ARTICLE Download: 12| View: 75| Comments: 0 | doi:10.20944/preprints201910.0165.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: growth hormone; traumatic brain injury; neural plasticity; neurogenesis; actin; nestin; striatum; thalamus
Online: 15 October 2019 (08:03:13 CEST)
Previously we demonstrated, in rats, that the treatment with growth hormone (GH) and rehabilitation, carried out immediately after a motor cortical ablation, significantly improved the motor affectation produced by the lesion and induced the re-expression of nestin in the contralateral motor cortex. Here we analyze cortical proliferation after ablation of the frontal motor cortex and investigate the re-expression of nestin in the contralateral motor cortex and the role of the striatum and thalamus in motor recovery. The rats were subjected to ablation of the frontal motor cortex in the dominant hemisphere or sham-operated and immediately treated with GH or vehicle (V), for five days. At 1 dpi (days after injury), 5 rats received daily injections (4 days) of bromodeoxyuridine and were sacrificed. The other 15 rats (n = 5 / group) underwent treatment and rehabilitation and were sacrificed at 25 dpi. GH induced the greatest number of proliferating cells in the perilesional cortex. GH and rehabilitation produced the functional recovery of the motor lesion and increased the expression of nestin in the striatum. In the thalamic ventral nucleus ipsilateral to the lesion, cells positive for nestin and actin were detected, but this was independent of GH. Our data suggest that GH-induced striatal nestin is involved in motor recovery.
Fri, 27 September 2019
ARTICLE Download: 22| View: 171| Comments: 0 | doi:10.20944/preprints201909.0302.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: multiple sclerosis; physical fitness; body composition; functional mobility; physiotherapy
Online: 27 September 2019 (03:03:10 CEST)
Background and objectives: Patients with multiple sclerosis (MS) have many potential factors (spasticity, immobilization, glucocorticoids use) which can deteriorate the anthropometrical status and body composition and may have the potential impact on the functional mobility and basic motor skills improvement after physiotherapy. The aim of the study was to assess the functional mobility and basic motor skills in patients with MS and to correlate them with disability and anthropometrical status and body composition parameters. Materials and Methods: Timed Up-and-Go test (TUG), and six-minute walk test (6MWT) were performed in 36 patients with MS before and after 4 weeks of physiotherapy. Body mass index (BMI), waist to height ratio (W/HtR), and waist-to-hip ratio (WHR) were assessed in this group. Body composition was evaluated by bioelectrical impedance analysis (BIA) and fat mass (FAT), fat free mass (FFM), total body water (TBW) and predicted muscle mass (PMM) were expressed as percentage of body mass. Clinical status was assessed by EDSS and AI scales. Results: After physiotherapy, there was a significant improvement in functional mobility and basic motor skills assessed by total distance in 6MWT (p<0.001) and in TUG trials (p<0.001). Positive significant correlations were found between the results obtained in both tests (either before and after physiotherapy) vs. FFM, TBW and PMM, whilst worse results in functional mobility and basic motor skills correlated significantly with higher WHtR, WHR and FAT (p<0.05). Clinical status (EDSS) were significantly related to the WHtR and body composition parameters with the same manner as the results in the either 6MWT and TUG. However, there were no significant relationships between BMI vs. either clinical status (EDSS, AI) and functional mobility tests results in patients with MS. Conclusions: Functional mobility and basic motor skills may be significantly improved during the physiotherapy, but they are related to the anthropometrical status and body composition of MS patients. Moreover, disability status is also significantly related to this parameters. Body composition deterioration seems to be the important target for the therapeutic intervention in MS patients. For proper nutritional status assessment in patients with MS, body composition analysis or WHtR instead BMI should to be used.
Tue, 24 September 2019
REVIEW Download: 69| View: 196| Comments: 0 | doi:10.20944/preprints201909.0270.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer’s disease; clinical trial fails; disease-modifying treatments; alzheimer’s disease biomarkers; combination treatment; clinical trial designs
Online: 24 September 2019 (11:23:25 CEST)
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’ methodological issues have also been criticized. Current 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 CSF biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of the Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are currently assessed in clinical trials. The abovementioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are consequential to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.
Mon, 9 September 2019
REVIEW Download: 74| View: 257| Comments: 0 | doi:10.20944/preprints201907.0265.v2
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Aging; Alzheimer’s disease; brain insulin resistance; db/db diabetic mouse model; diabetic cognopathy; insulin resistance; metabolic syndrome; mixed dementia; obesity; type 2 diabetes mellitus
Online: 9 September 2019 (06:12:15 CEST)
Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.
Fri, 16 August 2019
ARTICLE Download: 38| View: 171| Comments: 0
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: permutation entropy; irreversibility; gait; Alzheimer's disease; Mild Cognitive Impairment
Online: 16 August 2019 (07:24:00 CEST)
Gait is a basic cognitive propositive action that has been shown to be altered in late stages of neurodegenerative dementias. Nevertheless, alterations are less clear in mild forms of dementia, and the potential use of gait analysis as a biomarker of initial cognitive decline has hitherto mostly been neglected. We here report the results of a study of gait kinematic time series for two groups of patients (Mild Cognitive Impairment and mild Alzheimer's disease) and a group of matched control subjects. Two metrics based on permutation patterns are considered, respectively measuring the complexity and irreversibility of the time series. Results indicate that kinematic disorganisation is present at early phases of cognitive impairment; in addition, they depict a rich scenario, in which some joint movements display an increased complexity and irreversibility, while others a marked decrease. Beyond their potential use as biomarkers, complexity and irreversibility metrics can open a new door towards the understanding of the role of the nervous system in gait, as well as its adaptation and compensatory mechanisms.
Wed, 31 July 2019
ARTICLE Download: 69| View: 225| Comments: 0 | doi:10.20944/preprints201907.0345.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer’s Disease; Extreme Gradient Boosting; Deep Residual Learning; conolutional neural networks; machine learning; dementia
Online: 31 July 2019 (04:33:43 CEST)
Alzheimer's is a disease for which there is no cure. Diagnosing Alzheimer's Disease (AD) early facilitates family planning and cost control. The purpose of this study is to predict the presence of AD using socio-demographic, clinical, and Magnetic Resonance Imaging (MRI) data. Early detection of AD enables family planning and may reduce costs by delaying long-term care. Accurate, non-imagery methods also reduce patient costs. The Open Access Series of Imaging Studies (OASIS-1) cross-sectional MRI data were analyzed. A gradient boosted machine (GBM) predicted the presence of AD as a function of gender, age, education, socioeconomic status (SES), and Mini-Mental State Exam (MMSE). A Residual Network with 50 layers (ResNet-50) predicted CDR presence and severity from MRI's (multi-class classification). The GBM achieved a mean 91.3% prediction accuracy (10-fold stratified cross validation) for dichotomous CDR using socio-demographic and MMSE variables. MMSE was the most important feature. ResNet-50 using image generation techniques based on an 80% training set resulted in 98.99% three class prediction accuracy on 4,139 images (20% validation set) at Epoch 133 and nearly perfect multi-class predication accuracy on the training set (99.34%). Machine Learning methods classify AD with high accuracy. GBM models may help provide initial detection based on non-imagery analysis, while ResNet-50 network models might help identify AD patients automatically prior to provider review.
Wed, 24 July 2019
REVIEW Download: 138| View: 137| Comments: 0 | doi:10.20944/preprints201907.0265.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: aging; Alzheimer’s disease; brain insulin resistance; db/db diabetic mouse model; diabetic cognopathy; insulin resistance; metabolic syndrome; mixed dementia; obesity; type 2 diabetes mellitus
Online: 24 July 2019 (08:05:52 CEST)
Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) have become parallel global pandemics and current predictions indicate they will only increase over the coming decades. These pandemics may result from the coexistent increase of obesity and aging. T2DM is associated with cognitive impairments associated with both metabolic factors, diabetic cognopathy (DC) and an increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, intersects and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. It is difficult to condense so many links between T2DM and LOAD; however, five major intersections could be considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU remodeling with resulting impaired cerebral blood flow).
Fri, 7 June 2019
ARTICLE Download: 73| View: 296| Comments: 0 | doi:10.20944/preprints201906.0052.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Parkinson's disease; brain phosphorylome; PINK1, alpha-synuclein; microtubular cytoskeleton; autophagy; synaptic signaling
Online: 7 June 2019 (03:21:19 CEST)
Hereditary Parkinson’s disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response. We demonstrated the combination of PINK1-knockout with overexpression of SNCAA53T in double mutant (DM) mice to exacerbate locomotor deficits and to reduce lifespan. To survey posttranslational modifications of proteins underlying the pathology, brain hemispheres of old DM mice underwent quantitative label-free global proteomic mass spectrometry, focused on Ser/Thr-phosphorylations. As exceptionally strong effect, we detected >300-fold reductions of phosphoThr1928 in MAP1B, a microtubule-associated protein, and a similar reduction of phosphoSer3781 in ANK2, an interactor of microtubules. MAP1B depletion is known to trigger perturbations of microtubular mitochondria trafficking, neurite extension and synaptic function, so it was noteworthy that relevantly decreased phosphorylation was detected also for other microtubule and microfilament factors, namely MAP2S1801, MARK1S394, MAP1AT1794, KIF1AS1537, 4.1NS541, 4.1GS86 and ADD2S528. While the MAP1B heavy chain supports regeneration and growth cones, its light-chain assists DAPK1-mediated autophagy. Interestingly, relevant phosphorylation decreases of DAPK2S299, VPS13DS2429 and VPS13CS2480 in the DM brain affected regulators of autophagy, which are implicated in PD. Overall, significant downregulations were enriched for PFAM C2 domains, other kinases, and synaptic transmission factors upon automated bioinformatics, while upregulations were not enriched for selective motifs or pathways. Validation experiments confirmed the change of LC3 processing as reflection of excessive autophagy in DM brain, and dependence of ANK2/MAP1B expression on PINK1 levels. Our new data provide independent confirmation in a mouse model with combined PARK1/PARK4/PARK6 pathology that MAP1B/ANK2 phosphorylation events are implicated in Parkinsonian neurodegeneration. These findings expand on previous observations in D. melanogaster that the MAP1B ortholog futsch in the presynapse is a primary target of the PARK8 protein LRRK2, and on a report that MAP1B is a component of the pathological Lewy body aggregates in PD patient brains. Similarly, ANK2 gene locus variants are associated with the risk of PD, ANK2 interacts with PINK1/Parkin-target proteins such as MIRO1 or ATP1A2, and ANK2-derived peptides are potent inhibitors of autophagy.
Tue, 28 May 2019
REVIEW Download: 82| View: 160| Comments: 0 | doi:10.20944/preprints201905.0326.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: stroke; antibody therapy; monoclonal antibody; inflammation; acid-sensing ion channel; receptor; growth factors
Online: 28 May 2019 (10:05:26 CEST)
Acute ischemic strokes are the third leading cause of death and the leading cause of neurological disability worldwide. The oxygen and glucose deprivation associated with ischemic strokes not only leads to neuronal cell death, but also increases the inflammatory response and decreases functional output of the brain. The only intervention approved by US Federal Drug and Food Administration for treatment of ischemic strokes is tissue plasminogen activator (tPA), however, such treatment can only be given within 4.5 hours of the onset of stroke-like symptoms. This narrow time-range limits its application, and it also might induce detrimental rather than beneficial effects to stroke patients by treatment of the tPA. In order to reduce the infarct volume of an acute ischemic stroke while increasing the time period for treatment, emerging therapies reveal great potential by targeting inflammation, growth factors, ion channels, and neurotransmitter receptors with monoclonal antibody (MAB). With successfully application in the treatment of cancer patient by MAB, in this review, we will focus on recent advances on stroke therapy by using MAB on the treatment of stroke by targeting inflammation, growth factors, ion channels, and neurotransmitter receptors. Therefore, developing specific MAB targeting the signaling pathway of stroke will contribute to stroke therapy.
Mon, 27 May 2019
REVIEW Download: 32| View: 129| Comments: 0
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: blood-brain barrier; copper/iron homeostasis; neurodegenerative (Alzheimers, Parkinsons, Prion) disease; North Ronaldsay sheep
Online: 27 May 2019 (12:27:10 CEST)
The neurodegenerative diseases (Alzheimers, Parkinsons, amyotrophic lateral sclerosis, Huntingdons) and the prion disorders, have in common a dysregulation of metalloprotein chemistry involving redox metals (Cu,Fe,Mn). The consequent oxidative stress gives rise to protein plaques and neuronal cell death. An equilibrium exists between the functional requirement of the brain for Cu and Fe and their destructive potential with the production of reactive oxygen species. The importance of the brain barrier is highlighted in regulating the import of these metals. Upregulation of key transporters occurs in foetal and neonatal life when brain metal requirement is high and is down-regulated in adult life when need is minimal. By contrast a neonatal mode of CTR1 upregulation persists in feral N.Ronaldsay sheep. This has led to the premise that metal regulation may return to the default setting in ageing with implications for neurodegenerative disease.
Mon, 13 May 2019
ARTICLE Download: 52| View: 83| Comments: 0 | doi:10.20944/preprints201905.0153.v1
Online: 13 May 2019 (10:16:48 CEST)
A recent systematic review for 19 selected articles after searching through to 30 September 2017 showed vitamin D deficiency was associated with ischemic stroke (IS), not hemorrhagic stroke (HS). But a heterogeneity would be introduced with comparing the lowest and highest category of vitamin D. The aim of this article was to conduct an updated meta-analysis (UMA) with searching through to 31 March 2019. An interval collapsing method as information extraction was applied in order to decrease a heterogeneity among studies. Additional articles were selected from cited lists from 19 selected articles using citation discovery tools. Random effect model was applied if I-squared value was over 50%. A funnel plot and Egger’s test were used to detect a publication bias. After 5 new studies were added, the summary RRs [and their 95% confidence intervals] (I-squared value) were 1.52 [1.33–1.74] (0.0%) in IS, and 2.44 [1.34–4.46] (69.7%) in HS. This UMA supported the hypothesis that serum vitamin D deficiency was associated with an increased risk of HS as well as IS. Diverse public health programs against vitamin D deficiency status would be needed for higher risk group, especially elderly people.
Fri, 19 April 2019
ARTICLE Download: 47| View: 154| Comments: 0 | doi:10.20944/preprints201904.0212.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: stroke; post-stroke dementia; anaemia
Online: 19 April 2019 (09:41:13 CEST)
Background: Whilst lack of concentration is a known symptom of anaemia, its association with post-stroke dementia is unclear. Methods: We used data from a UK regional stroke register. To be eligible, patient must have survived to discharge and had anaemia by WHO criteria. Dementia status and other prevalent co-morbidities were assessed using ICD-10 codes. Patients were followed till May 2015 (mean follow-up 3.7 years, total person years = 27,769). Hazard Ratio for incident dementia was calculated using Cox-proportional hazards model controlling for potential confounders. Fine and Gray model was additionally constructed using mortality as the competing risk. Results: A total of 7,454 stroke patients were included with mean age (SD) of 75.9(12.3) years (50.2% men). Those with anaemia were older, has higher disability and co-morbidity burden prior to stroke. We observed a large amount of variation in the dementia incidence rates over time and that the hazard ratio increased every year. The significant association between anaemia and dementia incidence was lost after controlling for pre-stroke Modified Rankin score (HR1.17(0.97,1.40)). With every 20g/dL increase in Hb was associated with a significant reduction in the risk of dementia after adjustment for age, sex, stroke factors and disability but lost significance after adjustment for vascular risk factors. Competing risk analyses showed similar results. Conclusion: Whilst we found no evidence of anaemia as a risk factor for post-stroke dementia, the findings may be limited by potential under recognition of post stroke dementia.
Sat, 13 April 2019
ARTICLE Download: 63| View: 134| Comments: 0 | doi:10.20944/preprints201904.0152.v1
Online: 13 April 2019 (05:08:57 CEST)
Background: Formation and rupture of cerebral aneurysms may be related to certain types of configuration of the circle of Willis. Analysis of their interdependence can be of great importance. Methods: A group of 114 patients treated operatively for the cerebral aneurysm rupture and a group of 56 autopsied subjects were involved in the study. Four basic types of the circle of Willis configurations were formed–two symmetric types A and C, and two asymmetric types B and D. Results: A statistically significantly higher presence of asymmetry of the circle of Willis in the group of surgically treated subjects (p=0.006) with a significant presence of asymmetric Type B in this group (p=0.017) were determined. The presence of changes in the A1 segment in the group of subjects with solitary aneurysms on the anterior communicating artery showed a statistically significant presence in the group of autopsied subjects (p=0.0004). Analyzing the presence of symmetry of the circle of Willis between the two groups, that is, the total presence of symmetric types A and C indicated their statistically significant presence in the group of autopsied patients (p=0.043). Conclusion: Changes such as hypoplasia or aplasia of A1 and the resulting asymmetry of the circle of Willis directly affect the possibility of the rupture of cerebral aneurysms. Detection of the corresponding types of the circle of Willis after diagnostic examination can be the basis for the development of a protocol for monitoring such patients.
Mon, 1 April 2019
ARTICLE Download: 90| View: 215| Comments: 0 | doi:10.20944/preprints201904.0015.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: dysphagia; FEES; Parkinson’s disease; swallowing speed; screening; water test
Online: 1 April 2019 (13:32:41 CEST)
There is still a lack of a clinical test to reliably identify patients with Parkinson’s disease (PD) being at risk for aspiration. In this prospective, controlled, cross-sectional study we assessed if swallowing speed for water is a useful clinical test to predict aspiration proven by flexible endoscopic evaluation of swallowing (FEES). Due to this we measured the swallowing speed for 90 ml water in 115 consecutive and unselected PD outpatients of all clinical stages and 32 healthy controls. Average swallowing speed was lower in patients compared with controls (6.5 ± 3.9 ml/s vs. 8.5 ± 3.2 ml/s; p < 0.01). The disease-independent widely used threshold of < 10 ml/s showed insufficient sensitivity of 88% and specificity of 19% with unacceptable false-positive rates of 63% for patients and 69% for controls. Receiver operating characteristic (ROC) analysis was carried out to define a suitable cut-off value for detection of aspiration of water (area under the curve 0.72, p < 0.001) in PD patients. The optimized cut-off value was 5.5 ml/s with a sensitivity of 69% and a specificity of 64%. Overall, measuring swallowing speed is prone to methodological errors and not suitable as a screening instrument to predict aspiration in PD patients.
Fri, 1 February 2019
ARTICLE Download: 97| View: 542| Comments: 0 | doi:10.20944/preprints201902.0006.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: APOE gene; Apolipoprotein E; DNA methylation; Mild cognitive impairment; Hispanics.
Online: 1 February 2019 (09:22:48 CET)
Background: Biomarkers are essential for identification of individuals at high risk of mild cognitive impairment (MCI) for potential prevention of dementia. We investigated DNA methylation in the ApoE gene and plasmatic apolipoprotein E (ApoE) levels as MCI biomarkers in Colombian subjects with MCI and controls. Methods: 100 participants were included (71% women, average age, 70 yrs., range 43-91). MCI was diagnosed by neuropsychological testing, medical and social history, activities of daily living, cognitive symptoms and neuroimaging. Multivariate logistic regression models adjusted by age and gender were performed to examine the risk association of MCI with plasma ApoE and APOE methylation Results: MCI was diagnosed in 41 subjects (average age, 66.5±9.6 yrs.) and compared with 59 controls. Elevated plasma ApoE and APOE methylation of CpGs 165, 190, and 198 were risk factors for MCI (P<0.05). Higher CpG-227 methylation correlated with lower risk for MCI (P=0.002). Only CpG-227 was significantly correlated with plasmatic ApoE levels (correlation coefficient=-0.665; P=0.008). Conclusion: Differential APOE methylation and increased plasma ApoE levels were correlated with MCI. These epigenetic patterns can be used as potential biomarkers to identify early stages of MCI.
Mon, 24 December 2018
REVIEW Download: 131| View: 187| Comments: 0 | doi:10.20944/preprints201812.0267.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer’s disease; CTH gene; DNA methylation; epigenetics; epigenome-wide association study; methylome; MTHFR gene; nutrition; S-adenosylmethionine; vitamin B complex
Online: 24 December 2018 (04:48:53 CET)
DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer’s disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-L-methionine (SAM), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase (CTH) gene affects the enzyme that converts cystathionine to cysteine in the trans-sulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia – a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins. We emphasize the importance of supplementing vitamin B12 (methylcobalamin), vitamin B9 (folic acid), vitamin B6 (pyridoxine), and SAM to patients in early stages of LOAD.
Tue, 18 December 2018
ARTICLE Download: 68| View: 267| Comments: 0 | doi:10.20944/preprints201812.0210.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Parkinson’s; RBD; connectivity; phenotype; classification; network
Online: 18 December 2018 (03:58:08 CET)
Rapid eye movement sleep behavior disorder (RBD) is often prodromal to Parkinson’s disease (PD). Thus there should be detectable in vivo functional signatures shared between RBD and PD that aid in disease classification. To assess common in-vivo phenotypes, resting state data was collected on a 3T clinical MRI platform and a novel functional connectivity magnetic resonance imaging (fcMRI) approach, which combined independent component analysis (ICA) and graph theory, was used to evaluate deficits in interconnectivity among 15 PD, 14 RBD and 13 control participants. Whole brain and network-level analyses revealed the largest deficits in network connectivity in PD compared with controls, with less severe differences between RBD and controls. Importantly, the network-level analysis demonstrated decreased network interconnectivity, with the greatest aberrant networks in PD, and a subset in RBD. Additionally, a disease classification algorithm predicted PD cases by being trained on RBD cases with 0.87 sensitivity and 0.68 specificity. The functional alterations in cortical networks in RBD extended beyond the brainstem. These findings demonstrate progressive reductions in connectivity between brain networks, with less severe deficits in RBD than PD. Moreover, RBD phenotypes can be used to predict PD status in a cross-sectional sample, which suggests RBD is an intermediate phenotype.
Wed, 12 December 2018
REVIEW Download: 49| View: 180| Comments: 0 | doi:10.20944/preprints201812.0138.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: dengue fever; transverse myelitis; risk; systematic review
Online: 12 December 2018 (05:22:13 CET)
Dengue virus (DENV) is the most common arbovirus disease, with wide spectrum of presentation. Spinal cord involvement in dengue infection (DF) is rare. However, the risk of transverse myelitis (TM) following Dengue has not been systematically assessed. Methods: We undertook a systematic review of the English literature published from January 1974 to December 2017 to assess risk of TM and outcomes following DF. Data sources included MEDLINE, EMBASE Cochrane library, and references within identified articles. Results: We identified 242 potential studies, 62 were duplicates. A further 136 were excluded on the basis of title and abstract and 19 studies did not meet the eligibility criteria on full text screening. We included 25 publications involving 2672 cases of DF. 10.8% (289/2672) had neurological complications, of which 2.3% (61/2672) was TM. For articles reporting epidemiological data, the neurological complication was twice in males compared to female 67.7% (130/192) vs 32.7% (62/192) and 1.5 fold increase TM for males 59.3% (32/54) vs 40.7% (22/54). The mean age at presentation was 33.1years (Range 0.75 – 61), with onset at 11.7days. The method of diagnosing TM due to DF was mainly IgM seropositivity 92% (n=23/25) and the commonest treatment modality was steroid 78.3% (n=18/23). Only half had full recovery 50.8% (n=31/61). There was no mortality following dengue, however, the crude case fatality rate following TM was 3.3% (n=2/61). Conclusion: This review highlights the risk of TM following dengue. Although neurological complications are rare, especially TM, once set in, it is associated with a significant morbidity.
Thu, 6 December 2018
ARTICLE Download: 84| View: 187| Comments: 0 | doi:10.20944/preprints201812.0082.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Brain injury, coma, consciousness, cognitive motor dissociation, disorders of consciousness, ethics, neurorehabilitation, traumatic brain injury
Online: 6 December 2018 (10:05:52 CET)
Background: The vegetative state (VS)/unresponsive wakefulness syndrome (UWS) denotes brain-injured, awake patients who are seemingly without awareness. Still, up to 15% of these patients show signs of covert consciousness when examined by functional magnetic resonance imaging (fMRI) or EEG, which is known as cognitive motor dissociation (CMD). Most experts prefer the term unresponsive wakefulness syndrome to avoid the negative connotations associated with vegetative state and to highlight the possibility for CMD. However, the perception of VS/UWS by the public has never been studied systematically. Methods: Using an online crowdsourcing platform, we recruited 1297 participants from 32 countries. We investigated if vegetative state and unresponsive wakefulness syndrome might have a different influence on attitudes towards VS/UWS and CMD. Results: Participants randomized to be inquired about the vegetative state believed that CMD was less common (mean estimated frequency in unresponsive patients 38.07% ± SD 25.15) than participants randomized to unresponsive wakefulness syndrome (42.29% ± SD 26.63; p=0.016). Attitudes towards treatment withdrawal were similar. Most participants preferred unresponsive wakefulness syndrome (60.05%), although a sizeable minority favored vegetative state (24.21%; difference 35.84%, 95% CI 29.36 to 41.87; p<0.0001). Searches on PubMed and Google Trends revealed that unresponsive wakefulness syndrome is increasingly used by academics but not lay people.Discussion: Simply replacing vegetative state with unresponsive wakefulness syndrome may not be fully appropriate given that 1 of 4 prefer the first term. We suggest that physicians take advantage of the controversy around the terminology to explain relatives the concept of CMD and its ethical implications.
Tue, 30 October 2018
ARTICLE Download: 123| View: 158| Comments: 0 | doi:10.20944/preprints201810.0709.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: ALS; ALS rehabilitation; myomiRs; circulating miRNAs; muscle; motor neuron
Online: 30 October 2018 (07:15:24 CET)
Amyotrophic lateral sclerosis (ALS) is a rare, progressive, neurodegenerative disorder caused by degeneration of upper and lower motor neurons. The disease process leads from lower motor neuron involvement to progressive muscle atrophy, weakness, fasciculations for the upper motor neuron involvement to spasticity. Muscle atrophy in ALS is caused by a dysregulation in the molecular network controlling fast and slow muscle fibres. Denervation and reinnervation processes in skeletal muscle occur in the course of ALS and are modulated by rehabilitation. MicroRNAs (miRNAs) are small non-coding RNAs that modulate a wide range of biological functions under various pathophysiological conditions. MiRNAs can be secreted by various cell types and they are markedly stable in body fluids. MiR-1, miR-133 a, miR-133b, and miR-206 are called “myomiRs” and are considered markers of myogenesis during muscle regeneration and neuromuscular junction stabilization or sprouting. We observed a positive effect of a standard aerobic exercise rehabilitative protocol conducted for six weeks in 18 ALS patients during hospitalization in our center. We correlated clinical scales with molecular data on myomiRs. After six weeks of moderate aerobic exercise, myomiRNAs were down-regulated, suggesting an active proliferation of satellite cells in muscle and increased neuromuscular junctions. Our data suggest that circulating miRNAs modulate during skeletal muscle recovery in response to physical rehabilitation in ALS.
Mon, 1 October 2018
REVIEW Download: 229| View: 159| Comments: 0 | doi:10.20944/preprints201810.0014.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: IDO, kynurenine, pain, Sjögren’s syndrome, tryptophan
Online: 1 October 2018 (14:59:23 CEST)
For decades, neurologic and other extra glandular manifestations have been described in Sjögren’s syndrome (SS). More recently, neuropathic, psychological and cognitive alterations are being considered part of the disease. The lacrimal glands (LG), the ocular surface (OS), salivary glands (SG) and the central nervous system (CNS) are integrated to modulate the autonomic functions and, not just those organs, but also the hippocampus, which is linked to the autonomic nervous system, and modulate behavior responses appears to be compromised in the SS. Recent studies confirm that the tryptophan/kynurenine pathway (TKP) can be stimulated by interferon-γ (IFN-γ) and other cytokines, activating the indoleamine-pyrrole 2,3-dioxygenase (IDO) in SS. This pathway interferes on serotonergic and glutamatergic neurotransmission, mostly in the hippocampus, and other structures of the CNS. Although not demonstrated, it is plausible that this constant interference induces clinical signs of SS, and contributes to the discrepancy between symptoms and signs, towards manifestations of hyperalgesia and depression in patients with SS. Therapeutic strategies are being reexamined and new options designed and tested to regulate the involved steps of the TKP. In the future, the application of this concept may offer a clue to the mosaic of manifestations of SS.
REVIEW Download: 110| View: 190| Comments: 0 | doi:10.20944/preprints201810.0011.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: multiple sclerosis; pregnancy; epigenetics; experimental autoimmune encephalomyelitis
Online: 1 October 2018 (14:00:35 CEST)
The role of pregnancy in multiple sclerosis (MS) is of importance because many patients with MS are young women in the childbearing age who require information to inform their reproductive decisions. Pregnancy is now well-known to be associated with fewer relapses of MS and reduced activity of autoimmune encephalomyelitis (EAE). However, in women with multiple sclerosis, this benefit is not always sufficient to protect against a rebound of disease activity if disease modulating therapy is ceased for pregnancy. There is reason to be concerned that use of assisted reproductive therapies can be associated with relapses of MS. It is thought that the beneficial effects of pregnancy are due to the pregnancy-associated changes in the maternal immune system. There is some evidence of this in human studies and studies of EAE. There is also evidence that having been pregnant leads to better long-term outcome of MS. The mechanism for this is not fully understood but it could result from epigenetic changes resulting from pregnancy or parenthood. Further studies of the mechanisms of the beneficial effects of pregnancy could provide information that might be used to produce new therapies.
Sat, 29 September 2018
ARTICLE Download: 196| View: 598| Comments: 0 | doi:10.20944/preprints201809.0591.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: adverse events; immune checkpoint inhibitor; myasthenia gravis; myopathy; neuropathy; nivolumab; pembrolizumab
Online: 29 September 2018 (11:28:00 CEST)
Neuromuscular adverse events following cancer treatment with anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are relatively rare, yet potentially fatal. Using the PRISMA approach, we performed a systematic review to characterize the clinical presentation, diagnostic workup, and management of neuromuscular disorders (NMDs) in patients treated with nivolumab or pembrolizumab. Sixty-three publications on 85 patients (mean age 66,9 years (range 34–86); male/female 2.6:1; 59% metastatic melanoma) were identified from selected indexing databases until June 2018. Forty-eight patients had received nivolumab and 39 pembrolizumab. The mean number of PD-1 inhibitor treatment cycles prior to onset of symptoms was 3,6 (range 1–28). Symptoms included oculomotor (47%); respiratory (43%), bulbar (35%), and proximal weakness (35%); as well as muscle pain (28%). Diagnoses were categorized as myasthenia gravis (27%), neuropathy (23%), myopathy (34%) and a combination of these (16%). After critical review of the data, however, evidence did not support the stated NMD diagnosis in 13% of cases, while up to 14% of patients had signs of additional NMDs. PD-1 inhibitor associated myasthenia was associated with cardiac complications in almost 30% of patients and with a more rapid clinical progression compared with idiopathic myasthenia. Mortality was high despite adequate treatment strategies including corticosteroid, IV immunoglobulins and plasmapheresis. In conclusion, clinical presentation of NMDs associated with PD-1 inhibitors is often atypical, with significant overlap between myasthenia gravis and myopathy; and cardiac/respiratory complications are common, leading to more severe disease courses than idiopathic myasthenia.
Thu, 23 August 2018
ARTICLE Download: 121| View: 182| Comments: 0 | doi:10.20944/preprints201807.0194.v2
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: brain-derived neurotrophic factor; Frailty; Inflammasome proteins; Interleukin-1β; Peri-infarct area
Online: 23 August 2018 (07:59:58 CEST)
A risk of ischemic stroke increases exponentially after menopause. Even a mild-ischemic stroke can result in increased frailty. Frailty is a state of increased vulnerability to adverse outcomes, which subsequently increases risk of cerebrovascular events and severe cognitive decline, particularly after menopause. Several interventions to reduce frailty and subsequent risk of stroke and cognitive decline have been proposed in laboratory animals and patients. One of them is whole body vibration (WBV). WBV recuperates cerebral function and cognitive ability that deteriorates with increased frailty. The goal of the current study is to test the efficacy of WBV in reducing post-ischemic stroke frailty and brain damage in reproductively senescent female rats. Reproductively senescent Sprague–Dawley female rats were exposed to transient middle cerebral artery occlusion (tMCAO) and randomly assigned to either WBV or control groups. Animals placed in the WBV group underwent 30 days of WBV (40 Hz) treatment performed twice daily for 15 min each session, 5 days each week. The motor functions of animals belonging to both groups were tested intermittently and at the end of treatment period. Brains were then harvested for inflammatory markers and histopathological analysis. The results demonstrate a significant reduction in inflammatory markers and infarct volume with significant increases in brain-derived neurotrophic factor and improvement in functional activity after tMCAO in middle-aged female rats that were treated with WBV as compared to the control group. Our results may facilitate a faster translation of the WBV intervention for improved outcome after stroke, particularly among frail women.
Wed, 11 July 2018
ARTICLE Download: 193| View: 219| Comments: 0 | doi:10.20944/preprints201807.0194.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: brain-derived neurotrophic factor; frailty; inflammasome proteins; interleukin-1β; peri-infarct area
Online: 11 July 2018 (08:59:15 CEST)
A risk of ischemic stroke increases exponentially after menopause. Even a mild-ischemic stroke can result in increased frailty. Frailty is a state of increased vulnerability to adverse outcomes, which subsequently increases risk of cerebrovascular events and severe cognitive decline, particularly after menopause. Several interventions to reduce frailty and subsequent risk of stroke and cognitive decline have been proposed in laboratory animals and patients. One of them is whole body vibration (WBV). WBV improves brain hemodynamics and lessens frailty-related functional and cognitive deterioration. The goal of current study is to test the efficacy of WBV in reducing post-ischemic stroke frailty and brain damage in reproductively senescent female rats. Reproductively senescent Sprague–Dawley female rats were exposed to transient middle cerebral artery occlusion (tMCAO) and randomly assigned to either WBV or control groups. Animals placed in the WBV group underwent 30 days of WBV (40 Hz) treatment performed twice daily for 15 min each session for 5 days each week. The motor functions of animals belonging to both groups were tested intermittently and at the end of treatment period. Brains were then harvested for inflammatory markers and histopathological analysis. The results demonstrate a significant reduction in inflammatory markers, infarct volume, and significant increases in brain-derived neurotrophic factor and improvement in functional activity after tMCAO in middle-aged female rats that were treated with WBV as compared to the control group. Our results may help faster translation of the WBV intervention for improved outcome after stroke, particularly among frail women.
Thu, 28 June 2018
REVIEW Download: 256| View: 206| Comments: 0 | doi:10.20944/preprints201806.0460.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: neuro-degeneration; MS; demyelination; vascular disease; stroke; AD; vitamin D-OH 25; VDR; VDH; calcium
Online: 28 June 2018 (05:38:49 CEST)
It is widely known that vitamin D receptors have been found in neurons and glial cells and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical grey nuclei, and substantia nigra. The vitamin D helps the regulation of neurotrophin, neural differentiation and maturation, through the control operation of growing factors synthesis (ie NGF and GDNF), the trafficking of the septo-hyppocampal pathway, and the control of the synthesis process of different neuromodulators (such as Ach, DA, and GABA). Based on these assumptions, we have written this review in order to summarize the potential role of vitamin D in neurological pathologies. The work could be titanic, and might result very fuzzy and even incoherent, if we would not have conjectured to taper our first intentions and devoted our interests towards three mainstreams: demyelinating pathologies, vascular syndromes and neurodegeneration. Due to the lack of effective therapeutic options, a part from the disease modifying strategies, the role of different risk factors should be investigated in neurology, as far as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long term vitamin D deficiency, as a risk factor for the development of different types of neurological disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation.
Thu, 3 May 2018
ARTICLE Download: 207| View: 267| Comments: 0 | doi:10.20944/preprints201805.0070.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Hyperpolarized gas MRI; xenon; gas retention; Alzheimer’s disease; wash out; vascular
Online: 3 May 2018 (12:02:44 CEST)
Biomarkers have the potential to aid in the study of Alzheimer’s disease (AD); unfortunately, AD biomarker values often have a high degree of overlap between healthy and AD individuals. This study investigates the potential utility of a series of novel AD biomarkers, the sixty second 129Xe retention time, and the xenon washout parameter, based on the washout of hyperpolarized 129Xe from the brain of AD participants following inhalation. The xenon washout parameter is influenced by cerebral perfusion, T1 relaxation of xenon, and the xenon partition coefficient, all factors influenced by AD. Participants with Alzheimer’s disease (n=4) and healthy volunteers (n=4) were imaged using hyperpolarized 129Xe magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to determine the amount of retain xenon in the brain. At 60 sec post breath hold, AD patients retained significantly higher amounts of 129Xe compared to healthy controls. Data was fit to a pharmacokinetic model and the xenon washout parameter was extracted. Xenon washout in white and grey matter occurs at a slower rate in Alzheimer’s participants (129Xe half-life time of 42s and 43s, respectively) relative to controls (20s and 16s, respectively). Following larger scale clinical trials for validation, the xenon washout parameter has the potential to become a useful biomarker for the support of an AD diagnosis.
Thu, 26 April 2018
ARTICLE Download: 297| View: 518| Comments: 0 | doi:10.20944/preprints201804.0332.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Gilles de la Tourette syndrome (GTS); children and adults; motor and vocal/phonic tics; obsessive-compulsive disorder (OCD); non-coeliac gluten sensitivity (NCGS); gluten-free diet; one-year adherence
Online: 26 April 2018 (06:26:55 CEST)
The Gilles de la Tourette syndrome (GTS) and Non-Coeliac Gluten Sensitivity (NCGS) may be associated. We analyse the efficacy of a gluten-free diet (GFD) in 29 patients with GTS (23 children; 6 adults) in a prospective pilot study. All of them followed a GFD for one year. The YGTSS, Y-BOCS/CY-BOCS and GTS-QOL questionnaires were compared before and after the GFD. 74% of children and 50% of adults were males, not significant (NS). At the beginning of the study, 69% of children and 100% of adults had associated OCD (NS). At baseline, the YGTSS scores were 55.0 ± 17.5 (children) and 55.8 ± 19.8 (adults) (NS), the Y-BOCS/CY-BOCS scores were 15.3 (SD = 12.3) (children) and 26.8 (9.2) (adults) (p = 0.043), and the GTS-QOL scores were 42.8 ± 18.5 (children) and 64 ± 7.9 (adults) (p = 0.000). NCGS was frequent in both groups, with headaches reported by 47.0% of children and 83.6% of adults (p = 0.001). After one year on a GFD there was a marked reduction in measures of tics (YGTSS) (p = 0.001), and the intensity and frequency of OCD (Y-BOCS/CY-BOCS) (p = 0.001), along with improved QOL (p = 0.001) in children and adults. In conclusion, a GFD maintained for one year in GTS patients led to a marked reduction in tics and OCD both in children and adults.
Mon, 16 April 2018
ARTICLE Download: 259| View: 205| Comments: 0 | doi:10.20944/preprints201804.0196.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: gluten neuropathy; coeliac disease; gluten free diet; quality of life
Online: 16 April 2018 (08:19:54 CEST)
Background: Gluten neuropathy (GN) is defined as an otherwise idiopathic peripheral neuropathy in the presence of serological evidence of gluten sensitivity (positive antigliadin and/or transglutaminase or endomysium antibodies). We aimed to compare the quality of life (QoL) of GN patients with control subjects and to investigate the effect of a gluten free diet (GFD) on the QoL. Methods: All consecutive patients with GN attending a specialist neuropathy clinic were invited to participate. Overall Neuropathy Limitations Scale (ONLS) was used to assess the severity of neuropathy. The SF-36 questionnaire was used to measure participants’ QoL. A strict GFD was defined as effectively been able to eliminate all circulating gluten sensitivity-related antibodies whilst on the diet. Results: Fifty-three patients with GN and 53 age and gender matched controls were recruited. Compared to controls, GN showed significantly worse scores in physical functioning, role limitations due to physical health, energy/fatigue and general health subdomains of SF-36. After having adjusted for age, gender and disease severity, being on a strict GFD correlated with better SF-36 scores on the pain domain of the SF-36 (beta 0.317, p=0.019) and the overall health change domain of the SF-36 (beta 0.306, p=0.017). Conclusion: In GN physical dysfunctioning is the major determinant of poor QoL compared to controls. Routine checking for elimination of gluten sensitivity-related antibodies that results from a strict GFD should be encouraged as such elimination ameliorates the overall pain and health scores, indicating better QoL.
Tue, 3 April 2018
ARTICLE Download: 171| View: 255| Comments: 0 | doi:10.20944/preprints201804.0037.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: brain vessel; ischemic stroke; non-valvular atrial fibrillation
Online: 3 April 2018 (11:07:39 CEST)
Objective: It was aimed to investigate the cerebral vascular territories in stroke patients with NVAF as an etiologic factor. Material and Methods: A total of 104 patients who were referred to our hospital between January 2015 and September 2016, who were over 55 years of age, identified or documented as having a standard ECG or Holter ECG record on their medical history, and diagnosed with stroke were included. Our study was designed as a retrospective analysis of prospective data. Detailed history, physical examination and electrocardiography (ECG) evaluations of the patients were performed. Descriptive statistics were used in the detection of findings, and t-test, Pearson-square test and Fisher's exact test were used for differences analysis. Results: 53.8% (N = 56) of the patients were male and 46.2% (N = 48) were female. The mean age was 73.5. MCA was the most common site of vascular involvement in NVAF-dependent strokes. In MCA vascular territory, ischemic infarcts were detected most frequently in the upper and lower divisions. SCA and PCA followed MCA. Approximately 64% of the NVAF-related strokes were anterior circulation infarction (ASE) and 22% were posterior circulation infarct (PSE). There was a significant difference in age and past stroke history factors in favor of ASE (p<0.05). There was no significant difference between ASE and PSE in HT, cardiac history and DM factors (p>0.05). Conclusion: It was emphasized that the area of the vessel that underwent ischemia in the acutely displayed infarcts and the etiological factor for this vessel area could be predicted
Mon, 2 April 2018
REVIEW Download: 287| View: 349| Comments: 0 | doi:10.20944/preprints201804.0026.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: MS: Multiple sclerosis, TMS: transcranial magnetic stimulation, Evoked Potentials;
Online: 2 April 2018 (16:03:29 CEST)
Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory disease of the central nervous system (CNS), characterized by demyelination, axonal degeneration, and cognitive impairment. It also has an important impact on the quality of life of patients and their family members. An estimated 2,500,000 people in the world have multiple sclerosis. Neurophysiological parameters, like sensitivity to demyelination and the strength of excitatory and inhibitory synaptic interactions in the cerebral cortex, can be identified through transcranial magnetic stimulation (TMS) in patients affected by multiple sclerosis (MS). These parameters can be valid and objective parameters that can be correlated with the progression of MS, and can provide reliable indices for the severity of illness and the efficacy of drugs used to treat it. The discovery of specific and detailed neurophysiological parameters as surrogate end points for disease activity could represent an important step in clinical trials. Changes in cortical connectivity have already been demonstrated in MS, but in clinical practice, other measures are usually used to evaluate disease activity. We speculate that TMS may be more effective in identifying disease progression that leads to long-term disability, compared to standard surrogate markers, due to the fact that it represents a direct measure of synaptic transmission(s) in MS.
Mon, 26 February 2018
ARTICLE Download: 220| View: 247| Comments: 0 | doi:10.20944/preprints201802.0165.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leuco encephalopathy (CADASIL); Carotid Endarterectomy (CEA); Modified Rankin Scale (MRS); Computed Tomography(CT); Tissue plasminogen activator (tPA); Diffusion weighted Imaging (DWI); Recognition of Stroke in the Emergency Room (ROSIER) scale; Magnetic resonance Imaging (MRI); Internal Carotid Artery (ICA)
Online: 26 February 2018 (11:46:47 CET)
In advanced world stroke is one of the disabling cause of death that can be managed with thrombolysis if presents early despite further risk of intracerebral haemorrhage. Secondary prevention is an important objective in ischaemic stroke where recurrence is very high with subsequent stroke. Carotid End Arterectomy impact a definitive and effective role for both symptomatic and asymptomatic carotid stenosis for secondary stroke prevention in selective cases. Thrombolysis is a potential primary management for certain group whereas carotid surgery employs secondary preventative measure in a specified ischaemic stroke group.
Wed, 7 February 2018
ARTICLE Download: 352| View: 383| Comments: 0 | doi:10.20944/preprints201802.0056.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: cervical spondylosis; migraine; retrospective cohort study; population-based
Online: 7 February 2018 (06:40:48 CET)
Background: Few studies have investigated the longitudinal association between cervical spondylosis (CS) and migraine by using a nationwide population-based database. Methods: We conducted a retrospective cohort study from 2000 to 2011 identifying 27,930 cases of cervical spondylosis and 111,720 control subjects (those without cervical spondylosis) from a single database. The subjects were frequency-matched on the basis of sex, age, and diagnosis date. The non- cervical spondylosis cohort was four times the size of the cervical spondylosis cohort. To quantify the effects of cervical spondylosis on the risk of migraine, univariate and multivariate Cox proportional hazard regression analyses were used to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: After a 10-year follow-up controlling for potential confounding factors, overall migraine incidence was higher in the cervical spondylosis cohort than in the non- cervical spondylosis cohort (5.16 and 2.09 per 1,000 people per year, respectively; crude hazard ratio = 2.48, 95% confidence interval = 2.28–2.69) with an adjusted hazard ratio of 2.03 (95% confidence interval = 1.86–2.22) after accounting for sex, age, comorbidities, and medication. Individuals with myelopathy in the cervical spondylosis cohort had a 2.19 times (95% confidence interval = 1.80–2.66) higher incidence of migraine compared than did those in the non- cervical spondylosis cohort. Conclusion: Individuals with cervical spondylosis exhibited a higher risk of migraine than those without cervical spondylosis. The migraine incidence rate was even higher among individuals with cervical spondylotic myelopathy.
Wed, 20 December 2017
ARTICLE Download: 295| View: 738| Comments: 0 | doi:10.20944/preprints201712.0138.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: multiple sclerosis; spinal cord; transforming growth factor beta 1; active plaques
Online: 20 December 2017 (07:04:10 CET)
We recently reported that in the spinal cord of PPMS or SPMS patients, large areas of periplaque demyelinating lesions extend distance away from plaque borders. Such lesions are characterized by a progliotic TGF-beta 1 signature accompanied by: i) a low-grade inflammatory reaction, ii) an extensive astrocytosis and iii) a process of incomplete demyelination. It was proposed that, while efficiently dampening inflammation in MS spinal cords, TGF-beta 1 could promote astrocytosis, prevent remyelination and possibly trigger alterations of myelin synthesis. In light of these findings, a re-interpretation of two large neuropathological studies performed on MS brains and spinal cords is provided here. While results from these studies clearly showed that active plaques do not display any region-specific distribution, an important point was apparently overlooked and not discussed by the authors: a significantly higher percentage of inactive plaques was found in MS spinal cords as compared to brains and, conversely, the percentage of slowly-expanding (or smoldering) lesions was significantly lower in the spinal cord as compared to the brain. These data indicate that the spinal cord environment may be more favorable to the resolution of inflammation. Downstream of the autoimmune process leading to plaque formation, region-specific mechanisms may thus drive the outcome of active plaques. While inflammation triggers tissue destruction, inflammation may also be needed for effective tissue repair and an inappropriate dampening of inflammatory events may possibly translate into a poor level of remyelination in MS spinal cords. It is proposed here that TGF-beta 1 is involved in such a brain-spinal cord dissociation of active plaques outcome.
Wed, 13 September 2017
REVIEW Download: 472| View: 565| Comments: 0 | doi:10.20944/preprints201709.0050.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer's-disease; dementia; drug targeting; nanoemulsion; neuroinflammation; oxidative stress; scavenger receptors; sonoporation; transcranial ultrasound
Online: 13 September 2017 (05:44:29 CEST)
Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly SR-BI), making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such film-stabilized microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.
Thu, 31 August 2017
CASE REPORT Download: 810| View: 843| Comments: 0 | doi:10.20944/preprints201708.0106.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Aicardi-Goutiéres syndrome; interferon 1; melatonin; growth hormone; neurorehabilitation
Online: 31 August 2017 (12:30:11 CEST)
1) Background: The Aicardi-Goutières syndrome (AGS) is a rare congenital disease which courses with severe psychomotor delay in neurodevelopment. We studied a 3-years and 4-months old child with very important growth and weight affectation, microcephaly and loss of his developmental skills from 16-months of age, in which previous metabolic and genetic studies discarded any abnormality. Therefore diagnosis was cerebral palsy of unknown etiology. He presented spastic paraparesia, poor fine motricity, cognitive impairment and absence of oral communication. One year after discharge, a de novo mutation was detected in a single nucleotide in the gene IFIH1: c.2317G>C, being then diagnosed of AGS. 2) Methods: Blood analysis showed very low IGF-1 and slightly elevated liver transaminases. Treatment consisted in GH (0.04 mg/kg/day), melatonin (20 mg/day, and after 3-months 50 mg/day), and daily intense neurorehabilitation (5 days/week). Tests for evaluating childhood developmental milestones (GMFM-88, BDIST and the WeeFim test) were carried out every 3-months. 3) Results: The equivalent age at admission (10-months) increased to 24-months at discharge. There were clear improvements in spasticity, fine motor function, swallowing, cognition and autonomy as well as in communication, growth and weight. 4) Conclusion: Most likely melatonin blocked or decreased the interferon signature, allowing GH and neurorehabiltation to act on neurodevelopment.
Fri, 4 August 2017
ARTICLE Download: 349| View: 455| Comments: 0 | doi:10.20944/preprints201708.0013.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: permutation entropy; permutation complexity; pharmacological treatment
Online: 4 August 2017 (11:06:40 CEST)
In the clinical electrophysiologic practice, the reading and comparing electroencephalographic (EEG) recordings some times is insufficient and take to much time. That is why in the last years it has begun to introduce new methods of EEG analysis, that give a better and faster understanding of the EEG dynamics and allow a rapid intervention in the patient's treatment. Tools coming from the information theory or nonlinear system as an entropy and complexity have been shown to be a very good alternative to address this problem. In this work we introduce a novel method -the permutation Lempel-ziv complexity vs permutation entropy map. This method was applied to EEG of two patients with specific diagnosed pathologies during respective follow up processes of pharmacological changes in order to detect changes that are not evident with the usual inspection method. Our results show that the proposed method are useful for observing an evolutionary retrospective clinical effects of pharmacological interventions in both patients, and from these, to follow the clinical response to the proposed treatment.
Wed, 14 June 2017
REVIEW Download: 477| View: 612| Comments: 0 | doi:10.20944/preprints201706.0067.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Transition Medicine; Pediatric migraine; Pediatric; Migraine; Migraine in young adults
Online: 14 June 2017 (09:26:13 CEST)
Migraine is a common condition that affects children as they develop into adults. Transition of care from pediatric to adult care has becoming an increasingly popular topic in the medical literature. It has been suggested that discussions between patients, their families and providers should be initiated as early as age 13. Patients who are un or underprepared have poorer outcomes due to increased morbidity and worsening of their medical condition. Many children continue to have migraine into adulthood and if efforts are taken to ensure patients receive appropriate transfer of care, the results can significantly decrease the economic burden of this disease.
Tue, 6 June 2017
ARTICLE Download: 796| View: 713| Comments: 0 | doi:10.20944/preprints201706.0034.v1
Online: 6 June 2017 (08:39:30 CEST)
α-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial PD. A previous study showed that a variant of α-synuclein gene (SNCA), namely the 263bp allele of Rep1 was associated to faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in Parkinson’s Disease (PD) patients. We recruited and genotyped for SNCA-Rep1 426 PD patients with age at onset ≥40 years and disease duration ≥4 years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations and dementia. SNCA Rep1 263 carriers showed increased risk of both dementia (HR=3.03) and visual hallucinations (HR=2.69) compared to 263 non-carriers. In conclusion, SNCA Rep 1 263 allele is associated to a worst cognitive outcome in PD.
Mon, 30 January 2017
CONCEPT PAPER Download: 828| View: 831| Comments: 0 | doi:10.20944/preprints201612.0105.v5
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: csf; shunt; filtration; neurodegenerative; neuroimmunology; alzheimer; parkinson; guillain-barre; device; ventriculo-peritoneal shunt
Online: 30 January 2017 (14:22:03 CET)
Liquorpheresis (CSF filtration) comprises a therapeutical approach that has been proposed to treat several neurological conditions where antibodies, inflammatory mediators or abnormal peptides are the cause or play an important role in the pathogenesis of the disease. CSF replacement may be an alternative approach not explored so far. Here, we review previous experiences in the use of liquorpheresis in autoimmune and degenerative neurological diseases. Then we describe previous developments and provide some new technical innovations in order to design bidirectional CSF shunting systems. These systems can be complemented either with a deposit of artificial CSF or with a CSF filter, allowing CSF replacement or liquorpheresis respectively. Both options would lead to mechanical dilution of the patient’s CSF.
Thu, 5 January 2017
REVIEW Download: 1077| View: 816| Comments: 0 | doi:10.20944/preprints201701.0027.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: iPad; tablet computers; Stroke; neuro-rehabilitation
Online: 5 January 2017 (09:56:53 CET)
Neuro-rehabilitation services are essential in reducing post-stroke impairments, enhancing independence, and improving recovery in hospital and post-discharge. However these services are therapist-dependent and resource intensive. Patients’ disengagement and boredom in stroke units are common which adversely affect functional and psychological outcomes. Novel techniques such as use of iPads™ are increasingly researched to overcome such challenges. The aim of this review is to determine the feasibility, effectiveness, acceptability, and barriers to the use of iPads™ in stroke neuro-rehabilitation. Four databases and manual literature search were used to identify published studies using the terms “iPad”, “Stroke”, and “neuro-rehabilitation”. Studies were included in accordance with the review selection criteria. A total of 16 articles were included in the review. The majority of the studies focused on iPads use in speech and language therapy. Although of small scale, the studies highlighted that iPads are feasible, have the potential to improve rehabilitation outcomes, and can improve patient’s social isolation. Patients’ stroke severity and financial limitations are some of the barriers highlighted in this review. This review presents preliminary data supportive for the use of iPad technology in stroke neuro-rehabilitation. However, further research is needed to determine impact on rehabilitation goals acquisition, clinical efficacy, and cost-efficiency.
Mon, 2 January 2017
ARTICLE Download: 833| View: 900| Comments: 0 | doi:10.20944/preprints201701.0010.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Haemophilus influenza; Neisseria meningitidis; meningitis; vaccine efficacy evaluation; immunization schedule.
Online: 2 January 2017 (18:14:59 CET)
Meningitis is a severe disease associated with death in children under five with highest rates of infections under age of one. Vaccines for Neisseria meningitides and Haemophilus influenza are used to prevent the main causative agents of meningitis. Administration of H. influenzae type b (Hib) vaccine is recommended at 2, 4 and 6 months with a booster dose at 18 months. N. meningitidis has two commercially available vaccines, the pure polysaccharide is recommended at 24 months meanwhile the protein-conjugated vaccines at 12 months. We sought in this study to examine if coadministering the vaccines for the two main meningitis causing bacteria might be synergistic as a preliminary step towards the possibility of shuffling immunization schedule. So, we coadministered Hib vaccine with commercially available vaccines either quadrate (ACWY) polysaccharide meningococcal (Men) or conjugated meningococcal (Nim) vaccines in Balb/C mice (n = 6/group) and compared to each vaccine administered separately and controls. Thirty-five days post immunization, we measured specific antibodies titers. Hib vaccine increased Men antibody titers significantly for serotypes Y and W. When Hib vaccine was coadministrated with Nim, antibody titer for Y, W and A significantly increased. For serotype C, there was no significant difference in antibody titers among immunized groups. As for effect of meningococcal vaccines on Hib, Men significantly increased Hib antibody titers while Nim had no effect. Collectively, our data suggested that coadministration of Hib and Men or Nim vaccines was safe and had synergistic effect on immune responses elicited to both vaccines. Further studies are needed before immunization schedule modifications. Such immunization schedule recommendation should provide better protection against this life-threatening disease in young children.
Wed, 21 December 2016
CONCEPT PAPER Download: 561| View: 512| Comments: 0 | doi:10.20944/preprints201612.0105.v2
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: csf; shunt; filtration; neurodegenerative; neuroimmunology; alzheimer; parkinson; guillain-barre; device; ventriculo-peritoneal shunt
Online: 21 December 2016 (10:12:13 CET)
Liquorpheresis (CSF filtration) comprises a therapeutical approach that has been proposed to treat several neurological conditions where antibodies, inflammatory mediators or abnormal peptides are the cause or play an important role in the pathogenesis of the disease. Continuous or intermittent CSF replacement may be an alternative approach not explored so far.Here, we review previous experiences in the use of liquorpheresis in autoimmune and degenerative neurological diseases. Then we describe a bidirectional CSF shunt system allowing portable liquorpheresis. Alternatively, CSF can be replaced with artificial cerebrospinal fluid. Both options would lead to mechanical dilution of the patient’s CSF.
Mon, 28 November 2016
REVIEW Download: 1306| View: 1003| Comments: 0 | doi:10.20944/preprints201611.0138.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: computational imaging; midsagittal plane; inter-hemispheric fissure; symmetry analysis; neuroimaging
Online: 28 November 2016 (02:03:34 CET)
Brain is the most complex organ in the human body and it is divided into two hemispheres - left and right hemispheres. Left hemisphere is responsible for control of right side of our body whereas right hemisphere is responsible for control of left side of our body. Brain image segmentation from different neuroimaging modalities is one of the important parts in clinical diagnostic tools. Neuroimaging based digital imagery generally contain noise, inhomogeneity, aliasing artifacts, and orientational deviations. Therefore, accurate segmentation of brain images is a very difficult task. However, the development of accurate segmentation of brain images is very important and crucial for a correct diagnosis of any brain related diseases. One of the fundamental segmentation tasks is to identify and segment inter-hemispheric fissure/mid-sagittal plane, which separate the two hemispheres of the brain. Moreover, the symmetric/asymmetric analyses of left and right hemispheres of brain structures are important for radiologists to analyze diseases such as Alzheimer's, Autism, Schizophrenia, Lesions and Epilepsy. Therefore, in this paper we have analyzed the existing computational techniques used to find brain symmetric/asymmetric analysis in various neuroimaging techniques (MRI/CT/PET/SPECT), which are utilized for detecting various brain related disorders.
Sun, 27 November 2016
ARTICLE Download: 860| View: 755| Comments: 0 | doi:10.20944/preprints201611.0133.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: GH; syndrome of caudal regression; sacral agenesis; physiotherapy; neurogenic bladder; flaccid paraplegia
Online: 27 November 2016 (04:35:36 CET)
Caudal regression syndrome (CRS) is a congenital abnormality characterized by an incomplete development of the spinal cord (SC) and other abnormalities. We studied a 9-months old CRS child presenting: interruption of SC at L2-L3 level, sacral agenesis, lack of innervation of the inferior limbs (flaccid paraplegia) and neurogenic bladder and bowel. Given the effects of growth hormone (GH) on the proliferation, differentiation and migration of neural stem cells (NSCs), we treated him with GH and rehabilitation, trying to induce the recovery of main sequelae. GMFM-88 test score was 12.31%. After a blood analysis, GH treatment (0.3 mg/day, 5 days/week, 3 months and then 15 days without GH) and rehabilitation commenced. This protocol was followed during 5 years, being the last GH dose 1 mg/day. Blood analysis and physical exams were performed every 3 months initially and every 6 months later. Six months after commencing the treatment GMFM-88 score increased to 39.48%. Responses to sensitive stimuli appeared in most of the territories explored; 18 months later sensitive innervation was complete and the patient moved any muscle over the knees and controlled his sphincters. Three years later he walked with the help of canes, there was plantar flexion and GMFM-88 score was 78.48%. In summary, GH plus rehabilitation may be useful for innervating distal territories, below the level of the incomplete spinal cord in CRS. Most likely, GH acts on ependymal SC NSCs, as the hormone does in the neurogenic niches in the brain.