensory neurons that contact the cerebrospinal fluid (CSF) through the projection of a microvilliated apical process in the central canal, referred to as cerebrospinal fluid-contacting neurons (CSF-cNs). CSF-cNs respond to pH and osmolarity changes as well as mechanical stimuli associated with changes of flow and tail bending. In vivo time-lapse imaging in zebrafish embryos revealed that CSF-cNs are atypical neurons that do not lose their apical attachment and form a ring of actin at the apical junctional complexes (AJCs) that they retain during differentiation. We show that the actin-based protrusions constituting the microvilliated apical extension arise and elongate from this ring of actin, and we identify candidate molecular factors underlying every step of CSF-cN morphogenesis. We demonstrate that Crumbs 1 (Crb1), Myosin 3b (Myo3b), and Espin orchestrate the morphogenesis of CSF-cN apical extension. Using calcium imaging in crb1 and espin mutants, we further show that the size of the apical extension modulates the amplitude of CSF-cN sensory response to bending of the spinal cord. Based on our results, we propose that the apical actin ring could be a common site of initiation of actin-based protrusions in microvilliated sensory cells. Furthermore, our work provides a set of actors underlying actin-based protrusion elongation shared by different sensory cell types and highlights the critical role of the apical extension shape in sensory detection.

Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics.

Cerebrospinal fluid (CSF) is produced by the choroid plexuses within the ventricles of the brain and circulates through the subarachnoid space of the skull and spinal column to provide buoyancy to and maintain fluid homeostasis of the brain and spinal cord. The question of how CSF drains from the subarachnoid space has long puzzled scientists and clinicians. For many decades, it was believed that arachnoid villi or granulations, outcroppings of arachnoid tissue that project into the dural venous sinuses, served as the major outflow route. However, this concept has been increasingly challenged in recent years, as physiological and imaging evidence from several species has accumulated showing that tracers injected into the CSF can instead be found within lymphatic vessels draining from the cranium and spine. With the recent high-profile rediscovery of meningeal lymphatic vessels located in the dura mater, another debate has emerged regarding the exact anatomical pathway(s) for CSF to reach the lymphatic system, with one side favoring direct efflux to the dural lymphatic vessels within the skull and spinal column and another side advocating for pathways along exiting cranial and spinal nerves. In this review, a summary of the historical and contemporary evidence for the different outflow pathways will be presented, allowing the reader to gain further perspective on the recent advances in the field. An improved understanding of this fundamental physiological process may lead to novel therapeutic approaches for a wide range of neurological conditions, including hydrocephalus, neurodegeneration and multiple sclerosis.

Meningeal Lymphangiogenesis and Enhanced Glymphatic Activity in Mice with Chronically Implanted EEG Electrodes.

Chronic electroencephalography (EEG) is a widely used tool for monitoring cortical electrical activity in experimental animals. Although chronic implants allow for high-quality, long-term recordings in preclinical studies, the electrodes are foreign objects and might therefore be expected to induce a local inflammatory response. We here analyzed the effects of chronic cranial electrode implantation on glymphatic fluid transport and in provoking structural changes in the meninges and cerebral cortex of male and female mice. Immunohistochemical analysis of brain tissue and dura revealed reactive gliosis in the cortex underlying the electrodes and extensive meningeal lymphangiogenesis in the surrounding dura. Meningeal lymphangiogenesis was also evident in mice prepared with the commonly used chronic cranial window. Glymphatic influx of a CSF tracer was significantly enhanced at 30 d postsurgery in both awake and ketamine-xylazine anesthetized mice with electrodes, supporting the concept that glymphatic influx and intracranial lymphatic drainage are interconnected. Altogether, the experimental results provide clear evidence that chronic implantation of EEG electrodes is associated with significant changes in the brain's fluid transport system. Future studies involving EEG recordings and chronic cranial windows must consider the physiological consequences of cranial implants, which include glial scarring, meningeal lymphangiogenesis, and increased glymphatic activity.SIGNIFICANCE STATEMENT This study shows that implantation of extradural electrodes provokes meningeal lymphangiogenesis, enhanced glymphatic influx of CSF, and reactive gliosis. The analysis based on CSF tracer injection in combination with immunohistochemistry showed that chronically implanted electroencephalography electrodes were surrounded by lymphatic sprouts originating from lymphatic vasculature along the dural sinuses and the middle meningeal artery. Likewise, chronic cranial windows provoked lymphatic sprouting. Tracer influx assessed in coronal slices was increased in agreement with previous reports identifying a close association between glymphatic activity and the meningeal lymphatic vasculature. Lymphangiogenesis in the meninges and altered glymphatic fluid transport after electrode implantation have not previously been described and adds new insights to the foreign body response of the CNS.

Sleep-related and diurnal effects on brain diffusivity and cerebrospinal fluid flow.

The question of how waste products are cleared from the brain, and the role which sleep plays in this process, is critical for our understanding of a range of physical and mental illnesses. In rodents, both circadian and sleep-related processes appear to facilitate clearance of waste products. The purpose of this study was to investigate whether overnight changes in diffusivity, brain volumes, and cerebrospinal fluid flow measured with MRI are associated with sleep parameters from overnight high-density sleep EEG, and circadian markers. In healthy adults investigated with MRI before and after sleep EEG, we observed an increase in water diffusivity overnight, which was positively related to the proportion of total sleep time spent in rapid eye movement (REM) sleep, and negatively associated with the fraction of sleep time spent in non rapid eye movement (NREM) sleep. Diffusivity was also associated with the sleep midpoint, a circadian marker. CSF flow increased overnight; this increase was unrelated to sleep or diffusivity measures but was associated with circadian markers. These results provide evidence for both sleep related and diurnal effects on water compartmentalisation within the brain.

CSF dynamics as a predictor of cognitive progression.

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. The clinical significance of DESH with regard to cognitive decline in a community setting is not yet well defined. The goal of this work is to determine if DESH is associated with cognitive decline. Participants in the population-based Mayo Clinic Study of Aging (MCSA) who met the following criteria were included: age ≥ 65 years, 3T MRI, and diagnosis of cognitively unimpaired or mild cognitive impairment at enrollment as well as at least one follow-up visit with cognitive testing. A support vector machine based method to detect the DESH imaging features on T1-weighted MRI was used to calculate a "DESH score", with positive scores indicating a more DESH-like imaging pattern. For the participants who were cognitively unimpaired at enrollment, a Cox proportional hazards model was fit with time defined as years from enrollment to first diagnosis of mild cognitive impairment or dementia, or as years to last known cognitively unimpaired diagnosis for those who did not progress. Linear mixed effects models were fit among all participants to estimate annual change in cognitive z scores for each domain (memory, attention, language, and visuospatial) and a global z score. For all models, covariates included age, sex, education, APOE genotype, cortical thickness, white matter hyperintensity volume, and total intracranial volume. The hazard of progression to cognitive impairment was an estimated 12% greater for a DESH score of +1 versus -1 (HR 1.12, 95% CI 0.97-1.31, p = 0.11). Global and attention cognition declined 0.015 (95% CI 0.005-0.025) and 0.016 (95% CI 0.005-0.028) z/year more, respectively, for a DESH score of +1 vs -1 (p = 0.01 and p = 0.02), with similar, though not statistically significant DESH effects in the other cognitive domains. Imaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well-known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically as well as for selection in clinical trials.

Vascular origins of low-frequency oscillations in the cerebrospinal fluid signal in resting-state fMRI: Interpretation using photoplethysmography.

In vivo mapping of cerebrovascular oscillations in the 0.05-0.15 Hz remains difficult. Oscillations in the cerebrospinal fluid (CSF) represent a possible avenue for noninvasively tracking these oscillations using resting-state functional MRI (rs-fMRI), and have been used to correct for vascular oscillations in rs-fMRI functional connectivity. However, the relationship between low-frequency CSF and vascular oscillations remains unclear. In this study, we investigate this relationship using fast simultaneous rs-fMRI and photoplethysmogram (PPG), examining the 0.1 Hz PPG signal, heart-rate variability (HRV), pulse-intensity ratio (PIR), and the second derivative of the PPG (SDPPG). The main findings of this study are: (a) signals in different CSF regions are not equivalent in their associations with vascular and tissue rs-fMRI signals; (b) the PPG signal is maximally coherent with the arterial and CSF signals at the cardiac frequency, but coherent with brain tissue at ~0.2 Hz; (c) PIR is maximally coherent with the CSF signal near 0.03 Hz; and (d) PPG-related vascular oscillations only contribute to ~15% of the CSF (and arterial) signal in rs-fMRI. These findings caution against averaging all CSF regions when extracting physiological nuisance regressors in rs-fMRI applications, and indicate the drivers of the CSF signal are more than simply cardiac. Our study is an initial attempt at the refinement and standardization of how the CSF signal in rs-fMRI can be used and interpreted. It also paves the way for using rs-fMRI in the CSF as a potential tool for tracking cerebrovascular health through, for instance, the potential relationship between PIR and the CSF signal.

Impaired cerebrospinal fluid transport due to idiopathic subdural hematoma in pig: an unusual case.

BACKGROUND: We report the effects of the presentation of an idiopathic subdural hematoma (SDH) in an adult domestic pig on the glymphatic system, a brain-wide solute clearance system. This accidental finding is based on our recently published study that described this system for the first time in large mammals. Our current results define the need to investigate cerebrovascular pathologies that could compromise glymphatic function in gyrencephalic animal models as a tool to bridge rodent and human glymphatic studies. CASE PRESENTATION: The pig underwent intracisternal infusion of a fluorescent tracer under general anesthesia to delineate cerebrospinal fluid (CSF) pathways, and was euthanized at the end of 3 h of tracer circulation. During brain isolation, a hematoma measuring approximately 15 × 35 mm in size beneath the dura was evident overlying fronto-parietal brain surface. Interestingly, CSF tracer distribution was markedly reduced on dorsal, lateral and ventral surfaces of the brain when compared with a control pig that was infused with the same tracer. Furthermore, regional distribution of tracer along the interhemispheric fissure, lateral fissure and hippocampus was 4-5-fold reduced in comparison with a control pig. Microscopically, glial-fibrillary acidic protein and aquaporin-4 water channel immunoreactivities were altered in the SDH pig brain. CONCLUSIONS: This is the first case of impaired glymphatic pathway due to an idiopathic SDH in a pig. Potential etiology could involve an acceleration-deceleration injury inflicted prior to arrival at our housing facility (e.g., during animal transportation) leading to disruption of bridging veins along the superior sagittal sinus and impairing CSF pathways in the whole brain. This accidental finding of globally impaired glymphatic function sheds light on a novel consequence of SDH, which may play a role in the enhanced cognitive decline seen in elderly presenting with chronic SDH.