Introdução: independentemente do grau de incapacidade física, o declínio cognitivo tem sido considerado motivo de maior impacto em importantes aspectos da vida diária dos pacientes com Esclerose Múltipla (EM) como o gerenciamento de tarefas domésticas, participação na sociedade e manutenção do emprego. Alterações de Memória Episódica (ME) em pacientes com EM são comumente descritas na literatura, sendo observadas em 40% a 65% dos casos. Seu impacto já é observado em pacientes com Esclerose Múltipla Remitente-Recorrente (EMRR) incipiente e pode ser um indicador de pior prognóstico para evolução da doença. Adicionalmente, déficits na memória verbal bem como na velocidade de processamento de informação e função executiva predizem condição ocupacional dos portadores da doença. Há vários trabalhos transversais na literatura científica que visam investigar sobre alterações cognitivas encontradas nestes pacientes. Entretanto, os estudos longitudinais são escassos e estes têm revelado resultados inconclusivos e divergentes. Além disso, tanto nos estudos transversais quanto nos estudos longitudinais, não há preocupação em caracterizar de forma aprofundada o declínio da Memória Episódica Verbal (MEV) especificamente. Objetivo: neste estudo, investigamos a MEV de pacientes com EMRR e sua evolução através de avaliação longitudinal. Métodos: vinte e nove pacientes com EMRR foram submetidos a duas avaliações neuropsicológicas realizadas entre um intervalo de tempo médio de 4,5 anos. Vinte e seis controles saudáveis foram submetidos à uma única e idêntica avaliação neuropsicológica. Considerou-se nível de significância p < 0,05 para delinear diferenças estatísticas entre os grupos nas análises Mann Withney e Wilcoxon pareado. Resultados: não houve diferença estatística nos resultados dos testes de MEV entre a primeira e a segunda avaliação neuropsicológica realizada pelos pacientes. Houve discrepância estatística nos resultados dos testes de MEV entre o grupo de controles e grupo de pacientes no momento da avaliação inicial. Em contrapartida, no momento da segunda avaliação o grupo de pacientes não se diferenciou estatisticamente do grupo dos controles. Conclusões: a estabilização ou discreta melhora do desempenho dos pacientes com EMRR entre a avaliação inicial e o follow-up em testes de MEV, pode estar relacionada ao fato de que neste estudo foram incluídos predominantemente jovens adultos na amostra, com a forma clínica mais branda da doença. Possível processo de neuroplasticidade cerebral, ou mesmo inclusão de casos benignos da EM precisam ser considerados. Atrelado a isso, deve-se considerar que o breve período de follow-up pode não ter sido o suficiente para detectar possíveis déficits a longo prazo / Introduction: Regardless of the degree of physical disability, cognitive decline has been considered as having the greatest impact on important aspects of the daily life of Multiple Sclerosis (MS) patients, such as managing household tasks, participation in society and maintaining employment. Changes in Episodic Memory (EM) in MS patients are commonly described in the literature and are observed in 40% to 65% of cases. Its impact is already observed in patients with incipient Relapsing-Remitting Multiple Sclerosis (RRMS) and may be an indicator of a worse prognosis for disease progression. In addition, deficits in verbal memory as well as in the speed of information processing and executive function predict the occupational condition of the patients with the disease. There are several transversal works in the scientific literature that aim to investigate cognitive alterations found in these patients. However, longitudinal studies are scarce and these have revealed inconclusive and divergent results. Moreover, in both crosssectional studies and longitudinal studies, there is no concern to characterize in depth the decline of Verbal Episodic Memory (VEM) specifically. Objective: In this study, we investigated the VEM of patients with RRMS and its evolution through longitudinal evaluation. Methods: Twenty-nine patients with RRMS were submitted to two neuropsychological evaluations performed between a mean time interval of 4.5 years. Twenty-six healthy controls were submitted to a single and identical neuropsychological evaluation. A significance level of p < 0.05 was used to delineate statistical differences between the groups in the Mann Withney and Wilcoxon paired analyzes. Results: There was no statistical difference in the VEM results between the first and second neuropsychological evaluation performed by the patients. There was a statistical discrepancy in the VEM results between the control group and the patient group at the time of the initial evaluation. In contrast, at the time of the second evaluation, the group of patients did not differ statistically from the control group. Conclusions: The stabilization or discrete improvement in the performance of RRMS patients between the initial evaluation and the follow-up in the VEM trials may be related to the fact that in this study, predominantly young adults were included in the sample, with the mildest clinical form of the disease. Possible process of cerebral neuroplasticity, or even inclusion of benign cases of MS need to be considered. Coupled with this, one should consider that the brief follow-up period may not have been enough to detect possible long-term deficits

Introdução: A Esclerose Múltipla (EM) é uma doença autoimune desmielinizante que afeta drasticamente a capacidade motora, cognitiva, e sensitiva dos pacientes. Acreditase que o Retrovírus Endógeno Humano da família W (HERV-W) possa ter um papel na patogênese da doença. Assim, o objetivo deste trabalho foi analisar o transcriptoma desses indivíduos, e analisar os loci do HERV-W diferencialmente ativos. Materiais e Métodos: PBMC e soro de pacientes com EM em surto (GS), em condições avançadas (GA) e indivíduos saudáveis (GC) foram coletadas. Amplicons de envelope de HERV-W foram sequenciados em Ion Torrent e o RNAm foi sequenciado na plataforma Illumina HiSeq2500. Além da análise do HERV-W, análises de interação gênica foram feitas e citocinas inflamatórias e quimiocinas foram testadas. Resultados: Foram analisados 23 indivíduos com EM (16 GS e 7 GA) e 36 do GC. Os pacientes com EM apresentam 3x mais expressão de HERV-W do que os indivíduos controle. O sequenciamento de amplicon revelou que os grupos com EM apresentavam mais loci ativos do que o GC. Apesar limitações decorrentes de variações entre corridas, o transcriptoma demonstrou que o HERV-K11 era diferencialmente expresso no GS, e no GA, 19 HERVs estavam diferencialmente expressos. Loci novos e já descritos como ativos em outros estudos foram encontrados no presente trabalho. O perfil de interação gênica do GS demonstrou um caráter inflamatório, confirmados pela dosagem de citocinas, onde IL-6, IL-1?, TNF-?, IFN-? estavam elevadas nos indivíduos do GS. Já os indivíduos do GA apresentavam um perfil não inflamatório com vias de reparo neuronal inativadas. Conclusões: Os pacientes com EM apresentam maior nível de expressão e maior diversidade de expressão de HERV-W do que o GC. Apesar os perfis semelhantes de expressão, há loci diferencialmente expressos dependente do grupo estudado. Os pacientes com EM apresentam perfis distintos de expressão gênica onde os indivíduos GS apresentam um perfil inflamatório e no GA, um perfil neurodegenerativo. / Introduction: Multiple Sclerosis (MS) is an autoimmune disease which drastically affects motor, cognitive and sensitive capability of the patients. It seems that Human Endogenous Retrovirus W family (HERV-W) may play a role in MS pathogenesis. Therefore, the aim of this study was to analyze the transcriptome of these individuals and to analyze the HERV-W loci differentially expressed. Materials and Methods: PBMC and serum samples were collected from MS patients in relapsing conditions (GS), MS patients in advanced conditions (GA) and healthy individuals (GC). HERV-W Env amplicon was sequenced in Ion Torrent and mRNA was sequenced in illumina HISeq2500 platform. Besides HERV-W analysis, genic pathways analysis was performed and inflammatory cytokines and chemokines were tested. Results: A total of 23 MS patients (16 from GS and 7 from GA) and 36 from GC were enrolled in the study. MS patients presented 3-fold higher expression than healthy individuals. Amplicon sequencing revealed that MS groups presented more active loci than GC. Despite the limitations due to variations between sequencing runs, the transcriptome revealed that HERV-K11 was differentially expressed in GS, and 19 HERVs were differentially expressed in GA. New HERV-W loci and other loci that were reported as active loci previously are described here. The genic pathway analysis revealed that individuals from GS presented an inflammatory profile, also confirmed by cytokines dosage, where IL-6, IL-1?, TNF-?, IFN-? were significantly higher in GS. In the other hand, individuals from GA presented a non inflammatory profile with neuronal repair pathways inactivated Conclusions: MS patients present higher level and diversity of HERV-W expression than GC. Regardless the similar profile of HERV-W expression in MS groups, there are differentially expressed HERV-W loci depending of each MS group. MS patients present distinct genic expression profile, where GS presented an inflammatory pathway with vascular permeability, whereas GA presented a neurodegenerative profile

Multiple Sclerosis (MS), an autoimmune disorder marked by inflammation of the central nervous system, is associated with a myriad of symptoms. Individuals with MS are more likely to experience depressive symptoms, perhaps due to perceived cognitive impairments. Thus, we aimed to explore perceived stress and sleep deficits as potential mediators of the association between perceived cognitive deficits and depressive symptoms. We recruited a sample of 77 MS participants from an outpatient, university-based MS clinic in the United States. Participants ranged in age between 30 and 75 years old (M = 51.12; SD = 9.6), with more females than males (83% female; n = 64). Participants completed the Perceived Deficits Questionnaire, the Pittsburgh Sleep Quality Index, the Perceived Stress Scale, and the Center for Epidemiological Studies Depression Scale – Revised. Correlation analyses and mediation analyses were conducted with bootstrapping technique. Statistical analyses revealed that higher levels of perceived cognitive deficits were associated with lower quality of sleep, more perceived stress, and higher levels of depressive symptoms. Additionally, both perceived stress and sleep quality served as a significant mediator in the perceived cognitive impairments and depressive symptoms linkage. Our novel findings demonstrate the importance of underlying mechanisms (e.g., sleep quality and perceived stress) in the conceptualization of MS. Perceived stress and sleep quality are potentially modifiable factors, perhaps serving as a target for future treatment, to buffer risk of MS patients developing depression.

Balance disorders and falls are prevalent among multiple pathologies that affect the musculoskeletal or sensorineural systems. Annually, fall-related injuries put excessive economic burden on society and yet, current clinical balance assessment tools based on functional tests are inaccurate and have limited association with fall risk. Therefore, there is a growing need of an accurate balance and fall risk assessment tool for clinical use. The primary purpose of this research was to develop an accurate Center of Pressure (COP) based balance assessment tool to study postural instability and fall risk. Chapter 1 aimed at development of the COP based tool using cost effective equipment- a Wii Balance Board (WBB) and testing its accuracy and errors. The result of this study indicated that the WBB tool is reliable in assessing balance and the linearity and hysteresis errors in WBB tool are higher than force plates but it compares well in terms of cost, portability and availability. Chapter 2 aimed at assessing the relation between the radiographic parameters of balance, COP metrics, and health related quality of life in adults with spinal deformities. The results of this investigation revealed that just like radiographic parameters, COP metrics could help explain some variability in symptoms in patients with comparable extent of deformity. Chapter 3 attempted to establish a threshold value of COP metrics for binary classification of fall risk in patients with multiple sclerosis (MS). The findings of this study highlighted path length as an excellent predictor of future falls with high test accuracy, sensitivity and specificity. This dissertation concludes that the WBB tool has the potential to revolutionize balance and fall risk assessment in clinical fields such as geriatrics, rehabilitation, neurology, and orthopedics.

Bien que les vaccins représentent une avancée majeure pour la santé publique, le risque d’effets secondaires constitue une menace réelle pour leur acceptation par le grand public et les professionnels de santé. La France se classe, d’ailleurs, comme le pays manifestant la plus grande défiance envers le vaccin. Cela s’est souvent traduit pas des couvertures vaccinales faibles. L’origine de cette perte de confiance est, entre autres, liée à la polémique intense autour du vaccin anti-hépatite B (HB) et le risque de sclérose en plaques dans les années 1990. Le but de cette thèse est d’évaluer le lien potentiel entre vaccination et démyélinisation, en considérant deux exemples : les vaccins anti-VHB et anti-papillomavirus (HPV). Une approche méthodologique, progressive, fondée sur les preuves a été utilisée pour les deux vaccins. La génération d’hypothèse a considéré la plausibilité biologique, les rapports de cas publiés, les analyses de disproportionnalité conduites dans le système américain de pharmacovigilance des vaccins (i.e., Vaccine Adverse Event Reporting System (VAERS)), et l’analyse des signaux détectés par la surveillance passive. Concernant la vaccination anti-VHB, des analyses attendu/observé ont également été menées à partir des cas confirmés rapportés à la pharmacovigilance française dans les années 1990. Des revues systématiques de toutes les études individuelles ayant évalué la plausibilité de l’association entre démyélinisation et les deux vaccins considérés ont été réalisées, tandis que des méta-analyses ont permis d’obtenir des estimations de risque « poolées » à partir des preuves accumulées à ce jour. Les résultats restent mitigés pour les deux vaccins. Pour la vaccination anti-VHB, une plausibilité biologique faible et indirecte, l’analyse du signal français détecté en 1996 qui a révélé une disjonction complète entre les populations cible et rejointe, ainsi que les résultats des analyses de disproportionnalité dans VAERS sont des éléments en faveur d’une possible association entre démyélinisation centrale et vaccin anti-VHB. Cependant, ni la méta-analyse, ni les analyses attendu/observé (bien que leurs conclusions puissent être renversées par un facteur modéré de sous-notification), n’ont fourni de résultat statistiquement significatif. En tout état de cause, si un risque en excès existait, il serait faible et ne concernerait que l’adulte. Les recommandations actuelles qui minimisent la probabilité d’exposition à l’âge adulte, sont donc plus que justifiées. Pour la vaccination anti-HPV, le risque de démyélinisation centrale semble, à ce jour, écarté. Néanmoins, un doute subsiste concernant un possible risque en excès pour le syndrome de Guillain et Barré. Il serait nécessaire de conduire d’autres études, rendues difficiles par la rareté de l’événement, estimée à 1 cas pour 1,000,000 doses vendues. En conclusion, une association forte avec un risque de démyélinisation semble à exclure pour les deux vaccins, rendant la balance bénéfice/risque largement positive pour ces produits, dès lors qu’ils sont utilisés dans leurs populations cibles. Dans ce contexte, une communication scientifique, indépendante et claire est la clé pour promouvoir les programmes de vaccination et créer la confiance et l’adhésion du grand public. Les décisions politiques ont aussi une lourde responsabilité. En effet, les suspensions des campagnes nationales de vaccination peuvent avoir des conséquences délétères à long terme. Le futur de la pharmacovigilance des vaccins pourrait résider dans la mise en place d’un réseau collaboratif entre le patient et son médecin, via l’utilisation de SMS et smartphones, comme cela existe déjà en Australie. En plus de collecter les effets secondaires des vaccins, cela représenterait une opportunité unique de placer le patient au coeur du système de surveillance, lui offrant une voix et contribuant à restaurer sa confiance envers les vaccins, et même envers les décideurs de santé publique. / While vaccines represent a great achievement for public health, the risk of adverse effects is a real threat for vaccine acceptability by both the population and healthcare professionals. France still ranks as the country having the highest vaccine defiance. This often turned into poor vaccination coverages. This origin of this mistrust in vaccines is probably related to the intense polemic around anti-hepatitis B (HB) vaccination and the risk of multiple sclerosis in the 1990’s. The main aim of this thesis was to assess the putative link between vaccination and demyelinating disorders by considering two examples: anti-HB and anti-papillomavirus (HPV) vaccines. For both vaccines, methods adopted a stepwise evidence-based approach. Hypothesis generation was based on evidence regarding the biological plausibility, the published case reports, the disproportionality analyses conducted in the US Vaccine Adverse Event Reporting System (VAERS) and the analysis of signals detected by spontaneous reporting systems, if any. For the research question centered on the anti-HB vaccination, observed-to-expected analyses based on all confirmed cases reported to the French pharmacovigilance in the 1990’s were also conducted. Systematic reviews of all individual studies having assessed the possible association between demyelination and either anti-HB or HPV vaccines were then conducted while meta-analyses brought pooled risk estimates of all evidence published so far. Results were non-conclusive for both vaccines. For anti-HB vaccination, several elements could give credence to an association with central demyelination: a weak and indirect biological plausibility, the analysis of the French signal detected in the 1990’s which revealed a complete disjunction between the target and the joint populations, and the results of the disproportionality analyses in VAERS. Nevertheless, neither the meta-analysis nor the observed-to-expected analyses (although might be easily reversed by a moderate degree of underreporting), provided statistically significant findings. If the excess risk actually existed, it would be weak and would be a concern for adults only. The current recommendations which are minimizing the probability of the French population to be exposed at an adult age, are therefore more than justified. For the anti-HPV vaccination, after reviewing all materials available, the risk of central demyelination seems, at this date, unlikely. Nevertheless, a doubt remains regarding a possible excess risk of Guillain Barré Syndrome (GBS) in the follow of an anti-HPV immunization. More specific studies would be needed, although the rarity of this event renders its evaluation difficult. From the studies already conducted, it was estimated that this excess risk, if any, would be lower than 1 per 1,000,000 doses sold. To conclude, a strong association with a risk of central demyelination can be ruled out for both vaccines, making the benefit and risk balances still largely positive for both products if used in their current target populations. In that context, an independent, clear and scientifically-based communication is the key element to promote vaccination programmes and to generate the confidence and adherence of the general population. Political decisions also carry a heavy responsibility in ensuring trust towards vaccination programmes, as the suspension of national immunization campaigns which could have long-lasting deleterious consequences. The future of vaccine pharmacovigilance could rely on the implementation of a collaborative GP-patient network-based solution using SMS and smartphones, as already experimented in Australia. While collecting potential adverse effects of vaccines, it would also be a unique opportunity to place the patients at the heart of the surveillance system, giving them a voice and potentially contributing to restore their confidence in vaccines and even, in the decision-makers in the field of public health.

Improvements in fatigue and quality of life observed in primary and secondary progressive multiple sclerosis (MS) patients adhering to a modified Paleolithic dietary intervention (MPDI), nutritional supplementation, exercise, and neuromuscular electrical stimulation regime are hypothesized to be due primarily to the effect of diet. However, no research has been conducted evaluating effects of the dietary intervention alone thus, the purpose of this research was to evaluate a MPDI in the treatment of Relapsing-Remitting Multiple Sclerosis (RRMS). We tested effects of the MPDI in seventeen men and women (mean age: 36.3 ±4.7 years) with neurologist-verified RRMS. Nine subjects (one male) were randomized to a "usual care" (control) group and eight subjects (one male) were taught the MPDI. Both groups adhered to their assigned protocol for three months. Significant improvement was seen in Fatigue Severity Scale (FSS, p=0.03), Multiple Sclerosis Quality of Life-54 Physical Health (MSQOL-P, p=0.03), and Mental Health (MSQOL-M, p=0.02) scores from baseline in MPDI subjects compared to controls. Increased vitamin K serum levels (p=0.02) were also observed in MPDI subjects at three months compared to controls. Significantly reduced time to complete 9-Hole Peg Test (9-HPT) with the dominant hand (p=0.02) was also observed. Our results indicate trends for improved non-dominant 9-HPT (p=0.05), Metabolic Equivalent Tasks (METs, p=0.08), and 25-Foot Walk (25-FW, p=0.09) scores from baseline in MPDI subjects compared to controls. A Paleolithic diet may be useful in the treatment and management of MS, by reducing perceived fatigue, increasing mental and physical quality of life, increasing exercise capacity, and improving hand and leg function. The MPDI may also reduce inflammation as evidenced by increased vitamin K serum levels.

Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal insults remain unclear. While most axonal pathologies characterized in MS are a direct consequence of myelin loss, we propose that axonal pathologies also occur independent of demyelination. In support of this idea, we recently reported that mice that develop experimental autoimmune encephalomyelitis (EAE), a model commonly used to mimic the pathogenesis of MS, exhibit a structural and functional disruption of the axon initial segment (AIS), a subdomain of the axon that acts as the trigger-zone for action potential generation. Importantly, this disruption is independent of myelin loss. Although the mechanism responsible for AIS disruption remains unclear, we observed an attenuation of the AIS insult following treatment with a known scavenger of oxygen free radicals. To further investigate the role of oxidative stress in modulating AIS stability, we employed an in vitro model in which neurons were exposed to a spontaneous reactive oxygen and nitrogen species generator. Through this approach, we demonstrated that oxidative stress is capable of AIS modulation acting through induction of cytosolic calcium (Ca2+) influx from both extracellular and intracellular sources, resulting in calpain protease activation. Furthermore, because rises in intracellular Ca2+ are central to these and other mechanisms of AIS disruption, we next investigated the cisternal organelle (CO), an AIS-localized Ca2+-regulating structure. Although this organelle could prove to be central to AIS modulation, very little is known about the mechanisms regulating its stability. Through this line of investigation, we provide the first evidence of pathological alteration to the CO in a disease state. This disruption precedes loss of AIS protein clustering and axo-axonic GABAergic input in both EAE and MS postmortem tissue. Overall, these studies reveal a primary axonal insult, independent of myelin loss, in a disease classically characterized as a white-matter pathology. Instead, this insult is most likely driven by oxidative stress through local Ca2+ dysregulation at the AIS, providing novel therapeutic targets for MS.

SARM1 is an injury-induced nicotinamide adenine dinucleotide nucleosidase (NADase) that was previously shown to promote axonal degeneration in response to traumatic, toxic, and excitotoxic stressors. This raises the question of whether a SARM1-dependent program of axonal degeneration is central to a common pathway contributing to disease burden in neurological disorders. The degree to and mechanism by which SARM1 inactivation decreases the pathophysiology of such disorders is of interest to establish the rationale to pursue SARM1 as a therapeutic target. In this study, we compare the course and pathology of experimental autoimmune encephalomyelitis (EAE) in Sarm1-knockout (KO) mice and wild-type littermates to test the contribution of SARM1-dependent axonal degeneration specifically in the context of chronic, immune-mediated central nervous system (CNS) inflammation. The question of whether SARM1 loss in Sarm1-KO mice would inhibit, promote, or have a negligible impact on EAE-induced axonal degeneration and more broadly CNS inflammation was explored using a variety of analyses: quantification of clinical score in a chronic EAE model, CNS immune infiltrate profile, axon initial segment morphology in layer V cortical neurons, axonal transport disruption and transection in the lumbar spinal cord. Additionally, we have proposed a method for detecting SARM1 activation in situusing a novel SARM1-mCitrine bimolecular fluorescence complementation (BiFC) technique. Successful implementation of such a molecular tool would allow for a detailed, mechanistic approach to enhance our understanding of upstream intracellular signals that trigger SARM1 activation.

The purpose of this quantitative study was to examine an under-researched topic: the relationship between psychological resilience and personal growth with spousal caregivers of patients diagnosed with Multiple Sclerosis (MS). Chronic illnesses contribute to potentially stressful changes (i.e., lifestyle, quality of life, financial wellbeing, and interpersonal relationships) for the caregiver. The theoretical foundation for this study was Walsh's family resilience theory, which contends that resilience is vital for coping with stressful life experiences and leading a more successful life. Three separate analyses were conducted to examine the relationship between the total scores of the RS and the PGIS, the SWLS, and the EMS along with the background variables to see if the covariates contributed information about the relationship between these variables while controlling for gender, marital satisfaction, time since partner diagnosis, age of caregiver, whether the participant had previous interventions, whether the couple had children, current health status, duration of marriage, and life satisfaction. Based on the findings of the multiple-regression analysis, a significant relationship was found between resilience and personal growth of 115 caregivers of MS spouses. Further analysis showed a significant relationship between resilience and satisfaction with life, with marital satisfaction being the only other variable that was significant in the model. The information gathered in this study could contribute to social change for program planners and policy makers by revealing a need for innovative support services.

As a novel therapy for neurodegenerative diseases, transplantation of multipotent mesenchymal stromal cells (MSCs) requires extensive optimization in animal models before being implemented in clinical trials. It is a goal of our laboratory to understand the mechanism of action of these cells and to improve their therapeutic efficacy. To address these goals, this study aims to optimize the cell dosage, cell type, administration route and timing, and/or donor age for stem cell therapy in two mouse models of demyelinating diseases: globoid cell leukodystrophy (GLD; Krabbe’s disease) and experimental autoimmune encephalomyelitis (EAE). GLD is a neurodegenerative lysosomal storage disease caused by the deficiency of galactocerebrosidase (GALC). Accumulation of toxic byproducts in myelin producing oligodendrocytes leads to the demyelination of neurons and increase in brain inflammation. The twitcher mouse model of GLD was used to test the therapeutic effects of MSCs after injection through intracerebroventricular (ICV) or intraperitoneal (IP) routes. Weekly MSC IP injections and single IP GALC-transduced MSC injections were performed. Other twitcher mouse cohorts received temporal vein (TV) or intracerebral (IC) injections of GALC-containing adeno-associated virus serotype 9 (AAV9-GALC) with or without IP MSC injections. All GLD affected mice treated with peripheral MSC and/or vector therapy had extended lifespans with improved motor function. The ameliorating effects of MSCs were related to their potent anti-apoptotic and anti-inflammatory effects on the peripheral and central nervous systems. These results indicate a promising future for peripheral administration of MSCs and vectors as non-invasive, adjunct therapies for patients affected with GLD. A similar study was performed using the EAE mouse model of multiple sclerosis (MS), which is a demyelinating disease due to an autoimmune reaction to myelin. The results demonstrated that biological age of the donor reduces the ability of MSCs to alleviate symptoms and improve pathology in the EAE mouse model. Upon transplantation, the young, but not old, MSCs provided neuroprotective effects through immunomodulation and remyelination in the central nervous system (CNS). The age-related therapeutic differences corroborate recent findings that biologic aging occurs in stem cells and highlight the potential need for allogeneic transplantation of MSCs in older MS patients. / acase@tulane.edu