The Effects of the S1P Receptor Agonist Fingolimod (FTY720) on Central and Peripheral Myelin in Twitcher Mice.

Krabbe's disease (KD) is caused by mutations in the lysosomal enzyme galactocerebrosidase and is associated with psychosine toxicity. The sphingosine 1-phosphate receptor (S1PR) agonist fingolimod (FTY720) attenuates psychosine-induced cell death of human astrocytes, demyelination in cerebellar slices, as well as demyelination in the central nervous system of twitcher mice. Psychosine also accumulates in the peripheral nervous system in twitcher mice; however, effects of fingolimod on this peripheral myelin have not been examined. The aim of this study was to investigate the effects of fingolimod administration on peripheral and central markers of myelination. Here, we report that fingolimod administration (1 mg/kg/day) from postnatal day 5 (PND) onwards did not alter peripheral demyelination in the sciatic nerve of twitcher mice, despite significantly reducing myelin debris, glial reactivity, and neuronal damage in the cerebellum. We also find fingolimod administration improves twitching and mobility scores in twitcher mice. Importantly, we find that fingolimod significantly increases the lifespan of twitcher mice by approximately 5 days. These findings suggest differential effects of fingolimod on peripheral and central neuropathy in twitcher mice, which may explain its modest efficacy on behavior and lifespan.

Sex-Related Microglial Perturbation Is Related to Mitochondrial Changes in a Model of Alzheimer's Disease.

Many studies implicate microglia in the pathogenesis of Alzheimer's disease (AD) but precisely how these cells make their impact has not been determined to date. One contributory factor is likely to be the enhanced production of inflammatory mediators and it is now known that microglia with this secretory phenotype exhibit other adaptations including in their morphology, function, and metabolism. AD, like many neurological disorders, demonstrates a sex bias and recent evidence indicates that the sexual dimorphism in microglial function, which has been recognized for many years in early development, persists into adulthood and aging. Here, we demonstrate sex-related differences in microglia from post mortem tissue of male and female AD patients and a marked increase in the number of dystrophic and rod-shaped microglia in tissue from female AD patients compared with males. Furthermore, there was an increase in iron-laden microglia in tissue from female AD patients and this has been reported to reflect mitochondrial changes. To address this further, we assessed changes in microglia from male and female APP/PS1 mice and demonstrate that iron accumulation in microglia is increased to a greater extent in tissue prepared from females compared with males. This was associated with altered expression of genes coding for proteins that modulate mitochondrial function. The findings suggest that sex-related differences in the severity and perhaps incidence of AD may, at least in part, arise from sexual dimorphism in microglia.

The Modulatory Effects of DMF on Microglia in Aged Mice Are Sex-Specific.

There is a striking sex-related difference in the prevalence of many neurodegenerative diseases, highlighting the need to consider whether treatments may exert sex-specific effects. A change in microglial activation state is a common feature of several neurodegenerative diseases and is considered to be a key factor in driving the inflammation that characterizes these conditions. Among the changes that have been described is a switch in microglial metabolism towards glycolysis which is associated with production of inflammatory mediators and reduced function. Marked sex-related differences in microglial number, phenotype and function have been described in late embryonic and early postnatal life in rodents and some reports suggest that sexual dimorphism extends into adulthood and age and, in models of Alzheimer's disease, the changes are more profound in microglia from female, compared with male, mice. Dimethyl fumarate (DMF) is a fumaric acid ester used in the treatment of psoriasis and relapsing remitting multiple sclerosis and, while its mechanism of action is unclear, it possesses anti-inflammatory and anti-oxidant properties and also impacts on cell metabolism. Here we treated 16-18-month-old female and male mice with DMF for 1 month and assessed its effect on microglia. The evidence indicates that it exerted sex-specific effects on microglial morphology and metabolism, reducing glycolysis only in microglia from female mice. The data suggest that this may result from its ability to inactivate glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

Fingolimod Rescues Memory and Improves Pathological Hallmarks in the 3xTg-AD Model of Alzheimer's Disease.

Therapeutic strategies for Alzheimer's disease (AD) have largely focused on the regulation of amyloid pathology while those targeting tau pathology, and inflammatory mechanisms are less explored. In this regard, drugs with multimodal and concurrent targeting of Aß, tau, and inflammatory processes may offer advantages. Here, we investigate one such candidate drug in the triple transgenic 3xTg-AD mouse model of AD, namely the disease-modifying oral neuroimmunomodulatory therapeutic used in patients with multiple sclerosis, called fingolimod. In this study, administration of fingolimod was initiated after behavioral symptoms are known to emerge, at 6 months of age. Treatment continued to 12 months when behavioral tests were performed and thereafter histological and biochemical analysis was conducted on postmortem tissue. The results demonstrate that fingolimod reverses deficits in spatial working memory at 8 and 12 months of age as measured by novel object location and Morris water maze tests. Inflammation in the brain is alleviated as demonstrated by reduced Iba1-positive and CD3-positive cell number, less ramified microglial morphology, and improved cytokine profile. Finally, treatment with fingolimod was shown to reduce phosphorylated tau and APP levels in the hippocampus and cortex. These results highlight the potential of fingolimod as a multimodal therapeutic for the treatment of AD.

Modified Diet Use in Adults with Temporomandibular Disorders related to Rheumatoid Arthritis: A Systematic Review.

OBJECTIVE: Individuals presenting with rheumatoid arthritis (RA) frequently experience temporomandibular disorders (TMDs), which can result in limited ranges of mandibular motion, pain and fatigue on jaw function, and impaired mastication. As such, individuals with RA-related TMDs may consume a texture-modified diet in order to reduce the exacerbation of jaw pain and dysfunction, and to increase the ease of oral intake. These softer food options may not contain the recommended nutrients, vitamins, and minerals, and therefore, may not be nutritionally optimal. As unintentional body composition and weight changes are common in individuals with RA, there may be elevated risks of obesity or malnutrition in this patient subgroup. However, minimal researcth has been conducted to investigate the use of modified diets in this cohort, and therefore, the true level of risk to these patients cannot not be adequately determined. The aim of this study was to determine the prevalence of diet modifications in adults presenting with RA affecting the TMJ. METHODS: All available evidence presenting data on adults with RA who consume modified diets was systematically reviewed. A range of electronic databases were searched, including: EMBASE, PubMed, CINAHL, Web of Science, Elsevier Scopus, Science Direct, AMED, The Cochrane Database of Systematic Reviews, and ProQuest Dissertations and Theses A & I. Supplementary Google Scholar, reference list, and grey literature searches were also conducted. Independent reviewers assessed study eligibility, and methodological quality was rated using the Down's and Black assessment. RESULTS: One study was eligible for inclusion, and half (50.82%; CI: 37.7-63.86) of individuals with RA in this study consumed a modified diet. This study was rated to be of moderate quality. The primary limitation of this review was the lack of studies on this topic which were available for inclusion. CONCLUSIONS: Although from clinical practice, it is recognised that adults with TMD related to RA do modify their diets to cope with the functional impairment of TMD, this review confirms that minimal research has been conducted regarding the use of texture modified diets by this population. This is despite concerns regarding unintentional weight changes in this patient group. Further research investigating this area is warranted in order to improve patient outcomes and experience of care.

Fingolimod Rescues Demyelination in a Mouse Model of Krabbe's Disease.

Krabbe's disease is an infantile neurodegenerative disease, which is affected by mutations in the lysosomal enzyme galactocerebrosidase, leading to the accumulation of its metabolite psychosine. We have shown previously that the S1P receptor agonist fingolimod (FTY720) attenuates psychosine-induced glial cell death and demyelination both in vitro and ex vivo models. These data, together with a lack of therapies for Krabbe's disease, prompted the current preclinical study examining the effects of fingolimod in twitcher mice, a murine model of Krabbe's disease. Twitcher mice, both male and female, carrying a natural mutation in the galc gene were given fingolimod via drinking water (1 mg/kg/d). The direct impact of fingolimod administration was assessed via histochemical and biochemical analysis using markers of myelin, astrocytes, microglia, neurons, globoid cells, and immune cells. The effects of fingolimod on twitching behavior and life span were also demonstrated. Our results show that treatment of twitcher mice with fingolimod significantly rescued myelin levels compared with vehicle-treated animals and also regulated astrocyte and microglial reactivity. Furthermore, nonphosphorylated neurofilament levels were decreased, indicating neuroprotective and neurorestorative processes. These protective effects of fingolimod on twitcher mice brain pathology was reflected by an increased life span of fingolimod-treated twitcher mice. These in vivo findings corroborate initial in vitro studies and highlight the potential use of S1P receptors as drug targets for treatment of Krabbe's disease.SIGNIFICANCE STATEMENT This study demonstrates that the administration of the therapy known as fingolimod in a mouse model of Krabbe's disease (namely, the twitcher mouse model) significantly rescues myelin levels. Further, the drug fingolimod also regulates the reactivity of glial cells, astrocytes and microglia, in this mouse model. These protective effects of fingolimod result in an increased life span of twitcher mice.

The prevalence of oral stage dysphagia in adults presenting with temporomandibular disorders: a systematic review and meta-analysis.

OBJECTIVE: Temporomandibular disorders (TMDs) are the most commonly experienced non-dental orofacial pain disorders, with pain and dysfunction potentially resulting in oral stage dysphagia (OD). However, limited research has been conducted on this condition, with potential negative effects on clinical practice. Therefore, the aim of this study was to determine the prevalence of OD in adults presenting with TMDs, diagnosed as per the Research Diagnostic Criteria for Temporomandibular Disorders or the Diagnostic Criteria for Temporomandibular Disorders protocols. MATERIAL AND METHODS: A systematic review of the literature was completed. Nine electronic databases were searched from inception to January 2017, with no date/language restriction applied. Grey literature, conference proceedings, and reference lists were also searched. Studies presenting original data regarding OD prevalence in adults presenting with TMDs were included if they investigated impaired swallowing, mastication, masticatory pain or fatigue, or weight loss. Study eligibility and quality were assessed by two independent reviewers. Methodological quality was assessed using the Down's and Black tool. RESULTS AND CONCLUSIONS: This search yielded 20 eligible studies. Swallowing itself was impaired in only 9.3% of patients with TMDs. A range of additional OD signs and symptoms were also commonly reported (e.g. masticatory pain (87.4%) and fatigue (62%)). Study limitations included the small number of studies which were eligible for inclusion. As signs and symptoms of OD are frequently reported by patients with TMDs, psychometrically robust prospective research is warranted to determine current and optimal management of this condition.

The Prevalence of Oropharyngeal Dysphagia in Adults Presenting with Temporomandibular Disorders Associated with Rheumatoid Arthritis: A Systematic Review and Meta-analysis.

Temporomandibular disorders (TMDs) are the most frequent non-dental orofacial pain disorders and may be associated with rheumatoid arthritis (RA), resulting in oropharyngeal dysphagia (OD). However, clinicians' understanding of involvement with OD caused by RA-related TMDs is limited and the methodological quality of research in this field has been criticised. Therefore, the aim of this study was to systematically review the prevalence of oral preparatory and oral stage signs and symptoms of OD in adults presenting with TMDs associated with RA. A systematic review of the literature was completed. The following electronic databases were searched from inception to February 2016, with no date/language restriction: EMBASE, PubMed, CINAHL, Web of Science, Elsevier Scopus, Science Direct, AMED, The Cochrane Database of Systematic Reviews, and ProQuest Dissertations and Theses A & I. Grey literature and reference lists of the included studies were also searched. Studies reporting the frequency of OD in adults presenting with TMD and RA were included. Study eligibility and quality were assessed by three independent reviewers. Methodological quality was assessed using the Down's and Black tool. The search yielded 19 eligible studies. Typical difficulties experienced by RA patients included impaired swallowing (24.63%), impaired masticatory ability (30.69%), masticatory pain (35.58%), and masticatory fatigue (21.26%). No eligible studies reported figures relating to the prevalence of weight loss. Eligible studies were deemed on average to be of moderate quality. Study limitations included the small number of studies which met the inclusion criteria and the limited amount of studies utilising objective assessments. Valid and reliable prospective research is urgently required to address the assessment and treatment of swallowing difficulties in RA as TMJ involvement may produce signs and symptoms of OD.

Diagnostic Accuracy of the Modified Evan's Blue Dye Test in Detecting Aspiration in Patients with Tracheostomy: A Systematic Review of the Evidence.

Oropharyngeal aspiration (OPA) is a common occurrence in patients with tracheostomy. The modified Evan's blue dye test (MEBDT) is an easily administered bedside procedure for the assessment of tracheostomised patients. However, studies evaluating the diagnostic accuracy of the MEBDT reach conflicting results. Therefore, we conducted a systematic review to determine the overall accuracy of the MEBDT in detecting OPA in adults with tracheostomy. The search strategy incorporated searching electronic databases, checking reference lists and citations and retrieving unpublished data. Data of primary studies were extracted and examined by three independent reviewers. The assessment of the methodological quality of included studies was performed using the QUADAS-2 tool. Six studies met the inclusion criteria for this systematic review. The studies presented significant disparities in study design and patient characteristics. Furthermore, high discrepancies in the administration of MEBDT across studies were noted. Therefore, a meta-analysis was not considered appropriate. Sensitivity estimates varied widely across the studies (38-95 %), indicating that the MEBDT is unreliable in detecting OPA. However, the studies emerge with overall high specificity values, ranging from 79 to 100 %. This true negative rate suggests that the MEBDT correctly identifies patients without OPA. This review highlights the need for further research studies assessing the accuracy of the MEBDT in detecting aspiration in patients with tracheostomy, using a standardised and reliable procedure. Outcomes from such studies will update the current level of evidence in relation to the MEBDT and consequently define best clinical practice.