Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer’s disease and other proteinopathies

Abstract

Unhealthy lifestyle choices, poor diet, and aging can have negative influences on cognition, gradually increasing the risk for mild cognitive impairment (MCI) and the continuum comprising early dementia. Aging is the greatest risk factor for age-related dementias such as Alzheimer’s disease, and the aging process is known to be influenced by life events that can positively or negatively affect age-related diseases. Remarkably, life experiences that make the brain vulnerable to dementia, such as seizure episodes, neurotoxin exposures, metabolic disorders, and trauma-inducing events (e.g. traumatic injuries or mild neurotrauma from a fall or blast exposure), have been associated with negative effects on proteostasis and synaptic integrity. Functional compromise of the autophagy-lysosomal pathway, a major contributor to proteostasis, has been implicated in Alzheimer’s disease, Parkinson’s disease, obesity-related pathology, Huntington’s disease, as well as in synaptic degeneration which is the best correlate of cognitive decline. Correspondingly, pharmacological and non-pharmacological strategies that positively modulate lysosomal proteases are recognized as synaptoprotective through degradative clearance of pathogenic proteins. Here, we discuss life-associated vulnerabilities that influence key hallmarks of brain aging and the increased burden of age-related dementias. Additionally, we discuss exercise and diet among the lifestyle strategies that regulate proteostasis as well as synaptic integrity, leading to evident prevention of cognitive deficits during brain aging in pre-clinical models.

1. Aging and cognition decline

The World Health Organization has reported that people live longer now than ever before. The elderly population is expected to reach 1.6 billion by 2050, up from the staggering one billion in 2020. Currently, people 65 years old and older outnumber children under five (according to the United Nations World Population prospectus: The 2022 Summary). The world is facing a dramatic increase in the population of people older than 60 in low- and middle-income countries such as Brazil, China, India, the Russian Federation, and others. An expected result is that nearly 80% of older people will live in low and middle-income countries by 2050 (WHO, Aging - Facts and Sheets, accessed on January 28, 2021 - https://www.who.int/health-topics/aging). Therefore, the aging population will have critical impacts on economic, social, and public health policies in the coming years. Future public health decision-making will require a significant understanding of the aging process, aging-related changes in the brain, and associated diseases. Ambitious attempts are also working to develop therapies that can prevent or delay the effects of many risk factors that influence the health and independence of the elderly.

Biologically, aging is a process that results from the impact of diverse molecular and cellular damage over time, but it is not considered a disease or a pathological condition. However, the aging process can often lead to a gradual decline in physical and mental capacity, with feared links to developing age-related diseases affecting cognition such as Alzheimer’s disease (AD) and related dementias. Additionally, age-related neurodegenerative disorders are accelerating due to the global rise in life expectancy. Among the pool of age-related diseases, AD represents the greatest cause of death increase compared with the other major causes of death in older adults in the United States of America. It is the sixth leading cause of death in adults, and the number of deaths from AD has been on the rise since 2010, after which the age-adjusted death from AD rate increased by 28%, while death rates actually decreased for six of the ten major death causes (Curtin et al., 2021). Despite this growing prevalence, effective preventive therapies or disease-modifying treatments are lacking. Thus, as people reach middle age, urgent screening of cellular changes that affect brain health during aging are needed in order to initiate current and future pharmacological or non-pharmacological therapies.

In this review, we discuss how aging and other risk factors affect brain health, disturbing neuronal communication and homeostatic processes that often negatively influence cognition and gradually increase the risk of age-related diseases which may give rise to MCI and to early dementia. The negative influences of brain aging can disrupt the quality of life and add to the already enormous medical, social, and economic burden of caring for an elderly population.

2. Cognitive decline is correlated with synaptic pathology

During aging, the nervous system undergoes changes that progressively disturb synaptic integrity, leading to neural vulnerabilities. Although multiple factors influence normal aging, the age-related changes in cognition are often driven by a deterioration of white matter physiology (Valdes Hernandez Mdel et al., 2013). Such deterioration is often linked to distinct synaptic alterations in the hippocampus and prefrontal cortex, brain regions that mediate episodic and working memory which are the most vulnerable cognitive processes in aging (see Morrison et al., 2012; Henstridge et al., 2016). Furthermore, the aging process disrupts essential neurotransmitters affecting glutamatergic, dopaminergic, and serotonergic signaling (Gasiorowska et al., 2021; Segovia et al., 2001; Wang et al., 1998; Hedden & Gabrieli, 2004; Wenk et al., 1989; Lucki et al., 1998; Karrer et al., 2019). Reports also describe that aging downregulates genes involved in synaptic integrity and function (see Azpurua and Eaton, 2015; Berchtold et al., 2012). Therefore, aging affects the synaptic integrity which is critical for cognitive function.

In addition to the aging effects on the synaptic machinery and function, life events such as neurotrauma, mild traumatic brain injury (mTBI), exposure to neurotoxicants, and seizure events have been described as harmful conditions that affect synapse integrity and can lead to cognitive impairment late in life, consequently increasing the risk of age-related dementias. TBI research often focuses on the impact of an injury on neuronal tissue. However, advances in the field have shown that TBI has a major impact on synapse structure and function (see Jamjoom et al., 2021), even for mild TBI (see Przekwas et al., 2016). Accumulative evidence for synaptopathy from blast-related in vitro trauma models (Vogel III et al., 2015; Smith et al., 2016; Almeida et al., 2021) and in vivo models (Meabon et al., 2016; Ratliff et al., 2020) was also described. Associated synaptopathy was similarly described in other models of TBI, such as controlled cortical impact (Gao et al., 2011; Ansari et al., 2008a, 2008b) and lateral fluid percussion injury (Shojo & Kibayashi, 2006; Carlson et al., 2017). Thus, experimental evidence supports that different levels of neurotrauma cause a range of subtle to severe synaptic injuries and can trigger neurobiological events that initiate cognitive decline and increase the risk of cognitive disorders.

The synaptic vulnerability has also been described in neurotoxic events throughout the lifetime and linked to the onset of dementia. Exposure to neurotoxic agents has been associated with an increased risk of chronic neurological illnesses (Yokoyama et al., 1998; Bullman et al., 2005; Hayden et al., 2010), synaptic deterioration stemming from the induced seizures (Munirathinam & Bahr, 2004; Sánchez-Santed et al., 2004; Todorovic et al., 2012; Deshpande et al., 2014; Deshpande et al., 2016; Farizatto et al., 2017a; McDonough et al., 1997; Vegh & Reutens, 2019), and with the disruption of synaptic integrity during brain development (Rotenberg & Newmark, 2003; Santos et al., 2004). Nevertheless, subtoxic insults with neurotoxins lead to higher neuronal vulnerability, likely explaining the increased risk of brain disorders in survivors and raising the risk of dementia (see Munirathinam & Bahr, 2004; Mattson et al., 1992; Bahr et al., 1994; Baldi et al., 2011; Parron et al., 2011; Jones et al., 2010; Hayden et al., 2010).

Synaptic compromise, which is known as the best correlate of cognitive deterioration (Terry et al., 1991; Harris et al., 2010; DeKosky et al., 1990), has been linked to many neurological conditions such as AD (Selkoe, 2002), Parkinson’s disease (PD) (Day et al., 2006; Bellucci et al., 2016), frontotemporal dementia (Liu & Brun, 1996; Mackenzie et al., 2009; Lipton et al., 2001), motor neuron disease (Fischer et al., 2004; Frey et al., 2000), Huntington’s disease (Li et al., 2003), and multiple sclerosis (Mandolesi et al., 2015). Therefore, the loss of neuronal connectivity is a well-described consequence of brain vulnerabilities that inevitably leads to the disruption of cognitive function. This fact is particularly evident in aging, where varying degrees of synaptic deterioration can significantly impair brain function and contribute to the development of neurological disorders.

3. Proteostasis failure and synaptic dysfunction

Besides the disruption of synaptic integrity and functions, aging is also commonly associated with proteostasis dysfunction, which has been linked to the loss of synaptic markers and memory impairment, contributing to the development of age-related dementia. As neuronal cells are postmitotic and nondividing cells with long lives, the proteostatic machinery plays a vital role in maintaining cellular homeostasis.

The degradation of non-functional proteins and organelles through proteasomes and autophagy-lysosomal structures plays a major role in maintaining cellular homeostasis and preventing the accumulation of toxic protein complexes. The two major catabolic routes are called i) the ubiquitin proteasomal system (UPS) and ii) the autophagy-lysosome system. Although the UPS and autophagy-lysosome system act distinctly to degrade protein complexes, the UPS is often attributed as the cell’s primary source of protein degradation (Finley, 2009). Large protein inclusions and organelles are also frequently directed to the autophagy-lysosomal system (Yang & Klionsky, 2009), and there is evidence of crosstalk between this system and the UPS (Farizatto et al., 2017b; Korolchuk et al., 2010; Cohen-Kaplan et al., 2016; Liebl & Hoppe, 2016; Pohl & Dikic, 2019).

The aging process compromises the proteostatic network of the two interacting clearance systems, leading to reduced efficiency with regards to removing misfolded, old, or damaged proteins and organelles. Such compromise of proteostasis leads to gradual protein accumulation events and associated pathologies (see Taylor et al., 2011; Morimoto & Cuervo, 2009). Interestingly, proteinopathies in adults do not occur early in the lifespan. Alterations to the proteostasis network occur later with the influence of aging (see López-Otín et al., 2023), resulting in such changes as i) reduced expression of molecular chaperones in the human brain (Brehme et al., 2014; Shemesh et al., 2021), ii) altered proteasome activity (Sacramento et al., 2020; Schmidt & Finley, 2013; Saez & Vilchez, 2014; Keller et al., 2002), and iii) autophagy dysfunction (Lipinski et al., 2010; see Cuervo, 2003; Rubinsztein et al., 2011; Nixon & Yang, 2012). Together these compounding changes support the idea that aging is the major contributor to the loss of protein homeostasis and the increased burden of age-related protein accumulation diseases, thus contributing to the development of age-related dementia.

Age-related brain disorders are characterized by the presence of protein accumulations and aggregation events, which are pathological hallmarks of many neurodegenerative diseases (see Table 1), comprised of insoluble inclusions and protein aggregates in both the intra- and extracellular space (Knowles et al., 2014; see Wilson III et al., 2023). Although the primary cause of this protein accumulation stress is unknown, it has been accepted that some causative mutations and impairment of cellular quality control systems during adulthood are the leading cause of these proteinopathies (Soto & Pritzkow, 2018). Protein accumulation stress is a slow, cytotoxic, and progressive event that can affect cellular homeostasis, intracellular machinery, and cell-to-cell communication, triggering cellular dysfunction and loss of brain functionality.

Table 1 –

Brain diseases with protein accumulation pathology

Disease	protein involved
Alzheimer’s disease	Aβ, tau, α-synuclein, TDP-43
frontotemporal dementia	Tau, TDP-43
Parkinson’s disease	α-synuclein
Huntington’s disease	huntingtin
corticobasal degeneration	tau
progressive supranuclear palsy	tau
amyotrophic lateral sclerosis	tau, TDP-43
prion diseases	prion PrP
spinocerebellar ataxia	ataxin

Synaptic loss and aging-linked proteostasis failure are early signs of neurodegenerative disorders preceding neuronal loss (see Knopman et al., 2021; Wong & Krainc, 2021). However, failure in both synaptic and proteolytic systems can be attributed to multifactorial causes, and they do not appear to be completely independent of each other. For example, the UPS system regulates major pre- and postsynaptic proteins responsible for neurotransmission and synaptic plasticity (see Hedge, 2017). Autophagy is a modulator of neuronal excitation-inhibition balance through the degradation of postsynaptic receptors (Rowland et al., 2006; Shehata et al., 2012) and can modulate presynaptic vesicle and neurotransmission (Hernandez et al., 2012; Binotti et al., 2015). Interestingly, Kulkarmi and colleagues (2021) described that autophagosome mobility is regulated by synaptic activity in dendrites (not in axons). Similar changes in mobility due to synaptic activity were found for the proteasome (Bingol & Schuman, 2006), whereas mitochondria break with synaptic activity (Wang & Schwarz, 2009). Additionally, positive modulation of the autophagy-lysosomal pathway preserves synaptic integrity and neuronal functionality (Bendiske & Bahr, 2003; Muller-Steiner et al., 2006; Fleming & Rubinsztein, 2020; Hwang et al., 2019), and memory stimulation increases autophagy regulation, while autophagy inhibition is linked to memory dysfunction (Glatigny et al., 2019). Relatedly, accumulation of proteins such as amyloid-β and pathologic tau at synaptic terminals is toxic to synapses, causing synaptopathy that can lead to synaptic deterioration and eventual spread of the synaptic pathology (see Spire-Jones & Hyman, 2014; Rajmohan & Reddy, 2017). Indirectly, the physical barrier formed by protein accumulation due to decreased protein degradation, as described before, affects the synaptic machinery via disruption in axonal transport (Chevalier-Larsen & Holzbaur, 2006; Goldstein, 2012).

In sum, age-related cognitive decline is associated with evident synaptic pathology along with proteostatic stress in neuronal cells that precede neuronal death during neurodegenerative diseases. Therefore, it is crucial to emphasize the importance of early intervention in maintaining synaptic health associated with the modulation of protein homeostasis to prevent the onset or progression of neurological disorders.

4. Positive modulation of cleavage pathways and cognition preservation

Aging is a multifactorial decline of cellular functions during adulthood with hallmarks that often interact with each other. The hallmarks of aging can be classified based on their time-dependency of alterations, the possibility of accelerating aging, and the opportunity to decelerate, halt, or reverse aging (see López-Otín et al., 2023). Of the hallmarks listed in this review that represent common denominators of aging in different organisms, proteostasis stress and altered intercellular communication (endocrine, neuroendocrine, neuronal) were discussed and allied to age-associated cognitive decline and the risk of dementia.

Interestingly, the progressive age-related protein accumulation stress can be slowed by the positive modulation of the autophagy-lysosomal pathway (see Klionsky et al., 2021). For example, studies have targeted the lysosomal protein clearing function to offset lysosomal dysfunction linked with aging or neurodegenerative diseases (Butler et al., 2011; Hwang et al., 2019; Lee et al., 2010). One efficient strategy to positively modulate the lysosomal function is targeting the activation of proteases within lysosomes, such as cathepsin B (CatB), to improve or reestablish the protein degradation-avoiding toxicity events that leads to neurodegeneration. The lysosomal cysteine protease CatB has been shown to degrade amyloid-β42 (Aβ), which is the toxic form (Muller-Steiner et al., 2006; Wang et al., 2012; Butler et al., 2011; Hwang et al., 2019), and promote clearance of tau species (Bendiske & Bahr, 2003; Farizatto et al., 2017b). In cell culture, deficiency of CatB has been associated with the accumulation of amyloidogenic toxic proteins, cholesterol, and other lysosomal proteins (Cemark et al., 2016). Improvement against amyloid pathologies was also found through genetic deletion of the endogenous inhibitor of lysosomal cysteine proteases, which results in cathepsin-dependent effects (Wang et al., 2012; Yang et al., 2011; Sun et al., 2008), and through the upregulation of CatB expression using an adeno-associated virus (Embury et al., 2017). Besides the aging process that affects lysosomal hydrolases, including cathepsins (see Stoka et al., 2016), it should be noted that genetic inactivation of CatB (i) suspends the brain benefits of physical exercise in mice (Moon et al., 2016) and (ii) aggravates the plaque deposits and worsens the pathology in a mouse model of AD expressing a mutation in a human-linked protein (Muller-Steiner et al., 2006). Additionally, positive modulation of CatB for the enhancement of autophagy-lysosomal protein clearance activity was connected to reducing protein accumulation, recovering synaptic integrity, and improving cognitive ability in rodent models of MCI and AD (Butler et al., 2011; Farizatto et al., 2017b; Hwang et al., 2019). Therefore, positive modulation of autophagy-lysosomal pathway, targeting lysosomal proteases to promote protein clearing, appears to play an important role in supporting healthy brain connectivity.

Another strategy to induce the autophagy-lysosomal pathway to avoid protein accumulation stress and cell death is by targeting a kinase, namely the mammalian target of rapamycin (mTOR), which is a major regulator of the autophagic process. There is ample evidence of a diversity of compounds that target mTOR to modulate autophagy directly, such as rapamycin, or indirectly, like agents that act on PI3K, SHIP-1, and AMPK (see Heras-Sandoval et al., 2020; Johnson et al., 2013; Deng et al., 2022; Kocak et al., 2022). Additionally, modulation of mTOR to induce autophagy leads to neuroprotective effects against synaptic dysfunction and cognitive decline (Singh et al., 2017; Gao et al., 2021).

5. Lifestyle choices to promote autophagy and synaptic health to avoid age-related cognitive decline

Much effort has been directed at finding avenues to offset aging-related cellular dysfunction, for instance the stress on the autophagy-lysosomal pathway (a major component of proteostasis) and the corresponding synaptic decline. The following life choice strategies have the potential to positively influence brain health and reduce the impact of aging: physical activity and healthy eating habits. Evidence from a population-based perspective, the World Dementia Council jointly with the Alzheimer’s Association concluded that only two ways are known to reduce the risk of dementia: i) regular physical activity associated with the management of cardiovascular risk factors such as diabetes, obesity, smoking, and hypertension, and ii) a healthy diet (World Dementia Council, WDC Dementia Risk Reduction Statement, 2015; Baumgart et al., 2015).

Physical activity holds stronger evidence to preserve cognitive decline and dementia by a variety of neurological mechanisms such as (i) release of brain growth factors to promote neurogenesis, (ii) modulation of brain metabolism, (iii) release of anti-inflammatory cytokines, (iv) enhancement of mitochondrial function and biogenesis, and (v) modulated release of neurotransmitter to modulate cognition (see Chen and Nakagawa, 2023; Sujkowski et al., 2022).

Most recently, the effects of physical exercise to promote cognitive health was recently associated with the positive modulation of myokines irisin and CatB. Irisin and CatB were elevated in human plasma by the exercise of the type that improves memory and increases brain-derived neurotrophic factor expression (Lourenco et al., 2019; Wrann et al., 2013; Wrann, 2015; Moon et al., 2016; Gaitán et al., 2021). Irisin was also shown to rescue plasticity and memory functions in AD mice (Lourenco et al., 2019) and to prevent protein accumulation and neuronal cell death by enhancing lysosomal degradation in the PD model (Kam et a., 2022). While CatB positive modulation increases protein clearance and cognitive measures in models of AD, α-synucleinopathy, and mild cognitive impairment (Mueller-Steiner et al., 2006; Butler et al., 2011; Wang et al., 2012; Embury et al., 2017; Hwang et al., 2019).

Additionally, regular physical exercise has been described as an activator of autophagy degradation to reverse the proteostasis dysfunction linked with aging or neurodegenerative disorders (Almeida. et al., 2018; Melo et al., 2018; Andreotti et al., 2020; Jian hao et al., 2019; Shen et al., 2021; Wang et al., 2022). Yet, exercise-induced hippocampal neurogenesis was associated with increased expression of autophagy-related proteins (Jang, 2020; Moon et al., 2016; Cordina-Martinez et al., 2019). In experimental models of neurodegenerative diseases, the exercise-induced restoration of the autophagy-lysosomal pathway, prevention of synaptic integrity disruption, and alleviation of cognitive impairment (Jian et al., 2022). Similar exercise effects on the synaptic integrity were described in transgenic AD mice (Zhang et al., 2020), in PD (Ahlskog, 2018), and in multiples models of neurodegenerative disease (Dauwan et al., 2021).

Another strategy to promote a healthy aging process avoiding cognitive decline is by having a plant-based diet. The impact of nutrition on cognition has been extensively studied, and several natural extracts and components have been found to have beneficial effects on cognitive function. Plant extracts and their components have been shown to reduce proteinopathy (Lee et al., 2009; Kim et al., 2018) and improve cognitive functioning (Smith et al., 2014; Solfrizzi et al., 2018; Travica et al., 2020). Moreover, maintaining a healthy diet, such as the Mediterranean diet, which has a high intake of vegetables, legumes, fruits and cereals, and unsaturated fatty acids, has been found to reduce the risk of developing dementia by 40% compared to those who consume dairy products and meat regularly (Scarneas et al., 2006).

The idea of beneficial plant-based neuroprotective agents is supported by epidemiological studies, such as analyses of traditional medicine and diets rich in antioxidants and natural products that might promote healthy cognitive aging (Trichopoulou & Vasilopoulou, 2000; Willcox et al., 2007; Joseph et al., 2009; Spencer, 2009). Interestingly, many natural extracts, such as those rich in flavonoids, polyphenols, and polyamine, have also been described as autophagy inducers with a crucial impact on synaptic plasticity using in vitro and in vivo models of degenerative diseases (see Stachiotti & Corsetti, 2020; Shaikh et al., 2021; Liu & Li, 2020). There is also a suggested interplay between age-related oxidative stress and autophagy-lysosomal signaling (Butler & Bahr, 2006) that may be governed, at least in part, by lifestyle choices that influence synaptic resilience and thus cognitive function. In addition to the putative compensatory responses activated to offset proteinopathy through protease regulation, it is very likely such responses involve a variety of genes (“vitagenes”) that express proteins involved in cellular homeostasis for the protection of cell health during events of stress and/or pathogenesis (see Calabrese et al., 2010, 2012). While anti-inflammatory strategies involve the cautious interplay of redox interactions with endogenous and exogenous defense systems, also is the case of neuroprotective routes requiring a delicate balance between the actions of endogenous compensatory responses and exogenous modulation of such responses. Related to such dual consideration of parallel responses, ideas for multi-targeting methods to maintain brain health involve negative modulation of degenerative signaling in conjunction with the positive modulation of endogenous protective pathways (Qneibi et al., 2023; Caba et al., 2021), thereby working to treat the multifaceted nature of different types of pathogenic condition perhaps by incorporating a specific natural product with a specific type of conventional therapy.

Clearance of proteins and expended organelles by the autophagy-lysosomal pathway is essential for cellular quality control and energy homeostasis. Lysosomes represent both degradation centers and signaling hubs that play important roles in cellular homeostasis and adaptation to multiple conditions through the regulation of lysosomal biogenesis and endolysosomal trafficking (Yang & Wang, 2021). Innovative research on the protein clearance pathway continues to provide new insights to the current understanding of vital mechanistic details including i) regulation of switching mechanisms between degradative and secretory functions of endolysosomal compartments (Li et al., 2023), ii) autolysosomal acidification which was found reduced in neurons well before Alzheimer-type amyloid deposition, with build-up of APP-βCTF selectively detected in de-acidified autolysosomes (Lee et al., 2022), and iii) synaptic compensation and regeneration pathways thought to be potential avenues to delay the onset of dementia (Bendiske & Bahr, 2003; Mueller-Steiner et al., 2006; Viswanathan et al., 2012; Embury et al., 2017; Farizatto et al., 2017b; Bhembre et al., 2023). Lifestyle choices, such as physical activity and a plant-based diet, influence components of the autophagy-lysosomal pathway, perhaps explaining their impact on brain health to provide significant preservation of cognitive function. Therefore, there is growing evidence that stimulation of autophagy-lysosomal functionality is a feasible avenue to promote brain health and avoid age-related cognitive decline.

5. Final conclusions

Age-related weakening of the prodigious clearance activity known for the autophagy-lysosomal system, a major component of proteostasis, is thought to be a key contributor to cognitive deterioration during aging, as is the associated age-related synaptic loss often linked to the indication of dementia onset. The compromised protein clearance during the aging process contributes to a variety of protein accumulation pathology that is a hallmark of many neurodegenerative diseases such as AD, PD, and frontotemporal dementia. Furthermore, age-associated synaptic pathology, which can be amplified by life threaten episodes, is the best-correlated maker of cognitive decline, which can also be influenced by compromised proteostasis status.

Positive modulation of autophagy-lysosomal pathway associated with synaptic protective interventions has been described as a therapeutic avenue to prevent or treat age-related cognitive decline and dementias. Several lines of new research aim to develop new pharmacological agents to treat age-related disorders by targeting protein clearance systems.

Physical exercise and a healthy diet, two excellent examples of good lifestyle choices, protect the brain, at least in part, by improving autophagy-lysosomal pathways and the modulation of synaptic integrity. However, there still a need for more research to fully characterize the physical exercise (e.g. time, intensity, frequency, type) and diet (e.g. nutritional information) in order to tackle the objective of delaying age-related cognitive decline and preventing AD and related dementias.

Figure 1.

Optimizing proteostasis and synaptic integrity via lifestyle choices to mitigate progressive proteinopathies. The displayed outer shell indicates the protective effects of healthy physical activity and diet, in contrast to the risks of various vulnerabilities including i) aging, ii) early deterioration of cognitive functions (e.g. MCI), iii) initiation of proteinopathy which can occur years to decades before dementia onset, iv) toxin exposures which can have lasting neurological effects, and v) mild to severe TBI. Regarding the latter, neurological damage from TBIs can be immediate and can continue to evolve for an extended period. In addition, subconcussive neurotrauma may lead to persistent neurological complications, often when brain damage is not detected.