Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with different levels of severity, characterized by its core symptoms involving deficits in social communication and interaction, restrictive and repetitive patterns of behavior and interests, and sensory abnormalities.[4] In more severe cases, symptoms can greatly impact an individual’s ability to perform everyday tasks including interpreting social rules, forming relationships, and managing stress. While there is no cure for ASD, early interventions in children with autism, such as behavioral therapy, can enhance their ability to function independently and support their development by teaching them important social and communication skills.

Prevalence:

It was estimated in 2023 by the CDC’s Autism and Developmental Disabilities Monitoring Network that 1 in 36 children had been diagnosed with ASD.[1] ASD affects males nearly four times more than females, and this gender difference has a major gap in ASD research. Symptoms generally appear in early childhood around the age of 2. However, there are individual variations and challenges with diagnoses and treatment. Individuals with higher socioeconomic status and better access to healthcare are found to be diagnosed earlier. Cultural knowledge should be researched further to assess healthcare access and how the process of getting help is impacted by stigmas and cultural values.

Etiology:

There is no single cause of ASD, and the spectrum of severity often comes from combinations of genetic changes and environmental factors. There are a lot of theories, however, about the etiology and pathogenesis of ASD: imbalances in excitatory-inhibitory neural activity; altered network connectivity (because of abnormal synapse formation, neuroinflammation, or oxidative stress), and altered social predictive coding that leads to sensory abnormalities. There are also many genetic mutations (SNPs and CNVs) that have been associated with ASD and examined in their impact on certain signaling pathways. With behavioral symptoms being the key descriptor and diagnostic criteria, various pathway dysfunctions are being looked at to create subgroups within ASD to improve individual treatment, the article we read this week focused on the dopaminergic system.

Figure 1. ASD etiology simplified to highlight the many connections and potential for comorbidities in future research looking at underlying causes.[2]

Comorbidities:

ASD has several comorbidities that are separated into 3 clusters: psychiatric (ADHD, OCD, anxiety, etc.), multisystem (gastrointestinal disorders), and seizures. The diagnosis of these comorbidities can be so closely related to ASD that their known underlying mechanisms are being researched as potential explanations of ASD as well. In the paper we read, they talked about ADHD in relation to dopamine signaling. In ADHD, there are disruptions caused by reduced dopamine transporters and D2 receptors in the nucleus accumbens and midbrain (brain regions that may be vulnerable in ASD).

Dopamine System:

Dopamine is a monoamine neurotransmitter produced in the substantia nigra and ventral tegmental area brain regions. It has a major role in learning and motivated behavior, which is why it could contribute to the underlying neurobiological mechanisms of ASD. However, there is no single cause of dopamine dysfunction that we can pinpoint either in ASD cases.

Figure 2. Dopamine signaling and its downstream functions that may be the connection to ASD – synaptic plasticity and development.[4]

Pharmacological Treatments?

Although there are currently two FDA-approved drugs used to treat irritable and aggressive behaviors associated with ASD, there are no pharmacological interventions approved to treat the core symptoms of ASD. Antipsychotics and SSRIs are the most prescribed to individuals with autism to treat the comorbid symptoms like anxiety. Further research is needed to test new drugs that could potentially target the core symptoms of ASD.

Figure 3. Common intervention strategies for individuals with ASD.[3]

Questions to leave with:

• How can we improve school systems to best help teach individuals with autism?
• How can we increase inclusion in jobs for individuals with autism?
• Should we consider comorbidities when creating subtypes?
• How do the various genetic risk factors cause the behavioral symptoms?
• How does diagnostic criteria play into the sex-based gap (what are the differences in symptom manifestations)?

References:

Figure 1: Alzheimer’s disease[1] 

Alzheimer’s disease (AD) is one of the most common diseases related to decline in cognitive abilities, but at the same time its causes and hallmarks might be unknown to most people. AD is a gradual and progressive neurodegenerative disorder, which tends to affect the older population. Deficits related to this disorder is such of memory, language, attention, reasoning, comprehension, and judgement[2]. Generally, the decline in cognitive abilities can be defined by the term dementia, however, AD is the most common type of dementia. Pathological AD hallmarks can be categorized as amyloid-β-plaques (clumps of beta amyloid protein) and neurofibrillary tangles (bundles of tangles made up by tau protein) that develops in the brain[3]. A neuromodulator in the brain that has been revealed to be one of the factors of cognitive impairment and the AD pathology is dysregulated brain insulin signaling[4].

Figure 2: The comparison of a normal brain versus the AD brain, with the formations of neurofibrillary tangles and amyloid plaques. [5]

The progression of AD can be seen as a process with many implication factors, as understood with the implications with insulin signaling, but the process of AD is related to some precursors that can start already at the level of healthy eating patterns. Studies have found that a healthy diet is associated with a lower risk of AD[6]. A list of nutrients has been found to have a beneficial effect on the course of AD, such as vitamins B6, B12, folic acid, polyphenols, while on the other hand for example fatty acids promotes the progression of the disease[7]. Additionally, a study found that plant-based diets such as the Mediterranean diet, were associated with lower levels of oxidative stress and inflammation in comparison to a fast-food diet[8]. Healthy diets can be believed to affect underlies mechanisms such as oxidative stress and neuroinflammation[9], which further play a role in influencing pathways, the formation of plaques, and neural death[10]. The formation of plaques (tau accumulation) and neural death contribute to the formation of tangles inside the neurons which is a part of the progression of AD.

Figure 3: The impact of nutrition on the brain. [11]

In relation to both healthy lifestyle and impaired insulin signaling is diabetes type 2, which is a result of both of these. It has been found that people who suffer from diabetes type 2 have a higher likeliness for the progression of AD, because of the strong correlation[12]. So, the process starting at the food one consumes, can play are role in the progression of AD, and the different precursors and factors that play a role in the progression of AD. As can be seen with the interconnecting pathological features of neuroinflammation and insulin resistance that are two of the major factors of synaptic disruption and neurogenerative processes[13]. Diabetes connects with the insulin resistance, and nutrition play are role in the development of diabetes type 2 and neuroinflammation, which can all be tied to the progression of AD.

A big factor with Alzheimer’s disease is time, since there is no cure or treatment that will heal the disease, we are looking for options to give Alzheimer’s patients a longer time to live, maybe even a better quality of life. One of these options can be understood to be nutrition, and your lifestyle. Therefore, interventions should or could be implied as early as possible to minimize the development of the disease. By looking at small bits of the progression of this disease, hopefully we are slowly understanding more on how to deal with Alzheimer`s disease.

[1] What is Alzheimer’s Disease? (n.d.). YouTube. https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.youtube.com%2Fwatch%3Fv%3D7F-t9yvPP_0&psig=AOvVaw01G76eZhQmR8VmBscxeREB&ust=1707882712431000&source=images&cd=vfe&opi=89978449&ved=0CBMQjRxqFwoTCMDYuYa1p4QDFQAAAAAdAAAAABBV
[2] Kumar, A., Sidhu, J., Goyal, A., et al. Kumar, A. (2022, June 5). Alzheimer Disease. StatPearls – NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK499922/
[3] What happens to the brain in Alzheimer’s disease? (n.d.). National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/what-happens-brain-alzheimers-disease
[4] Akhtar, A., & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochemistry International, 135, 104707. https://doi.org/10.1016/j.neuint.2020.104707
[5] Amyloid Plaques and Neurofibrillary tangles | BrightFocus Foundation. (2015, July 1). https://www.brightfocus.org/news/amyloid-plaques-and-neurofibrillary-tangles
[6] Hu, N., Yu, J. T., Tan, L., Wang, Y. L., Sun, L., & Tan, L. (2013). Nutrition and the risk of Alzheimer’s disease. BioMed research international, 2013, 524820. https://doi.org/10.1155/2013/524820
[7] Śliwińska, S., & Jeziorek, M. (2021). The role of nutrition in Alzheimer’s disease. Roczniki Panstwowego Zakladu Higieny, 72, 29–39. https://doi.org/10.32394/rpzh.2021.0154
[8] Aleksandrova, K., Koelman, L., & Rodrigues, C. E. (2021). Dietary patterns and biomarkers of oxidative stress and inflammation: A systematic review of observational and intervention studies. Redox Biology, 42, 101869. https://doi.org/10.1016/j.redox.2021.101869
[9] Aleksandrova, K., Koelman, L., & Rodrigues, C. E. (2021). Dietary patterns and biomarkers of oxidative stress and inflammation: A systematic review of observational and intervention studies. Redox Biology, 42, 101869. https://doi.org/10.1016/j.redox.2021.101869
[10] Akhtar, A., & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochemistry International, 135,104707. https://doi.org/10.1016/j.neuint.2020.104707
[11] What we know about Alzheimer’s disease and nutrition. (n.d.). Nutri-facts. https://www.nutri-facts.org/en_US/news/articles/what-we-know-about-alzheimers-disease-and-nutrition.html
[12] Akhtar, A., & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochemistry International, 135,104707. https://doi.org/10.1016/j.neuint.2020.104707
[13] Ibid.

Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder that impairs cognitive functions, specifically memory, making it the leading cause of dementia.[4] Despite not knowing the specific etiology and pathogenesis of AD, the hallmarks are amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs).[1] Recent research has suggested that dysfunctional insulin signaling as well as neuroinflammation accelerate the progression of AD and its associated cognitive decline. Therefore, there is potential in targeting molecules involved in insulin’s signaling pathway including IDE, IRS, PI3K, mTOR, and GSK-3b for future treatment or prevention of AD.

Figure 1. Two major hallmarks of Alzheimer’s disease: Aβ plaques and NFTs. [7]

Insulin Signaling – Why is it Important to AD?

Insulin, typically associated with glucose metabolism, has a regulatory role in the brain where it helps promote synaptic plasticity, neurotransmission, and neurogenesis. This is why insulin signaling is important and could be implicated in the progression of AD because when it is functioning properly improves cognitive function.

Insulin Resistance – A Possible Cause of AD?

Insulin resistance happens when the body becomes less responsive to the effects of insulin hormones. This can occur when there are lower levels of insulin binding to its receptors because insulin’s receptors can become desensitized. This can mean that even with insulin hormones being present, they might not bind to their receptors and activate their downstream pathways. Insulin resistance boosts oxidative stress, cytokines production (leading to neuroinflammation), and apoptosis. Insulin resistance leads to Alzheimer’s because it triggers a cascade of disrupted molecules in insulin’s signaling pathways, such as IDE, IRS, PI3K, mTOR, and caspases (Nrf2 and NF-kB).

Figure 2. Role of the insulin signaling pathway (insulin and its various molecules) in neurodegeneration and Alzheimer’s disease. [5]

Amyloid-Beta to Aβ Plaques

Amyloid-beta peptides are cleaved from the glycoprotein amyloid precursor protein (APP) that plays a major role in neuronal development and signaling. Amyloid-β plaques occur when amyloid-beta proteins clump together outside of the cells. When plaques build up they may block cell-to-cell signaling at synapses or activate an immune response that causes excess cytokines to be released and may be a leading contributor to neuroinflammation in AD cases.

Figure 3. Formation of Amyloid-β plaques from the precursor APP protein. [3]

Tau Proteins to Neurofibrillary Tangles

In healthy neurons, tau proteins help to stabilize and coordinate microtubules, which help give neurons their structure. When insulin signaling is disrupted and PI3K pathways are not being activated properly, Akt does not phosphorylate GSK and inactivate it. When GSK is active it phosphorylates the tau proteins, causing them to break away from the microtubules and clump together into NFTs. Neurofibrillary tangles accumulate inside the cell and block neuron’s normal functioning, including the synaptic communication between neurons. Tau proteins leaving microtubules could also play a role in neurodegeneration because microtubules would not stabilize the cell structure and neuron extensions.

Figure 4. Formation of NFTs from tau hyperphosphorylation. [2]

What Goes Wrong in Insulin Signaling Pathways?

IRS

The insulin receptor substrate relays the signal from the insulin receptor to activate the downstream responses. However, in Alzheimer’s IRS-1 is downregulated, which negatively affects the PI3K pathway. Reduced activation of PI3K/Akt enhances the activation of GSK-3b which increases tau phosphorylation and causes the formation of NFTs.

Figure 5. Insulin signaling pathway shown simplified to highlight IRS activation of PI3K pathway. [9]

PI3K and mTOR

Insulin resistance disrupts the PI3K signaling pathway, impacting the activation of mTOR. Since the PI3K pathway activates the mTOR gene to produce nutrients, proteins, and lipids that help other cells grow and create a healthy environment. In AD, with the PI3K pathway not activating mTOR, mTOR can’t produce nutrients to help insulin grow and produce more cells, which creates a bad cycle.

Figure 6. PI3K signaling pathway activation of the mTOR pathway involved in cell growth. [8]

IDE

IDE is an enzyme that breaks down insulin and the amyloid-beta protein. In AD, hyperinsulinemia (too much insulin) and insulin resistance affect the activity of IDE, causing insulin to compete with amyloid-beta to bind to the enzyme IDE. When insulin resistance occurs, lower levels of IDE happen because there is a downregulation of the PI3K signaling. Both reduce the clearance and degradation of amyloid-β in the brain, leading to the accumulation of Aβ plaques.

Figure 7. Insulin decreases the IDE-mediated beta-amyloid (Aβ) degradation through competitive inhibition. Insulin resistance also plays a role as it lowers the IDE expression and decreases IDE-mediated Aβ degradation. [6]

Caspases (NF-kB and Nrf2)

Disrupted insulin signaling (or insulin resistance) activates NF-kB, a proinflammatory transcription factor that releases cytokines and contributes to neuroinflammation, further impacting the progression of AD.

Nrf2 is a regulatory transcription factor that is activated in response to oxidative stress, promoting antioxidation. However, in Alzheimer’s Nrf2 levels are decreased, leading to an increase in insulin resistance and oxidative stress.

References