Granuloprival cerebellar cortical degeneration in a Yorkshire Terrier and Lagotto Romagnolo dog.

Granuloprival degeneration is an uncommon form of cerebellar cortical degeneration (CCD). A 3-month-old Yorkshire Terrier and a 7-month-old Lagotto Romagnolo dog were presented with a history of progressive cerebellar dysfunction including wide-based stance, cerebellar ataxia, intention tremors, and loss of menace response despite normal vision. Magnetic resonance imaging of the brain identified marked diffuse decrease of the cerebellum size. Euthanasia was performed in both cases because of progression of clinical signs. Histopathological examination identified marked diffuse thinning of the granular cell layer with almost complete loss of the granular cell neurons, providing a definitive diagnosis of granuloprival CCD. Granuloprival CCD should be considered as a differential diagnosis in Yorkshire Terrier and Lagotto Romagnolo dogs with post-natal progressive clinical signs of cerebellar dysfunction.

Microanatomical findings with relevance to trigeminal ganglion enhancement on post-contrast T1-weighted magnetic resonance images in dogs.

Introduction: Trigeminal ganglion contrast enhancement (TGCE) is reported to be a normal and a common finding on magnetic resonance imaging studies of dogs, cats and humans. The intent of the present study was to describe the anatomical characteristics of the trigeminal ganglion, its surrounding structures, and histological features that are relevant to explain or hypothesize on the reason for TGCE on T1-weighted post-contrast MRI studies of the brain in dogs. Methods: Eight dog cadavers were dissected to study the anatomy of the trigeminal ganglion. The presence and anatomy of vessels was studied by dissection and by histological techniques. Two trigeminal ganglia were isolated and stained with hematoxylin-eosin (HE). Two other trigeminal ganglia included in the trigeminal canal and trigeminal cavity were decalcified with formic acid/formalin for 12 weeks and stained with HE to study the related vessels. Additionally, a corrosion cast was obtained from a separate canine specimen. Results: Leptomeninges and a subarachnoid space were identified at the level of the trigeminal nerve roots and the trigeminal ganglion. No subarachnoid space was identified and leptomeninges were no longer present at the level of the three trigeminal nerve branches. Small arterial vessels ran to and supplied the trigeminal ganglion, passing through the dura mater. No venous plexus was visualized at the level of the trigeminal ganglion in the dissections. A complex arterial vascular network was identified within the leptomeningeal covering of the trigeminal ganglion and was best appreciated in the corrosion cast. Histological examination revealed small-to moderate-sized blood vessels located in the epineurium around the ganglion; from there a multitude of arterioles penetrated into the perineurium. Small endoneurial branches and capillaries penetrated the ganglion and the trigeminal nerve branches. Discussion: Limitations to this study include the limited number of canine specimens included and the lack of electron microscopy to further support current hypotheses included in our discussion. In conclusion, this study provides further support to the theory that TGCE in dogs may be due an incomplete blood-nerve barrier or blood-ganglion barrier at the interface between the central nervous system and the peripheral nervous system.

Primary Feline Tauopathy: Clinical, Morphological, Immunohistochemical, and Genetic Studies.

Tauopathies are a group of neurodegenerative diseases characterized by the pathological aggregation of hyperphosphorylated tau in neurons and glia. Primary tauopathies are not uncommon in humans but exceptional in other species. We evaluate the clinical, neuropathological, and genetic alterations related to tau pathology in 16 cats aged from 1 to 21 years with different clinical backgrounds. Interestingly, a 10-year-old female cat presented a six-year progressive history of mental status and gait abnormalities. The imaging study revealed generalized cortical atrophy. Due to the poor prognosis, the cat was euthanatized at the age of ten. Neuropathological lesions were characterized by massive neuronal loss with marked spongiosis and associated moderate reactive gliosis in the parietal cortex, being less severe in other areas of the cerebral cortex, and the loss of Purkinje cells of the cerebellum. Immunohistochemical methods revealed a 4R-tauopathy with granular pre-tangles in neurons and coiled bodies in oligodendrocytes. Deposits were recognized with several phospho-site antibodies (4Rtau, tau5, AT8, PFH, tau-P Thr181, tau-P-Ser 262, tau-P Ser 422) and associated with increased granular expression of active tau kinases (p38-P Thr180/Tyr182 and SAPK/JNK-P Thr138/Thr185). The genetic study revealed well-preserved coding regions of MAPT. No similar alterations related to tau pathology were found in the other 15 cats processed in parallel. To our knowledge, this is the first case reporting a primary 4R-tauopathy with severe cerebral and Purkinje cell degeneration in an adult cat with neurological signs starting at a young age.

Standardization of canine meningioma grading: Validation of new guidelines for reproducible histopathologic criteria.

Canine meningiomas are currently graded using the human grading system. Recently published guidelines have adapted the human grading system for use in dogs. The goal of this study was to validate the new guidelines for canine meningiomas. To evaluate the inter-observer agreement, 5 veterinary surgical pathologists graded 158 canine meningiomas following the human grading system alone or with the new guidelines. The inter-observer agreement for histologic grade and each of the grading criteria (mitotic grade, invasion, spontaneous necrosis, macronucleoli, small cells, hypercellularity, pattern loss and anaplasia) was evaluated using the Fleiss kappa index. The diagnostic accuracy (sensitivity and specificity) was assessed by comparing the diagnoses obtained with the 2 grading systems with a consensus grade (considered the reference classification). The consensus histologic grade was obtained by agreement between 4 experienced veterinary neuropathologists following the guidelines. Compared with the human grading alone, the canine-specific guidelines increased the inter-observer agreement for: histologic grade (κ = 0.52); invasion (κ = 0.67); necrosis (κ = 0.62); small cells (κ = 0.36); pattern loss (κ = 0.49) and anaplasia (κ = 0.55). Mitotic grade agreement remained substantial (κ = 0.63). The guidelines improved the sensitivity in identifying grade 1 (95.6%) and the specificity in identifying grade 2 (96.2%) meningiomas. In conclusion, the new grading guidelines for canine meningiomas are associated with an overall improvement in the inter-observer agreement and higher diagnostic accuracy in diagnosing grade 1 and grade 2 meningiomas.

Lumbar vertebral canal stenosis due to marked bone overgrowth after routine hemilaminectomy in a dog.

BACKGROUND: Bone overgrowth after decompressive surgery for lumbar stenosis resulting in recurrence of neurological signs has not been reported in veterinary literature. However, there are few cases described in human medicine. CASE PRESENTATION: A 13-month-old entire female dog, a crossbreed between a Springer Spaniel and a Border Collie, weighing 24 kg, was referred with a 5-day history of progressive spastic paraplegia, indicative of a T3-L3 myelopathy. Magnetic resonance (MR) imaging revealed a right-sided L2-L3 compressive extradural lesion, compatible with epidural haemorrhage, which was confirmed by histopathology. The lesion was approached via right-sided L2-L3 hemilaminectomy and was successfully removed. One-year postoperatively the dog re-presented with pelvic limb ataxia. MR and computed tomography (CT) images demonstrated excessive vertebral bone formation affecting the right articular processes, ventral aspect of the spinous process of L2-L3, and contiguous vertebral laminae, causing spinal cord compression. Revision surgery was performed, and histopathology revealed normal or reactive osseous tissue with a possible chondroid metaplasia and endochondral ossification, failing to identify a definitive reason for the bone overgrowth. Nine-month postoperatively, imaging studies showed a similar vertebral overgrowth, resulting in minimal spinal cord compression. The patient remained stable with mild proprioceptive ataxia up until the last follow-up 18 months post-revision surgery. CONCLUSION: This is the first report in the veterinary literature of bone overgrowth after lumbar hemilaminectomy which resulted in neurological deficits and required a revision decompressive surgery.

Intracranial Granular Cell Tumours in Three Dogs: Atypical Magnetic Resonance Imaging Features and Immunohistochemical Study.

Intracranial granular cell tumours (GCT) are uncommon neoplasms of uncertain cellular origin that are rarely reported in dogs. This case series describes three aged dogs that presented with neurological signs in which magnetic resonance (MR) imaging revealed plaquelike extra-axial lesions that were hypointense on T2-weighted (T2w) images. The surgical biopsy of the lesions and necropsies were followed by histochemical characterisation with periodic acid-Schiff (PAS) staining and immunohistochemistry with ubiquitin, S-100, and SOX-10 to elucidate the cellular origin. The immunohistochemical study indicated that these intracranial GCTs were not of Schwann cell origin. In conclusion, GCTs should be considered a differential diagnosis of intracranial, extra-axial hypointense brain lesions on T2w MR images.

Metastatic Multifocal Malignant Peripheral Nerve Sheath Tumour in the Cervicothoracic Spinal Cord of a Dog Initially Mimicking Meningomyelitis.

A nine year old cross-breed dog was presented with a two week history of ambulatory tetraparesis and proprioceptive ataxia affecting all four limbs. Meningomyelitis of Unknown Origin (MUO) was presumptively diagnosed based on the magnetic resonance imaging (MRI) findings and cerebrospinal fluid (CSF) analysis. The dog received a tapering dose of glucocorticoids and cyclosporine, showing significant improvement and the stabilization of the clinical signs for seven months. After this period, the dog showed an acute clinical deterioration and a follow-up MRI revealed new multiple lesions affecting different spinal nerve roots along the cervicothoracic spinal cord. Following euthanasia, a final diagnose of multiple malignant peripheral nerve sheath tumors (MPNSTs) was made based on the histopathological examination. MPNSTs can affect the cranial nerves, spinal nerves or the associated nerve roots at any location and can lead to secondary spinal cord compression. The aim of the present case report is to describe the clinical presentation and atypical MRI findings of a dog with histologically confirmed multiple MPNSTs. According to the reviewed literature, this is the first reported case of simultaneous MPNSTs in the cervicothoracic spinal cord of a dog.

Spinocerebellar ataxia in the Bouvier des Ardennes breed is caused by a KCNJ10 missense variant.

BACKGROUND: In Belgian Malinois, a KCNJ10 variant causes progressive spinocerebellar degeneration. HYPOTHESIS/OBJECTIVES: Describe the clinical, diagnostic, pathological and genetic features of spinocerebellar degeneration in the Bouvier des Ardennes breed. ANIMALS: Five affected Bouvier des Ardennes puppies with spinocerebellar ataxia (SCA), 8 healthy related dogs, and 63 healthy unrelated Bouvier des Ardennes. METHODS: Sequential case study. RESULTS: Clinical signs started at 6 weeks of age in 1 puppy with severe signs of cerebellar disease, and at 7 to 10 weeks of age in the 4 remaining puppies with milder signs of spinocerebellar disease. The first puppy displayed severe intention tremors and rapidly progressive generalized hypermetric ataxia, whereas the 4 others developed a milder progressive SCA. Euthanasia after progression to nonambulatory status was performed by 8 weeks of age in the first puppy, and before 11 months of age in the 4 remaining puppies. Histopathology revealed cerebellar spongy degeneration and a focal symmetrical demyelinating myelopathy. All cases were homozygous for KCNJ10 XM_545752.6:c.986T>C(p.(Leu329Pro)), which is pathogenic for SCA with (or without) myokymia, seizures or both (SAMS) and spongy degeneration and cerebellar ataxia (SDCA) 1 in Belgian Malinois dogs. All sampled parents were heterozygous and none of the healthy dogs were homozygous for this recessive variant. This variant has an allele frequency of 15% in the 63 healthy dogs studied. CONCLUSIONS AND CLINICAL IMPORTANCE: Inherited spinocerebellar degeneration also affects the Bouvier des Ardennes breed and is caused by a KCNJ10 variant. It can present with a spectrum of severity grades, ranging from severe cerebellar to milder spinocerebellar signs.

Bona fide atypical scrapie faithfully reproduced for the first time in a rodent model.

Atypical Scrapie, which is not linked to epidemics, is assumed to be an idiopathic spontaneous prion disease in small ruminants. Therefore, its occurrence is unlikely to be controlled through selective breeding or other strategies as it is done for classical scrapie outbreaks. Its spontaneous nature and its sporadic incidence worldwide is reminiscent of the incidence of idiopathic spontaneous prion diseases in humans, which account for more than 85% of the cases in humans. Hence, developing animal models that consistently reproduce this phenomenon of spontaneous PrP misfolding, is of importance to study the pathobiology of idiopathic spontaneous prion disorders. Transgenic mice overexpressing sheep PrPC with I112 polymorphism (TgShI112, 1-2 × PrP levels compared to sheep brain) manifest clinical signs of a spongiform encephalopathy spontaneously as early as 380 days of age. The brains of these animals show the neuropathological hallmarks of prion disease and biochemical analyses of the misfolded prion protein show a ladder-like PrPres pattern with a predominant 7-10 kDa band. Brain homogenates from spontaneously diseased transgenic mice were inoculated in several models to assess their transmissibility and characterize the prion strain generated: TgShI112 (ovine I112 ARQ PrPC), Tg338 (ovine VRQ PrPC), Tg501 (ovine ARQ PrPC), Tg340 (human M129 PrPC), Tg361 (human V129 PrPC), TgVole (bank vole I109 PrPC), bank vole (I109I PrPC), and sheep (AHQ/ARR and AHQ/AHQ churra-tensina breeds). Our analysis of the results of these bioassays concludes that the strain generated in this model is indistinguishable to that causing atypical scrapie (Nor98). Thus, we present the first faithful model for a bona fide, transmissible, ovine, atypical scrapie prion disease.

Clinical and magnetic resonance imaging features, and pathological findings of spinal lymphoma in 27 cats.

This multicentric retrospective study describes the clinical and MRI features and pathological studies of spinal lymphoma in 27 cats. MRI characteristics and their possible correlations with histopathological findings were studied. The most frequent neurological signs were rapidly progressive paraparesis (62.9%) or paraplegia (22.2%). Bimodal age distribution was found with 40.7% of cats aged ≤2.5 years (63.6% of them FeLV positive), and 44.4% of cats aged ≥8 years (16.7% of them FeLV positive). Spinal lymphoma was generally presented on MRI as an ill-defined epidural focal lesion with moderate to severe spinal cord compression, expanding more than one vertebral body. MRI lesions were typically localized in the lumbar vertebral segment (p = 0.01), circumferential to the spinal cord (p = 0.04), hyperintense on T2-weighted sequences (p = 4.3e-06), and isointense on T1-weighted sequences (p = 8.9e-07). The degree and pattern of contrast enhancement were variable. Other morphological patterns included paravertebral masses with extension into the vertebral canal and lesions centered in the spinal nerve roots. Involvement of vertebrae and adjacent spinal soft tissues was present in 74% of cases when present vertebral involvement was characterized by cortical sparing. When follow-up MRI studies (n = 4) were performed after treatment new lesions of similar nature but different localizations and extension were observed. Confirmation of spinal lymphoma was performed by CSF analysis in 4/27 (14.8%) of cases, by FNA in 6/27 (22.2%) of cases, by surgical biopsy in 10/27 (37%) of cases, by FNA and surgical biopsy in 1/27 (3.7%) of cases, by CSF, FNA, surgical biopsy and postmorten examination in 1/27 (3.7%) of cases, and postmorten studies in 5/27 (18.5%) of cases. Antemortem diagnosis was achieved in 22/27 (81.5%) cats. The presence of necrosis in histopathological studies as an unfavorable prognostic indicator of survival was significantly more probable when lesions were not hyperintense on T2-weighted sequences (p = 0.017). Spinal lymphoma in cats is a complex entity with heterogeneous imaging and histopathological appearance. However, certain MRI features may support a tentative diagnosis, which in a group of cases can be confirmed when combined with the CSF findings. For the rest of the cases, tissue sampling assisted by imaging findings remains necessary for definitive diagnosis.

First Case of a Cerebrocortical Ganglioglioma in a Dog.

Gangliogliomas are extremely rare tumors of the nervous system composed of neoplastic glial and neuronal cells. The aim of the present paper is to describe the clinical presentation, magnetic resonance imaging (MRI) findings and histopathological and immunophenotypical characteristics of a cerebral cortex ganglioglioma in a 7-year-old Border Collie. The dog presented an acute onset of tonic-clonic epileptic seizures. MRI revealed a well-defined large intra-axial mass located on the left forebrain, mainly affecting the frontal cortex. Following humane euthanasia, the histopathological examination of the mass revealed a diffuse proliferation of neoplastic glial cells mixed with anomalous neuronal bodies. Immunohistochemical analyses confirmed the presence of two different populations of neoplastic cells. Most neoplastic glial cells were immunoreactive to glial fibrillary acidic protein (GFAP) and the other subset of neoplastic cells were positive to neuronal markers such as PGP 9.5, synaptophysin (SYN) and neuron-specific enolase (NSE), suggestive of neuronal cells. These findings confirmed the diagnosis of a cerebrocortical ganglioglioma. To the authors knowledge, this is the first description of a ganglioglioma of the cerebral cortex in a dog.

Polysulfone tailor-made implant for the surgical correction of a frontoparietal meningoencephalocoele in a cat.

Case summary: A 6-week-old entire female domestic shorthair cat was presented for evaluation of a soft bulge and a palpable skull defect on the forehead, present since adoption a few days earlier. The neurological examination revealed an absent menace response bilaterally and apparent blindness, localising the lesion to the occipital cortex. The main differential diagnoses were meningocoele (MC) and meningoencephalocoele (MEC). Surgical repair was proposed once the cat reached adult size. Meanwhile, the cat developed seizures and was treated with anticonvulsant therapy. At 6 months of age, CT confirmed a frontoparietal MEC with associated porencephaly. Based on a three-dimensional printed skull mould, a polysulfone implant was created. The meninges were dissected from the skin, a durectomy was performed and samples of the protruding brain were obtained. Part of the cerebrospinal fluid was drained until the size of the protruding brain decreased enough to be included below the implant that was anchored on top of the skull with cerclages. Histopathology confirmed the diagnosis of MEC. Three years and 7 months later, the cat had partially recovered vision but continued to seize monthly despite antiepileptic drugs. Relevance and novel information: MC/MEC is a relatively uncommon disease reported in companion animals, and only four cases of surgical management have been described, and did not use a polysulfone tailor-made implant. In human medicine, surgical intervention is the treatment of choice. This case highlights a new implant option for surgical correction of MEC with good long-term result and no complications after 3 years and 7 months.

Standardisation of canine meningioma grading: Inter-observer agreement and recommendations for reproducible histopathologic criteria.

The human grading system is currently applied to canine meningioma, although it has not been validated in dogs. The present study focused on standardising the human grading system applied to canine meningioma. Four veterinary neuropathologists graded 186 canine meningiomas as follows: Grade I tumour, with <4 mitoses/2.37 mm2 ; Grade II tumour, with ≥4 mitoses/2.37 mm2 , brain invasion or at least three of the following criteria: sheeting architecture, hypercellularity, small cells, macronucleoli, necrosis; Grade III tumour, with ≥20 mitoses/2.37 mm2 or anaplasia. Slides with grading disagreement were reviewed to define a consensus diagnosis and to assess reproducible criteria. Concordance between histologic grade and the consensus diagnosis, as well as intra- and inter-observer agreements for each criterion, were statistically analysed. Concordance between histologic grade and consensus diagnosis ranged from 59% to 100%, with lower concordance for Grade I and II tumours. The lowest inter-observer agreement was recorded for macronucleoli, small cells, hypercellularity and sheeting architecture. Tumour invasion and necrosis displayed fair agreement, while moderate agreement was reached for mitotic grade and anaplasia. The following recommendations were issued to improve the reproducibility of canine meningioma grading: (1) Assess mitotic grade in consecutive HPFs within the most mitotically active area; (2) Define invasion as neoplastic protrusions within central nervous tissue without pial lining; (3) Report spontaneous necrosis; (4) Report prominent nucleoli when visible at ×100; (5) Report pattern loss when visible at ×100 in >50% of the tumour; (6) Report necrosis, small cells, hypercellularity and macronucleoli, even when focal; (7) Report anaplasia if multifocal.

Systemic cellular viroimmunotherapy for canine high-grade gliomas.

BACKGROUND: Oncolytic viruses constitute a growing field of interest, both in human and veterinary oncology, given that they are particularly helpful for treating non-surgical tumors and disseminated cancer, such as high-grade gliomas. Companion dogs present malignant gliomas with biological, genetic, phenotypic, immunological, and clinical similarities to human gliomas. These features favor comparative approaches, leading to the treatment of canine oncological patients to achieve translational applications to the human clinic. The systemic administration of oncolytic viruses presents a challenge due to their limitations in effectively targeting tumors and metastases. Therefore, the aim of this study is to evaluate the safety and antitumor activity of a virotherapy used in spontaneous canine tumors. METHODS: Ten dogs with high-grade rostrotentorial gliomas underwent weekly systemic endovenous cellular virotherapy with dCelyvir (canine mesenchymal stem cells infected with the canine oncolytic adenovirus ICOCAV17) for 8 weeks. Efficacy was determined in seven dogs according to the Response Assessment in Veterinary Neuro-Oncology criteria considering clinical status and MRI measurements. Medical history, physical and neurological examinations, and vaccination status were evaluated prior to and during follow-up. Safety was evaluated by physical examinations and hematological and biochemical changes in peripheral blood. Immune populations were analyzed by flow cytometry in peripheral blood and by gene expression and immunohistochemistry in the tumor microenvironment. RESULTS: The treatment was well tolerated and major adverse effects were not observed. Two dogs had partial responses (76% and 86% reduction in tumor size), and 3/7 showed stable disease. ICOCAV17 was detected in peripheral blood in nine dogs, and a correlation between the ICOCAV17 particles and anti-canine adenovirus (CAV) antibodies was observed. ICOCAV17 was detected in 3/9 tumor tissues after necropsies. Regarding tumor-infiltrating lymphocytes, the dogs with disease stabilization and partial response tended to have reduced memory B-cell infiltration and increased monocyte/macrophage lineage cells. CONCLUSIONS: These findings indicate that dCelyvir is safe and presents efficacy in canine rostrotentorial high-grade gliomas. These data are relevant to the ongoing phase Ib regulated human clinical trial that is administering this virotherapy to children, adolescents, and young adults with diffuse pontine glioma. Celyvir should be further explored as a treatment in veterinary and human neuro-oncology.

Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal.

Delivery of adeno-associated viral vectors (AAVs) to cerebrospinal fluid (CSF) has emerged as a promising approach to achieve widespread transduction of the central nervous system (CNS) and peripheral nervous system (PNS), with direct applicability to the treatment of a wide range of neurological diseases, particularly lysosomal storage diseases. Although studies in small animal models have provided proof of concept and experiments in large animals demonstrated feasibility in bigger brains, there is not much information on long-term safety or durability of the effect. Here, we report a 7-year study in healthy beagle dogs after intra-CSF delivery of a single, clinically relevant dose (2 × 1013 vg/dog) of AAV9 vectors carrying the canine sulfamidase, the enzyme deficient in mucopolysaccharidosis type IIIA. Periodic monitoring of CSF and blood, clinical and neurological evaluations, and magnetic resonance and ultrasound imaging of target organs demonstrated no toxicity related to treatment. AAV9-mediated gene transfer resulted in detection of sulfamidase activity in CSF throughout the study. Analysis at tissue level showed widespread sulfamidase expression and activity in the absence of histological findings in any region of encephalon, spinal cord, or dorsal root ganglia. Altogether, these results provide proof of durability of expression and long-term safety for intra-CSF delivery of AAV-based gene transfer vectors encoding therapeutic proteins to the CNS.

Polyphenols and IUGR Pregnancies: Intrauterine Growth Restriction and Hydroxytyrosol Affect the Development and Neurotransmitter Profile of the Hippocampus in a Pig Model.

Intrauterine growth restriction (IUGR) refers to poor growth of a fetus during pregnancy due to deficient maternal nutrition or oxygen supply. Supplementation of a mother's diet with antioxidants, such as hydroxytyrosol (HTX), has been proposed to ameliorate the adverse phenotypes of IUGR. In the present study, sows were treated daily with or without 1.5 mg of HTX per kilogram of feed from day 35 of pregnancy (at 30% of the total gestational period), and fetuses were sampled at day 100 of gestation. Fetuses were classified as normal body weight (NBW) or low body weight (LBW) as a consequence of IUGR, constituting four groups: NBW-Control, NBW-HTX, LBW-Control, and LBW-HTX. The brain was removed, and the hippocampus, amygdala, and prefrontal cortex were rapidly dissected. Neuronal markers were studied by immunohistochemistry, and a decrease in the number of mature neurons in the hippocampal Cornu Ammonis subfield 1 (CA1) and the Dentate Gyrus (DG) regions was observed in LBW fetuses together with a higher number of immature neurons and other alterations in neuronal morphology. Furthermore, IUGR conditions altered the neurotransmitter (NT) profile, since an increase in the serotonin (5-HT) pathway was observed in LBW fetuses. Supplementation with HTX was able to reverse the morphological and neurochemical changes, leading both characteristics to values similar to those of NBW fetuses.

Classical BSE prions emerge from asymptomatic pigs challenged with atypical/Nor98 scrapie.

Pigs are susceptible to infection with the classical bovine spongiform encephalopathy (C-BSE) agent following experimental inoculation, and PrPSc accumulation was detected in porcine tissues after the inoculation of certain scrapie and chronic wasting disease isolates. However, a robust transmission barrier has been described in this species and, although they were exposed to C-BSE agent in many European countries, no cases of natural transmissible spongiform encephalopathies (TSE) infections have been reported in pigs. Transmission of atypical scrapie to bovinized mice resulted in the emergence of C-BSE prions. Here, we conducted a study to determine if pigs are susceptible to atypical scrapie. To this end, 12, 8-9-month-old minipigs were intracerebrally inoculated with two atypical scrapie sources. Animals were euthanized between 22- and 72-months post inoculation without clinical signs of TSE. All pigs tested negative for PrPSc accumulation by enzyme immunoassay, immunohistochemistry, western blotting and bioassay in porcine PrP mice. Surprisingly, in vitro protein misfolding cyclic amplification demonstrated the presence of C-BSE prions in different brain areas from seven pigs inoculated with both atypical scrapie isolates. Our results suggest that pigs exposed to atypical scrapie prions could become a reservoir for C-BSE and corroborate that C-BSE prions emerge during interspecies passage of atypical scrapie.