Association between single moderate to severe traumatic brain injury and long-term tauopathy in humans and preclinical animal models: a systematic narrative review of the literature

Abstract

Background The initiation, anatomic pattern, and extent of tau spread in traumatic brain injury (TBI), and the mechanism by which TBI leads to long-term tau pathology, remain controversial. Some studies suggest that moderate to severe TBI is sufficient to promote tau pathology; however, others suggest that it is simply a consequence of aging. We therefore conducted a systematic narrative review of the literature addressing whether a single moderate to severe head injury leads to long-term development of tauopathy in both humans and animal models. Methods Studies considered for inclusion in this review assessed a single moderate to severe TBI, assessed tau pathology at long-term timepoints post-injury, comprised experimental or observational studies, and were peer-reviewed and published in English. Databases searched included: PUBMED, NCBI-PMC, EMBASE, Web of Science, Academic Search Premiere, and APA Psychnet. Search results were uploaded to Covidence®, duplicates were removed, and articles underwent an abstract and full-text screening process. Data were then extracted and articles assessed for risk of bias. Findings Of 4,150 studies screened, 26 were eligible for inclusion, of which 17 were human studies, 8 were preclinical animal studies, and 1 included both human and preclinical animal studies. Most studies had low to moderate risk of bias. Most human and animal studies (n = 12 and 9, respectively) suggested that a single moderate to severe TBI resulted in greater development of long-term tauopathy compared to no history of head injury. This conclusion should be interpreted with caution, however, due to several limitations: small sample sizes; inconsistencies in controlling for confounding factors that may have affected tau pathology (e.g., family history of dementia or neurological illnesses, apolipoprotein E genotype, etc.), inclusion of mostly males, and variation in reporting injury parameters. Interpretation Results indicate that a single moderate to severe TBI leads to greater chronic development of tauopathy compared to no history of head injury. This implies that tau pathology induced may not be transient, but can progressively develop over time in both humans and animal models. Targeting these tau changes for therapeutic intervention should be further explored to elucidate if disease progression can be reversed or mitigated.

Lifetime Traumatic Brain Injury and Cognitive Domain Deficits in Late Life: The PROTECT-TBI Cohort Study

“…Pre-clinical research suggests that the initial acute injury should result in a precipitous cognitive impairment while the chronic phase of accumulating proteinopathies should result in a progressive dementia-like process and thus more rapid cognitive decline over subsequent decades 8 (see Figure 1). However, these pre-clinical findings remain contested given the small study samples, uncontrolled confounders and predominant male populations in the studies 9,10 . Indeed, the more rapid cognitive decline has not yet been borne out in the literature.…”

Clinical Outcomes After Traumatic Brain Injury and Exposure to Extracranial Surgery

“…Surgical techniques, although necessary to correct the traumatized anatomy, can also substantially affect variables, including lung function, intravascular distribution, and surgical stress . Exposure to anesthesia may be both neuroprotective and neurotoxic for certain at-risk populations, such as pediatric participants, elderly individuals, or neurologically frail people, given that anesthetic mechanisms are heterogeneous and differentially affect the cerebral metabolic rate, cerebral perfusion pressure, and autonomic function, along with inflammatory, immunologic, and endocrine pathways …”

Hypothermia impairs glymphatic drainage in traumatic brain injury as assessed by dynamic contrast-enhanced MRI with intrathecal contrast

“…The impairment of this drainage system in TBI can aggravate the parenchymal accumulation of damage-associated molecules, such as amyloid-beta and extracellular tau, in the brain ( Ren et al, 2013 ; Iliff et al, 2014 ; Piantino et al, 2019 ). Because the progression of amyloid-beta and tau pathology is strongly correlated with the degree of cognitive impairment ( Wu et al, 2020 ), moderate to severe TBI is correlated with a two- to fourfold increased risk of developing subsequent cognitive impairment ( Walker et al, 2022 ). However, how glymphatic dysfunction is associated with misfolded protein aggregates and whether hypothermia can promote glymphatic drainage to alleviate protein aggregation in TBI remain poorly understood.…”