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Guest Blog – Go with the flow

Today we’re going to cover all things blood flow. But first things first, a history lesson. Come on, you know you find them a little bit interesting, admit it.

The history of the study of the cerebral vasculature pre-dates Harvey, all the way to the Egyptians and before. As you can imagine, the building sites of the great pyramids were not a place where the health and safety police had come knocking. Injuries and death from falling masonry were frequent and one of the most prominent Egyptian physicians, Imhotep, made use of these injured individuals as case studies to learn more about how the body works. The Edwin Smith papyrus, believed to have been penned by Imhotep, contains a number of case reports written in beautifully antique language.

In case six of the series, a patient presents with a gaping fracture of the skull. When palpated, the open wound is described as having “something therein throbbing and fluttering”. This was a time when the heart was known to be a pump, and the vessels were recognized as carrying blood, but the circulatory system was centuries from being described. Many of these reports seem to include “instructions concerning..” things which have been crushed, smashed or are gaping and the rather depressing conclusion Imhotep draws from the majority of them is that they are “an ailment not to be treated”. This rather effectively demonstrates both the importance of the brain, and the importance of cerebral blood flow.

Centuries later, in 1684, Thomas Willis describes the circle of blood vessels at the base of the brain. He begins by suggesting the function of this network of vessels is to mix the blood before it enters the brain, but later suggests that they are for the blood to be allowed to go into diverse regions of the brain. Indeed, he goes on to say that “if by chance one or two should be stopt, there might easily be found another passage instead of them”. He then goes on to describe a man who died of a tumour who’s right carotid artery had been entirely occluded but who – because of the circle of Willis and the blood flow being able to find ‘another passage’ – managed to live an entirely normal life and showed no obvious signs of disability.

Around one in three adults in the UK has high blood pressure. In England, 31% of men and 26% of women have high blood pressure.

Official attempts to measure cerebral blood flow did not really get off the ground until the very late 1800s, nearly 200 years after Willis’ treatise on the vasculature. These involved all sorts of horrors including cutting the ends off arteries and measuring pressure and flow in cats and monkeys and ferrets. Actual measurements in man didn’t begin until the early-40s when techniques had been developed which allowed the measurement of blood flow without the need to cut the persons neck open. Although the first papers did use what is terrifyingly described as a ‘neck cuff’.

So why do we care about all of this? It’s because the brain is the most energy costly organ in the body – taking up only around 2% of the body’s total weight but consuming around 20% of its energy. In terms of blood flow, this is about 50ml per 100g of brain tissue per minute. Let’s put that in perspective. This paragraph thus far should take you about 15 seconds to read. In that time just over a third of a pint of blood has been sent to your brain. It gets there through networks of arteries and capillaries and is distributed at a ratio of about 1:4 white matter: grey matter. That means your grey matter, where the cell bodies of your neurons reside, is getting around four times as much blood as the white matter. This can cause all sorts of problems which we’ll get into later.

About now was when I was going to launch into an analogy about pipework and blood flow, in terms of flow, pressure and resistance when I read a wonderful paper on the regulation of cerebral blood flow from 2016.1 They spend a whole paragraph talking about the laws of physics which might apply to blood flow in terms of viscosity of fluids, length and width of tubes, etc., then spend the rest of the paragraph explaining how really, blood flow and the vasculature doesn’t actually conform to any of these laws. But as analogies go it’s the most useful one so I’m going to choose to ignore the fact that blood vessels aren’t straight or rigid, and that blood doesn’t behave like a Newtonian fluid.

As liquid is pumped through pipes it exerts a natural pressure on those pipes. Various things can affect that pressure including the viscosity of the liquid as well as the diameter of the pipes, thicker liquid and obstructed pipes are going to cause the liquid to flow differently and therefore the pressure that it exerts on those pipes to be different. In your body you have three main types of pipe taking blood to things; arteries, arterioles and capillaries. The diameter gets smaller as you go down the list and this means the force required to push blood through them, the resistance, is higher and so the speed the blood flows slows down. This is good because nutrient exchange happens in the smallest vessels, the capillaries, so you want things to be going slow enough to exchange efficiently.

In the brain, capillary networks differ between regions. Studies have shown that some areas of the hippocampus, a region of the brain important for memory, have a significantly lower capillary density than other regions. If you couple this information with the fact that those same regions are often the ones that suffer the most neuronal loss in dementia, you can see why cerebral blood flow is important.

But let’s start with some pathology outside the brain before we get into the details of that. Hypertension, or high blood pressure, is bad for all kinds of reasons. You significantly increase your chances of having a stroke or a heart attack, but it can also have long term effects on brain health. This is because of the way blood vessels respond to high pressure. The vessels within the brain undergo remodelling to cope with the increased pressure, they often become stiffer to prevent them from rupturing. As part of this stiffening process, the endothelial cells of the vascular tree also change. These are the cells that form the inner part of the tube system and are the ones in direct contact with the blood.

We’ll take a slight detour here into the blood brain barrier, which is a collection of cells designed to regulate what gets in and out of the brain.

Around one in three adults in the UK has high blood pressure. In England, 31% of men and 26% of women have high blood pressure.

As I just mentioned, hypertension can cause changes in your blood brain barrier, making it leaky. This leaky blood brain barrier is the source of much research as it is often a hallmark of the normal aging process. But it presents somewhat of a chicken and egg problem. An example of this is glucose transport. As mentioned up top, your brain is very energy hungry so needs a lot of glucose. The leaky blood brain barrier does not transport glucose as well as the intact one so this might starve the brain. But then is the pathology in the brain caused because it’s starving, or does the pathology alter the vessels and cause the brain to starve?

People with high blood pressure have been found to have increased risk of lesions in the white matter of their brain. This is thought to be because the blood vessels that supply these regions of the brain are often relatively short and straight, and so are more susceptible to the stiffening effects of high blood pressure mentioned above. But why are these white matter lesions important? Well you can think of the brain as a series of telephone exchanges. All the buildings with all the activity going on are in the grey matter, all the wires going between the buildings are in the white matter. That means if you start to lose the wiring, the buildings won’t talk to each other properly. And that is what happens in aging, and particularly in dementia.

In traditional Alzheimer’s disease – which is, as we know, the most prevalent type of dementia – the white matter starts to deteriorate around the hippocampus, the area of the brain known to be involved in learning and memory. But in vascular dementia – the kind of dementia that can happen after a stroke or develop as the result of long-term hypertension – the white matter damage is much more diffuse. And the symptoms of disease reflect that. Both types of dementia have problems with memory, but whereas Alzheimer’s patients have much more prevalent issues with episodic memory, vascular dementia patients have additional perceptual and visuospatial problems.

Together what these things show is that blood flow to the brain and the cells which make up the blood brain barrier are vital for the maintenance of good brain health. The old adage for people trying to lose weight was always ‘a moment on the lips, a lifetime on the hips’, which I feel should be able to be adapted to something like ‘a moment on the lips, a lifetime on the brain’ but I can’t get it to rhyme well. So I’ll stick to the party line and just say keep an eye on your cardiovascular system, one day it might just save your brain.

1 Fantini S., et al. Cerebral blood flow and autoregulation: current measurement techniques and prospects for noninvasive optical methods. 2016. Neurophotonics.


Author

Dr Yvonne Couch

Dr Yvonne Couch [1] is an Alzheimer’s Research UK Fellow at the University of Oxford. Yvonne studies the role of extracellular vesicles and their role in changing the function of the vasculature after stroke, aiming to discover why the prevalence of dementia after stroke is three times higher than the average. It is her passion for problem solving and love of science that drives her, in advancing our knowledge of disease. Yvonne has joined the team of staff bloggers at Dementia Researcher, and will be writing about her work and life as she takes a new road into independent research.

Follow @dr_yvonne_couch [2]