The Impact of Aging on Multiple Sclerosis.

PURPOSE OF REVIEW: Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disorder of the central nervous system. Age is one of the most important factors in determining MS phenotype. This review provides an overview of how age influences MS clinical characteristics, pathology, and treatment. RECENT FINDINGS: New methods for measuring aging have improved our understanding of the aging process in MS. New studies have characterized the molecular and cellular composition of chronic active or smoldering plaques in MS. These lesions are important contributors to disability progression in MS. These studies highlight the important role of immunosenescence and the innate immune system in sustaining chronic inflammation. Given these changes in immune function, several studies have assessed optimal treatment strategies in aging individuals with MS. MS phenotype is intimately linked with chronologic age and immunosenescence. While there are many unanswered questions, there has been much progress in understanding this relationship which may lead to more effective treatments for progressive disease.

Dual-mode scramjet control using optical emission sensors.

Closed-loop fueling control of a dual-mode scramjet was successfully demonstrated using optical emission spectroscopy as the sole sensor for controller feedback. The optical emission from species of interest (O H ∗, C H ∗, C2∗) was first characterized throughout the combustor. The relative emission intensity between species pairs was studied over a range of fueling conditions and imaging locations throughout a dual-mode scramjet combustor flow path. The pair of emissive species (C2∗/O H ∗) and imaging location that were the most sensitive to changes in fueling condition were selected for use in the control system. Changes in optical transmission of the observation windows and the impact on fuel control were explored. To our knowledge, this paper is the first demonstration of fueling control of a dual-mode scramjet using only optical emission spectroscopy as feedback.

Development of a Premixed Combustion Capability for Dual-Mode Scramjet Experiments.

Hypersonic air-breathing engines rely on scramjet combustion processes, which involve high-speed, compressible, and highly turbulent reacting flows. The combustion environment and the turbulent flames at the heart of these engines are difficult to simulate and study in the laboratory under well controlled conditions. Typically, wind-tunnel testing is performed that more closely approximates engine development rather than a careful investigation of the underlying physics that drives the combustion process. The experiments described in this paper, along with companion data sets, aim to isolate the chemical kinetic effects and turbulence-chemistry interaction from the fuel-air mixing process in a dual-mode scramjet combustion environment. A unique fuel injection approach is adopted that produces a uniform fuel-air mixture at the entrance to the combustor and results in premixed combustion. This approach relies on the mixing enhancement of a precombustion shock train upstream of the dual-mode scramjet's combustor. For the first time a stable flame, anchored on a cavity flameholder, is reported for a scramjet combustor operating in premixed fuel-air mode. The new experimental capability has enabled numerous companion studies involving advanced diagnostics such as coherent anti-Stokes Raman scattering (CARS), particle image velocimetry (PIV), and planar laser induced fluorescence (PLIF).

Pearls & Oy-sters: Late-Onset Cobalamin C Deficiency Presenting With Subacute Combined Degeneration.

Cobalamin C (CblC) deficiency is a rare inborn error in cobalamin (vitamin B12) metabolism which results in impaired intracellular processing of dietary vitamin B12. This leads to a wide range of clinical manifestations including cognitive impairment, psychiatric symptoms, myelopathy, thrombotic events, glomerulonephritis, and pulmonary arterial hypertension. CblC deficiency typically presents in the pediatric population but can also present in adulthood. Diagnosis in adults can be challenging due to the rarity of this condition and its myriad clinical presentations. CblC deficiency is treatable, so early diagnosis is important in preventing permanent neurologic damage. Although CblC deficiency results from a defect in vitamin B12 metabolism, B12 levels remain normal. Diagnosis depends on testing metabolites altered by vitamin B12 dysfunction such as methylmalonic acid (MMA) and homocysteine. We presented a case of a 20-year-old woman who presented with chronic progressive lower extremity weakness and sensory changes. She was eventually diagnosed with subacute combined degeneration because of CblC deficiency and effectively treated. This case highlights the importance of considering inborn errors of metabolism in adult patients and including testing of metabolites such as MMA and homocysteine when suspecting vitamin B12 dysfunction.

Radiographic evolution of myelitis in a case of glial fibrillary acidic protein (GFAP) astrocytopathy.

Autoimmune glial fibrillar acidic protein (GFAP) astrocytopathy is a rare autoimmune neuroinflammatory disorder that affects the central nervous system. We present a case of GFAP astrocytopathy in a middle-aged male who presented with constitutional symptoms, encephalopathy and lower extremity weakness and numbness. Initially MRI of the spine was normal, but he subsequently developed longitudinally extensive myelitis and meningoencephalitis. Workup for infectious aetiologies was negative and the patient's clinical course worsened despite broad antimicrobial coverage. Ultimately, he was found to have anti-GFAP antibodies in his cerebral spinal fluid consistent with GFAP astrocytopathy. He was treated with steroids and plasmapheresis with clinical and radiographic improvement. This case demonstrates the temporal evolution of myelitis on MRI in a case of steroid-refractory GFAP astrocytopathy.

Comprehensive Characterization of Cerebrovascular Dysfunction in Blast Traumatic Brain Injury Using Photoacoustic Microscopy.

Blast traumatic brain injury (bTBI) is a leading contributor to combat-related injuries and death. Although substantial emphasis has been placed on blast-induced neuronal and axonal injuries, co-existing dysfunctions in the cerebral vasculature, particularly the microvasculature, remain poorly understood. Here, we studied blast-induced cerebrovascular dysfunctions in a rat model of bTBI (blast overpressure: 187.8 ± 18.3 kPa). Using photoacoustic microscopy (PAM), we quantified changes in cerebral hemodynamics and metabolism-including blood perfusion, oxygenation, flow, oxygen extraction fraction, and the metabolic rate of oxygen-4 h post-injury. Moreover, we assessed the effect of blast exposure on cerebrovascular reactivity (CVR) to vasodilatory stimulation. With vessel segmentation, we extracted these changes at the single-vessel level, revealing their dependence on vessel type (i.e., artery vs. vein) and diameter. We found that bTBI at this pressure level did not induce pronounced baseline changes in cerebrovascular diameter, blood perfusion, oxygenation, flow, oxygen extraction, and metabolism, except for a slight sO2 increase in small veins (<45 µm) and blood flow increase in large veins (≥45 µm). In contrast, this blast exposure almost abolished CVR, including arterial dilation, flow upregulation, and venous sO2 increase. This study is the most comprehensive assessment of cerebrovascular structure and physiology in response to blast exposure to date. The observed impairment in CVR can potentially cause cognitive decline due to the mismatch between cognitive metabolic demands and vessel's ability to dynamically respond to meet the demands. Also, the impaired CVR can lead to increased vulnerability of the brain to metabolic insults, including hypoxia and ischemia.

Islet Autoantibody Measurements from Dried Blood Spots on Filter Paper Strongly Correlate to Serum Levels.

Type 1 diabetes (T1D) is increasing in incidence and predictable with measurement of serum islet autoantibodies (iAb) years prior to clinical disease onset. Identifying iAb positive individuals reduces diabetic ketoacidosis and identifies individuals for T1D prevention trials. However, large scale screening for iAb remains challenging as assays have varying sensitivities and specificities, insulin autoantibodies remain difficult to measure and venipuncture is generally required to obtain serum. We developed an approach to reliably measure all four major iAb, including insulin autoantibodies, from dried blood spots (DBS) on filter-paper. By spiking iAb positive serum into iAb negative whole blood in a dose titration, we optimized the conditions for autoantibody elution from filter paper as measured by fluid phase radioimmunoassays. After assessing stability of measuring iAb from DBS over time, we then screened iAb from DBS and the corresponding serum in new-onset T1D (n = 52), and controls (n = 72) which included first-degree relatives of T1D patients. iAb measured from eluted DBS in new-onset T1D strongly correlated with serum measurements (R2 = 0.96 for mIAA, GADA = 0.94, IA-2A = 0.85, ZnT8A = 0.82, p<0.01 for each autoantibody). There were no false positives in control subjects, and 5/6 with previously unknown iAb positivity in sera were detected using DBS. With further validation, measuring iAb from DBS can be a reliable method to screen for T1D risk.