Frontotemporal Lobar Degeneration: Neurodegeneration The Path to Prevention Part 2

Frontotemporal Lobar DegenerationI hope everyone enjoyed part 1 on neurodegeneration.  Today, in part 2, I will focus on probably the least understood and studied form of neurodegeneration out of the diseases I mentioned in part 1, Frontotemporal Lobar Degeneration (FTLD).  In this post, and get ready because it’s a long one, I will outline what FTLD is and provide evidence showing that this condition is likely caused by dysregulation in the immune and/or metabolic systems, ultimately leading to the contribution of the wonderful thing called chronic inflammation to the disease state.  While reading this post, keep in mind that an ancestral approach to diet and lifestyle is related to marked improvement in metabolic, autoimmune, and chronic inflammatory conditions.  I will not speak specifically to the benefits in this post; however, you can check out some of the paleo diet testimonials here.

What is Frontotemporal Lobar Degeneration

Frontotemporal Lobar Degeneration is a fatal, progressive, degenerative disease in which brain cells are destroyed.  Specifically, as the name of the condition suggests, the cell death is localized to the frontal and temporal lobes of the brain.  What is also interesting is that the cause(s) and mechanisms behind the condition are not fully understood.  FTLD is listed from the second most common cause of early onset dementia, preceded by Alzheimer’s disease (1, 2, 3), to equal to the prevalence of Alzheimer’s in certain populations (1, 2, 3).

Three symptom based classifications of FTLD exist:  Behavioural-Varient Frontotemporal Dementia (“bvFTD”), Semantic Dementia (“SD”), and Progressive Nonfluent Aphasia (“PHFA”) (2).  I will not bore you with all the details of the symptomatology of each classification as, unfortunately, the end result is the same.  Please reference the cited articles or use Google for more information if you wish.

FTLD can further be classified by the type of histopathology (changes in tissue due to disease) seen in patients with FTLD, and can be grouped into 3 subcategories based on the type of inclusion bodies seen in neuronal cells of the brain: FTLD with Tau inclusions (“FTLD-TAU”); FTLD with tau-negative, ubiquitin and TDP-43 positive inclusions (“FTLD-U and FTLD-TDP”); and Fused in Sarcoma positive FTLD (“FTLD-FUS) (2).  Basically what occurs in FTLD is that inclusions somehow begin to develop within the cells of the affected regions of the brain.  An inclusion is simply a mis-folded, or mis-formed, protein that gets stuck within the cell itself.  This does not seem to be a normal process and appears to lead to cell toxicity and subsequent cell death.  Each different type of misfolded protein relates to the categorization of the condition noted above (i.e. misfolded Tau protein inclusions classify as FTLD-Tau).  Interestingly, the majority of the inclusions seen in the different categories of FTLD are seen in other neurodegenerative diseases (2), they simply just accumulate only in the frontal and temporal lobes of the brain.

Generally speaking, FTLD is strongly related to genetics with up to 40% of patient’s having a suggestive history of familial transmission (2, 3); however, only 10% – 14% of patients have an autosomal dominant inheritance pattern (2, 3).  Here is a definition of autosomal dominant inheritance.  However, we should be careful here since we know that genetics is very complicated with a large number of factors playing a role.  Therefore, just because you have an autosomal dominant gene mutation, may not be fully sufficient for you to develop the disease, depending on the disease.  Furthermore, keep in mind that the penetrance of the autosomal dominant gene mutations associated with FTLD is not complete (3) (the mutation does not cause the disease 100% of the time).  Aside from autosomal dominant inheritance, a number of genetic risk factors have been identified for FTLD (3).  Basically, this means that certain genes increase (or decrease) one’s risk for developing the disease; in such instances, the penetrance of the disease is less than an autosomal dominant gene mutation.  In light of the above statistics, it is also clear that since only approximately 10% – 14% of cases are based on an autosomal dominant inheritance pattern, with incomplete penetrance, other factors, such as environment, must play a role in disease expression.

Aside: If the above is not sufficient in convincing you that there are more things than just genetics influencing disease development, keep in mind that other diseases with strong familial linkage are well known to be very strongly linked to environmental factors.  For example, Type 2 Diabetes shows an 80% concordance in identical twins, meaning that if one of the twins develops Type 2 Diabetes there is a 4 out of 5 chance that the other will develop it also.  However, even with 80% concordance, it is well known that environment (i.e. lifestyle factors) plays a huge, arguably primary, role in the development of Type 2 Diabetes.  Basically, just because you are genetically at risk for a disease, may not be sufficient for you to develop the condition.  There is likely an environmental trigger(s) that leads to either gene expression, gene down regulation, disrupts your body’s natural homeostasis, or provides some type of protective mechanism.  Check out Chris Kresser’s articles on Diabesity.

Now that you have a sufficient understanding of what FTLD consists of (classifications, histopathology, and basic genetics), let’s begin to talk about the specifics of what is suggested as causative factors of the condition.  If you want some more info on what FLTD consists of, have a read of these 2 further references (4, 5).

Frontotemporal Lobar Degeneration – Oxidative Stress and Inflammation

As I mentioned in part one of this series, all neurodegenerative conditions are tied to chronic inflammation, whether it be systemic (outside of the central nervous system), isolated in the central nervous system, or a combination of both (6).  Regarding FTLD specifically, the verdict is still out on whether chronic inflammation initiates the onset of the disease, or whether it is a byproduct of the condition itself.  Like I mentioned above, research on FTLD is still in it’s infancy compared to other neurodegenerative diseases; however, with some of the recent research findings it looks like systemic inflammation, a weakened ability of the central nervous system to deal with stress, and dysregulated immune responses seem to be at the heart of the issue.  Obviously, these things likely are all tied together.

Let’s look at some of the evidence to support my above comment…

Mutations in what scientists call the progranulin (PGRN) gene are linked to the development of FTLD, specifically FTLD-TDP.  Around the time of this genetic discovery, one study (7) found that PGRN knockout mice (simulated mutated human PGRN gene) were more vulnerable to systemic infection as they were less able to properly regulate their immune systems to deal with said infection, leading to prolonged inflammation.  What’s more interesting is that these mice also showed a higher level of brain involvement during systemic infection.  This finding lead the researchers to propose the possibility that due to their inability to properly regulate the immune systems during infection, chronic infections and/or inflammation may lead to the accumulation of brain damage over the course of one’s life.  The researchers also noted that, during periods of central nervous system stress (i.e. oxidative stress), these mice had an increased level of immune response in the central nervous system itself, leading to greater neuronal cell death than regular mice.  There was also evidence of increased susceptibility of the central nervous system to oxygen and glucose deprivation; again, leading to increased levels of cell death compared to regular mice exposed to the same stressor.

A review article revealed that a number of studies performed on mice show that both mutation in the genes related to FTLD-TDP and the genes related to FTLD-TAU lead to different mechanisms of inflammatory dysregulation in the central nervous system (8); basically, regardless of the identified gene mutation, the brain is more susceptible to stress and/or produces an inappropriate response to certain stressors.

Another study revealed that gene mutations causing FTLD-FUS, can possibly reduce an individual’s capacity to properly respond to, and repair, DNA damage that can occur from a number of different types of stressors including oxidative stress (9).  While this study was in vitro (think petri dish stuff), they did also show evidence of their findings on brain samples of human subjects.

Previous evidence supports increased levels of systemic inflammatory markers in FTLD mice; but promisingly, a more recent study revealed a connection between systemic inflammatory markers and symptomatic FTLD human patients for the first time in 2011 (10).  Keep in mind that this connection was only seen in symptomatic FTLD patients with PGRN mutations, and not in asymptomatic individuals with PGRN mutations, meaning that the connection between systemic and neuroinflammation in FTLD may be more complex than this connection seems to imply.  However, another very recent study, published in March 2013 has also shown elevated markers of systemic inflammation in FTLD patients (12).  Specifically, the identified inflammatory marker, in the most recently cited study, is tied to many types of autoimmune diseases (12).  Is this evidence that systemic inflammation is a causative factor…Maybe?  Stay tuned for more on autoimmunity below.

Another recent discovery is the involvement of stress granules in the development and/or progression of FTLD-TDP and FTLD-FUS (11).  In normal subjects, stress granules accumulate in neuronal cells that are exposed to some type of stress (oxidative stress, oxygen depletion, viral infection, mechanical head injury, exposure to sorbitol, heat stress, etc.) and are considered protective as they regulate cellular protective mechanisms.  However, once the stressor has passed, the stress granules disassemble and a return to homeostasis occurs (11).  Conversely, in subjects with genetic mutation causing FLTD there appears to be dysregulation of stress granule assembly and dis-assembly leading the researchers in the referenced review article (11) to propose 2 mechanisms by which stress granules could be involved in the onset and/or progression of FTLD.

While most of the evidence in human patient’s does not indicate elevated levels of systemic inflammatory markers, other than the 2 studies I referenced above, keep in mind that in part one of this series I provided reference to solid evidence showing that systemic inflammation can most definitely influence central nervous system inflammation.  That being said, and given the fact the there is a great deal of evidence showing that individuals with mutations causing FTLD more than likely have an inability to regulate neuronal inflammation and immune response to properly protect the brain from damage, I think it would be more than ideal to absolutely limit exposure to chronic levels of systemic inflammation.  And, as well all know, a lot of this boils down to our environment and what we put into our bodies.

Ultimately, given that most of the above information is coming from animal and in-vitro experimental models, the verdict is still out on the exact cause(s) of this disease and much more work still has to be done on the research front.  However, many of the studies on FTLD, including the ones listed above, seem to be coming to a similar conclusion:  regardless of the specific mechanism(s) identified, dysregulation of the immune/inflammatory response is central.

Frontotemporal Lobar Degeneration and Autoimmunity

Autoimmunity, while very closely tied to chronic inflammation, is still slightly different.  Chronic inflammation can be caused by many different things, one such cause is when one’s immune system is primed to attack cells that normally occur in the body (i.e. nerve, myelin, liver, pancreas, etc), this is autoimmunity on a nutshell.  Each type of autoimmune condition relates to a specific cell type the immune system is attacking.  Another interesting thing is that certain autoimmune conditions tend to cluster together in people, leading to the idea that certain types of autoimmune conditions are related to one another.  Basically certain types of autoimmune conditions are considered risk factors for the development of other autoimmune conditions.

In a very interesting recent study (12), elevated systemic markers of inflammation were found in human subjects carrying PGRN mutations.  I know I mentioned this fact above; however, what I did not mention was that the researchers also revealed a higher prevalence of certain clusters of autoimmune conditions in certain FTLD populations, mainly those carrying mutations causing FTLD-TDP (PGRN mutations).  Specifically, the autoimmune diseases with higher prevalence in this population included rheumatoid arthritis, systemic lupus, psoriasis, colitis, and coeliac disease.  Furthermore, the study also discusses the fact that 40% of people with rheumatoid arthritis and systemic lupus erythematosus have circulating anti-PGRN antibodies leading to a 50% reduction in circulating PGRN levels; thus, mimicking the reduction in PGRN levels seen in individuals who have PGRN gene mutations.  Therefore, the researchers suggest that sustained autoimmune pathology could actually lead to FTLD-TDP without any PGRN gene mutation.  Cool right!  These are extremely interesting findings and while FTLD may or may not be an autoimmune disease itself (further research will make this determination) this study further strengthens the idea that FTLD is tied to immune dysregulation of some type.

Frontotemporal Lobar Degeneration and Metabolic Dysregulation

Although metabolic dysregulation is still related to inflammatory pathways and autoimmunity, let’s take a small step back from inflammation specifically.  A very recent study from September 2013 (13) found evidence of glucose hypometabolism in the regions of the brain normally affected by FTLD, very similar to findings specific to Alzheimer’s disease leading to the term Type III diabetes for Alzheimer’s.  Specifically, they gathered asymptomatic and symptomatic patients with PGRN mutations and measured the glucose metabolism of their brains.  The most interesting thing about this study was that this hypometabolism was found, not only in symptomatic patients, but also in asymptomatic patients up to 7 years before their typical familial onset of disease.  Very interesting, and clearly showing that something funky is occurring well prior to actual symptom onset.  Even more reason to start reducing inflammation and ensuring proper metabolic function throughout life.  I would love to see some type of study on brain ketone metabolism in FTLD, I wonder if it’s altered also? If not then we may have a solid reason for a mild ketogenic diet, and/or a cyclic ketosis approach for people with high genetic risk of FTLD (see Grain Brain).

Frontotemporal Lobar Degeneration and Leaky Gut?

A recent study on transgenic mice that showed inclusion (TDP-43) patterns similar to ALS, revealed that gastrointestinal complication appear to cause earlier death than would be expected from the presenting level of neurodegeneration.  Although this was a study on an animal model of ALS, keep in mind that ALS and FTLD both show TDP-43 inclusion pathology and are considered to be on a similar disease spectrum.  That being said, this is simply an animal model, a very specific animal model at that.  However, along with the above information showing a connection with coeliac disease, this study does provide some evidence indicating that scientists may want to start looking at the prevalence of GI tract issues in FTLD patients, and possible root causes of the condition in this area (i.e. leaky gut, SIBO, etc.).

Frontotemporal Lobar Degeneration – Takeaway

While we don’t have one solid final answer as to what causes each specific type of FTLD, it is quite clear that research findings are showing a connection to dysregulation of the immune system and metabolism as a causative factor.  Basically, whether it’s autoimmunity, chronic systemic/neuroinflammation, or altered brain metabolism, individuals with genetic risk of FTLD seem to have less of an ability to deal effectively with environmental stressors.  Meaning that it would be ideal for these individuals to reduce their exposure, as much as possible, to things that cause chronic inflammation and oxidative or chemical stress.  On that note, it would also be ideal to nourish the body with sufficient, proper nutrition to provide the optimal fuel the body it needs to do it’s best at dealing with stress exposure that is unavoidable.  Interestingly enough, all of these suggested causative mechanisms of FTLD are exactly the things that an ancestral/paleo lifestyle improve.  Not only that, but it also provides ideal nutrition in the form of vitamins, minerals, and energy required by the body to ensure it is armed with what it needs to properly respond and deal with unavoidable stress.  Again, please refer to my resources page to find plenty of books explaining the benefits of an ancestral lifestyle relating to inflammation.  Although, the more I write about this topic, the more I feel that I may put together a post, or series of posts, about limiting inflammation through lifestyle factors myself.  But for now, you can check out these links:

What is inflammation, Anti-inflammatory foods, reduce inflammation naturally, what is inflammation

Stay tuned for Part 3 of this series which will focus on Type II diabetes related neurodegeneration.


The Barefoot Golfer




















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  5. April

    Excellent article, thank you so much!! Very helpful.

    1. The Barefoot Golfer
      Twitter: barefootgolfer1
      (Post author)

      Thank you for the feedback. I am glad it was helpful!


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