Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

Arytenoid mucosal injury in young Thoroughbred horses 14 investigation of a proposed aetiology and clinical significance

AIM: To determine whether trauma to the larynx caused by nasotracheal intubation induced mucosal ulceration of the arytenoid cartilages of adult horses, and to determine the incidence of such ulceration in yearling Thoroughbred horses and its effect on athletic performance. METHODS: Laryngeal trauma was induced in a group of 21 adult horses by introduction of a nasogastric tube into the trachea three times within 5 min. Injury to the arytenoid cartilages or vocal cords was subjectively assessed immediately after intubation, and thereafter at weekly intervals for 10 weeks. The outcome and athletic performance of 33 Thoroughbred yearling horses with idiopathic disease of the arytenoid cartilages, diagnosed at the yearling sales, were evaluated and compared to those of control horses of the same gender and age, from the same sale. \ud RESULTS: Mucosal injury was noted immediately after intubation in every horse. Evidence of injury to the vocal or corniculate processes of the arytenoid cartilages or vocal cords was still apparent in 10/21 (48%) horses 1 week after intubation, five of which developed persistent lesions that remained present and unchanged from 28 days following intubation until the end of the 10-week observation period. All persistent lesions were nodules or focal swellings of the vocal cords or arytenoid cartilages, and there was no evidence of mucosal ulceration, infection or discharge. Mucosal ulceration of the vocal processes was the most common abnormality detected in the yearlings, affecting 16/33 (48%) that were diagnosed with idiopathic arytenoid disease at the yearling sales. Five of the 33 (15%) horses were diagnosed with arytenoid chondritis at the time of sale and were excluded from the performance outcome analysis. Of the 28 horses diagnosed with arytenoid abnormalities excluding chondritis, 19 (68%) raced with no history of respiratory-related problems, two (7%) were subsequently diagnosed with laryngeal hemiplegia, and seven (25%) were lost to follow-up. The case animals were 2.7 times more likely to race than control horses, but there was no difference between cases and controls in the likelihood of starting more than three times. CONCLUSIONS: This study showed that nasotracheal intubation in adult horses could result in immediate mucosal trauma, persistent swelling, and focal scarring of the arytenoid cartilages, but this did not mimic mucosal ulceration or chondritis of the arytenoid cartilages observed in yearling Thoroughbred horses. The population studied, however, may not accurately represent the population in which idiopathic disease occurs. In this study, arytenoid mucosal ulceration detected at sale did not commonly progress to arytenoid chondritis. However, a study of a larger population of horses with untreated, naturally occurring disease is required to confirm these findings. CLINICAL RELEVANCE: It is unlikely that trauma from nasogastric intubation caused arytenoid mucosal ulceration, therefore this procedure should not necessarily be discouraged. This study did not find evidence that horses diagnosed with arytenoid mucosal ulceration at yearling sales had a reduced performance history, therefore it is reasonable to continue to pass horses with uncomplicated arytenoid mucosal ulceration during post-sale endoscopic examination. However, monitoring of the lesions and treatment, if required, may be indicated in the post-sale period

Pathophysiology and diagnosis of third carpal bone disease in horses: A review

Third carpal bone (C3) disease is a significant cause of lameness in Standardbred and Thoroughbred horses. The bone density of C3 increases as a result of exercise, reducing the compliance of the bone and predisposing it to injury. Currently, the most widely used method of diagnosis is subjective radiography using the tangential view. Radiographically, increases in bone mineral density (BMD) appear as sclerosis but it is not known at what point increases in sclerosis indicate the onset of disease or increased risk of C3 fracture. A quantitative assessment of the BMD of C3 in horses would improve understanding of the changes that occur within this bone and guide athletic management, as it is thought that BMD changes precede articular cartilage damage. Methods of non-invasive bone-mineral analysis used for the detection of osteoporosis in humans include single photon absorptiometry (SPA), dual x-ray absorptiometry (DXA), computed tomography (CT), radioabsorptiometry (RA), quantitative ultrasonography (QU) and magnetic resonance imaging (MRI). To date, DXA and RA are the most commonly used methods of quantitative non-invasive bone-mineral analysis in horses. The cost of equipment and difficulties in performing DXA in live animals preclude the routine use of this technique for diagnostic purposes. RA may become clinically applicable to C3 analysis in horses, but small variations in x-ray beam angle when taking the tangential view significantly affect results, making this technique clinically inapplicable at this time. Currently, methods of quantitative non-invasive bone-mineral analysis of C3 in horses are not suited to clinical application

The quantitative assessment of photodensity of the third carpal bone in the horse

AIM: To determine whether variation in x-ray-beam angle significantly affected photodensity of the third carpal bone (C3) in the horse using the tangential radiographic view, and indirectly determine whether radioabsorptiometry (RA) could be used to assess differences in bone mineral density (BMD) of C3 between exercised and non-exercised horses. METHODS: The left distal carpal row was isolated post-mortem from 2-year-old Thoroughbred horses that had been either exercised (n=7) for up to 14 weeks using a standard training regimen for racehorses, or not exercised (n=7). The effect of variation in x-ray-beam angle on photodensity was determined on these isolated carpal bones in vitro. Image analysis was used to assess photodensity (compared to a known thickness of aluminium) of four regions of interest (ROI) in C3 and one ROI in the fourth carpal bone (C4) of 14 isolated distal rows of carpal bones of the horse. The isolated carpal bones were placed flat on a x-ray cassette and radiographed at 90° (i.e. with the x-ray beam perpendicular to the cassette). The x-ray-beam angle was varied in the dorsal sagittal plane by 5° increments to a total of 15° from 90° and from a base angle of 60° (the x-ray-beam angle at which the tangential view is taken in clinical cases). RESULTS: Variation in beam angle of <10° from 90° significantly affected photodensity, and photodensity was significantly affected when the angle was varied <5° from 60°. When taken at an x-ray-beam angle of 60°, the abaxial aspect of the radial facet of C3 had a consistently higher photodensity than the rest of C3 and C4. The photodensity of the third and fourth carpal bones was higher in exercised horses than in non-exercised horses. CONCLUSION: As variation in x-ray-beam angle significantly affected photodensity, RA using the tangential view is not considered clinically applicable for assessing BMD of C3 and the accuracy of subjective assessment of BMD of C3 using the tangential view in horses is questionable