Characterization of microtubule-associated protein tau isoforms and Alzheimer's disease-like pathology in normal sheep (Ovis aries): relevance to their potential as a model of Alzheimer's disease.

Alzheimer's disease is a chronic neurodegenerative disease that accounts for up to 80% of all dementias. Characterised by deteriorations of memory and cognitive function, the key neuropathological features are accumulations of ß-amyloid and hyperphosphorylated tau, as 'plaques' and 'tangles', respectively. Despite extensive study, however, the exact mechanism underlying aggregate formation in Alzheimer's disease remains elusive, as does the contribution of these aggregates to disease progression. Importantly, a recent evaluation of current Alzheimer's disease animal models suggested that rodent models are not able to fully recapitulate the pathological intricacies of the disease as it occurs in humans. Therefore, increasing attention is being paid to species that might make good alternatives to rodents for studying the molecular pathology of Alzheimer's disease. The sheep (Ovis aries) is one such species, although to date, there have been few molecular studies relating to Alzheimer's disease in sheep. Here, we investigated the Alzheimer's disease relevant histopathological characteristics of 22 sheep, using anti-ß-amyloid (Abcam 12267 and mOC64) and phosphorylation specific anti-tau (AT8 and S396) antibodies. We identified numerous intraneuronal aggregates of both ß-amyloid and tau that are consistent with early Alzheimer's disease-like pathology. We confirmed the expression of two 3-repeat (1N3R, 2N3R) and two 4-repeat (1N4R, 2N4R) tau isoforms in the ovine brain, which result from the alternative splicing of two tau exons. Finally, we investigated the phosphorylation status of the serine396 residue in 30 sheep, and report that the phosphorylation of this residue begins in sheep aged as young as 2 years. Together, these data show that sheep exhibit naturally occurring ß-amyloid and tau pathologies, that reflect those that occur in the early stages of Alzheimer's disease. This is an important step towards the validation of the sheep as a feasible large animal species in which to model Alzheimer's disease.

Epaxial muscle atrophy is more evident in large dogs with intervertebral disc disease than in dogs with ischaemic myelopathy.

Cross-sectional area (CSA) decreases and fat infiltration increases in epaxial muscles of Dachshunds with intervertebral disc disease (IVDD), but less is known about large breed dogs with IVDD. The aim here was to investigate thoracolumbar epaxial muscle CSA and fat infiltration in large breed dogs with compressive IVDD and acute non-compressive nucleus pulposus extrusion (ANNPE) or fibrocartilaginous embolism (FCE). This retrospective study included large breed dogs with MRI-confirmed IVDD (n = 17) and ANNPE or FCE (n = 13). The CSA and fat infiltration of the thoracolumbar M. longissimus and Mm. multifidi were assessed from T1-weighted transverse MR images using Osirix. The CSA was significantly smaller in dogs with compressive IVDD than in dogs with non-compressive ANNPE or FCE for Mm. multifidi (p = 0.015), M. longissimus (p = 0.070), and these two muscles combined (p = 0.016). Fat infiltration in all muscle measurements was significantly higher in dogs with compressive IVDD than in dogs with non-compressive ANNPE or FCE (all P < 0.050). A significant positive correlation existed between age, duration of clinical signs, and fat infiltration, suggesting more fat infiltration in older dogs with more chronic signs. These signs of muscle atrophy are likely caused by denervation and secondary disuse due to chronic spinal cord compression and prolonged duration of clinical signs.

Interthalamic adhesion size in aging dogs with presumptive spontaneous brain microhemorrhages: a comparative retrospective MRI study of dogs with and without evidence of canine cognitive dysfunction.

OBJECTIVE: Spontaneous brain microhemorrhages in elderly people are present to some degree in Alzheimer's disease patients but have been linked to brain atrophy in the absence of obvious cognitive decline. Brain microhemorrhages have recently been described in older dogs, but it is unclear whether these are associated with brain atrophy. Diminution of interthalamic adhesion size-as measured on MRI or CT-has been shown to be a reliable indicator of brain atrophy in dogs with canine cognitive dysfunction (CCD) in comparison with successfully aging dogs. We hypothesized that aging dogs with brain microhemorrhages presenting for neurologic dysfunction but without obvious features of cognitive decline would have small interthalamic adhesion measurements, like dogs with CCD, compared with control dogs. The objective of this study was to compare interthalamic adhesion size between three groups of aging (>9 years) dogs: (1) neurologically impaired dogs with presumptive spontaneous brain microhemorrhages and no clinical evidence of cognitive dysfunction (2) dogs with CCD (3) dogs without clinical evidence of encephalopathy on neurologic examination (control dogs). MR images from 52 aging dogs were reviewed and measurements were obtained of interthalamic adhesion height (thickness) and mid-sagittal interthalamic adhesion area for all dogs, in addition to total brain volume. Interthalamic adhesion measurements, either absolute or normalized to total brain volume were compared between groups. Signalment (age, breed, sex), body weight, presence and number of SBMs, as well as other abnormal MRI findings were recorded for all dogs. RESULTS: All interthalamic adhesion measurement parameters were significantly (P < 0.05) different between control dogs and affected dogs. Both dogs with cognitive dysfunction (12/15; 80%) and dogs with isolated brain microhemorrhages had more microhemorrhages than control dogs (3/25; 12%). Affected dogs without cognitive dysfunction had significantly more microhemorrhages than dogs with cognitive dysfunction. In addition to signs of cognitive impairment for the CCD group, main clinical complaints for SBM and CCD dogs were referable to central vestibular dysfunction, recent-onset seizure activity, or both. Geriatric dogs with spontaneous brain microhemorrhages without cognitive dysfunction have similar MRI abnormalities as dogs with cognitive dysfunction but may represent a distinct disease category.

Canine Cognitive Dysfunction: Pathophysiology, Diagnosis, and Treatment.

Canine cognitive dysfunction (CCD) is the canine analog of human Alzheimer disease (AD). The pathophysiology of CCD/AD is multifaceted. CCD is common in aged (>8 years) dogs, affecting between 14% and 35% of the pet dog population. Apparent confusion, anxiety, disturbance of the sleep/wake cycle, and decreased interaction with owners are all common clinical signs of CCD. Although there is no cure for CCD, several proven effective therapeutic approaches are available for improving cognitive ability and maintaining a good quality of life; instituting such therapies early in the disease course is likely to have the greatest positive clinical effect.

A randomised trial of a medium-chain TAG diet as treatment for dogs with idiopathic epilepsy.

Despite appropriate antiepileptic drug treatment, approximately one-third of humans and dogs with epilepsy continue experiencing seizures, emphasising the importance for new treatment strategies to improve the quality of life of people or dogs with epilepsy. A 6-month prospective, randomised, double-blinded, placebo-controlled cross-over dietary trial was designed to compare a ketogenic medium-chain TAG diet (MCTD) with a standardised placebo diet in chronically antiepileptic drug-treated dogs with idiopathic epilepsy. Dogs were fed either MCTD or placebo diet for 3 months followed by a subsequent respective switch of diet for a further 3 months. Seizure frequency, clinical and laboratory data were collected and evaluated for twenty-one dogs completing the study. Seizure frequency was significantly lower when dogs were fed the MCTD (2·31/month, 0-9·89/month) in comparison with the placebo diet (2·67/month, 0·33-22·92/month, P=0·020); three dogs achieved seizure freedom, seven additional dogs had ≥50 % reduction in seizure frequency, five had an overall <50 % reduction in seizures (38·87 %, 35·68-43·27 %) and six showed no response. Seizure day frequency were also significantly lower when dogs were fed the MCTD (1·63/month, 0-7·58/month) in comparison with the placebo diet (1·69/month, 0·33-13·82/month, P=0·022). Consumption of the MCTD also resulted in significant elevation of blood ß-hydroxybutyrate concentrations in comparison with placebo diet (0·071 (sd 0·035) v. 0·053 (sd 0·028) mmol/l, P=0·028). There were no significant changes in serum concentrations of glucose (P=0·903), phenobarbital (P=0·422), potassium bromide (P=0·404) and weight (P=0·300) between diet groups. In conclusion, the data show antiepileptic properties associated with ketogenic diets and provide evidence for the efficacy of the MCTD used in this study as a therapeutic option for epilepsy treatment.

Comparison of cross sectional area and fat infiltration of the epaxial muscles in dogs with and without spinal cord compression.

This study investigated the cross sectional area (CSA) and fat infiltration of the epaxial muscles in Dachshunds with compressive spinal cord lesions due to intervertebral disc herniation (IVDH) and in dogs with non-compressive spinal cord lesions with fibrocartilaginous embolism (FCE). The CSA and fat infiltration of the multifidi and longissimus dorsi muscles were determined from T1 weighted magnetic resonance images. Difference in CSA and fat infiltration between the lesion- and non-lesion side in the Dachshunds was assessed using mixed model analysis. Difference in CSA and fat infiltration between Dachshunds and FCE dogs was analysed with independent sample t-tests. There was no difference in CSA or fat infiltration between sides in the Dachshunds. FCE dogs had greater CSA (multifidus P = 0.036, longissimus P < 0.001) and less fat infiltration compared to Dachshunds (longissimus P = 0.017). Duration of neurological deficits, age, body size and conformation are likely to have influenced the difference between the groups.

Quantitative ultrasonography for assessment of bone mineral density in the canine radius and tibia.

Quantitative ultrasound allows noninvasive assessment of cortical bone density. Potential applications include monitoring of fracture healing, rehabilitation, and skeletal diseases. The objectives of this study were to determine the three most accessible portals to obtain speed of sound measurements of the radius and tibia with an Omnisense multisite quantitative ultrasound device and to determine probe-dependent intra- and interoperator variability for speed of sound measurements of the radius and tibia in six healthy hounds. The radius was most accessible at the cranial proximal metaphysis, the cranial middiaphysis, and medial distal metaphysis. Speed of sound measurements were possible at these sites on the radius with acceptable intra- and interoperator variation (1.6-4.6%). Measurements differed significantly when performed with different probes at the cranial proximal radial metaphysis. The tibia was most accessible at the cranial proximal metaphysis, the medial middiaphysis, and medial distal metaphysis. The medial middiaphyseal and mediodistal tibial sites allowed measurements with lowest intra- and interoperator variation (< 3.5%). A smaller probe allowed tibial measurements with lowest interoperator variation. Measurements did not differ significantly at each tibial site when different probes were used. Measurements did not differ significantly between observers when measuring with the same probe at each specific site on radius and tibia. A medium-size probe allowed for most time-efficient measurements and the least number of failed measurements on the radius and tibia. Speed of sound can be consistently measured by different observers on the radius and tibia in healthy hounds.