Joan Coates - Academia.edu (original) (raw)
Papers by Joan Coates
Veterinary Surgery, Mar 1, 1995
A model simulating acute-compressive spinal cord trauma at the second lumbar spinal cord segment ... more A model simulating acute-compressive spinal cord trauma at the second lumbar spinal cord segment (100 g, 300 seconds) was used to evaluate the efficacy of a vehicle control, methylprednisolone sodium succinate (MPSS), and a 2 1-aminosteroid compound (U74389G). Dogs were allocated into one of five treatment groups (A to E) using ultrasonographic determination of spinal cord diameters to ensure even distribution of spinal cord diameters among the treatment groups. Initial dosages of the vehicle control (A), methylprednisolone (30 mg/kg of body weight) (B), or U74389G (30 mg/kg, 3 mg/kg, or 10 mg/kg of body weight) (C, D, or E, respectively) were administered intravenously 30 minutes after trauma. Dosages were reduced by one-half for 2 and 6 hour treatments. Then every 4 hours for 42 hours, dosages were reduced one-third and one-sixth from the original dose of methylprednisolone and U74389G, respectively. Neurological examinations were performed daily for 2 1 days. Histopathological examination of the traumatized spinal cord showed malacic and degenerative lesions. Although significant differences in some portions of the neurological and histopathologic examinations were observed, clinical efficacy for MPSS and U74389G could not be established in this model.
Journal of Neuroscience Research, Dec 21, 2013
Canine Degenerative Myelopathy (DM) is a progressive adult-onset multisystem degenerative disease... more Canine Degenerative Myelopathy (DM) is a progressive adult-onset multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general proprioceptive ataxia and spastic upper motor neuron paresis in pelvic limbs, which progress to flaccid tetraplegia and dysphagia. The purpose of this study was to characterize DM as a potential disease model for ALS. We previously reported that intercostal muscle atrophy develops in dogs with advanced stage DM. To determine if other components of the thoracic motor unit (MU) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MN) and dorsal root ganglia (DRG), and in motor and sensory nerve root axons from DMaffected Boxers and Pembroke Welsh Corgis (PWCs). No alterations in MNs, or motor root axons were observed in either breed. However, advanced stage PWCs exhibited significant losses of sensory root axons, and numerous DRG sensory neurons displayed evidence of degeneration. These results indicate that intercostal muscle atrophy in DM is not preceded by physical loss of the motor neurons innervating these muscles, or of their axons. Axonal loss in thoracic sensory roots and sensory nerve death suggest sensory involvement may play an important role in DM disease progression. Further analysis of the mechanisms responsible for these morphological findings would aid in the development of therapeutic intervention for DM and some forms of ALS.
Blood-based biomarkers are much-needed diagnostic and prognostic tools for ALS. Canine degenerati... more Blood-based biomarkers are much-needed diagnostic and prognostic tools for ALS. Canine degenerative myelopathy (DM) is recognized animal disease model to study the biology of human ALS. Serum derived exosomes are potential carrier that transport intercellular hormone-like messengers, together with their stability as carrier of proteins and RNA, make them ideal as biomarkers for a variety of diseases and biological processes. We study exosomal TDP-43 pattern as a surrogate biomarker that reflects biochemical changes in central nervous system. We isolated exosomes from canine serum using commercial exosome isolation reagents. TDP-43 and SOD1 profile in spinal cord homogenate lysate and that of serum-derived exosomes were found elevated in dogs with DM. We conclude levels of spinal cord TDP-43 and serum-derived exomes were similar in TDP-43 profiling, which warrant further investigation of disease sensitivity and specificity for establishing as a blood-based biomarker in canine DM.
Journal of Veterinary Internal Medicine, 2021
Background: Degenerative myelopathy (DM) in dogs shares similarities with superoxide dismutase 1-... more Background: Degenerative myelopathy (DM) in dogs shares similarities with superoxide dismutase 1-associated human amyotrophic lateral sclerosis (ALS). Brain microstructural lesions are quantified using diffusion tensor imaging (DTI) in ALS patients. Objective: Characterize brain neurodegenerative changes in DM-affected dogs using DTI. Animals: Sixteen DM-affected and 8 control dogs. Methods: Prospective observational study. Brain DTI was performed at baseline and every 3 months on DM-affected dogs and compared to controls. Fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated on specified regions of interest. Gait scores (0, normal to 14, tetraplegia) were assigned at each scan. Diffusion tensor imaging values in DM-affected dogs were compared to controls, gait scores, and evaluated over time. Results: Mean age was 5.7 years (SD 3.2) in controls and 9.7 years (SD 1.4) in DMaffected dogs. In DM-affected dogs, mean baseline gait score was 4 (SD 1), and mean score change from baseline to last scan was 4.82 (SD 2.67). Nine dogs had ≤3 scans; 7 had >3 scans. Accounting for age, no differences in DTI indices were identified for any brain or proximal spinal cord regions between DM-affected dogs and controls (P > .05). Diffusion tensor imaging values poorly correlated with gait scores (R 2 < .2). No significant changes were identified in diffusion indices over time (P > .05). Conclusions and Clinical Importance: Diffusion tensor imaging indices did not differentiate DM-affected from control dogs, detect longitudinal changes, or differentiate disease severity. Findings do not yet support brain DTI as an imaging biomarker.
GeroScience, 2019
Altered microglia function contributes to loss of CNS homeostasis during aging in the brain. Few ... more Altered microglia function contributes to loss of CNS homeostasis during aging in the brain. Few studies have evaluated age-related alterations in spinal cord microglia. We previously demonstrated that lumbar spinal cord microglial expression of inducible nitric oxide synthase (iNOS) was equivalent between aging, neurologically normal dogs and
Journal of Veterinary Internal Medicine, 2019
BackgroundThe intranasal (IN) route for rapid drug administration in patients with brain disorder... more BackgroundThe intranasal (IN) route for rapid drug administration in patients with brain disorders, including status epilepticus, has been investigated. Status epilepticus is an emergency, and the IN route offers a valuable alternative to other routes, especially when these fail.ObjectivesTo compare IN versus IV midazolam (MDZ) at the same dosage (0.2 mg/kg) for controlling status epilepticus in dogs.AnimalsClient‐owned dogs (n = 44) with idiopathic epilepsy, structural epilepsy, or epilepsy of unknown origin manifesting as status epilepticus.MethodsRandomized parallel group clinical trial. Patients were randomly allocated to the IN‐MDZ (n = 21) or IV‐MDZ (n = 23) group. Number of successfully treated cases (defined as seizure cessation within 5 minutes and lasting for ≥10 minutes), seizure cessation time, and adverse effects were recorded. Comparisons were performed using the Fisher's exact and Wilcoxon rank sum tests with statistical significance set at α < .05.ResultsIN‐MD...
Molecular Neurobiology, 2019
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progres... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons and grim prognosis. Over the last decade, studies on neurodegenerative diseases pointed on the role of glia in supporting the proper function of neurons. Particularly, oligodendrocytes were shown to be essential through myelin production and supplying axons with energy metabolites via monocarboxylate transporters (MCT). We have used dogs with naturally occurring degenerative myelopathy (DM) which closely resembles features observed in human ALS. We have performed two types of analysis of spinal cord tissue samples: histology and molecular analysis. Histology included samples collected from dogs that succumbed to the DM at different disease stages, which were compared to age-matched controls as well as put in the context of young spinal cords. Molecular analysis was performed on spinal cords with advanced DM and age-matched samples and included real-time PCR analysis of selected gene products related to the function of neurons, oligodendrocytes, myelin, and MCT. Demyelination has been detected in dogs with DM through loss of eriochrome staining and decreased expression of genes related to myelin including MBP, Olig1, and Olig2. The prominent reduction of MCT1 and MCT2 and increased MCT4 expression is indicative of disturbed energy supply to neurons. While Rbfox3 expression was not altered, the ChAT production was negatively affected. DM in dogs reproduces main features of human ALS including loss of motor neurons, dysregulation of energy supply to neurons, and loss of myelin, and as such is an ideal model system for highly translational studies on therapeutic approaches for ALS.
Gene Therapy, 2017
CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neur... more CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for the development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function and development of histopathological myocardial lesions. Progressive increases in the plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in the heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system.
Disease Models & Mechanisms, 2017
Targeting the CB2 receptor afforded neuroprotection in SOD1G93A mutant mice, a model of amyotroph... more Targeting the CB2 receptor afforded neuroprotection in SOD1G93A mutant mice, a model of amyotrophic lateral sclerosis (ALS). The neuroprotective effects of CB2 receptors were facilitated by their up-regulation in the spinal cord in SOD1G93A mutant mice. Herein, we have investigated whether a similar CB2 receptor up-regulation, as well as parallel changes in other endocannabinoid elements, are evident in the spinal cord of dogs with degenerative myelopathy (DM), caused from mutations in the superoxide dismutase 1 gene (SOD1). We used well-characterized post-mortem spinal cords from unaffected and DM-affected dogs. Tissues were used first to confirm the loss of motor neurons using Nissl staining, which was accompanied by glial reactivity (elevated GFAP and Iba-1 immunoreactivity). Next, we investigated possible differences in the expression of endocannabinoid genes measured by qPCR between DM-affected and control dogs. We found no changes in the CB1 receptor (also found with CB1 recep...
Veterinary Clinics of North America: Small Animal Practice, 2000
Small Animal Neurological Emergencies, 2012
Science translational medicine, Jan 11, 2015
The most common form of the childhood neurodegenerative disease late infantile neuronal ceroid li... more The most common form of the childhood neurodegenerative disease late infantile neuronal ceroid lipofuscinosis (also called Batten disease) is caused by deficiency of the soluble lysosomal enzyme tripeptidyl peptidase 1 (TPP1) resulting from mutations in the TPP1 gene. We tested whether TPP1 gene transfer to the ependyma, the epithelial lining of the brain ventricular system, in TPP1-deficient dogs would be therapeutically beneficial. A one-time administration of recombinant adeno-associated virus (rAAV) expressing canine TPP1 (rAAV.caTPP1) resulted in high expression of TPP1 predominantly in ependymal cells and secretion of the enzyme into the cerebrospinal fluid leading to clinical benefit. Diseased dogs treated with rAAV.caTPP1 showed delays in onset of clinical signs and disease progression, protection from cognitive decline, and extension of life span. By immunostaining and enzyme assay, recombinant protein was evident throughout the brain and spinal cord, with correction of the...
Handbook of Veterinary Neurology, 2011
Handbook of Veterinary Neurology, 2011
Lower motor neuron (LMN) signs (more than one location, may include cranial nerves): diffuse LMN ... more Lower motor neuron (LMN) signs (more than one location, may include cranial nerves): diffuse LMN diseases, polyneuropathy (see Chapter 7) Brain and spinal cord signs: pelvic limb paresis and seizures Systemic disease and CNS signs: fever, anorexia, ataxia, or seizures Generalized pain: meningitis Cerebral cortex and brainstem: cerebrum seizures and cranial nerve deficits, blindness, severe gait deficits, head tilt, circling Forebrain: blindness with normal pupils (may be seen with brain swelling, hydrocephalus) (see Chapter 11) Cerebellum and paresis: head tremor, ataxia, severe gait deficits, paresis Ascending paralysis: pelvic limb paresis progressing to tetraparesis (focal cervical spinal cord lesion must be ruled out) BOX 15-1 TABLE 15-1 Etiology of Systemic Diseases * Classification Acute Progressive Chronic Progressive CHAPTER 15 Systemic or Multifocal Signs Continued Sphingolipidoses GM1-gangliosidosis type 1 (Norman-Landing disease) β-d-Galactosidase C-Beagle cross (4-7 mo), Portuguese water dog (4-5 mo), English springer spaniel (4-5 mo), Alaskan husky, Shiba dog; F-DSH (2-3 mo); B-Friesian (birth); O-Coopworth Romney (1 mo), Suffolk (4 mo) C, F-Cerebellar ataxia, corneal clouding, tremor, seizures, paralysis, skeletal, facial dysmorphism; B, O-ataxia, recumbency; enzyme assays, DNA testing AR 257-264 GM1-gangliosidosis type 2 (Derry disease) β-d-Galactosidase F-Siamese, Korat (7 mo), DSH; O-Suffolk (4-6 mo) Same; O-rapid progression AR 265-267 GM2-gangliosidosis (Tay-Sachs disease) (Variant B) β-n-acetyl hexosaminidase A (α-subunit) C-German shorthair pointer (6-12 mo) Cerebellar ataxia; urine screening; enzyme assay Unknown 268,269 GM2-gangliosidosis (Sandhoff disease) (Variant O) β-n-acetyl hexosaminidase B (β-subunit) C-Golden retriever; toy poodle, F-DSH-Japan, Korat, Burmese-Europe (2-3 mo); S-Yorkshire Same; S-cerebellar ataxia, weakness Unknown 270-274 GM2AB-gangliosidosis (Bernheimer-Seitelberger disease) (Variant AB) GM2 activator protein deficiency C-Japanese spaniel (18 mo); F-Korat (18 mo) Same Unknown 275,276 Galactosialidosis Galactosialidosis with α-neuraminidase C-Schipperke (5 yr) Cerebellar ataxia Unknown 278 Glucocerebrosidosis (Gaucher disease) β-d-Glucocerebrosidase C-Sydney silky dog (6-8 mo); O-unknown; S-unknown Cerebellar ataxia; enzyme assay; biopsy AR(S) 279-281 Globoid cell leukodystrophy (Krabbe disease) β-d-galactosyl ceramidase (accumulation of psychosine) C-West Highland white terrier (2-5 mo), Cairn terrier (2-5 mo), beagle (4 mo), poodle (2 yr), basset hound (1.5-2 yr), blue tick hound (4 mo), pomeranian (1.5 yr), Irish setter (6 mo); F-DSH, DLH (5-6 wk); O-Dorset (4-18 mo) Cerebellar ataxia, tremor, paraparesis, neuropathy; muscle/nerve biopsy, enzyme assay; DNA testing AR or unknown 282-292 Metachromatic leukodystrophy Arylsulfatase A F-DSH (2 wk) Progressive motor dysfunction, seizures, opisthotonus, neuropathy Unknown 293 Sphingomyelinosis (Niemann-Pick disease type A) Sphingomyelinase C-Miniature poodle (2-4 mo); F-Balinese, Siamese (2-3 mo); B-Hereford (5 mo) Cerebellar ataxia, tremor, paraparesis, neuropathy; biopsy Unknown, AR-Siamese 294-298 (Niemann-Pick disease type C) Cholesterol esterification deficiency C-Boxer (9 mo); F-DSH (2-4 mo) C-Cerebellar ataxia, hepatomegaly, neuropathy; F-cerebellar ataxia, hepatic; enzyme testing, DNA testing Unknown 299,300 Mucopolysaccharidoses MPS I (Hurler syndrome) α-L-iduronidase C-Plott hound (3-6 mo), mixedbreed (3-6 mo); F-DSH (10 mo) Growth retardation, facial deformity, lameness, corneal opacity, cardiac; urine screening, enzyme testing, DNA testing AR 301,302 MPS II Iduronate-2-sulfate sulfatase C-Labrador retriever (5 yr) Cerebellar ataxia, exercise intolerance, corneal opacity, facial dysmorphism; urine screening, enzyme assay AR 303 MPS III (A, B, D) Sulfamidase A-heparin sulphamidase B-Nacetyl-alpha-Dglucosaminidase C-acetyl-CoA-alphaglucosaminide N-acetyltransferase D-n-acetylglucosamine 6-sulphatase C-Huntaway dog (IIIA) (18 mo), Schipperke (IIIB) (3 yr) wirehaired dachshund (IIIA) (3); B-breed unknown-Australia (IIIB) (2 yr); G-nubian (IIID) (birth) Cerebellar ataxia, tremor, retinal degeneration, corneal opacity; G-weakness; urine screening, enzyme assay, DNA testing AR 304-312 MPS VI (Maroteaux-Lamy disease) N-acetylgalactosamine 4-sulfase (arylsulfatase B) C-Miniature pinscher (6 mo); F-Siamese cat, DSH (4-7 mo) Growth retardation, facial deformity, corneal opacity, spinal fusion; urine screening, enzyme testing, DNA testing AR 313-315 MPS VII (Sly syndrome) β-d-glucouronidase C-Mixed breed; F-DSH C-Paraparesis, cardiac; F-growth retardation, facial deformity, corneal opacity, spinal fusion, cardiac; urine screening, enzyme testing, DNA testing AR 316,317 Disease Subgroup Storage Disease (Human Disease) Enzyme Deficiency Species-Breed (age at onset) Clinical Signs; Diagnosis Inheritance Reference All-Visual deficits, cerebellar ataxia, myoclonus, seizures of varying degree; tissue biopsy (autofluorescence) CLN 1 Palmitoyl protein thioesterase I C-Dachshund (mo) AR(S) Katz ML personal communication CLN 2 Tripeptidyl-peptidase C-Dachshund (4-5 mo) AR 318 CLN 4 (not confirmed) Unknown C-Tibetan terrier (4-6 yr) AR 319,320 CLN 5 Soluble lysosomal membrane protein C-Border collie (2 yr); O-borderdale (15 mo); B-Devon (12 mo) AR 321-323 CLN 6 Endoplasmic reticulum membrane protein C-Australian shepherd (1-2 yr) O-South Hampshire (3 mo), Merino (7 mo) Unknown or AR (O) 324-327 CLN 8 Membrane protein of the endoplasmic reticulum C-English setter (2 yr) AR 328,329 CSTD Cathepsin D C-American bulldog (2-4 yr); O-White Swedish landrace AR 330-332 CLN4 (Kuf's disease) Arylsulfatase G C-American Staffordshire terrier (>1 yr variable) AR 335,334 Unknown C-Australian cattle dog (1-2 yr), Australian shepherd (more than one NCL), Chihuahua (2 yr), cocker spaniel (1.5-6 yr), collie, dachshund (4.5 yr), dalmatian (6 mo-1 yr), golden retriever (2 yr), Japanese retriever (3 yr), Labrador retriever, miniature schnauzer, poodle, Polish lowland sheepdog (0.5-4.5 yr), saluki (2 yr), spitz, Welsh corgi (6-8 yr); F-Siamese cat, Japanese DSH, European DSH (<1 yr); B-beefmaster (12 mo), Devon (12 mo), Holstein (adult); O-Rambouillet (4 mo); G-nubian (4 mo); E-Icelandic × Peruvian paso Unknown 335-356
Veterinary Surgery, 1995
A model simulating acute‐compressive spinal cord trauma at the second lumbar spinal cord segment ... more A model simulating acute‐compressive spinal cord trauma at the second lumbar spinal cord segment (100 g, 300 seconds) was used to evaluate the efficacy of a vehicle control, methylprednisolone sodium succinate (MPSS), and a 21‐aminosteroid compound (U74389G). Dogs were allocated into one of five treatment groups (A to E) using ultrasonographic determination of spinal cord diameters to ensure even distribution of spinal cord diameters among the treatment groups. Initial dosages of the vehicle control (A), methylprednisolone (30 mg/kg of body weight) (B), or U74389G (30 mg/kg, 3 mg/kg, or 10 mg/kg of body weight) (C, D, or E, respectively) were administered intravenously 30 minutes after trauma. Dosages were reduced by one‐half for 2 and 6 hour treatments. Then every 4 hours for 42 hours, dosages were reduced one‐third and one‐sixth from the original dose of methylprednisolone and U74389G, respectively. Neurological examinations were performed daily for 21 days. Histopathological exam...
Veterinary Radiology <html_ent glyph="@amp;" ascii="&"/> Ultrasound, 1995
... Small An-imal Surgery and Medicine (Coates, Sorjonen, Simpson, Miller), Scott-Ritchey Researc... more ... Small An-imal Surgery and Medicine (Coates, Sorjonen, Simpson, Miller), Scott-Ritchey Research Center (Steiss, Vaughn, Cox), Pathobiology ... pulsatility index (PI = [peak systolic velocity - minimum diastolic velocity]imean ve-locity) and systolicidiastolic ratio (SID ratio = peak ...
Veterinary Radiology <html_ent glyph="@amp;" ascii="&"/> Ultrasound, 1995
Page 1. ULTRASONOGRAPHIC ANATOMY OF THE NORMAL CANINE SPINAL CORD AND CORRELATION WITH HISTOPATHO... more Page 1. ULTRASONOGRAPHIC ANATOMY OF THE NORMAL CANINE SPINAL CORD AND CORRELATION WITH HISTOPATHOLOGY AFTER INDUCED SPINAL CORD TRAUMA SUSAN T. FINN-BODNER, DVM, MS, JUDITH ...
Veterinary Pathology, 2009
Postmortem examination was performed on 18 Pembroke Welsh Corgi dogs (mean age 12.7 years) with c... more 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.
Veterinary Clinics of North America: Small Animal Practice, 2010
Canine degenerative myelopathy (DM) was first described in 1973 by Averill as an insidious, progr... more Canine degenerative myelopathy (DM) was first described in 1973 by Averill as an insidious, progressive, general proprioceptive (GP) ataxia and upper motor neuron (UMN) spastic paresis of the pelvic limbs beginning in late adulthood, ultimately leading to paraplegia and necessitating euthanasia. 1 Until recently, presence of primary axonal degeneration and nerve fiber loss that was restricted to spinal cord white matter and most severe in the mid to caudal thoracic region was compatible with a diagnosis of DM. The disease was termed "degenerative myelopathy" because of its histopathologic nature as a nonspecific degeneration of spinal cord tissue of undetermined cause. In 1975, Griffiths and Duncan published a series of cases with similar clinical signs and histologic changes in the white matter. They also reported hyporeflexia and nerve root involvement, and they termed the condition chronic degenerative radiculomyelopathy. 2 Though most of the dogs in these initial reports were German Shepherd Dogs (GSD), other breeds were represented. Nonetheless, for many years, DM was considered an UMN and GP disease in the GSD. 3 More recently DM has been recognized as a common problem in a number of breeds with an overall prevalence of 0.19%. 4 Additionally, the clinical spectrum of DM has been broadened to involve both the UMN and lower motor neuron (LMN) systems. 5 A recent advance in the molecular genetics of DM indicates that this canine disease may share pathogenic mechanisms with some forms of human amyotrophic lateral sclerosis (ALS-Lou Gehrig's disease). 5
Proceedings of the National Academy of Sciences, 2009
Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog... more 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. Hom...
Veterinary Surgery, Mar 1, 1995
A model simulating acute-compressive spinal cord trauma at the second lumbar spinal cord segment ... more A model simulating acute-compressive spinal cord trauma at the second lumbar spinal cord segment (100 g, 300 seconds) was used to evaluate the efficacy of a vehicle control, methylprednisolone sodium succinate (MPSS), and a 2 1-aminosteroid compound (U74389G). Dogs were allocated into one of five treatment groups (A to E) using ultrasonographic determination of spinal cord diameters to ensure even distribution of spinal cord diameters among the treatment groups. Initial dosages of the vehicle control (A), methylprednisolone (30 mg/kg of body weight) (B), or U74389G (30 mg/kg, 3 mg/kg, or 10 mg/kg of body weight) (C, D, or E, respectively) were administered intravenously 30 minutes after trauma. Dosages were reduced by one-half for 2 and 6 hour treatments. Then every 4 hours for 42 hours, dosages were reduced one-third and one-sixth from the original dose of methylprednisolone and U74389G, respectively. Neurological examinations were performed daily for 2 1 days. Histopathological examination of the traumatized spinal cord showed malacic and degenerative lesions. Although significant differences in some portions of the neurological and histopathologic examinations were observed, clinical efficacy for MPSS and U74389G could not be established in this model.
Journal of Neuroscience Research, Dec 21, 2013
Canine Degenerative Myelopathy (DM) is a progressive adult-onset multisystem degenerative disease... more Canine Degenerative Myelopathy (DM) is a progressive adult-onset multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general proprioceptive ataxia and spastic upper motor neuron paresis in pelvic limbs, which progress to flaccid tetraplegia and dysphagia. The purpose of this study was to characterize DM as a potential disease model for ALS. We previously reported that intercostal muscle atrophy develops in dogs with advanced stage DM. To determine if other components of the thoracic motor unit (MU) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MN) and dorsal root ganglia (DRG), and in motor and sensory nerve root axons from DMaffected Boxers and Pembroke Welsh Corgis (PWCs). No alterations in MNs, or motor root axons were observed in either breed. However, advanced stage PWCs exhibited significant losses of sensory root axons, and numerous DRG sensory neurons displayed evidence of degeneration. These results indicate that intercostal muscle atrophy in DM is not preceded by physical loss of the motor neurons innervating these muscles, or of their axons. Axonal loss in thoracic sensory roots and sensory nerve death suggest sensory involvement may play an important role in DM disease progression. Further analysis of the mechanisms responsible for these morphological findings would aid in the development of therapeutic intervention for DM and some forms of ALS.
Blood-based biomarkers are much-needed diagnostic and prognostic tools for ALS. Canine degenerati... more Blood-based biomarkers are much-needed diagnostic and prognostic tools for ALS. Canine degenerative myelopathy (DM) is recognized animal disease model to study the biology of human ALS. Serum derived exosomes are potential carrier that transport intercellular hormone-like messengers, together with their stability as carrier of proteins and RNA, make them ideal as biomarkers for a variety of diseases and biological processes. We study exosomal TDP-43 pattern as a surrogate biomarker that reflects biochemical changes in central nervous system. We isolated exosomes from canine serum using commercial exosome isolation reagents. TDP-43 and SOD1 profile in spinal cord homogenate lysate and that of serum-derived exosomes were found elevated in dogs with DM. We conclude levels of spinal cord TDP-43 and serum-derived exomes were similar in TDP-43 profiling, which warrant further investigation of disease sensitivity and specificity for establishing as a blood-based biomarker in canine DM.
Journal of Veterinary Internal Medicine, 2021
Background: Degenerative myelopathy (DM) in dogs shares similarities with superoxide dismutase 1-... more Background: Degenerative myelopathy (DM) in dogs shares similarities with superoxide dismutase 1-associated human amyotrophic lateral sclerosis (ALS). Brain microstructural lesions are quantified using diffusion tensor imaging (DTI) in ALS patients. Objective: Characterize brain neurodegenerative changes in DM-affected dogs using DTI. Animals: Sixteen DM-affected and 8 control dogs. Methods: Prospective observational study. Brain DTI was performed at baseline and every 3 months on DM-affected dogs and compared to controls. Fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated on specified regions of interest. Gait scores (0, normal to 14, tetraplegia) were assigned at each scan. Diffusion tensor imaging values in DM-affected dogs were compared to controls, gait scores, and evaluated over time. Results: Mean age was 5.7 years (SD 3.2) in controls and 9.7 years (SD 1.4) in DMaffected dogs. In DM-affected dogs, mean baseline gait score was 4 (SD 1), and mean score change from baseline to last scan was 4.82 (SD 2.67). Nine dogs had ≤3 scans; 7 had >3 scans. Accounting for age, no differences in DTI indices were identified for any brain or proximal spinal cord regions between DM-affected dogs and controls (P > .05). Diffusion tensor imaging values poorly correlated with gait scores (R 2 < .2). No significant changes were identified in diffusion indices over time (P > .05). Conclusions and Clinical Importance: Diffusion tensor imaging indices did not differentiate DM-affected from control dogs, detect longitudinal changes, or differentiate disease severity. Findings do not yet support brain DTI as an imaging biomarker.
GeroScience, 2019
Altered microglia function contributes to loss of CNS homeostasis during aging in the brain. Few ... more Altered microglia function contributes to loss of CNS homeostasis during aging in the brain. Few studies have evaluated age-related alterations in spinal cord microglia. We previously demonstrated that lumbar spinal cord microglial expression of inducible nitric oxide synthase (iNOS) was equivalent between aging, neurologically normal dogs and
Journal of Veterinary Internal Medicine, 2019
BackgroundThe intranasal (IN) route for rapid drug administration in patients with brain disorder... more BackgroundThe intranasal (IN) route for rapid drug administration in patients with brain disorders, including status epilepticus, has been investigated. Status epilepticus is an emergency, and the IN route offers a valuable alternative to other routes, especially when these fail.ObjectivesTo compare IN versus IV midazolam (MDZ) at the same dosage (0.2 mg/kg) for controlling status epilepticus in dogs.AnimalsClient‐owned dogs (n = 44) with idiopathic epilepsy, structural epilepsy, or epilepsy of unknown origin manifesting as status epilepticus.MethodsRandomized parallel group clinical trial. Patients were randomly allocated to the IN‐MDZ (n = 21) or IV‐MDZ (n = 23) group. Number of successfully treated cases (defined as seizure cessation within 5 minutes and lasting for ≥10 minutes), seizure cessation time, and adverse effects were recorded. Comparisons were performed using the Fisher's exact and Wilcoxon rank sum tests with statistical significance set at α < .05.ResultsIN‐MD...
Molecular Neurobiology, 2019
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progres... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons and grim prognosis. Over the last decade, studies on neurodegenerative diseases pointed on the role of glia in supporting the proper function of neurons. Particularly, oligodendrocytes were shown to be essential through myelin production and supplying axons with energy metabolites via monocarboxylate transporters (MCT). We have used dogs with naturally occurring degenerative myelopathy (DM) which closely resembles features observed in human ALS. We have performed two types of analysis of spinal cord tissue samples: histology and molecular analysis. Histology included samples collected from dogs that succumbed to the DM at different disease stages, which were compared to age-matched controls as well as put in the context of young spinal cords. Molecular analysis was performed on spinal cords with advanced DM and age-matched samples and included real-time PCR analysis of selected gene products related to the function of neurons, oligodendrocytes, myelin, and MCT. Demyelination has been detected in dogs with DM through loss of eriochrome staining and decreased expression of genes related to myelin including MBP, Olig1, and Olig2. The prominent reduction of MCT1 and MCT2 and increased MCT4 expression is indicative of disturbed energy supply to neurons. While Rbfox3 expression was not altered, the ChAT production was negatively affected. DM in dogs reproduces main features of human ALS including loss of motor neurons, dysregulation of energy supply to neurons, and loss of myelin, and as such is an ideal model system for highly translational studies on therapeutic approaches for ALS.
Gene Therapy, 2017
CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neur... more CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for the development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function and development of histopathological myocardial lesions. Progressive increases in the plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in the heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system.
Disease Models & Mechanisms, 2017
Targeting the CB2 receptor afforded neuroprotection in SOD1G93A mutant mice, a model of amyotroph... more Targeting the CB2 receptor afforded neuroprotection in SOD1G93A mutant mice, a model of amyotrophic lateral sclerosis (ALS). The neuroprotective effects of CB2 receptors were facilitated by their up-regulation in the spinal cord in SOD1G93A mutant mice. Herein, we have investigated whether a similar CB2 receptor up-regulation, as well as parallel changes in other endocannabinoid elements, are evident in the spinal cord of dogs with degenerative myelopathy (DM), caused from mutations in the superoxide dismutase 1 gene (SOD1). We used well-characterized post-mortem spinal cords from unaffected and DM-affected dogs. Tissues were used first to confirm the loss of motor neurons using Nissl staining, which was accompanied by glial reactivity (elevated GFAP and Iba-1 immunoreactivity). Next, we investigated possible differences in the expression of endocannabinoid genes measured by qPCR between DM-affected and control dogs. We found no changes in the CB1 receptor (also found with CB1 recep...
Veterinary Clinics of North America: Small Animal Practice, 2000
Small Animal Neurological Emergencies, 2012
Science translational medicine, Jan 11, 2015
The most common form of the childhood neurodegenerative disease late infantile neuronal ceroid li... more The most common form of the childhood neurodegenerative disease late infantile neuronal ceroid lipofuscinosis (also called Batten disease) is caused by deficiency of the soluble lysosomal enzyme tripeptidyl peptidase 1 (TPP1) resulting from mutations in the TPP1 gene. We tested whether TPP1 gene transfer to the ependyma, the epithelial lining of the brain ventricular system, in TPP1-deficient dogs would be therapeutically beneficial. A one-time administration of recombinant adeno-associated virus (rAAV) expressing canine TPP1 (rAAV.caTPP1) resulted in high expression of TPP1 predominantly in ependymal cells and secretion of the enzyme into the cerebrospinal fluid leading to clinical benefit. Diseased dogs treated with rAAV.caTPP1 showed delays in onset of clinical signs and disease progression, protection from cognitive decline, and extension of life span. By immunostaining and enzyme assay, recombinant protein was evident throughout the brain and spinal cord, with correction of the...
Handbook of Veterinary Neurology, 2011
Handbook of Veterinary Neurology, 2011
Lower motor neuron (LMN) signs (more than one location, may include cranial nerves): diffuse LMN ... more Lower motor neuron (LMN) signs (more than one location, may include cranial nerves): diffuse LMN diseases, polyneuropathy (see Chapter 7) Brain and spinal cord signs: pelvic limb paresis and seizures Systemic disease and CNS signs: fever, anorexia, ataxia, or seizures Generalized pain: meningitis Cerebral cortex and brainstem: cerebrum seizures and cranial nerve deficits, blindness, severe gait deficits, head tilt, circling Forebrain: blindness with normal pupils (may be seen with brain swelling, hydrocephalus) (see Chapter 11) Cerebellum and paresis: head tremor, ataxia, severe gait deficits, paresis Ascending paralysis: pelvic limb paresis progressing to tetraparesis (focal cervical spinal cord lesion must be ruled out) BOX 15-1 TABLE 15-1 Etiology of Systemic Diseases * Classification Acute Progressive Chronic Progressive CHAPTER 15 Systemic or Multifocal Signs Continued Sphingolipidoses GM1-gangliosidosis type 1 (Norman-Landing disease) β-d-Galactosidase C-Beagle cross (4-7 mo), Portuguese water dog (4-5 mo), English springer spaniel (4-5 mo), Alaskan husky, Shiba dog; F-DSH (2-3 mo); B-Friesian (birth); O-Coopworth Romney (1 mo), Suffolk (4 mo) C, F-Cerebellar ataxia, corneal clouding, tremor, seizures, paralysis, skeletal, facial dysmorphism; B, O-ataxia, recumbency; enzyme assays, DNA testing AR 257-264 GM1-gangliosidosis type 2 (Derry disease) β-d-Galactosidase F-Siamese, Korat (7 mo), DSH; O-Suffolk (4-6 mo) Same; O-rapid progression AR 265-267 GM2-gangliosidosis (Tay-Sachs disease) (Variant B) β-n-acetyl hexosaminidase A (α-subunit) C-German shorthair pointer (6-12 mo) Cerebellar ataxia; urine screening; enzyme assay Unknown 268,269 GM2-gangliosidosis (Sandhoff disease) (Variant O) β-n-acetyl hexosaminidase B (β-subunit) C-Golden retriever; toy poodle, F-DSH-Japan, Korat, Burmese-Europe (2-3 mo); S-Yorkshire Same; S-cerebellar ataxia, weakness Unknown 270-274 GM2AB-gangliosidosis (Bernheimer-Seitelberger disease) (Variant AB) GM2 activator protein deficiency C-Japanese spaniel (18 mo); F-Korat (18 mo) Same Unknown 275,276 Galactosialidosis Galactosialidosis with α-neuraminidase C-Schipperke (5 yr) Cerebellar ataxia Unknown 278 Glucocerebrosidosis (Gaucher disease) β-d-Glucocerebrosidase C-Sydney silky dog (6-8 mo); O-unknown; S-unknown Cerebellar ataxia; enzyme assay; biopsy AR(S) 279-281 Globoid cell leukodystrophy (Krabbe disease) β-d-galactosyl ceramidase (accumulation of psychosine) C-West Highland white terrier (2-5 mo), Cairn terrier (2-5 mo), beagle (4 mo), poodle (2 yr), basset hound (1.5-2 yr), blue tick hound (4 mo), pomeranian (1.5 yr), Irish setter (6 mo); F-DSH, DLH (5-6 wk); O-Dorset (4-18 mo) Cerebellar ataxia, tremor, paraparesis, neuropathy; muscle/nerve biopsy, enzyme assay; DNA testing AR or unknown 282-292 Metachromatic leukodystrophy Arylsulfatase A F-DSH (2 wk) Progressive motor dysfunction, seizures, opisthotonus, neuropathy Unknown 293 Sphingomyelinosis (Niemann-Pick disease type A) Sphingomyelinase C-Miniature poodle (2-4 mo); F-Balinese, Siamese (2-3 mo); B-Hereford (5 mo) Cerebellar ataxia, tremor, paraparesis, neuropathy; biopsy Unknown, AR-Siamese 294-298 (Niemann-Pick disease type C) Cholesterol esterification deficiency C-Boxer (9 mo); F-DSH (2-4 mo) C-Cerebellar ataxia, hepatomegaly, neuropathy; F-cerebellar ataxia, hepatic; enzyme testing, DNA testing Unknown 299,300 Mucopolysaccharidoses MPS I (Hurler syndrome) α-L-iduronidase C-Plott hound (3-6 mo), mixedbreed (3-6 mo); F-DSH (10 mo) Growth retardation, facial deformity, lameness, corneal opacity, cardiac; urine screening, enzyme testing, DNA testing AR 301,302 MPS II Iduronate-2-sulfate sulfatase C-Labrador retriever (5 yr) Cerebellar ataxia, exercise intolerance, corneal opacity, facial dysmorphism; urine screening, enzyme assay AR 303 MPS III (A, B, D) Sulfamidase A-heparin sulphamidase B-Nacetyl-alpha-Dglucosaminidase C-acetyl-CoA-alphaglucosaminide N-acetyltransferase D-n-acetylglucosamine 6-sulphatase C-Huntaway dog (IIIA) (18 mo), Schipperke (IIIB) (3 yr) wirehaired dachshund (IIIA) (3); B-breed unknown-Australia (IIIB) (2 yr); G-nubian (IIID) (birth) Cerebellar ataxia, tremor, retinal degeneration, corneal opacity; G-weakness; urine screening, enzyme assay, DNA testing AR 304-312 MPS VI (Maroteaux-Lamy disease) N-acetylgalactosamine 4-sulfase (arylsulfatase B) C-Miniature pinscher (6 mo); F-Siamese cat, DSH (4-7 mo) Growth retardation, facial deformity, corneal opacity, spinal fusion; urine screening, enzyme testing, DNA testing AR 313-315 MPS VII (Sly syndrome) β-d-glucouronidase C-Mixed breed; F-DSH C-Paraparesis, cardiac; F-growth retardation, facial deformity, corneal opacity, spinal fusion, cardiac; urine screening, enzyme testing, DNA testing AR 316,317 Disease Subgroup Storage Disease (Human Disease) Enzyme Deficiency Species-Breed (age at onset) Clinical Signs; Diagnosis Inheritance Reference All-Visual deficits, cerebellar ataxia, myoclonus, seizures of varying degree; tissue biopsy (autofluorescence) CLN 1 Palmitoyl protein thioesterase I C-Dachshund (mo) AR(S) Katz ML personal communication CLN 2 Tripeptidyl-peptidase C-Dachshund (4-5 mo) AR 318 CLN 4 (not confirmed) Unknown C-Tibetan terrier (4-6 yr) AR 319,320 CLN 5 Soluble lysosomal membrane protein C-Border collie (2 yr); O-borderdale (15 mo); B-Devon (12 mo) AR 321-323 CLN 6 Endoplasmic reticulum membrane protein C-Australian shepherd (1-2 yr) O-South Hampshire (3 mo), Merino (7 mo) Unknown or AR (O) 324-327 CLN 8 Membrane protein of the endoplasmic reticulum C-English setter (2 yr) AR 328,329 CSTD Cathepsin D C-American bulldog (2-4 yr); O-White Swedish landrace AR 330-332 CLN4 (Kuf's disease) Arylsulfatase G C-American Staffordshire terrier (>1 yr variable) AR 335,334 Unknown C-Australian cattle dog (1-2 yr), Australian shepherd (more than one NCL), Chihuahua (2 yr), cocker spaniel (1.5-6 yr), collie, dachshund (4.5 yr), dalmatian (6 mo-1 yr), golden retriever (2 yr), Japanese retriever (3 yr), Labrador retriever, miniature schnauzer, poodle, Polish lowland sheepdog (0.5-4.5 yr), saluki (2 yr), spitz, Welsh corgi (6-8 yr); F-Siamese cat, Japanese DSH, European DSH (<1 yr); B-beefmaster (12 mo), Devon (12 mo), Holstein (adult); O-Rambouillet (4 mo); G-nubian (4 mo); E-Icelandic × Peruvian paso Unknown 335-356
Veterinary Surgery, 1995
A model simulating acute‐compressive spinal cord trauma at the second lumbar spinal cord segment ... more A model simulating acute‐compressive spinal cord trauma at the second lumbar spinal cord segment (100 g, 300 seconds) was used to evaluate the efficacy of a vehicle control, methylprednisolone sodium succinate (MPSS), and a 21‐aminosteroid compound (U74389G). Dogs were allocated into one of five treatment groups (A to E) using ultrasonographic determination of spinal cord diameters to ensure even distribution of spinal cord diameters among the treatment groups. Initial dosages of the vehicle control (A), methylprednisolone (30 mg/kg of body weight) (B), or U74389G (30 mg/kg, 3 mg/kg, or 10 mg/kg of body weight) (C, D, or E, respectively) were administered intravenously 30 minutes after trauma. Dosages were reduced by one‐half for 2 and 6 hour treatments. Then every 4 hours for 42 hours, dosages were reduced one‐third and one‐sixth from the original dose of methylprednisolone and U74389G, respectively. Neurological examinations were performed daily for 21 days. Histopathological exam...
Veterinary Radiology <html_ent glyph="@amp;" ascii="&"/> Ultrasound, 1995
... Small An-imal Surgery and Medicine (Coates, Sorjonen, Simpson, Miller), Scott-Ritchey Researc... more ... Small An-imal Surgery and Medicine (Coates, Sorjonen, Simpson, Miller), Scott-Ritchey Research Center (Steiss, Vaughn, Cox), Pathobiology ... pulsatility index (PI = [peak systolic velocity - minimum diastolic velocity]imean ve-locity) and systolicidiastolic ratio (SID ratio = peak ...
Veterinary Radiology <html_ent glyph="@amp;" ascii="&"/> Ultrasound, 1995
Page 1. ULTRASONOGRAPHIC ANATOMY OF THE NORMAL CANINE SPINAL CORD AND CORRELATION WITH HISTOPATHO... more Page 1. ULTRASONOGRAPHIC ANATOMY OF THE NORMAL CANINE SPINAL CORD AND CORRELATION WITH HISTOPATHOLOGY AFTER INDUCED SPINAL CORD TRAUMA SUSAN T. FINN-BODNER, DVM, MS, JUDITH ...
Veterinary Pathology, 2009
Postmortem examination was performed on 18 Pembroke Welsh Corgi dogs (mean age 12.7 years) with c... more 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.
Veterinary Clinics of North America: Small Animal Practice, 2010
Canine degenerative myelopathy (DM) was first described in 1973 by Averill as an insidious, progr... more Canine degenerative myelopathy (DM) was first described in 1973 by Averill as an insidious, progressive, general proprioceptive (GP) ataxia and upper motor neuron (UMN) spastic paresis of the pelvic limbs beginning in late adulthood, ultimately leading to paraplegia and necessitating euthanasia. 1 Until recently, presence of primary axonal degeneration and nerve fiber loss that was restricted to spinal cord white matter and most severe in the mid to caudal thoracic region was compatible with a diagnosis of DM. The disease was termed "degenerative myelopathy" because of its histopathologic nature as a nonspecific degeneration of spinal cord tissue of undetermined cause. In 1975, Griffiths and Duncan published a series of cases with similar clinical signs and histologic changes in the white matter. They also reported hyporeflexia and nerve root involvement, and they termed the condition chronic degenerative radiculomyelopathy. 2 Though most of the dogs in these initial reports were German Shepherd Dogs (GSD), other breeds were represented. Nonetheless, for many years, DM was considered an UMN and GP disease in the GSD. 3 More recently DM has been recognized as a common problem in a number of breeds with an overall prevalence of 0.19%. 4 Additionally, the clinical spectrum of DM has been broadened to involve both the UMN and lower motor neuron (LMN) systems. 5 A recent advance in the molecular genetics of DM indicates that this canine disease may share pathogenic mechanisms with some forms of human amyotrophic lateral sclerosis (ALS-Lou Gehrig's disease). 5
Proceedings of the National Academy of Sciences, 2009
Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog... more 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. Hom...