Author Of 2 Presentations
P0103 - Liothyronine treatment of MS patients alters proteins in CSF related to angiogenesis and immune function (ID 438)
Abstract
Background
Thyroid hormones have effects on a variety of glial and immune cell populations that appear to be involved in the pathogenesis of multiple sclerosis (MS). Since tri-iodothyronine (T3) is believed to mediate the most important thyroid hormone actions, liothyronine (synthetic T3) may have the potential to induce reparative mechanisms and limit neurodegeneration in MS.
Objectives
To utilize proteomics to assess the effect of liothyronine treatment on the cerebrospinal fluid (CSF) proteome in MS.
Methods
We utilized CSF collected from 18 patients with MS enrolled in a single center trial of oral liothyronine for 24 weeks. Participants received liothyronine according to a standardized dose-titration schedule. Participants continued their maintenance MS immune therapies during the study. Eligibility criteria included euthyroid patients, 18-58 years old, 2010 McDonald MS and Expanded Disability Status Scale (EDSS) score 3.0-7.5. Main exclusion was known thyroid dysfunction. The primary outcome was safety and tolerability of liothyronine. CSF was collected at baseline and end of study (24 weeks) as an exploratory outcome for treatment response. SOMAscan platform (DNA aptamer based detection of proteins) was used to detect and quantify a panel of 1314 proteins in the CSF.
Results
Study participants had a mean age of 45.9 ± 8.8 years, F:M ratio of 7:9, relapsing disease (11/16), mean disease duration of 9 years and median EDSS of 3.5. Of the measured proteins, 46 changed (19 increased and 27 decreased) over the course of the study (p<0.05). These included proteins related to immune function such as TACI, NKp46, IgA and IgD and angiogenesis such as Cadherin-5, sTIE-1 and ANGPT2. Enrichment analyses using PANTHER and STRING databases noted that the biological processes that were over-represented included – angiogenesis and innate and adaptive immune function. Angiogenesis related proteins predominantly demonstrated an increase with liothyronine treatment while the majority of immune related proteins decreased with treatment.
Conclusions
Changes in CSF proteins involved in central nervous system immune cell function and promotion of angiogenesis were seen with a short course of liothyronine treatment in people with MS. A larger clinical trial would help determine whether these observed changes have a biological effect that is clinically meaningful.
P0442 - Cerebrovascular disease and Alzheimer’s disease neuropathology in multiple sclerosis. (ID 422)
Abstract
Background
Multiple sclerosis (MS) is associated with an increased risk of ischemic stroke and this association is not accounted for by traditional vascular risk factors. Few neuropathologic human studies have examined the relation of MS to cerebrovascular disease (CVD) and other common neuropathology of aging.
Objectives
To examine associations of MS with pathologically-proven CVD and Alzheimer’s disease (AD), among community-dwelling persons with and without MS who died and came to autopsy.
Methods
Participants were enrolled in one of two clinical-pathologic studies of aging, the Rush Memory and Aging Project and the Religious Orders Study. We matched (1:2) all autopsied MS subjects (n=14) with persons without MS (n =28), on gender, balancing by race, years of education, and age of death. MS was identified by the medical history or postmortem neuropathological examination. Pathological diagnosis of MS was made when one or more areas of primary demyelination were encountered in the periventricular white matter in the cerebrum or brainstem. Uniform neuropathologic examination documented brain infarcts, and separately gross and microscopic infarcts, and cerebral vessel pathologies including atherosclerosis. A global AD score was based on a modified Bielschowsky silver stain detecting plaques and neurofibrillary tangles, and immunohistochemistry documented amyloid load and tangle density. Analyses employed the generalized estimating equation for categorical variables and linear mixed model of a logarithmic scale for continuous variables.
Results
In the total group (n=42), participants were 79% female, 93% white, with a mean age-at-death of 85.0 years (SD=8.2). Five patients had a clinical diagnosis of MS, seven a pathological diagnosis, and two both diagnoses. MS cases were more likely to have one or more brain infarcts (10/14 (71.4%) MS cases and 7/28 (25.0%) controls, OR=7.02, 95% CI[2.44, 20.17], p=0.0003), and more likely to have one or more gross infarcts (8/14 (57.1%) MS cases and 5/28 (17.9%) controls, OR=5.92, 95% CI [2.49, 14.10], p=<0.0001). There was no difference in number of microinfarcts (p=0.07) or severity level of vessel pathologies including atherosclerosis (p=0.56), arteriolosclerosis (p=0.99), or cerebral amyloid angiopathy (p=0.09). Cases had higher levels of global AD pathology than controls (Coefficient (SE)=1.10(0.49), p=0.03). There were no significant differences in amyloid load (p=0.13) or tangles density (p=0.50).
Conclusions
In keeping with clinical studies showing that MS is associated with stroke, we found that persons with MS were more likely to have neuropathologically-confirmed brain infarcts, and gross infarcts in particular. There was no difference in cerebral vessel pathology. MS was also associated with AD pathology. This study was limited by a small sample size. Further studies will elucidate pathways linking MS to neuropathology of aging, stroke, and cognitive impairment.