Deciphering Amyotrophic Lateral Sclerosis: What Phenotype, Neuropathology and Genetics Are Telling Us about Pathogenesis

Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. But they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they all are characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Putting this together, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS and ALS is a syndrome. But since multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principle component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms can be identified and understood, ALS therapy could rationally target progression and stop disease—a goal that seems increasingly achievable.Stem Cell and Regenerative Biolog

Demographics and Physical Properties of Gas Out/Inflows at 0.4 < z < 1.4

We present Keck/LRIS spectra of over 200 galaxies with well-determined redshifts between 0.4 and 1.4. We combine new measurements of near-ultraviolet, low-ionization absorption lines with previously measured masses, luminosities, colors, and star formation rates to describe the demographics and properties of galactic flows. Among star-forming galaxies with blue colors, we find a net blueshift of the FeII absorption greater than 200 km/s (100 km/s) towards 2.5% (20%) of the galaxies. The fraction of blueshifted spectra does not vary significantly with stellar mass, color, or luminosity but does decline at specific star formation rates less than roughly 0.8 Gyr^{-1}. The insensitivity of the blueshifted fraction to galaxy properties requires collimated outflows at these redshifts, while the decline in outflow fraction with increasing blueshift might reflect the angular dependence of the outflow velocity. The low detection rate of infalling gas, 3 to 6% of the spectra, suggests an origin in (enriched) streams favorably aligned with our sightline. We find 4 of these 9 infalling streams have projected velocities commensurate with the kinematics of an extended disk or satellite galaxy. The strength of the MgII absorption increases with stellar mass, B-band luminosity, and U-B color, trends arising from a combination of more interstellar absorption at the systemic velocity and less emission filling in more massive galaxies. Our results provides a new quantitative understanding of gas flows between galaxies and the circumgalactic medium over a critical period in galaxy evolution.Comment: Accepted version in 2-column format with embedded figure

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

PRISM: a novel research tool to assess the prevalence of pseudobulbar affect symptoms across neurological conditions.

Pseudobulbar affect (PBA) is a neurological condition characterized by involuntary, sudden, and frequent episodes of laughing and/or crying, which can be socially disabling. Although PBA occurs secondary to many neurological conditions, with an estimated United States (US) prevalence of up to 2 million persons, it is thought to be under-recognized and undertreated. The PBA Registry Series (PRISM) was established to provide additional PBA symptom prevalence data in a large, representative US sample of patients with neurological conditions known to be associated with PBA.Participating clinicians were asked to enroll ≥20 consenting patients with any of 6 conditions: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's disease (PD), stroke, or traumatic brain injury (TBI). Patients (or their caregivers) completed the Center for Neurologic Study-Lability Scale (CNS-LS) and an 11-point scale measuring impact of the neurological condition on the patient's quality of life (QOL). Presence of PBA symptoms was defined as a CNS-LS score ≥13. Demographic data and current use of antidepressant or antipsychotic medications were also recorded.PRISM enrolled 5290 patients. More than one third of patients (n = 1944; 36.7%) had a CNS-LS score ≥13, suggesting PBA symptoms. The mean (SD) score measuring impact of neurological condition on QOL was significantly higher (worse) in patients with CNS-LS ≥13 vs <13 (6.7 [2.5] vs. 4.7 [3.1], respectively; P<0.0001 two-sample t-test). A greater percentage of patients with CNS-LS ≥13 versus <13 were using antidepressant/antipsychotic medications (53.0% vs 35.4%, respectively; P<0.0001, chi-square test).Data from PRISM, the largest clinic-based study to assess PBA symptom prevalence, showed that PBA symptoms were common among patients with diverse neurological conditions. Higher CNS-LS scores were associated with impaired QOL and greater use of antipsychotic/antidepressant medications. These data underscore a need for greater awareness, recognition, and diagnosis of PBA

Outcomes research in amyotrophic lateral sclerosis: lessons learned from the amyotrophic lateral sclerosis clinical assessment, research, and education database

To examine the care of patients with ALS following the publication of the standardized recommendations for the management of patients with amyotrophic lateral sclerosis (ALS) published in 1999 by the American Academy of Neurology. Specific aspects of ALS patient management have been evaluated serially using a national Amyotrophic Lateral Sclerosis Clinical Assessment, Research, and Education (ALS CARE) database to encourage compliance with these recommendations and to assure continuing quality improvement. The most recent analysis of 5,600 patients shows interesting epidemiological observations and treatment trends. Proper management of many ALS symptoms has increased substantially since the first publication of the guidelines, and awareness of pseudobulbar affect has increased. Other recommendations are underutilized: Only 9% undergo percutaneous endoscopic gastrostomy, although this procedure was recommended in 22% of patients; and noninvasive positive pressure ventilation was used by only 21% of patients despite being associated with improved 5-year survival rates. This observational database has been a useful tool in monitoring compliance with the standard of care for patients with ALS and may have resulted in greater adherence to guidelines

Amyotrophic lateral sclerosis : moving towards a new classification system

Amyotrophic lateral sclerosis is a progressive adult-onset neurodegenerative disease that primarily affects upper and lower motor neurons, but also frontotemporal and other regions of the brain. The extent to which each neuronal population is affected varies between individuals. The subsequent patterns of disease progression form the basis of diagnostic criteria and phenotypic classification systems, with considerable overlap in the clinical terms used. This overlap can lead to confusion between diagnosis and phenotype. Formal classification systems such as the El Escorial criteria and the International Classification of Diseases are systematic approaches but they omit features that are important in clinical management, such as rate of progression, genetic basis, or functional effect. Therefore, many neurologists use informal classification approaches that might not be systematic, and could include, for example, anatomical descriptions such as flail-arm syndrome. A new strategy is needed to combine the benefits of a systematic approach to classification with the rich and varied phenotypic descriptions used in clinical practice

Published PBA symptom prevalence estimates by primary neurological condition.

<p>Shading indicates multiple estimates. AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; CNS-LS, Center for Neurologic Study–Lability Scale; MS, multiple sclerosis; PBA, pseudobulbar affect; PD, Parkinson’s disease; PRISM, PBA Registry Series; TBI, traumatic brain injury. ^aPatient interview; ^bCNS-LS ≥13 (higher estimate), CNS-LS ≥21, lower estimate; ^c Poeck criteria: pathological affect could be mood congruent (emotional lability) or incongruent (pathological laughing and crying); ^dRetrospective review of hospital or clinic records; ^eMailed questionnaire; ^fEmotional lability questionnaire (ELQ); ^gAscertainment method unknown; ^hPatient interview, Poeck criteria; ⁱBrief questionnaire (uncontrollable laughing/crying when not happy/sad); ^jCNS-LS ≥13 (highest estimate), CNS-LS ≥17 (middle estimate), Cummings Involuntary Emotional Expression Disorder criteria (lowest estimate); ^kCNS-LS ≥17 (lower estimate), CNS-LS ≥13 (higher estimate); ^lPathological Laughing and Crying Scale (PLACS) ≥10 and score of ≥2 on PLACS items 2 (frequency), 13 (loss of voluntary control), and 18 (distress/embarrassment); ^mPatient interview House (lower estimate), and Kim (higher estimate) criteria; ⁿPatient interview House criteria; ^oPatient interview Kim criteria; ^pPatient interview Kim criteria (lower estimate; n = 516) and modified Kim criteria (patient report only without corroboration from relatives; higher estimate); ^qPatient interview Kim criteria at hospital admission (lower estimate) and at 3 months (higher estimate) following stroke.</p