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IntroductionTrigeminal 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.MethodsEight 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.ResultsLeptomeninges 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.DiscussionLimitations 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.

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.

Abstract A 12‐year‐old mixed‐breed dog was presented for a follow‐up examination after ablation of an auricular mast cell tumour. An abdominal ultrasound and computed tomography were performed and an irregular, ill‐defined and partially mineralised lesion was observed around the caudal duodenal flexure without evidence of metastasis. The cytologic examination was highly suggestive of a granular cell tumour. Partial surgical ablation with histological and immunohistochemical examination of the lesion confirmed the diagnosis. According to our review of the literature, this is the first report documenting an abdominal granular cell tumour in a dog.

Alzheimer's disease (AD) is one of the leading causes of dementia in late life. Although the cause of AD neurodegenerative changes is not fully understood, extensive evidence suggests that the misfolding, aggregation and cerebral accumulation of amyloid beta (Aβ) and tau proteins are hallmark events. Recent reports have shown that protein misfolding and aggregation can be induced by administration of small quantities of preformed aggregates, following a similar principle by which prion diseases can be transmitted by infection. In the past few years, many of the typical properties that characterize prions as infectious agents were also shown in Aβ aggregates. Interestingly, prion diseases affect not only humans, but also various species of mammals, and it has been demonstrated that infectious prions present in animal tissues, particularly cattle affected by bovine spongiform encephalopathy (BSE), can infect humans. It has been reported that protein deposits resembling Aβ amyloid plaques are present in the brain of several aged non-human mammals, including monkeys, bears, dogs, and cheetahs. In this study, we investigated the presence of Aβ aggregates in the brain of aged cattle, their similarities with the protein deposits observed in AD patients, and their capability to promote AD pathological features when intracerebrally inoculated into transgenic animal models of AD. Our data show that aged cattle can develop AD-like neuropathological abnormalities, including amyloid plaques, as studied histologically. Importantly, cow-derived aggregates accelerate Aβ amyloid deposition in the brain of AD transgenic animals. Surprisingly, the rate of induction produced by administration of the cattle material was substantially higher than induction produced by injection of similar amounts of human AD material. Our findings demonstrate that cows develop seeding-competent Aβ aggregates, similarly as observed in AD patients.

Abstract 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.

Key Clinical Message Gliosarcoma, a rare cerebral neoplasm, has not been linked to hippocampal changes in cats. We report a case of complex partial seizures with orofacial involvement, revealing gliosarcoma concurrent with bilateral hippocampal sclerosis. Abstract A 16‐year‐old neutered female domestic shorthair cat presented with acute inappetence, ataxia, disorientation, and vacant staring. Brain MRI revealed an ill‐defined, round, intra‐axial mass in the right piriform lobe, showing hyperintensity on T2W, T2‐FLAIR, and T2*W, and hypointensity on T1W images. The lesion exhibited mass effect and contrast enhancement in its center. Bilateral hyperintensity on T2‐FLAIR images and contrast enhancement were observed in the hippocampus. Brain histologic and immunohistochemical analysis revealed cerebral gliosarcoma with concurrent hippocampal sclerosis. Feline LGI1‐antibody testing on the serum and/or CSF was not performed due to insufficient biomaterial. Although retrospective testing on brain tissue was considered, it ultimately proved unfeasible, preventing us from ruling out antibody‐associated limbic encephalitis. In conclusion, cerebral gliosarcoma should be included in feline intracranial tumor differentials, warranting brain MRI and feline LGI1‐antibody testing in cats showing complex partial seizures with orofacial involvement. In our case, the prognosis remained poor due to the presence of a high‐grade glioma.

In humans, tenascin-C (TN-C) expression has been detected in more aggressive neoplasms of the central nervous system, such as gliomas and meningiomas. No study has analyzed the immune expression of TN-C in canine meningioma. The current study aimed to investigate the immunohistochemical distribution of TN-C in different grades of canine meningiomas. Twenty-one cases of canine meningioma (12 grade I, 6 grade II, and 3 grade III) were analyzed. All samples were examined by immunohistochemistry with the following antibodies: TN-C, epithelial membrane antigen (EMA), Ki-67, pan-cytokeratin (Pan CK), and vimentin. The histopathological diagnosis of meningioma was reinforced with the positive labeling of vimentin (moderate to strong) and EMA (mild to moderate) in neoplastic cells in most cases, independently of its grade or subtype. The immunoreactivity of TN-C was irregular: mild in grade I, moderate in grade II, and moderate to severe in grade III neoplasms. Usually, immune positivity was observed in the stroma and perivascular space in all subtypes. In addition, the concentric whorls of neoplastic cells were labeled positive in some psammomatous and transitional meningiomas. The reaction to TN-C was more significant in grade II and III tumors. The immunohistochemical findings of the current study suggest that TN-C can act as a stromal marker, mainly in grade II or III meningiomas.

Abstract 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.

Phosphatase and tensin homolog (PTEN) is a critical tumor suppressor gene with a vital role in regulating cell proliferation, migration, and survival. The loss of PTEN function, either by genetic alterations or decreased protein expression, is frequent in human gliomas and has been correlated with tumor progression, grade, therapeutic resistance, and decreased overall survival in patients with glioma. While different genetic mutations in PTEN gene have been occasionally reported in canine gliomas, no alterations in protein expression have been reported. This study investigates the immunohistochemical expression of PTEN in canine gliomas to evaluate possible alterations, as those reported in human gliomas. Immunohistochemical PTEN expression and pattern distribution were analyzed in 37 spontaneous canine gliomas. Among gliomas, 52.6% cases showed high PTEN expression and 48.6% displayed reduced (13.5%) or highly reduced (35.1%) immunopositivity. Most oligodendrogliomas showed high expression (73.7%), while the majority of astrocytomas (69.2%) showed a reduced or highly reduced expression. A reduced PTEN expression was mostly associated with a heterogeneous loss of PTEN immunopositivity. These observations are in line with those reported in human gliomas and provide a rationale for future studies regarding abnormalities in PTEN expression and PI3K/Akt/mTor pathway in canine gliomas, to evaluate its prognostic and therapeutic implications.

Glioma is the most common primary brain tumor in dogs and predominantly affects brachycephalic breeds. Diagnosis relies on CT or MRI imaging, and the proposed treatments include surgical resection, chemotherapy, and radiotherapy depending on the tumor’s location. Canine glioma from domestic dogs could be used as a more powerful model to study radiotherapy for human glioma than the murine model. Indeed, (i) contrary to mice, immunocompetent dogs develop spontaneous glioma, (ii) the canine brain structure is closer to human than mice, and (iii) domestic dogs are exposed to the same environmental factors than humans. Moreover, imaging techniques and radiation therapy used in human medicine can be applied to dogs, facilitating the direct transposition of results. The objective of this study is to fully characterize 5 canine glioma cell lines and to evaluate their intrinsic radiosensitivity. Canine cell lines present numerous analogies between the data obtained during this study on different glioma cell lines in dogs. Cell morphology is identical, such as doubling time, clonality test and karyotype. Immunohistochemical study of surface proteins, directly on cell lines and after stereotaxic injection in mice also reveals close similarity. Radiosensitivity profile of canine glial cells present high profile of radioresistance.

Abstract 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.

Abstract 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.

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.

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.

Abstract 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.

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.

Abstract Background Gliomas in dogs remain poorly understood. Objectives To characterize the clinicopathologic findings, diagnostic imaging features and survival of a large sample of dogs with glioma using the Comparative Brain Tumor Consortium diagnostic classification. Animals Ninety‐one dogs with histopathological diagnosis of glioma. Methods Multicentric retrospective case series. Signalment, clinicopathologic findings, diagnostic imaging characteristics, treatment, and outcome were used. Tumors were reclassified according to the new canine glioma diagnostic scheme. Results No associations were found between clinicopathologic findings or survival and tumor type or grade. However, definitive treatments provided significantly (P = .03) improved median survival time (84 days; 95% confidence interval [CI], 45‐190) compared to palliative treatment (26 days; 95% CI, 11‐54). On magnetic resonance imaging (MRI), oligodendrogliomas were associated with smooth margins and T1‐weighted hypointensity compared to astrocytomas (odds ratio [OR], 42.5; 95% CI, 2.42‐744.97; P = .04; OR, 45.5; 95% CI, 5.78‐333.33; P

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.

Abstract Background Aquaporin-4 (AQP4) is in growing recognition as potential marker for cancer progression, differentiation and therapeutic intervention. No information is available about AQP4 expression in the normal canine brain. The aim of this histopathological study is to confirm the presence of AQP4 by immunohistochemistry technique in a group of non-pathological canine brains and to describe its expression and distribution across the brain. Results Twelve non-pathological canine brains of various ages (ranging from 21 days to 17 years) and breeds were included in the study. Immunohistochemical expression of AQP4 was analyzed using formalin-fixed paraffin-embedded brain tissue sections. The findings were correlated between AQP4 expressing cells and astrocytes using glial fibrillary acidic protein (GFAP). AQP4 expression was more marked in the astrocyte foot processes of subpial, perivascular and periventricular surfaces in all specimens. The majority of the canine brain sections (9/12) presented with an AQP4 predilection for white matter tracts. Interestingly, the two youngest dogs (21 days and 3 months old) were characterized by diffuse AQP4 labelling in both grey and white matter tracts. This result may suggest that brain development and ageing may play a role in the AQP4 distribution throughout the canine brain. Conclusions This is the first study to describe immunohistochemical distribution of AQP4 in normal canine brains. The AQP4 expression and distribution in non-pathological canine brains was comparable to other species. Larger studies are needed to substantiate the influence of breed and ageing on AQP4 expression in the normal canine brain.

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.

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.

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.

Intracranial gliomas are associated with a poor prognosis, and the most appropriate treatment is yet to be defined. The objectives of this retrospective study are to report the time to progression and survival times of a group of dogs with histologically confirmed intracranial gliomas treated with surgical debulking and adjuvant temozolomide chemotherapy. All cases treated in a single referral veterinary hospital from 2014 to 2021 were reviewed. Inclusion criteria comprised a histopathological diagnosis of intracranial glioma, adjunctive chemotherapy, and follow-up until death. Cases were excluded if the owner declined chemotherapy or there was insufficient follow-up information in the clinical records. Fourteen client-owned dogs were included with a median time to progression (MTP) of 156 days (95% CI 133–320 days) and median survival time (MST) of 240 days (95% CI 149–465 days). Temozolomide was the first-line adjuvant chemotherapy but changed to another chemotherapy agent (lomustine, toceranib phosphate, or melphalan) when tumour relapse was either suspected by clinical signs or confirmed by advanced imaging. Of the fourteen dogs, three underwent two surgical resections and one, three surgeries. Survival times (ST) were 241, 428, and 468 days for three dogs treated twice surgically and 780 days for the dog treated surgically three times. Survival times for dogs operated once was 181 days. One case was euthanized after developing aspiration pneumonia, and all other cases after progression of clinical signs due to suspected or confirmed tumour relapse. In conclusion, the results of this study suggest that debulking surgery and adjuvant chemotherapy are well-tolerated options in dogs with intracranial gliomas in which surgery is a possibility and should be considered a potential treatment option. Repeated surgery may be considered for selected cases.

Case summary In this report we describe the occurrence of intracranial meningioma in two adult cats from the same litter. The location of the meningioma varied: one tumour was at the level of the brainstem, and the other was affecting the temporal and piriform lobes. The cat with the brainstem meningioma was treated with radiotherapy and the littermate had a rostrotentorial craniectomy for tumour removal. Both cats had a histopathological diagnosis of grade I meningioma of a predominantly fibrous subtype. Relevance and novel information Cases of familial meningioma in cats have not previously been described in the veterinary literature. However, familial meningioma is well described in humans and it is possible that cases are underestimated in animals. We discuss the possible genetic background and other causes, as well as challenges we may face in veterinary medicine in identifying these associations.

La pandemia de COVID19 ha puesto en evidencia la transversalidad profesional en el ámbito de la salud, cuando médicos, veterinarios, epidemiólogos, inmunólogos, juristas, sociólogos, ambientalistas, políticos, etc. hemos tenido que colaborar para encontrar y aplicar soluciones al problema. A lo largo de la historia los veterinarios hemos aprendido cómo la salud y la enfermedad de los animales repercutían directa o indirectamente en la población humana. Las zoonosis, enfermedades transmisibles de los animales a los humanos, son un buen ejemplo de ello. Utilizando la historia haremos un recorrido de algunos de estos procesos, para ver cómo los veterinarios han actuado, implicándose y colaborando con otros profesionales, para llegar al concepto actual de una única salud ('One Health'). La necesidad de la cooperación multidisciplinar para poder enfrentarnos de forma efectiva a pandemias como la que vivimos en la actualidad resulta fundamental.

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.

Intracranial neoplasia is frequently encountered in dogs. After a presumptive diagnosis of intracranial neoplasia is established based on history, clinical signs and advanced imaging characteristics, the decision to treat and which treatment to choose must be considered. The objective of this study is to report survival times (ST) for dogs with intracranial meningiomas and gliomas treated with surgical resection alone (SRA), to identify potential prognostic factors affecting survival, and to compare the results with the available literature. Medical records of 29 dogs with histopathologic confirmation of intracranial meningiomas and gliomas treated with SRA were retrospectively reviewed. For each dog, signalment, clinical signs, imaging findings, type of surgery, treatment, histological evaluation, and ST were obtained. Twenty-nine dogs with a histological diagnosis who survived >7 days after surgery were included. There were 15 (52%) meningiomas and 14 (48%) gliomas. All tumors had a rostrotentorial location. At the time of the statistical analysis, only two dogs were alive. Median ST for meningiomas was 422 days (mean, 731 days; range, 10-2735 days). Median ST for gliomas was 66 days (mean, 117 days; range, 10-730 days). Kaplan-Meier analysis indicated that ST was significantly longer for meningiomas than for gliomas (P7 days postoperatively, SRA might be an appropriate treatment, particularly for meningiomas, when radiation therapy is not readily available. Also, the presence of midline shift and ventricular compression might be negative prognostic factors for dogs with meningiomas.

Case summary A 5-year-old neutered male domestic shorthair cat presented with an 18-month history of facial tics, and progressive general ataxia, weakness, lethargy and anorexia of 2 weeks’ duration. MRI of the brain showed a well-defined heterogeneous hyperintense mass on T1-weighted and T2-weighted images, with central hypointensity in the rostral commissure and septum pellucidum, and perilesional hyperintensity in fluid-attenuated inversion recovery, suggestive of perilesional oedema. Gross examination in a transverse section of the brain at the level of the septum pellucidum revealed a 0.2 cm brown soft mass. Histopathological examination identified a biphasic neoplastic proliferation of mesenchymal and neuroepithelial cell populations. Fusiform cells were predominately distributed in bundles showing a high degree of anisocytosis and marked immune-positive reaction to vimentin immunochemistry, confirming a sarcomatous origin. Additionally, high numbers of astrocytic cells were identified by an intense immunopositive reaction to glial fibrillary acidic protein and negative reaction to oligodendrocyte transcription factor 2 immunochemistry. Vascular invasion of the neoplasia into the wall of a medium branch of the rostral cerebral artery was present (secondary Scherer structures). Based on these characteristics, the tumour was defined as a gliosarcoma. Gliosarcoma is a recognised astrocytoma grade IV anaplastic glial cell tumour with sarcomatous differentiation. Relevance and novel information To our knowledge, this is the first report describing a cerebral gliosarcoma in a cat including clinical, MRI, macroscopic and histopathological features and immunolabelling characteristics.

En este artículo revisamos los diferentes aspectos relacionados con la utilización de animales en la docencia del Grado de Veterinaria. Desde los aspectos legales y éticos que la regulan a las diferentes experiencias alternativas publicados por docentes de diferentes centros de formación veterinaria de todo el mundo. Incluimos la visión de los estudiantes de nuestra universidad. Proponemos alternativas surgidas en nuestro centro y propuestas de futuro para mejorar la calidad docente en la formación veterinaria.

Supplementation of a mother’s diet with antioxidants, such as hydroxytyrosol (HTX), has been proposed to ameliorate the adverse phenotypes of fetuses at risk of intrauterine growth restriction. 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 total gestational period), and individuals were sampled at three different ages: 100-day-old fetuses and 1-month- and 6-month-old piglets. After euthanasia, the brain was removed and the hippocampus, amygdala, and prefrontal cortex were dissected. The profile of the catecholaminergic and serotoninergic neurotransmitters (NTs) was characterized and an immunohistochemical study of the hippocampus was performed. The results indicated that maternal supplementation with HTX during pregnancy affected the NT profile in a brain-area-dependant mode and it modified the process of neuron differentiation in the hippocampal CA1 and GD areas, indicating that cell differentiation occurred more rapidly in the HTX group. These effects were specific to the fetal period, concomitantly with HTX maternal supplementation, since no major differences remained between the control and treated groups in 1-month- and 6-month-old pigs.

A two-year-old, Irish Wolfhound dog presented with a history of progressive neurological signs. Neurological exam revealed disorientation, absence of menace response, reduction of right nasal sensation, hypermetria and ataxia with reduction of proprioception in all four limbs. MRI findings were compatible with laminar neuronal necrosis and possible bilateral cortical cerebral atrophy. Grossly, a severe bilateral reduction of the gray matter with flattening of gyri, mainly in frontal and parietal cerebral areas, was observed. Histologically, multiple, segmental, bilateral, and symmetric areas of neuronal loss, necrosis and degeneration, in a laminar pattern, associated with a reactive gliosis were observed. Immunohistochemical studies showed severe reduction of neuronal bodies, proliferation and hypertrophy of astrocytes and microglia. Few perivascular B and T cells were demonstrated. Based on these data, we show some of the neuroinflammatory events that occur during CNS repair in a chronic phase of this condition.

ABSTRACT: A three-year-old female African pygmy hedgehog (Atelerix albiventris), born and domiciled in Brazil, presented apathy, prostration, and difficulty to stay standing. Its parents were siblings but did not present clinical signs related to this condition. As its clinical condition worsened, the animal was euthanized and referred for necropsy. No gross lesions were found in the central nervous system (CNS). Histologically, there was vacuolation with axonal degeneration in the white matter of the CNS and in peripheral nervous tissue. The Kluver-Barrera (KB) stain confirmed demyelination in vacuolated areas. Immunohistochemistry using several neural markers confirmed astrocytosis and microgliosis associated with vacuolated areas. In addition, there was a mild decrease in the immuno intensity of myelin proteolipid protein (PLP) in these areas. These results suggest a genetic origin of the present demyelination, which resulted in the wobbly syndrome described in this report.

One of the characteristics of prions is their ability to infect some species but not others and prion resistant species have been of special interest because of their potential in deciphering the determinants for susceptibility. Previously, we developed different in vitro and in vivo models to assess the susceptibility of species that were erroneously considered resistant to prion infection, such as members of the Leporidae and Equidae families. Here we undertake in vitro and in vivo approaches to understand the unresolved low prion susceptibility of canids. Studies based on the amino acid sequence of the canine prion protein (PrP), together with a structural analysis in silico, identified unique key amino acids whose characteristics could orchestrate its high resistance to prion disease. Cell- and brain-based PMCA studies were performed highlighting the relevance of the D163 amino acid in proneness to protein misfolding. This was also investigated by the generation of a novel transgenic mouse model carrying this substitution and these mice showed complete resistance to disease despite intracerebral challenge with three different mouse prion strains (RML, 22L and 301C) known to cause disease in wild-type mice. These findings suggest that dog D163 amino acid is primarily, if not totally, responsible for the prion resistance of canids.

Interspecies transmission of prions is a well-established phenomenon, both experimentally and under field conditions. Upon passage through new hosts, prion strains have proven their capacity to change their properties and this is a source of strain diversity which needs to be considered when assessing the potential risks associated with consumption of prion contaminated protein sources. Rabbits were considered for decades to be a prion resistant species until proven otherwise recently. To determine the extent of rabbit susceptibility to prions and to assess the effects of passage of different prion strains through this species a transgenic mouse model overexpressing rabbit PrPC was developed (TgRab). Intracerebral challenges with prion strains originating from a variety of species including field isolates (ovine SSBP/1 scrapie, Nor98- scrapie; cattle BSE, BSE-L and cervid CWD), experimental murine strains (ME7 and RML) and experimentally obtained ruminant (sheepBSE) and rabbit (de novo NZW) strains were performed. On first passage TgRab were susceptible to the majority of prions (Cattle BSE, SheepBSE, BSE-L, de novo NZW, ME7 and RML) tested with the exception of SSBP/1 scrapie, CWD and Nor98 scrapie. Furthermore, TgRab were capable of propagating strain-specific features such as differences in incubation periods, histological brain lesions, abnormal prion (PrPd) deposition profiles and proteinase-K (PK) resistant western blotting band patterns. Our results confirm previous studies proving that rabbits are not resistant to prion infection and show for the first time that rabbits are susceptible to PrPd originating in a number of other species. This should be taken into account when choosing protein sources to feed rabbits.

A 7-month-old, entire female, domestic shorthair cat was referred to our behavioural service owing to soiling in the house and a play-related problem. The owners’ complaints were that the cat had never used the litter tray, and it did not know how to play. After reviewing the behavioural history, a problem of substrate preferences acquisition was suspected with regard to the elimination problem. During the consultation, the physical examination was unremarkable, but the neurological examination revealed a moderate and hypermetric ataxic gait, and a bilateral lack of menace response. Some degree of visual impairment was suspected. The problem was located in the central nervous system (CNS); specifically, an intracranial and multifocal problem was diagnosed. After a complete work-up (complete ophthalmological examination, complete blood count and a complete biochemistry panel, feline immunodeficiency virus/feline leukaemia virus test, thorax radiographs, abdominal ultrasound, brain magnetic resonance imaging [0.2 T], cerebrospinal fluid analysis and a urinary metabolic screen test), a degenerative CNS problem was suspected. No treatment was prescribed for the neurological problem. Regarding the problem of soiling in the house, reward-based training with a clicker was used, and the cat partially improved in a few weeks. Three months later, the cat was referred to the neurology service in status epilepticus. A symptomatic treatment was prescribed, with a mild response. After 2 years of treatment and a progressive worsening, the cat was euthanased. Necropsy revealed spongiform polioencephalomyelopathy. In order to rule out prion aetiology a PrPsc inmunohistochemistry assay was performed, and the results were negative. Congenital spongiform polioencephalomyelopathy (CSP) was diagnosed. We strongly suggest that the cat’s behavioural clinical signs were caused by the CSP, causing learning impairment. To the best of our knowledge, this would be the first case in which a congenital degenerative disease affected a cat’s capability to learn, leading to behavioural signs as the main complaint of the owners, even before neurological signs are detected by the owners.

Glioblastoma (GBM) is the most common aggressive primary brain tumor in adults, with a short survival time even after aggressive therapy. Non-invasive surrogate biomarkers of therapy response may be relevant for improving patient survival. Previous work produced such biomarkers in preclinical GBM using semi-supervised source extraction and single-slice Magnetic Resonance Spectroscopic Imaging (MRSI). Nevertheless, GBMs are heterogeneous and single-slice studies could prevent obtaining relevant information. The purpose of this work was to evaluate whether a multi-slice MRSI approach, acquiring consecutive grids across the tumor, is feasible for preclinical models and may produce additional insight into therapy response. Nosological images were analyzed pixel-by-pixel and a relative responding volume, the Tumor Responding Index (TRI), was defined to quantify response. Heterogeneous response levels were observed and treated animals were ascribed to three arbitrary predefined groups: high response (HR, n = 2), TRI = 68.2 ± 2.8%, intermediate response (IR, n = 6), TRI = 41.1 ± 4.2% and low response (LR, n = 2), TRI = 13.4 ± 14.3%, producing therapy response categorization which had not been fully registered in single-slice studies. Results agreed with the multi-slice approach being feasible and producing an inverse correlation between TRI and Ki67 immunostaining. Additionally, ca. 7-day oscillations of TRI were observed, suggesting that host immune system activation in response to treatment could contribute to the responding patterns detected.

Como neurólogo veterinario, docente e investigador, presentamos como utilizamos los animales en nuestras actividades cotidianas. En cuanto a la investigación con animales, ofrecemos alternativas al uso de los animales de laboratorio y proponemos la optimización de su uso mediante los bancos de tejidos animales. También destacamos la importancia de las medidas legislativas y en especial de los comités de bioética para regular todas estas actividades.

BackgroundPattern Recognition techniques can provide invaluable insights in the field of neuro-oncology. This is because the clinical analysis of brain tumors requires the use of non-invasive methods that generate complex data in electronic format. Magnetic Resonance (MR), in the modalities of spectroscopy (MRS) and spectroscopic imaging (MRSI), has been widely applied to this purpose. The heterogeneity of the tissue in the brain volumes analyzed by MR remains a challenge in terms of pathological area delimitation.Methodology/principal findingsA pre-clinical study was carried out using seven brain tumor-bearing mice. Imaging and spectroscopy information was acquired from the brain tissue. A methodology is proposed to extract tissue type-specific sources from these signals by applying Convex Non-negative Matrix Factorization (Convex-NMF). Its suitability for the delimitation of pathological brain area from MRSI is experimentally confirmed by comparing the images obtained with its application to selected target regions, and to the gold standard of registered histopathology data. The former showed good accuracy for the solid tumor region (proliferation index (PI)>30%). The latter yielded (i) high sensitivity and specificity in most cases, (ii) acquisition conditions for safe thresholds in tumor and non-tumor regions (PI>30% for solid tumoral region; ≤5% for non-tumor), and (iii) fairly good results when borderline pixels were considered.Conclusions/significanceThe unsupervised nature of Convex-NMF, which does not use prior information regarding the tumor area for its delimitation, places this approach one step ahead of classical label-requiring supervised methods for discrimination between tissue types, minimizing the negative effect of using mislabeled voxels. Convex-NMF also relaxes the non-negativity constraints on the observed data, which allows for a natural representation of the MRSI signal. This should help radiologists to accurately tackle one of the main sources of uncertainty in the clinical management of brain tumors, which is the difficulty of appropriately delimiting the pathological area.

The pathogenesis of natural scrapie and other prion diseases remains unclear. Examining transcriptome variations in infected versus control animals may highlight new genes potentially involved in some of the molecular mechanisms of prion-induced pathology. The aim of this work was to identify disease-associated alterations in the gene expression profiles of the caudal medulla oblongata (MO) in sheep presenting the symptomatic phase of natural scrapie. The gene expression patterns in the MO from 7 sheep that had been naturally infected with scrapie were compared with 6 controls using a Central Veterinary Institute (CVI) custom designed 4×44K microarray. The microarray consisted of a probe set on the previously sequenced ovine tissue library by CVI and was supplemented with all of the Ovis aries transcripts that are currently publicly available. Over 350 probe sets displayed greater than 2-fold changes in expression. We identified 148 genes from these probes, many of which encode proteins that are involved in the immune response, ion transport, cell adhesion, and transcription. Our results confirm previously published gene expression changes that were observed in murine models with induced scrapie. Moreover, we have identified new genes that exhibit differential expression in scrapie and could be involved in prion neuropathology. Finally, we have investigated the relationship between gene expression profiles and the appearance of the main scrapie-related lesions, including prion protein deposition, gliosis and spongiosis. In this context, the potential impacts of these gene expression changes in the MO on scrapie development are discussed.