We tested the independent utility of β-amyloid precursor protein (β-APP) immunohistochemical staining as evidence of brain trauma in the deaths of young children. Blinded reviewers retrospectively reviewed immunostained brain tissues from homicidal deaths, age-matched control cases without evidence of trauma, as well as cases of sudden infant death syndrome (SIDS). The reviewers correctly identified five of the seven cases with documented inflicted head trauma. However, one of seven age-matched control cases and one of 10 SIDS/sudden unexplained death in infancy (SUDI) cases demonstrated staining patterns similar to those seen in cases of inflicted trauma. We discuss these cases and the circumstances surrounding them with the intent to explain the difficulties associated with immunohistological interpretation of axonal injury. Although the utility of β-APP is quite powerful if not confounded by global hypoxic-ischemic injury, ultimately, β-APP studies should be only one piece of information in the determination of cause and manner of death.
"A␤PP occurs in neurons of normal adult cortex and in neurons in AD cortex . Of interest, A␤PP has been identified as a reliable axonal injury marker in traumatic brain injury      . Indeed, we found A␤PP appeared in injured axons in AD brain but not in normal axons in control brains presumably because it accumulates at sites of axonal injury with impaired axonal transport of the A␤PP. "
[Show abstract][Hide abstract] ABSTRACT: The goal of this study was to show that myelin and axons in cortical gray matter are damaged in Alzheimer's disease (AD) brain. Superior temporal gyrus gray matter of AD patients (9 male, 14 female) was compared to cognitively normal controls (8 male, 7 female). Myelin basic protein (MBP) and a degraded myelin basic protein complex (dMBP) were quantified by Western blot. Brain sections were immunostained for MBP, dMBP, axonal neurofilament protein (NF), autophagy marker microtubule-associated proteins 1A/B light chain 3B precursor (LC3B), amyloid-β protein precursor (AβPP), and amyloid markers amyloid β1-42 (Aβ1-42) and FSB. Co-immunoprecipitation and mass spectroscopy evaluated interaction of AβPP/Aβ1-42 with MBP/dMBP. Evidence of axonal injury in AD cortex included appearance of AβPP in NF stained axons, and NF at margins of amyloid plaques. Evidence of myelin injury in AD cortex included (1) increased dMBP in AD gray matter compared to control (p < 0.001); (2) dMBP in AD neurons; and (3) increased LC3B that co-localized with MBP. Evidence of interaction of AβPP/Aβ1-42 with myelin or axonal components included (1) greater binding of dMBP with AβPP in AD brain; (2) MBP at the margins of amyloid plaques; (3) dMBP co-localized with Aβ1-42 in the core of amyloid plaques in AD brains; and (4) interactions between Aβ1-42 and MBP/dMBP by co-immunoprecipitation and mass spectrometry. We conclude that damaged axons may be a source of AβPP. dMBP, MBP, and NF associate with amyloid plaques and dMBP associates with AβPP and Aβ1-42. These molecules could be involved in formation of amyloid plaques.
"Careful examination of a field of ␤-APP labeled axons will also illustrate stages in the process reflecting axonal swelling, focal constriction within axonal swelling, axonal fragmentation or axotomy and formation of proximal and distal axonal bulbs (Fig. 6A). Importantly, however, ␤-APP labeling is not diagnostic of or specific to traumatic axonal injury since such labeling has also been reported, for example, after ischemia (Waxman et al., 1992), in multiple sclerosis (Mahad et al., 2009); in herpes simplex encephalitis (Mori et al., 2005), in HIV infection (Raja et al., 1997) and a variety of types of brain injury in adults (Stys, 2005; Coleman, 2005) and pediatric subjects (Johnson et al., 2011). Axonal injury after TBI is frequently associated with vascular damage manifested as petechial hemorrhages in both white matter and the cortical ribbon (Gorrie et al., 2001). "
[Show abstract][Hide abstract] ABSTRACT: In the middle of the last century it had been thought that a good recovery of function and behavior would occur after traumatic brain injury (TBI) in very young human beings. A recent major change in thinking states that early childhood TBI may result in a severe compromise of normal brain growth and development such that TBI, rather, may compromise later normal development resulting in a need for very long term patient care and management. The mechanisms of injury and pathology within the injured brain are reviewed and compared between when injury occurs at or close to the time of birth, in an infant, in a young child, in a child between ages 5 and 10, in young and older adolescents and in young adulthood. Our understanding of pathophysiological responses by cells of the human central nervous system has recently greatly increased but has really only served to illustrate the great complexity of interactions between different types of cell within the growing and developing CNS. The hypothesis is developed that the outcome for a very young patient differs with the relative state of development of injured cells at the locus of injury. And that the potential for either repair, re-instatement of normal cellular and organ function or for continued normal development is much reduced after an early brain insult (EBI) compared with TBI in a slightly older child or young adult patient. The advent of increasingly sophisticated non-invasive imaging technology has allowed assessment of the influence and time course of brain pathology both early and late after TBI. This has generated greater confidence on the part of clinicians in forecasting outcomes for an injured patient. But our increased understanding has still not allowed development of therapeutic strategies that might ameliorate the effect of an injury. It is suggested that an improved integration of major clinical and scientific effort needs to be made to appreciate the import of multiple interactions between cells forming the neurovascular unit in order to improve any potential for post-traumatic recovery after TBI in neonates and young children.
International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 12/2011; 30(3):167-83. DOI:10.1016/j.ijdevneu.2011.12.008 · 2.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The "Shaken Baby" syndrome (SBS) is the subject of intense controversy; the diagnosis has in the past depended on the triad of subdural haemorrhage (SDH), retinal haemorrhage and encephalopathy. While there is no doubt that infants do suffer abusive injury at the hands of their carers and that impact can cause catastrophic intracranial damage, research has repeatedly undermined the hypothesis that shaking per se can cause this triad. The term non-accidental head injury has therefore been widely adopted. This review will focus on the pathology and mechanisms of the three physiologically associated findings which constitute the "triad" and are seen in infants suffering from a wide range of non-traumatic as well as traumatic conditions. "Sub" dural bleeding in fact originates within the deep layers of the dura. The potential sources of SDH include: the bridging veins, small vessels within the dura itself, a granulating haemorrhagic membrane and ruptured intracranial aneurysm. Most neuropathologists do not routinely examine eyes, but the significance of this second arm of the triad in the diagnosis of Shaken Baby syndrome is such that it merits consideration in the context of this review. While retinal haemorrhage can be seen clinically, dural and subarachnoid optic nerve sheath haemorrhage is usually seen exclusively by the pathologist and only rarely described by the neuroradiologist. The term encephalopathy is used loosely in the context of SBS. It may encompass anything from vomiting, irritability, feeding difficulties or floppiness to seizures, apnoea and fulminant brain swelling. The spectrum of brain pathology associated with retinal and subdural bleeding from a variety of causes is described. The most important cerebral pathology is swelling and hypoxic-ischaemic injury. Mechanical shearing injury is rare and contusions, the hallmark of adult traumatic brain damage, are vanishingly rare in infants under 1 year of age. Clefts and haemorrhages in the immediate subcortical white matter have been assumed to be due to trauma but factors specific to this age group offer other explanations. Finally, examples of the most common causes of the triad encountered in clinical diagnostic and forensic practice are briefly annotated.
Hannah R Wardill, Richard M Logan, Joanne M Bowen, Ysabella Z A Van Sebille, Rachel J Gibson
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