What is brain shrinkage/’atrophy’ in dementia
When receiving a diagnosis of dementia, many people hear for the first time the term brain ‘atrophy’. The term is usually given by the clinician providing the diagnosis when discussing their brain scan. For example, “you have mild atrophy in your brain, suggesting that you might have the early stages of Mild Cognitive Impairment/Alzheimer’s disease/other forms of dementia.” But what is actually meant with this term ‘atrophy’ and what does it refer to specifically?
Let’s find out.
Atrophy – the basics
Atrophy comes from the Ancient Greek word ‘atrophia’ meaning literally ‘to waste away’. Clinically, it refers to a disease process during which the cells or tissue of our body ‘wastes away’, causing that tissue to shrink. For example, people with certain muscular diseases have a shrinkage of their muscles, meaning the cells in their muscles have ‘wasted away’ for some reasons causing their muscles to shrink. The same principle applies to the brain where atrophy refers to the ‘wasting away’ of brain cells. In this context, it means that the brain cells (including nerve cells which are one type of brain cell) are ‘wasting away’ and eventually dying, causing the brain to shrink.
Why are the brain cells wasting away?
The reasons why brain cells are wasting away and dying can be various for different brain disease, however, for dementia, the majority of brain cells are wasting away and dying because of proteins which amass/accumulate in or around the nerve cells. Indeed, all dementias, with the exception of vascular dementia, are caused by the accumulation of such proteins. I recommend reading my following blog entry (see here) which explains in more detail the difference between different dementias and their underlying proteins. But let’s take Alzheimer’s disease, the most common form of dementia, as an example of how atrophy emerges in the brain. Alzheimer’s disease is caused by two proteins – amyloid and tau – which accumulate causing the disease process (pathophysiology) of Alzheimer’s disease.
So, how do amyloid and tau affect the nerve cells and make them ‘waste away’ causing atrophy?
Atrophy in dementia
The exact mechanisms of how amyloid and tau accumulation affect the healthy functioning of nerve cells are still being investigated. However, we already know that amyloid is commonly accumulating outside of the nerve cells. Amyloid is an important protein in the cell wall of healthy nerve cells but when it gets disassembled/recycled it can result in very ‘sticky’ proteins sticks (so-called fibrils) of amyloid. These amyloid fibrils are outside of the nerve cell and waiting to be transported away by the body for recycling. However, during ageing the transporting away/recycling process seems to slow down – to unknown reasons so far – which means that an increasing amount of ‘sticky’ amyloid fibrils are outside of the nerve cells. If there is a large amount of these ‘sticky’ amyloid fibrils around they start glueing together. We can compare it to glueing lasagne sheets lengthwise together – creating larger fibrils (so-called amyloid oligomers). In the last stage these amyloid oligomers ‘clump’ together in a random fashion into ‘ball-like’ structures, resulting in amyloid plaques. It is those amyloid oligomers and plaques which create a real problem for the brain, as they are very difficult to take apart and recycle. Like in life, clearing up a big sticky mess is an effortful job. The same is true for amyloid plaques. The more amyloid plaques are around the nerve cells (see Figure below), the more the function of the nerve cells gets affected leading to some ‘wasting away’ or dying. But our brain could certainly cope with a few nerve cells dying from time to time due to the excessive amyloid surrounding its cells. However, another key in the ‘wasting away’ of brain cells, is the second protein causing Alzheimer’s disease – tau.
In contrast to amyloid, tau is accumulating inside of the nerve cell. The pathophysiology of tau accumulation is a bit more complicated than amyloid so let’s just take it for granted that it is accumulating. The key to understand is that tau has a very important role in healthy nerve cells to support and facilitate the transport of nutrients and other molecules to different parts of the nerve cell. Once tau starts accumulating, this transport mechanism starts to fail, which means that certain parts of the cell do not get anymore their required nutrients and molecules, which means the nerve cell starts starving. On top of that, tau is important to give one part of the nerve cell (the axon) stability as it is part of the nerve cells skeleton (the cytoskeleton). The axon is critical in the communication between different nerve cells and sending nerve signal onwards. Once the tau accumulates it fails to provide the axon stability, which often starts to collapse because of the accumulating tau (see Figure below). In the end, the nerve cell is therefore starving and collapsing once tau accumulates, causing it to ‘waste away’ and die.
We can see now that the pathophysiology of dementia affects the functioning of nerve cells and leads to them ‘wasting away’ and eventually dying. The nerve cells death only happens at first for a few cells but once the disease spread many nerve cells waste away and die. When the nerve cell death only happens on a very small scale, as at the beginning of the disease, we can only see the nerve cell loss under the microscope. Only once nerve cells have died on a very large scale, we can see the nerve cell loss with our eye (in scientific speak on a ‘macroscopic’ level to distinguish it from a microscopic level). It is only at the macroscopic cell loss stage, ie on a larger scale, that we can see this nerve cell wasting/loss on brain scans, such as CT (Computer Tomography) or MRI (Magnetic Resonance Imaging) commonly used for dementia diagnostics. It is this large scale nerve cells loss we can see on brain imaging, clinicians often mean when talking about brain ‘atrophy’.
How does atrophy look like on a brain scan?
Atrophy on brain scans
Below I show an MRI brain scan. We can see the skull and the corticospinal fluid surrounding the brain (Figure). The brain itself has two colours on this type of MRI scan – a withe-ish colour and a grey-ish colour. The white-ish colour indicates the so-called white matter, which is basically the nerve fibre bundles connecting different brain regions with each other. The white matter is not as important to atrophy as they grey matter – the greyish coloured brain regions. The grey matter (zoomed-in part of the Figure) is where most of the cells bodies of our nerve cells sit. We can see that the majority of the nerve cells can be found on the outer regions of the brain – the so-called brain cortex – it’s like a grey ribbon around the brain. Since atrophy is mostly affecting the nerve cells, it is, therefore, the brain cortex (where the majority of nerve cells sit), where we can see atrophy brain changes in dementia on brain scans.
Let’s have a look now at MRI scans for healthy people and people with dementia. We can see for the healthy brain that there are few if no ‘gaps’ between the different grey matter regions of the brain. When giving my neuroanatomy lecture to medical students, I often like to say that a healthy brain looks ‘plump’. If we compare it now to the brain scan of someone with dementia, we can see that there are more ‘gaps’ between the brain regions and it looks as if the brain has ‘shrunk’ (see Figure below). We now know that this ‘shrinkage’ is caused by atrophy – the wasting away/dying nerve cells. Since there are fewer nerve cells around the brain looks less plump and seems to shrink. The atrophy/shrinkage is therefore an indicator that the dementia disease process might be happening in those brain regions. However, we need to careful as we do not know which proteins, such as amyloid or tau, are causing the atrophy or maybe some other pathophysiological process. Clinicians use therefore atrophy as a ‘proxy measure’ for a dementia disease process in the brain, since it is much harder to measure amyloid or tau directly in the brain – for now, at least.
The other ‘proxy measure’ atrophy provides clinicians is that it allows estimating how advanced dementia is in the brain. For most people the more atrophy they show on brain scans the more advanced dementia – however, be aware that this varies significantly between individuals and clinicians take other factors into account to determine disease progression, such as everyday functioning and cognition. We can see in the below figure that in moderate and severe dementia, the ‘gaps’ in the brain get increasingly larger, indicating that more and more nerve cells have wasted away /died and therefore there is a larger degree of atrophy visible on the brain scans. For clinicians, it is this increasing ‘absence’ of nerve cells indicated by atrophy that provides them with important information for diagnosis and disease progression. In other words, atrophy is measuring the ‘presence of an absence’ – the absence of nerve cells.
The final proxy measure atrophy provides clinicians is that it can corroborate the symptoms of someone with dementia. What do I mean by that? The brain is highly specialised for its functions, with certain brain regions performing certain functions. For example, there are specific brain regions responsible for our vision or for our movement or for our memory. Clinicians can therefore check whether the symptoms a person presents with at their clinic are corroborated by the brain regions affected by the disease. Atrophy for example in the memory specific brain regions would suggest that the person has memory problems. If, however, there is no atrophy in the memory-specific brain region but the person has memory symptoms, then these symptoms might be due to another cause (for example, depression can often present with memory symptoms but cause little to no atrophy in the brain).
We now know that atrophy means nerve cells death and is caused by the accumulation of proteins in dementia. But where do the dead nerve cells go? Do they just disappear?
Once the nerve cell dies, it gets dismantled and recycled by the body, which is the general physiological process of our body to deal with dead cells of any kind. So for most nerve cells, nothing remains and the space they previously occupied is either left empty or filled by corticospinal fluid or the surrounding brain tissue. Often the only remnants of nerve cells are the tau fibrils and amyloid plaques. Like a negative image, the proteins fibrils and plaques still are where the nerve cells used to be, giving an indication as to what has gone.
In summary, atrophy is a macroscopic measure of nerve cells wasting away and dying. Clinicians use atrophy as an indication as to whether a person as an ongoing dementia disease process, such as amyloid and tau accumulating, occurring in their brain. Clinicians also use atrophy on brain scans as a proxy measure for checking the progression of dementia, as well as a confirmation that the symptoms are caused by dementia.
Who would have thought that the ‘presence of an absence’ has such significant relevance for dementia?