Adeno-associated virus serotypes 9 and rh10 mediate strong neuronal transduction of the dog brain.

Canine models have many advantages for evaluating therapy of human central nervous system (CNS) diseases. In contrast to nonhuman primate models, naturally occurring canine CNS diseases are common. In contrast to murine models, the dog's lifespan is long, its brain is large and the diseases affecting it commonly have the same molecular, pathological and clinical phenotype as the human diseases. We compared the ability of four intracerebrally injected adeno-associated virus vector (AAV) serotypes to transduce the dog brain with green fluorescent protein as the first step in using these vectors to evaluate both delivery and efficacy in naturally occurring canine homologs of human diseases. Quantitative measures of transduction, maximum diameter and area, identified both AAV2/9 and AAV2/rh10 as significantly more efficient than either AAV2/1 or AAV2/5 at transducing cerebral cortex, caudate nucleus, thalamus and internal capsule. Fluorescence co-labeling with cell-type-specific antibodies demonstrated that AAV2/9 and AAV2/rh10 were capable of primarily transducing neurons, although glial transduction was also identified and found to be more efficient with the AAV2/9 vector. These data are a prerequisite to evaluating the efficacy of recombinant AAV vectors carrying disease-modifying transgenes to treat naturally occurring canine models in preclinical studies of human CNS disease therapy.

Postmortem evaluation of 435 cases of intracranial neoplasia in dogs and relationship of neoplasm with breed, age, and body weight.

BACKGROUND: Intracranial neoplasia of dogs is frequently encountered in veterinary medicine, but large-scale studies on prevalence are lacking. OBJECTIVES: To determine the prevalence of intracranial neoplasia in a large population of dogs examined postmortem and the relationship between breed, age, and weight with the presence of primary intracranial neoplasms. ANIMALS: All dogs that underwent postmortem examination from 1986 through 2010 (n = 9,574), including dogs with a histopathologic diagnosis of primary (n = 227) and secondary (n = 208) intracranial neoplasia. METHODS: Retrospective evaluation of medical records from 1986 through 2010. RESULTS: Overall prevalence of intracranial neoplasia in this study's population of dogs was 4.5%. A statistically significant higher prevalence of primary intracranial neoplasms was found in dogs with increasing age and body weights. Dogs ≥15 kg had an increased risk of meningioma (odds ratio 2.3) when compared to dogs <15 kg. The Boxer, Boston Terrier, Golden Retriever, French Bulldog, and Rat Terrier had a significantly increased risk of primary intracranial neoplasms while the Cocker Spaniel and Doberman Pinscher showed a significantly decreased risk of primary intracranial neoplasms. CONCLUSIONS AND CLINICAL IMPORTANCE: Intracranial neoplasia in dogs might be more common than previous estimates. The study suggests that primary intracranial neoplasia should be a strong differential in older and larger breed dogs presenting with signs of nontraumatic intracranial disease. Specific breeds have been identified with an increased risk, and others with a decreased risk of primary intracranial neoplasms. The results warrant future investigations into the role of age, size, genetics, and breed on the development of intracranial neoplasms.

Polymicrogyria in standard poodles.

BACKGROUND: Polymicrogyria is a disorder of cerebrocortical migration resulting in increased numbers of small, disorganized gyri. This disorder occurs in Standard Poodles and in cattle. OBJECTIVES: To describe the clinical, electroencephalographic, imaging, and histopathologic features in poodles with polymicrogyria. ANIMALS: Five Standard Poodles with histologically confirmed polymicrogyria. METHODS: Retrospective case series. Cases were obtained by personal communication with 1 of 2 authors (TJVW, DPO). RESULTS: All dogs had cortical blindness and other neurologic abnormalities including gait and behavioral changes. Magnetic resonance imaging of 3 dogs showed multiple disorganized gyri, which were especially apparent on T2-weighted dorsal plane images. Electroencephalogram (EEG) of 1 dog revealed epileptiform discharges, including both spike and spike and wave discharges with voltage maximum potentials over the parietal/occipital region. The EEG supported that the repetitive behavior displayed by the dog was a complex partial motor seizure. One dog had concurrent hydrocephalus. All dogs had occipital lobe involvement and 2 dogs had involvement of other lobes. CLINICAL IMPORTANCE: The cases presented here demonstrate a larger age range (7 weeks to 5 years) and a decreased frequency of associated hydrocephalus when compared with the previous report.

Apparent diffusion coefficient reveals gray and white matter disease, and T2 mapping detects white matter disease in the brain in feline alpha-mannosidosis.

BACKGROUND AND PURPOSE: Methods to locate and identify brain pathology are critical for monitoring disease progression and for evaluating the efficacy of therapeutic intervention. The purpose of this study was to detect cell swelling, abnormal myelin, and astrogliosis in the feline model of the lysosomal storage disease alpha-mannosidosis (AMD) by using diffusion and T2 mapping. MATERIALS AND METHODS: Average apparent diffusion coefficient (ADC(av)) and T2 were measured by imaging the brains of five 16-week-old cats with feline AMD on a 4.7T magnet. ADC(av) and T2 data from affected cats were compared with data from age-matched normal cats. Brains were collected from both affected and normal cats following imaging, and histology was compared with quantitative imaging data. RESULTS: Gray matter from AMD cats demonstrated a 13%-15% decrease in ADC(av) compared with that in normal cats. White matter from AMD cats exhibited an 11%-16% decrease in ADC(av) and a 5%-12% increase in T2 values compared with those in normal control cats. Histologic evidence of neuronal and glial swelling, abnormal myelin, and astrogliosis was consistent with changes in ADC(av) and T2. CONCLUSION: ADC(av) and T2 data can be used to quantify differences in the gray and white matter in the feline AMD brain and may serve as surrogate markers of neuronal swelling, abnormal myelin, and astrogliosis associated with this disease. These studies may be helpful in assessing the efficacy of experimental therapies for central nervous system disease associated with lysosomal storage diseases.

Infection and establishment of latency in the dog brain after direct inoculation of a nonpathogenic strain of herpes simplex virus-1.

A number of diseases affecting the CNS occur in the dog and can be used as models for gene therapy in a large brain. HSV-1 has several potential advantages as a vector to transfer genes into the CNS. However, the ability of HSV-1 to infect CNS cells varies among species and no information was available for the dog. When the nonpathogenic 1716 strain of HSV-1 was injected into the brains of normal dogs it established a latent infection without signs of pathology. Thus, it appears to be suitable as a vector for therapeutic, or marker genes, in this species.

Histopathology, electrodiagnostic testing, and magnetic resonance imaging show significant peripheral and central nervous system myelin abnormalities in the cat model of alpha-mannosidosis.

Alpha-mannosidosis is a disease caused by the deficient activity of alpha-mannosidase, a lysosomal hydrolase involved in the degradation of glycoproteins. The disease is characterized by the accumulation of mannose-rich oligosaccharides within lysosomes. The purpose of this study was to characterize the peripheral nervous system (PNS) and central nervous system (CNS) myelin abnormalities in cats from a breeding colony with a uniform mutation in the gene encoding alpha-mannosidase. Three affected cats and 3 normal cats from 2 litters were examined weekly from 4 to 18 wk of age. Progressively worsening neurological signs developed in affected cats that included tremors, loss of balance, and nystagmus. In the PNS, affected cats showed slow motor nerve conduction velocity and increased F-wave latency. Single nerve fiber teasing revealed significant demyelination/remyelination in affected cats. Mean G-ratios of nerves showed a significant increase in affected cats compared to normal cats. Magnetic resonance imaging of the CNS revealed diffuse white matter signal abnormalities throughout the brain of affected cats. Quantitative magnetization transfer imaging showed a 8%-16% decrease in the magnetization transfer ratio in brain white matter of affected cats compared to normal cats, consistent with myelin abnormalities. Histology confirmed myelin loss throughout the cerebrum and cerebellum. Thus, histology, electrodiagnostic testing, and magnetic resonance imaging identified significant myelination abnormalities in both the PNS and CNS that have not been described previously in alpha-mannosidosis.

Magnetization transfer imaging of the canine brain: a review.

Magnetization transfer imaging is a modality capable of examining the non-water components of brain tissue by examining the effects they have on water protons. It may be used qualitatively to increase the visibility of lesions seen during magnetic resonance angiography and following the administration of an intravenous paramagnetic contrast medium. Quantitatively, it can be used to examine the effect of pathology on magnetization transfer contrast, to provide a measurement of myelination, as well as to quantify disease progression in trauma, neoplasia, neurodegeneration and other disorders of the brain. This paper reviews the theory of magnetization transfer imaging, its applications, and provides an example of its use in examining the canine brain.

Neurosurgical emergencies.

The neurologic patient is considered a neurosurgical emergency when delay of treatment may influence the patient's outcome. Diseases of the spinal cord, brain, and peripheral nerves are presented in this article. Diagnostic tools (i.e., advanced imaging and electrophysiologic tests), differential diagnoses, treatment options (conventional and controversial), whether the patient requires surgery, and the optimal time for surgical intervention are discussed.

Dental and craniofacial findings in eight miniature schnauzer dogs affected by myotonia congenita: preliminary results.

Myotonia is a clinical sign characterized by the delay of skeletal muscle relaxation following the cessation of a voluntary activity or the termination of an electrical or mechanical stimulus. Recently, Miniature Schnauzers with myotonia congenita associated with defective chloride ion conductance across the skeletal muscle membrane were identified. Congenital myotonia in these dogs appears to follow an autosomal recessive mode of inheritance. Craniofacial and dental findings of eight Miniature Schnauzer dogs with myotonia congenita are described in the present paper. These findings include: delayed dental eruption of both deciduous and permanent dentition: persistent deciduous dentition; unerupted or partially erupted permanent teeth: crowding and rotation of premolar and or incisor teeth: missing teeth: increased interproximal space between the maxillary fourth premolar and first molar teeth: decreased interproximal space between the maxillary canine and lateral incisor teeth: inability to fully close the mouth due to malocclusion: distoclusion: and, decreased mandibular range of motion. A long narrow skull with a flattened zygomatic arch and greater mandibular body curvature were also consistent findings in the affected dogs. The small number of dogs studied prevents conclusive statements about the origin of these abnormalities, however it is interesting that only 1 of 45 unaffected Miniature Schnauzer dogs showed similar traits.

Congenital myotonic myopathy in the miniature schnauzer: an autosomal recessive trait.

Myotonia is a clinical sign characterized by a delay in skeletal muscle relaxation following electrical or mechanical stimulation. A series of related miniature schnauzer dogs with congenital myotonic myopathy were studied. A composite pedigree of six affected litters and the results of a planned breeding between two affected animals are consistent with an autosomal recessive mode of inheritance.

A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog.

Myotonia congenita is an inherited disorder of sarcolemmal excitation leading to delayed relaxation of skeletal muscle following contractions. Mutations in a skeletal muscle voltage-dependent chloride channel, CIC-1, have been identified as the molecular genetic basis for the syndrome in humans, and in two well characterized animal models of the disease: the myotonic goat, and the arrested development of righting (adr) mouse. We now report the molecular genetic and electrophysiological characterization of a canine CIC-1 mutation that causes autosomal recessive myotonia congenita in miniature Schnauzers. The mutation results in replacement of a threonine residue in the D5 transmembrane segment with methionine. Functional characterization of the mutation introduced into a recombinant CIC-1 and heterologously expressed in a cultured mammalian cell line demonstrates a profound effect on the voltage-dependence of activation such that mutant channels have a greatly reduced open probability at voltages near the resting membrane potential of skeletal muscle. The degree of this dysfunction is greatly diminished when heterodimeric channels containing a wild-type and mutant subunit are expressed together as a covalent concatemer strongly supporting the observed recessive inheritance in affected dog pedigrees. Genetic and electrophysiological characterization of the myotonic dog provides a new and potentially valuable animal model of an inherited skeletal muscle disease that has advantages over existing models of myotonia congenita.

Severe neurologic sequelae in a dog after treatment of hypoadrenal crisis.

A 3-year-old mixed-breed dog was evaluated for lethargy, weakness, anorexia, and vomiting. The dog was dehydrated, hyponatremic, hypochloremic, and hypoglycemic. Results of an ACTH stimulation test indicated hypoadrenocorticism. Treatment to restore cardiovascular stability and serum electrolyte balance caused serum sodium concentration to increase by 32 mEq/L within 48 hours, and the dog developed severe neurologic signs that persisted for approximately 3 weeks. Magnetic resonance imaging revealed cerebrocortical lesions on day 6 and more severe lesions, including diffuse atrophy of the cerebral hemispheres, at 23 weeks after initial evaluation; however, the dog recovered complete neurologic function. Serum sodium concentration should be monitored during treatment for hypoadrenal crisis to avoid rapid increases that can cause CNS damage.

MRI and electrophysiological abnormalities in a case of canine globoid cell leucodystrophy.

A six-month-old West Highland white terrier with progressive, multifocal neurological disease was diagnosed with canine globoid cell leucodystrophy (GCL). Magnetic resonance imaging (MRI) of the brain was performed, as well as electrophysiological testing (including brainstem auditory evoked response, peripheral nerve conduction velocity, repetitive stimulation, F wave analysis and electromyography). MRI findings were consistent with diffuse, symmetrical white matter disease. Electrodiagnostic testing revealed evidence of peripheral neuropathy and an abnormal brainstem auditory evoked response. These observations were consistent with the pathological changes in central and peripheral white matter described for canine GCL, and resembled what has been described in human patients. It is believed that the tests may raise the suspicion of GCL in dogs and may aid in monitoring disease progression.

Acute fulminating myasthenia gravis in five dogs.

Acute fulminating myasthenia gravis (MG) was diagnosed in 5 dogs. Acute fulminating generalized MG in dogs is characterized by sudden onset of megaesophagus and frequent regurgitation of large volumes of fluid. Generalized muscle weakness can worsen and lead to recumbency within days. Despite appropriate supportive care, weakness is not alleviated by rest. Respiratory failure caused by aspiration pneumonia and loss of strength in muscles involved with respiration is a common cause of death. In dogs with acute onset of regurgitation, MG should be considered as a differential diagnosis. Clinicians should be aware of the risk of rapid progression to quadriparesis if aspiration pneumonia develops.

A case of canine central nervous system cryptococcosis: management with fluconazole.

A three-year-old, female Labrador retriever was presented for acute generalized seizures. Disseminated cryptococcosis with central nervous system (CNS) involvement was diagnosed by serum and cerebrospinal fluid (CSF) fungal titers, histopathological examination, and magnetic resonance imaging (MRI). Fluconazole therapy resulted in prolonged, substantial clinical improvement for a period of one year. This report documents the diagnosis of a case of cryptococcal meningoencephalitis and its management with the new antifungal agent, fluconazole.

Quantification of cerebral ventricular volume in English bulldogs.

Quantitative measurement of cerebral ventricle volume of eight English bulldogs was performed using magnetic resonance (MR) imaging. The mean ventricular volume was 14.8 ml. with a range of 8.6 ml.-38.1 ml. The mean ventricular volume of two beagles was 2.2 ml with a range of 0.7 ml.-3.7 ml. The percent of intracranial volume occupied by ventricle was found to be significantly larger in bulldogs (14.0%; S.D. = 7.9%) than in beagles (Range = 1.0-4.8%). The relationship between the percent of intracranial volume occupied by ventricle and measurements of body weight, age, sex, and various measures of skull anatomy of the bulldog was also determined. The relationship between ventricular volume and neurologic dysfunction was examined. There was a possible trend between high percent of intracranial volume occupied by ventricle and low body weight. This study will serve as a pilot study for examining the relationship between ventricular volume and neurologic disease in bulldogs.

A retrospective evaluation of 51 cases of peripheral nerve sheath tumors in the dog.

Fifty-one cases of canine peripheral nerve sheath tumors were reviewed. Signalment, presenting clinical signs, duration of clinical signs, physical and neurological examination findings, results of diagnostic procedures, type of surgery performed, tumor location, relapse-free intervals and survival times, and causes of death were evaluated. Tumors were divided into three anatomical groups: tumors involving nerves distal to the brachial or lumbosacral plexus (Peripheral Group), tumors involving nerves of the brachial or lumbosacral plexus (Plexus Group), and tumors involving the vertebral canal (Root Group). The most common clinical findings were unilateral forelimb lameness and muscle atrophy. The most useful diagnostic tests were myelography and electromyography. Although there was no significant difference, dogs in the Root Group tended to have shorter relapse-free intervals and survival times than dogs in the Plexus Group. The overall prognosis for surgical management of peripheral nerve sheath tumors is guarded to poor.