iliff lab research

 
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Sleep, waste and neurodegeneration at the crossroads of the CNS

Everyone knows that they should probably get more sleep. But do the consequences of poor sleep extend beyond feeling tired the next day? Sleep worsens with age, and is frequently disrupted after concussion (mild traumatic brain injury, mTBI). But is worsening sleep part of the reason that the aging and post-traumatic brain are vulnerable to the development of neurodegenerative conditions like Alzheimer’s or Parkinson’s disease, or chronic traumatic encephalopathy? What other cellular changes take place as we age and after mTBI that promote the neuropathological changes underlying these conditions?

These are the types of questions that the Iliff lab seeks to answer. Using cellular and molecular biology, advanced imaging approaches including in vivo 2-photon microscopy, we seek to define the basic mechanisms governing glymphatic exchange and lymphatic clearance of interstitial wastes from the brain, CSF secretion and reabsorption, blood-brain barrier function and cerebral blood flow regulation.

To answer these questions, we make use of rodent models of neurodegenerative diseases and TBI. We also work through diverse network of clinical and bioinformatic collaborators to address these questions using genetic, transcriptomic and histopathological approaches in human subjects.

 
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the role of perivascular aqp4 in the development of protein mis-aggregation

Neurodegenerative diseases are characterized by the age-related mis-aggregation of different peptides and proteins that are believed to underlie disease progression: amyloid beta and tau in Alzheimer’s disease, alpha synuclein in Parkinson’s disease, tau in chronic traumatic encephalopathy. Our lab has demonstrated that these proteins are cleared from the brain interstitium by perivascular glymphatic exchange, and that this process slows with aging and following traumatic brain injury.

In two NIH-funded studies we are evaluating whether changes in the expression and localization of the perivascular astroglial water channel aquaporin-4 (AQP4) that occur with age and following brain injury contribute to the slowing of glymphatic pathway function, and promote the development of amyloid plaques and tau aggregation. These studies will provide important new insights into the mechanisms rendering the aging and post-traumatic brain vulnerable to pathological aggregate deposition.

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Development of a Non-Invasive MRI-Based Measure of Glymphatic Function in Human Subjects

Based on rodent studies, impairment of glymphatic pathway function is proposed to contribute to the development of neurodegenerative diseases. Yet approaches to evaluating glymphatic function in the human brain to date are invasive and may not be suitable for widespread clinical use.

In a human neuroimaging study funded by the Paul G. Allen Family Foundation (Co-PIs Rooney and Iliff), a collaborative team based out of OHSU is using in-scanner EEG measurements with dynamic magnetic resonance spectroscopy to evaluate whether glymphatic function can be captured in human subjects whether by measuring sleep-wake changes in brain lactate levels.

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Changes in Choroid Plexus Function in the Development of Neurodegenerative Disease

Cerebrospinal fluid (CSF) is produced by the choroid plexus, located in the ventricles of the brain, and plays an important role in brain physiology. While the choroid plexus and CSF production can be dynamically regulated, the relationship between sleep states and CSF composition is not well understood. Since both inefficient waste clearance and sleep disruption are prominent features of Alzheimer’s disease this project will determine the role of the choroid plexus in the regulation of sleep-wake glymphatic homeostasis through modulation of CSF dynamics. Combining omics technologies, dynamic in vivo microscopy approaches in animal models, and validation in human choroid plexus this study will inform prospective therapeutic strategies that will be widely applicable to diseases of impaired protein clearance, including Alzheimer’s disease.

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Quantifying the influence of yogic breathwork on cerebrospinal circulation (yildiz, pi)

Selda Yildiz, NIH-NCCIH K99/R00 Career Transition Award. Mentors: Dr. Barry Oken (OHSU), Miranda Lim (OHSU), Bill Rooney (OHSU), Crystal Park (UConn), Jeffrey Iliff (UW).

The practices of yogic breathwork have been demonstrated to be effective for a wide range of health conditions including sleep and neurological conditions. While underlying mechanisms are still not fully known, one previously studied mechanism for the health benefits of yogic breathwork is through parasympathetic activation as evidenced by decreased respiration rate, heart rate and blood pressure, and increased heart rate variability. Another mechanism for explaining the health benefits of yogic breathwork can be its direct influence on CSF circulation, which to date has not been investigated due to lack of non-invasive methodology. The goals of Selda’s NIH-NCCIH K99/R00 career transition award are to (1) determine the influence of an 8-week yogic breathwork intervention on CSF flow dynamics; (2) determine the influence of an 8-week yogic breathwork intervention on CSF circulation (flow dynamics and glymphatic function), and; (3) measure the effects of the breathwork intervention on participants’ long-term sleep patterns, and correlate the degree of sleep improvement with the changes in CSF circulation.