Hypertension May Accelerate Neurodegeneration by Reducing Clearance of Metabolic Waste via Cerebrospinal Fluid Drainage

I missed the open access paper noted here when it appeared last year. It is an interesting addition to the growing body of evidence that shows drainage of cerebrospinal fluid from the brain to be an important mechanism for clearance of metabolic waste. That the drainage paths become impaired with age contributes to the aggregation of proteins such as amyloid-β, involved in the development of Alzheimer's disease. Thus approaches to restore drainage in one way or another should prove quite effective for a range of neurodegenerative conditions. We will find out whether or not this is the case over the next few years as groups like Leucadia and EnClear move beyond animal studies and into human trials.

Cerebrospinal fluid (CSF) aids in the removal of metabolic waste from the brain. The exact anatomical pathways and mechanisms underlying how solutes in the interstitial fluid (ISF) are transported towards CSF remain unclear. Historically, it has been thought that solutes exit the brain along a network of perivascular spaces (PVSs) surrounding cerebral arteries, against the direction of blood flow. Recent in vivo experiments in rodents have shown the opposite: CSF enters the brain along arterial PVSs, and this flow plays a vital role in driving the clearance of amyloid-β (Aβ) from the ISF at more downstream locations

In both cases, indirect experimental evidence suggests that fluid within PVSs is transported via bulk flow and possibly driven by arterial pulsations derived from the cardiac cycle. To evaluate fluid motion within the PVS we have adapted in vivo two-photon imaging to allow measurement of CSF flow speeds simultaneously with recordings of cardiac and respiratory cycles. We have also performed synchronized measurements of the artery diameter and heartbeat to determine vessel wall dynamics. The analysis confirms that CSF bulk flow in the PVS is pulsatile, at the same frequency as the cardiac cycle, and in the same direction as blood flow. Our results are highly consistent with a fluid transport mechanism - perivascular pumping - wherein vascular wall kinetics directly drive pulsatile CSF bulk flow in the PVS.

Finally, we show that high blood pressure, a condition that affects close to half of the world's adult population, disrupts the perivascular pump and sharply slows CSF transport in the PVS. Earlier studies have shown that arterial hypertension promotes the accumulation and aggregation of Aβ. We speculate that hypertension-induced reduction of PVS fluid transport contributes directly to the associations between arterial hypertension and Alzheimer's disease.

Link: https://doi.org/10.1038/s41467-018-07318-3