Traumatic brain injury (TBI) is one of the most common causes of disability and death in people. About 1.6 million individuals suffer traumatic brain injuries in the United States every year. TBI can cause a process of injury which may ultimately cause a variety of neurodegenerative diseases and other health issues. Many of the neurodegenerative diseases following TBI include health issues such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).
The mechanisms underlying the pathogenesis which result in these type of neurodegenerative diseases, however, are still completely misunderstood. Where many of the health issues following TBI have a high incidence, there are currently only several treatment approaches which can help prevent the pathological development of chronic neurological diseases.
An understanding of the mechanisms underlying TBI and neurodegenerative diseases is fundamental to determine the possible connection between these health issues, to allow the safe and effective diagnosis and treatment. In the following article, we discuss the pathological mechanisms of neurodegenerative diseases and how they’re associated with traumatic brain injury (TBI), including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).
Pathological Mechanisms of Neurodegenerative Diseases
Although many neurological diseases may have different symptoms, AD, PD, and ALS have several common characteristics. Each neurodegenerative disease is caused by genetic risk factors, however, most cases are idiopathic or unknown. The pathological mechanisms of these health issues are ultimately characterized by the degeneration of brain cells or neurons together with several common symptoms. Moreover, abnormal clusters or dysfunction of the substances amyloid-β (Aβ), α-synuclein, and superoxide dismutase (SOD1) are generally found in AD, PD. Although the exact pathological mechanisms of neurodegenerative diseases have not been fully determined, it has been suggested that oxidative stress, glutamatergic excitotoxicity, and neuroinflammation play fundamental roles in neurological diseases such as AD, PD, and ALS.
AD has a tremendous prevalence among older adults which can greatly decrease their rate of survival and their overall quality of life. In 2008, as many as 24 million people worldwide had dementia, where most had AD, a number which is expected to double every 20 years as the population ages. The pathological mechanisms of AD include the presence of neuritic plaques and the loss of cholinergic neurons or brain cells in the human brain, however, the underlying risk factors leading to these events are still unclear. Neurodegeneration in AD is believed to happen due to the accumulation of amyloid β-peptide (Aβ) in plaques in the brain tissue however its aggregation and toxicity are still completely misunderstood.
Research studies have demonstrated that oxidative stress may play a fundamental role in the pathogenesis of AD because of increased neurotoxic markers of lipid peroxidation, such as 4-hydroxynonenal, in human participants, increased brain protein oxidation in AD, increased nuclear DNA oxidation in the brain of AD patients, 30 percent increased activity of the free radical scavenging enzyme SOD-1 in cell lines of AD patients, and considerable evidence that beta amyloid creates free radical peptides. In addition, it has been demonstrated that free radicals and lipid peroxidation caused by Aβ can ultimately result in neuronal death in AD. In vitro and animal research studies have demonstrated that the antioxidant effect of cannabinoids was able to prevent neurodegeneration in the neurological disease, suggesting the role of oxidative stress in AD.
Neuroinflammation has also been associated wit Aβ toxicity which has likewise been connected to oxidative stress by inflammatory cytokine activity. The purpose of inflammation is to restore cellular homeostasis and balance redox equilibrium, however, inflammation changes with co-localized Aβ deposits, inflammatory-related proteins, and activated microglial cells in AD. Microglia and astroglia recognize misfolded proteins which can trigger an immune response that may be responsible for the progression and severity of the neurodegenerative disease. The microglial cells promote Aβ clearance and support neuroprotective properties in early stages of AD, but as the health issue progresses, inflammatory cytokines downregulate Aβ clearance genes and promote Aβ accumulation, ultimately causing neurodegeneration. Moreover, cytokines can trigger the creation of arachidonic acid which aggravates neurodegeneration by increasing extracellular levels of glutamate, known to cause excitotoxicity in AD as well as causing the creation of superoxide free radicals which are responsible for cellular death. Furthermore, research studies suggest that non-enzymatically glycated tau causes oxidative stress which results in cytokine gene expression and release of Aβ-peptide in AD, demonstrating pathological mechanisms between cytokines and oxidative stress which causes the progression and severity of AD. In addition, oxidative damage from reactive oxygen species and lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), can restrict glutamate transporters, causing a decreased glutamate uptake that is fundamental for neuronal survival, an increased glutamate concentration in the synaptic cleft, and subsequent excitotoxicity which ultimately causes neurodegeneration in AD.
Neurodegenerative Diseases in Functional Neurology
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repeated blunt force impacts to the head with the transfer of acceleration and deceleration forces to the brain or repetitive mild traumatic brain injuries, although the central pathological mechanisms for the development of neurodegeneration in CTE has not been discovered. CTE has been associated with behavioral and personality changes, parkinsonism, and dementia. Research studies demonstrated similarities between CTE and Alzheimer’s disease but these were different in the predominance of tau protein deposition over amyloid. The tau protein deposition in CTE has been previously demonstrated to restrict kinesin-dependent transport of peroxisomes and the loss of peroxisomes makes the cells vulnerable to oxidative stress, ultimately causing neurodegeneration. This tau protein deposition, which occurs in AD, also restricts the transport of amyloid precursor protein (APP) in axons or dendrites, causing its accumulation in the cell body. Along with tau proteins, portions of TDP43, a nuclear RNA/DNA binding protein which controls the transcription of thousands of genes, have been demonstrated in AD, PD, ALS, and CTE, which cause the misfolding of SOD1, affecting the surrounding cells with free-radical damage. The research studies have also demonstrated the purpose of oxidative stress in CTE neurodegeneration and in other neurological diseases.
Chronic inflammation has also been demonstrated in CTE and AD, which is believed to aggravate neurodegeneration and, as previously mentioned, it is ultimately associated with oxidative stress though inflammatory cytokines. Moreover, it has been demonstrated that after the initial head trauma in CTE, microglia activate and release toxic levels of cytokines and excitotoxins, such as glutamate, where the excitotoxins restrict phosphatases, resulting in hyperphosphorylated tau, neurotubule dysfunction, and neurofibrillary tangle deposition, all of which are fundamental factors of CTE. Research studies have also demonstrated a synergy between proinflammatory cytokines and glutamate receptors which increase reactive oxygen species and worsens neurodegeneration in the injured brain associated with TBI and neurological diseases.
Parkinson’s disease is the second most prevalent neurodegenerative disease with a prevalence of approximately 0.3 percent of the older adult population. PD is characterized by the development of α-synuclein rich Lewy bodies and subsequent death of the dopaminergic neurons of the substantia nigra. Several genetic risk factors have also been demonstrated, including mutations to the ubiquitin-proteasome system. Although the pathological mechanisms which trigger dopaminergic degeneration in non-hereditary PD are still unclear, it has been suggested that oxidative modification or carbonylation of the lysine-rich N-terminus and the non-amyloid factor of α-synuclein may ultimately cause an α-synuclein aggregation.
The reactive carbonyls created as secondary products in oxidative stress have been demonstrated to develop lysine adducts and promote α-synuclein aggregation in vitro. Additionally, animal models of PD utilizing agents, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have demonstrated the increased development of superoxide in dopaminergic cells associated with the cortex. Furthermore, mitochondrial localization of α-synuclein has been demonstrated to promote oxidative stress in vitro. Neuroinflammation is believed to be a partial cause for the oxidative stress in PD with activated microglial cells demonstrated in the substantia nigra and striatum of deceased PD patients. Activated microglia were also demonstrated in rhesus monkeys up to 14 years after model induction. In addition, glutamatergic excitotoxicity is believed to play a fundamental role in PD. Rotigotine, an FDA approved dopamine receptor agonist, has been suggested to improve the efficiency of glutamate transporter 1 (GLT-1) and has been demonstrated to support neuroprotection against glutamatergic excitotoxicity in dopaminergic cell culture as well as a variety of other functions in the human brain in Parkinson’s disease.
ALS is a fatal neurodegenerative disease characterized by the death of motor neurons in the central nervous system (CNS) and it is the most common motor neuron disease. Approximately 10 percent of all ALS cases have been associated with genetic causes while the majority are idiopathic or of unknown cause. Mutations affecting superoxide dismutase (SOD1) are responsible for almost 20 percent of all familial cases, however, this is responsible for only 2 percent of all overall cases. Despite the characterized mutations, the exact pathological mechanisms of ALS have yet to be fully determined.
Research studies utilizing SOD1 mutant mouse models have demonstrated the development of SOD1 aggregates. Given the fundamental role of SOD1 in detoxification of superoxide radicals, it has been previously mentioned that loss of function could cause increased cellular exposure to reactive oxygen species, however, this hypothesis has been challenged by outcome measures in the normal development of SOD1 deficient mice in the absence of considerable traumatic injuries. Furthermore, research studies demonstrated that SOD1 mutant animals ultimately demonstrated no considerable improvement in symptomatic progression with knockout or coexpression of wild type SOD1 which suggests that the mutation results not in the loss of function but rather in the gain of toxic properties. Research studies in rats and human patients suggest that, similar to α-synuclein and Aβ, SOD1 mutation cause the development of potentially cytotoxic protein aggregates even in patients without SOD1 mutations. Additionally, the catalysis changes achieved by several mutant variants causes decreased astroglial reuptake of glutamate through restriction of GLT-1. Riluzole, an FDA approved treatment for ALS, has been suggested to help improve glutamatergic excitotoxicity with increased glutamate uptake through GLT-1 and blockade of sensitive channels. Oxidative stress is also involved in neuronal death and in the progression of ALS.
Given its fundamental role in maintaining and regulating damage from neuroinflammation and excitotoxicity, it is possible that oxidative stress also plays a fundamental role in the pathophysiology of AD, PD, and ALS in a similar fashion to TBI. As such, addressing oxidative stress in neurodegeneration could serve as an effective treatment strategy in neuroprotection.
Despite the prevalence of TBI the significant neurological sequelae associated with such injuries, diagnosis, and treatment of TBI remains greatly misunderstood. In addition, the causing factors connected to TBI and neurodegenerative diseases, such as AD, PD, ALS, and CTE, have not been fully determined. Several processes, including oxidative stress and neuroinflammation, have also been found to be common between secondary TBI and several neurodegenerative diseases. In particular, oxidative stress appears to be the key mechanism connecting neuroinflammation and glutamatergic excitotoxicity in both TBI and neurological diseases. It is possible that the oxidative cascade caused by TBI ultimately causes and results in the characteristic pathologies of neurodegenerative diseases through oxidation or carbonylation of essential proteins.
Due to the high prevalence of TBI and neurodegenerative diseases, the development of new safe and effective treatment approaches for TBI is fundamental. Given the essential role that oxidative stress plays in connecting secondary injury and neurodegeneration, detection of ROS and key byproducts could serve as a method or technique for the diagnosis and treatment of potential cellular damage. Finally, these reactive species may serve as a viable therapeutic target for reducing long-term neurodegenerative disease risk following TBI, helping to reduce the disability and death as well as improve the quality of life of individuals in the United States that suffer from traumatic brain injury (TBI) and other health issues.
TBI is among one of the most common causes of disability and death among the general population in the United States. According to a variety of research studies, mild, moderate, and severe traumatic brain injury has been associated with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, as well as a variety of other neurodegenerative diseases. It is fundamental to understand the pathophysiological mechanisms of neurodegenerative diseases while further research studies are still required to determine the association between TBI and neurological diseases. – Dr. Alex Jimenez D.C., C.C.S.T. Insight
Neuropathy Treatment with LLLT
Traumatic brain injury (TBI) is one of the most common causes of disability and death in people. About 1.6 million individuals suffer traumatic brain injuries in the United States every year. TBI can cause a process of injury which may cause a variety of neurodegenerative diseases and health issues, such as Alzheimer’s disease (AD). The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 .
Curated by Dr. Alex Jimenez
Additional Topic Discussion: Chronic Pain
Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.
Neural Zoomer Plus for Neurological Disease
Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural ZoomerTM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural ZoomerTM Plus is designed to assess an individual’s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural ZoomerTM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention.
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