An Unlikely Relationship: The Link Between Alzheimer’s Disease and Type 2 Diabetes

In a society that values convenience, it should not come as a shock that 1 in 4 Americans eats fast food every day. Aside from poor eating habits, it has been found that nearly 70% of one’s waking hours are spent being sedentary, and yes that is referring to the copious amount of time you spend on the couch binge watching Netflix. Taking all of these factors into consideration, it is not surprising that nearly 40% of Americans are obese, not simply overweight, but obese. The more weight that an individual has, the greater the risk of their body becoming resistant to insulin, and developing type 2 diabetes. And if the threat of developing type 2 diabetes isn’t enough to consider changing your lifestyle, maybe learning that it nearly doubles your chances of developing Alzheimer’s Disease will.

It’s time to start spending less time in the McDonald’s drive thru, and more time thinking about your health.

How are Type 2 Diabetes and Alzheimer’s Disease related anyway? The Power of Insulin

Insulin is a hormone that is created in the pancreas that plays vital roles throughout the entire body. Not only does it maintain proper blood sugar levels, but it also assists the body in using and storing energy depending on its metabolic needs. Insulin is what turns your Big Mac into energy that your body can use. 

Image result for grand big mac
https://www.google.com/search?q=grand+big+mac&source=lnms&tbm=isch&sa=X&sqi=2&ved=0ahUKEwjo9ezBpvjdAhUKTcAKHUV1BTcQ_AUIDigB&biw=1440&bih=826#imgrc=fmyEcPsLjNyMyM:

Insulin Resistance: What happens when insulin can’t do it’s job?: The link between Type 2 Diabetes and Alzheimer’s Disease

So if type 2 diabetes (T2D) is defined by insulin resistance, how does that relate to Alzheimer’s Disease (AD)?

Insulin has a special role in the brain. It works to protect neurons, strengthen connections, and plays vital roles in cognition and memory. If insulin can’t function in the brain, these processes are disrupted.

(Memory loss and impaired cognition are two symptoms of Alzheimer’s Disease)  

The brains of AD patients usually have two main “tell-tale” signs signifying that Alzheimer’s was present: amyloid-beta plaques and neurofibrillary tangles.

alzheimers-plaque-az
https://www.askdoctork.com/how-does-alzheimers-wreak-so-much-havoc-in-the-brain-201506258011

It is believed that insulin resistance in Alzheimer’s Disease may be the result of an accumulation of these amyloid beta plaques in the brain, and in supporting this theory, there are many additional hypotheses as to how this insulin resistance develops in the brain.

TNF-α and Inflammation

It is believed that prolonged inflammation is responsible for insulin resistance in both T2D and AD.

In Type 2 Diabetes: As mentioned above, being obese has been linked to the development of T2D. It’s simple: as fat cells accumulate, inflammatory molecules also accumulate, and one of the instigators of this inflammation is a pro-inflammatory cytokine known as TNF-α. 

In Alzheimer’s Disease: Prolonged inflammation is often a defining characteristic in Alzheimer’s brains. This inflammation is often the result of immune cells in the brain known as microglia. These cells often release inflammatory molecules in response to the accumulation of the amyloid beta particles described earlier. Interestingly enough, research has shown that in order for these amyloid beta instigators to cause insulin resistance in AD patients, the TNF-α receptor must be present.

It’s a fairly reasonable conclusion that the inflammatory mechanisms of TNF-α may explain the prolonged inflammation causing inadequate insulin signaling in both AD and T2D.

And there you have it, a link between two unlikely partners in a toxic relationship. 

Figure 1
http://diabetes.diabetesjournals.org/content/63/7/2262.figures-only

Figure 1. This image depicts inflammation in the brain and periphery mediated by TNF-α and its relationship to AD and T2D.

Gangliosides and Insulin Resistance

Gangliosides have also been found to play an important role in insulin resistance.

Ganglioside GM3:

Insulin resistance mediated through TNF-α, as described above, is dependent on the accumulation of GM3.

  • As GM3 accumulates in the cell membrane, it causes tension that pulls insulin receptors out of their normal location.
    • It is believed that the accumulation of GM3 is the result of amyloid beta plaques interfering with proper ganglioside metabolism.
  • When insulin receptors are no longer in the correct spot, they become unrecognizable to the molecules that play a role in insulin signaling.
  • When proper signaling can no longer occur, insulin will not be able to perform its functions in the body, and insulin resistance will result.
http://www.pnas.org/content/104/34/13678

Figure 2. This image displays the accumulation of GM3 rendering proper insulin signaling defective.

Ganglioside GM1:

The ganglioside GM1 is a binding site for amyloid beta oligomers (ABOs) and is thus responsible for the accumulation of ABOs into toxic amyloid beta plaques. Interestingly enough, research has found that diabetes increases the accumulation of these toxic plaques, and you have yet another link between the two diseases.

Related image
https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-find-way-to-prevent-accumulation-of-amyloid-plaque-a-hallmark-of-alzheimers-disease/

So what’s the point?

https://steemit.com/sirwinchester/@sirwinchester/you-are-what-you-eat-how-food-affects-our-mood-and-brain-health

Stop taking the easy way out when it comes to your health, it could save your life. 

  • Take some time instead of the 2 minutes you spend in the drive thru, and make a meal!
    • Here are a few recipes you can try that are SUPER simple, healthy, and relatively quick:
      • “31 Healthy Dinner Recipes that take 30 Minutes or Less”
        • visit: https://pin.it/4ejzhyj6ha7yae
  • Stop binge watching Game of Thrones on the couch!
    • You could try watching it on your phone from the comfort of an elliptical or stair climber, trust me, it works!
  • Take care of your body; you only get one, and I hate to break it to you, but health care professionals can’t cure every ailment.
    • Just so you are aware: there are no known cures for Type 2 Diabetes or Alzheimer’s Disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996155/

https://www.mayoclinic.org/diseases-conditions/diabetes/symptoms-causes/syc-20371444

https://www.dosomething.org/us/facts/11-facts-about-american-eating-habits

https://www.askdoctork.com/how-does-alzheimers-wreak-so-much-havoc-in-the-brain201506258011

http://diabetes.diabetesjournals.org/content/63/7/2262https://www.healthnutnews.com/alzheimers-type-3-diabetes/

 

 

 

 

 

Here’s what you may (not) know about Alzheimer’s disease: Is your diet leading to cognitive impairment?

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory loss and other cognitive impairments such as thinking and behavior. AD is a type of dementia and can be very debilitating on the body of the patient and also significantly affect the relationships that one has with their family and friends.

 

 Alright, so you’re on your computer or you’re watching Netflix at home and your stomach starts to rumble and you get up to get a snack-what do you grab? Do you go for those veggies sitting in your fridge, decide to make a salad, or say “to heck with being healthy, lets eat some cake and order in Dominos.” While I love ‘junk food’ just as much as the next person, I’m not sure I’ll be reaching for that dessert as much anymore after finding out that type 2 diabetes is a major risk factor for Alzheimer’s disease. Now, just to be clear, I’m not saying that eating a continuous high-fat diet will cause you to have symptoms characteristic of dementia or AD, but I am saying that we, as a society, should start paying closer attention to what we are eating.

 

Wait, so you’re telling me that there’s a link between my diet, developing type 2 diabetes, and getting AD? How in the world is this possible? I’m glad you asked! There are mechanisms found at the molecular level that help bring this association to light, specifically in regards to insulin signaling, and inflammation.

 

Insulin Resistance Signaling

As you’re eating whatever snack you decided on earlier, the food is being broken down into smaller molecules (i.e., glucose) that can be used for energy and metabolism. When there becomes an increased amount of glucose in the body, a hormone, namely insulin, is release. This key hormone helps to breakdown glucose so that the body can use it efficiently and effectively. However, in type 2 diabetes, this entire process is inhibited in some way, thus producing insulin resistance, characterized by having insulin but lacking the proper signaling in the brain. This resistance to insulin can have some negative affects on the brain and body overall. This impaired insulin signaling happening in the brain has been detected in a post-mortem analysis of the brain (the only way to actually ‘diagnose’ AD, as well) in the hippocampus region.

 

Inflammation

This is an important part of the type 2 diabetes-AD story. Inflammation in type 2 diabetes is mediated by macrophages in adipose tissue that also intersects with ER stress and thus can also be linked to insulin resistance through the TNF-alpha pathway. However, in the brain, this notion of inflammation is mediated by microglia cells that impairs synaptic functioning, also plays a role in ER stress, and is associated with insulin resistance signaling in the brain (specifically with the insulin receptors). This problem of insulin resistance may be due to the fact that there is activation of PKR (protein kinase R) by the TNF-alpha signaling, which would further lead to a potential inhibition of insulin receptor substrate (IRS) in the PI3K/Akt pathway (more on this in a bit).

The PI3K/Akt pathway is important as it is involved in cell growth and proliferation. But what exactly is going wrong in this pathway that leads to cognitive decline and AD? This pathway is overactive in the AD brain and is not being properly shut off. Let’s take a closer look:

 

This pathway is activated by insulin and leads to a phosphorylation cascade of events that activate a number of different enzymes in the cell. When this pathway is overactive, it leads to insulin resistance in the brain, similar to what is seen in type 2 diabetes due to unhealthy eating habits. Furthermore, when this pathway is constantly being turned on, our bodies try to compensate for this constant activation by decreasing the number of insulin receptors. This ultimately means that there are less receptors for insulin to bind to, and thus less activation of the pathway. However, this essentially leads to insulin resistance in the brain and can be fatal, as mentioned above.

Figure 2. Schematic of the PI3K/Akt pathway.

This over activation can also lead to hyperphosphorylation of the tau protein in the brain-once these start sticking together too much, they create what is called neurofibrillary tangles. This excess phosphorylated tau protein and NFTs can lead to formation of amyloid-beta plaques, which are all highly characteristic of AD.

 

For more info on tau protein, NFTs, and amyloid-beta plaques: https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease

 

Finally, it has also been shown that the hormone leptin plays a major role in helping link type 2 diabetes and AD together. Leptin activates the PI3K/Akt, pathways, which aid in neuronal survival and thus decreasing tau protein phosphorylation and amyloid beta plaques. Thus, if leptin is mutated or inhibited in some way, these pathways aren’t activated, and thus leads to neurodegenerative disease, such as Alzheimer’s. Leptin receptor activation has also been shown to improve the impaired insulin growth factor cell signaling pathway (insulin receptors), thus to normalize cell repair and other processes. This would help to generate normal insulin receptor activation and thus decrease the symptoms seen with AD.

Figure 3. A research study that examined the role of a high-fat diet and the leptin pathway. They found that the mice given the high-fat diet produced the MMP2 enzyme that cut leptin receptors in the brain (hypothalamus), which thus prevents leptin from binding to its receptors. This helps to put together why your brain doesn’t tell your stomach to stop eating because you are full.

So, what? Is there a cure? What’s the big picture anyway?

 

While there is no cure for AD, it is all about helping the person cope with the symptoms, help relieve the pain and suffering, as well as provide hope for not only the patient but also the family. As you can see, it is quite evident that type 2 diabetes and AD are major risk factors for each other, and it is important to maintain a healthy diet and try to exercise regularly. It may be difficult at times to resist those McDonald’s fries, but a non high-fat diet could go a long way in preventing AD. There is still SO much unknown about Alzheimer’s, but that’s the beauty of science. With advancements in technology and understanding the pathophysiology behind AD and type 2 diabetes, there is always hope for more research to be done in the attempt to finding a cure.

 

Image 1 from: https://emedmultispecialtygroup.com/2018/03/20/alzheimers-disease-symptoms-care/

Image 2 from: https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-q-and-a-identifying-alzheimers-in-its-earliest-stages/

Image 3 from: https://www.researchgate.net/figure/Aberrant-brain-insulin-signaling-in-Alzheimers-Disease-AD-Schematic-outline-of_fig1_279729041

Image 4 from: https://medicalxpress.com/news/2018-08-destructive-mechanism-blocks-brain.html

What do diet and memory have in common?

Alzheimer’s disease (AD) involves degeneration of tissue in the brain while type 2 diabetes (T2D) involves an problem with insulin resistance. At first glance it may seem that these two diseases are vastly different and have no connection. How could a disorder of glucose regulation in the blood have anything to do with neurons dying in the brain? Interestingly, recent research has suggested an intimate connection between the two diseases. It turns out that the onset of either of these two diseases will increase the likelihood the other will develop. Like many diseases, type 2 diabetes and Alzheimer’s disease involve overlapping neurochemical pathways resulting in a complex interaction between the two.

Insulin resistance in the body and brain

Insulin is a vital hormone used in glucose regulation in the body. When this molecule binds to insulin receptors, it signals the cell to let glucose in to be used in energy metabolism. In type 2 diabetes, this process is hindered. Insulin continues to be excreted by the pancreas but cells are unable to respond to it preventing glucose from entering cells. This resistance to insulin can have negative effects on both the body and brain. In the brain, insulin is used not only for energy metabolism but can also play a critical role in signaling. Insulin in the brain can be used for hunger regulation and spacial memory tasks. If this molecule is not being used properly in the brain, bad things happen.

What came first, the insulin resistance or the neuronal degeneration?

It is unclear whether degeneration of neurons in AD causes T2D or insulin resistance causes neuronal death. There is evidence for both cases suggesting that the onset of either of these diseases involves many different aspects. On one hand, it is thought that insulin resistance can arise from over inflammation of the brain due to an abnormal immune response. On the other hand, insulin resistance can be more directly correlated to a poor diet resulting in excess fat on the body. Both of these theories are valid and a combination of both is probably what is happening in most cases of AD-T2D comorbidity. Insulin resistance from excess fat reduces regulation of neuron growth causing some neurons to be destroyed when they shouldn’t and some unnecessary neurons to remain. The death of neurons from an abnormal inflammatory response can lead to a cascade of events leading to further degeneration and insulin resistance within the brain.

Where do neurofibrillary tangles fit in?

Neurofibrillary tangles are composed of clusters of proteins that conglomerate in the brain. The Tau protein is commonly used in neurons to strengthen microtubules and increase the efficiency of transport within the cell. These proteins have a tendency to be misshapen due to problems with insulin resistance further up the signaling pathway. When these proteins are misshapen, they will not do their job in the cell and will clump together. This causes problems in the brain by increasing toxicity and ultimately causing neurons to die. The death of these neurons are what causes many of the symptoms commonly associated with Alzheimer’s disease such as amnesia.

What to take away from this research

  • Alzheimer’s disease is a result of neurodegeneration
  • Type 2 diabetes is a result of insulin resistance throughout the body and brain
  • These two diseases are linked through complex interacting mechanisms in the brain
  • Diet and exercise can be helpful to prevent the onset of both diseases
  • Genetics can play a role
  • Further research is necessary to fully understand how these two diseases are linked but some aspects of the connection have been uncovered

 

 

 

Image Sources:

researchfeatures.com

alsnewstoday.com

 

 

What causes autism?

 

Introduction to autism:

Autism spectrum disorder is a developmental disease that results in impaired functioning in social communication and abnormal behaviors. People with autism generally use less eye contact, fail to know when or when not to use non-verbal gestures, and fail to recognize the emotions of others. Abnormal behaviors seen in autism include but are not limited to repetitive ritualistic behaviors, extreme interests in specific topics, and a need for unvarying routine. While it is difficult to draw the line between a normal and abnormal brain, research has suggested evidence that with autism spectrum disorder there are differences in neurochemical pathways that limit normal functioning of people with the disease.

Environmental causes:

The complex interaction among neural processes associated with autism begins early in development. During pregnancy, even slight changes in the environment can result in tremendous change in the development of the child. A pregnant mother could become infected with a minor pathogen and pass the infection on to the child through the placenta. This transfer may induce a change in the child’s immune response resulting in excess inflammation. Unfortunately, there is only so much preventative action mothers can take during pregnancy. Proper nutrition and avoidance of harmful chemicals and pathogens is all a mother can do to diminish problems with development. It is important for mothers to know that everything they do could in some way affect the baby, but it is also important to know that it is impossible to reduce all environmental risks down to nothing. Along with countless environmental factors associated with ASD, numerous genes have also been identified.

 

Genetic influences:

Thousands of genes have been linked to ASD creating a nightmare for scientists trying to fully understand why this disease occurs. One of the most common genetic abnormalities seen in ASD is a mutation in the MECP2 gene. This gene codes for a protein used in regulating the transcription of other genes. It helps to regulate synapse formation in the brain and makes sure that only necessary connections are made in the brain. People who have an alteration in this gene will have abnormal connections of neurons causing miscommunication among brain domains. Related to this gene is the process seen with the mTOR pathway. In this pathway, unused connections of the brain are removed allowing for normal communication between neurons. This pruning process is essential in normal brain functioning and it thought to be severely impaired in autism resulting in an unusually high density of neurons.

The role of the immune system:

The immune system plays a large role in both in peripheral body tissue and the nervous system. It is used to eliminate intruding pathogens and rid the body of any harmful substances. To do this, a close interaction of T and B cells is orchestrated. T-cells are a type of white blood cells used in initiating an immune response. They release chemicals that cause inflammation and notify the rest of the body where the infection is. These cells are also used in the destruction of harmful pathogens and infected cells. B-cells release antibodies that attach to invading substances and mark them for destruction by T-cells. It is thought that an abnormality of this general process in the brain leads to symptoms associated with autism. Careful regulation of these cells allows normal brains to eliminate harmful substances while preserving delicate brain tissue. In autistic brains, however, regulation of these immune cells is hindered causing excess inflammation. It is this point where many aspects of autism are thought to arise. The extra chemicals in the brain causes excess inflammation without enough regulation. From here, abnormalities in other brain processes are initiated leading to permanent damage during development.

Conclusion:

The pathophysiology of autism is extremely complex and difficult to map out. There are many different aspect of the disease that affect different pathways in neurochemistry. While we do know many of these parts and how they interact with each other, the exact order of events remains unknown. Perhaps genetic predispositions lead to higher probability of in utero infection leading to a malfunctioning immune response in the brain etc. Or perhaps the pathophysiology is much less linear and requires interaction between different processes all at once. Nevertheless, a complete understanding of ASD may never be reached but further research on the disease could provide helpful insight for prevention and treatment of ASD.

Autism: Trying to Put the Pieces Together

What is autism and why does it matter?

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by challenges in social communication and restricted, ritualistic or repetitive behaviors. As a spectrum disorder it varies greatly in the type and severity of symptoms the individual experiences.

ASD has three categories, broken down by how severe the diagnosis is: high-functioning, autism, and severe autism. One key thing to note however is that a person can fluctuate in their location on the spectrum throughout time as it is not a rigid system and they continue to grow and develop.

This disease continues to become more and more prevalent as years go on. In a 2014 study done by the CDC’s Autism and Developmental Disabilities Monitoring Network it was found that about 1 in 59 children were identified to have ASD, an increase of 15% since the two-year prior 2012 study. With this prevalence on the rise researchers have begun trying to find a link that will explain ASD and how it has multiple, perhaps interlocking, causes.

So, what do we know?

Autism is at least in part genetic.

We know there is a genetic factor by looking at the concordance rate within families, the probability that if one sibling has autism another in the family will also have autism. For identical twins this value is 77%, in fraternal twins it lies at 31%, and regular siblings are around 20%. What we learn from these numbers is that it accounts for a lot of the risk but not all of it. Identical twins do not hold 100% so it cannot be solely genetic. Environmental factors come into play with the fraternal twins, holding the similar but not same genetic coding but sharing the same environment, at 31% but regular siblings at 20%. An 11% difference due to the shared environment.

It’s been found that there are over 1,000 identified genes linked to autism we cannot say one single gene causes it due to its spectrum. It may be one gene for one child/ family but a combination for another, each case is different. We are starting to group them together by their roles and pathways. Genetic mutations play their own role adding in to the overall problem and each case will have different ones, this is how it was not passed genetically from the parents but was created within the child.

The genes involved tend to code for proteins that regulate gene transcription, excitatory/ inhibitory signaling, and overall brain development. These mutations can be a due to a change or lack of single letter, an entire section or even the entire gene leading to profound effects on the brain. These include location errors of the neurons leading to altered morphologies and malformation, dysregulation of development commonly involving plasticity, maintenance, autophagy which is the body’s ability to consume its old or unnecessary cells, and much more.

Autism is at least in part caused by environment.

We know that while the fetus is growing and developing, especially during brain development, it is very vulnerable and susceptible to different agents. Exposure to some of these agents increase the risk of autism. It was found that mothers who were diagnosed with two or more infections during pregnancy were at a higher risk of having a child with autism than those with one. Certain infectious agents themselves can also cause autism.

Problems in the immune system, especially regarding inflammation and abnormalities, have shown links to autism as well. Autistic children are more likely to have inflamed areas of the brain in addition to having denser, more neuronal regions as well. This is due to different pathways being nonfunctional such as autophagy which cleans up old and nonrequired neurons for the generation of better connections.

Some of this is even more prevalent due to zinc deficiencies as many components of the immune system require zinc to function properly. Without a properly functioning immune system the CNS won’t develop regularly. Immune responses can vary greatly, however with improper regulation autistic brains have reduced ability for knowing when to stop which leads to inflammation and damage within the brain.

 

Overall, autism is a very complex disorder with multiple causes likely interconnected. We are simply barely below the surface of what is all involved from genetic to environmental components. As more research comes out we are able to understand this disorder better and keep adding pieces to the puzzle that is autism.

Autism: A Different Brain

Background:

Autism Spectrum Disorder (ASD) has steadily increased over the years. The CDC estimates that autism prevalence will increase to 1 in 59 children in the United States. This is a substantial increase from data in 2004 that showed autism prevalence was 1 in 166 children1. ASD is a relatively new disorder. Its pathogenesis has eluded scientists since its initial characterization in 1943 by physician Leo Kanner2. Since then, ASD has evolved into an umbrella term for a disorder that is characterized by a myriad of behaviors. Repetitive behaviors, impaired social interactions, and language and communications abnormalities are a few of the many different common symptoms of ASD. Although researchers are still unsure of an exact mechanism in which ASD undergoes, they have a few pieces figured out of the complex puzzle that is ASD.

Too Many Neurons, Too Many Connections:

One of the most common findings of different research efforts is that ASD patients suffer due to impaired neural connectivity. This impaired connectivity stems from the significantly increased number of neurons present in autistic patients. The increased number of neurons diminishes the process of shaping and fine-tuning of neural circuits in ASD patients3. The impaired connections in the brain also cause reduced lateralization of the brain which is needed for higher order brain functions. A specific study exhibited that the corpus callosum of ASD patients had increased white matter (from too many neurons), and that this increase in size of corpus callosum inhibited the lateralization of each hemisphere that is used for language production and comprehension3. Simply, there are too many connections between too many neurons which as you can imagine creates too many signals for an autistic patient to comprehend, hence the symptomatic behaviors. This may cause someone to the question: What is causing the increase in neurons and connections seen with ASD?

Precious Pruning:

During “normal” development, cells prune unneeded connections between neurons. Microglia are the cells responsible for this synaptic pruning in babies’ brains. In autism, however, this pruning is not present. Therefore, they have nearly twice as many neurons after development compared to someone without ASD. This leads us to the next question: Why is there no synaptic pruning in ASD? Autophagy is not occurring in ASD brains; therefore, they are not getting a decline in synapses. Autophagy is related to the mTOR pathway, which induces cell growth, differentiation and survival, and down-regulates apoptotic signals and inhibits autophagy. In autism, the mTOR pathway is overactive, inhibiting the process of autophagy. If there is no autophagy, then there is no synaptic pruning, and ultimately leads to an excess of neurons. Researchers have then studied genes and risk factors during development to cause the lack of pruning.

Genetics Role in Autism:

After extensive research, it is clear that many certain genes and environmental factors contribute to the development of autism. There is no “autism gene.” However, there are affected genes that fit into several clusters that may underlie ASD. Mutated NLGN3/4, SHANK3, NRX1 genes alter the synaptic function and lead to autistic disorders such as Asperger’s syndrome3.  Other strong contributors to ASD are TSC1/2, PTEN, and NF1 which are associated with autophagy and the mTOR pathway. Finally, another cluster of genes that control gene transcription and translation are related to the pathogenesis of ASD. Mutations of these genes are hypothesized to cause a loss of normal constraints on synaptic activity-induced protein synthesis. This specific loss may be one of the several mechanisms leading to ASD.

Summary:

Autism’s complicated umbrella is covering many families across the world. Understanding ASD will be more important than ever as we see its prevalence increasing across the United States. Although it is a very complex disorder, pieces have been placed together by researchers. Many genes affect ASD. In my mind, it makes the most sense focusing on the specific cluster of genes including TSC1/2, PTEN, and NF1. Mutations in these genes, which are associated with the mTOR pathway, could cause over-activation of this pathway. If the mTOR pathway in ASD is overactive, it inhibits the process of autophagy. This causes a lack of synaptic pruning, which proceeds by microglial autophagy. If microglia are inhibited, a build-up of neurons and connections between these could occur. The increased connectivity and neurons cause the symptoms associated with ASD. These are not all of the pieces to this puzzling umbrella disorder, but it is a starting point to understanding ASD.

 

  1. https://www.autismspeaks.org/science-news/cdc-increases-estimate-autisms-prevalence-15-percent-1-59-children
  2. https://www.spectrumnews.org/opinion/viewpoint/leo-kanners-1943-paper-on-autism/
  3. https://moodle.cord.edu/pluginfile.php/723245/mod_resource/content/0/pathophys%20of%20ASD%202017.pdf

Autism On the Rise – Can it Be Prevented?

Autism is a relatively newly recognized disorder that is quickly affecting more and more children as time progresses, affecting 1 in 68 today compared to just 1 in 150 in 2000. While much progress has been made in recent decades with the understanding of the mechanisms of autism, its cause is still widely misunderstood. There is no solid proof of the exact cause of autism, but it seems that individuals with susceptible genes are triggered by environmental toxins and deficiencies, leading to defects in neural signaling. Because environmental factors can trigger gene expression for autism, the preventions and treatments of autism are intriguing areas of study.

 

What is Autism?

Autism is a spectrum disorder, which means it has varying degrees of severity. All classifications of the autism spectrum involve difficulty socializing and communicating with others, and most cases involve repetitive behavior.

 

What Goes Wrong in the Brain?

  • Increased number of neurons leading to oversized and overactive temporal and frontal lobes
  • Ineffective elimination of unnecessary synapses
  • Imbalance of excitatory and inhibitory neurotransmitters
  • Heightened levels of immune cells in the brain
  • Defective blood-brain barrier

How Do Toxicities Lead to Autism?

There are over 77,000 man-made toxins in our environment that were not meant to be taken in by humans. Toxins, whether they are pesticides, heavy metals, or plastics, must be removed from our bodies through innate mechanisms, or the biochemical processes in our bodies will go haywire. When an individual has a toxic overload, their body is depleting all of its amino acids in attempt to detoxify. Unfortunately, these depleted amino acids are necessary for normal brain function, and this inability to efficiently detoxify the body can lead to autism.

 

Most people understand that pesticides and fossil fuels are harmful to our health, but one overlooked toxicity is heavy metals. A lot of metals are essential to our body’s function, such as iron, but when any of them are too concentrated, problems arise. Specifically, high concentrations of copper in the body are very common in autistic individuals. Copper is an antagonist to zinc, which means they work together to make sure concentrations of each stay in check. When copper levels are too high, zinc is depleted. Low zinc levels have been correlated to autism because it leads to a dysfunctional immune system.

Does Gut Dysfunction Affect Immunity?

The answer to this question is yes. Scientists are now saying that at least 80% of our immune systems reside in our gut, and at least 90% of autoimmune diseases correlate with gut dysfunction. So fixing our guts will fix all of our health problems? Well, actually in most cases, yes. A compromised immune system is pointed to as one of the main factors in developing autism, and we just learned that 80% of our immunity lies within our gut. But first, lets learn how our guts became compromised in the first place.

“Leaky Gut” has been coined as the term describing increased intestinal permeability. It means that the large intestine is letting things through its walls that shouldn’t be leaking through. Bacterial cells can leak through the weak gut lining into the bloodstream, eventually into the brain where they can wreak havoc on neurons. Leaky gut can be caused by a variety of factors, including an imbalanced microbiome, poor diet, stress, and toxicities. Remarkably, repairing “leaky gut” in autistic individuals has been shown to dramatically decrease symptoms.

Can Autism Be Prevented or Cured?

It has been proven that a compromised immune system is correlated with the development of autism. Therefore, keeping an eye on a child’s immune function as it develops could be key in preventing autism. Three factors that have a negative effect on immune function are inflammation, nutrient deficiencies, and toxic overload. They can be addressed in a variety of ways:

  • One of the most prominent causes of inflammation is leaky gut
    • To fix leaky gut, removing food allergens is a great place to start
    • Additionally, restore healthy gut bacteria with probiotics, and stay away from antibiotics
  • Nutrient deficiencies can be tested for and supplemented until levels are healthy again
  • Once inflammation and deficiencies are taken care of, the body has a much easier time detoxifying and reducing free radicals

 

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ASD: What’s the Deal?

What is autism? This is a very difficult question for people to answer for a variety of reasons. The biggest reason is because a wide spectrum of symptoms is experienced by individuals. This is because Autism Spectrum Disorders (ASD) are not caused by a specific gene mutation, but rather by a vast variety of environmental and genetic factors that all play a part in how the disease is presented in individual cases. Three of these factors will be discussed: Neural Connectivity, Mirror Neurons, and Excitation-Inhibition Imbalance. After discussing these factors, hopefully we will have a better understanding of what may lie as the root of the problem for ASD.

Neural Connectivity

In individuals’ brains with ASD, there is a significantly increased number of neurons. This is because there is a problem with ‘pruning’. In healthy brains, non-functional neurons are pruned away to give more room for working neurons to work and actually increase their power. This pruning process is done a lot with the mTOR pathway. This pathway enables apoptosis (cell death) and autophagy (cell absorption) to take place and effectively prune out the areas that are overgrown/unneeded. When the pruning does not take place, it leaves a crowded circuit causing lots of extra ‘noise’ causing the brain to function less efficiently. This is analogous to plants. Unhealthy branches are pruned off to give room for healthy ones to grow further and make the whole plant healthier.

Mirror Neurons

Do you ever wonder why you yawn when you see somebody else yawn? This is because of mirror neurons. Mirror neurons form connections that enable an individual to learn from its environment by imitation. In individuals’ brains with ASD, these mirror neurons are much less concentrated and possibly broken. This could possibly be the cause of those with ASD to have a lack of empathy for those around them. This could also cause lack of understanding of other individual’s movements and lead to the poor development of communication skills exhibited by many of those who suffer from ASD.

E/I Imbalance

There is a delicate balance in the brain called excitation and inhibition. Glutamate neurotransmitters are excitatory and GABA neurotransmitters are inhibitory. When working effectively, this balance gives the proper action potential to cells enabling them to fire or to rest. However, when this balance is not maintained only glutamate neurotransmitters can be activated. This causes excessive excitation in the cell. The glutamate then becomes excitotoxic and can kill cells, causing further damage to neurons and neural connections in the brain.

Closing 

Though we have just scratched the surface of the possible causes of ASD, this does help to give us an insight into what is happening in the brains of those around us that live with ASD. It’s important for us to try to understand these things as ASD is becoming more and more prevalent as 1 in 68 children today are diagnosed as being on the spectrum in some way, shape, or form, so we likely know someone living with ASD or we will know someone living with it in the future. As we know there is no real cure for ASD right now, but the first step to curing something is to understand what is going on and to identify the problem. Hopefully sometime soon we can start to put all of the pieces in place and figure out what is going on.

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Neural Connectivity-Understanding Autism

With a rising frequency of affected individuals and increasing visibility in society, diving into the current knowledge of how autism affects the brain is important to inform us on how individuals with ASD’s (Autism Spectrum Disorders) experience the world from a different perspective. The following topics are of interest when considering autism’s cause and how the symptoms play out for individuals at any point on the spectrum. One of the most impactful and studied components of autism is the neuronal function/dysfunction that occurs in individuals with ASD’s.

Neural Connectivity and development:

In brains with autism, dysfunctional neural connectivity plays a large role in the manifestation of common symptoms seen in individuals with ASDs. Neurons are vital in passing chemical information from areas of the body to different areas of the brain. In brains of individuals with autism, these conversations between neurons are affected by an increased number of neurons and a lack of good communication between individual neurons. This concept can be understood by thinking about a 10-way phone conversation. With all ten individuals talking at once, it is impossible to pick out important bits of information and communicate the correct message to all the individuals! This is similar to the type of dysfunction seen in the neurons of brains with autism.

Another common developmental abnormality in brains with ASDs is the improper migration of neurons. This migration occurs before being born, and helps to place neurons where they need to be to function properly and align with each other. This has been connected to genetic mutations in the Reelin (RELN) gene that plays a huge role in the proper migration of neurons.

Genetic Mutations Contributing to Synaptic Malformation 

In nervous system, synapses are the gaps located between neurons which neurotransmitters and other molecules travel across to transmit signals to the next neuron in line. This process is vital to the proper communication between neurons, and outcomes in the cells. In individuals with ASDs, a common trait seen is malformed synapses between neurons. These malformations cause signaling, which is already at an increased level, to be inaccurate at transferring chemical information.

There are a few genetic mutations studied that play a role in the malformation of synapses in brains with ASD’s. This class of mutations has to do with the formation of Neurexin and Neuroligin, trans-membrane proteins tasked with physically docking the pre-synaptic (sending) neuron with the post-synaptic (receiving) neuron. Mutations causing deletions or mutated versions of these proteins negatively affect the ability of signals to reach the receiving neuron correctly.

These abnormalities play one piece in the puzzle of ASD’s, but is an important one to understand symptoms manifested in individuals with autism. Individuals with autism have symptoms related to complex malfunctions in the nervous system, immune system, and environmental stimuli that combine to create the experience of life with an autism spectrum disorder.

Rodent Models for Autism Spectrum Disorder

Autism is defined by a set of symptoms which includes impaired social interactions, repetitive or restrictive behaviors, and language abnormalities. According to the CDC, in 2014 1 in 59 children was identified as having autism spectrum disorder (ASD), a 250% increase from a similar survey done in 2000.

ASD poses an issue for society, “The total costs per year for children with ASD in the United States were estimated to be between $11.5 billion – $60.9 billion (2011 US dollars). This significant economic burden represents a variety of direct and in-direct costs, from medical care to special education to lost parental productivity” (cdc.gov). The total cost per year is projected to increase as cases of ASD increases.

Autism Spectrum Disorder: The Basics

ASD is very complicated (for further details, check out other blog posts on this site!) and has many moving parts already, and scientists do not even know the entire story yet. But here are some factors that are linked to autism:

Connectivity of Neurons
The brain is commonly likened to a circuit: neurons are wires and the chemicals are like electricity flowing through the wires. But a neuron is a wire that makes connections to more than one output. In autism, many neurons are not making good connections to their target outputs. Individuals with autism have too many possible outputs on the neuron which gets in the way of sending a clear message; this is a result of improper synaptic pruning. This essentially causes noise in the circuit by allocating the signal to the incorrect neurons thereby dampening the signal to the target output.

 Immunity
The immune system is extremely important in keeping us healthy by fighting off germs and diseases. However, when the immune system is active when we are not sick, that poses problems for our bodies. Our immune system releases chemicals that tell our bodies there is something off about the environment, and those messages trigger a larger response. A common characterization of that response is inflammation, which in turn causes an entire cascade of biological responses.

During or before fetal development, a mother can contract an infection and the immune response of the mother can have an impact on the developing fetus. The mother’s immune can trigger a subsequent inflammatory response in the fetus, initiating a cascade of biological responses as a result.

Due to the complexity and prevalence of ASD, much more research should be done to better characterize it and to find possible treatments. Unfortunately, this is easier said than done, largely as a result of the complexity and unknown factors of ASD.

Animal Models

Current rodent models are models of autism, not for autism, meaning current models mimic symptoms of autism, but do not contain the entire picture of the disorder. Therefore, there are several animal models to attempt to cover as much of the disorder as possible. Typically, the models can be grouped into several categories:

Environmentally Induced
This mirrors maternal infection that leads to immune dysregulation. This can be done using chemicals found in the body (such as chemicals used in immune response), or other chemicals known to induce ASD-like symptoms.

Physical Damage
Physical damage or lesions seek to target a specific area of the brain to learn more about which structures in the brain are most vital for the development of ASD. However, when the brain is damaged, it takes measures to heal itself, notably neurons moving to fill the space of the damaged area. This makes it difficult to say for-certain damage to one area caused a specific behavior as presented in autism.

Genetic Modifications
Studying ASD with genetic modifications is very difficult because ASD is not caused by a single gene, but rather many genes functioning and influencing each other. However, by studying other diseases that share ASD pathology and that are impacted by a single gene; scientists can better study the complicated behavioral factors of autism through different diseases. Genetic modifications do not supply a model that presents with the same physical issues present in individuals with ASD, such as neuronal wiring discussed earlier.

There are limitations to any model, but there are large limitations with the available models for autism. State of the art behavioral software recently has been developed to a level that would prove useful for disorders as complicated as ASD, which will aid in the validity of studies, but as mentioned there is not a single model we can rely on to study autism. We must take a holistic approach and try to piece information learned from various models together to get a more complete picture of autism spectrum disorder.

Sources:
https://www.cdc.gov/ncbddd/autism/data.html
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137861/pdf/fso-01-63.pdf
https://www.ncbi.nlm.nih.gov/pubmed/28499914

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