Multiple sclerosis presented as clinically isolated syndrome: the need for early diagnosis and treatment

Sigliti-Henrietta Pelidou, Sotirios Giannopoulos, Sotiria Tzavidi, Georgios Lagos, Athanassios P KyritsisDepartment of Neurology, University of Ioannina School of Medicine, GreeceObjective: To aid in the timely diagnosis of patients who present with clinically isolated syndrome (CIS).Patients and methods: We studied 25 patients (18 women, 7 men), originally presented in our clinic with a CIS suggestive of multiple sclerosis (MS). All patients underwent the full investigation procedure including routine tests, serology, cerebrospinal fluid (CSF) examinations, evoked potentials (EPs), and magnetic resonance imaging (MRI) of brain and cervical spinal cord. Patients were imaged at baseline, and every three months thereafter up to a year.Results: The CIS was consisted of optic neuritis in 12 cases, incomplete transverse myelitis (ITM) in 7 cases, Lhermitte sign in 2 cases, internuclear ophthalmoplegia (INO) in 2 cases, mild brainstem syndrome in 1 case, and tonic-clonic seizures in 1 case. Using the baseline and three-month scans 18/25 (72%) patients developed definite MS in one year of follow up while 7 (28%) had no further findings during this observation period. Immunomodulatory treatments were applied to all definite MS patients.Conclusion: In light of new treatments available, MRIs at 3 month intervals are helpful to obtain the definite diagnosis of MS as early as possible.Keywords: multiple sclerosis, clinically isolated syndrome, optic neuritis, transverse myeliti

Vitamin D receptor gene polymorphisms in multiple sclerosis patients in northwest Greece

<p>Abstract</p> <p>Background</p> <p>Polymorphisms of the vitamin D receptor (VDR) gene have been linked to both multiple sclerosis (MS) and osteoporosis. We examined the frequency of the Taq-I and Bsm-I polymorphisms of the vitamin D receptor (VDR) gene in 69 patients with MS and 81 age and sex-matched healthy individuals. Genotyping of Taq-I (rs731236) and Bsm-I (rs1544410) was performed using TaqMan^®SNP Genotyping Assay. All patients and controls had determination of body mass index (BMI), bone mineral density (BMD) and smoking history.</p> <p>Results</p> <p>The mean age of patients was 39 ± 10.5 years compared to 38.7 ± 10.7 years of the controls (p = 0.86), the BMI was 24.8 ± 4.2 kg/m²compared to 25.7 ± 4.8 kg/m²of the controls (p = 0.23), the BMD in the lumbar spine 0.981 ± 0.15 compared to 1.025 ± 013 of the controls (p = 0.06) and the total hip BMD was 0.875 ± 0.14 compared to 0.969 ± 0.12 of the controls (p < 0.001). There were no differences of the Taq-I (TT, CT, CC) and Bsm-I genotypes (GG, GA, AA) and allelic frequencies between MS and control individuals. Multivariate analysis also failed to show any association of the Taq-I and Bsm-I polymorphisms and MS or sex, BMI, BMD and smoking history.</p> <p>Conclusions</p> <p>This study suggests that the Taq-I and Bsm-I polymorphisms of the VDR gene are not associated with MS risk, BMI or BMD in the Greek population studied.</p

Systematic review of the association between Alzheimer's disease and chronic glaucoma.

A potential association between Alzheimer's disease (AD) and chronic glaucoma has been suggested but results of epidemiological studies have been inconsistent. Therefore, we performed a systematic review and critical appraisal of this literature. We searched systematically in PubMed from December 1964 to September 2013 and identified 239 articles potentially relevant for abstract and full-text review. Statistical heterogeneity (variability) across studies was evaluated using the Cochran Q test and the I (2) statistic, and the Newcastle-Ottawa score was used to assess study quality. Ten studies were finally selected. Compared to non-demented participants, patients with AD had a statistically significant decreased risk of glaucoma but the results were very heterogeneous, and thus summary estimates were not reported (I (2), 89%; P heterogeneity, <0.001). The study results ranged from large positive relative risks identified in small and poorly-conducted studies to weak inverse associations or null estimates observed in some cohort and record-linkage studies, but the summary estimates were essentially driven by a large retrospective cohort using medical claims that may be afflicted by underdiagnosis bias. There was also evidence for substantial publication bias (Egger's P≤0.01). The association of AD and glaucoma is heterogeneous and most studies are small and inadequately designed. Large prospective studies with long follow-ups are warranted to clarify this association

Reasons for failed trials of disease-modifying treatments for alzheimer disease and their contribution in recent research

Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials&apos; methodological issues have also been criticized. Drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers-such as Tau positron emission tomography, neurofilament light chain (blood and Cerebrospinal fluid (CSF) biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)-to clinical trials allows more precise staging of AD. Additionally, use of Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are assessed in clinical trials. The above-mentioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are relevant to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies. © 2019 by the authors

Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials&rsquo; methodological issues have also been criticized. Drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers&mdash;such as Tau positron emission tomography, neurofilament light chain (blood and Cerebrospinal fluid (CSF) biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)&mdash;to clinical trials allows more precise staging of AD. Additionally, use of Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are assessed in clinical trials. The above-mentioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are relevant to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies

Double hit viral parasitism, polymicrobial CNS residency and perturbed proteostasis in Alzheimer's disease: A data driven, in silico analysis of gene expression data

The aim of this study was to determine the interaction of peripheral immunity vs. the CNS in the setting of AD pathogenesis at the transcriptomic level in a data driven manner. For this purpose, publicly available gene expression data from the GEO Datasets repository. We performed differential gene expression and functional enrichment analyses were performed on the five retrieved studies: (a) three hippocampal cortex (HC) studies (b) one study of peripheral blood mononuclear cells (PBMC) and (c) one involving neurofibrillary tangle – containing neurons of the entorhinal cortex (NFT EC). Subsequently, BLAST was used to determine protein conservation between human proteins vs. microbial, whereas putative protein / oligopeptide antigenicity were determined via RANKPep. Gene ontology and pathway analyses revealed significantly enriched viral parasitism pathways in both PBMC and NFT – EC datasets, mediated by ribosomal protein families and epigenetic regulators. Among these, a salient viral pathway referred to Influenza A infection. NFT – EC annotations included leukocyte chemotaxis and immune response pathways. All datasets were significantly enriched for infectious pathways, as well as pathways involved in impaired proteostasis and non – phagocytic cell phagosomal cascades. In conclusion, our in silico analysis outlined an ad hoc model of AD pathophysiology in which double hit (PBMC and NFT-EC) viral parasitism is mediated by eukaryotic translational hijacking, and may be further implicated by impaired immune responses. Overall, our results overlap with the antimicrobial protection hypothesis of AD pathogenesis and support the notion of a pathogen – driven etiology. © 2020 Elsevier Lt