Aging with a traumatic brain injury: Could behavioral morbidities and endocrine symptoms be influenced by microglial priming?

Highlights

• Age-at-injury differentially affects cognition and learning.

• Endocrine dysfunction after TBI may impact the way an individual ages.

• Injury-induced inflammation changes with age, possibly reflecting microglial priming.

• Aging and injury are inflammatory priming events, such that either one can exacerbate the other.

Abstract

A myriad of factors influence the developmental and aging process and impact health and life span. Mounting evidence indicates that brain injury, even moderate injury, can lead to lifetime of physical and mental health symptoms. Therefore, the purpose of this mini-review is to discuss how recovery from traumatic brain injury (TBI) depends on age-at-injury and how aging with a TBI affects long-term recovery. TBI initiates pathophysiological processes that dismantle circuits in the brain. In response, reparative and restorative processes reorganize circuits to overcome the injury-induced damage. The extent of circuit dismantling and subsequent reorganization depends as much on the initial injury parameters as other contributing factors, such as genetics and age. Age-at-injury influences the way the brain is able to repair itself, as a result of developmental status, extent of cellular senescence, and injury-induced inflammation. Moreover, endocrine dysfunction can occur with TBI. Depending on the age of the individual at the time of injury, endocrine dysfunction may disrupt growth, puberty, influence social behaviors, and possibly alter the inflammatory response. In turn, activation of microglia, the brain’s immune cells, after injury may continue to fuel endocrine dysfunction. With age, the immune system develops and microglia become primed to subsequent challenges. Sustained inflammation and microglial activation can continue for weeks to months post-injury. This prolonged inflammation can influence developmental processes, behavioral performance and age-related decline. Overall, brain injury may influence the aging process and expedite glial and neuronal alterations that impact mental health.

Introduction

Mounting evidence indicates that brain injury, even moderate injury, can lead to lifetime of significant neuropsychiatric problems (e.g., anxiety, depression, cognitive deterioration), which develop and persist years after injury. Mechanical forces from a traumatic brain injury (TBI) and ensuing pathophysiological processes can compromise and disrupt neuronal circuits, leading to cerebral edema, neuroinflammation (Acerini et al., 2006, Age limits and adolescents, 2003, Anderson and Moore, 1995, Anderson et al., 2011, Anderson et al., 2012, Andrews et al., 1998, Auble et al., 2014, Aungst et al., 2014, Barrientos et al., 2015). Moreover these neuroinflammatory processes may progress after the initial head injury and contribute to the development of neuropsychiatric complications (Witcher et al., 2015). Notably, the age at which injury occurs is a key factor for functional recovery and long-term recovery. Thus, recovery of function depends on parameters such as biological age at the time of injury (age-at-injury), injury location, severity and number of previous injuries. Experimental and clinical data indicate that microglia, innate immune cells of the CNS, develop and maintain a pro-inflammatory profile long after the acute effects of the TBI have dissipated. This may set the stage for glial dysfunction and hyperactivity to subsequent challenges, such as infection, stress, or subsequent injury. In addition, endocrine dysfunction has also been reported, associated with damage to the pituitary and the hypothalamic-pituitary-adrenal (HPA) axis (Popovic et al., 2004). These elements of a TBI limit the brain’s capacity for regenerative and restorative activities to regain function after acquiring a neurological injury (Barrientos et al., 2015, Blakemore et al., 2010, Boake et al., 2005). Overall, TBI may cause long-term CNS issues that affect bidirectional communication between the immune system, endocrine system, and the brain that contributes to functional decline, disability, and neuropsychiatric illness.