Head injury and the risk of AD in the MIRAGE study

Guo, Zhichun; Cupples, L. Adrienne; Kurz, Alexander; Auerbach, Sanford; Volicer, Ladislav; Chui, Helena; Green, R. C.; Sadovnick, A. Dessa; Duara, Ranjan; DeCarli, Charles; Johnson, Kathleen; Go, Rodney C.P.; Growdon, John H.; Haines, Jonathan L.; Kukull, Walter A.; Farrer, Lindsay A.

doi:10.1212/wnl.54.6.1316

Cited by 442 publications

(306 citation statements)

References 44 publications

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“…Loss of PDE4A from spines with advancing age leads to dysregulation of cAMP-Ca 2+ signaling and increased kinase phosphorylation of tau in pyramidal cell circuits. However, it has long been appreciated that head injury is also a significant risk factor for AD (39) as well as CTE (34,40). More recently, psychological trauma has been identified as a risk factor for AD as well (41).…”

Section: Discussionmentioning

confidence: 99%

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex

Carlyle¹,

Nairn²,

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

120

156

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The pattern of neurodegeneration in Alzheimer's disease (AD) is very distinctive: neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau selectively affect pyramidal neurons of the aging association cortex that interconnect extensively through glutamate synapses on dendritic spines. In contrast, primary sensory cortices have few NFTs, even in late-stage disease. Understanding this selective vulnerability, and why advancing age is such a high risk factor for the degenerative process, may help to reveal disease etiology and provide targets for intervention. Our study has revealed age-related increase in cAMP-dependent protein kinase (PKA) phosphorylation of tau at serine 214 (pS214-tau) in monkey dorsolateral prefrontal association cortex (dlPFC), which specifically targets spine synapses and the Ca 2+ -storing spine apparatus. This increase is mirrored by loss of phosphodiesterase 4A from the spine apparatus, consistent with increase in cAMP-Ca 2+ signaling in aging spines. Phosphorylated tau was not detected in primary visual cortex, similar to the pattern observed in AD. We also report electron microscopic evidence of previously unidentified vesicular trafficking of phosphorylated tau in normal association cortex-in axons in young dlPFC vs. in spines in aged dlPFC-consistent with the transneuronal lesion spread reported in genetic rodent models. pS214-Tau was not observed in normal aged mice, suggesting that it arises with the evolutionary expansion of corticocortical connections in primates, crossing the threshold into NFTs and degeneration in humans. Thus, the cAMP-Ca 2+ signaling mechanisms, needed for flexibly modulating network strength in young association cortex, confer vulnerability to degeneration when dysregulated with advancing age.

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Section: Discussionmentioning

confidence: 99%

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex

Carlyle¹,

Nairn²,

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

120

156

View full text Add to dashboard Cite

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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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“…Well over 10 million Americans are expected to have the condition by 2050 as the population continues to age. 9 Many risk factors are well-characterized, including age and family history, 10 -14 whereas many others are under investigation, including education level, 15,16 head trauma, 17,18 high blood pressure, 19 caloric intake, and high cholesterol. 20,21 Regarding genetic factors, rare mutations on genes coding for amyloid precursor protein, presenilin 1, and presenilin 2 have been identified that are deterministic for early-onset AD.…”

mentioning

confidence: 99%

Incorporating ethnicity into genetic risk assessment for Alzheimer disease: the REVEAL study experience

Christensen

Roberts

Royal

et al. 2008

Genetics in Medicine

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Purpose: To describe how investigators in a multisite randomized clinical trial addressed scientific and ethical issues involved in creating risk models based on genetic testing for African American participants. Methods: The following informed our decision whether to stratify risk assessment by ethnicity: evaluation of epidemiological data, appraisal of benefits and risks of incorporating ethnicity into calculations, and feasibility of creating ethnicityspecific risk curves. Once the decision was made, risk curves were created based on data from a large, diverse study of first-degree relatives of patients with Alzheimer disease. Results: Review of epidemiological data suggested notable differences in risk between African Americans and whites and that Apolipoprotein E genotype predicts risk in both groups. Discussions about the benefits and risks of stratified risk assessments reached consensus that estimates based on data from whites should not preclude enrolling African Americans, but population-specific risk curves should be created if feasible. Risk models specific to ethnicity, gender, and Apolipoprotein E genotype were subsequently developed for the randomized clinical trial that oversampled African Researchers are identifying a growing number of genetic markers that are associated with increased or decreased risk for common, complex diseases. Consequently, the development of genetic risk assessment and risk communication strategies are areas of critical importance, especially given that laypersons often have a difficult time in understanding probabilistic information. 1,2 Protocols for disclosing genetic information have been developed and refined for various forms of cancer, 3-6 but similar efforts have been made only recently for other diseases. 7,8 One area of recent focus is Alzheimer disease (AD).AD is the most common form of dementia among the elderly, affecting an estimated five million individuals in the United States. Well over 10 million Americans are expected to have the condition by 2050 as the population continues to age. 9 Many risk factors are well-characterized, including age and family history, 10 -14 whereas many others are under investigation, including education level, 15,16 head trauma, 17,18 high blood pressure, 19 caloric intake, and high cholesterol. 20,21 Regarding genetic factors, rare mutations on genes coding for amyloid precursor protein, presenilin 1, and presenilin 2 have been identified that are deterministic for early-onset AD. 22 Apolipoprotein E (APOE), in contrast, affects susceptibility to AD and has three major forms. APOE ⑀3, the most common allele, is found in over half the US population. The ⑀4 allele is associated with increased risk for AD whereas the ⑀2 allele has a protective effect. 23,24 The ⑀4 allele is neither necessary nor sufficient for AD though, and individuals with the ⑀2 allele still have risk for AD. APOE variants are also associated with other conditions such as hyperlipoproteinemia and atherosclerosis 25 and may play a role in the development of ma...

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Head injury and the risk of AD in the MIRAGE study

Cited by 442 publications

References 44 publications

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex

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

Incorporating ethnicity into genetic risk assessment for Alzheimer disease: the REVEAL study experience

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