Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations.

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing

Implementation of a Central Sensorimotor Integration Test for Characterization of Human Balance Control During Stance

Balance during stance is regulated by active control mechanisms that continuously estimate body motion, via a “sensory integration” mechanism, and generate corrective actions, via a “sensory-to-motor transformation” mechanism. The balance control system can be modeled as a closed-loop feedback control system for which appropriate system identification methods are available to separately quantify the sensory integration and sensory-to-motor components of the system. A detailed, functionally meaningful characterization of balance control mechanisms has potential to improve clinical assessment and to provide useful tools for answering clinical research questions. However, many researchers and clinicians do not have the background to develop systems and methods appropriate for performing identification of balance control mechanisms. The purpose of this report is to provide detailed information on how to perform what we refer to as “central sensorimotor integration” (CSMI) tests on a commercially available balance test device (SMART EquiTest CRS, Natus Medical Inc, Seattle WA) and then to appropriately analyze and interpret results obtained from these tests. We describe methods to (1) generate pseudorandom stimuli that apply cyclically-repeated rotations of the stance surface and/or visual surround (2) measure and calibrate center-of-mass (CoM) body sway, (3) calculate frequency response functions (FRFs) that quantify the dynamic characteristics of stimulus-evoked CoM sway, (4) estimate balance control parameters that quantify sensory integration by measuring the relative contribution of different sensory systems to balance control (i.e., sensory weights), and (5) estimate balance control parameters that quantify sensory-to-motor transformation properties (i.e., feedback time delay and neural controller stiffness and damping parameters). Additionally, we present CSMI test results from 40 subjects (age range 21–59 years) with normal sensory function, 2 subjects with results illustrating deviations from normal balance function, and we summarize results from previous studies in subjects with vestibular deficits. A bootstrap analysis was used to characterize confidence limits on parameters from CSMI tests and to determine how test duration affected the confidence with which parameters can be measured. Finally, example results are presented that illustrate how various sensory and central balance deficits are revealed by CSMI testing

Structural-Thermal-Optical-Performance (STOP) Model Development and Analysis of a Field-widened Michelson Interferometer

An integrated Structural-Thermal-Optical-Performance (STOP) model was developed for a field-widened Michelson interferometer which is being built and tested for the High Spectral Resolution Lidar (HSRL) project at NASA Langley Research Center (LaRC). The performance of the interferometer is highly sensitive to thermal expansion, changes in refractive index with temperature, temperature gradients, and deformation due to mounting stresses. Hand calculations can only predict system performance for uniform temperature changes, under the assumption that coefficient of thermal expansion (CTE) mismatch effects are negligible. An integrated STOP model was developed to investigate the effects of design modifications on the performance of the interferometer in detail, including CTE mismatch, and other three- dimensional effects. The model will be used to improve the design for a future spaceflight version of the interferometer. The STOP model was developed using the Comet SimApp'TM' Authoring Workspace which performs automated integration between Pro-Engineer, Thermal Desktop, MSC Nastran'TM', SigFit'TM', Code V'TM', and MATLAB. This is the first flight project for which LaRC has utilized Comet, and it allows a larger trade space to be studied in a shorter time than would be possible in a traditional STOP analysis. This paper describes the development of the STOP model, presents a comparison of STOP results for simple cases with hand calculations, and presents results of the correlation effort to bench-top testing of the interferometer. A trade study conducted with the STOP model which demonstrates a few simple design changes that can improve the performance seen in the lab is also presented

The Sensor Technology and Rehabilitative Timing (START) Protocol: A Randomized Controlled Trial for the Rehabilitation of Mild Traumatic Brain Injury

BACKGROUND: Clinical practice for rehabilitation after mild traumatic brain injury (mTBI) is variable, and guidance on when to initiate physical therapy is lacking. Wearable sensor technology may aid clinical assessment, performance monitoring, and exercise adherence, potentially improving rehabilitation outcomes during unsupervised home exercise programs. OBJECTIVE: The objectives of this study were to: (1) determine whether initiating rehabilitation earlier than typical will improve outcomes after mTBI, and (2) examine whether using wearable sensors during a home-exercise program will improve outcomes in participants with mTBI. DESIGN: This was a randomized controlled trial. SETTING: This study will take place within an academic hospital setting at Oregon Health & Science University and Veterans Affairs Portland Health Care System, and in the home environment. PARTICIPANTS: This study will include 160 individuals with mTBI. INTERVENTION: The early intervention group (n = 80) will receive one-on-one physical therapy 8 times over 6 weeks and complete daily home exercises. The standard care group (n = 80) will complete the same intervention after a 6- to 8-week wait period. One-half of each group will receive wearable sensors for therapist monitoring of patient adherence and quality of movements during their home exercise program. MEASUREMENTS: The primary outcome measure will be the Dizziness Handicap Inventory score. Secondary outcome measures will include symptomatology, static and dynamic postural control, central sensorimotor integration posturography, and vestibular-ocular-motor function. LIMITATIONS: Potential limitations include variable onset of care, a wide range of ages, possible low adherence and/or withdrawal from the study in the standard of care group, and low Dizziness Handicap Inventory scores effecting ceiling for change after rehabilitation. CONCLUSIONS: If initiating rehabilitation earlier improves primary and secondary outcomes post-mTBI, this could help shape current clinical care guidelines for rehabilitation. Additionally, using wearable sensors to monitor performance and adherence may improve home exercise outcomes

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands

Localization and Broadband Follow-up of the Gravitational-wave Transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams. </p

A randomized, controlled pilot study of the effects of vitamin D supplementation on balance in Parkinson's disease: Does age matter?

OBJECTIVES:To explore if short term, high dose vitamin D supplementation is safe and improves balance in persons with Parkinson's disease (PD). METHODS:A pilot randomized, double-blind intervention trial to measure the effects of 16 weeks of high dose vitamin D (10,000 IU/day) on balance as well as other motor and non-motor features of PD. We measured balance, gait, strength, falls, cognition, mood, PD severity, and quality of life before and after 16 weeks of high dose vitamin D supplementation or placebo. All participants also received 1000 mg calcium once daily. RESULTS:Fifty-one randomized participants completed sixteen weeks of high dose vitamin D supplementation or placebo. The intervention resulted in a rise in serum concentrations of vitamin D (25-OH) (30.2 ng/ml to 61.1 ng/ml) and was well tolerated with no serious adverse events. Serum vitamin D (25-OH) levels rose steadily and did not suggest a leveling off at the end of the 16 weeks. There was not an improvement in the primary endpoint, balance as measured by the Sensory Organization Test (p = 0.43). A post hoc analysis examining treatment effects in younger (ages 52-66) versus older (ages 67-86) participants found a significant improvement in the SOT of 10.6 points in the younger half of the cohort (p = 0.012). CONCLUSIONS:Short term, high dose vitamin D supplementation appears safe in persons with PD, but did not significantly improve balance as measured with the Sensory Organization Test in this pilot study population. A post hoc analysis suggests that vitamin D may have potential for improving balance in a younger population with PD. High dose vitamin D supplementation in PD needs further study especially in light of new research suggesting that mega doses and even moderate doses (as low as 4000IU a day) may increase falls in an older populations. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01119131

Companion Pipeline and Supplemental Data - Preventable risk factors of Parkinson's disease: Population attributable fractions in a case-control study in the Deep South United States

The complete R-based Posit project to reproduce the analyses and output in the article "Preventable risk factors of Parkinson’s disease: Population attributable fractions in a case-control study in the Deep South United States". Includes .Rproj file, renv lockfile for associated packages, folder with all workflow scripts, and wrapper scripts for output generation both with and without use of the targets R package. See README.md for content details Access can also be found on GitHub at https://github.com/cfmurch/DeepSouth_PD_PAF For questions please contact Chad Murchison at [email protected]

Population fraction of Parkinson’s disease attributable to preventable risk factors

Abstract Parkinson’s disease is the fastest-growing neurologic disease with seemingly no means of prevention. Intrinsic risk factors (age, sex, and genetics) are inescapable, but environmental factors are not. We identified repeated blows to the head in sports/combat as a potential new risk factor. 23% of PD cases in females were attributable to pesticide/herbicide exposure, and 30% of PD in males were attributable to pesticides/herbicides, military-related chemical exposures, and repeated blows to the head, and therefore could have potentially been prevented

Companion Pipeline - Population fraction of Parkinson's disease attributable to preventable risk factors

&lt;p&gt;The complete R-based Posit project to reproduce the analyses and output in the article "Population fraction of Parkinson's disease attributable to preventable risk factors".&nbsp; All data can be found in in the 'input' folder. &nbsp;Also includes .Rproj file, renv lockfile for associated packages, folder with all workflow scripts, and wrapper scripts for output generation. See README.md for additional content details.&lt;/p&gt;&lt;p&gt;Access can also be found on GitHub at &lt;a href="https://github.com/cfmurch/DeepSouth_PD_PAF"&gt;https://github.com/cfmurch/DeepSouth_PD_PAF&lt;/a&gt;&lt;/p&gt;&lt;p&gt;For questions please contact Chad Murchison at &lt;a href="mailto:[email protected]"&gt;[email protected]&lt;/a&gt;&lt;/p&gt