Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link

Ramos‐Cejudo, Jaime; Wısnıewskı, Thomas; Marmar, Charles R.; Zetterberg, Henrik; Blennow, Kaj; Leon, Mony J. de; Fossati, Silvia

doi:10.1016/j.ebiom.2018.01.021

Cited by 287 publications

(233 citation statements)

References 109 publications

Supporting

Mentioning

205

Contrasting

Order By: Relevance

“…There has been growing attention to mTBI and the development of dementia later in life [55]. Potential underlying mechanisms between TBI and later development of AD include diffused axonal damage, persistent inflammation and vascular dysfunctions [7,56]. While aberrant Tau pathology induced by TBI is considered a high-risk factor for chronic traumatic encephalopathy (CTE), the production and accumulation of brain Aβ species are still considered as the main pathophysiological link between TBI and AD.…”

Section: Discussionmentioning

confidence: 99%

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

Zeng

Pluimer

et al. 2020

Preprint

View full text Add to dashboard Cite

Introduction: Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored. Methods:We established a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, and examined the time courses of microvascular injury, blood-brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also determined the brain clearance of βamyloid, as well as amyloid pathology and cognitive functions after mTBI in the 5xFAD mouse model of AD.Results: mTBI induced microvascular injury with BBB breakdown, pericyte loss and cerebral blood flow reduction in mice, which preceded gliosis. mTBI also impaired brain amyloid clearance via the vascular pathways. More importantly, mTBI accelerated amyloid pathology and cognitive impairment in the 5xFAD mice.Discussion: Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD. Ethics approval and consent to participateThe animal experiments were approved by the Institutional Animal Care and Use Committee at the University of Southern California per NIH guidelines. BackgroundAlzheimer's disease (AD) is an age-related progressive neurodegenerative condition, manifesting amyloid plaque and neurofibrillary tangle formation, neurovascular and neuroimmune dysfunctions, and cognitive impairment [1,2]. While advanced aging increases the likelihood of AD, genetic inheritance and environmental risk factors also contribute significantly [3]. For example, Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for AD [4]. TBI is a leading cause of death and disability, particularly in young adults, resulting in a great impact on productivity and dependence on health care in later life [5,6]. Both clinical and preclinical studies have demonstrated that TBI triggers multiple neurodegenerative cascades, including axonal and dendritic damage, excitatory toxicity, neuroinflammation and cell death [7,8], as well as cerebrovascular impairment such as edema, circulatory insufficiency, and blood-brain barrier (BBB) breakdown [9,10], exhibiting a high similarity with AD [6,11]. TBI is highly prevalent during military service and contact sports, and doubles the risk of developing AD and dementia [12,13]. More importantly, it also exacerbates certain pathological events that are specific to AD, including the brain's overproduction and accumulation of β-amyloid (Aβ), and neurofibrillary tangles consisting of hyperphosphorylated Tau [14]. Yet the underlying mechanisms remain elusive.Histological and neuroimaging assessments have demonstrated that microvascular injury with...

show abstract

Section: Discussionmentioning

confidence: 99%

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

Zeng

Pluimer

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Studies of individuals who died after a TBI event had amyloid plaques present in all age groups (Johnson, Stewart, & Smith, 2010;Ramos-Cejudo et al, 2018). However, among patients who died from nonneurological causes, plaques were only seen in elderly individuals (Johnson et al, 2010;Ramos-Cejudo et al, 2018). Therefore, TBI or repeated head injuries (mTBI) is a strong risk factor for both CTE and Alzheimer's disease (Gavett et al, 2010;Sivanandam & Thakur, 2012 Future studies will correlate the levels of these two candidate biomarkers with neurocognitive testing.…”

Section: Discussionmentioning

confidence: 99%

“…or saliva(Gonzalez-Begne et al, 2009;Kapsogeorgou, Abu-Helu, Moutsopoulos, & Manoussakis, 2005), as seen in brain cancer, poses an exciting avenue to painlessly diagnose disease.In the present study, we report the isolation and characterization of EVs from saliva and for the first time profiled the expression of Alzheimer disease genes in three groups of patients: acutely head injured emergency department (ED) patients, patients diagnosed with a concussion from an outpatient concussion clinic, and controls. Given the literature surrounding head injury and Alzheimer's disease(Becker, Kapogiannis, & Greig, 2018;Grinberg et al, 2016;Julien et al, 2017;Mendez, Paholpak, Lin, Zhang, & Teng, 2015;Ramos-Cejudo et al, 2018), we hypothesized that patients with mTBI would express Alzheimer's disease genes at significantly greater levels than controls. Our aim is to determine whether those gene expression profiles changed after mTBI and if the changes of the biomarkers could be potentially used to diagnose mTBI to prognosticate future development of postconcussion syndrome (PCS) or CTE, a disease characterized by tau protein deposition and amyloid beta plagues similar to those seen in Alzheimer's disease(Gavett et al, 2010).2 | MATERIALS AND METHODSAll participants and/or their relatives in addition to normal healthy control subjects gave written informed consent.…”

mentioning

confidence: 99%

Potential biomarkers to detect traumatic brain injury by the profiling of salivary extracellular vesicles

Cheng

Pereira

Raukar

et al. 2019

Journal Cellular Physiology

View full text Add to dashboard Cite

Traumatic brain injury (TBI) is a common cause of death and acquired disability in adults and children. Identifying biomarkers for mild TBI (mTBI) that can predict functional impairments on neuropsychiatric and neurocognitive testing after head trauma is yet to be firmly established. Extracellular vesicles (EVs) are known to traffic from the brain to the oral cavity and can be detected in saliva. We hypothesize the genetic profile of salivary EVs in patients who have suffered head trauma will differ from normal healthy controls, thus constituting a unique expression signature for mTBI. We enrolled a total of 54 subjects including for saliva sampling, 23 controls with no history of head traumas, 16 patients enrolled from an outpatient concussion clinic, and 15 patients from the emergency department who had sustained a head trauma within 24 hr. We performed real‐time PCR of the salivary EVs of the 54 subjects profiling 96 genes from the TaqMan Human Alzheimer's disease array. Real‐time PCR analysis revealed 57 (15 genes, p < 0.05) upregulated genes in emergency department patients and 56 (14 genes, p < 0.05) upregulated genes in concussion clinic patients when compared with controls. Three genes were upregulated in both the emergency department patients and concussion clinic patients: CDC2, CSNK1A1, and CTSD ( p < 0.05). Our results demonstrate that salivary EVs gene expression can serve as a viable source of biomarkers for mTBI. This study shows multiple Alzheimer's disease genes present after an mTBI.

show abstract

“…A plausible mechanism of transmission is the propagation of abnormal proteins along damaged white matter pathways. Furthermore, TBI can initiate cerebrovascular pathology, which in turn could mediate in neurodegeneration including AD-like dementia [Ramos-Cejudo et al, 2018].…”

Section: Cardiovascular and Cerebrovascular Pathologiesmentioning

confidence: 99%

Exploratory Data Analysis in a Six-Year Longitudinal Study in Healthy Brain Aging

Gómez-Ramírez

Villanueva

Payo

et al. 2019

Preprint

View full text Add to dashboard Cite

Alzheimer’s Disease (AD) is a complex, multifactorial and comorbid condition. The asymptomatic behavior in early stages of the disease is a paramount obstacle to formulate a preclinical and predictive model of AD. Not surprisingly, the AD drug approval rate is one of the lowest in the industry, an exiguous 0.4%. The identification of risk factors, preferably obtained by the subject herself, is sorely needed given that the incidence of Alzheimer’s disease grows exponentially with age [Ferri et al., 2005], [Ganguli and Rodriguez, 2011].During the last 7 years, researchers at Proyecto Vallecas have collected information about the project’s volunteers, aged 70 or more. The Proyecto Vallecas dataset includes information about a wide range of factors including magnetic resonance imaging, genetic, demographic, socioeconomic, cognitive performance, subjective memory complaints, neuropsychiatric disorders, cardiovascular, sleep, diet, physical exercise and self assessed quality of life. The subjects in each visit were diagnosed as healthy, mild cognitive impairment (MCI) or dementia.In this study we perform Exploratory Data Analysis to summarize the main characteristics of this unique longitudinal dataset. The objective is to characterize the evolution of the collected features over time and most importantly, how their dynamics are related to cognitive decline. We show that the longitudinal dataset of Proyecto Vallecas, if conveniently exploited, holds promise to identifying either factors promoting healthy aging and risk factors related to cognitive decline.

show abstract

Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link

Cited by 287 publications

References 109 publications

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

Potential biomarkers to detect traumatic brain injury by the profiling of salivary extracellular vesicles

Exploratory Data Analysis in a Six-Year Longitudinal Study in Healthy Brain Aging

Contact Info

Product

Resources

About