[show abstract][hide abstract] ABSTRACT: Oxidative stress, inflammation, and increased cholesterol levels are all mechanisms that have been associated with Alzheimer's disease (AD) pathology. Several epidemiologic studies have reported a decreased risk of AD with fish consumption. This pilot study was designed to evaluate the effects of supplementation with omega-3 fatty acids alone (ω-3) or omega-3 plus alpha lipoic acid (ω-3 + LA) compared to placebo on oxidative stress biomarkers in AD. The primary outcome measure was peripheral F2-isoprostane levels (oxidative stress measure). Secondary outcome measures included performance on: Mini-Mental State Examination (MMSE), Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL), and Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Thirty-nine AD subjects were randomized to one of three groups: 1) placebo, 2) ω-3, or 3) ω-3 + LA for a treatment duration of 12 months. Eighty seven percent (34/39) of the subjects completed the 12-month intervention. There was no difference between groups at 12 months in peripheral F2-isoprostane levels (p = 0.83). The ω-3 + LA and ω-3 were not significantly different than the placebo group in ADAS-cog (p = 0.98, p = 0.86) and in ADL (p = 0.15, p = 0.82). Compared to placebo, the ω-3 + LA showed less decline in MMSE (p < 0.01) and IADL (p = 0.01) and the ω-3 group showed less decline in IADL (p < 0.01). The combination of ω-3 + LA slowed cognitive and functional decline in AD over 12 months. Because the results were generated from a small sample size, further evaluation of the combination of omega-3 fatty acids plus alpha-lipoic acid as a potential treatment in AD is warranted.
Journal of Alzheimer's disease: JAD 09/2013; · 4.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: MIF and its receptor, CD74, are pivotal regulators of the immune system. Here, we demonstrate for the first time that partial MHC class II constructs comprised of linked β1α1 domains with covalently attached antigenic peptides (also referred to as recombinant T-cell receptor ligands - RTLs) can inhibit MIF activity by not only blocking the binding of rhMIF to immunopurified CD74, but also downregulating CD74 cell-surface expression. This bifunctional inhibition of MIF/CD74 interactions blocked downstream MIF effects, including enhanced secretion of proinflammatory cytokines, anti-apoptotic activity, and inhibition of random migration that all contribute to the reversal of clinical and histological signs of EAE. Moreover, we demonstrate that enhanced CD74 cell-surface expression on monocytes in mice with EAE and subjects with multiple sclerosis can be downregulated by humanized RTLs, resulting in reduced MIF binding to the cells. Thus, binding of partial MHC complexes to CD74 blocks both the accessibility and availability of CD74 for MIF binding and downstream inflammatory activity.
European Journal of Immunology 04/2013; · 4.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Incidental T2 white matter hyperintensities (WMHs) in headache patients on brain magnetic resonance imaging (MRI) may prompt concern for demyelinating disease. OBJECTIVE: We reviewed brain MRI studies in patients with headaches without known demyelinating disease to determine the prevalence meeting imaging criteria for multiple sclerosis (MS) using two different definitions of "juxtacortical" and "periventricular". METHODS: Consecutive patients undergoing pre- and post-contrast MRI for headaches over a 25-month period were retrospectively identified. Exclusions included patients under age 10 and over 55 years or with known demyelinating disorder. Patients were classified as meeting: 1) Barkhof and 2) 2010 McDonald dissemination in space criteria for MS based on: FLAIR/T2 scans for WMH and enhanced T1-weighted images for enhancement. Both groups were further differentiated by defining "periventricular" and "juxtacortical" as WMH contacting ventricle and cortex (Barkhof "touching", McDonald "touching") versus WMH within 3 mm (Barkhof - 3 mm, McDonald - 3 mm). RESULTS: 326/564 (58%) studies met inclusion criteria. WMH prevalence was 168/326 (51.53%). Barkhof "touching" criteria were met in 4/168 (2.4%) and in 12/168 (7.1%) of the 3 mm group. McDonald criteria were met in 41/168 (24.4%) for "touching" and 58/168 (34.5%) for 3 mm, respectively. CONCLUSION: Barkhof and McDonald criteria were met in 2.4-7.1% and 24.4-34.5%, respectively.
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: To compare the use of fall prevention strategies by people with multiple sclerosis (MS) who do or do not fall. DESIGN: Prospective cohort. SETTING: All assessments were completed between January, 2011 and December, 2011. Data used in this analysis were collected as part of an observational study that included baseline assessment followed by prospective counting of falls using fall calendars. PARTICIPANTS: 58 people with MS of any subtype, aged 18-50 years, with Expanded Disability Status Scale ≤ 6.0, recruited from MS clinics at the Portland VA Medical center and Oregon Health & Science University and from the surrounding areas. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The main outcome measures were the occurrence of falls over three months and scores on the Fall Prevention Strategy Survey (FPSS), and relationships between fall prevention strategy use reported on the FPSS and falls. RESULTS: 52 subjects completed the study. Of these, 33 (63%) fell at least once in the 3 month period and 19 (36%) did not fall. The mean total FPSS score for the fallers was significantly higher than for the non-fallers (mean 8.1 vs 4.0, range 0-20 vs 0-15, s.d. 6.4 vs 4.1, p = 0.007), and FPSS scores correlated with monthly fall rates (Rho = 0.49, p = 0.01). A higher proportion of fallers than non-fallers used the strategies of turning on lights at home, asking others for help, and talking to a healthcare professional about fall prevention. However, both groups rarely talked to a healthcare professional about fall prevention or asked a provider to check whether any medications might increase fall risk. CONCLUSION: People with MS who fall use more fall prevention strategies than those who do not fall.
Archives of physical medicine and rehabilitation 02/2013; · 2.18 Impact Factor
[show abstract][hide abstract] ABSTRACT: Multiple sclerosis (MS) has traditionally been considered an autoimmune inflammatory disorder leading to demyelination and clinical debilitation as evidenced by our current standard anti-inflammatory and immunosuppressive treatment regimens. While these approaches do control the frequency of clinical relapses, they do not prevent the progressive functional decline that plagues many people with MS. Many avenues of research indicate that a neurodegenerative process may also play a significant role in MS from the early stages of disease, and one of the current hypotheses identifies mitochondrial dysfunction as a key contributing mechanism. We have hypothesized that pathological permeability transition pore (PTP) opening mediated by reactive oxygen species (ROS) and calcium dysregulation is central to mitochondrial dysfunction and neurodegeneration in MS. This focused review highlights recent evidence supporting this hypothesis, with particular emphasis on our in vitro and in vivo work with the mitochondria-targeted redox enzyme p66ShcA.
[show abstract][hide abstract] ABSTRACT: Background. Many people with MS fall, but the best method for identifying those at increased fall risk is not known. Objective. To compare how accurately fall history, questionnaires, and physical tests predict future falls and injurious falls in people with MS. Methods. 52 people with MS were asked if they had fallen in the past 2 months and the past year. Subjects were also assessed with the Activities-specific Balance Confidence, Falls Efficacy Scale-International, and Multiple Sclerosis Walking Scale-12 questionnaires, the Expanded Disability Status Scale, Timed 25-Foot Walk, and computerized dynamic posturography and recorded their falls daily for the following 6 months with calendars. The ability of baseline assessments to predict future falls was compared using receiver operator curves and logistic regression. Results. All tests individually provided similar fall prediction (area under the curve (AUC) 0.60-0.75). A fall in the past year was the best predictor of falls (AUC 0.75, sensitivity 0.89, specificity 0.56) or injurious falls (AUC 0.69, sensitivity 0.96, specificity 0.41) in the following 6 months. Conclusion. Simply asking people with MS if they have fallen in the past year predicts future falls and injurious falls as well as more complex, expensive, or time-consuming approaches.
[show abstract][hide abstract] ABSTRACT: Rheumatologic diseases may cause neurologic disorders that mimic multiple sclerosis (MS). A panel of serum autoantibodies is often obtained as part of the evaluation of patients suspected of having MS.
To determine, in light of recently revised diagnostic criteria for MS, neuromyelitis optica, and Sjogren's Syndrome, if testing for autoantibodies in patients with a confirmed diagnosis of MS would reveal a frequency or demonstrate a clinical utility divergent from previous reports or lead to identification of undiagnosed cases of Sjogren's Syndrome.
Convenience sample cross-sectional study of MS patients recruited from the OHSU Multiple Sclerosis Center.
Autoantibodies were detected in 38% (35/91) of patients with MS and were not significantly associated with disease characteristics or severity. While four patients had SSA antibodies, none met diagnostic criteria for Sjogren's Syndrome.
Rheumatologic autoantibodies are frequently found in MS patients and are not associated with disease severity or systemic rheumatologic disease. Our demonstration of the low specificity of these autoantibodies suggests that the diagnostic utility and cost-effectiveness of testing is not supported when there is strong clinical suspicion of MS and low clinical suspicion of rheumatologic disease.
PLoS ONE 01/2013; 8(6):e65385. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Unexpected consequences arise from our incomplete knowledge of the immune system. Who, for example, would have predicted that natalizumab, a monoclonal antibody targeting α4 integrin on leukocytes, would dramatically increase the risk of developing progressive multifocal leukoencephalopathy without causing notable immunosuppression? Thus, any new immunomodulatory therapy in humans must be approached with caution.
[show abstract][hide abstract] ABSTRACT: To determine whether Ginkgo biloba extract (ginkgo) improves cognitive function in persons with multiple sclerosis (MS).
Persons with MS from the Seattle and Portland VA clinics and adjacent communities who scored 1 SD or more below the mean on one of 4 neuropsychological tests (Stroop Test, California Verbal Learning Test II [CVLT-II], Controlled Oral Word Association Test [COWAT], and Paced Auditory Serial Addition Task [PASAT]) were randomly assigned to receive either one 120-mg tablet of ginkgo (EGb-761; Willmar Schwabe GmbH & Co, Germany) or one placebo tablet twice a day for 12 weeks. As the primary outcome, we compared the performance of the 2 groups on the 4 tests at exit after adjusting for baseline performance.
Fifty-nine subjects received placebo and 61 received ginkgo; 1 participant receiving placebo and 3 receiving ginkgo were lost to follow-up. Two serious adverse events (AEs) (myocardial infarction and severe depression) believed to be unrelated to the treatment occurred in the ginkgo group; otherwise, there were no significant differences in AEs. The differences (ginkgo - placebo) at exit in the z scores for the cognitive tests were as follows: PASAT -0.2 (95% confidence interval [CI] -0.5 to 0.1); Stroop Test -0.5 (95% CI -0.9 to -0.1); COWAT 0.0 (95% CI -0.2 to 0.3); and CVLT-II 0.0 (95% CI -0.3 to 0.3); none was statistically significant.
Treatment with ginkgo 120 mg twice a day did not improve cognitive performance in persons with MS. Classification of evidence: This study provides Class I evidence that treatment with ginkgo 120 mg twice a day for 12 weeks does not improve cognitive performance in people with MS.
[show abstract][hide abstract] ABSTRACT: Axonal spheroids occur as part of the pathology of a variety of neurologic diseases. Reactive oxygen species (ROS) trigger formation of spheroids, axonal severing, and Ca(2+) overload. The mechanisms by which ROS lead to the spheroid formation at specific axonal sites remain elusive. Here, using adult mouse primary neurons, we investigate the role of Ca(2+), its regulating systems, and cytoskeletal changes in formation of axonal spheroids triggered by ROS. The results reveal that dramatically higher axoplasmic Ca(2+) levels occur at the sites of axonal spheroids than in the rest of the axon. High focal axoplasmic Ca(2+) levels correlate with focal aggregation of the reverse Na(+)/Ca(2+) exchanger 1, voltage-gated N-type Ca(2+) channel α1B subunit, and actin at the sites of spheroids in individual axons. This study provides new insights into the mechanism of a spheroid formation at specific sites along axons undergoing oxidative stress and a basis for new neuroprotective strategies.
Journal of Neuroscience 08/2012; 32(35):12028-37. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: The availability of the second-generation therapies for relapsing multiple sclerosis (MS), natalizumab and fingolimod, provides new treatment options for MS but also presents new challenges. Both natalizumab and fingolimod appear to be more effective than the interferon beta products and glatiramer acetate, but both have more safety problems than do the first-generation therapies. Treatment with natalizumab is associated with a significant risk of patients developing progressive multifocal leukoencephalopathy (PML), which the JC virus causes. We now are able to risk stratify MS patients into high- and low-risk groups for developing PML on the basis of the presence or absence of antibodies to the JC virus, history of prior use of immunosuppressants, and duration of therapy with natalizumab. Fingolimod appears to be associated with a risk of asystole and sudden death. It may also increase the risk of serious herpes infections and paradoxical activation of MS. More information is needed about these serious side effects from fingolimod to allow us to use it safely in patients.
Current Neurology and Neuroscience Reports 07/2012; 12(5):489-91. · 3.78 Impact Factor
[show abstract][hide abstract] ABSTRACT: Reactive oxygen species (ROS) released by microglia and other inflammatory cells can cause axonal degeneration. A reduction in axonal transport has also been implicated as a cause of axonal dystrophies and neurodegeneration, but there is a paucity of experimental data concerning the effects of ROS on axonal transport. We used live cell imaging to examine the effects of hydrogen peroxide on the axonal transport of mitochondria and Golgi-derived vesicles in cultured rat hippocampal neurons.
Hydrogen peroxide rapidly inhibited axonal transport, hours before any detectable changes in mitochondrial morphology or signs of axonal degeneration. Mitochondrial transport was affected earlier and was more severely inhibited than the transport of Golgi-derived vesicles. Anterograde vesicle transport was more susceptible to peroxide inhibition than retrograde transport. Axonal transport partially recovered following removal of hydrogen peroxide and local application of hydrogen peroxide inhibited transport, suggesting that the effects were not simply a result of nerve cell death. Sodium azide, an ATP synthesis blocker, had similar effects on axonal transport, suggesting that ATP depletion may contribute to the transport inhibition due to hydrogen peroxide.
These results indicate that inhibition of axonal transport is an early consequence of exposure to ROS and may contribute to subsequent axonal degeneration.
[show abstract][hide abstract] ABSTRACT: To describe the clinical characteristics of encounters with patients misdiagnosed with multiple sclerosis (MS).
A cross-sectional Internet-based physician survey of MS specialists was performed.
The response rate for the survey was 50.4%. Of those who responded, the majority (95%) reported having evaluated 1 or more patients who had been diagnosed with MS, but who they strongly felt did not have MS, within the last year. The majority of respondents (>90%) also reported the use of disease-modifying therapy in a proportion of these patients. Most respondents (94%) found clinical encounters with these patients equally or more challenging than giving a new diagnosis of MS. Fourteen percent of respondents reported that they did not always inform such patients of their opinion that they did not have MS.
The misdiagnosis of MS is common and has significant consequences for patient care and health care system costs. Caring for a patient with a misdiagnosis of MS is challenging, and at times honest disclosure of a misdiagnosis represents an important ethical concern for neurologists. More data are needed on this patient population to improve diagnostic acumen and the care of these patients.
[show abstract][hide abstract] ABSTRACT: Although multiple sclerosis (MS) has traditionally been considered to be an inflammatory disease, recent evidence has brought neurodegeneration into the spotlight, suggesting that accumulated damage and loss of axons is critical to disease progression and the associated irreversible disability. Proposed mechanisms of axonal degeneration in MS posit cytosolic and subsequent mitochondrial Ca(2+) overload, accumulation of pathologic reactive oxygen species (ROS), and mitochondrial dysfunction leading to cell death. In this context, the role of the p66 isoform of ShcA protein (p66) may be significant. The ShcA isoform is uniquely targeted to the mitochondrial intermembrane space in response to elevated oxidative stress, and serves as a redox enzyme amplifying ROS generation in a positive feedforward loop that eventually mediates cell death by activation of the mitochondrial permeability transition pore. Consequently, we tested the hypothesis that genetic inactivation of p66 would reduce axonal injury in a murine model of MS, experimental autoimmune encephalomyelitis (EAE). As predicted, the p66-knockout (p66-KO) mice developed typical signs of EAE, but had less severe clinical impairment and paralysis than wild-type (WT) mice. Histologic examination of spinal cords and optic nerves showed significant axonal protection in the p66-KO tissue, despite similar levels of inflammation. Furthermore, cultured p66-KO neurons treated with agents implicated in MS neurodegenerative pathways showed greater viability than WT neurons. These results confirm the critical role of ROS-mediated mitochondrial dysfunction in the axonal loss that accompanies EAE, and identify p66 as a new pharmacologic target for MS neuroprotective therapeutics.
European Journal of Neuroscience 02/2012; 35(4):562-71. · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background. Recombinant T-cell receptor ligand 1000 (RTL1000) is a single-chain protein construct containing the outer two domains of HLA-DR2 linked to myelin-oligodendrocyte-glycoprotein- (MOG-) 35-55 peptide. Analogues of RTL1000 induce T-cell tolerance, reverse clinical and histological disease, and promote repair in experimental autoimmune encephalomyelitis (EAE) in DR2 transgenic, C57BL/6, and SJL/J mice. Objective. Determining the maximum tolerated dose, safety, and tolerability of RTL1000 in multiple sclerosis (MS) subjects. Methods. This was a multicenter, Phase I dose-escalation study in HLA-DR2(+) MS subjects. Consecutive cohorts received RTL1000 doses of 2, 6, 20, 60, 200, and 100 mg, respectively. Subjects within each cohort randomly received a single intravenous infusion of RTL1000 or placebo at a 4 : 2 ratio. Safety monitoring included clinical, laboratory, and brain magnetic resonance imaging (MRI) evaluations. Results. Thirty-four subjects completed the protocol. All subjects tolerated the 2-60 mg doses of RTL1000. Doses ≥100 mg caused hypotension and diarrhea in 3 of 4 subjects, leading to discontinuation of further enrollment. Conclusions. The maximum tolerated dose of RTL1000 in MS subjects is 60 mg, comparable to effective RTL doses in EAE. RTL1000 is a novel approach for MS treatment that may induce immunoregulation without immunosuppression and promote neural repair.
[show abstract][hide abstract] ABSTRACT: Mitochondria are essential to neuronal viability and function due to their roles in ATP production, intracellular calcium regulation, and activation of apoptotic pathways. Accordingly, mitochondrial dysfunction has been indicated in a wide variety of neurodegenerative diseases, including Alzheimer's disease (AD), Huntington's disease, amyotrophic lateral sclerosis, stroke, and multiple sclerosis (MS). Recent evidence points to the permeability transition pore (PTP) as a key player in mitochondrial dysfunction in these diseases, in which pathologic opening leads to mitochondrial swelling, rupture, release of cytochrome c, and neuronal death. Reactive oxygen species (ROS), which are inducers of PTP opening, have been prominently implicated in the progression of many of these neurodegenerative diseases. In this context, inactivation of a mitochondria-targeted redox enzyme p66ShcA (p66) has been recently shown to prevent the neuronal cell death leading to axonal severing in the murine model of MS, experimental autoimmune encephalomyelitis (EAE). To further characterize the response of neurons lacking p66, we assessed their reaction to treatment with stressors implicated in neurodegenerative pathways. Specifically, p66-knockout (p66-KO) and wild-type (WT) neurons were treated with hydrogen peroxide (H(2)O(2)) and nitric oxide (NO), and assessed for cell viability and changes in mitochondrial properties, including morphology and ROS production. The results showed that p66-KO neurons had greater survival following treatment with each stressor and generated less ROS when compared to WT neurons. Correspondingly, mitochondria in p66-KO neurons showed diminished morphological changes in response to these challenges. Overall, these findings highlight the importance of developing mitochondria-targeted therapeutics for neurodegenerative disorders, and emphasize p66, mitochondrial ROS, and the PTP as key targets for maintaining mitochondrial and neuronal integrity.
[show abstract][hide abstract] ABSTRACT: Previous studies demonstrated that patients with multiple sclerosis (MS) experience more hearing loss than age-matched control subjects. Patients with MS also exhibit deficits processing auditory stimuli, including speech in a background of noise. These findings suggest that auditory deficits in the MS population can result from damage to central neural pathways in addition to peripheral hearing structures. To assess auditory processing functions in patients with MS, this study used auditory event-related potentials (AERPs)—specifically, the auditory brain stem response (ABR) and long-latency AERPs including the P300. AERPs recorded from 20 patients with MS were compared to AERPs from 20 healthy control subjects. When ABR stimuli (clicks) were presented monaurally, there were no significant differences between groups in component latencies or amplitudes for waves I through V. However, binaural presentation of the same stimuli elicited wave V ABR components significantly greater in amplitude for the control group compared with the MS group. Long-latency AERP results showed no significant differences between groups for N100 latency and amplitude or for P300 latency. P300 component amplitude was significantly greater for control subjects compared with patients with MS. It is probable that neural degeneration and impaired neural transmission within the MS group contributed to these AERP results. AERPs are useful tools that can be used to assess peripheral and central auditory functions as well as cognitive processing abilities in patients with MS. AERPs could be used to evaluate neural integrity, disease progression, and treatment efficacy in this population.