Taking pictures of your brain - MRIs and Alzheimer's Disease

Currently, the only confirmation of Alzheimer's Disease is made post-mortem; by looking at the brain after death. Additionally, current therapies seem to work best when Alzheimer's is not in an advanced stage. Therefore, early, accurate diagnoses of Alzheimer's is crucial to the welfare and caregiving of patients.

Although there are other possibilities, neuroimaging is arguably the best candidate for early detection of Alzheimer's. 'Imaging' is just a fancy way of saying 'let me take a picture'. Neuroimaging, therefore, is the ability to take a picture of your nervous system. In this case, we're talking about the brain.

Since this isn't my area of expertise, I was thrilled that my friend and fellow graduate student, Ms. Joey Contreras (@JoeyAnnette) agreed to answer some basic questions about neuroimaging in Alzheimer's Disease. Joey is doing her grad work in a lab that is well-renowned for terrific work in neuroimaging in Alzheimer's and other disorders. 

1.    What is an MRI?

MRI stands for Magnetic Resonance Imaging. An MRI scanner uses magnetic fields and radio waves to be able to form images of structures within the body, like the brain. This technique is really helpful in medical imaging research because it’s a non-invasive, safe procedure that does not require exposure to any radiation (like positron emission tomography, PET). 

When MRI is applied to the investigation of brain disorders we call this “neuroimaging” and it’s often the tool of choice because you can visualize and differentiate between different types of brain tissue. The two major types of brain tissue are called grey matter and white matter. 

Grey matter (GM), which is normally a pinkish grey color in a living brain, is the part that contains all the cell bodies, dendrites, and axon terminals of neurons (highlighted with red arrow). The other major tissue in the brain is referred to as white matter (WM). White matter is named because of its whitish color, which is made up of axons connecting different parts of grey matter to each other (shown by the blue arrow). Basically, these axons are like the major highways for information to travel in the brain. The green arrow denotes cerebral spinal fluid (CSF), which acts as a cushion, protecting the brain and spine from injury.

            During Alzheimer’s disease (AD) the brain experiences major damage in the form of overall loss of grey matter as well as loss of or abnormal WM. Additionally, abnormalities in GM and WM have been found to be correlated with cognitive decline (a major indicator of disease progression with Alzheimer’s disease). In this regard, its important to get a comprehensive picture of exactly what changes are occurring as the disease progresses and even before diagnosis occurs, this is where getting a good picture of brain can help.  

To speak on this a little more, the problem with Alzheimer’s disease is that by the time you start to notice cognitive decline (noticeable memory loss) years of underlying abnormal neuropathology may already have occurred.  Using neuroimaging techniques, we may be able to detect a problem even before the patient does if they come in early enough.

2. What is an fMRI

Similar to MRI, fMRI stands for functional magnetic resonance imaging. This type of imaging is unique in that it measures brain activity by detecting changes in blood flow in different areas of the brain. This technique takes advantage of the fact that when an area of the brain is in use, blood flow to that region will be greater.  This is what’s essentially called a BOLD (blood-oxygen-level dependent) signal.  

The advantage of fMRI over MRI is that fMRI can monitor brain activity and detect functional differences in brain regions when the brain in engaged in a task (ie, memory task, motor task, etc) or disengaged (at rest).  In terms of diagnosing Alzheimer’s disease, there is no single test that can be used. As a result, a medical evaluation which includes past and current medical standing, mental status, physical and neurological exams, blood tests, and of course brain imaging data (fMRI, MRI etc) go into establishing a diagnosis.

            Often times when MRI is used to aid in diagnosing AD.  It does so by looking for similar patterns such as a reduction in grey matter (indicated by red circle in top image, and arrows in bottom image ), resulting in enlarged ventricles (indicated by red arrows in top image) and overall dramatic volumetric loss in medial temporal lobes.

In terms of helping diagnosis AD, fMRI is a bit less straightforward. However, there is a lot of evidence to suggest the carriers of the e4 allele of the apolipoprotien E (APOE) gene (associated with increased risk for late-onset AD) correlate strongly with functional brain activation patterns in older adults despite normal cognitive abilities (Bookheimer et al, 2000),. This would suggest that fMRI can help elucidate changes in the brain that would otherwise be undetectable in a high-risk population for AD (for more in depth review on this look for Rishacher et al, 2013)

3. What are the problems with the field that have hampered progress in diagnosing AD?

            Imaging studies involving neurodegenerative diseases and dementias such as AD are very informative regarding structural and functional changes in  the brain which are underlie the observed clinical symptoms such as cognitive decline. They play an important role in aiding and supplementing additional data for making an accurate diagnosis as well as ruling out other diagnoses. Further studies with advanced MRI and fMRI techniques will likely provide even more information about pathology associated with AD. 

However the problem now is that these techniques are still relatively new in a young field (neuroscience). As a result there is a lot more room for improvement and accuracy. For instance, resolution is something that the field of neuroimaging still struggles with immensely. Think of it in terms of TV screens. When the TV first came the image was pixelated and fuzzy. This is very true for MRI and fMRI but instead of pixels we have something called voxels. 

Voxels are essentially a 3D pixel and the smaller the voxel the more accurate the picture. As time progresses we, as a field, are getting better at this going from a 5 mm³ voxel to current 1 mm³ voxels or smaller. Better resolution means more accurate representation of brain tissue in both time and space, which is incredibly important if we want to make accurate diagnostic boundaries.  We also need to do a better job in terms of identifying and using appropriate statistical methods that will allow us to analyze and integrate large imaging data sets and different types of imaging data.

4.    How do you see the field of neuroimaging contributing to the diagnosis/treatment of Alzheimer’s in the future

  Neuroimaging has major potential. In the last 10 years we have seen exponential growth in this area as well as the emergence of a new field called brain connectomics. Brain connectomics is the marriage of network science theory with neuroimaging.

 Basically, this field uses information from MRI, fMRI and other imaging sequences (which I can go into at another time) and analyze it in a new way, helping to predict how information flows and model anatomical and functional pathways in the brain.  

The field of neuroimaging and brain connectomics holds promise in two ways. First, it will be able to identify early pathological changes that may otherwise have been undetectable. Second, we could also use fMRI to assess the effects of various treatments (e.q. get a baseline assessment of functional brain changes and comparing that to how that same brain might change or improve with treatment). 

This would allow us to better monitor and personalize treatments for patients.  Basically this field has the potential to better predict cognitive impairment, even before the onset of clinical symptoms, creating promising biomarkers for understanding AD.

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Thanks, Joey!! 

Joey's work:

The goal of my project is to identify and characterize the subtle changes that occur in both structural and functional connectivity in the brain during the early prodromal to clinical stages of Alzheimer’s disease (AD). Recent evidence indicates that cognitive alterations as well as anatomical abnormalities in AD begin manifesting years before they can be detected by traditional methods. In order to assess the brain from a systems perspective, I have begun to use brain connectomics (a very powerful methodology that relies on network science). This allows me to assess and understand how brain networks are affected at different stages of neurodegeneration. 

The tangles of tau - breaking down highways

In a stereotypical brain from an Alzheimer's patient, there is the presence of amyloid plaque and tau tangles. We have already covered amyloid deposits in a previous post. Today, we will be discussing this tau thing. What is it? And, what the heck does it have to do with Alzheimer's Disease?

What is the link between Alzheimer's Disease and tau protein?

Post-mortem brains from Alzheimer's patients often have tau tangles (also called neurofibrillary tangles. The pictures below shows a magnified version of what these tangles look like (tau tangles are on the right, amyloid deposits on the left).

Image taken from bigthink.com

What are tau tangles aka neurofibrillary tangles?

These tangles are composed of a bunch of abnormal tau protein stuck together.

What is tau? why does it clump together during Alzheimer's Disease?

In order to answer this question, I think we should first go over what microtubules are. Microtubules allow the transport of materials across the neurons.

Here is an analogy - if your neuron is a city, then microtubules are the roads. You see, your neuron is constantly making stuff that it needs to send to different parts of the cell. One way to do that would be to simply make something and let it diffuse through the cell. But, this would not be very efficient. Therefore, the cell sets up it's own roadways in order to keep delivery organized and efficient.

Here's the really neat thing. These roadways are entirely dynamic! If the cell is done sending one protein to one part of the cell, it can send workers to that road and break down that roadway.

From Nature Reviews

And this is where tau becomes important. You see, what tau does, it helps the workers know whether or not to break a highway down. Sort of like a beacon to say - this road needs to stay!

Microtubules - the roadway of cells. (Image taken from absoluterights.com)

What happens to tau in AD?

Tau gets hyperphosphorylated in AD.

Wait, stop using big words, you showoff. What does that 'phosphorylation' mean?

Phosphorylation occurs when a phosphate group is thrown onto a protein.

Every protein in every cell of your body is under tight control. This is because, evolution has ensured that every protein can be made, destroyed or made to disappear as the cell needs it. Phosphorylation is one of these regulatory processes. By throwing a phosphate group onto a protein, you can change what that protein is doing.

Okay, what does phosphorylation do to tau?

Well, here's the weird thing about tau, it can exist in three forms---

1. Unphosphorylated - this is the form we have been talking about - when this form is present, the cell knows that that roadway needs to stay.

2. Phosphorylated - This is the green signal for the roadway to be taken apart. Let me reiterate, that this is normal. This phosphorylation-unphosphorylation allows the dynamic rearrangement of the roads in the cell.

3. Hyperphosphorylated - This is bad news bears. This is when the tau starts to misbehave and clumps together.

Okay, this is getting too sciency again. What are you even talking about?

Here's the gist so far - Tau is important to maintain normal function in the cell. During Alzheimer's this protein gets too many phosphate groups put on it. This makes the cell lose a bunch of it's roadways for no good reason.

And, what's worse is that all that hyperphosphorylated tau starts to clump together and form those aforementioned tau tangles.

What do these tau tangles do that's so bad?

Just like the amyloid plaque story, this isn't so cut and dry. Many believe that these deposits lead downstream to neuronal death. And, as we've discussed earlier, neuronal death is a key component of the cognitive issues in Alzheimer's Disease.

Is there a link between this tau stuff and the a-beta stuff?

Yes, there have been many studies that show that a-beta can actually lead to tau hyperphosphorylation (the bad version of tau). There are also a small number of studies, that are studying whether the converse is true - that tau can affect a-beta production.

Can we reduce this hyperphosphorylation?

There have been attempts to target the things that regulate the phosphorylation of tau. These have had limited to no success.

Okay, I'm bored. Summarize this.

Okay, here goes. Tau itself is not bad. The neuron needs it. But, for reasons that remain unclear, tau converts to a form (hyperphosphorylated). And this form arguably leads to cell death. And that, in turn leads to the tau tangles we observe in the brains of Alzheimer's patients.


Let me know what you guys think. Did anything still seem confusing? Please reach out to me at @AlzBlog101 or @NipunChopra7 .

The insidious beta-amyloid

First of all, thank you for all your feedback and constructive criticism. I aim to incorporate those into my writing and hopefully continue to make the writing both informative and devoid of too much neuroscience jargon.

One of the post-mortem hallmarks of Alzheimer's disease is the presence of amyloid plaques (also called senile plaques, neuritic plaques, etc.). For over 3 decades, researchers have been trying to understand what these plaques are made of, and how they contribute to the pathology of Alzheimer's Disease.

Today's blog post will explore questions about these plaques and their insidious component - beta-amyloid.

What are plaques made of?

Plaque usually means "sticky material.". Amyloid plaque is made of oligomerized beta-amyloid strands. That is just a fancy way of saying - a bunch of beta-amyloid stuck together.

What is beta-amyloid?

It's a short fragment of a larger protein, which is potentially toxic in Alzheimer's Disease.

What causes this beta-amyloid to stick together?

Bits of beta-amyloid clump together due to certain chemical properties that each strand has. An easy analogy is if you have a dog, you know that dog hair tends to clump together (and form, what my roommate calls 'bales' of hair). So, essentially, these bits of beta-amyloid clump together and form larger bits of beta-amyloid, which, in turn, form the larger plaque.

Dog hair - in case you're like my mom and hate dogs (and have therefore never seen it clump together). Love you, momsie!

What causes the singular beta-amyloid to form in the first place?

Beta-amyloid is cut out from a larger parent protein called Amyloid Precursor Protein (APP).

Why is APP being cut in the first place? Why not just get rid of it entirely?

When APP is cut in the 'right' way, fragments are made which are important to normal processes of the neuron. Therefore, getting rid of it entirely (even if we could it) would have deleterious effects on the normal function of neurons.

What cuts the amyloid-beta fragment out of APP?

There are enzymes in cells that play a variety of functions. A few enzymes are capable of cutting APP at distinct spots, releasing fragments of differing lengths. In this figure below, the blue fragment is the APP protein, and the little green fragment is the harmful beta-amyloid fragment. The scissors, represent 2 enzymes that cut it out.

Cleavage of APP by enzymes (Credit - McGill University)

An analogy might help here. If you consider APP to be a long string in length, depending on where along the string two sequential cuts are made, you would get fragments of differing lengths. The length of these fragments are crucial - because they determine whether beta-amyloid will form, or other largely non-toxic fragments are formed.

Okay, this is getting complicated, give me a summary, Nipun

Amyloid plaque is composed of beta-amyloid fragments. These fragments are cut out of a larger protein called APP by certain enzymes.

What does amyloid plaque do? 

This is where the story gets interesting (note: whenever a scientist says "interesting", he/she means - "controversial").

Let's take the traditional position first. Many believe that amyloid plaque disrupts normal cellular function and this leads to cell death. How? Well, it's possible that this plaque inserts into the cell membrane disrupting the balance of electric charge between the inside and outside of the cell.

Or, amyloid plaque may activate reactions inside the neuron that lead to it's death. Imagine the cell as your apartment, and a receptor (refer to post #1 for a better understanding of a receptor) as your doorbell. Normally, when someone rings your doorbell, you look through your peep-hole, see that it's your boyfriend/girlfriend, and all is well. In your neurons this is a normal, beneficial protein binding to the receptor and saying, "Okay this is business as usual, carry on."

But, imagine if the doorbell rang, and you realized this was at your door ---

(Insidious Donald Trump = insidious a-beta. Photo credit - greenrushinvestors.com)

That face would send anyone into a frenzy. You might even consider blowing up your own house, just so you don't have to interact with THAT HAIR. Well, that's what the cell decides to do - it sees beta-amyloid and decides to shut down shop to protect other cells nearby.

Or, it may attract the attention of your immune system which would, in turn, lead to more of the aforementioned Donald Trump effects. (If only there was an immune system that would take out the trash that is Donald Trump, amirite?)

FYI - Fellow grad students, check out Sakono and Zako (2010) for a review on A-beta formation (http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2010.07568.x/epdf), if you want to read more.

So, what's the controversy?

Well, you see, there are those who believe that beta-amyloid has nothing to do with causing the disease at all. They believe, that this beta-amyloid is a consequence of the disease, not a cause of it. You know - what came first, the chicken or the egg*?

The chicken or the egg* (Image credit: The Guardian)

Is there any evidence to support this? Actually, yes. You see, there are patients who have normal levels of plaques, but advanced Alzheimer's Disease. As a corollary, there are those who have amyloid plaque hallmarks in their brain (post-mortem), but never showed the cognitive decline correlated with Alzheimer's Disease.

Why do we care? Why not just try to treat it anyway?

If amyloid plaque comes after whatever is causing the disease, reducing levels of plaque would have no impact on the disease. 

Should we waste all that funding (and all those countless graduate student hours) on what is potentially a dead end?

YES! Along with the topic of tau tangles (next week's post), Amyloid plaque is our best target for the treatment of Alzheimer's. Plus, there is some promising clinical data that suggests that reducing amyloid levels results in improved cognition. 

What's your opinion, Nipun, Mr. Neuroscientist?

My opinion is that beta-amyloid plays a causative role (along with tau) in Alzheimer's Disease, and is therefore a part of the puzzle. And, therefore, warrants further understanding.

My head is reeling, Nipun, this was supposed to be simple. Summarize this shit and let me go.

Fair enough. Here's the gist. Beta-amyloid is likely to be harmful for neurons. And, likely to be one of the underlying causes of Alzheimer's Disease. And, is therefore a target for drug therapies for treating this disorder.

Follow the blog on twitter at @AlzBlog101, and me on twitter at @NipunChopra7. Let me know what made sense/what didn't. What you liked, what you didn't. All that good stuff. Thanks for reading! Thank you to Emily Neitzel (@EmilyNeitzel) for editing this post.

*It is logically congruent that the egg came first. Because, the species from which chickens evolved, laid an egg, which was the very first chicken. Think about it. Therefore, the egg came first (because it's parent was chicken-like, but not quite a chicken).