The effect of an acute systemic inflammatory insult on the chronic effects of a single mild traumatic brain injury

Collins-Praino, Lyndsey E.; Arulsamy, Alina; Katharesan, Viythia; Corrigan, Frances

doi:10.1016/j.bbr.2017.08.035

Cited by 38 publications

(24 citation statements)

References 72 publications

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“…Subsequent studies confirmed that LPS at 30 DPI exaggerated memory recall deficits in TBI mice as well ( 208 ). Another group has since reported that LPS 5 DPI causes an exaggerated inflammatory response in TBI rats ( via impact acceleration) which is associated with depressive-like behavior and cognitive impairments 3 months post-injury ( 215 ). These results emphasize the chronic nature of the inflammatory response to TBI and confirm that subsequent post-injury immune challenges influence outcome and elicit exaggerated behavioral deficits.…”

Section: Post-injury Peripheral Immune Challenge Worsens Recovery Folmentioning

confidence: 99%

The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease

2018

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The post-injury inflammatory response is a key mediator in long-term recovery from traumatic brain injury (TBI). Moreover, the immune response to TBI, mediated by microglia and macrophages, is influenced by existing brain pathology and by secondary immune challenges. For example, recent evidence shows that the presence of beta-amyloid and phosphorylated tau protein, two hallmark features of AD that increase during normal aging, substantially alter the macrophage response to TBI. Additional data demonstrate that post-injury microglia are “primed” and become hyper-reactive following a subsequent acute immune challenge thereby worsening recovery. These alterations may increase the incidence of neuropsychiatric complications after TBI and may also increase the frequency of neurodegenerative pathology. Therefore, the purpose of this review is to summarize experimental studies examining the relationship between TBI and development of AD-like pathology with an emphasis on the acute and chronic microglial and macrophage response following injury. Furthermore, studies will be highlighted that examine the degree to which beta-amyloid and tau accumulation as well as pre- and post-injury immune stressors influence outcome after TBI. Collectively, the studies described in this review suggest that the brain’s immune response to injury is a key mediator in recovery, and if compromised by previous, coincident, or subsequent immune stressors, post-injury pathology and behavioral recovery will be altered.

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Section: Post-injury Peripheral Immune Challenge Worsens Recovery Folmentioning

confidence: 99%

The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease

2018

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“…Furthermore, a positron emission tomography (PET) study on American football players has shown microglia activation many years after the last mTBI [31], and chronic microglia activation is associated with the development of CTE [32]. Studies using rodent models have yielded data on the relationship between inflammation and behavioural deficits after mild TBI [29,[33][34][35][36][37]. However, relatively little is known about the role of inflammation in the pathophysiology of sequelae following mild TBI in humans, as compared to moderatesevere TBI [29].…”

Section: Inflammationmentioning

confidence: 99%

An integrated perspective linking physiological and psychological consequences of mild traumatic brain injury

et al. 2019

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Despite the often seemingly innocuous nature of a mild traumatic brain injury (mTBI), its consequences can be devastating, comprising debilitating symptoms that interfere with daily functioning. Currently, it is still difficult to pinpoint the exact cause of adverse outcome after mTBI. In fact, extensive research suggests that the underlying etiology is multifactorial. In the acute and early sub-acute stages, the pathophysiology of mTBI is likely to be dominated by complex physiological alterations including cellular injury, inflammation, and the acute stress response, which could lead to neural network dysfunction. In this stage, patients often report symptoms such as fatigue, headache, unstable mood and poor concentration. When time passes, psychological processes, such as coping styles, personality and emotion regulation, become increasingly influential. Disadvantageous, maladaptive, psychological mechanisms likely result in chronic stress which facilitates the development of long-lasting symptoms, possibly via persistent neural network dysfunction. So far, a systemic understanding of the coupling between these physiological and psychological factors that in concert define outcome after mTBI is lacking. The purpose of this narrative review article is to address how psychophysiological interactions may lead to poor outcome after mTBI. In addition, a framework is presented that may serve as a template for future studies on this subject.

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“…AD [57,58] and MS [59] are two such devastating diseases. ALS and PD+ syndromes may also be autoimmune and inflammatory in nature, as may TBI or chronic traumatic encephalopathy (CTE) [21,60,61]. Of course, the second capability of stem cells, to actually regenerate dead or diseased neurons, also needed experimentation.…”

Section: Discussionmentioning

confidence: 99%

Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year phase 1 study of 113 injections in 31 patients

Duma¹,

Kopyov²,

Kopyov³

et al. 2019

Mol Biol Rep

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We have chosen to test the safety of human intracerebroventricular (ICV) brain injections of autologous non-geneticallymodified adipose-derived stromal vascular fraction (ADSVF). In this IRB-approved trial, 24 patients received ICV ADSVF via an implanted reservoir between 5/22/14 and 5/22/17. Seven others were injected via their ventriculo-peritoneal shunts. Ten patients had Alzheimer's disease (AD), 6 had amyotrophic lateral sclerosis (ALS), 6 had progressive multiple sclerosis (MS-P), 6 had Parkinson's "Plus" (PD+), 1 had spinal cord injury, 1 had traumatic brain injury, and 1 had stroke. Median age was 74 (range 41-83). Injections were planned every 2-3 months. Thirty-one patients had 113 injections. Patients received SVF injection volumes of 3.5-20 cc (median:4 cc) containing 4.05 × 10 5 to 6.2 × 10 7 cells/cc, which contained an average of 8% hematopoietic and 7.5% adipose stem cells. Follow-up ranged from 0 to 36 months (median: 9.2 months). MRIs post injection(s) were unchanged, except for one AD patient whose hippocampal volume increased from < 5th percentile to 48th percentile (NeuroQuant ® volumetric MRI). Of the 10 AD patients, 8 were stable or improved in tests of cognition. Two showed improvement in P-tau and ß-amyloid levels. Of the 6 MS-P patients all are stable or improved. Four of 6 ALS patients died of disease progression. Twelve of 111 injections (11%) led to 1-4 days of transient meningismus, and mild temperature elevation, which resolved with acetaminophen and/or dexamethasone. Two (1.8% of injections) required hospitalization for these symptoms. One patient (0.9% of injections) had his reservoir removed and later replaced for presumed infection. In this Phase 1 safety trial, ADSVF was safely injected into the human brain ventricular system in patients with no other treatment options. Secondary endpoints of clinical improvement or stability were particularly promising in the AD and MS-P groups. These results will be submitted for a Phase 2 FDA-approved trial.

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The effect of an acute systemic inflammatory insult on the chronic effects of a single mild traumatic brain injury

Cited by 38 publications

References 72 publications

The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease

The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease

An integrated perspective linking physiological and psychological consequences of mild traumatic brain injury

Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year phase 1 study of 113 injections in 31 patients

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