Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias

Plassman, Brenda L.; Havlik, Richard J.; Steffens, David C.; Helms, Michael J.; Newman, Tiffany N.; Drosdick, Deborah; Phillips, Caroline; Gau, B. A.; Welsh‐Bohmer, Kathleen A.; Burke, James R.; Guralnik, Jack M.; Breitner, John C.S.

doi:10.1212/wnl.55.8.1158

Cited by 762 publications

(606 citation statements)

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“…The most common form of AD is sporadic AD (SAD), accounting for more than 90% of all disease cases. While apolipoprotein E e4 allele is the best-documented genetic risk factor for SAD (Corder et al 1993;Saunders et al 1993;Strittmatter et al 1993), traumatic brain injury (TBI) represents the most robust environmental AD risk factor (Schofield et al 1997;Nemetz et al 1999;Plassman et al 2000;Jellinger et al 2001). TBI has been shown to induce an increase in cerebrospinal fluid (CSF) Ab levels (Raby et al 1998), as well as Ab deposition in the human brain (Nicoll et al 1995), and Ab plaques have been found within days after a single incident of TBI in humans (Roberts et al 1991;Graham et al 1995).…”

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confidence: 99%

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

Conte

Uryu

Fujimoto

et al. 2004

Journal of Neurochemistry

142

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Traumatic brain injury is a well-recognized environmental risk factor for developing Alzheimer's disease. Repetitive concussive brain injury (RCBI) exacerbates brain lipid peroxidation, accelerates amyloid (Ab) formation and deposition, as well as cognitive impairments in Tg2576 mice. This study evaluated the effects of vitamin E on these four parameters in Tg2576 mice following RCBI. Eleven-month-old mice were randomized to receive either regular chow or chow-supplemented with vitamin E for 4 weeks, and subjected to RCBI (two injuries, 24 h apart) using a modified controlled cortical impact model of closed head injury. The same dietary regimens were maintained up to 8 weeks post-injury, when the animals were killed for biochemical and immunohistochemical analyses after behavioral evaluation. Vitamin E-treated animals showed a significant increase in brain vitamin E levels and a significant decrease in brain lipid peroxidation levels. After RBCI, compared with the group on regular chow, animals receiving vitamin E did not show the increase in Ab peptides, and had a significant attenuation of learning deficits. This study suggests that the exacerbation of brain oxidative stress following RCBI plays a mechanistic role in accelerating Ab accumulation and behavioral impairments in the Tg2576 mice.

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mentioning

confidence: 99%

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

Conte

Uryu

Fujimoto

et al. 2004

Journal of Neurochemistry

142

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“…However, it is not clear whether these inflammatory "footprints" observed in the late stages of the pathogenesis of PD may merely be a reflection of reactive gliosis after the occurrence of the initial neuronal injuries. On the other hand, increasing evidence has suggested that early-life occurrence of inflammation in the brain, either as a result of exposure to infectious agents or brain injury, plays an important role in later-life development of PD (Ravenholt and Foege, 1982;Factor et al, 1988;Mattock et al, 1988;Williams et al, 1991;Casals et al, 1998;Plassman et al, 2000). The likelihood that inflammation plays a key role in the earlier stages of PD is significantly enhanced by the observation that the midbrain region is particularly rich in microglia (Lawson et al, 1990;Kim et al, 2000), which are readily activated by immunological challenges and neuronal injuries (Kreutzberg, 1996).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Dopaminergic Neurotoxicity of the Pesticide Rotenone and Inflammogen Lipopolysaccharide: Relevance to the Etiology of Parkinson's Disease

et al. 2003

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Parkinson's disease (PD) is characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway resulting in movement disorders. Although its etiology remains unknown, PD may be the final outcome of interactions among multiple factors, including exposure to environmental toxins and the occurrence of inflammation in the brain. In this study, using primary mesencephalic cultures, we observed that nontoxic or minimally toxic concentrations of the pesticide rotenone (0.5 nM) and the inflammogen lipopolysaccharide (LPS) (0.5 ng/ml) synergistically induced dopaminergic neurodegeneration. The synergistic neurotoxicity of rotenone and LPS was observed when the two agents were applied either simultaneously or in tandem. Mechanistically, microglial NADPH oxidase-mediated generation of reactive oxygen species appeared to be a key contributor to the synergistic dopaminergic neurotoxicity. This conclusion was based on the following observations. First, inhibition of NADPH oxidase or scavenging of free radicals afforded significant neuroprotection. Second, rotenone and LPS synergistically stimulated the NADPH oxidase-mediated release of the superoxide free radical. Third and most importantly, rotenone and LPS failed to induce the synergistic neurotoxicity as well as the production of superoxide in cultures from NADPH oxidase-deficient animals. This is the first demonstration that low concentrations of a pesticide and an inflammogen work in synergy to induce a selective degeneration of dopaminergic neurons. Findings from this study may be highly relevant to the elucidation of the multifactorial etiology of PD and the discovery of effective therapeutic agents for the treatment of the disease.

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“…[16][17][18] What is less clear is whether mild TBI can also lead to cognitive impairment, with several studies showing negative results. [19][20][21] More than one million concussions occur annually in this country, with 300,000 resulting from sports-related activities.…”

Section: Discussionmentioning

confidence: 99%

Multiple Episodes of Mild Traumatic Brain Injury Result in Impaired Cognitive Performance in Mice

Creeley¹,

Wozniak²,

Bayly³

et al. 2004

Acad Emergency Med

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Objectives: Results from recent studies on animal models of concussion suggest that multiple, rather than single, episodes of mild traumatic brain injury result in impaired cognitive performance in mice. The objective of the present study was to administer multiple impacts to the heads of mice while directly measuring the force of the impacts to determine how these parameters are related to transient loss of consciousness, cognitive deficits, and potential neuropathologic effects. Methods: Seven-week-old male C57BL/6 mice were randomly assigned to experimental conditions involving three impacts (weight-drop method) to the head to induce mild traumatic brain injury or to sham control procedures. Some impacted (n ¼ 10) and sham control (n ¼ 10) mice were evaluated behaviorally and tested for spatial learning using the Morris water maze (MWM), whereas other impacted (n ¼ 10) and sham control (n ¼ 5) mice were used for histopathologic analysis. Results: The mean (6SD) force of impact was 19 (63.5) N. Impacted mice took longer to regain consciousness compared with sham control mice (p \ 0.0005). Behavioral test results showed that the groups did not differ on activity or sensorimotor tests or during cued trials in the MWM. Impacted mice exhibited impaired spatial learning performance during place trials in the MWM (p \ 0.05). Silver staining revealed a contra-coup type of injury involving ventral brain structures in contact with or in close proximity to the skull. Conclusions: This multiple-impact model, delivered within a specifiable force range, results in transient, reversible loss of consciousness, a contra-coup brain injury, and cognitive impairment. Key words: traumatic brain injury; concussion; memory; cognition; mice. ACADEMIC EMERGENCY MED-ICINE 2004; 11:809-819. It is not clear whether mild traumatic brain injury (TBI) causes demonstrable long-term cognitive impairment in humans. A number of earlier epidemiologic studies suggest that this may be the case, but the use of retrospective designs, lack of appropriate control groups, and an inability to correct for several confounding factors did not allow for a straightforward interpretation of the results. [1][2][3][4] More recently, a number of studies of athletes who have experienced a sports-related concussion suggest that symptomatology and cognitive impairment can last for one week 5 and, in some cases, up to three months. 6 Animal models have been used to study the behavioral and neuropathologic sequelae associated with TBI. [7][8][9][10] In three of these studies, in which slightly different murine models of mild TBI were used, the results suggested that mild single impacts did not produce discernible learning/memory deficits when behavioral testing was conducted more than three days after impact. [8][9][10] In contrast, multiple mild impacts have usually been found to produce significant effects on behavior, but the nature of these changes has been inconsistent across studies. For example, DeFord et al. 10 reported that multiple mild impacts ...

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Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias

Abstract: Moderate and severe head injuries in young men may be associated with increased risk of AD and other dementias in late life. However, the authors cannot exclude the possibility that other unmeasured factors may be influencing this association.

Cited by 762 publications

References 34 publications

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

Synergistic Dopaminergic Neurotoxicity of the Pesticide Rotenone and Inflammogen Lipopolysaccharide: Relevance to the Etiology of Parkinson's Disease

Multiple Episodes of Mild Traumatic Brain Injury Result in Impaired Cognitive Performance in Mice

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