Spontaneous early-onset neurodegeneration in the brainstem and spinal cord of NSG, NOG, and NXG mice.

The spectrum of background, incidental, and experimentally induced lesions affecting NSG and NOG mice has been the subject of intense investigation. However, comprehensive studies focusing on the spontaneous neuropathological changes of these immunocompromised strains are lacking. This work describes the development of spontaneous early-onset neurodegeneration affecting both juvenile and adult NSG, NOG, and NXG mice. The study cohort consisted of 367 NSG mice of both sexes (including 33 NSG-SGM3), 61 NOG females (including 31 NOG-EXL), and 4 NXG females. These animals were primarily used for preclinical CAR T-cell testing, generation of humanized immune system chimeras, and/or tumor xenograft transplantation. Histopathology of brain and spinal cord and immunohistochemistry (IHC) for AIF-1, GFAP, CD34, and CD45 were performed. Neurodegenerative changes were observed in 57.6% of the examined mice (affected mice age range was 6-36 weeks). The lesions were characterized by foci of vacuolation with neuronal degeneration/death and gliosis distributed throughout the brainstem and spinal cord. IHC confirmed the development of gliosis, overexpression of CD34, and a neuroinflammatory component comprised of CD45-positive monocyte-derived macrophages. Lesions were significantly more frequent and severe in NOG mice. NSG males were considerably more affected than NSG females. Increased lesion frequency and severity in older animals were also identified. These findings suggest that NSG, NOG, and NXG mice are predisposed to the early development of identical neurodegenerative changes. While the cause of these lesions is currently unclear, potential associations with the genetic mutations shared by NSG, NOG, and NXG mice as well as unidentified viral infections are considered.

Clinically Manifesting, Naturally Occurring Fowl Glioma in a Leghorn Chicken in Germany.

Fowl glioma-inducing virus (FGV), a strain of avian leukosis virus (ALV) subgroup A, is the causal agent of fowl glioma characterized by multiple nodular astrocytic growths, gliosis, and lymphocytic encephalitis. Also associated with FGV infection are cases of cerebellar hypoplasia, perineuromas, and nonsuppurative myocarditis. Though fowl glioma has been recognized in several countries, most reports of FGV infection come from Japan. A 9-mo-old brown leghorn from a German farm with nine leghorns was presented to a veterinarian with an impaired general health with torticollis, tremor, and incoordination. Histopathology revealed multifocal nodular astrocytic growths, gliosis, and a lymphoplasmacytic encephalitis. Immunohistochemically, neoplastic astrocytes showed positivity for anti-ALV antibody. FGV was detected in the brain with nested reverse transcription-polymerase chain reaction (RT-PCR) and subsequent sequencing of PCR product. The remaining eight birds were screened for the presence of ALV with real-time RT-PCR. Four leghorns tested positive for exogenous ALV in nested RT-PCR with an identical nucleotide sequence as the leghorn with neurological symptoms. To the authors' knowledge this is the first report of a natural FGV infection in a brown leghorn in Germany with clinical manifestation.

Glioma aviar de manifestación clínica y natural en un pollo Leghorn en Alemania. El virus inductor del glioma del pollo (FGV), una cepa del subgrupo A del virus de la leucosis aviar (ALV), es el agente causal del glioma del pollo caracterizado por crecimientos astrocíticos nodulares múltiples, gliosis y encefalitis linfocítica. También se asocian con la infección por este virus, casos de hipoplasia cerebelar, perineuromas y miocarditis no supurativa. Aunque el glioma aviar se ha reconocido en varios países, la mayoría de los informes de infección por el virus inductor del glioma del pollo provienen de Japón. Un pollo Leghorn marrón de nueve meses de edad proveniente de una granja alemana con nueve aves Leghorns fue remitido a una clínica veterinaria con problemas de salud en general, tortícolis, temblores y falta de coordinación. La histopatología reveló crecimientos astrocíticos nodulares multifocales, gliosis y encefalitis linfoplasmocítica. Inmunohistoquímicamente, los astrocitos neoplásicos mostraron reacción positiva para anticuerpos contra el virus de la leucosis aviar. El virus inductor del glioma del pollo se detectó en el cerebro mediante transcripción reversa y reacción en cadena de la polimerasa anidada (RT-PCR) y con secuenciación posterior del producto de PCR. Las ocho aves restantes se examinaron para detectar la presencia del virus de la leucosis aviar mediante RT-PCR en tiempo real. Cuatro aves Leghorn dieron positivo para virus exógenos de leucosis mediante RT-PCR anidada y con una secuencia de nucleótidos idéntica a la del ave Leghorn con síntomas neurológicos. De acuerdo con el conocimiento de los autores, este es el primer informe de una infección natural por el virus inductor del glioma del pollo en un ave Leghorn marrón en Alemania que presentaba manifestaciones clínicas.

A case of feline temporal lobe epilepsy with hippocampal sclerosis and dentate gyrus malformation.

A two-months-old, male, mixed breed cat presented with epileptic seizures. The cat was diagnosed with drug-resistant epilepsy, and died at 3-years of age. No gross lesion was found at necropsy. Histopathologically, the dentate gyrus granule cell layer of the hippocampus was irregularly arranged. Granule cells were dispersed and ectopic cells were sporadically observed in the molecular layer. The granule cells had an enlarged cytoplasm and swollen nucleus. Immunohistochemistry for NeuN and GFAP confirmed severe neuronal loss and mild gliosis in CA1. Binucleation and ischemic change were observed in the remaining pyramidal cells. This report describes a case of feline temporal lobe epilepsy and hippocampal sclerosis associated with dentate gyrus malformation.

Magnetic Resonance Imaging Correlates of White Matter Gliosis and Injury in Preterm Fetal Sheep Exposed to Progressive Systemic Inflammation.

Progressive fetal infection/inflammation is strongly associated with neural injury after preterm birth. We aimed to test the hypotheses that progressively developing fetal inflammation leads to neuroinflammation and impaired white matter development and that the histopathological changes can be detected using high-field diffusion tensor magnetic resonance imaging (MRI). Chronically instrumented preterm fetal sheep at 0.7 of gestation were randomly assigned to receive intravenous saline (control; n = 6) or a progressive infusion of lipopolysaccharide (LPS, 200 ng intravenous over 24 h then doubled every 24 h for 5 days to induce fetal inflammation, n = 7). Sheep were killed 10 days after starting the infusions, for histology and high-field diffusion tensor MRI. Progressive LPS infusion was associated with increased circulating interleukin (IL)-6 concentrations and moderate increases in carotid artery perfusion and the frequency of electroencephalogram (EEG) activity (p < 0.05 vs. control). In the periventricular white matter, fractional anisotropy (FA) was increased, and orientation dispersion index (ODI) was reduced (p < 0.05 vs. control for both). Histologically, in the same brain region, LPS infusion increased microglial activation and astrocyte numbers and reduced the total number of oligodendrocytes with no change in myelination or numbers of immature/mature oligodendrocytes. Numbers of astrocytes in the periventricular white matter were correlated with increased FA and reduced ODI signal intensities. Astrocyte coherence was associated with increased FA. Moderate astrogliosis, but not loss of total oligodendrocytes, after progressive fetal inflammation can be detected with high-field diffusion tensor MRI.

Myelopathy and Reactive Microgliosis and Astrogliosis in Equine Back Pain.

Equine chronic back pain (CBP) has been linked to different pathologic processes, which directly or indirectly involve spinal structures. Thus, making diagnosis and management very challenging with most horses with the condition recommended for early retirement from athletic activity. This study described the spinal cord lesions and the development of reactive microgliosis and astrocytosis in the spinal cords of horse with CBP. Thoracolumbar spinal cord segments from three horses euthanized because of unresolved CBP were dissected and grossly and histopathologically examined. The expression of activated microglia and astrocytes were demonstrated immunohistochemically using polyclonal rabbit anti-Iba-1 and anti-glial fibrillary acidic protein antibodies, respectively. All horses had radiological evidence of varying degrees of kissing spine involving six to nine vertebrae with the majority of the lesions graded between 2 and 5. Grossly, there was myelomalacia with intramedullary hemorrhages. The gray matters of the spinal cords were characterized by hemorrhagic malacic lesions with medullary disintegration. Reactive microgliosis and astrocytosis were evident in the spinal dorsal horns. White matter lesions include axonal swollen and/or loss, satellitosis, and varying degrees of dilation of myelin sheaths with some containing macrophages. In conclusion, the presence of reactive microgliosis and astrogliosis in the spinal dorsal horn indicates that they are possible precipitating factors in the development of equine CBP.

Astrocytic changes with aging and Alzheimer's disease-type pathology in chimpanzees.

Astrocytes are the main homeostatic cell of the central nervous system. In addition, astrocytes mediate an inflammatory response when reactive to injury or disease known as astrogliosis. Astrogliosis is marked by an increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Some degree of astrogliosis is associated with normal aging and degenerative conditions such as Alzheimer's disease (AD) and other dementing illnesses in humans. The recent observation of pathological markers of AD (amyloid plaques and neurofibrillary tangles) in aged chimpanzee brains provided an opportunity to examine the relationships among aging, AD-type pathology, and astrocyte activation in our closest living relatives. Stereologic methods were used to quantify GFAP-immunoreactive astrocyte density and soma volume in layers I, III, and V of the prefrontal and middle temporal cortex, as well as in hippocampal fields CA1 and CA3. We found that the patterns of astrocyte activation in the aged chimpanzee brain are distinct from humans. GFAP expression does not increase with age in chimpanzees, possibly indicative of lower oxidative stress loads. Similar to humans, chimpanzee layer I astrocytes in the prefrontal cortex are susceptible to AD-like changes. Both prefrontal cortex layer I and hippocampal astrocytes exhibit a high degree of astrogliosis that is positively correlated with accumulation of amyloid beta and tau proteins. However, unlike humans, chimpanzees do not display astrogliosis in other cortical layers. These results demonstrate a unique pattern of cortical aging in chimpanzees and suggest that inflammatory processes may differ between humans and chimpanzees in response to pathology.

Pathologic and molecular findings associated with atypical porcine pestivirus infection in newborn piglets.

Atypical porcine pestivirus (APPV) has been associated with congenital tremor (CT) type A-II in newborn piglets. Although the number of APPV-based studies is increasing, the associated pathologic findings in infected piglets are underreported. This study describes the histopathologic features of spontaneous APPV infection in CT-affected piglets and complements a previous report by our group. Four two-day-old piglets with CT were evaluated by histopathology, immunohistochemistry (IHC), and molecular assay. The main histopathologic findings at the brain and spinal cord included neuronal necrosis, gliosis, neuronophagia, satellitosis, demyelination, Wallerian degeneration, and Purkinje cell necrosis. An IHC assay designed to detect the proliferation of glial fibrillary acidic protein (GFAP) in affected areas of the brain and spinal cord revealed that the proliferation of GFAP + cells and fibers was predominant in APPV-infected piglets relative to asymptomatic piglets of the same age group. The RT-nested-PCR assays identified APPV RNA in the cerebrum, cerebellum, and brainstem of all piglets; other viruses known to produce similar manifestations were not detected. These results suggest that the APPV-induced histopathologic findings are predominantly degenerative and necrotic and correlate with our previous findings. Consequently, it is proposed that neuronal necrosis, gliosis, neuronophagia, and satellitosis should be considered as important histologic features of APPV-induced infection in symptomatic CT piglets.

Feline Infectious Peritonitis: Immunohistochemical Features of Ocular Inflammation and the Distribution of Viral Antigens in Structures of the Eye.

Feline infectious peritonitis (FIP) is a serious, widely distributed systemic disease caused by feline coronavirus (FCoV), in which ocular disease is common. However, questions remain about the patterns of ocular inflammation and the distribution of viral antigen in the eyes of cats with FIP. This study characterized the ocular lesions of FIP including the expression of glial fibrillary acidic protein and proliferating cell nuclear antigen by Müller cells in the retina in cases of FIP and to what extent macrophages are involved in ocular inflammation in FIP. Immunohistochemistry for FCoV, CD3, CD79a, glial fibrillary acidic protein, calprotectin, and proliferating cell nuclear antigen was performed on paraffin sections from 15 naturally occurring cases of FIP and from controls. Glial fibrillary acidic protein expression was increased in the retina in cases of FIP. Müller cell proliferation was present within lesions of retinal detachment. Macrophages were present in FIP-associated ocular lesions, but they were the most numerous inflammatory cells only within granulomas (2/15 cats, 13%). In cases of severe inflammation of the ciliary body with damage to blood vessel walls and ciliary epithelium (3/15, 20%), some macrophages expressed FCoV antigens, and immunolabeling for calprotectin on consecutive sections suggested that these FCoV-positive macrophages were likely to be recently derived from blood. In cases of severe and massive inflammation of most ocular structures (4/15, 26%), B cells and plasma cells predominated over T cells and macrophages. These results indicate that gliosis can be present in FIP-affected retinas and suggest that breakdown of the blood-ocular barrier can allow FCoV-bearing macrophages to access the eye.

Glial scar-modulation as therapeutic tool in spinal cord injury in animal models.

PURPOSE: Spinal Cord injury represents, in veterinary medicine, most of the neurological attendances and may result in permanent disability, death or euthanasia. Due to inflammation resulting from trauma, it originates the glial scar, which is a cell interaction complex system. Its function is to preserve the healthy circuits, however, it creates a physical and molecular barrier that prevents cell migration and restricts the neuroregeneration ability. METHODS: This review aims to present innovations in the scene of treatment of spinal cord injury, approaching cell therapy, administration of enzyme, anti-inflammatory, and other active principles capable of modulating the inflammatory response, resulting in glial scar reduction and subsequent functional improvement of animals. RESULTS: Some innovative therapies as cell therapy, administration of enzymes, immunosuppressant or other drugs cause the modulation of inflammatory response proved to be a promising tool for the reduction of gliosis. CONCLUSION: Those tools promise to reduce gliosis and promote locomotor recovery in animals with spinal cord injury.

Glial scar-modulation as therapeutic tool in spinal cord injury in animal models

Abstract Purpose: Spinal Cord injury represents, in veterinary medicine, most of the neurological attendances and may result in permanent disability, death or euthanasia. Due to inflammation resulting from trauma, it originates the glial scar, which is a cell interaction complex system. Its function is to preserve the healthy circuits, however, it creates a physical and molecular barrier that prevents cell migration and restricts the neuroregeneration ability. Methods: This review aims to present innovations in the scene of treatment of spinal cord injury, approaching cell therapy, administration of enzyme, anti-inflammatory, and other active principles capable of modulating the inflammatory response, resulting in glial scar reduction and subsequent functional improvement of animals. Results: Some innovative therapies as cell therapy, administration of enzymes, immunosuppressant or other drugs cause the modulation of inflammatory response proved to be a promising tool for the reduction of gliosis. Conclusion: Those tools promise to reduce gliosis and promote locomotor recovery in animals with spinal cord injury.

Aquaporin 11, a regulator of water efflux at retinal Müller glial cell surface decreases concomitant with immune-mediated gliosis.

BACKGROUND: Müller glial cells are important regulators of physiological function of retina. In a model disease of retinal inflammation and spontaneous recurrent uveitis in horses (ERU), we could show that retinal Müller glial cells significantly change potassium and water channel protein expression during autoimmune pathogenesis. The most significantly changed channel protein in neuroinflammatory ERU was aquaporin 11 (AQP11). Aquaporins (AQP, 13 members) are important regulators of water and small solute transport through membranes. AQP11 is an unorthodox member of this family and was assigned to a third group of AQPs because of its difference in amino acid sequence (conserved sequence is only 11 %) and especially its largely unknown function. METHODS: In order to gain insight into the distribution, localization, and function of AQP11 in the retina, we first developed a novel monoclonal antibody for AQP11 enabling quantification, localization, and functional studies. RESULTS: In the horse retina, AQP11 was exclusively expressed at Müller glial cell membranes. In uveitic condition, AQP11 disappeared from gliotic Müller cells concomitant with glutamine synthase. Since function of AQP11 is still under debate, we assessed the impact of AQP11 channel on cell volume regulation of primary Müller glial cells under different osmotic conditions. We conclude a concomitant role for AQP11 with AQP4 in water efflux from these glial cells, which is disturbed in ERU. This could probably contribute to swelling and subsequent severe complication of retinal edema through impaired intracellular fluid regulation. CONCLUSIONS: Therefore, AQP11 is important for physiological Müller glia function and the expression pattern and function of this water channel seems to have distinct functions in central nervous system. The significant reduction in neuroinflammation points to a crucial role in pathogenesis of autoimmune uveitis.

Atypical nodular astrocytosis in simian immunodeficiency virus-infected rhesus macaques (Macaca mulatta).

BACKGROUND: Simian immunodeficiency virus (SIV), a model for HIV pathogenesis, is associated with neuropathology. METHODS: Five SIV-infected animals were selected following a database search of 1206 SIV-infected animals for nodular or astrocytic lesions. Two of five had neurologic dysfunction, and 3 of 5 were incidental findings. RESULTS: Histologic examination revealed multifocal nodular foci in the gray and white matter formed by interlacing astrocytes with abundant cytoplasm and large, reactive nuclei. Nodules were often enmeshed with small capillaries. Immunohistochemistry revealed variable immunoreactivity for a panel of markers: GFAP (4/5), vimentin (5/5), Glut-1 (1/5), CNPase (0/5), S100 (5/5), Iba1 (0/5), Ki67 (0/5), and p53 (4/4). In situ hybridization failed to detect any SIV RNA (0/5). Immunohistochemistry for simian virus 40, rhesus cytomegalovirus, and rhesus lymphocryptovirus failed to detect any antigen within the lesions. CONCLUSION: The immunoreactivity of p53 in the lesions compared with adjacent tissue suggests a local derangement in astrocyte proliferation and function.

Bilateral hippocampal malformation and concurrent granulomatous meningoencephalitis in a dog with refractory epilepsy.

A 5-year-old dog was referred with a history of anorexia and apathy for 3 weeks and acute status epilepticus. Ten weeks later the animal was humanely destroyed due to refractory epilepsy despite anti-epileptic medical treatment. Microscopical examination of the brain revealed bilateral malformation of the dentate gyrus with abnormal gyration. Cornu ammonis segments comprised of sparse pyramidal cells accompanied by marked gliosis. Additionally, there was severe generalized disseminated granulomatous meningoencephalitis, mainly localized to the white matter of the cerebral hemispheres. This is the first description of bilateral hippocampal malformation in a dog.

Sudden behavior change in a cat.

A 5-year-old, spayed female, domestic short-haired cat had a 10-day history of sudden behavioral changes followed by seizures. Blood parameters were in the reference ranges, and radiographs failed to detect a mass lesion in the brain. Euthanasia was followed by rabies testing, which was negative. Gross lesions were absent. Histologic changes were present only in the brain and consisted of foci of hippocampal pyramidal cell loss, mild gliosis, pallor of the associated neuropil, and neovascularization.

Neuroaxonal dystrophy in Australian Merino lambs.

Neuroaxonal dystrophy (NAD) is a morphological abnormality in man and animals that is characterized by the occurrence of numerous axonal swellings (spheroids) in the nervous system. NAD has been described in Suffolk lambs in the USA, Merino lambs in Australia and several breeds of sheep in New Zealand. This paper describes the clinicopathological changes of only the second occurrence of NAD reported in Merino lambs. There were some features (myelin loss, gliosis and visual impairment) in these Australian cases that have not been reported previously in ovine NAD. Application of immunohistochemical markers of axonal transport suggested that disruption of this transport mechanism contributed to spheroid development.

Gliosis in the amygdala following myocardial infarction in the rat.

We observed gliosis with cell death in the rat amygdala 3 and 14 days after myocardial infarction (MI). Cresyl violet-positive neurons had condensed cytoplasm, and Fluoro-Jade B-positive cells were detected in the amygdala 14 days, not 3 days, after MI. Only a few glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes and ionized calcium-binding adapter molecule 1 (Iba-1)-immunoreactive microglia showed activated form; hypertrophied cytoplasm, and highly ramified and retracted processes of astrocytes and microglia in the amygdala at 3 days after MI, respectively. At 14 days after MI, many astrocytes and most of microglia showed activated forms. These results suggest that MI may induce neuronal death and reactive gliosis in the amygdala.

Lesion profiles and gliosis in the brainstem of 135 Swiss cows with bovine spongiform encephalopathy (BSE).

Lesion profiles are considered to be an important tool for the comparison of the various animal and human spongiform encephalopathies and to obtain information upon prion strain variations. Histological and immunohistochemical reactions (PrPsc, GFAP) in 13 brain areas at 4 levels in the brainstem from 135 BSE-positive and 45 BSE-negative cases were retrospectively evaluated. In this retrospective study a lesion profile based on histological features was worked out on the basis of BSE cases originating from Switzerland over a period of ten years. They were confirmed post mortem by histology and immunohistology. Our findings were reviewed in comparison with lesion profiles published in England. No striking differences comparing type and quality of lesions in the relevant areas between the Swiss and the English cases were evident. Moreover, the lesion profiles and the character of the lesions did not differ between animals born before or after the offal feeding ban, which supports the hypothesis that the Swiss epidemic is sustained by the same single, stable strain of the BSE agent, which is probably the same as in the English epidemic. There was a good correlation between PrPsc accumulation and spongiform changes, in particular in those areas which were morphologically most affected. Astrocytosis in BSE was quantified. A significant rise in GFAP-positive cells could be shown comparing the brain stem nuclei of BSE affected with BSE-unaffected cattle, despite considerable variation between the cases and between the nuclei. The observed astrocytosis did correlate with vacuolation of the neuropil and of perikarya as well as with PrPsc accumulation.

Spinal cord effects from lumbar myelographic injection technique in the dog.

To characterize spinal cord effects of needle placement using lumbar puncture myelography technique, lumbar puncture was performed in 5 dogs and computed tomography images of the spinal column were acquired in the transverse plane at the level of the puncture site after contrast injection and both before and after needle removal. The spinal cords were punctured during needle placement and parenchymal contrast enhancement was present in 4 of 5 dogs. Although no dogs exhibited overt neurological abnormalities following computed tomographic imaging, hemorrhage, gliosis and axonal degeneration were confirmed microscopically in all subjects. These results suggest that spinal cord morbidity is induced when lumbar myelography is performed using currently accepted technique.

[Retrospective analysis of cases with a diagnosis of cerebrocortical necrosis and its relation with type 5 bovine herpesvirus]. / Análisis retrospectivo de casos con diagnóstico de necrosis cerebrocortical y su relación con herpesvirus bovino tipo 5.

In order to demonstrate the association of bovine herpesvirus type 5 (BHV-5) and cerebrocortical necrosis (CCN), 89 such cases were examined in cattle from three regions of Buenos Aires Province, Argentina, registered between 1970-1999. Hematoxylin-eosin staining and BHV-5 in situ hybridization were performed on paraffin-embedded neural tissues. The severity of microscopic lesions was scored according to a 0-3 scale. Morbidity, mortality and lethality rates between groups depending on age and regions were determined. The highest prevalence of CCN was detected between 1979 and 1984, particularly during the spring. Differences in morbidity and mortality rates between groups of age and regions were not detected (P > 0.05). Amaurosis (48%), ptyalism (42%), circling (40%), ataxia (36%) and bruxism (37%) were frequently observed. Lesions were predominantly found in anterior and posterior cortex (90.6%) and diencephalon (36.5%). Meningitis and perivascular cuffing (94.4%) and focal (78%) or diffuse (73%) gliosis were predominant in cerebrum. Focal necrosis was observed in 66.6% of cases. BHV-5 was isolated from 9/19 cases since 1992 and BHV-5 DNA was detected by in situ hybridization in 3/9 cases. No virus was identified in brain tissues with severe lesions. These findings indicate the association of BHV-5 in neurological disease previously reported as CCN.

A canine case of gliosis with cyst formation in the posterior fossa.

A 5-month-old male Great Pyrenees with symptoms of convulsions, circling, and a head tilt was referred to the Animal Medical Center of Nihon University. On a magnetic resonance image (MRI), a cyst in the posterior fossa was noted and a part of the cyst enhanced by gadoteridol. Based on MRI and clinical findings, the patient was tentatively diagnosed with a cyst formation tumor, and an operation to open the cyst and remove the part enhanced by contrast was performed. Postoperatively, the clinical course was good. Pathologically, the removed tissue was diagnosed as a gliosis with cyst formation.