The paper by Rotstein and Levine (Reference Rotstein and Levine2020) presents an excellent analysis and is novel and well written. The paper shines a light on the role of early-life immune system functioning in late-life cognitive functioning.
The study results indicate that some childhood infectious diseases (i.e. measles) are associated with better cognitive functioning in old age. The analysis is elegant because the association between early-life viral exposure and late-life cognitive functioning is examined in more than one way.
The paper raises a significant question regarding the possible mechanism underlying the positive association between the number of childhood infectious diseases and cognitive functioning in old age. One explanation is that the study data may be missing a whole population of infants who have died (i.e. selective mortality). An alternative explanation of the findings may be that these common childhood infectious diseases (which are usually not life threatening) are actually associated with less cognitive deterioration later in life, regardless of various confounding factors (e.g. education).
The paper cites relevant literature that provides related examples of early-life infectious diseases having a protective effect on health in later life. For instance, the Varicella-zoster virus that causes chickenpox is reported to have an inverse association with glioma (Amirian et al., Reference Amirian2016). Similarly, measles and/or combined childhood infections (chickenpox, measles, mumps, pertussis, and rubella) were found protective for Hodgkin’s disease(Alexander et al., Reference Alexander2000).
Cognitive functionings, non-pathological age-related cognitive changes, and the risk of dementia can be influenced by the developmental environment, health, and lifestyle over the life span as well as heritable factors. It is not a new concept that early-life stressors leave their fingerprints throughout the individual life span by modulation of the inflammatory and the nervous systems and have an essential impact on brain functioning. In that context, we can consider viral infections as an acute physical stressor. Different stressors require a variety of responses, and so the nature of the stressor determines the neuronal populations that perceive a potential threat as well as the stress mediators involved in the adaptive response (Joels and Baram, Reference Joels and Baram2009).
The basis of the vulnerability of the developing brain to the adverse cognitive effects of early-life stress has been an area of intense research. This vulnerability results in large part from developmental processes that are still taking place during the early-life stress period. In rodents, for example, the organization of the hippocampal formation and the limbic circuit, involved in cognitive functions, take place mainly after birth, continuing through the first few weeks of life. In humans, the development of this circuit is characterized by a particularly prolonged trajectory, and refinement of cortical synapses and connectivity patterns continues for years into the adolescent period (Chen and Baram, Reference Chen and Baram2016).
The study of neurodegenerative diseases has led to an augmented investigation of the environmental factors involved in their origins and progression. Mounting evidence indicates that oxidative stress contributes to the etiology and the progression of neurodegenerative diseases (Concetta Scuto et al., Reference Concetta Scuto2019).
It is noteworthy to consider the magnitude of the stressor. Evidence dates from the mid to late 1970s, to understand the adaptive response of cells and organisms as a whole, to a moderate (usually intermittent) stress, which is the hormesis mechanism (Mattson, Reference Mattson2008). In general, viruses result in an imbalance in the cellular redox environment, which depending on the virus and the cell could result in multiple responses (e.g. antioxidant defenses) that can be the common final pathway behind the hormesis mechanism (Camini et al., Reference Camini, da Silva Caetano, Almeida and de Brito Magalhaes2017). Hormesis is a biphasic dose–response that displays a low-dose stimulation and a high-dose inhibition. Hormesis defines thresholds of adaptive responses for a given system in which low doses of exposure to substances can incur positively adaptive mechanisms, while higher concentrations evoke dysfunctional or toxic effects (Calabrese et al., Reference Calabrese2016). Accumulating evidence of the past two decades has revealed that the mechanisms and processes of the hormetic dose–response are critical for all biological systems, including the brain and the neurovascular system (Calabrese, Reference Calabrese2016).
It is now well established that the capacity for preconditioning to protect the brain from various types of chemical, hypoxic, metabolic, and physical trauma acts by a hormetic mechanism (Calabrese et al., Reference Calabrese2016). A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to novel approaches for the prevention and treatment of many different diseases. Rotstein and Levine point out the possible importance of some viral exposures as a prevention factor for cognitive decline and maybe even dementia (Rotstein and Levine, Reference Rotstein and Levine2020).
In the western world, the incidence of most infectious diseases has declined. The observation gave rise to the hygiene hypothesis. Griffin and Mark propose that a paucity of exposure to environmental pathogens retards proper immune system development, and consequently decreases its ability to effectively thwart a variety of effectors with degenerative consequences, such as those associated with chronic inflammatory responses in diseases as seemingly diverse as those of the brain (Rook, Reference Rook2010). The findings of Rotstein and Levine (Reference Rotstein and Levine2020), stand in line with Griffin and Mrak that found the possibility that building a better immune system – through exposure to “friendly” organisms during immune system development – would enable microglia to prevent the insidious progression of the neuropathological changes and dementia of AD, are intriguing and deserve further research (Griffiin and Mrak, Reference Griffiin and Mrak2009).
At present, global efforts are underway to defeat the COVID-19 virus. The paper of Rotstein and Levine was written before the pandemic but maybe read in that context. That is to say that epigenetics and, in particular, the exposure to viruses are an important consideration in the ecological environment. This possible environmental effect is one of the most interesting points that transpire from the paper.
Only since the hygiene hypothesis appeared have we been wondering if the immune systems of people living in clean and modern cities are appropriate (Rook, Reference Rook2010). The manuscript raises thoughts on whether childhood viral infections may be beneficial to cognition in old age. Based on Rotstein and Levine, it appears that hygiene might reduce the resilience to cognitive impairment in later life. One can only postulate how wither this result extends to COVID-19.
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The paper by Rotstein and Levine (Reference Rotstein and Levine2020) presents an excellent analysis and is novel and well written. The paper shines a light on the role of early-life immune system functioning in late-life cognitive functioning.
The study results indicate that some childhood infectious diseases (i.e. measles) are associated with better cognitive functioning in old age. The analysis is elegant because the association between early-life viral exposure and late-life cognitive functioning is examined in more than one way.
The paper raises a significant question regarding the possible mechanism underlying the positive association between the number of childhood infectious diseases and cognitive functioning in old age. One explanation is that the study data may be missing a whole population of infants who have died (i.e. selective mortality). An alternative explanation of the findings may be that these common childhood infectious diseases (which are usually not life threatening) are actually associated with less cognitive deterioration later in life, regardless of various confounding factors (e.g. education).
The paper cites relevant literature that provides related examples of early-life infectious diseases having a protective effect on health in later life. For instance, the Varicella-zoster virus that causes chickenpox is reported to have an inverse association with glioma (Amirian et al., Reference Amirian2016). Similarly, measles and/or combined childhood infections (chickenpox, measles, mumps, pertussis, and rubella) were found protective for Hodgkin’s disease(Alexander et al., Reference Alexander2000).
Cognitive functionings, non-pathological age-related cognitive changes, and the risk of dementia can be influenced by the developmental environment, health, and lifestyle over the life span as well as heritable factors. It is not a new concept that early-life stressors leave their fingerprints throughout the individual life span by modulation of the inflammatory and the nervous systems and have an essential impact on brain functioning. In that context, we can consider viral infections as an acute physical stressor. Different stressors require a variety of responses, and so the nature of the stressor determines the neuronal populations that perceive a potential threat as well as the stress mediators involved in the adaptive response (Joels and Baram, Reference Joels and Baram2009).
The basis of the vulnerability of the developing brain to the adverse cognitive effects of early-life stress has been an area of intense research. This vulnerability results in large part from developmental processes that are still taking place during the early-life stress period. In rodents, for example, the organization of the hippocampal formation and the limbic circuit, involved in cognitive functions, take place mainly after birth, continuing through the first few weeks of life. In humans, the development of this circuit is characterized by a particularly prolonged trajectory, and refinement of cortical synapses and connectivity patterns continues for years into the adolescent period (Chen and Baram, Reference Chen and Baram2016).
The study of neurodegenerative diseases has led to an augmented investigation of the environmental factors involved in their origins and progression. Mounting evidence indicates that oxidative stress contributes to the etiology and the progression of neurodegenerative diseases (Concetta Scuto et al., Reference Concetta Scuto2019).
It is noteworthy to consider the magnitude of the stressor. Evidence dates from the mid to late 1970s, to understand the adaptive response of cells and organisms as a whole, to a moderate (usually intermittent) stress, which is the hormesis mechanism (Mattson, Reference Mattson2008). In general, viruses result in an imbalance in the cellular redox environment, which depending on the virus and the cell could result in multiple responses (e.g. antioxidant defenses) that can be the common final pathway behind the hormesis mechanism (Camini et al., Reference Camini, da Silva Caetano, Almeida and de Brito Magalhaes2017). Hormesis is a biphasic dose–response that displays a low-dose stimulation and a high-dose inhibition. Hormesis defines thresholds of adaptive responses for a given system in which low doses of exposure to substances can incur positively adaptive mechanisms, while higher concentrations evoke dysfunctional or toxic effects (Calabrese et al., Reference Calabrese2016). Accumulating evidence of the past two decades has revealed that the mechanisms and processes of the hormetic dose–response are critical for all biological systems, including the brain and the neurovascular system (Calabrese, Reference Calabrese2016).
It is now well established that the capacity for preconditioning to protect the brain from various types of chemical, hypoxic, metabolic, and physical trauma acts by a hormetic mechanism (Calabrese et al., Reference Calabrese2016). A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to novel approaches for the prevention and treatment of many different diseases. Rotstein and Levine point out the possible importance of some viral exposures as a prevention factor for cognitive decline and maybe even dementia (Rotstein and Levine, Reference Rotstein and Levine2020).
In the western world, the incidence of most infectious diseases has declined. The observation gave rise to the hygiene hypothesis. Griffin and Mark propose that a paucity of exposure to environmental pathogens retards proper immune system development, and consequently decreases its ability to effectively thwart a variety of effectors with degenerative consequences, such as those associated with chronic inflammatory responses in diseases as seemingly diverse as those of the brain (Rook, Reference Rook2010). The findings of Rotstein and Levine (Reference Rotstein and Levine2020), stand in line with Griffin and Mrak that found the possibility that building a better immune system – through exposure to “friendly” organisms during immune system development – would enable microglia to prevent the insidious progression of the neuropathological changes and dementia of AD, are intriguing and deserve further research (Griffiin and Mrak, Reference Griffiin and Mrak2009).
At present, global efforts are underway to defeat the COVID-19 virus. The paper of Rotstein and Levine was written before the pandemic but maybe read in that context. That is to say that epigenetics and, in particular, the exposure to viruses are an important consideration in the ecological environment. This possible environmental effect is one of the most interesting points that transpire from the paper.
Only since the hygiene hypothesis appeared have we been wondering if the immune systems of people living in clean and modern cities are appropriate (Rook, Reference Rook2010). The manuscript raises thoughts on whether childhood viral infections may be beneficial to cognition in old age. Based on Rotstein and Levine, it appears that hygiene might reduce the resilience to cognitive impairment in later life. One can only postulate how wither this result extends to COVID-19.