Philip A. March

Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis

Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.

Clinical Characterization of a Familial Degenerative Myelopathy in Pembroke Welsh Corgi Dogs

BACKGROUND Adult dogs with degenerative myelopathy (DM) have progressive ataxia and paresis of the pelvic limbs, leading to paraplegia and euthanasia. Although most commonly reported in German Shepherd dogs, high disease prevalence exists in other breeds. OBJECTIVE Our aim was the clinical and histopathologic characterization of familial degenerative myelopathy (FDM) in Pembroke Welsh Corgi (PWC) dogs. ANIMALS Twenty-one PWCs were prospectively studied from initial diagnosis until euthanasia. METHODS Neurologic examination, blood tests, cerebrospinal fluid (CSF) analysis, electrodiagnostic testing, and spinal imaging were performed. Concentrations of 8-iso-prostaglandin F2alpha (8-isoprostane) were measured in CSF. Routine histochemistry was used for neuropathology. Deoxyribonucleic acid and pedigrees were collected from 110 dogs. RESULTS Median duration of clinical signs before euthanasia was 19 months. Median age at euthanasia was 13 years. All dogs were nonambulatory paraparetic or paraplegic, and 15 dogs had thoracic limb weakness at euthanasia. Electrodiagnostic testing and spinal imaging were consistent with noncompressive myelopathy. No significant difference was detected in 8-isoprostane concentrations between normal and FDM-affected dogs. Axonal and myelin degeneration of the spinal cord was most severe in the dorsal portion of the lateral funiculus. Pedigree analysis suggested a familial disease. CONCLUSIONS AND CLINICAL IMPORTANCE Clinical progression of FDM in PWC dogs was similar to that observed in other breeds but characterized by a longer duration. Spinal cord pathology predominates as noninflammatory axonal degeneration. Oxidative stress injury associated with 8-isoprostane production is not involved in the pathogenesis of FDM-affected PWC dogs. A familial disease is suspected.

The feline model of neuroAIDS: understanding the progression towards AIDS dementia.

Feline immunodeficiency virus (FIV) is a neurotropic lentivirus that produces a protracted state of immunodeficiency and encephalopathy in the cat. Recent evidence has shown several similarities to the natural progression of human immunodeficiency virus infection (HIV-1) associated degenerative effects on the central and peripheral nervous systems. Similar to HIV-1, FIV-induced encephalopathy neurovirulence is strain dependent, results in progressive immunodeficiency and increasing early peripheral but not brain viral load, preferentially affects the developing nervous system, produces quantifiable behavioural and neurophysiological impairment that is not directly linked to neuronal infectivity, and induces neuronal injury and loss both in vivo and in vitro. This paper highlights the cumulative scientific body of evidence supporting the use of the feline model of neuroAIDS.

Seizures: Classification, Etiologies, and Pathophysiology

Epilepsy is a disorder of recurrent seizures that are neural in origin. Partial seizures are usually due to a structural cerebrocortical lesion and may be simple or complex. Brain injuries may alter inherent neuronal properties and neuronal circuits and lead to recurrent excitatory activity. Potentiation of excitatory synapses and depression of inhibitory synapses are probable critical events in epileptogenesis. The pathogenic factors underlying primary or idiopathic generalized seizures are not as well understood. A more diffuse or multifocal state of neuronal excitability may be the result of early congenital events that are magnified over time. The progression of subclinical neuronal excitatory activity to a clinical seizure may relate directly to the phenomenon of cortical plasticity.

Degenerative Myelopathy in 18 Pembroke Welsh Corgi Dogs

Postmortem examination was performed on 18 Pembroke Welsh Corgi dogs (mean age 12.7 years) with clinical signs and antemortem diagnostic tests compatible with a diagnosis of degenerative myelopathy. Tissue sections from specific spinal cord and brain regions were systematically evaluated in all dogs. Axonal degeneration and loss were graded according to severity and subsequently compared across different spinal cord segments and funiculi. White matter lesions were identified in defined regions of the dorsal, lateral, and ventral funiculi. The dorsolateral portion of the lateral funiculus was the most severely affected region in all cord segments. Spinal cord segment T12 exhibited the most severe axonal loss. Spinal nerve roots, peripheral nerves, and brain sections were within normal limits, with the exception of areas of mild astrogliosis in gray matter of the caudal medulla. Dogs with more severe lesions showed significant progression of axonal degeneration and loss at T12 and at cord segments cranial and caudal to T12. Severity of axonal loss in individual dogs positively correlated with the duration of clinical signs. The distribution of axonal degeneration resembled that reported in German Shepherd Dog degenerative myelopathy but differed with respect to the transverse and longitudinal extent of the lesions within more clearly defined funicular areas. Although these lesion differences might reflect disease longevity, they could also indicate a form of degenerative myelopathy unique to the Pembroke Welsh Corgi dog.

Effects of feline immunodeficiency virus on cognition and behavioral function in cats.

Experimental intravenous challenge of 8-week old cats with the Maryland isolate of feline immunodeficiency virus, Maryland isolate (FIV-MD) was investigated for its effects on cognitive and behavioral function at 12 months postinfection. Six cats infected with FIV-MD were compared with age-matched controls on several behavioral measures. These measures included an open field observation, locomotion tests, traversing planks of various widths for food reinforcement, and a spatial learning task. No group differences were observed on any measure of locomotion. Differences were present with exploratory and stationary activity in the open field observation, with infected cats exhibiting higher levels of exploratory activity and in less stationary activity compared with that of control cats. In the plank-walking experiment, infected cats were less able to successfully cross progressively narrower planks compared with control animals. A holeboard paradigm was constructed to test spatial learning and memory, in which cats were required to locate food reinforcement based on position in the holeboard array. As a group, FIV-infected cats committed more reference (exploring an unbaited cup) and working memory (returning to a previously visited baited cup) errors than control cats. The main difference demonstrated was a higher activity level and associated distractibility in FIV-infected cats that appears to be related to their overall deficient performance when learning new tasks. These results indicate that behavioral function is altered and cognition is quantitatively impaired in FIV-infected cats.

Evaluation of hypothermia-induced analgesia and influence of opioid antagonists in leopard frogs (Rana pipiens)

Hypothermia results in diminished voluntary muscle activity, and is frequently used as a means of providing deep anesthesia to ectotherms and some mammals. In ectotherms, however, it is unclear if hypothermia produces true pain insensation. A needle-probe thermometer was used to demonstrate in frogs (Rana pipiens) that local hypothermia (9 degrees C) could be induced by placement of a tourniqueted leg into ice water (6 degrees C) for 10 min in contrast to the contralateral nontourniqueted leg (21.8 degrees C) kept out of ice water. Analgesia was tested by placement of dilutions of acetic acid on the rear leg. Further tests using groups of 10 frogs demonstrated that frogs with local hypothermia tolerated greater concentrations of acetic acid (mean acetic acid test score = 11) than morphine (10 mg/kg)-treated (9.6) or nontreated (5.8) frogs. Additional studies showed that morphine analgesia was blocked with naloxone doses as low as 0.01 mg/kg and hypothermia-induced analgesia at 10 mg/kg. Naltrexone blocked morphine analgesia at dosages as low as 0.01 mg/kg and hypothermia-induced analgesia at 0.10 mg/kg. In summary, this study demonstrates that hypothermia induces significant analgesia in an amphibian, and that this analgesia is partially blocked by naloxone and naltrexone, suggesting that the effect is mediated at least partially by opioid receptors.

Vertebral Malformation, Syringomyelia, and Ventricular Septal Defect in a Dromedary Camel (Camelius Dromedarius)

An occipitoatlantoaxial malformation and ventricular septal defect (VSD) were diagnosed in a 36-hour-old female camel. Physical examination revealed a firm protrusion of the dorsal aspect of the atlas and axis, tilting of the head to the left, and a grade V/VI systolic murmur. Neurological examination revealed proprioceptive deficits and ataxia of all 4 limbs. Radiographic examination and necropsy demonstrated malformation, fusion of the atlas to the occiput and hypoplasia of the dens of the axis, and subluxation of the atlantoaxial joint. Dorsoventral laxity of the atlantoaxial joint was also present, with compression of the cervical spinal cord. A 1.5-cm-diameter VSD was observed also. Histopathologic examination of the cervical spinal cord revealed a cavity extending from the level of the first to fourth cervical segment, dorsal to the central canal, 5 cm long and 1–2 mm in diameter. The cells around the cavity were positive for glial fibrillary acidic protein and sporadically positive for vimentin. This cavitary structure was consistent with syringomyelia, which was lined by glial cells, surrounded by edematous white matter with Wallerian-like degeneration and with neuronal necrosis in the adjacent dorsal horns.