Presence of the apolipoprotein E (APOE) 4 allele has been associated with increased incidence and faster progression of neurodegenerative diseases, poorer recovery from neurologic insult, and decreased cognitive function in the well-elderly. The specific association between APOE genotype and recovery from severe traumatic brain injury (TBI) is conflicting with many groups finding the APOE 4 allele to be associated with poorer outcome while others have found no association. The purpose of this study was to investigate the association between APOE 4 allele presence and recovery during the two years after injury from severe TBI in light of other potential covariates, such as age, race, gender, hypotension or hypoxia before hospital admission and severity of injury. APOE genotype was determined for 123 subjects with severe TBI. Glasgow outcome score (GOS) and mortality were collected at 3, 6, 12, and 24 months after injury. Results showed individuals improved over the two year period following injury and those with the 4 allele had a slower recovery rate than those without the APOE 4 allele over the two year period. We did not however find significant differences in GOS at individual time points when controlling for other covariates. Our findings suggest that APOE 4 allele presence influences recovery rate from severe TBI independent of other covariates. The findings of this study are unique in that they address not only the relationship between APOE 4 allele presence and outcome from severe TBI, but also describe differences in trajectory of recovery by APOE 4 allele presence.
"Understanding the variability in response to injury between individuals promises to be key to advances in clinical management. Existing studies have demonstrated detrimental outcome associated with the apolipoprotein E ε4 allele,1 and there is evidence for allele‐specific differences in outcome for other genes, including catechol‐o‐methyltransferase (COMT), dopamine D2 receptor (DRD2), phosphoprotein p53 (TP53), and the calcium channel alpha‐1 subunit (CACNA1).2 The mitochondrial genome has received little attention, despite mitochondria playing a central role in the pathophysiology of TBI. "
[Show abstract][Hide abstract] ABSTRACT: Objective
Traumatic brain injury (TBI) is a multifactorial pathology with great interindividual variability in response to injury and outcome. Mitochondria contain their own DNA (mtDNA) with genomic variants that have different physiological and pathological characteristics, including susceptibility to neurodegeneration. Given the central role of mitochondria in the pathophysiology of neurological injury, we hypothesized that its genomic variants may account for the variability in outcome following TBI.
We undertook an analysis of mitochondrial haplogroups in a large, well‐characterized cohort of 1,094 TBI patients. A proportional odds model including age, brain computed tomography characteristics, injury severity, pupillary reactivity, mitochondrial haplogroups, and APOE was applied to Glasgow Outcome Score (GOS) data.
mtDNA had a significant association with 6‐month GOS (p = 0.008). Haplogroup K was significantly associated with favorable outcome (odds ratio = 1.64, 95% confidence interval = 1.08–2.51, p = 0.02). There was also a significant interaction between mitochondrial genome and age (p = 0.002), with a strong protective effect of both haplogroups T (p = 0.015) and K (p = 0.017) with advancing age. We also found a strong interaction between APOE and mitochondrial haplogroups (p = 0.001), indicating a protective effect of haplogroup K in carriers of the APOE ε4 allele.
These findings reveal an interplay between mitochondrial DNA, pathophysiology of TBI, and aging. Haplogroups K and T, which share a common maternal ancestor, are shown as protective in TBI. The data also suggest that the APOE pathways interact with genetically regulated mitochondrial functions in the response to acute injury, as previously reported in Alzheimer disease. Ann Neurol 2014;75:186–195
Annals of Neurology 02/2014; 75(2). DOI:10.1002/ana.24116 · 9.98 Impact Factor
"In contrast to the original CDE, we do not recommend collection of DNA samples for genomic analysis as a core data element. While there are multiple adult studies that support an effect of the apoE-e4 genotype on outcomes of TBI (Alexander et al., 2007; Crawford et al., 2002; Friedman et al., 1999; Ost et al., 2008), the current literature for these effects in children is quite limited and not sufficiently compelling to allow us to recommend this collection as a core data element (Moran et al., 2009). From an ethical standpoint, there is significant controversy regarding the collection of genetically-identifiable material from children. "
[Show abstract][Hide abstract] ABSTRACT: Biospecimens represent a critically important resource in pediatric brain injury research. Data from these specimens can be used to identify and classify injury, understand the molecular mechanisms underlying different types of brain injury, and ultimately identify therapeutic targets to tailor treatments for individual patient needs. To realize the full potential of biospecimens in pediatric traumatic brain injury (TBI), standardization and adoption of best practice guidelines are needed to ensure the quality and consistency of specimens. Multiple groups, including the National Cancer Institute (NCI), the International Society for Biological and Environmental Repositories (ISBER), and the Organisation for Economic Co-operation and Development (OECD), have previously published best practice guidelines for biospecimen resources. Recommendations have also been provided by the Biospecimens and Biomarkers Workgroup of the interagency TBI Common Data Elements (CDE) initiative. The recommendations from all of these sources, however, focus exclusively on adult biospecimen collection. There are no published pediatric-specific biospecimen collection guidelines. An additional workgroup was formed to specifically address this gap. The aim of the Pediatric TBI CDE Biospecimens and Biomarkers Workgroup was to provide recommendations for best practice guidelines to standardize the quality and accessibility of biospecimens for pediatric brain injury research in general, and for pediatric TBI research in particular. Consensus recommendations were developed by review of previously published adult-specific recommendations, including the recommendations of the original TBI Common Data Elements Biospecimens and Biomarkers Workgroup, and by participation in the interagency workshop "Common Data Elements for TBI Research: Pediatric Considerations," held in Houston, Texas in March of 2010. These recommendations represent expert opinion on this subject. The authors of this article were members of the Biospecimens Workgroup. We hope that with adoption of these best practices, future investigators will be able to obtain biospecimens in a consistent way that meets the needs of pediatric patients, and helps to accelerate acquisition of pediatric-specific biomarker data.
Journal of neurotrauma 11/2011; 29(4):672-7. DOI:10.1089/neu.2011.1861 · 3.71 Impact Factor
"One of the best candidate sources of cognitive variability in DLBCL patients is the apolipoprotein E (ApoE) e4 allele. ApoE e4 is the sole clearly established risk-mediating variable for sporadic AD (Corder et al., 1993) and has also been implicated in moderating cognitive outcomes in an array of conditions and interventions including blunt head trauma (Alexander et al., 2007), subarachnoid hemorrhage (Louko, Vilkki, & Niskakangas, 2006), cardiovascular disease (Vogels et al., 2007), coronary artery bypass graft (Lelis et al., 2006), carotid endarterectomy (Heyer et al., 2005), obstructive sleep apnea (O'Hara et al., 2005), and possibly MS (Burwick et al., 2006). ApoE e4 may increase vulnerability to cognitive dysfunction induced by cancer treatments (Correa et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Cognitive impairment is now recognized as a frequent consequence of treatments for cancers localized outside the central nervous system (CNS). In contrast, little attention has been given to the potentially deleterious cognitive effects from non-CNS cancers themselves. The present case study proposes that cognitive deficits occur in a subset of treatment-naive patients with diffuse large B-cell lymphoma in whom no gross evidence of lymphoma-related CNS involvement is apparent. Evidence is presented from a case study and elaborate putative mechanisms centering on deleterious effects of B-cell-mediated inflammatory cytokine secretion on neurons. Moreover, this case study speculates that genetic variability involving apolipoprotein E or other factors may mediate cognitive variability among these patients.
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