Automated Analysis of the Two-Minute Walk Test in Clinical Practice Using Accelerometer Data.

One of the core problems for people with multiple sclerosis (pwMS) is the impairment of their ability to walk, which can be severely restrictive in everyday life. Therefore, monitoring of ambulatory function is of great importance to be able to effectively counteract disease progression. An extensive gait analysis, such as the Dresden protocol for multidimensional walking assessment, covers several facets of walking impairment including a 2-min walk test, in which the distance taken by the patient in two minutes is measured by an odometer. Using this approach, it is questionable how precise the measuring methods are at recording the distance traveled. In this project, we investigate whether the current measurement can be replaced by a digital measurement method based on accelerometers (six Opal sensors from the Mobility Lab system) that are attached to the patient's body. We developed two algorithms using these data and compared the validity of these approaches using the results from 2-min walk tests from 562 pwMS that were collected with a gold-standard odometer. In 48.4% of pwMS, we detected an average relative measurement error of less than 5%, while results from 25.8% of the pwMS showed a relative measurement error of up to 10%. The algorithm had difficulties correctly calculating the walking distances in another 25.8% of pwMS; these results showed a measurement error of more than 20%. A main reason for this moderate performance was the variety of pathologically altered gait patterns in pwMS that may complicate the step detection. Overall, both algorithms achieved favorable levels of agreement (r = 0.884 and r = 0.980) with the odometer. Finally, we present suggestions for improvement of the measurement system to be implemented in the future.

Transgenic lysyl oxidase homolog 1 overexpression in the mouse eye results in the formation and release of protein aggregates.

Sequence variants in LOXL1 coding for the secreted enzyme lysyl oxidase homolog 1 (LOXL1) associate with pseudoexfoliation (PEX) syndrome, a condition that is characterized by the deposition of extracellular fibrillar PEX material in the anterior eye and other parts of the body. Since the specific role of LOXL1 in the pathogenesis of PEX is unclear, and an increase in its expression was reported for early stages of PEX syndrome, we generated and studied transgenic mice with ocular overexpression of its mouse ortholog Loxl1. The chicken ßB1-crystallin promoter was used to overexpress Loxl1 in the lenses of ßB1-crystallin-Loxl1 transgenic mice. Transgenic lenses contained high levels of the protein LOXL1 and its mRNA, which were both not detectable in lenses of wildtype littermates. In wildtype mice, immunoreactivity for LOXL1 was mainly seen extracellularly in region of the ciliary zonules. ßB1-crystallin-Loxl1 littermates showed an additional diffuse immunostaining in lens fibers and capsule, and in the inner limiting membrane and retina indicating secretion of soluble LOXL1 from transgenic lenses. In addition, lens fibers of transgenic animals contained multiple distinct spots of very intense LOXL1 immunoreactivity. By transmission electron microscopy, those spots correlated with electron-dense round or oval bodies of 20-50 nm in diameter which were localized in the rough endoplasmic reticulum and not seen in wildtype lenses. Immunogold electron microscopy confirmed that the electron-dense bodies contained LOXL1 indicating aggregation of insoluble LOXL1. Similar structures were seen in the extracellular lens capsule suggesting their secretion from lens fibers. Otherwise, no changes were seen between the eyes of ßB1-crystallin-Loxl1 mice and their wildtype littermates, neither by light microscopy and funduscopy of whole eyes, nor by scanning and quantitative transmission electron microscopy of ciliary epithelium and zonules. At one month of age, intraocular pressure was significantly higher in transgenic mice than in wildtype littermates. No differences in IOP were seen though at 2-5 months of age. We conclude that LOXL1 has a strong tendency to aggregate in the rER when expressed in vivo at high amounts. A similar scenario, involving intracellular aggregation of LOXL1 and secretion of LOXL1 aggregates into the extracellular space, may be involved in the early pathogenetic events in eyes of PEX patients.