Mild traumatic brain injury increases vulnerability to cerebral ischemia in mice

Weil, Zachary M.; Karelina, Kate; Whitehead, Bailey; Velazquez-Cruz, Ruth; Oliverio, Robin; Pinti, Mark V.; Nwafor, Divine C.; Nicholson, Samuel; Fitzgerald, Julie; Hollander, John M.; Brown, Candice M.; Zhang, Ning; DeVries, A. Courtney

doi:10.1016/j.expneurol.2021.113765

Cited by 14 publications

(5 citation statements)

References 68 publications

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“…6,29 This hypothesis is supported by animal models showing increased vulnerability to cerebral ischemia after TBI via induced vascular dysfunction, which leads to worsened stroke outcomes secondary to impaired reperfusion. 30 Trauma-induced coagulopathy (either hypocoagulable or hypercoagulable states) and blunt cerebrovascular injury (traumatic dissections) have also been hypothesized to contribute to stroke risk. 31,32 However, trauma-induced coagulopathy is most evident within 24 hours of injury and the risk remains for approximately 5 days postinjury and typically resolves within 14 days of injury.…”

Section: Discussionmentioning

confidence: 99%

Traumatic Brain Injury and Long-Term Risk of Stroke Among US Military Veterans

Schneider,

Peltz,

et al. 2023

Stroke

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Background: Traumatic brain injury (TBI) is associated with significant morbidity, but the association of TBI with long-term stroke risk in diverse populations remains less clear. Our objective was to examine the long-term associations of TBI with stroke and to investigate potential differences by age, sex, race and ethnicity, and time since TBI diagnosis. Methods: Retrospective cohort study of US military veterans aged 18+ years receiving healthcare in the Veterans Health Administration system between October 1, 2002 and September 30, 2019. Veterans with TBI were matched 1:1 to veterans without TBI on age, sex, race and ethnicity, and index date, yielding 306 796 veterans with TBI and 306 796 veterans without TBI included in the study. In primary analyses, Fine-Gray proportional hazards models adjusted for sociodemographics and medical/psychiatric comorbidities were used to estimate the association between TBI and stroke risk, accounting for the competing risk of mortality. Results: Participants were a mean age of 50 years, 9% were female, and 25% were of non-White race and ethnicity. Overall, 4.7% of veterans developed a stroke over a median follow-up of 5.2 years. Veterans with TBI had 1.69 times (95% CI, 1.64–1.73) increased risk of any stroke (ischemic or hemorrhagic) compared to veterans without TBI. This increased risk was highest in the first-year post-TBI diagnosis (hazard ratio [HR], 2.16 [95% CI, 2.03–2.29]) but remained elevated for 10+ years. Similar patterns were observed for secondary outcomes, with associations of TBI with hemorrhagic stroke (HR, 3.92 [95% CI, 3.59–4.29]) being stronger than with ischemic stroke (HR, 1.56 [95% CI, 1.52–1.61]). Veterans with both mild (HR, 1.47 [95% CI, 1.43–1.52]) and moderate/severe/penetrating injury (HR, 2.02 [95% CI, 1.96–2.09]) had increased risk of stroke compared to veterans without TBI. Associations of TBI with stroke were stronger among older compared to younger individuals ( P interaction-by-age<0.001) and were weaker among Black veterans compared to other race and ethnicities ( P interaction-by-race<0.001). Conclusions: Veterans with prior TBI are at increased long-term risk for stroke, suggesting they may be an important population to target for primary stroke prevention measures.

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Section: Discussionmentioning

confidence: 99%

Traumatic Brain Injury and Long-Term Risk of Stroke Among US Military Veterans

Schneider,

Peltz,

et al. 2023

Stroke

View full text Add to dashboard Cite

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“…The neuroprotective effect of insulin administration has been reported in vivo ( 56 ) and in animal models ( 50 , 51 , 57 ) by alleviating glutamate excitotoxicity and reducing inflammatory response. Insulin-like growth factor I (another ligand of insulin receptor signaling) ( 58 , 59 ), Thiazolidinedione (TZD, known as insulin sensitizing drug) ( 60 , 61 ), and the incretins GLP-1 and GIP ( 62 , 63 ) were all reported efficacy in preventing apoptosis, oxidative stress, and neuroinflammation and improving neurological deficit after TBI in animal model. A TZD drug, Pioglitazone, was reported to be associated with a lower risk of recurrent ischemic events in a multicenter, double-blind trial involving non-diabetic patients with IR ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

Insulin resistance is associated with an unfavorable outcome among non-diabetic patients with isolated moderate-to-severe traumatic brain injury – A propensity score-matched study

Cao

Wang²,

Gao³

et al. 2022

Front. Neurol.

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BackgroundHyperglycemia is an independent risk factor for the poor prognosis in patients with traumatic brain injury (TBI), and stress-induced impaired insulin function is the major factor of hyperglycemia in non-diabetic patients with TBI. Several types of research suggested that insulin resistance (IR) is related to the poor prognosis of neurocritical ill patients; here we focused on the role of IR in non-diabetic patients after TBI.MethodsWe performed a prospective observational study with the approval of the Ethics Committee of our institute. IR was accessed via the update Homeostasis Model Assessment (HOMA2) of IR, a computer-calculated index by glucose and insulin level. HOMA2 ≥ 1.4 was considered as the threshold of IR according to the previous studies. The glycemic variability (GV) indices were calculated by fingertip blood glucose concentration at an interval of 2 h within 24 h to explore the relationship between IR and GV. The outcome was the 6-month neurological outcome evaluated with the Glasgow outcome scale.ResultsA total of 85 patients with isolated moderate-to-severe TBI (admission GCS ≤ 12) were finally included in our study, 34 (40%) were diagnosed with IR with HOMA2 ≥ 1.4. After propensity score matching (PSM), 22 patients in IR group were matched to 34 patients in non-IR group. Patients with IR suffered increased systemic glycemic variation after isolated moderate-to-severe TBI. IR was a significant factor for the poor prognosis after TBI (OR = 3.25, 95% CI 1.03–10.31, p = 0.041).ConclusionsThe IR estimated by HOMA2 was associated with greater GV and an unfavorable outcome after isolated moderate-to-severe TBI. Ameliorating impaired insulin sensitivity may be a potential therapeutic strategy for the management of TBI patients.

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“…Studies of the chronic effects of repetitive mTBI on vascular morphology in human subjects have demonstrated an expanded perivascular space around large caliber vessels on MRI [ 64 ]. Given the evidence for vascular structural changes, functional alterations and cognitive impairment in rodent models [ 42 , 46 , 78 ] and vascular comorbidities in human subjects with CTE, we sought to investigate the vascular changes in CTE DLF cortex using fluorescent microscopy and three-dimensional (3-D) imaging of blood vessel morphology within optically cleared tissue blocks.…”

Section: Introductionmentioning

confidence: 99%

Three dimensional evaluation of cerebrovascular density and branching in chronic traumatic encephalopathy

Rosen¹,

Kirsch²,

Horowitz³

et al. 2023

acta neuropathol commun

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Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI) and characterized by perivascular accumulations of hyperphosphorylated tau protein (p-tau) at the depths of the cortical sulci. Studies of living athletes exposed to RHI, including concussive and nonconcussive impacts, have shown increased blood–brain barrier permeability, reduced cerebral blood flow, and alterations in vasoreactivity. Blood–brain barrier abnormalities have also been reported in individuals neuropathologically diagnosed with CTE. To further investigate the three-dimensional microvascular changes in individuals diagnosed with CTE and controls, we used SHIELD tissue processing and passive delipidation to optically clear and label blocks of postmortem human dorsolateral frontal cortex. We used fluorescent confocal microscopy to quantitate vascular branch density and fraction volume. We compared the findings in 41 male brain donors, age at death 31–89 years, mean age 64 years, including 12 donors with low CTE (McKee stage I–II), 13 with high CTE (McKee stage III–IV) to 16 age- and sex-matched non-CTE controls (7 with RHI exposure and 9 with no RHI exposure). The density of vessel branches in the gray matter sulcus was significantly greater in CTE cases than in controls. The ratios of sulcus versus gyrus vessel branch density and fraction volume were also greater in CTE than in controls and significantly above one for the CTE group. Hyperphosphorylated tau pathology density correlated with gray matter sulcus fraction volume. These findings point towards increased vascular coverage and branching in the dorsolateral frontal cortex (DLF) sulci in CTE, that correlates with p-tau pathology.

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Mild traumatic brain injury increases vulnerability to cerebral ischemia in mice

Cited by 14 publications

References 68 publications

Traumatic Brain Injury and Long-Term Risk of Stroke Among US Military Veterans

Traumatic Brain Injury and Long-Term Risk of Stroke Among US Military Veterans

Insulin resistance is associated with an unfavorable outcome among non-diabetic patients with isolated moderate-to-severe traumatic brain injury – A propensity score-matched study

Three dimensional evaluation of cerebrovascular density and branching in chronic traumatic encephalopathy

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