Specificity and sensitivity of betaAPP in head injury.

INTRODUCTION: Beta-amyloid precursor protein (betaAPP) expression has been found in traumatic brain injury, hypoxia, ischemia and infection which affect axonal transport. Although betaAPP is a sensitive marker for detecting axonal damage, it has become non-specific for a particular type of injury. The aim of this study was to identify a difference in the pattern, distribution and intensity of betaAPP expression in head injury compared to hypoxic/ischemic insults. MATERIALS AND METHODS: Thirteen primary head injury and 12 primary hypoxic/ischemic cases were selected. The anterior and posterior parts of corpus callosum, internal capsule (basal ganglia), middle cerebellar peduncles (cerebellum) and pons were examined and stained immunohistochemically for betaAPP antibody. A computerized system of image analysis was used to examine the intensity (strength of staining) and density (area fraction) of betaAPP. RESULTS: Significant differences were observed in the overall intensity and density of betaAPP expression (p < 0.05) and in all 5 brain regions in cases of head injury compared to the hypoxic/ischemic group (p < 0.05). Positive staining for betaAPP was found in all regions in all cases of head injury, however, 4 out of 12 cases of hypoxia/ischemia were positive for betaAPP. One case expressed positivity in all 5 regions, 2 cases exhibited positivity in the pons alone, with only 1 case exhibiting immunoreactivity in the posterior corpus callosum and internal capsule. Differences in the pattern of betaAPP expression identified a predominantly granular pattern with a dirty background seen in hypoxia/ischemia, while fusiform swellings, beaded and thick filaments with clear background were observed in head injury. CONCLUSION: There are differences in the pattern, distribution and intensity of betaAPP in head injury compared to hypoxia/ischemia. These could be due to pathophysiological differences. The results may be helpful in differentiating head injury from hypoxia in medicolegal cases.     

The usefulness of diffusion tensor imaging in detection of diffuse axonal injury in a patient with head trauma

Diffuse axonal injury is the predominant mechanism of injuries in patients with traumatic brain injury. Neither conventional brain computed tomography nor magnetic resonance imaging has shown sufficient sensitivity in the diagnosis of diffuse axonal injury. In the current study, we attempted to demonstrate the usefulness of diffusion tensor imaging in the detection of lesion sites of diffuse axonal injury in a patient with head trauma who had been misdiagnosed as having a stroke. A 44-year-old man fell from a height of about 2 m. Brain magnetic resonance imaging (32 months after onset) showed leukomalactic lesions in the isthmus of the corpus callosum and the left temporal lobe. He presented with mild quadriparesis, intentional tremor of both hands, and trunkal ataxia. From diffusion tensor imaging results of 33 months after traumatic brain injury onset, we found diffuse axonal injury in the right corticospinal tract (centrum semiovale, pons), both fornices (columns and crus), and both inferior cerebellar peduncles (cerebellar portions). We think that diffusion tensor imaging could be a useful tool in the detection of lesion sites of diffuse axonal injury in patients with head trauma.     

弥漫性轴突损伤胆碱能纤维改变的实验研究

目的通过大鼠弥漫性脑损伤模型观察海马及乳头体内的轴突损伤,了解轴突损伤后上述结构中胆碱酯酶纤维的变化,探讨轴突损伤与伤后记忆功能障碍的相关性.方法用Marmarou介绍的落体打击装置致伤动物,对海马和乳头体区脑组织进行胆碱酯酶(AChE)纤维染色.结果该模型较好地模拟了轴突损伤的表现,简便实用.在这个模型中轴突损伤的最常见部位为桥脑基底部和小脑上脚,其次为大脑半球白质、海马和乳头体.海马结构内含有大量胆碱酯酶阳性染色纤维.与对照组相比中,损伤10天海马CA1区,CA3区,齿状回分子层和乳头体内纤维密度明显低于对照组大鼠(P＜0.01).结论大鼠损伤后海马区和乳头体内胆碱酯酶阳性纤维明显减少,这可能是弥漫性轴突损伤病人记忆功能损害的原因.     

Accumulation of beta-amyloid precursor protein in axons correlates with CNS expression of SIV gp41

Axonal damage represented by accumulation of beta-amyloid precursor protein (beta-APP) develops in numerous central nervous system (CNS) diseases including human immunodeficiency virus (HIV) infection. To study the underlying mechanisms of axonal damage associated with HIV CNS infection, the amount of axonal beta-APP immunostaining in the corpus callosum of 24 simian immunodeficiency virus (SIV)-infected macaques and 3 control macaques was measured by computerized image analysis. The amounts of beta-APP accumulation were then compared with time post-inoculation, extent and character of CNS inflammation, and viral load in the CNS measured by the amount of immunohistochemical staining for the viral transmembrane protein gp41. Significant increases over control values were present in 10 of 24 SIV-infected animals. SIV encephalitis was present in 9 of the 10 animals with elevated beta-APP Increases in beta-APP correlated most strongly with levels of SIV gp41 in the brain (p = 0.005), but significant associations with macrophage infiltration and microglial activation (p = 0.04) and infiltration by cytotoxic lymphocytes (p = 0.05) also were identified. These data demonstrate that beta-APP accumulation in the white matter of SIV-infected macaques develops during SIV infection in close correlation with levels of viral replication and may serve as a sensitive marker of neuronal/axonal damage mediated by viral proteins.     

Non-missile head injury: report of a patient surviving for 6 years

A female patient with non-missile head injury is described. She showed slight improvement in her level of consciousness, and survived for 6 1/2 years after injury. At autopsy, the white matter lesions were localized rather than diffuse in distribution. In addition to lesions in the corpus callosum, anterior commissure and dorsolateral quadrant of the rostral brain stem, those in the parasagittal cerebral white matter, and in the hilus of the dentate nucleus and superior cerebellar peduncle were considered to be due to primary axonal injury. A cavity in the frontal white matter was remarkable in that there was no evidence to indicate expansion of the lesion due to haemorrhage. These features suggested that the injurious physical forces had acted parallel to the direction of the axons.     

Magnetisation transfer of normal appearing white matter in primary progressive multiple sclerosis.

Patients with primary progressive multiple sclerosis may develop severe disability despite a paucity of lesions on conventional magnetic resonance imaging, raising the possibility that intrinsic changes in normal appearing white matter (NAWM) contribute to disability. This study has measured magnetisation transfer ratio (MTR), an index of tissue damage, of NAWM in 52 patients with primary progressive multiple sclerosis and 26 healthy controls. Absolute values of MTR were obtained from the genu of the corpus callosum and pons, and mean values were calculated from bilateral regions in the centrum semiovale, frontal white matter, parieto-occipital white matter and posterior limb of the internal capsule. The median MTR was lower in all regions in patients compared to controls. Median values (per cent units) were significantly lower in corpus callosum (39.73 vs 40.63; P=0.01), frontal white matter (39.11 vs 39.59; P=0.01) and centrum semiovale (37.21 vs37.82; P<0.05). This study has demonstrated small but widespread decreases in MTR in NAWM in primary progressive multiple sclerosis supporting the hypothesis that there are intrinsic changes in NAWM which may contribute to disability in this patient group.     

A disorder of axonal development, necrotizing myopathy, cardiomyopathy, and cataracts: a new familial disease

We report severe congenital encephalopathy and profound hypotonia associated with necrotizing myopathy, cardiomyopathy, and cataracts in 3 infants, including 2 sisters. Brain scans suggested agenesis of the corpus callosum. Neuropathological findings consisted of severe atrophy of the corpus callosum (not the usual agenesis with longitudinal callosal bundles), atrophy of the white matter, and absence of pyramidal tracts in the medulla. Multiple axonal swellings were present in the white matter and in Purkinje cells. Except for the corpus subthalamicum, gray matter structures were preserved. These findings are considered to be the expression of a primary disorder of axonal development leading to a reduction in interneuronal synaptic contacts. It is suggested that the anomaly may be due to an extension of the normal phenomenon of axonal elimination, related to a primary defect of the axonal cytoskeleton. The concept of a primary axonal disorder may also apply to other, mostly familial, conditions with progressive atrophy of the cerebral white matter and corpus callosum.     

Characteristics of diffusion-tensor imaging for healthy adult rhesus monkey brains

Diffusion-tensor imaging can be used to observe the microstructure of brain tissue. Fractional ani- sotropy reflects the integrity of white matter fibers. Fractional anisotropy of a young adult brain is low in gray matter, high in white matter, and highest in the splenium of the corpus callosum. Thus, we selected the anterior and posterior limbs of the internal capsule, head of the caudate nucleus, semioval center, thalamus, and corpus callosum （splenium and genu） as regions of interest when using diffusion-tensor imaging to observe fractional anisotropy of major white matter fiber tracts and the deep gray matter of healthy rhesus monkeys aged 4-8 years. Results showed no laterality dif- ferences in fractional anisotropy values. Fractional anisotropy values were low in the head of cau- date nucleus and thalamus in gray matter. Fractional anisotropy values were highest in the sple- nium of corpus callosum in the white matter, followed by genu of the corpus callosum and the pos- terior limb of the internal capsule. Fractional anisotropy values were lowest in the semioval center and posterior limb of internal capsule. These results suggest that fractional anisotropy values in major white matter fibers and the deep gray matter of 4-8-year-old rhesus monkeys are similar to those of healthy young people.     

Differential effects of distinct central nervous system regions on cell migration and axonal extension of neural precursor transplants

Transplantation of neural precursor cells (NPCs) is a promising therapeutic strategy in CNS injury. However, the adult CNS lacks instructive signals present during development and, depending on the region and type of transplant, may be inhibitory for neuron generation and axonal growth. We examined the effects of the white matter in different regions of the adult CNS on the properties of NPC transplants with respect to cell survival, differentiation, migration, and axonal growth. NPCs were prepared from day 13.5 embryonic spinal cord of transgenic rats that express the human placental alkaline phosphatase (AP) reporter. These NPCs were injected unilaterally into the cervical spinal cord white matter and into the corpus callosum of adult rats and were analyzed immunohistochemically 2 weeks later. NPCs survived in both regions and differentiated into astrocytes, oligodendrocytes, and neurons, with no apparent differences in survival or phenotypic composition. However, in the spinal cord white matter, graft‐derived cells, identified as precursors and glial cells, migrated from the injection site rostrally and caudally, whereas, in the corpus callosum, graft‐derived cells did not migrate and remained at the injection site. Importantly, graft‐derived neurons extended axons from the grafting site along the corpus callosum past the midline, entering into the contralateral side of the corpus callosum. These results demonstrate dramatic differences between white matter regions in the spinal cord and brain with respect to cell migration and axonal growth and underscore the importance of considering the effects of the local CNS environment in the design of effective transplantation strategies. © 2012 Wiley Periodicals, Inc.     

White matter alterations following thromboembolic stroke: a β-amyloid precursor protein immunocytochemical study in rats

Thromboembolic stroke in rats leads to a well-described pattern of histopathological and behavioral abnormalities. However, limited data are available in animal models concerning the response of the white matter to embolic events. The purpose of this study was to document patterns of white matter abnormalities using β-amyloid precursor protein (βAPP) immunocytochemistry as a marker of axonal damage. Twelve male Wistar rats underwent photochemically induced right common carotid artery thrombosis (CCAT) or sham procedures. At 3 days after CCAT, rats were perfusion-fixed and sections immunostained for the visualization of βAPP or stained with hematoxylin and eosin for routine histopathological analysis. As previously described, CCAT produced small ipsilateral embolic infarcts and ischemic cell change within gray matter structures including the medial cerebral cortex, striatum, hippocampus and thalamus. In areas of frank infarction, numerous reactive profiles were observed within borderzones of the damaged site. However, βAPP immunocytochemistry also revealed reactive axonal profiles within various white matter tracts including the corpus callosum, external capsule and fimbria of the hippocampus. In many cases, the presence of axonal damage could not be appreciated with routine hematoxylin and eosin staining. These data indicate that CCAT leading to platelet embolization to the brain not only produces embolic infarcts but also produces more subtle white matter abnormalities. Previously undetected white matter damage would be expected to participate in the sensorimotor and cognitive behavioral deficits following embolic stroke. Received: 8 August 1997 / Revised, accepted: 10 November 1997     

Cerebral lymphoma associated with lesions of multiple sclerosis

A 24 year-old man experienced a left retrobulbar neuritis which improved completely after 2 months of non-steroid antiinflammatory therapy. One month after the end of the treatment he developed a Korsakoff-like amnestic syndrome. Three months later he complained of horizontal diplopia. A CT Scan showed a diffuse enhancement of the periventricular areas, corpus callosum and fornix. Diplopia and CT scan abnormalities disappeared after the administration of tetracosactide. Subsequently a progressive worsening of the neurological condition developed, including a 1 1/2 syndrome of Fisher. In C.S.F. proteins ranged from 35 to 66 mg/dl, gammaglobulins from 4 to 5 per cent, cells from 2.2 to 6.8 per mm3 without abnormal cells. Rounded areas of enhancement were observed on CT scan in pons and right occipital lobe. Usual biological tests, abdominal echography and lymphography were normal. Death occurred 15 months after the onset of symptoms. Neuropathological examination showed: 1) a cerebral lymphoma of probable B origin with distinct masses in right occipital lobe and pontine tegmentum and a more diffuse perivascular infiltration on the left side in the amygdaloid nucleus, fourth temporal gyrus, sublenticular area, hypothalamus and in the right internal capsule; 2) multiple small clear-cut foci of demyelination with myelin-axonal dissociation bilaterally in the optic pathways, periventricular regions, corona radiata, cerebral and cerebellar white matter, sublenticular areas, temporal lobes, splenium of the corpus callosum and fornices with secondary atrophy of the mamillary bodies. Both recent and old plaques were observed. Inflammatory perivascular cuffing, when present, consisted of small nontumoral lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Late measures of microstructural alterations in severe neonatal hypoxic–ischemic encephalopathy by MR diffusion tensor imaging

Neonatal hypoxic–ischemic encephalopathy is a major cause of brain damage in infants, and is associated with periventricular white matter injury and chronic neurological dysfunctions. However, the mechanisms of the chronic white matter injury and reorganization are still unclear. In this study, in vivo diffusion tensor imaging (DTI) was employed to evaluate the late changes of white matter microstructural integrity in the rat brains at 10 weeks after severe neonatal hypoxic–ischemic insults at postnatal day 7. In the fractional anisotropy directionality map, qualitative evaluation showed that a dorsoventrally oriented fiber bundle extended from the corpus callosum into the cyst in the anterior brain, whilst the posterior peri-infarct areas had similar fiber orientations as the contralateral internal capsule, optic tract and fimbria of hippocampus. Compared to the contralateral hemisphere, significantly higher fractional anisotropy, axial diffusivity and diffusion trace value were observed quantitatively in the distal end of the extended fiber bundle connecting the anterior and posterior white matters rostrocaudally. A significantly lower fractional anisotropy but higher axial and radial diffusivities and trace were also found in the ipsilateral corpus callosum, proximal external capsule and anterior commissure, while slightly lower fractional anisotropy and axial diffusivity were noticed in the ipsilateral internal capsule and optic nerve. It was suggested that increased fractional anisotropy, axial diffusivity and trace characterize white matter reorganization in chronic neonatal hypoxic–ischemic insults, whereas reduction in fractional anisotropy appears to characterize two types of white matter lesions, with significantly higher axial and radial diffusivities and trace being primary and slightly lower axial diffusivity being secondary. Combined with fractional anisotropy directionality map, in vivo DTI provides important indices to differentiate the chronic effects of severe neonatal hypoxic–ischemic injury and recovery globally, quantitatively and non-invasively.     

White matter tract injury and cognitive impairment in human immunodeficiency virusinfected individuals

Approximately half of those infected with the human immunodeficiency virus (HIV) exhibit cognitive impairment, which has been related to cerebral white matter damage. Despite the effectiveness of antiretroviral treatment, cognitive impairment remains common even in individuals with undetectable viral loads. One explanation for this may be subtherapeutic concentrations of some antiretrovirals in the central nervous system (CNS). We utilized diffusion tensor imaging and a comprehensive neuropsychological evaluation to investigate the relationship of white matter integrity to cognitive impairment and antiretroviral treatment variables. Participants included 39 HIV-infected individuals (49% with acquired immunodeficiency syndrome [AIDS]; mean CD4=529) and 25 seronegative subjects. Diffusion tensor imaging indices were mapped onto a common whole-brain white matter tract skeleton, allowing between-subject voxelwise comparisons. The total HIV-infected group exhibited abnormal white matter in the internal capsule, inferior longitudinal fasciculus, and optic radiation; whereas those with AIDS exhibited more widespread damage, including in the internal capsule and the corpus callosum. Cognitive impairment in the HIV-infected group was related to white matter injury in the internal capsule, corpus callosum, and superior longitudinal fasciculus. White matter injury was not found to be associated with HIV viral load or estimated CNS penetration of antiretrovirals. Diffusion tensor imaging was useful in identifying changes in white matter tracts associated with more advanced HIV infection. Relationships between diffusion alterations in specific white matter tracts and cognitive impairment support the potential utility of diffusion tensor imaging in examining the anatomical underpinnings of HIV-related cognitive impairment. The study also confirms that CNS injury is evident in persons infected with HIV despite effective antiretroviral treatment.     

Ultrastructural evidence of axonal shearing as a result of lateral acceleration of the head in non-human primates

Summary The concept of shearing of axons at the time of non-impact injury to the head was first suggested in the middle of this century. However, no experimental model of diffuse axonal injury (DAI) has provided morphological confirmation of this concept. Evidence from experiments on invertebrate axons suggests that membrane resealing after axonal transection occurs between 5 and 30 min after injury. Thus, ultrastructural evidence in support of axonal shearing will probably only be obtained by examination of very short-term survival animal models. We have examined serial thin sections from the corpus callosum of non-human primates exposed to lateral acceleration of the head under conditions which induce DAI. Tearing or shearing of axons was obtained 20 and 35 min after injury, but not at 60 min. Axonal fragmentation occurred more frequently at the node/paranode but also in the internodal regions of axons. Fragmentation occurred most frequently in small axons. Axonal shearing was associated with dissolution of the cytoskeleton and the occurrence of individual, morphologically abnormal membranous organelles. There was no aggregation of membranous organelles at 20 and 35 min but small groups did occur in some axons at 60 minutes. We suggest that two different mechanisms of injury may be occurring in non-impact injury to the head. The first is shearing of axons and sealing of fragmented axonal membranes within 60 min. A second mechanism occurs in other fibres where pertubation of the axon results in axonal swelling and disconnection at a minimum of 2 h after injury.Supported by NIH grant number NS-08803-21, the Wellcome Trust, the Royal Society, London and the Institute of Neurological Sciences, University of Glasgow. Part of this work was presented at the Ist International Neurotrauma Symposium, Fukishima, Japan and the IVth European Meeting of Neuropathology, Berlin Dedication: The authors would like this work to be a tribute to Professor J. H. Adams upon his retiral. His research into diffuse axonal injury inspired the authors to undertake this study.     

轻度认知功能障碍与脑白质弥散张量成像的相关性研究

目的通过磁共振弥散张量成像研究不同区域脑白质损害与轻度认知功能(MCI)的关系。方法纳入2015年7月至2016年2月我院的住院患者56例为研究对象,其中MCI组34例,认知功能正常组22例。所有研究对象进行一般情况检查,完成神经心理学量表检测。通过头颅磁共振弥散张量成像(DTI)检查对不同脑区白质纤维进行部分各向异性(FA)值测量。结果 MCI组患者与认知功能正常组相比,右侧额叶FA值(0.335±0.068)、左侧颞叶白质FA值(0.391±0.032)及胼胝体膝部FA值(0.658±0.053)降低,差异具有统计学意义(P0.05)。将上述FA值和MMSE、Mo CA量表中各认知域进行典型相关分析,结果显示右侧额叶白质FA值与注意与计算力呈正相关,左侧颞叶白质和胼胝体膝部FA值与记忆力呈正相关(P0.05)。结论 MCI患者注意与计算力的障碍可能与右侧额叶白质损害有关,而左侧颞叶白质及胼胝体膝部白质的损害可能导致早期的记忆障碍。DTI可能成为超早期识别与诊断MCI的新方法。     

Regional networks underlying interhemispheric connectivity: an EEG and DTI study in healthy ageing and amnestic mild cognitive impairment

Interhemispheric coherence derived from electroencephalogram (EEG) recordings is a measure of functional interhemispheric connectivity. Diffusion tensor imaging (DTI) determines the integrity of subcortical fiber tracts. We studied the pattern of subcortical fiber tracts underlying interhemispheric coherence and its alteration in 16 subjects with amnestic mild cognitive impairment (MCI), an at risk syndrome for Alzheimer's disease, and 20 cognitively healthy elderly control subjects using resting state EEG and high resolution DTI at 3 T. We used a multivariate network approach based on principal component analysis to determine effects of coherence on the regional pattern of diffusivity. Temporo-parietal coherence in the alpha band was significantly correlated with diffusivity in predominantly posterior white matter tracts including posterior corpus callosum, parietal, temporal and occipital lobe white matter, thalamus, midbrain, pons, and cerebellum, both in MCI subjects and controls (P < 0.05). In MCI subjects, frontal coherence in the alpha band was significantly correlated with a predominately frontal pattern of diffusivity including fiber tracts of the anterior corpus callosum, frontal lobe white matter, thalamus, pons, and cerebellum (P < 0.05). The study provides a methodology to access specific networks of subcortical fiber tracts subserving the maintenance of interhemispheric resting state coherence in the human brain.     

Tissue tears in the white matter after lateral fluid percussion brain injury in the rat: relevance to human brain injury

A characteristic feature of severe diffuse axonal injury in man is radiological evidence of the “shearing injury triad” represented by lesions, sometimes haemorrhagic, in the corpus callosum, deep white matter and the rostral brain stem. With the exception of studies carried out on the non-human primate, such lesions have not been replicated to date in the multiple and diverse rodent laboratory models of traumatic brain injury. The present report describes tissue tears in the white matter, particularly in the fimbria of Sprague-Dawley rats killed 12, 24, and 48 h and 7 days after lateral fluid percussion brain injury of moderate severity (2.1–2.4 atm). The lesions were most easily seen at 24 h when they appeared as foci of tissue rarefaction in which there were a few polymorphonuclear leucocytes. At the margins of these lesions, large amounts of accumulated amyloid precursor protein (APP) were found in axonal swellings and bulbs. By 1 week post-injury, there was macrophage infiltration with marked astrocytosis and early scar formation. This lesion is considered to be due to severe deformation of white matter and this is the first time that it has been identified reproducibly in a rodent model of head injury under controlled conditions. Received: 25 February 1999 / Revised: 7 June 1999 / Accepted: 22 June 1999