Genetic vulnerability following traumatic brain injury: the role of apolipoprotein E

Nathoo, Narendra; Chetty, Runjan; Dellen, James R. van; Barnett, Geoffrey

doi:10.1136/mp.56.3.132

Cited by 81 publications

(42 citation statements)

References 69 publications

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“…Animal models suggest a link between the E4 allele and increased mortality, extent of damage and poor repair following brain trauma [82][83][84] . The human E4 allele has been associated with various disorders with prominent cognitive dysfunction, including otherwise normal patients with memory complaints, Alzheimers disease and poor outcomes in stroke and traumatic brain injury 85,86 . Our group evaluated the relationship of the APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard-dose chemotherapy.…”

Section: Genetics Of Neural Repairmentioning

confidence: 99%

Candidate mechanisms for chemotherapy-induced cognitive changes

2007

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The mechanism(s) for chemotherapy-induced cognitive changes are largely unknown; however, several candidate mechanisms have been identified. We suggest that shared genetic risk factors for the development of cancer and cognitive problems, including low-efficiency efflux pumps, deficits in DNA-repair mechanisms and/or a deregulated immune response, coupled with the effect of chemotherapy on these systems, might contribute to cognitive decline in patients after chemotherapy. Furthermore, the genetically modulated reduction of capacity for neural repair and neurotransmitter activity, as well as reduced antioxidant capacity associated with treatmentinduced reduction in oestrogen and testosterone levels, might interact with these mechanisms and/ or have independent effects on cognitive function.Studies associating cognitive changes with cancer chemotherapy have been reported since the mid 1970s 1 ; however, systematic research on the cognitive side effects of chemotherapy did not appear until the 1990s. Over the past 10 years, neuropsychological studies of cancer survivors 2-8 and emerging data from longitudinal studies that include pretreatment neuropsychological assessments 9,10 have found evidence supporting the influence of chemotherapy on cognitive functioning, although negative studies have also been reported [11][12] . The cognitive changes associated with chemotherapy are typically subtle (functioning is reduced but often remains in the normal range), and occur across various domains of cognition, including working memory, executive function and processing speed [13][14][15][16] , but not the retrieval of remote memories (see BOX 1 for a description of the cognitive functions that can be affected by chemotherapy). Furthermore, although acute cognitive changes during chemotherapy are common 14,15 , long-term post-treatment cognitive changes seem to persist in only a subgroup (17-34%) of cancer survivors. Historically, cognitive changes in cancer patients were assumed to be related to psychological factors such as depression or anxiety, or other side effects of cancer treatments like fatigue. However, most of the studies cited above have found evidence for persistent post-chemotherapy cognitive changes after statistically controlling for © 2007 Nature Publishing Group Correspondence to T.A.A. ahlest@mskcc.org. Competing interests statementThe authors declare no competing financial interests. 17,18 . A reduction in the volume of brain structures important for cognitive functioning (such as the frontal cortex) and changes in the integrity of white-matter tracks that connect brain structures have been associated with changes in cognitive functioning, and have been seen using structural magnetic resonance imaging (MRI) on patients after chemotherapy. Recent data from a longitudinal study of breast cancer patients, who were evaluated with structural and functional MRI before treatment and 1 and 12 months after treatment, have suggested a pattern of reduced activation in frontal areas during a working memory...

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Section: Genetics Of Neural Repairmentioning

confidence: 99%

Candidate mechanisms for chemotherapy-induced cognitive changes

2007

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“…However, many of these studies have drawn conclusions based on isolated and/or marginally significant findings in small samples, and some have not employed validated measures. Moreover, a number of other studies (Chamelian et al, 2004;Han et al, 2007;Hiekkanen et al, 2007;Jiang et al, 2008;Millar et al, 2003;Moran et al, 2009;Nathoo et al, 2003;Ponsford et al, 2007;Teasdale et al, 2005) have found no significant relationship between the ApoE e4 allele and TBI as assessed by the GCS, CT, or MRI changes; GOS/GOSE, cognitive, neuropsychological, and psychosocial measures; and emotional functioning over periods ranging from 6 months to an average of 18 years post-TBI. One study by Willemse-van Son and colleagues (2008) found that moderate-to-severe TBI patients possessing the e4 allele had a significantly better outcome on the GOS.…”

Section: Introductionmentioning

confidence: 95%

The Association between Apolipoprotein E and Traumatic Brain Injury Severity and Functional Outcome in a Rehabilitation Sample

Ponsford

McLaren

Schönberger

et al. 2011

Journal of Neurotrauma

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Traumatic brain injury (TBI) can result in significant disability, but outcome is variable. The impact of known predictors accounts for a limited proportion of the variance in outcomes. Apolipoprotein E (ApoE) genotype has been investigated as an additional source of variability in injury severity and outcome, with mixed findings reflecting variable methodology and generally limited sample sizes. This study aimed to examine whether possession of the ApoE ɛ4 allele was associated with greater acute injury severity and poorer long-term outcome in patients referred for rehabilitation following TBI. ApoE genotype was determined for 648 patients with TBI, who were prospectively followed up a mean of 1.9 years post-injury. Hypotheses that ɛ4 carriers would have lower Glasgow Coma Scale (GCS) scores and longer post-traumatic amnesia (PTA) duration were not supported. Prediction of worse Glasgow Outcome Scale-Extended (GOSE) scores for ɛ4 carriers was supported with greater susceptibility seen in females. These results indicate the ApoE ɛ4 allele may be associated with poorer long-term outcome, but not acute injury severity. Possible mechanisms include differential effects of the ɛ4 allele on inflammatory and cellular repair processes, and/or amyloid deposition.

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“…APOE3 is the most common allele. APOE4 has been associated with a high risk for AD in many studies, irrespective of race or geographical location (10,17,28,31,37). Nevertheless, the APOE4 allele alone is neither necessary nor sufficient for the development of AD (13,44).…”

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confidence: 99%

Effect of Apolipoprotein E on the Cerebral Load of Latent Herpes Simplex Virus Type 1 DNA

Burgos

Ramı́rez

Sastre

et al. 2006

J Virol

115

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Herpes simplex virus type 1 (HSV-1) is neurotropic and enters a latent state lasting the lifetime of the host. This pathogen has recently been proposed as a risk factor for Alzheimer's disease (AD) in conjunction with apolipoprotein E4 (ApoE4). In a murine acute infection model, we showed that viral neuroinvasiveness depends directly on the overall ApoE dosage and especially on the presence of isoform ApoE4. If an interaction between ApoE and HSV-1 is involved in AD, it may occur during latency rather than during acute infection. Certainly, ApoE plays an important role in late-onset AD, i.e., at a time in life when the majority of people harbor HSV-1 in their nervous system. In the present work, wild-type, APOE knockout, APOE3, and APOE4 transgenic mice were used to analyze the influence of the ApoE profile on the levels of latent virus DNA. The knockout mice had significantly lower concentrations of the virus in the nervous system than the wild-type mice, while the APOE4 mice had very high levels in the brain compared to the APOE3 animals. ApoE4 seems to facilitate HSV-1 latency in the brain much more so than ApoE3. The APOE dosage correlated directly with the HSV-1 DNA concentration in the brain, strengthening the hypothesis that HSV-1, together with ApoE, might be involved in AD.

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Genetic vulnerability following traumatic brain injury: the role of apolipoprotein E

Cited by 81 publications

References 69 publications

Candidate mechanisms for chemotherapy-induced cognitive changes

Candidate mechanisms for chemotherapy-induced cognitive changes

The Association between Apolipoprotein E and Traumatic Brain Injury Severity and Functional Outcome in a Rehabilitation Sample

Effect of Apolipoprotein E on the Cerebral Load of Latent Herpes Simplex Virus Type 1 DNA

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