Biology subjects

Iliff, J. J.

Publications and source records attributed to Iliff, J. J..

7 recordsLinked to original sources

bioRxiv2026

Hormonal Modulation of Subjective Sleep Quality and Perivascular Space Volume Across the Menstrual Cycle: An Observational Dense-Sampling Study

Background Hormonal fluctuations during the menstrual cycle (and their suppression) are accompanied by altered mood, cognition, and sleep, yet their relationship to subjective sleep quality and glymphatic function - a sleep-dependent brain waste-clearance pathway that involves perivascular spaces (PVS) - is unclear. Methods We examined daily oestradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), subjective sleep quality, and MRI-derived PVS volume (PVSV) in a single healthy woman across two 30-day periods: during her physiological menstrual cycle and, one year later, under oral contraceptive pill (OCP) use. We employed linear regression models to examine whether hormones are associated with sleep quality and PVSV, and whether they moderate the sleep quality-PVSV association during the physiological menstrual cycle. Subsequently, we conducted permutation-based Spearman rank correlations to assess whether day-to-day changes in sleep quality were associated with corresponding changes in PVSV across the physiological menstrual cycle and OCP use. False discovery rate (FDR) correction was used to control for multiple comparisons. Findings Higher LH levels were associated with poorer sleep quality during the physiological cycle (b=2.15, 95% CI 0.64 to 3.67, pFDR=0.028), while FSH moderated the sleep quality-PVSV association (b=-92.98, 95% CI -160.15 to -25.81, pFDR=0.034), suggesting that lower FSH was associated with lower PVSV, whereas this association reversed at elevated FSH levels characteristic of the periovulatory window. During the physiological menstrual cycle, day-to-day decreases in sleep quality were associated with synchronous increases in PVSV, driven by centrum semiovale PVSV ({rho}=0.55, 95% CI 0.30 to 0.67, pperm=0.0095). This association was absent during OCP use and differed between hormonal milieus ({Delta} {rho}=0.72, p=0.040). Interpretation Ovulation is characterized by poor sleep quality and reduced PVSV, potentially reflecting noradrenergic modulation. The association between sleep quality and PVSV day-to-day changes is shaped by the hormonal milieu, being absent under OCP. PVSV increase associated with poor sleep may reflect elevated sleep pressure promoting vasomotor-mediated cerebrospinal fluid inflow.

neuroscience↗

bioRxiv2026

Aquaporin-4 mislocalization from astrocyte endfeet prolongs survival in a prion-cerebral amyloid angiopathy model

Aquaporin 4 (AQP4) water channels are polarized to astrocytic endfeet at blood vessel interfaces, and lose polarity in vascular diseases, including stroke, chronic traumatic encephalopathy, and Alzheimers disease. AQP4 modulates water influx and efflux in the interstitial fluid, yet how AQP4 localization impacts cerebral amyloid angiopathy (CAA) remains poorly understood. Here we show that astrocytic end feet and AQP4 are displaced from amyloid-bearing vessels in a prion-CAA mouse model that expresses GPI-anchorless PrPC. Displacing AQP4 genetically through deleting alpha-syntrophin (Snta1-/-) led to a marked prolongation in survival, together with reduced microglial inflammation and C1q, in prion-CAA-affected mice. Additionally, synaptic structural proteins were better maintained. Finally, the level and distribution of prion aggregates were similar among the mice, indicating that prion conversion and spread was not affected. These results suggest that reducing AQP4 water channel function slows the decline in a vascular amyloid disease by reducing neuroinflammation.

neuroscience↗

bioRxiv2023

Preliminary cross-sectional investigations into the human glymphatic system using multiple novel non-contrast MRI methods.

We discuss two potential non-invasive MRI methods to cross-sectionally study two distinct facets of the glymphatic system and its association with sleep and aging. We apply diffusion-based intravoxel incoherent motion (IVIM) imaging to evaluate pseudodiffusion coefficient, D*, or cerebrospinal fluid (CSF) movement across large spaces like the subarachnoid space (SAS). We also performed perfusion-based multi-echo, Hadamard encoded multi-delay arterial spin labeling (ASL) to evaluate whole brain cortical cerebral blood flow (CBF) and transendothelial exchange (Tex) of water from the vasculature into the perivascular space and parenchyma. Both methods were used in young adults (N=9, 6F, 23{+/-}3 years old) in the setting of sleep and sleep deprivation. To study aging, 10 older adults, (6F, 67{+/-}3 years old) were imaged after a night of normal sleep only and compared with the young adults. D* in SAS was significantly (p<0.05) lesser after sleep deprivation (0.014{+/-}0.001 mm2/s) than after normal sleep (0.016{+/-}0.001 mm2/s), but was unchanged with aging. Cortical CBF and Tex on the other hand, were unchanged after sleep deprivation but were significantly lower in older adults (37{+/-}3 ml/100g/min, 476{+/-}66 ms) than young adults (42{+/-}2 ml/100g/min, 624{+/-}66 ms). IVIM was thus, sensitive to sleep physiology and multi-echo, multi-delay ASL was sensitive to aging.

neuroscience↗

bioRxiv2021

Sleep Dependent Changes of Lactate Concentration in Human Brain

Lactate is an important cellular metabolite that is present at high concentrations in the brain, both within cells and in the extracellular space between cells. Small animal studies demonstrated high extracellular concentrations of lactate during wakefulness with reductions during sleep and/or anesthesia with a recent study suggesting the glymphatic activity as the mechanism for the reduction of lactate concentrations. We have recently developed a rigorous non-invasive imaging approach combining simultaneous magnetic resonance spectroscopy (MRS) and polysomnography (PSG) measurements, and here, we present the first in-vivo evaluation of brain lactate levels during sleep-wake cycles in young healthy humans. First, we collected single voxel proton MRS (1H-MRS) data at the posterior cingulate with high temporal resolution (every 7.5 sec), and simultaneously recorded PSG data while temporally registering with 1H-MRS time-series. Second, we evaluated PSG data in 30 s epochs, and classified into four stages Wake (W), Non-REM sleep stage 1 (N1), Non-REM sleep stage 2 (N2), and Non-REM sleep stage 3 (N3). Third, we determined lactate signal intensity from each 7.5-s spectrum, normalized to corresponding water signal, and averaged over 30-s for each PSG epoch. In examinations of nine healthy participants (four females, five males; mean age 24.2 ({+/-}2; SD) years; age range: 21-27 years) undergoing up to 3-hour simultaneous MRS/PSG recordings, we observed a group mean reduction of [4.9 {+/-} 4.9] % in N1, [10.4 {+/-} 5.2] % in N2, and [24.0 {+/-} 5.8] % in N3 when compared to W. Our finding is consistent with more than 70 years of invasive lactate measurements from small animal studies. In addition, reduced brain lactate was accompanied by a significant reduction the apparent diffusion coefficient of brain lactate. Taken together, these findings are consistent with the loss of lactate from the extracellular space during sleep while suggesting lactate metabolism is altered and/or lactate clearance via glymphatic exchange is increased during sleep. Significance StatementThis study describes a non-invasive magnetic resonance spectroscopy/polysomnography technique that allows rigorous measurement of brain metabolite levels together with simultaneous characterization of brain arousal state as either wakeful or one of the several sleep states. The results provide the first in-vivo demonstration of reductions in brain lactate concentration and diffusivity during sleep versus wakefulness in young healthy human brain. These findings are consistent with invasive small-animal studies showing the loss of extracellular lactate during sleep, and support the notion of altered lactate metabolism and/or increased glymphatic activity in sleeping human brain.

neuroscience↗

bioRxiv2021

Pulsation changes link to impaired glymphatic function in a mouse model of vascular cognitive impairment

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the glial-vascular unit and accumulation of amyloid-{beta} (A{beta}) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including A{beta} removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of A{beta}. Male wild- type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning and memory. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Since our findings show that BCAS may influence VCI by impaired glymphatic drainage and reduced vascular pulsation we propose that these additional targets need to be considered when treating VCI.

neuroscience↗

bioRxiv2020

Varying perivascular astroglial endfoot dimensions along the vascular tree maintain perivascular-interstitial flux through the cortical mantle

The glymphatic system is a recently defined brain-wide network of perivascular spaces along which cerebrospinal fluid (CSF) and interstitial solutes exchange. Astrocyte endfeet encircling the perivascular space form a physical barrier in between these two compartments, and fluid and solutes that are not taken up by astrocytes move out of the perivascular space through the junctions in between astrocyte endfeet. However, little is known about the anatomical structure and the physiological roles of the astrocyte endfeet in regulating the local perivascular exchange. Here, visualizing astrocyte endfoot-endfoot junctions with immunofluorescent labeling against the protein megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1), we characterized endfoot dimensions along the mouse cerebrovascular tree. We observed marked heterogeneity in endfoot dimensions along vessels of different sizes, and of different types. Specifically, endfoot size was positively correlated with the vessel diameters, with large vessel segments surrounded by large endfeet and small vessel segments surrounded by small endfeet. This association was most pronounced along arterial, rather than venous segments. Computational modeling simulating vascular trees with uniform or varying endfeet dimensions demonstrates that varying endfoot dimensions maintain near constant perivascular-interstitial flux despite correspondingly declining perivascular pressures along the cerebrovascular tree through the cortical depth. These results describe a novel anatomical feature of perivascular astroglial endfeet and suggest that endfoot heterogeneity may be an evolutionary adaptation to maintain perivascular CSF-interstitial fluid exchange through deep brain structures.

neuroscience↗

bioRxiv2017

Aquaporin-4 dependent glymphatic solute transport in rodent brain

The glymphatic system is a brain-wide metabolite clearance pathway, impairment of which in post-traumatic and ischemic brain or healthy aging is proposed to contribute to intracerebral accumulation of amyloid-{beta} and tau proteins. Glymphatic perivascular influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent publication that failed to find an effect of Aqp4 knockout on perivascular CSF tracer influx and interstitial fluid (ISF) tracer dispersion, four independent research groups have herein re-examined the importance of Aqp4 in glymphatic fluid transport. We concur in finding that CSF tracer influx, as well as fluorescently-tagged amyloid-{beta} efflux, are significantly faster in wild-type mice than in three different transgenic lines featuring disruption of the Aqp4 gene and one line in which AQP4 expression lacks the critical perivascular localization (Snta1 knockout). These data validate the role of AQP4 in supporting fluid and solute transport and efflux in brain in accordance with the glymphatic system model.

neuroscience↗