Fight Aging!

The brain generates half a liter of cerebrospinal fluid every day, which circulates through the brain and is then drained from the brain via pathways that, for the most part, have only recently been studied in any great depth. Yet cerebrospinal fluid drainage is most likely critical to maintaining the health of the brain via removal of metabolic waste. All of the drainage channels discovered to date atrophy in some way with aging, and there is evidence for several to be particularly degraded in Alzheimer's disease.

Today's open access paper revises what is known of one potential drainage path, showing that it is likely more relevant than previously thought in this context. Like other recent work on the glymphatic system, it illustrates that the brain remains one of the least well explored structures in the body, and that we cannot take present consensus for granted when it comes to many of the fine details of anatomy and function.

To what degree is neurodegeneration a matter of failed clearance of waste from the brain? The most practical way to find out is to restore cerebrospinal fluid drainage in old people, an accomplishment that still lies a fair way in the future, given the present state of research. Leucadia Therapeutics will soon enough trial an approach to restore drainage through the cribriform plate, but this only drains a small portion of the brain, the olfactory bulb where Alzheimer's disease begins. Other approaches targeting the broader drainage of the brain will be needed in order to treat more advanced stages of neurodegenerative disease.

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer's disease

Cerebrospinal fluid (CSF) imparts neurorestorative functions, serving unique roles in development, immunity, and brain maintenance. It exchanges with brain interstitial fluid (ISF) by traversing a brain-wide network of perivascular spaces (PVS). Notably, CSF-ISF exchange has been demonstrated to facilitate the clearance of metabolic brain waste, such as β-amyloid. PVS are often regarded as Virchow-Robin spaces (VRS), yet the anatomy and boundaries of these spaces have never been clearly depicted. Indeed, original descriptions disputed VRS structure, although subsequent literature generally summarizes them as homogeneous perivascular reflections comprised of simple pial membranes. Some have suggested that CSF crosses pial membranes to enter PVS by percolating through pial pores that localize to adventitia of leptomeningeal vessels. However, others argue against the existence of PVS and the localization of associated pial pores.

Whereas these theories form the bases for current PVS models, anatomic evidence remains limited and little work has been published since the time of early PVS descriptions. Surprisingly few investigations have comprehensively and systematically evaluated the morphology of pia mater or the fluid pathways next to cerebral vessels, and discrepant reporting has resulted in an abundance of nomenclatures and partial anatomic descriptions. Given inconsistent interpretations, this study was undertaken with the aim of elucidating pial and PVS structure and tracer movement patterns at cerebral cortical surfaces in mice.

We show that pia is perforated and permissive to PVS fluid flow. Furthermore, we demonstrate that pia is comprised of vascular and cerebral layers that coalesce in variable patterns along leptomeningeal arteries, often merging around penetrating arterioles. Heterogeneous pial architectures form variable sieve-like structures that differentially influence cerebrospinal fluid (CSF) transport along PVS. Additionally, pial layers atrophy with age. Old mice also exhibit areas of pial denudation that are not observed in young animals, but pia is unexpectedly hypertrophied in a mouse model of Alzheimer's disease. Moreover, pial thickness correlates with improved CSF flow and reduced β-amyloid deposits in PVS of old mice.

In conclusion, we show that PVS morphology in mice is variable and that the structure and function of pia suggests a previously unrecognized role in regulating CSF transport and amyloid clearance in aging and disease.