Whether the integrity of normal-appearing white matter (NAWM) is preserved in neuromyelitis optica spectrum disorders (NMOSD) is open to debate. To examine whether the tissue integrity of NAWM in ...NMOSD is compromised compared to that in healthy controls and patients with multiple sclerosis (MS), we prospectively enrolled 14 patients with NMOSD, 12 patients with MS, and 10 controls for clinical functional assessments and quantitative imaging, including T1 relaxation time (T1) and magnetization transfer ratio (MTR) at 7 Tesla. Cognitive performance on the Paced Auditory Serial Addition Test with a 3-second interstimulus interval (PASAT-3) was significantly lower in the NMOSD compared to the MS group (mean number of correct answers, 34.1 vs. 47.6; p = 0.006), but there were no differences in disease duration or disability. Histograms of T1 and MTR maps of NAWM demonstrated a decreased peak height in patients with NMOSD compared to the healthy controls, but not compared to patients with MS. Using 7T quantitative magnetic resonance imaging (MRI), this study showed that the NAWM in patients with NMOSD is abnormal, with reduced myelin signal; this was not previously observed using MRI at a lower field strength.
Alzheimer's Disease (AD) is a debilitating disease that leads to severe cognitive impairment and functional decline. The role of tau hyperphosphorylation and amyloid plaque deposition in the ...pathophysiology of AD has been well described; however, neuroinflammation and oxidative stress related to sustained microglial activation is thought to play a significant role in the disease process as well. NRF-2 has been identified in modulating the effects of inflammation and oxidative stress in AD. Activation of NRF-2 leads to an increased production of antioxidant enzymes, including heme oxygenase, which has been shown to have protective effects in neurodegenerative disorders such as AD. Dimethyl fumarate and diroximel fumarate (DMF) have been approved for the use in relapsing-remitting multiple sclerosis. Research indicates that they can modulate the effects of neuroinflammation and oxidative stress through the NRF-2 pathway, and as such, could serve as a potential therapeutic option in AD. We propose a clinical trial design that could be used to assess DMF as a treatment option for AD.
STAT (Signal Transducer and Activator of Transcription) transcription factors are constitutively activated in most hematopoietic cancers. We previously identified a target gene, LPP/miR-28 (LIM ...domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. miR-28 exerts negative effects on thrombopoietin receptor signaling and platelet formation. Here, we demonstrate that, in transformed hematopoietic cells, STAT5 and p53 must be synergistically bound to chromatin for induction of LPP/miR-28 transcription. Genome-wide association studies show that both STAT5 and p53 are co-localized on the chromatin at 463 genomic positions in proximal promoters. Chromatin binding of p53 is dependent on persistent STAT5 activation at these proximal promoters. The transcriptional activity of selected promoters bound by STAT5 and p53 was significantly changed upon STAT5 or p53 inhibition. Abnormal expression of several STAT5-p53 target genes (LEP, ATP5J, GTF2A2, VEGFC, NPY1R and NPY5R) is frequently detected in platelets of myeloproliferative neoplasm (MPN) patients, but not in platelets from healthy controls. In conclusion, persistently active STAT5 can recruit normal p53, like in the case of MPN cells, but also p53 mutants, such as p53 M133K in human erythroleukemia cells, leading to pathologic gene expression that differs from canonical STAT5 or p53 transcriptional programs.
Fatigue in multiple sclerosis — A brief review Induruwa, Isuru; Constantinescu, Cris S; Gran, Bruno
Journal of the neurological sciences,
12/2012, Letnik:
323, Številka:
1
Journal Article
Recenzirano
Abstract Fatigue is the most common and debilitating symptom in multiple sclerosis (MS) and is believed to be distinctly different from fatigue seen in other chronic conditions. It can affect a ...patient's mood, sleep and have a detrimental effect on their quality of life. In the recent years much literature has emerged in an attempt to elucidate the potential causes and treatment of this common symptom. This review article aims to examine the most recent theories on the pathophysiology of fatigue in MS as well as its association with sleep and depression. We describe the pharmacological and non-pharmacological approaches to its treatment and propose a multidisciplinary, patient enabled and individualised manner to the management of fatigue in MS.
The cause of multiple sclerosis (MS) remains unknown. It is largely regarded as being an inflammatory autoimmune disease and has been reported in association with other inflammatory/autoimmune ...diseases. We performed a prospective study in 658 consecutive patients diagnosed with MS attending our outpatient MS management clinic between June 2002 and June 2003. Prevalence of associated conditions in these patients was calculated and compared with values from population studies using chi-square tests, odds ratios and confidence intervals. The MS population had significantly increased rates of asthma, inflammatory bowel disease, type I diabetes mellitus, pernicious anaemia, autoimmune thyroid disease, uveitis, seronegative spondyloarthropathies, bipolar disorder and melanoma compared to the general population. Both T helper type 1 (Th1)-mediated and T helper type 2 (Th2)-mediated diseases were significantly increased compared to the general population. There were also interesting associations seen with polyglandular autoimmune syndrome and rare single case associations.
MS is associated with several other conditions. This work does not give evidence for the hypothesis that MS and atopy, reflecting Th1 and Th2 polarization, respectively, are mutually exclusive. Further work, ideally with a matched control population, is indicated.
The present study is aimed at determining the effect of cigarette smoking (CS) on serum uric acid (UA) levels quantitatively before and after smoking cessation among people with MS (pwMS). ...Additionally, a possible correlation between UA levels and both disability progression and disease severity was also investigated. A retrospective cross-sectional study was conducted using the Nottingham University Hospitals MS Clinics database. It involves 127 people with definite MS recorded when reporting the latest smoking status and the clinical diagnosis. All necessary demographics and clinical characteristics were collected. We found that smoker pwMS had significantly lower serum UA levels than non-smoker pwMS (
-value = 0.0475), and this reduction was recovered after smoking cessation (
-value = 0.0216). However, the levels of disability or disease severity were not correlated with the levels of serum UA in current smoker pwMS, measured by the expanded disability status scale (EDSS; r = -0.24;
-value = 0.38), multiple sclerosis impact scale 29 (MSIS-29; r = 0.01;
-value = 0.97) and MS severity score (MSSS; r = -0.16;
-value = 0.58), respectively. Our result suggests that the reduction in UA levels is more likely a consequence of oxidative stress triggered by many risk factors, including CS, and could be considered a potential indicator of smoking cessation. In addition, the absence of a correlation between UA levels and disease severity and disability suggests that UA is not an optimal biomarker for disease severity and disability prediction among current smoker, ex-smoker or non-smoker pwMS.
Cognitive impairment is one of the frequent and early findings in multiple sclerosis (MS).
To determine the relation between cognitive abnormalities and the extent of macroscopic and microscopic ...tissue damage in the corpus callosum (CC), revealed by conventional magnetic resonance imaging (MRI), magnetisation transfer imaging (MTI) and diffusion tensor imaging (DTI).
Conventional dual-echo, DTI and MTI of the brain were obtained from 36 patients with relapsing remitting (RR) MS, and 13 age and gender matched normal controls. Voxels from CC were identified using a tractography based algorithm. Mean apparent diffusion coefficient (ADC(av)) and MT ratio were measured for the CC as defined by tractography. Corpus callosum area (CCA) was measured using edge detection on the mid-sagittal slice on high resolution MRI images. The Expanded Disability Status Scale (EDSS) and Paced Auditory Serial Addition Test (PASAT) were scored.
Nine patients (25%) were found to be cognitively impaired. The CCA was not significantly different in the whole cohort of patients from controls (608.2 (428.6-713.0) mm(2) vs 674.2 (585.8-754.4) mm(2), p = 0.1), but was smaller in cognitively impaired than unimpaired group (417 (290-634) mm(2) vs 652 (511-718) mm(2), p = 0.04). The mean MT ratio of CC in patients was lower than in controls (0.41 (0.39-0.042) vs 0.43 (0.42-0.43), p<0.001). The ADC(av) in the CC in patients was higher than in controls (0.94 (0.89-0.99) vs 0.87 (0.85-0.89), p<0.001). PASAT was correlated with mean MT ratio (r = 0.47, p = 0.0046), ADC(av) (r = -0.53, p = 0.0012), CCA (r = 0.42, p = 0.01) and total T(2) lesion load (r = -0.4, p = 0.017), but not with T(2) lesion load within the CC (r = -0.24, p = 0.16), disease duration (r = -0.2, p = 0.24) or EDSS (r = -0.27, p = 0.12).
ADC(av), MTR and atrophy measures in the CC may offer a sensitive method detecting subtle macroscopic and microscopic changes associated with cognitive impairment in MS.
Multiple sclerosis (MS) is characterised by widespread damage of the central nervous system that includes alterations in normal-appearing white matter (NAWM) and demyelinating white matter (WM) ...lesions. Neurite orientation dispersion and density imaging (NODDI) has been proposed to provide a precise characterisation of WM microstructures. NODDI maps can be calculated for the Neurite Density Index (NDI) and Orientation Dispersion Index (ODI), which estimate orientation dispersion and neurite density. Although NODDI has not been widely applied in MS, this technique is promising in investigating the complexity of MS pathology, as it is more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations. We conducted a meta-analysis of studies using NODDI metrics to assess brain microstructural changes and neuroaxonal pathology in WM lesions and NAWM in patients with MS. Three reviewers conducted a literature search of four electronic databases. We performed a random-effect meta-analysis and the extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger’s tests were used to assess publication bias. We identified seven studies analysing 374 participants (202 MS and 172 controls). The NDI in WM lesions and NAWM were significantly reduced compared to healthy WM and the standardised mean difference of each was −3.08 (95%CI −4.22 to (−1.95), p ≤ 0.00001, I2 = 88%) and −0.70 (95%CI −0.99 to (−0.40), p ≤ 0.00001, I2 = 35%), respectively. There was no statistically significant difference of the ODI in MS WM lesions and NAWM compared to healthy controls. This systematic review and meta-analysis confirmed that the NDI is significantly reduced in MS lesions and NAWM than in WM from healthy participants, corresponding to reduced intracellular signal fraction, which may reflect underlying damage or loss of neurites.
Early reports have detailed a range of neurological symptoms in patients with the SARS-CoV-2 infection. However, there is a lack of detailed description and incidence of the neurological disorders ...amongst hospitalized COVID-19 patients. We describe a range of neurological disorders (other than non-specific neurological symptoms), including their clinical, radiological, and laboratory findings, encountered in our cohort of COVID-19 patients admitted to a large tertiary institution.
We reviewed our prospectively collated database of all adult Neurology referrals, Neurology and Stroke admissions and Neurological multi-disciplinary team meetings for all hospitalized patients with suspected or proven COVID-19 from 17 March 2020 to 31 August 2020.
Twenty-nine of 1,243 COVID-19 inpatients (2.3%) presented with COVID-19-related neurological disorders. The mean age was 68.9 ± 13.5(SD) years, age range of 34-97 years, and there were 16 males. Twenty two patients had confirmed, five were probable and two had suspected COVID-19 infection according to the WHO case classification. Eight patients (27%) required critical care admission. Neurological symptoms at presentation included acute confusion and delirium, seizures, and new focal neurological deficits. Based on the pre-defined neurological phenotype, COVID-19 patients were grouped into four main categories. Sixteen patients had cerebrovascular events (13 with acute ischemic stroke and three had hemorrhagic features), seven patients were found to have inflammatory, non-inflammatory and autoimmune encephalopathy (including two with known Multiple Sclerosis), whilst disorders of movement and peripheral nervous system were diagnosed in three patients each.
Although the exact prevalence and etiology remain unclear, new onset of neurological disorders, in addition to anosmia, is non-sporadic during the acute COVID-19-infection. Longitudinal follow-up of these patients is required to determine the clinical and functional outcome, treatment response and long-term effects of the SARS-CoV-2 infection.
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