Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel α-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.

Objective Universal design principles advocate inclusion of end users in every design stage, including research and development. Brain-computer interfaces (BCIs) have long been described as potential tools to enable people with amyotrophic lateral sclerosis (ALS) to operate technology without moving. Therefore the objective of the current study is to determine the opinions and priorities of people with ALS regarding BCI design. This information will guide BCIs in development to meet end user needs. Methods Telephone survey of 61 people with ALS from the University of Michigan’s Motor Neuron Disease Clinic. Results Regarding BCI design, participants prioritized accuracy of command identification of at least 90% (satisfying 84% of respondents), speed of operation comparable to at least 15-19 letters-per-minute (satisfying 72%), and accidental exits from a standby mode not more than once every 2-4 hours (satisfying 84%). While 84% of respondents would accept using an electrode cap, 72% were willing to undergo outpatient surgery and 41% to undergo surgery with a short hospital stay in order to obtain a BCI. Conclusions People with ALS expressed a strong interest in obtaining BCIs, but current BCIs do not yet provide desired BCI performance.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of motor neurons that leads to paralysis and eventually death. There is evidence that atrophy occurs in the primary motor cortex (M1), but it is unclear how the disease affects the intrinsic connectivity of this structure. Thus, the goal of this study was to examine interhemispheric coupling of low frequency blood-oxygen-level dependent (BOLD) signal fluctuations in M1 using functional connectivity magnetic resonance imaging during rest. Because disease progression is rapid, high-functioning patients were recruited to assess neural changes in the relatively early stages of ALS. Twenty patients with limb-onset ALS participated in this study. A parceling technique was employed to segment both precentral gyri into multiple regions of interest (ROI), thus increasing sensitivity to detect changes that exist along discretely localized regions of the motor cortex. We report an overall systemic decrease in functional connectivity between right and left motor cortices in patients with limb-onset ALS. Additionally, we observed a pronounced disconnection between dorsal ROI pairs in the ALS group compared to the healthy control group. Furthermore, measures of limb functioning correlated with the connectivity data from dorsal ROI pairs in the ALS group, suggesting a symptomatic relationship with interhemispheric M1 connectivity.

This manuscript explores human factor issues involved in designing and evaluating brain-computer interface (BCI) systems for users with severe motor disabilities. Using participatory research paradigms and qualitative methods, this work draws attention to personal and relational factors that act as barriers to, or mediators of, user acceptance of this technology.

Metal exposures are an intriguing potential culprit in the cause of sporadic amyotrophic lateral sclerosis (ALS). For one, there are numerous case reports linking different metals to an ALS phenotype. Furthermore, some investigators have demonstrated higher levels of certain metals in the blood, bone, cerebrospinal fluid, urine, or spinal cords of patients with ALS compared to controls. There are also many case-control studies looking at the possible association of certain metals with the development of ALS. We have reviewed the relevant literature regarding metal exposures and the risk of developing ALS. We found that many different metals have been implicated as having a role in ALS, but there is more literature investigating the role of lead than any other metal. Despite many studies, the role, if any, of this metal in the pathogenesis of ALS remains unclear. Similarly, other metals either have inconclusive, conflicting, or insufficient results in order to make a definitive conclusion. One explanation for these findings is that metal exposures alone are insufficient for the development of ALS. Perhaps an interaction between the metal exposure and an individual’s genetic makeup is required to produce epigenetic changes that ultimately lead to ALS.

Noninvasive ventilation (NIV) appears to improve survival and quality of life in patients with amyotrophic lateral sclerosis (ALS), but little is known about predictors of NIV tolerance. NIV use was assessed and clinical predictors of tolerance were investigated, using predictive modeling, in ALS patients diagnosed and followed in our clinic until death over a 4-year time period. Patients were prescribed NIV based on current practice parameters when respiratory symptoms were present or forced vital capacity was less than 50%. We prescribed NIV in 52% (72) of patients. For those prescribed NIV, information regarding tolerance was available for 50 patients, with 72% (36) tolerant to its use. Tolerance was six times more likely in limb-onset than bulbar-onset ALS patients, with a trend toward reduced tolerance in those with lower forced vital capacity at NIV initiation. Age, gender, and duration of disease were not predictors of NIV tolerance. We conclude that a majority of ALS patients who are prescribed NIV can successfully become tolerant to its use.

No abstract

No abstract