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DOE OSTI2020

MicroRNAs as disease progression biomarkers and therapeutic targets in experimental autoimmune encephalomyelitis model of multiple sclerosis

Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain, spinal cord and optic nerve leading to demyelination. Focal demyelination is associated with relapsing-remitting multiple sclerosis, while progressive forms of the disease show axonal degeneration and neuronal loss. The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity. MicroRNAs (miRNAs) are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases. A review of recent studies with the experimental autoimmune encephalomyelitis animal model (mostly female mice 6–12 weeks of age) has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset (asymptomatic) stage when assessed in blood plasma and urine exosomes, and spinal cord tissue. The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes, brain and spinal cord tissue, and at the post-peak (chronic) stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue. Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease. Interestingly, experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a, miR-23b, miR-497, miR-26a, and miR-20b, or by suppression of miR-182, miR-181c, miR-223, miR-155, and miR873. Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course. Additionally, studies should be performed with male mice of a similar age, and with aged male and female mice.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2019

MicroRNAs in blood and cerebrospinal fluid as diagnostic biomarkers of multiple sclerosis and to monitor disease progression

Multiple sclerosis is a chronic autoimmune disease of the central nervous system. It is the main cause of non-traumatic neurological disability in young adults. Multiple sclerosis mostly affects people aged 20–50 years; however, it can occur in young children and much older adults. Factors identified in the distribution of MS include age, gender, genetics, environment, and ethnic background. Multiple sclerosis is usually associated with progressive degrees of disability. The disease involves demyelination of axons of the central nervous system and causes brain and spinal cord neuronal loss and atrophy. Diagnosing multiple sclerosis is based on a patient’s medical history including symptoms, physical examination, and various tests such as magnetic resonance imaging, cerebrospinal fluid and blood tests, and electrophysiology. The disease course of multiple sclerosis is not well correlated with the biomarkers presently used in clinical practice. Blood-derived biomarkers that can detect and distinguish the different phenotypes in multiple sclerosis may be advantageous in personalized treatment with disease-modifying drugs and to predict response to treatment. The studies reviewed have shown that the expression levels of a large number of miRNAs in peripheral blood, serum, exosomes isolated from serum, and cerebrospinal fluid are altered in multiple sclerosis and can distinguish the disease phenotypes from each other. Further studies are warranted to independently validate these findings so that individual or pairs of miRNAs in serum or cerebrospinal fluid can be used as potential diagnostic markers for adult and pediatric multiple sclerosis and for monitoring disease progression and response to therapy.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

Iron Heterogeneity in Early Active Multiple Sclerosis Lesions

Objective: Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains, suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown. Methods: We used synchrotron X-ray fluorescence imaging, histology, and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients. Results: Immunopattern II early active lesions contain 64% more iron (95% confidence interval [CI] = 17-127, p = 0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95% CI = 3–64%, p = 0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95% CI = -40 to -14%, p < 0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p < 0.001). Microfocused X-ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, whereas macrophages in immunopattern III lesions contain little iron. Interpretation: Iron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions. This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin, or different demyelination mechanisms, and paves the way for developing new or using existing iron-sensitive magnetic resonance imaging techniques to differentiate among immunopatterns in the general nonbiopsied MS patient population.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2013

Gray Matter Is Targeted in First-Attack Multiple Sclerosis

The cause of multiple sclerosis (MS), its driving pathogenesis at the earliest stages, and what factors allow the first clinical attack to manifest remain unknown. Some imaging studies suggest gray rather than white matter may be involved early, and some postulate this may be predictive of developing MS. Other imaging studies are in conflict. To determine if there was objective molecular evidence of gray matter involvement in early MS we used high-resolution mass spectrometry to identify proteins in the cerebrospinal fluid (CSF) of first-attack MS patients (two independent groups) compared to established relapsing remitting (RR) MS and controls. We found that the CSF proteins in first-attack patients were differentially enriched for gray matter components (axon, neuron, synapse). Myelin components did not distinguish these groups. The results support that gray matter dysfunction is involved early in MS, and also may be integral for the initial clinical presentation.

Environmental Molecular Sciences Laboratory↗

NASA NTRS1999

Physiologic and thermal responses of male and female patients with multiple sclerosis to head and neck cooling

Personal cooling systems are used to alleviate symptoms of multiple sclerosis and to prevent increased core temperature during daily activities. The objective of this study was to determine the thermal and physiologic responses of patients with multiple sclerosis to short-term maximal head and neck cooling. A Life Support Systems, Inc. Mark VII portable cooling system and a liquid cooling helmet were used to cool the head and neck regions of 24 female and 26 male patients with multiple sclerosis in this study. The subjects, seated in an upright position at normal room temperature (approximately 22 degrees C), were cooled for 30 min by the liquid cooling garment, which was operated at its maximum cooling capacity. Oral, right, and left ear temperatures and cooling system parameters were logged manually every 5 min. Forearm, calf, chest, and rectal temperatures, heart rate, and respiration rate were recorded continuously on a U.F.I., Inc. Biolog ambulatory monitor. This protocol was performed during the winter and summer to investigate the seasonal differences in the way patients with multiple sclerosis respond to head and neck cooling. No significant differences were found between the male and female subject group's mean rectal or oral temperature responses during any phase of the experiment. The mean oral temperature decreased significantly (P < 0.05) for both groups approximately 0.3 degrees C after 30 min of cooling and continued to decrease further (approximately 0.1-0.2 degrees C) for a period of approximately 15 min after removal of the cooling helmet. The mean rectal temperatures decreased significantly (P < 0.05) in both male and female subjects in the winter studies (approximately 0.2-0.3 degrees C) and for the male subjects during the summer test (approximately 0.2 degrees C). However, the rectal temperature of the female subjects did not change significantly during any phase of the summer test. These data indicate that head and neck cooling may, in general, be used to reduce the oral and body temperatures of both male and female patients with multiple sclerosis by the approximate amount needed for symptomatic relief as shown by other researchers. However, thermal response of patients with multiple sclerosis may be affected by gender and seasonal factors, which should be considered in the use of liquid cooling therapy.

NASA Discipline Environmental Health↗

DOE OSTI2012

Visualizing Iron Deposition in Multiple Sclerosis Cadaver Brains

To visualize and validate iron deposition in two cases of multiple sclerosis using rapid scanning X-Ray Fluorescence (RS-XRF) and Susceptibility Weighted Imaging (SWI). Two (2) coronal cadaver brain slices from patients clinically diagnosed with multiple sclerosis underwent magnetic resonance imaging (MRI), specifically SWI to image iron content. To confirm the presence of iron deposits and the absence of zinc-rich myelin in lesions, iron and zinc were mapped using RS-XRF. MS lesions were visualized using FLAIR and correlated with the absence of zinc by XRF. XRF and SWI showed that in the first MS case, there were large iron deposits proximal to the draining vein of the caudate nucleus as well as iron deposits associated with blood vessels throughout the globus pallidus. Less iron was seen in association with lesions than in the basal ganglia. The presence of larger amounts of iron correlated reasonably well between RS-XRF and SWI. In the second case, the basal ganglia appeared normal and acute perivascular iron deposition was absent. Perivascular iron deposition is seen in some but not all MS cases, giving credence to the use of SWI to assess iron involvement in MS pathology in vivo.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2016

PET Imaging Study of S1PR1 Expression in a Rat Model of Multiple Sclerosis

Upregulation of sphingosine-1-phosphate receptor 1 (S1PR1) expression in multiple sclerosis (MS) lesions is associated with neuroinflammatory response. This study investigated the correlation between neuroinflammation and S1PR1 expression in the spinal cord of an experimental autoimmune encephalomyelitis (EAE) rat model of MS, using the S1PR1 positron emission tomography (PET) radiotracer [11C]TZ3321. MicroPET imaging studies of [11C]TZ3321 were performed to measure uptake of [11C]TZ3321 in the spinal cord of EAE rats. Immunohistochemical staining was performed to confirm the overexpression of S1PR1 and other inflammatory biomarkers. MicroPET imaging demonstrated a 20–30 % increase in [11C]TZ3321 uptake in the lumbar spinal cord of EAE rats versus sham controls at 35–60 min post injection. The increased uptake of [11C]TZ3321 was correlated with the overexpression of S1PR1 in the lumbar spinal cord of EAE rats that was confirmed by immunohistochemical staining. Upregulated S1PR1 expression was associated with glial cell activation and immune cell infiltration. MicroPET imaging modality with a specific radioligand [11C]TZ3321 is able to assess the expression of S1PR1 in EAE rat lumbar spinal cord. This may provide a new approach to the assessment of neuroinflammatory response in MS and other inflammatory diseases.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2018

Comparison of two different methods of image analysis for the assessment of microglial activation in patients with multiple sclerosis using (R)-[N-methyl-carbon-11]PK11195

Chronic active multiple sclerosis (MS) lesions have a rim of activated microglia/macrophages (m/M) leading to ongoing tissue damage, and thus represent a potential treatment target. Activation of this innate immune response in MS has been visualized and quantified using PET imaging with [ 11C]-(R)-PK11195 (PK). Accurate identification of m/M activation in chronic MS lesions requires the sensitivity to detect lower levels of activity within a small tissue volume. We assessed the ability of kinetic modeling of PK PET data to detect m/M activity in different central nervous system (CNS) tissue regions of varying sizes and in chronic MS lesions. Ten patients with MS underwent a single brain MRI and two PK PET scans 2 hours apart. Volume of interest (VOI) masks were generated for the white matter (WM), cortical gray matter (CGM), and thalamus (TH). The distribution volume (VT) was calculated with the Logan graphical method (LGM-VT) utilizing an image-derived input function (IDIF). The binding potential (BPND) was calculated with the reference Logan graphical method (RLGM) utilizing a supervised clustering algorithm (SuperPK) to determine the non-specific binding region. Masks of varying volume were created in the CNS to assess the impact of region size on the various metrics among high and low uptake regions. Chronic MS lesions were also evaluated and individual lesion masks were generated. The highest PK uptake occurred the TH and lowest within the WM, as demonstrated by the mean time activity curves. In the TH, both reference and IDIF based methods resulted in estimates that did not significantly depend on VOI size. However, in the WM, the test-retest reliability of BPND was significantly lower in the smallest VOI, compared to the estimates of LGM-VT. These observations were consistent for all chronic MS lesions examined. In this study, we demonstrate that BPND and LGM-VT are both reliable for quantifying m/M activation in regions of high uptake, however with blood input function LGM-VT is preferred to assess longitudinal m/M activation in regions of relatively low uptake, such as chronic MS lesions.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2011

Toxicity of Gamma Knife Radiosurgery in the Treatment of Intracranial Tumors in Patients With Collagen Vascular Diseases or Multiple Sclerosis

Purpose: To assess toxicity in patients with either a collagen vascular disease (CVD) or multiple sclerosis (MS) treated with intracranial radiosurgery. Methods and Materials: Between January 2004 and April 2009, 6 patients with MS and 14 patients with a CVD were treated with Gamma Knife radiosurgery (GKRS) for intracranial tumors. Treated lesions included 15 total brain metastases in 7 patients, 11 benign brain tumors, 1 low grade glioma, and 1 cavernous malformation. Toxicities were graded by the Radiation Therapy Oncology Group Acute/Late Radiation Morbidity Scoring Criteria. 'Rare toxicities' were characterized as those reported in the scientific literature at an incidence of <5%. Results: Median follow-up time was 16 months. Median dose to the tumor margin was 13.0 Gy (range, 12-21 Gy). Median size of tumor was 5.0 cm{sup 3} (range, 0.14-7.8 cm{sup 3}). Of the 14 patients with CVD, none experienced a Grade 3 or 4 toxicity or a toxicity characterized as rare. Of the 6 patients with MS, 3 experienced rare toxicities, and two of these were Grade 3 toxicities. Rare complications included a patient experiencing both communicating hydrocephalus and facial nerve palsy, as well as 2 additional patients with motor cranial nerve palsy. High-grade toxicities included the patient with an acoustic neuroma requiring ventriculoperitoneal shunt placement for obstructive hydrocephalus, and 1 patient with a facial nerve schwannoma who experienced permanent facial nerve palsy. Interval between radiosurgery and high-grade toxicities ranged from 1 week to 4 months. Conclusions: Our series suggests that patients with MS who receive GKRS may be at increased risk of rare and high-grade treatment-related toxicity. Given the time course of toxicity, treatment-related edema or demyelination represent potential mechanisms.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

NASA NTRS1997

Enhancement of Cognitive Processing by Multiple Sclerosis Patients Using Liquid Cooling Technology: A Case Study

Cognitive dysfunction is a common symptom in patients with multiple sclerosis (MS). This can have a significant impact on the quality of life of both the patient and of their primary care giver. This case study explores the possibility that liquid cooling therapy may be used to enhance the cognitive processing of MS patients in the same way that it provides temporary relief of some physical impairment. Two MS patients were presented a series of pattern discrimination tasks before and after being cooled with a liquid cooling garment for a one hour period. The subject whose ear temperature was reduced during cooling showed greater electroencephalographic (EEG) activity and scored much better on the task after cooling. The patient whose ear temperature was unaffected by cooling showed less EEG activity and degraded performance after the one hour cooling period.

Montgomery, Leslie D.↗

NASA NTRS1997

Assessment of Cognitive Processing by Multiple Sclerosis Patients Using Electroencephalographic Energy Density Analysis

Montgomery, Leslie D.↗

DOE OSTI2020

Membrane stiffness and myelin basic protein binding strength as molecular origin of multiple sclerosis

Myelin basic protein (MBP) and its interaction with lipids of the myelin sheath plays an important part in the pathology of multiple sclerosis (MS). Previous studies observed that changes in the myelin lipid composition lead to instabilities and enhanced local curvature of MBP-lipid multilayer structures. We investigated the molecular origin of the instability and found that the diseased lipid membrane has a 25% lower bending rigidity, thus destabilizing smooth >1µm curvature radius structures such as in giant unilamellar vesicles. MBP-mediated assembling of lipid bilayers proceeds in two steps, with a slow second step occurring over many days where native lipid membranes assemble into well-defined multilayer structures, whereas diseased lipid membranes form folded assemblies with high local curvature. For both native and diseased lipid mixtures we find that MBP forms dense liquid phases on top of the lipid membranes mediating attractive membrane interactions. Furthermore, we observe MBP to insert into its bilayer leaflet side in case of the diseased lipid mixture, whereas there is no insertion for the native mixture. Insertion increases the local membrane curvature, and could be caused by a decrease of the sphingomyelin content of the diseased lipid mixture. These findings can help to open a pathway to remyelination strategies.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS1997

Enhancement of Cognitive Processing by Multiple Sclerosis Patients Using Liquid Cooling Technology: A Case Study

Recent neuropsychological studies demonstrate that cognitive dysfunction is a common symptom in patients with multiple sclerosis. In many cases the presence of cognitive impairment affects the patient's daily activities to a greater extent than would be found due to their physical disability alone. Cognitive dysfunction can have a significant impact on the quality of life of both the patient and that of their primary caregiver. Two cognitively impaired male MS patients were given a visual discrimination task before and after a one hour cooling period. The subjects were presented a series of either red or blue circles or triangles. One of these combinations, or one fourth of the stimuli, was designated as the "target" presentation. EEG was recorded from 20 scalp electrodes using a Tracor Northern 7500 EEG/ERP system. Oral and ear temperatures were obtained and recorded manually every five minutes during the one hour cooling period. The EEG ERP signatures from each series of stimuli were analyzed in the energy density domain to determine the locus of neural activity at each EEG sampling time. The first subject's ear temperature did not decrease during the cooling period. It was actually elevated approximately 0.05 C by the end of the cooling period compared to his mean of control period value. In turn, Subject One's discrimination performance and cortical energy remained essentially the same after body cooling. In contrast, Subject Two's ear temperature decreased approx. 0.8 C during his cooling period. Subject Two's ERROR score decreased from 12 during the precooling control period to 2 after cooling. His ENERGY value increased approximately 300%, from a precooling value of approximately 200 to a postcooling value of nearly 600. These findings might be interpreted by the following three-part hypothesis: (1) the general cognitive impairment of MS patients may be a result of low or unfocused metabolic energy conversion in the cortex; (2) such differences show up most strongly in reduced energy in the occipital region during the initial processing of the precooling period visual stimulus which may indicate impaired early visual processing; and (3) increased postcooling activation in the le ft angular gyrus may result in enhanced higher-level reasoning related to processing visual task information. By this hypothesis the superior performance of Subject Two following body cooling may be a result of increased neural activation in his early visual recognition and processing centers.

Montgomery, Leslie D.↗

NASA NTRS1999

EEG Analysis of the Effects of Therapeutic Cooling on the Cognitive Performance of Multiple Sclerosis Patients

The objective of this project was to determine whether a controlled period of head and torso cooling would enhance the cognitive performance of multiple sclerosis patients. Nineteen MS patients (11 men and 8 women) participated in the study. Control data were taken from nineteen healthy volunteers (12 men and 7 women). All but six of nineteen MS patients tested improved their cognitive performance, as measured by their scores on the Rao test battery. A second objective was to gain insight into the neurological effects of cooling. Visual evoked potentials (VEPs) stimulated by a reversing checkerboard pattern were recorded before and after cooling. We found that cooling selectively benefited the cognitive performance of those MS patients whose pre-cooling VEPs were abnormally shaped (which is an indication of visual pathway impairment due to demyelinization). Moreover, for female MS patients, the degree of cognitive performance improvement following cooling was correlated with a change in the shape of their VEPs toward a more normal shape following cooling.

Montgomery, Leslie D.↗

DOE OSTI2015

In vivo quantitative whole‐brain T 1 rho MRI of multiple sclerosis

Background To apply quantitative whole‐brain T 1 ‐rho (T 1ρ ) and T 2 imaging to the detection and quantification of brain changes resulting from multiple sclerosis (MS). Methods Twenty‐three MS patients with clinically isolated syndrome (10) and relapsing remitting MS (13) phenotypes, compared with 24 age‐matched healthy controls were imaged at 3 Tesla. An axial T 1ρ ‐weighted three‐dimensional turbo spin echo sequence with a variable flip angle and fluid suppression was used. Spin‐lock times of 0, 20, 40, 60, 80, and 100 ms were used. Corresponding T 2 maps were also acquired. Results Whole brain white matter (WM) T 1ρ maps were elevated compared with controls ( P = 0.002). WM lesion T 1ρ and T 2 values were highly correlated (r = 0.83), but T 1ρ demonstrated 25% better contrast to noise ratio ( P < 0.001). WM lesion T 1ρ correlated with disease duration. Gray matter T 1ρ was negatively correlated with the Expanded Disability Status Scale, r = −0.45, P = 0.03. Normal appearing gray matter and cortical gray matter lesions were negatively correlated on T 1ρ , but not on T 2 (r T1ρ = −0.63, p T1ρ = 0.03; r T2 = −0.17, p T2 = 0.6). Conclusion T 1ρ MRI demonstrates enhanced lesion contrast compared with T 2 , and in some cases may provide complementary information. T 1ρ may provide a useful measure of demyelinating processes in MS. J. MAGN. RESON. IMAGING 2015;42:1623–1630.

Gonyea, Jay V.↗

NASA NTRS1995

Rheoencephalographic (REG) Assessment of Head and Neck Cooling for use with Multiple Sclerosis Patients

We have prepared a computer program (RHEOSYS:RHEOencephalographic impedance trace scanning SyStem) that can be used to automate the analysis of segmental impedance blood flow waveforms. This program was developed to assist in the post test analysis of recorded impedance traces from multiple segments of the body. It incorporates many of the blood flow, segmental volume, and vascular state indices reported in the world literature. As it is currently programmed, seven points are selected from each blood flow pulse and associated ECG waveforrn: 1. peak of the first ECG QRS complex, 2. start of systolic slope on the blood flow trace, 3. maximum amplitude of the impedance pulse, 4. position of the dicrotic notch, 5. maximum amplitude of the postdicrotic segment, 6. peak of the second ECG QRS complex, and 7. start of the next blood flow pulse. These points we used to calculate various geometric, area, and time-related values associated with the impedance pulse morphology. RHEOSYS then calculates a series of 34 impedance and cardiac cycle parameters which include pulse amplitudes; areas; pulse propagation times; cardiac cycle times; and various measures of arterial and various tone, contractility, and pulse volume. We used this program to calculate the scalp and intracranial blood flow responses to head and neck cooling as it may be applied to lower the body temperatures of multiple sclerosis patients. Twelve women and twelve men were tested using a commercially available head and neck cooling system operated at its maximum cooling capacity for a period of 30 minutes. Head and neck cooling produced a transient change in scalp blood flow and a significant, (P<0.05) decrease of approx. 30% in intracranial blood flow. Results of this experiment will illustrate how REG and RHEOSYS can be used in biomedical applications.

Montogomery, Leslie D.↗

DOE OSTI2018

Ozone, NO2 and PM10 are associated with the occurrence of multiple sclerosis relapses. Evidence from seasonal multi-pollutant analyses

Highlights: • Season-dependent associations between short term exposure to NO{sub 2} and O{sub 3} and risk of MS relapses were observed. • Confirmation of PM10-associated risk of MS relapses. • A multi-pollutant approach should be systematically intended, especially when assessing level of PM{sub 10} and NO{sub 2.} • Individual characteristics should be considered alongside other MS relapses risk factors. Triggers of multiple sclerosis (MS) relapses are essentially unknown. PM{sub 10} exposure has recently been associated with an increased risk of relapses.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2018

Long-term exposure to air pollution and the incidence of multiple sclerosis: A population-based cohort study

Highlights: • No associations of MS incidence with PM{sub 2.5} and NO{sub 2} were observed. • There was a tendency for increasing MS incidence in relation to O{sub 3.} • Females exhibited a higher risk of developing MS in association with O{sub 3} than males. Evidence of the adverse neurological effects of exposure to ambient air pollution is emerging, but little is known about its effect on the development of multiple sclerosis (MS), the most common autoimmune disease of the central nervous system.

54 ENVIRONMENTAL SCIENCES↗