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Axonal pathology is increasingly identified by β-amyloid precursor protein (βAPP) immunohistochemistry in the brains of patients who may or may not have a history of trauma. The presence of βAPP-IR+ has been variously interpreted as either that diffuse traumatic axonal injury (TAI) is indeed a universal finding in cases of fatal traumatic brain injury (TBI) or there are other causes of βAPP-IR+ axons which under certain circumstances may be sufficient to mimic TBI and therefore make the medico-legal interpretation of certain cases very difficult. To address some of the uncertainties we have undertaken a detailed analysis of the amount and distribution of βAPP immunohistochemistry in 63 cases of fatal TBI, 17 cases of patients dying after cardiac arrest, 12 cases dying in association with status epilepticus, 3 cases of carbon monoxide (CO) poisoning, 13 cases of hypoglycaemia and in 60 controls. Three patterns of βAPP-IR+ were identified. First, diffuse multi-focal, second, corresponding to the outline of an infarct or haematoma, and thirdly a mixture of the two. The first pattern was seen in cases of the lesser grades of TAI, CO poisoning, and hypoglycaemia, the second pattern in cases in which there was evidence of raised intracranial pressure and the third in cases of severe TAI. It is concluded that the proper interpretation of cases requires the examination of a sufficient number of blocks (n=15), processing using standardised protocols including βAPP immunohistochemistry and in some cases the mapping of any IR+ on anatomical line diagrams. βAPP carried out on a small number of randomly taken blocks is likely to lead to misinterpretation of the clinico-pathological correlations and possibly to a miscarriage of justice. [Copyright &y& Elsevier]

Although mild traumatic brain injury is associated with behavioral dysfunction and histopathological alterations, few studies have assessed the temporal pattern of regional apoptosis following mild brain injury. Anesthetized rats were subjected to mild lateral fluid-percussion brain injury (1.1–1.3 atm), and brains were evaluated for the presence of in situ DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling, TUNEL) and morphologic characteristics of apoptotic cell death (nuclear and cytoplasmic condensation, presence of apoptotic bodies). Significant numbers of apoptotic TUNEL(+) cells were observed in the injured parietal cortex and underlying white matter up to 72 h post-injury (P<0.05 compared to sham-injured-injured), with maximal numbers present at 24 h. Apoptosis was confirmed by the presence of 180–200 bp nuclear DNA fragments in tissue homogenates. The appearance of apoptotic TUNEL(+) cells in the injured cortex was preceded by a marked decrease in immunoreactivity for the anti-cell death protein, Bcl-2, as early as 2 h post-injury. This decrease in cellular Bcl-2 staining was not accompanied by a concomitant loss of staining for the pro-cell death Bax protein, suggesting that post-traumatic neuronal death in the cortex may be dependent on altered cellular ratios of Bcl-2:Bax. In the hippocampus, no significant increase in apoptotic TUNEL(+) cells was observed compared to sham-injured-injured animals. However, selective neuronal loss was evident in the CA3 region at 24 h post-injury, that was preceded by an overt loss of neuronal Bcl-2 immunoreactivity at 6 h. No changes in either cellular Bcl-2 or Bax expression were observed in the thalamus or white matter at any time post-injury.Taken together from these data, we suggest that apoptosis contributes to cell death in both gray and white matter, and that decreases in cellular Bcl-2 may, in part, be associated with both apoptotic and non-apoptotic cell death following mild brain trauma. [Copyright &y& Elsevier]

Abstract: Approximately 4000 human beings experience a traumatic brain injury each day in the United States ranging in severity from mild to fatal. Improvements in initial management, surgical treatment, and neurointensive care have resulted in a better prognosis for traumatic brain injury patients but, to date, there is no available pharmaceutical treatment with proven efficacy, and prevention is the major protective strategy. Many patients are left with disabling changes in cognition, motor function, and personality. Over the past two decades, a number of experimental laboratories have attempted to develop novel and innovative ways to replicate, in animal models, the different aspects of this heterogenous clinical paradigm to better understand and treat patients after traumatic brain injury. Although several clinically-relevant but different experimental models have been developed to reproduce specific characteristics of human traumatic brain injury, its heterogeneity does not allow one single model to reproduce the entire spectrum of events that may occur. The use of these models has resulted in an increased understanding of the pathophysiology of traumatic brain injury, including changes in molecular and cellular pathways and neurobehavioral outcomes. This review provides an up-to-date and critical analysis of the existing models of traumatic brain injury with a view toward guiding and improving future research endeavors. [Copyright &y& Elsevier]

Abstract: The practicing Forensic Pathologist is likely to encounter case material in which either the cause of death or a major contribution to the cause of death is underlying damage to or disease of the central nervous system. While it is good practice in many instances to have a working relationship with a Department of Neuropathology, from which advice and practical help can be sought, there may be instances when the Forensic Pathologist needs to proceed on a basis of a working knowledge of Forensic Neuropathology up to and including how to examine the specimen and take tissue blocks for processing and subsequent histological examination. Some of the more common conditions of the central nervous system such as damage consequent to hypoxia-ischaemia, hypoglycemia and epilepsy, the encephalopathies associated with altered sodium concentration, deficiency due to Vitamin B1 and various neurodegenerative diseases that manifest as dementia and include Alzheimer''s disease, cortical Lewy body disease and the prion disorders, are outlined in this article. [Copyright &y& Elsevier]

Abstract: Epidemiological and pathological studies suggest that head injury is a significant risk factor for subsequent neurodegeneration and cognitive decline in later life. The precise mechanisms for the development of post-traumatic neurodegenerative change are unclear but we hypothesize that persistence of inflammatory processes in the brain may play a key role and that some individuals are more susceptible to such changes based on their genetic make-up. In support of this hypothesis we present evidence of persistent elevated microglial activity in long-term survivors of head injury and the suggestion of an association between the extent of this activity and interleukin-1 genotype. [Copyright &y& Elsevier]