April 10-April 17, 2010
Abstracts/talks on vitamin D and MS to be presented at
62nd Annual Meeting of the American Academy of Neurology (AAN)
Gestational Vitamin D and the Risk of Multiple Sclerosis in the Offspring
Fariba Mirzaei, Karin Michels, Kassandra Munger, Eilis O'Reilly, Tanuja Chitnis, Edward Giovannucci, Alberto Ascherio, Boston, MA
To study the effect of maternal vitamin D exposure during pregnancy on multiple sclerosis (MS) in the offspring.
Vitamin D may have a protective role in the etiology of MS but the effect of gestational vitamin D on MS has not been studied.
In-utero vitamin D exposure and risk of adult onset MS was examined among a cohort of 35,794 nurses whose mothers' participated in the Nurses' Mothers' Study. The Nurses' Mothers' Study is a subcohort of the Nurses' Health Study and the Nurses' Health Study II which was restricted to nurses with living, biological mothers who completed a questionnaire in 2001 about their experiences and diet during pregnancy with their nurse-daughter. We studied the association between maternal milk intake, maternal dietary vitamin D intake, and predicted maternal serum 25(OH) D during pregnancy and their daughters' risk of developing MS.
MS was diagnosed in 199 women. Risk of MS was lower among women born to mothers with high milk or vitamin D intake in pregnancy. The age adjusted relative risk (RR) of MS among the nurse-daughters was 0.44 (95% CI: 0.16 to 1.23; p for trend=0.001) for mothers consuming 4 glasses of milk per day or more as compared with those consuming milk less than 3 glasses per month, and 0.55 (95% CI: 0.35 to 0.88; p for trend=0.001) for mothers in the highest quintile of dietary vitamin D intake compared with those in the lowest. The predicted 25(OH) vitamin D level in the pregnant mothers was also inversely associated with the risk of MS in their daughters (age adjusted RR comparing extreme quintiles= 0.58; 95% CI: 0.37 to 0.90; p for trend=0.001).
These results are consistent with a protective effect of maternal milk and vitamin D intake on risk of developing MS.
Category - Neuroepidemiology/Health Services and Outcomes Research - Other
Sunday, April 11, 2010 4:15 PM
Platform Session: Integrated Neuroscience: Pediatric Demyelinating Disorders (3:45 PM-5:00 PM)
Vitamin D Metabolites Are Linked to Clinical and MRI Outcomes in Multiple Sclerosis Patients
Bianca Weinstock-Guttman, Robert Zivadinov, Jun Qu, Eunjin Bang, David Hojnacki, Frederick Munschauer, Niels Bergsland, Sarah Hussein, Laura Willis, Marya Cherneva, Murali Ramanathan, Buffalo, NY
To evaluate the association between Vitamin D (Vit D) metabolites levels versus clinical and brain MRI injury parameters in multiple sclerosis (MS) patients.
Epidemiological studies suggest an increased risk for MS development in population with low sun exposure but also in individuals with low Vit D serum levels. Immunological anti-inflammatory protective effects of Vit D shown in preliminary studies provide a strong rational to evaluate this factor in relation to MS disease progression.
The study population consisted of 237 MS patients (185 F:52 M; mean age SD: 45.5 10.6 years and mean disease duration: 13.9 8.4 years) and 22 healthy volunteers (15 F: 7 M, 40.9 2.5 years). Capillary-liquid chromatography-mass spectrometry (LC-MS/MS) was used to quantify levels of 25-hydroxyvitamin D3 (25(OH)VD3), 25-hydroxyvitamin D2 (25(OH)VD2), 1, 25-dihydroxyvitamin D3 (1, 25(OH)2VD3) and 24(R), 25-dihydroxyvitamin D3 (24, 25(OH)2VD3) from subjects serum. The Kurtzke Extended Disability Status Scale (EDSS) and MS Severity Scale (MSSS) were used as disability measures. The MRI measures included: contrast-enhancing lesions volume (CE-LV), T2-LV, T1-LV, gray matter fraction (GMF), white matter fraction (WMF) and brain parenchymal fraction (BPF). Regression methods were used to test the associations of vitamin D and its metabolites to clinical and to MRI measures of brain lesion (CE-LV, T2-LV, T1-LV) and brain atrophy (BPF, GMF, WMF). RESULTS: MS patients had significantly lower levels of 1, 25(OH)2VD3 (p = 0.001) and 24, 25(OH)2VD3 (p = 0.005) compared to healthy subjects. The 25(OH)VD3 to 24, 25(OH)2VD3 ratio was associated with the EDSS (p = 0.010), MSSS (p=0.018) and the presence of progressive MS (p = 0.050). The 25(OH)VD3 to 24, 25(OH)2VD3 ratio was also associated with T2-LV (p = 0.044), T1-LV (p = 0.039) and BPF (p = 0.012).
Vit D and its metabolites show significant associations with disability and MRI measures in MS.
Category - MS and Related Diseases - Clinical Science
Thursday, April 15, 2010 7:30 AM
Poster Discussion Session V: Multiple Sclerosis and Related Diseases: Drug Mechanisms (7:30 AM-12:00 PM)
Potential Factors Influencing Vitamin D Metabolism in Multiple Sclerosis Patients
Jodie M. Burton, Calgary, AB, Canada
To systematically evaluate risk factors that impair vitamin D metabolism common to a Multiple Sclerosis (MS) population.
Vitamin D insufficiency is a well accepted risk factor in MS development and may impact disease activity in those already diagnosed. Supplementation up to 50,000 IU/wk is becoming common-place in MS centers across North America. Despite adherence, some patients do not mount an appropriate response to supplementation. Genetic factors may partly explain this, but other factors appear to influence the response to supplementation; many are common in the MS population. These factors include minimal sun exposure, obesity, pregnancy, diabetes, smoking, ethanol abuse, and use of oral contraceptives, vitamin A and anticonvulsants.
Medline (1955-present) and EMBASE (1980-present) were searched using MESH headings and keyword searching. Hand searches and reviews of abstracts in the last 5 years at relevant conferences were also undertaken. Search terms include: vitamin D, cholecalciferol, vitamin A, retinol, retinoic acid, smoking, tobacco, pregnancy, puerperium, lactation, obesity, body mass index (BMI), diet, exercise, ethanol, alcohol, anticonvulsants, antiepileptics, diabetes, glucose tolerance, gender, sex, race, skin color, sun exposure, UV, UVB, UV radiation, contraceptives, and birth control. All findings are restricted to human. Relevant articles not in English will be translated. Papers will be graded for level of evidence using AAN criteria.
Preliminary results suggest that obesity/high BMI are risk factors for low serum 25(OH)D, a result potentiated in those with dark skin color. Anticonvulsants, vitamin A, pregnancy and type II diabetes also appear to be risk factors for low 25(OH)D while contraceptive use is associated with relatively higher 25(OH)D values.
The following systematic review will assess the evidence for risk factors for impaired response to vitamin D supplementation. Identification of these may support supplementation with higher doses of vitamin D, greater surveillance of response and modification of risk factors to improve vitamin D metabolism.
Category - MS and Related Diseases - Clinical Science
Tuesday, April 13, 2010 3:00 PM
Poster Session II: Multiple Sclerosis and Related Diseases: Clinical Research/Biomarkers (3:00 PM-7:30 PM)
Novel Neuroprotective Outcomes of Vitamin D in Models of Multiple Sclerosis
Scott Sloka, Waterloo, ON, Canada, Claudia Silva, Janet Wang, Yan Fan, Luanne M. Metz, Peter K. Stys, Wee Yong, Calgary, AB, Canada
To explore the potential of vitamin D to protect neurons and axons against inflammatory insults in multiple sclerosis (MS).
Multiple sclerosis (MS) is an inflammatory disorder that causes CNS demyelination and axonal injury. Vitamin D exposure correlates inversely with MS prevalence and has several immunomodulatory characteristics but a neuroprotective role has not been demonstrated in MS.
Human T cells pretreated with vitamin D were co-cultured with human neurons. Neuronal survival was determined using real time confocal microscopy. Imaging algorithms tracked cell trajectories, cell velocity and cell proximity to neuronal structures. Levels of LFA-1, FasL and CD40L, all previously implicated in T cell killing of neurons, were analyzed by FACS. Alteration of neuronal structure was explored using image quantification of cytoskeletal component-labeled neurons. Expression of apoptosis genes was assessed using PCR apoptosis arrays. The impact of vitamin D on murine EAE severity and on axonal counts within spinal cord using toluidine-blue Epon was determined.
Killing of neurons by activated T cells to 25% of baseline levels was normalized by vitamin D pretreatment to 70% of baseline, as T cell expression of FasL, CD40L and LFA-1 was reduced. Proportionally fewer vitamin D-pretreated T cells clustered near neuronal structures; neurons exposed to vitamin D demonstrated more extensive neuritic outgrowth. Some apoptotic genes were downregulated in vitamin D treated neurons, and some anti-apoptotic genes were upregulated. Treatment of EAE mice from peak disease reduced clinical severity and decreased axonal loss by 20% in the dorsal column of L1 spinal cord segments.
Vitamin D reduces neuronal injury in EAE and has the potential to reduce neuronal and axonal loss in the context of MS. Supported by: NeuroScience Canada and the Canadian Institutes of Health Research.
Category - MS and Related Diseases - Basic Science
Thursday, April 15, 2010 2:00 PM
Scientific Sessions: Multiple Sclerosis: Clinical Immunology (1:15 PM-2:30 PM)
25-OH Vitamin D3 Reduces Interferon Gamma and Interleukin-17 Release from CD4+ T-Cells
Edward Knapp, Christopher Eckstein, Peter Calabresi, Baltimore, MD
To determine the effect of 25-OH-vitamin D3 (25-OH D) at physiologically relevant concentrations on T-cell proliferation and cytokine release.
Many multiple sclerosis patients are vitamin D deficient, generating widespread interest in the role of vitamin D on immune cells. Prior in vitro studies have mostly been done using the active hormone 1-25-OH vit D3 (calcitriol) and non-physiological concentrations of the storage form 25-OH vit D3. One explanation for why clinical trials of vitamin D have been negative or only revealed modest benefits is that an effective dose was not used to obtain effective blood levels in these studies.
Negatively selected CD4+ T-cells from healthy controls were stimulated with anti-CD3 and anti-CD28 and cultured for 3-14 days in the presence of 25-OH D. Supernatants were collected at 72 hours after stimulation or restimulation for cytokine ELISA. T-cell subsets were sorted by flow cytometry into nave, central memory and effector memory populations and examined for changes in cytokines.
Interferon gamma (IFNg) release was reduced by approximately 50% after 72-hour culture with 25-OH D concentrations of 48nM (p=0.0275), 72nM (p=0.0370), and 96nM (p=0.0277). Release of IL-17 is also reduced by 85% from baseline at these concentrations (p=0.0205, 0.0044, 0.0004, respectively). IFNg release is reduced by over 50% in both TCM and TEM cell subsets following 48-hour exposure to 48nM 25-OH D, and by 62% in TEM exposed to 96nM 25-OH D. There was no difference in CD4+ T-cell proliferation between 25-OH D-treated and controls.
One of the beneficial effects of vitamin D on human immune cells may be due to reduction in release of IFNg and IL-17, both of which have proinflammatory effects. Importantly, the effects were seen at concentrations of 25-OH D which are physiologically achievable. More studies are needed to determine the clinical significance of these effects.
Category - MS and Related Diseases - Basic Science
Thursday, April 15, 2010 7:30 AM
Poster Session V: Multiple Sclerosis and Related Diseases: Drug Mechanisms II (7:30 AM-12:00 PM)
Vitamin D, Fall Frequency, and Cognitive Function in Free-Living Elders
Amie Peterson, Nora Mattek, Aaron Clemons, Gene Bowman, Teresa Buracchio, Jeffrey Kaye, Joseph Quinn, Portland, OR
To determine plasma vitamin D (25-hydroxyvitamin D) content in a community of free-living elders and its relationship with fall frequency, locomotion, and cognitive status.
A role for vitamin D in the nervous system is implied by clinical studies demonstrating an association with falls and less clearly cognitive performance in the elderly. The presence of Vitamin D receptors throughout the brain provides more support.
The Intelligent Systems for Assessment of Aging Changes Study (ISAAC) is a home-based cohort study of age-associated changes in motor and cognitive function among independently living seniors over age 70. Subjects have sensor systems in their homes to monitor activity measures, complete weekly on-line health questionnaires, and receive yearly clinical, cognitive, and laboratory testing. Vitamin D was available in 154 participants. Vitamin D levels were compared to weekly self-reported falls, tests of motor function (e.g. Tinetti Gait and Balance scores, timed gait, and automated continuous activity monitoring) and cognitive function (standardized psychometric battery, and Mini-Mental State Examination; MMSE).
Average age was 85 years; 74% were women. Mean vitamin D was 38.0ng/ml (range=9-90 ng/ml). Twenty-four percent (n=37) reported at least one fall within 6 months of vitamin D collection. The mean vitamin D of non-fallers was significantly greater 39.7ng/ml(SD 15.3), than both one-time fallers 34.1ng/ml(SD 9.8), and multiple-fallers 28.6ng/ml(SD 11.8) (p=0.03). Vitamin D was also greater in subjects with higher MMSE scores; 42.815ng/ml for MMSE=30(n=42), 36.714.4ng/ml for MMSE=27-29(n=89), and 34.813.1ng/ml for MMSE 22-26(n=21) (p=0.05).
Vitamin D is frequently low in community dwelling elderly. Greater plasma vitamin D levels are associated with fewer falls and higher MMSE scores. Longitudinal follow-up ascertaining dementia and future morbidity risks, as well as trials examining if improvement in vitamin D status affects falls and cognition are needed. Supported by: NIH AG08017, AG024059, AG024978, OCTRI grant, Dept of Veteran's Affairs, NCCAM K23 AT004777(GLB).
Category - Behavioral Neurology - Dementia/Memory
Wednesday, April 14, 2010 3:00 PM
Poster Session IV: Behavioral Neurology: Memory (3:00 PM-7:30 PM)