Brain imaging, also called neuroimaging, encompasses a range of different techniques which can be used for dementia diagnostics. Some of the neuroimaging techniques have been around for many years, while others are cutting-edge.
But how can the different neuroimaging techniques support a diagnosis of dementia and what are the changes seen in dementia on brain scans?
Neuroimaging encompasses a whole range of different techniques, from the commonly used to the rather obscure. One could write a book on all available neuroimaging techniques for dementia, however, for the purpose of the questions above, I will focus on three main neuroimaging techniques which are highly relevant for dementia diagnostics. They are 1) Computer Tomography; 2) Magnetic Resonance Imaging, and 3) Positron Emission Tomography. Let’s explore each one, in turn, to see how they can support dementia diagnostics.
Computer Tomography – CT
Computer Tomography, abbreviated CT and sometimes referred to as CAT, is the most commonly used neuroimaging technique. The reason why it is so commonly used is that it is widely available, with nearly every hospital having a CT – at least in economically developed countries.
How does CT work?
In essence, CT is a sophisticated X-ray machine, which can take 3D X-ray pictures of our body, including our brain. Conventional X-ray machine creates 2D images for one direction, whereas CT works by using X-rays from multiple angles to produce a 3D image. For example, for a brain CT, it takes multiple images from multiple angles of our head, which are then reconstructed by a computer to produce a 3D image of the brain. On a brain CT scan (see picture below), we can see the skull as a bright white structure surrounding our brain. The brain itself is shown in a grey-ish colour and we can also see some black part surrounding the brain and inside the brain. These black parts are corticospinal fluid (CSF) which surrounds our brain to protect it, provide it with nutrients and remove its waste materials.
How do changes in dementia appear on a CT scan?
As a quick reminder, all dementias – with exception of vascular dementia – are caused by excessive proteins in the brain. The excessive proteins become toxic to the nerve cells in the brain and the nerve cells start dying. These dying nerve cells are removed by the body as they are not useful anymore, leaving gaps in the brain tissue. Because of the gaps left behind by the dead nerve cells, the overall brain tissue shrinks. Clinicians refer to this shrinkage of brain tissue as ‘atrophy’. On a brain CT scan, we can observe such atrophy by seeing the brain tissue (the grey part) to shrink. Compare for example the health brain below in the picture with the brain having Alzheimer’s disease. We can see that the Alzheimer’s disease brain appears shrunk compared to the healthy brain. Often the shrinkage is noticed because the corticospinal fluid, appearing black on CT scans, fills the gaps of the brain tissue (see red arrows on the picture).
Clinicians often corroborate the clinical symptoms of dementia, such as memory loss and spatial disorientation in Alzheimer’s disease, by looking for atrophy on CT scans. In particular, a brain region called the hippocampus, which is important for our memory and orientation, shows often shrinkage in people who have Alzheimer’s disease. Identifying the shrinkage in the hippocampus on a CT scan confirms therefore to the clinicians that a disease process, like Alzheimer’s disease, is likely causing the memory and orientation symptoms. In the above picture, the hippocampus is indicated by the two shorter arrows showing that this brain region has significantly shrunk and we would expect therefore the person with such a scan to have memory and spatial orientation problems.
Despite CT being a well-used and widely available technique, it has a few shortcomings. For one it is an X-ray technique, meaning that people are exposed to small-dose radiation/X-rays when undergoing the scans. That might be fine for a scan once in a while, however, repeated scans in short succession need to be carefully considered. The other shortcoming is that the scans are fairly low resolution. We can see clearly the brain but the distinction of different brain regions is much harder or not possible. Finally, one critical shortcoming for dementia is that CT make it very hard to distinguish different brain tissues from each other.
Why is the distinction of different brain tissue types important for dementia?
To understand this, we need to take a step back and explore the two main tissue types in the brain – grey matter and white matter. Grey matter is mostly located on the surface of the brain and contains the cell bodies of nerve cells. White matter is mostly located in the inner parts of the brain and contains the connections between different nerve cells. We know that for most dementias, the grey matter is earliest affected by the disease and shows atrophy/shrinkage. Hence, identification of grey matter changes is for most dementias the critical aspect. However, since CT does not distinguish between grey and white matter it can be very challenging to detect more subtle grey matter changes at the beginning of the dementia disease process. Another neuroimaging technique comes to the rescue for this as it can distinguish grey and white matter – Magnetic Resonance Imaging.
Magnetic Resonance Imaging – MRI
Magnetic Resonance Imaging, abbreviated MRI, is a sophisticated neuroimaging technique than CT. MRI overcomes all the shortcomings of CT as it is not reliant on radiation – the actual functioning of MRI is quite complex but suffice to say it uses large, superconducting magnets to produce high-resolution images of the brain. Not only that, but it can also distinguish grey and white matter brain regions (see picture).
It is therefore the perfect neuroimaging technique to detect very subtle changes for dementia, even when people might have no or very few symptoms. MRI is also much for versatile than CT as it can use different sequences which can highlight different brain tissue types. The final advantage is that MRI cannot only be used for imaging the structure of the brain – so-called structural neuroimaging – like CT but it can be also used for functional neuroimaging. Functional neuroimaging, as the name implies, allows us to look at and check the functioning of the brain. The most commonly used functional MRI technique looks at how much oxygen different brain regions use. The usage of oxygen tells us how active or inactive a brain region is and is, therefore, a great proxy measure to brain activity levels.
What’s not to like about MRI and why not use it instead of CT? The reason is that MRI is less available and only larger hospital will have MRI machines as they are far more costly to run and maintain than CT machine. MRI is therefore used much less often for dementia diagnostics and often only requested when it is unclear whether someone has dementia or whether they have a rarer form of dementia.
How do brain changes in dementia appear on MRI?
For structural MRI, we want to detect similar changes to CT, in particular shrinkage/atrophy of the brain. Because of its higher resolution, we can detect the shrinkage of brain areas potentially much earlier using MRI compared to CT (see picture). I am not sure it is clear enough in the below picture, but it shows that the atrophy on the MRI is mostly caused by shrinkage of the grey matter while the white matter remains largely intact.
We can also follow these brain changes over time as MRI does not use any X-rays and therefore does not increase the radiation levels of people undergoing MRI scanning. Finally, MRI also allows detecting not only grey matter changes but also specific white matter changes in the brain. It does this by changing how the superconducting magnetics work, so-called different ‘sequences’ of the scanner. This means we can take with one MRI scan different images which are either specific for the grey matter or white matter allowing us to check and diagnose different brain changes.
MRI is an incredibly powerful and highly flexible neuroimaging technique which can be used for dementia diagnostics, with the caveat being that it is not as widely available. However, functional MRI is rarely used for clinical diagnostics in dementia, even though it is theoretically possible. There are several reasons for this but one of the main reasons is that there is another neuroimaging technique, which really comes to shine when investigating functional brain changes in disease – Positron Emission Tomography.
Positron Emission Tomography – PET
Positron Emission Tomography, abbreviated PET, is the final neuroimaging technique we are going to explore for dementia diagnostics. PET’s strength is in measuring various forms of brain activity, so-called functional neuroimaging. PET, like MRI, is extremely versatile in its use as we cannot only measure overall brain activity but also specific chemical, protein and inflammation levels within the brain. However, there is a price to pay in that PET has a lower resolution than MRI and also exposed people again to low levels of radiation, like CT.
In contrast to CT, for PET the radiation is measured is actually coming from inside of the people undergoing the scan and then measured by the PET scanner. The reason why the radiation comes from inside is that people undergoing scanning get an infusion or injection with substances to measure those chemical, protein or inflammation levels. The injection/infusion includes specific chemicals, called ligands, which emit low-level radiation and are designed to attach themselves to specific brain chemicals, proteins or inflammation we want to measure in the brain. We can measure with PET, therefore, the radiation coming from the ligands which have attached themselves to specific molecules in the brain, before the ligands are eventually flushed out of the brain and body – usually after an hour or so.
How do we measure dementia brain changes with PET?
There are three main ligands which are commonly used in PET for dementia diagnostics. The most common ligand is called FDG (FDG is short for fluorodeoxyglucose), as it is a ligand which is made out of glucose (sugar) and includes the chemical fluoride. Since the FDG ligand includes glucose it is taken up by the cells for their metabolism, as glucose provides energy for the cells. We can then measure how much FDG has been taken up by the cells in the brain, which gives us an indication of how active and healthy they are. We already know that when we have dementia disease processes in our brain, our nerve cells do not work anymore correctly and die, which means they use less glucose. We can detect therefore on the PET scan brain areas which have less glucose metabolism, indicating that dementia disease processes might be happening in this brain area. For example in the FDG-PET brain scan below (see picture) we can see that the brain area on the left seems to be working normally, while the same brain area on the right shows a strong reduction in glucose metabolism, indicating a change in metabolism and potential nerve cell loss. Overall, this gives a good indication of brain activity levels and we can also track these changes over time.
Even more amazing, we can also use PET to measure levels of dementia proteins in the brain. Such protein-based PET scans are still quite new and not commonly used and are only available for two proteins associated with dementia – amyloid and tau. Amyloid PET has been around now for several years and has shown impressive results as we can observe now for the first time how the proteins accumulate in the living brain. This is important as we can determine the levels of amyloid before it becomes toxic to the nerve cells and they die, which means we can intervene earlier in the disease before the nerve cells are lost. Tau PET is even newer and still very much used on an experimental level for research studies and not for diagnostics, but might be available in the future, hence I briefly mention it here. It is therefore still not clear yet whether it has regular use for dementia diagnostics in the future.
Finally, for completion sake, we should also mention that there is currently a lot of research happening into PET ligands for neuroinflammation in dementia. Neuroinflammation in dementia is thought to indicate that the body’s immune system reacts to the increasing protein accumulation. It is therefore a proxy measure of dementia disease processes but can be very sensitive to pick up the earliest changes in the brain when the disease starts. For now, neuroinflammation PET is only available for research or experimental purposes, but, similar to tau PET, might have future use for dementia diagnostics.
What’s not to like about PET then?
Indeed it is a great and very flexible technique, however, the caveat is that PET is again not as widely available as CT and often only available in highly specialised hospitals. Even if a hospital has a PET, they often only provide FDG-PET and no amyloid, tau or neuroinflammation PET as the ligands for amyloid, tau and inflammation require additional very expensive machinery. Therefore, the more sophisticated PET is only found in very large or research-intensive hospitals, and it is – so far- rarely used for diagnostics of dementia and if then only for people for whom the diagnosis is unclear.
Taken together, different neuroimaging techniques are available for dementia diagnostics. Structural neuroimaging methods (CT, MRI) are often used for dementia diagnostics and detect shrinkage/atrophy in specific brain regions. The shrinkage is caused by the death of nerve cells in that region, corroborating the clinical symptoms. Functional neuroimaging methods (fMRI, PET) are less commonly used for diagnostics of dementia, instead, they are often employed only for research studies or clinical trials. Nevertheless, amyloid PET has emerged as a potential diagnostic functional neuroimaging technique which is used in large hospitals.
Overall, neuroimaging is an extremely important diagnostic technique for dementia, in particular for people where the diagnosis is unclear or who might have one of the rarer forms of dementia (see also my blog entry on types of dementia). CT and MRI will likely remain diagnostic techniques for dementia, however, the arrival of potential blood biomarkers for amyloid and tau raises the question as to whether we need functional neuroimaging for dementia diagnostics in the future. Only time will tell.