An unexpected limitation was recently dis- covered in the ability of the brain to obtain sufficient oxygen from the bloodstream (capillary dysfunction). This phenomenon and the implications of capillary dysfunction for normal brain aging and dementia are now under investigation by the ARCADIA research team.

The brain needs oxygen

Although the brain only accounts for around 2% of body mass, it receives 20% of the volume of blood pumped around the body by the heart. This is because brain function requires a continual supply of large volumes of oxygen, and if supply is cut off, by a stroke (blood clot), for example, the result will be rapid onset of paralysis, speech disturbance or loss of consciousness. Diseases caused by limitations in the brain’s blood supply are known as cardiovascular diseases, and are typically caused by narrowing or clotting in the blood vessels that supply the brain. Cardiovascular diseases are especially common in individuals with risk factors such as high blood pressure, smoking, high cholesterol count etc.

Alzheimer’s disease – and a paradox

Alzheimer’s disease affects approximately 5% of the population over the age of 65. The incidence is more than 20% in individuals aged 90-plus, and its prevalence is thus expected to rise with increasing life expectancy. The disease develops slowly, gradually affecting the sufferer’s recall, acquired skills, behaviour and personality.

In Alzeheimer’s disease, deposits of harmful proteins form in the brain tissue, and the condition is commonly referred to as a neurodegenerative disease. This means that the brain tissue gradually loses its function and deteriorates without any sign of capillary dysfunction. Over the last decade, therapies have been developed to eliminate or counter the formation of the harmful protein deposits, yet none has so far been effective in human beings. It has long been known that the risk factors for developing Alzheimer’s disease are largely the same as those for cardiovascular disease and stroke.

Under the effects of oxygen deprivation, brain tissue readily forms the type of protein deposits seen in Alzheimer’s disease. However, blood flow in the brain is not critically reduced in the years preceding onset of the initial symptoms of Alzheimer’s disease. This has led researchers to exclude diseases of the brain’s blood vessels as the cause of Alzheimer’s, and this serious form of dementia is consequently regarded as a neurodegenerative disorder rather than a disease caused by capillary dysfunction.

Rethinking physiological first principles

The assumption that oxygen deprivation in the brain is caused exclusively by impaired blood flow arose out of a coincidence in the way researchers apply the findings from classical capillary physiology: that is, the study of how nutrients and waste products are transported between the smallest blood vessels, the capillaries, and, for example, brain tissue.

Oxygen transport from the blood to cells in tissue may be described for a capillary by what is known as a flow-diffusion equation. For different rates of blood passage through a single capillary, the equation indicates the volume of oxygen to which the tissue has access (Figure 1). It is not, however, possible, based on the properties of a single capillary, to draw a general conclusion as to the volume of oxygen available from the millions of capillaries supplying blood to, for example, 1 mm3 of brain tissue. The blood travels at different rates through individual capillaries, and Figure 2 illustrates why dysfunction in the capillary wall, for example, leads researchers to overestimate the volume of oxygen available to the tissue.

Capillary dysfunction

For a number of years, researchers have sought to understand the scale of the error made if no allowance is made for the reduction in tissue access to oxygen caused by dysfunctional capillary flow. There is now evidence that this capillary dysfunction could, in theory, become so severe that oxygenation of brain tissue is drastically reduced, even at blood flow rates currently regarded as normal. The hypothesis is therefore that oxygen deprivation is the cause of the characteristic protein de- posits found in Alzheimer’s disease, even if the patients’ blood flow is not critically low.

By means of a systematic review of the literature, we found that the risk factors for developing Alzheimer’s disease are, in fact, characterised by very early changes in the capillary wall and its functioning. The ARCADIA research centre was set up to investigate whether capillary dysfunction might be the cause of the cognitive impairments that occur with advancing age. There are currently no methods for determining capillary flow patterns, and ARCA- DIA’s first project will consequently be to develop advanced methods for detecting this phenomenon. The project, undertaken by an interdisciplinary partnership of physicists, engineers, chemists, statisticians, biologists and medical clinicians, has so far found evidence that state-of-the-art scanning methods can be used to detect capillary dysfunction in patients with Alzheimer’s disease.

By Leif Østergaard

Leif Østergaard (b. 1965), MD (1994), holds an MSc in astronomy, physics and mathematics (1992) from Aarhus University. He gained his PhD and DMSc (Doctor Medicinae) from Aarhus University in 2000 for a thesis on cerebral microcirculation. Professor Østergaard is currently consultant physician at the Department of Neuroradiology, Aarhus University Hospital, and director of the Center of Functionally Integrative Neuroscience (CFIN) and MINDLab, Aarhus University.