CASE REPORT | doi:10.20944/preprints202009.0297.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: SARS-CoV-2; COVID-19; CNS; infant; Choroid plexus
Online: 13 September 2020 (16:16:59 CEST)
Coronavirus disease 2019 (COVID-19) was initially characterized as a respiratory illness. Neurological manifestations were reported mostly in severely affected patients. Routes for brain infection and the presence of virus particles in situ have not been well described, raising controversy about how the virus causes neurological symptoms. Here, we report the autopsy findings of a 1-year old infant with COVID-19. In addition to pneumonitis, meningitis and multiple organ damage related to thrombosis, a previous encephalopathy may have contributed to additional cerebral damage. SARS-CoV-2 infected the choroid plexus, ventricles, and cerebral cortex. This is the first evidence of SARS-CoV-2 detection in an infant post-mortem brain.
Fri, 16 October 2020
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; diagnosis; Health services; clinical care
Online: 16 October 2020 (08:58:18 CEST)
Designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation is Science and Technology (COST) (https://www.cost.eu/cost-actions/what-are-cost-actions/ ) - COST action 15111 - from 2016 to 2020. The main goal of the Cost Action was to assess the existing fragmented knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report on the recommendations for clinical diagnosis, heath services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS (https://www.cost.eu/actions/CA15111/#tabs|Name:overview).
Wed, 15 January 2020
REVIEW | doi:10.20944/preprints202001.0148.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: nerve hydrodissection; pain management; ultrasonography; neuropathic pain
Online: 15 January 2020 (12:09:56 CET)
Nerve hydrodissection (HD), a technique used when treating nerve entrapments, involves using an anesthetic or solution such as saline or 5% dextrose solution to separate the nerve from the surrounding tissue, fascia, or adjacent structures. This technique aims to treat neuropathic pain, or pain caused by the nerve. Ultrasound-guided HD of peripheral nerves has gained significant attention in the medical profession and pain management fields in recent years. This is due to a number of high impact publications of randomized control trials demonstrating the efficacy and safety of this technique for the treatment of carpal tunnel syndrome. Even the 20th edition of Harrison’s Principles of Internal Medicine textbook lists injection of 5% dextrose as an alternative local treatment that does not have the side effects of corticosteroids. At present, there is no review of the current literature on this technique. This manuscript will summarize and discuss the following: 1) the different approaches to doing ultrasound-guided HD of nervous structures, 2) its usages in different clinical situations, 3) its clinical pearls, 4) the solution used, and 5) the postulated mechanisms of action.
Fri, 17 April 2020
COMMUNICATION | doi:10.20944/preprints202004.0304.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: COVID-19; SARS-CoV-2; Neurology; coronavirus
Online: 17 April 2020 (15:27:14 CEST)
The recently emerged coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- CoV-2) is the newest threat to human health. It has already infected more than half a million people worldwide, leading to a lot of deaths. Although it causes mild flu-like disease in most patients, lethality may increase to more than 20% in elderly subjects, especially those with comorbidities, like hypertension, diabetes or lung and cardiac disease, and the mechanisms are still elusive. Common symptoms at the onset of illness are fever, cough, myalgia or fatigue, headache, and diarrhea or constipation. Interestingly, respiratory viruses have also placed themselves as relevant agents for CNS pathologies. Here we discuss several CNS related features, referred by several patients, especially at the beginning of the disease. Thus, we also discuss the possibility by which SARS-CoV-2 may affect the olfactive system of patients, either directly or indirectly.
Mon, 28 November 2016
REVIEW | 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.
Sat, 25 April 2020
REVIEW | doi:10.20944/preprints202004.0453.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: neurology; clinical features; coronavirus; stroke; encephalitis; headache; delirium
Online: 25 April 2020 (02:36:21 CEST)
The Coronavirus disease due to SARS-CoV-2 emerged in Wuhan city, China in December 2019 and rapidly spread more than 200 countries as a global health pandemic. There are more 3 million confirmed cases and around 207,000 fatalities. The primary manifestation is respiratory and cardiac but neurological manifestations are being reported in the literature as case reports and case series. The most common reported symptoms to include headache and dizziness followed by encephalopathy and delirium. Among the complications noted are Cerebrovascular accident, Guillian barre syndrome, acute transverse myelitis, and acute encephalitis. The most common peripheral manifestation was hyposmia. It is further noted that sometimes the neurological manifestations can precede the typical features like fever and cough and later on typical manifestations develop in these patients. Hence a high index of suspicion is required for timely diagnosis and isolation of cases to prevent the spread in neurology wards. We present a narrative review of the neurological manifestations and complications of COVID-19. Our aim is to update the neurologists and physicians working with suspected cases of COVID-19 about the possible neurological presentations and the probable neurological complications resulting from this novel virus infection.
Thu, 31 August 2017
CASE REPORT | 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.
Mon, 2 January 2017
ARTICLE | 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.
Thu, 5 January 2017
REVIEW | 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, 30 January 2017
CONCEPT PAPER | 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.
Sun, 27 November 2016
ARTICLE | 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.
Wed, 20 December 2017
ARTICLE | 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.
Tue, 6 June 2017
ARTICLE | 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.
Sat, 29 September 2018
ARTICLE | 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.
Tue, 26 January 2021
ARTICLE | doi:10.20944/preprints202101.0530.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer’s disease; biomarker; prognosis; P53; mass spectrometry
Online: 26 January 2021 (10:01:35 CET)
Despite the increasing number of individuals affected by Alzheimer’s disease (AD) every year, no effective therapy has been developed to treat this neurodegenerative disease yet. The current methods for AD diagnosis are effective for clinical confirmation of the disease only when symptoms become apparent, years after molecular damage started within the patients’ brains. As higher expression of a conformationally altered p53 has been correlated with AD, we developed a mass spectrometry-based method for highly sensitive, specific, and reproducible quantification of a p53 conformational variant in plasma samples of patients with known clinical outcome. In particular, we tested the prognostic performance of an AD-specific 2D3A8-immunoselected p53 peptide (AZ 284™) in different sets of individuals progressing from both cognitively unimpaired (CU) and mild cognitive impairment (MCI) patients progressing to AD dementia. Our data showed that quantitative analysis of AZ 284™ is a reliable tool for predicting AD progression up to 6 years prior to dementia onset with AUC >90%. Taken together, these results support the implementation of p53 conformational variant quantification as an affordable and powerful diagnostic tool for early, non-invasive AD diagnosis.
Wed, 14 June 2017
REVIEW | 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.
Fri, 1 February 2019
ARTICLE | 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.
Sun, 7 June 2020
ARTICLE | doi:10.20944/preprints202006.0103.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: clinical medecine; physiopathology; COVID-19; neurological manifestations; kidney disease; cytokine; corticosteroids; intravenous immunoglobulins
Online: 7 June 2020 (15:50:37 CEST)
Severe disease and uremia are risk factors for neurological complications of coronavirus disease-2019 (COVID-19). An in-depth analysis of a case series was conducted to describe the neurological manifestations of patients with COVID-19 and gain pathophysiological insights that may guide clinical decision-making – especially with respect to the cytokine release syndrome (CRS). Extensive clinical, laboratory, and imaging phenotyping was performed in five patients. Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Neurological disturbances were remarkably accompanied by laboratory evidence of CRS. SARS-CoV-2 was undetectable in the cerebrospinal fluid. Hyperalbuminorachy and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain MRI findings comprised evidence of acute leukoencephalitis (n = 3, of whom one with a hemorrhagic form), cytotoxic edema mimicking ischemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted – resulting in rapid recovery from neurological disturbances in two cases. Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory, and imaging similarities with those of chimeric antigen receptor-T cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.
Wed, 13 September 2017
REVIEW | 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, 26 April 2018
ARTICLE | 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.
Fri, 17 April 2020
COMMUNICATION | doi:10.20944/preprints202004.0305.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: multiple sclerosis; tuberculosis; immunosuppressive therapy; Latent tuberculosis
Online: 17 April 2020 (15:34:17 CEST)
Tuberculosis (TB) is an infectious-contagious disease caused by M. tuberculosis (Koch’s bacillus). About one-quarter of the world’s population is infected with that bacillus and at risk of developing TB disease. Latent tuberculosis corresponds to people who have been infected by TB bacteria but are not (yet) ill. The most vulnerable population to TB activation includes HIV infected, drug abuse and autoimmune disease patients. Multiple Sclerosis (MS) is a chronic and autoimmune neurological disease caused by lymphocytic infiltration. Its prevalence worldwide is 22.2 million cases of MS. There is a relation between TB and MS: due to immunomodulation or immunosuppression treatment of MS (reactivation of latent infection), or due to the intense inflammatory response before the infection of the bacillus (increased susceptibility to the development of autoimmune diseases). Screening for TB includes complete patient history, physical exam, chest radiography, and Tuberculin Skin Test or IGRA (Interferon Gamma Release Assay). This investigation is suggested when MS drugs (immunomodulatory and immunosuppressant medications) are prescribed. If a patient has positive results, the treatment for MS should not be delayed for the finishing TB treatment. In this paper, considering the high prevalence of tuberculosis, we recommend that TB screening should be also done at the moment of Multiple Sclerosis diagnosis.
Wed, 21 December 2016
CONCEPT PAPER | 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.
Sat, 19 September 2020
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: SARS-CoV-2; COVID-19; CNS; infant; Choroid plexus
Online: 19 September 2020 (04:49:18 CEST)
Coronavirus disease 2019 (COVID-19) was initially characterized as a respiratory illness. Neurological manifestations were reported mostly in severely affected patients. Routes for brain infection and the presence of virus particles in situ have not been well described, raising controversy about how the virus causes neurological symptoms. Here, we report the autopsy findings of a 1-year old infant with COVID-19. In addition to pneumonitis, meningitis and multiple organ damage related to thrombosis, a previous encephalopathy may have contributed to additional cerebral damage. SARS-CoV-2 infected the choroid plexus, ventricles, and cerebral cortex. This is the first evidence of SARS-CoV-2 detection in an infant post-mortem brain.
Tue, 6 July 2021
ARTICLE | doi:10.20944/preprints202107.0134.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Diffusion Magnetic Resonance Imaging; White Matter; Fractional anisotropy; Multi-centre; Reproducibility; Imaging artefacts; Ageing
Online: 6 July 2021 (11:29:06 CEST)
In clinical diagnostics and longitudinal studies, the reproducibility of MRI assessments is of high importance in order to detect pathological changes, but developments in MRI hard- and software often outrun extended periods of data acquisition and analysis. This could potentially introduce artefactual changes or masking pathological alterations. However, if and how changes of MRI hardware, scanning protocols or preprocessing software affect complex neuroimaging outcomes from e.g. diffusion weighted imaging (DWI) remains largely understudied. We therefore compared DWI outcomes and artefact severity of 121 healthy participants (age range 19-54 years) who underwent two matched DWI protocols (Siemens product and Center for Magnetic Resonance Research sequence) at two sites (Siemens 3T Magnetom Verio and Skyrafit). After differing preprocessing steps, 3D-fractional anisotropy (FA) maps obtained by tensor fitting were processed with tract-based spatial statistics (TBSS). Inter-scanner and inter-sequence variability of skeletonised FA values reached up to 5% and differed largely in magnitude and direction across the brain. Preprocessing including unringing reduced the Gibbs ringing artefact, and head motion estimates were significantly lower at Skyra. We here demonstrate that DTI outcome measures strongly depend on imaging site and software, and that these biases vary between brain regions. These regionally inhomogeneous biases may exceed and considerably confound physiological effects such as ageing, highlighting the need to harmonise data acquisition and analysis. Future studies thus need to implement novel strategies to augment neuroimaging data reliability and replicability.
Fri, 4 August 2017
ARTICLE | 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.
Fri, 7 June 2019
ARTICLE | 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 | 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.
Wed, 12 May 2021
ARTICLE | doi:10.20944/preprints202105.0267.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer’s disease; AD; blood-based biomarker; p53; unfolded p53; U-p53
Online: 12 May 2021 (11:21:18 CEST)
Background: Research continues to search for blood-based biomarkers sensitive to Alzheimer’s disease (AD) pathology during the initial stages when symptoms of cognitive decline are not yet apparent. A blood-based biomarker candidate is metalloprotein p53, the conformation of which was previously found to be altered in peripheral cells from individuals with mild cognitive impairment (MCI) and AD, presenting as an unfolded p53 (U-p53) conformational variant. Methods: Plasma samples from the well-characterized Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort were used to identify the clinically relevant AZ 284® peptide, specifically present in samples from individuals with symptomatic AD. The AZ 284® peptide, which is a marker of the U-p53 conformational variant (U-p53AZ), was identified by immunoprecipitation (IP) with a novel U-p53 conformational variant-specific antibody followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing. Using IP-LC surface-activated chemical ionization (SACI) MS/MS analysis, the prognostic and diagnostic performance of U-p53AZ were examined in the longitudinal AIBL cohort, including 252 plasma samples derived from 214 elderly individuals. For the prognostic analyses, U-p53AZ levels were assessed at 36, 72, and 90 months after baseline assessment. Results: The prognostic performance of U-p53AZ to predict the progression to AD from preclinical or prodromal AD was high, with area under the receiver operating characteristic curve (AUC) values close to or above 0.90. Furthermore, U-p53AZ predicted the progression to AD more than 6 years prior to symptom onset with positive and negative predictive values of about 90%. Additionally, the estimated prognostic performance of U-p53AZ was superior to other main risk factors (i.e., age, sex, and either alone or in combination with amyloid status. Furthermore, U-p53AZ had high diagnostic performance to differentiate cognitively normal individuals from those with AD (AUC values >0.88). Conclusion: These findings support the use of U-p53AZ as a prognostic blood-based biomarker accurately predicting the progression to AD dementia during the preclinical and prodromal stages at least 6 years before receiving the clinical diagnosis of AD dementia.
Mon, 9 September 2019
REVIEW | 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.
Mon, 1 April 2019
ARTICLE | 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.
Wed, 7 February 2018
ARTICLE | 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.
Mon, 2 April 2018
REVIEW | 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.
Wed, 31 July 2019
ARTICLE | 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.
Fri, 12 June 2020
REVIEW | doi:10.20944/preprints202006.0147.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: PSP; Progressive Supranuclear Palsy; 4R-tau; four-repeat tau; MAPT; Microtubule-associated ligand; PET; Positron Emission Tomography
Online: 12 June 2020 (09:41:06 CEST)
Progressive supranuclear palsy (PSP) is a sporadic parkinsonism tauopathy characterised by the deposition of aggregations of abnormal, hyperphosphorylated four-repeat tau (4R-tau). A revised clinical diagnostic criterion for PSP allows early presentations for the full spectrum of clinical phenotypes to be recognised enabling doctors to make a more accurate diagnosis. The major genetic risk factor for sporadic PSP is a common variant in the gene encoding microtubule-associated protein tau (MAPT). Research into the biochemical and pathological pathways of tau is vital to improve the chances of developing an effective diagnostic biomarker to monitor tau pathogenesis. Neuroimaging biomarkers, such as tau PET ligands, are proving the most successful tool in providing a differential diagnosis between neurodegenerative disorders. There are currently no effective treatments for PSP, however tau-directed therapies in the last five years have rapidly advanced. Latest tau therapies are proposed to have disease-modifying effects by reducing toxic aggregations of tau through manipulating tau gene expression. After encouraging results from long awaited trials, additional funding is being injected into this field and with new results expected, this proves an exciting area for scientific discovery. This paper reviews advances in pathophysiology, diagnosis, biomarkers and disease-modifying therapeutic treatments for PSP.
Mon, 26 February 2018
ARTICLE | 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.
Tue, 3 April 2018
ARTICLE | 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
Tue, 24 September 2019
REVIEW | 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.
Thu, 3 May 2018
ARTICLE | 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.
Tue, 18 December 2018
ARTICLE | 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.
Fri, 27 September 2019
ARTICLE | 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, 16 June 2020
REVIEW | doi:10.20944/preprints202006.0198.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: loss of taste and smell; dysgeusia; anosmia; chemosensory dysfunction; SARS-CoV-2; COVID-19
Online: 16 June 2020 (07:46:15 CEST)
Early detection, isolation, and management of COVID-19 patients are crucial to contain the current pandemic. The CDC in USA recently included "sudden loss of taste (dysgeusia/ageusia) and smell (anosmia/hyposmia)” as symptoms of COVID-19. If these symptoms are reliable forerunner symptoms of COVID-19, then it may facilitate early detection and containment of the disease. Hence, we systematically evaluated the contemporary evidence on dysgeusia and anosmia as trigger symptoms in COVID-19. Ovid MEDLINE, EBSCO host, and Web of Science databases were searched between December 25, 2019-May 30, 2020.Of the 13 identified records, eight (totaling 11,054 COVID-19 patients), were included, as per the selection criteria. The studies emanated mostly from the European community, as well as China, the USA, and Iran. In total, anosmia and dysgeusia symptoms were present in 74.9 % and 81.3% ambulatory as well as hospitalized, mild-to-severe cases of COVID-19 patients, respectively. The European, US, and Iran data indicate that olfactory, and gustatory symptoms appear prior to general COVID-19 symptoms in a majority of the patients. To our knowledge, this is the first systematic review analyzing the prevalence of chemosensory dysfunction in COVID-19. Further, studies are essential to evaluate their utility as harbingers of COVID-19 onset, and to establish clinical practice guidelines.
Fri, 13 November 2020
REVIEW | doi:10.20944/preprints202011.0396.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: neurodegenerative disease; Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; Huntington’s disease; multiple sclerosis; tryptophan; kynurenines; biomarkers; personalized medicine
Online: 13 November 2020 (20:57:22 CET)
Neurodegenerative diseases are multifactorial, initiated by a series of the causative complex which develops into a certain clinical picture. The pathogenesis and disease course vary from patient to patient. Thus, it should be likewise to the treatment. Peripheral biomarkers are to play a central role for tailoring a personalized therapeutic plan for patients who suffered from neurodegenerative diseases such as Alzheimer’s diseases, Parkinson’s disease, and multiple sclerosis, among others. Nevertheless, the use of biomarkers in clinical practice is still underappreciated and data presented in biomarker research for clinical use is still uncompelling, compared to abundant data available for drug research and development. So is the case with kynurenines (KYNs) and the kynurenine pathway (KP) enzymes which have been associated with a wide range of diseases including cancer, autoimmune diseases, inflammatory diseases, neurologic diseases, and psychiatric disorders. This review article discusses current knowledge of the KP alteration observed in the central nervous system as well as the periphery, its involvement in pathogenesis and disease progression, and emerging evidence of roles of microbiota to the gut-brain axis, searching for practical peripheral biomarkers which ensure personalized treatment plans for neurodegenerative diseases.
Mon, 15 March 2021
REVIEW | doi:10.20944/preprints202103.0365.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Real-time MR imaging; CSF; cilia sensing; aquaporin; nitric oxide; amyloid-ß; glymphatic system; hydrocephalus
Online: 15 March 2021 (10:36:20 CET)
With the advent of real-time MRI, the motion and passage of cerebrospinal fluid can be visualized without gating and exclusion of low-frequency waves. This imaging modality gives insights into low-volume, rapidly oscillating cardiac-driven movement as well as sustained, high-volume, slowly oscillating inspiration-driven movement.Inspiration means a spontaneous or artificial increase in the intrathoracic dimensions independent of body position. Alterations in thoracic diameter enable the thoracic and spinal epidural venous compartments to be emptied and filled, producing an upward surge of cerebrospinal fluid inside the spine during inspiration; this surge counterbalances the downward pooling of venous blood toward the heart.Real-time MRI, as a macroscale in vivo observation method, could expand our knowledge of neurofluid dynamics, including how astrocytic fluid preloading is adjusted and how brain buoyancy and turgor are maintained in different postures and zero gravity.Along with these macroscale findings, new microscale insights into aquaporin-mediated fluid transfer, its sensing by cilia and its tuning by nitric oxide will be reviewed. By incorporating clinical knowledge spanning several disciplines, certain disorders—congenital hydrocephalus with Chiari malformation, idiopathic intracranial hypertension and adult idiopathic hydrocephalus—are interpreted and reviewed according to current concepts, from the basics of the interrelated systems to their pathology.
Sun, 20 September 2020
ARTICLE | doi:10.20944/preprints202009.0470.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: kynurenines; tryptophan; indoleamine 2,3-dioxygenase; single nucleotide polymorphisms; Parkinson’s diseases; neurodegenerative diseases
Online: 20 September 2020 (14:27:12 CEST)
Earlier studies reported alterations of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism in Parkinson’s disease (PD). The first rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase were observed upregulated, resulting elevated KYN/TRP ratios in the serum and cerebrospinal fluid samples of patients with PD. An increasing number of single nucleotide polymorphisms (SNPs) have been identified in a population of PD. However, little is known if genetic variations of the IDO contribute to disturbance of the KYN metabolism in and the pathogenesis of PD. SNP analysis of IDO1 was performed by allelic discrimination assay with fluorescently labelled TaqMan probes and a subgroup analysis was conducted according to the age of PD onset. The frame shifts variant rs34155785, intronic variant rs7820268, and promotor region variant rs9657182 SNPs of 105 PD patients without comorbidity were analyzed and compared to 129 healthy controls. No significant correlation was found in three SNPs between PD patients and healthy controls. However, the subgroup analysis revealed that A alleles of rs7820268 SNP or rs9657182 SNP carriers contribute to later onset of PD than non-carriers. The study suggested that SNPs of IDO1 influenced the age onset of PD and genotyping of SNPs in certain alleles potentially serves as a risk biomarker of PD.
Mon, 14 September 2020
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Parkinson’s disease; precision medicine; personalized medicine; GBA; Glucocerebrosidase; GCase; LRRK2; Leucine-rich repeat kinase-2; Dopamine; PD drug trials; PD risk variants
Online: 14 September 2020 (00:22:59 CEST)
Parkinson’s disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove “precise“ or “personalized“ enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.
Sun, 7 June 2020
REVIEW | doi:10.20944/preprints202006.0074.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: COVID-19; myasthenia gravis; respiratory management
Online: 7 June 2020 (09:28:09 CEST)
The outbreak of COVID-19 has brought unprecedented risks and challenges to everyone in the world. Myasthenia gravis is an autoimmune disease of the nervous system. Infection can worsen it and cause severe symptoms such as myasthenia crisis and respiratory failure. At present, the pandemic of COVID-19 may promote the aggravation of patients with MG. This article focuses on the respiratory management of MG patients during the epidemic of COVID-19.
Mon, 24 December 2018
REVIEW | 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.
Thu, 28 June 2018
REVIEW | 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.
Mon, 1 October 2018
REVIEW | 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.
Thu, 26 March 2020
ARTICLE | doi:10.20944/preprints202003.0389.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Parkinson’s disease; physical activity; sedentary way; non-motor symptoms; apathy; dopaminergic therapy
Online: 26 March 2020 (14:15:49 CET)
Physical activity (PA) is a factor that may have an influence on the symptoms of Parkinson’s disease (PD). The aim of this study was to identify the potential determinants of spontaneous PA in the PD patient group. 134 PD patients aged 65.2±9.2 years, Hoehn-Yahr scale ≤ 4, Mini Mental State Examinaton (MMSE) ≥ 24 were examined. For the study purposes, the authors analyzed: age, sex, education, history of PD, dopaminergic treatment, the severity of PD symptoms using Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn-Yahr scale. Additionally all participants were evaluated through a set of scales for specific neuropsychiatric symptoms including: depression, anxiety, apathy, fatigue and sleep disorders. An analysis of linear regression was used with backward elimination. In the total explanatory model, 12% of the variability in activity (R2=0.125; F(16.133)=2.185; p<0.01), the significant predictor was starting therapy with the dopamine agonist (DA) (β= 0.420; t= 4.068; p=0.000), which was associated with a longer duration of moderate PA. In the total explanatory model, for more than 13% of the variance in time spent sitting (R2=0.135; F(16.130)=2.267; p<0.01), the significant predictors were secondary education and the results of the UPDRS. The patients with secondary and vocational education, those starting treatment with DA and those with a less severe degree of Parkinson’s symptoms (UPDRS) spent less time sitting in a day. It is possible to identify determinants of spontaneous PA. It may elucidate consequences in terms of influence on modifiable conditions of PA and the proper approach to patients with unmodifiable PA factors.
Thu, 1 July 2021
ARTICLE | doi:10.20944/preprints202107.0014.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: EEG; music therapy; acoustic features; machine learning; emotional-response predictions
Online: 1 July 2021 (11:12:19 CEST)
Music has the ability to evoke a wide variety of emotions in human listeners. Research has shown that treatment for depression and mental health disorders is significantly more effective when it is complemented by music therapy. However, because each human experiences music-induced emotions differently, there is no systematic way to accurately predict how people will respond to different types of music at an individual level. In this experiment, a model is created to predict humans’ emotional responses to music from both their electroencephalographic data (EEG) and the acoustic features of the music. By using recursive feature elimination (RFE) to extract the most relevant and performing features from the EEG and music, a regression model is fit and accurately correlates the patient’s actual music-induced emotional responses and model’s predicted responses. By reaching a mean correlation of r = 0.788, this model is significantly more accurate than previous works attempting to predict music-induced emotions (e.g. a 370% increase in accuracy as compared to Daly et al. (2015)). The results of this regression fit suggest that accurately predicting how people respond to music from brain activity is possible. Furthermore, by testing this model on specific features extracted from any musical clip, music that is most likely to evoke a happier and pleasant emotional state in an individual can be determined. This may allow music therapy practitioners, as well as music-listeners more broadly, to select music that will improve mood and mental health.
Mon, 16 April 2018
ARTICLE | 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, 7 September 2021
COMMUNICATION | doi:10.20944/preprints202109.0133.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: cerebrospinal fluid; alpha-synuclein; skin biopsy; seeded aggregation assays; tau, amyloid; Lewy body dementia
Online: 7 September 2021 (16:26:51 CEST)
The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy Body Dementia (LBD), which includes Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer pathology as well as novel biomarkers were discussed.
Tue, 30 October 2018
ARTICLE | 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.
Fri, 16 August 2019
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, 11 July 2018
ARTICLE | 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, 6 December 2018
ARTICLE | 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.
Fri, 19 April 2019
ARTICLE | 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 | 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.
Wed, 12 December 2018
REVIEW | 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.
Wed, 24 July 2019
REVIEW | 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).
Mon, 1 October 2018
REVIEW | 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.
Mon, 22 March 2021
ARTICLE | doi:10.20944/preprints202103.0542.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Smartwatches, Artificial Intelligence, Movement Disorders, Parkinson’s Disease
Online: 22 March 2021 (15:37:13 CET)
Smartwatches provide technology-based assessments in Parkinson’s disease (PD). We present results for sensor validation and disease classification via Machine Learning (ML). A comparison setup was designed with two different series of Apple smartwatches, one Nanometrics seismometer and a high-precision shaker to measure tremor-like amplitudes and frequencies. Clinical smartwatch measurements were acquired from a prospective study including 450 participants with PD, differential diagnoses (DD) and healthy participants. All participants wore two smartwatches and within a 15-min examination. Symptoms and medical history were captured on the paired smartphone. A broad range of different ML classifiers were cross-validated. Amplitude and frequency differences between smartwatches and the seismometer were under the level of clinical significance. The most advanced task of distinguishing PD vs DD was evaluated with 74,1% balanced accuracy, 86,5% precision and 90,5% recall by Multilayer Perceptrons. Deep Learning architectures significantly underperformed in all classification tasks. Smartwatches are capable of capturing subtle-tremor signs with low noise. This study provided the largest PD sample size of two-hand smartwatch measurements and our preliminary ML-evaluation shows that such a system provides powerful means for diagnosis classification and new digital biomarkers but it remains challenging for distinguishing similar disorders.
Sat, 23 May 2020
REVIEW | doi:10.20944/preprints202005.0378.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: intestinal flora; myasthenia gravis; research progress; autoimmune disease; EAMG
Online: 23 May 2020 (16:40:23 CEST)
Human intestinal flora refers to a large and diverse microbial population present in the digestive tract of the human body, which plays a significant role in the establishment of human immune homeostasis and the normal function of the immune system. Myasthenia Gravis is an autoimmune disease of the neuromuscular junction, mainly involved in the anti-acetylcholine receptor antibody, cellular immune dependence, and complement1. At present, studies have found that the intestinal flora of Myasthenia Gravis is different from that of healthy people. Probiotic therapy has been shown effective in the experimental autoimmune Myasthenia Gravis animal models. This article reviews the relationship between intestinal flora and Myasthenia Gravis, to provide new ideas for further study of the pathogenesis and clinical treatment of Myasthenia Gravis.
Thu, 23 August 2018
ARTICLE | 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.
Fri, 29 January 2021
REVIEW | doi:10.20944/preprints202101.0625.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer’s disease; dementia, beta-amyloid; germ theory; drug development; clinical trials; herpes; spirochetes; Chlamydia pneumoniae; Porphyromonas gingivalis; toxoplasma; mycobacteria
Online: 29 January 2021 (13:57:18 CET)
There is now considerable evidence that several infectious agents (viruses, bacteria, or parasites) may play a contributing role in the development of Alzheimer’s disease (AD). The six primary suspects are herpes viruses, spirochetal bacteria, Chlamydia pneumoniae, Porphyromonas gingivalis, mycobacteria, and toxoplasma parasites. Also, some of the antimicrobial and antiviral agents that are used to treat them have shown promise for AD interventions. I describe this evidence and assert it is now time to accelerate clinical trials of these existing drugs, already federally approved, to determine if such treatments can delay, halt, or reverse AD.
Fri, 11 September 2020
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: COVID-19; SARS-CoV-2; hepatic encephalopathy; CIGB-258
Online: 11 September 2020 (05:49:43 CEST)
Hepatic encephalopathy is a complex life-threatening neuropsychiatric syndrome, which can be associated with acute inflammation. It can be found in cases of acute liver failure caused by a viral infection. Reports of patients infected with SARS-CoV-2 have described hepatic encephalopathy. Therapy with immunomodulators can be an effective choice for this clinical condition. CIGB-258 is an immunomodulatory peptide with anti-inflammatory properties derived from cellular stress protein 60 (HSP60). We report a case of a 55-years-old woman diagnosed with COVID-19 and hepatic encephalopathy characterized by episodes of anxiety, delirium, confusion and seizure, according to her clinical history, laboratory and radiological data. Levels of aspartate aminotransferase, alanine aminotransferase , plasma ammonia and alkaline phosphatase were increased and inflammatory biomarkers such as interleukin 6 and 10 were over the normal range. The patient received an intravenous administration of 1 mg of CIGB-258, every 12 hours during four days, followed by 1 mg daily for another three days without adverse reactions. Neurological symptoms disappeared completely at by the fourth days after starting therapy, and inflammatory biomarkers noticeably decreased, but not all of them reach the normal values. This case highlights the outcomes of a severe COVID-19 patient with hepatic encephalopathy, treated with CIGB-258. The patient recovered successfully and the liver enzymes, plasma ammonia and biomarkers associated with hyperinflammation were reduced. These results support clinical investigations of CIGB-258 as a therapeutic agent in COVID-19.TRIAL REGISTRATION: RPCEC00000313
Mon, 14 December 2020
REVIEW | doi:10.20944/preprints202012.0322.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Cerebrospinal fluid; real-time MRI; hydrocephalus; space flight disease; aquaporin; spontaneous intracranial hypotension; neural tube defect
Online: 14 December 2020 (10:21:21 CET)
New experimental and clinical findings question the historic view of hydrocephalus and its 100-year-old classification. In particular, real-time MRI evaluation of CSF flow and detailed insights into brain water regulation on the molecular scale indicate the existence of at least three main mechanisms that determine the dynamics of neurofluids. (i) Inspiration is a major driving force (ii) Adequate filling of brain ventricles by balanced cerebrospinal fluid upsurge is sensed by cilia (iii) The perivascular glial network connects the ependymal surface to the pericapillary Virchow-Robin spaces. Hitherto, these aspects have not been considered a common physiologic framework improving knowledge and therapy for severe disorders of normal-pressure and post-haemorrhagic hydrocephalus, spontaneous intracranial hypotension and spaceflight disease.
Fri, 13 August 2021
COMMUNICATION | doi:10.20944/preprints202108.0302.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: stroke; liposome; cerebrovascular disease; oxidative stress; dementia
Online: 13 August 2021 (15:37:59 CEST)
Neuroprotective strategies for stroke remain inadequate. Nanoliposomes comprised of phos-phatidylcholine, cholesterol and monosialogangliosides (NL) induced an antioxidant protective response in endothelial cells exposed to amyloid insults. We tested the hypotheses that NL will preserve SH-SY5Y neuroblastoma cell viability following hypoxic injury and will reduce injury in mice following middle cerebral artery occlusion (MCAO). Neuroblastoma were exposed to 20-hour physoxic (5% oxygen) or hypoxic (1% oxygen) condition without or with NL (100 or 300 µg/mL). Viability was measured using calcein-AM fluorescence and SH-SY5Y gene expression of antioxidant proteins heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and superoxide dismutase 1 (SOD1) were measured by quantitative polymerase chain reaction. C57BL/6J mice were treated with saline (N=8) or NL (10000 ug/mL, N=7) while undergoing 60-minute MCAO followed by reperfusion. Day 2 post-injury neurologic impairment score and infarction size were compared. Neuroblastoma showed reduced viability following hypoxia that was reversed by NL. NL increased gene expression of HO-1, NQO1 and SOD1 versus controls. NL-treated mice showed reduced neurologic impairment and brain infarct size (18.8±2% versus 27.3±2.3%, p=0.017) versus controls. NL reduced stroke injury in mice subjected to MCAO likely through induction of an antioxidant stress response. NL is a candidate novel agent for stroke.
Fri, 6 August 2021
ARTICLE | doi:10.20944/preprints202108.0162.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: vertigo; migraine; cytokines; inflammation; vestibular disorders; hearing loss
Online: 6 August 2021 (12:29:43 CEST)
Background: Meniere disease (MD) is an inner ear disorder associated with comorbidities such as autoimmune diseases or migraine. This study describes clinical and cytokine profile in MD according to the age of onset of the condition. Methods: A cross-sectional study including 83 MD patients: 44 with early onset MD (EOMD, <35 years old), and 39 with late onset MD (LOMD, > 50 years old), 64 patients with migraine and 55 controls was carried out. Clinical variables and cytokines levels of CCL3, CCL4, CCL18, CCL22, CXCL1 and IL-1β were compared among the different groups. Results: CCL18 levels were higher in patients with migraine or MD than in controls. Elevated levels of IL-1β were observed in 11.4% EOMD and in 10.3% LOMD patients and these levels were not dependent on the age of individuals. EOMD had a longer duration of the disease (p=0.004) and a higher prevalence of migraine than LOMD (p=0.045). Conclusions: Patients with EOMD have a higher prevalence of migraine than LOMD, but migraine is not associated with any cytokine profile in patients with MD. The levels of CCL18, CCL3 and CXCL4 were different between patients with MD or migraine and controls.
Mon, 23 August 2021
HYPOTHESIS | doi:10.20944/preprints202108.0454.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer’s disease; DNA damage; somatic mutation; integrin; synaptic adhesion
Online: 23 August 2021 (14:34:00 CEST)
Alzheimer’s disease (AD) is a genetically complex senile neurodegeneration with unknown etiology. The first gene discovered to be mutated in early-onset AD, the amyloid precursor protein (APP), has been widely assumed as a causal factor in the disease cascade due to its generation of Aβ species. APP has an evolutionarily conserved biological role and activates a signaling program with notable similarities to integrin—a cell adhesion receptor with a wide array of functions. Intriguingly, several AD genome-wide association study (GWAS) candidate genes, including the SHARPIN locus recently reported by us and others, influence signaling of the integrin pathway. Integrins are focal adhesion regulators and serve in nervous system development, synaptic plasticity, and Tau phosphorylation. These observations suggest that the function of APP probably goes beyond Aβ generation in AD. Aging—the strongest risk factor for AD—is associated with various clock-like events in cells. For instance, neurons are continuously impacted by stochastic ‘hits’ to their genomes in aging, in the forms of DNA damage, insertion-deletions, copy-number variations (CNVs) and other types of somatic mutations. DNA damage and somatic mutations can result in neoplastic changes and cancer in mitotically active cells. However, their consequences in post-mitotic cells such as aging neurons are less defined. The current hypothesis holds that the stochastic loss of DNA sequence data at random loci in aging affects longer genes by chance more frequently. As a result, the biological processes coordinated by long genes may be more vulnerable to such random aging effects. Curiously, as shown by us and others, long genes are strongly enriched for synapse- and cell adhesion-related ontologies, more than any other biological process or cellular compartment. In addition, among various cell types, neurons possess the highest levels of long gene expression and are therefore more vulnerable to such harmful effects. The long gene vulnerability hypothesis provides a simple link between aging and the genetic landscape of AD and warrants new strategies for disease modification.
Mon, 28 December 2020
ARTICLE | doi:10.20944/preprints202012.0705.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Rituximab; Multiple Sclerosis; Neuromyelitis Optica; demyelinating diseases
Online: 28 December 2020 (13:22:04 CET)
Background: Rituximab is a monoclonal antibody widely used in the treatment of inflammatory and autoimmune disorders. Despite reports of its effectiveness in the treatment of demyelinating diseases of central nervous system (DDCNS), it is not yet approved for use in these disorders. The aim of this study was to investigate the effectiveness and safety of low dose rituximab in three different subgroups of DDCNS including relapsing-remitting multiple sclerosis (RRMS), secondary-progressive multiple sclerosis (SPMS) and neuromyelitis-optica-spectrum disorders (NMOSD).Methods: In a prospective cohort study, we monitored expanded-disability-status-scale (EDSS), relapses (new attacks) and serum-IgG levels to assess effectiveness and drug-adverse-events for safety in patients with RRMS, SPMS and NMOSD. These patients were candidates to receive rituximab according to our common practice protocol. We switched patients to rituximab if there was poor response to first line therapies. We follow a low dose protocol in our center (500 mg twice, two weeks apart, repeating every six months) and these patients treated in a 4-year period were assessed retrospectively for evaluation of our protocol’s safety and effectiveness. Results: 99 patients (42 RRMS, 43 SPMS and 14 NMOSD) received rituximab for a range of 12 to 40 months period. New attacks occurred in 8 RRMS (19%), 10 SPMS (23%) and 1 NMOSD (7%) patients. EDSS decreased in RRMS and NMOSD cases. Serum-IgG levels decremented in SPMS and NMOSD patients. Drug-adverse-events happened in two cases.Conclusion: In this study, low dose rituximab showed substantial effectiveness in preventing disease progression with a considerably good safety profile.
Thu, 2 September 2021
ARTICLE | doi:10.20944/preprints202109.0043.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: aphasia; acute ischemic stroke; length of stay; mRS; NIHSS
Online: 2 September 2021 (14:39:03 CEST)
We aimed to reveal the disease burden of aphasia after acute ischemic stroke (AIS) at the national level and investigate the impact of aphasia on tertiary care resources and patient outcomes. The local database from the Cluj-Napoca Emergency County Hospital (CNECH), the second largest stroke center in Romania was used to export demographics, baseline clinical and laboratory data, inpatient length of stay (LOS), NIH Stroke Scale (NIHSS), and discharge modified Rankin Scale (mRS) score data for all AIS patients admitted during March 2019. Of 92 patients included in the study, 30 (32.6 %) had aphasia on admission. In a marginally significant unadjusted hierarchical multiple regression model, individuals with aphasia had a LOS of 1.86 days longer than stroke survivors without aphasia. In an adjusted version of the model, the NIHSS score at baseline was a significant predictor for LOS. In addition, the presence of aphasia was associated with a 1.49 increase in the mean mRS score. Aphasia was a marginally significant predictor for increased LOS. Presence of aphasia was more likely to produce a poor functional outcome. Considering an estimated impact of approximately EUR 3 million on direct medical expenditure annually, future policymaking efforts should improve prevention of stroke and improved access to post-stroke aphasia care in Romania.
Mon, 12 April 2021
BRIEF REPORT | doi:10.20944/preprints202104.0312.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Tinzaparin; African swine fever; heparin shortage; fraxiparin; neurosurgery; perioperative anticoagulation
Online: 12 April 2021 (14:06:07 CEST)
Background An outbreak of African swine fever (ASF) in China in 2020 has led to an unprecedented shortage of fraxiparin. Most patients, especially those kept in hospital for surgery, are currently treated with prophylactic anticoagulation (AC). In search of alternatives for fraxiparin, we found no sufficient data on alternatives for neurosurgical patients, such as tinzaparin of European origin. We compared fraxiparin and tinzaparin concerning adverse events (bleeding versus thromboembolic events) in neurosurgical patients. Methods Between 2012 and 2018, 517 neurosurgical patients with benign and malignant brain tumors as well as 297 patients with subarachnoid hemorrhage (SAH) were treated in the Department of Neurosurgery, University Hospital Leipzig receiving prophylactic anticoagulation within 48 hours. In 2015, prophylactic anticoagulation was switched from fraxiparin to tinzaparin throughout the university hospital. In a retrospective manner, the frequency and occurrence of adverse events (rebleeding and thromboembolic events) in connection with the substance used was analyzed. Statistical analysis was performed using Fisher’s exact test and the chi-squared test. Results Rebleeding rates were similar in both fraxiparin and tinzaparin cohorts in patients being treated for meningioma, glioma, and SAH combined (8.8 vs 10.3%). Accordingly, the rates of overall thromboembolic events were not significantly different (5.5% vs 4.3%). The severity of rebleeding did not vary. There was no significant difference among subgroups when compared for deep vein thrombosis (DVT) or pulmonary embolism (PE). Conclusion In this retrospective study, tinzaparin seems to be a safe alternative to fraxiparin for AC in patients undergoing brain tumor surgery or suffering from SAH.
Sun, 19 April 2020
REVIEW | doi:10.20944/preprints202004.0314.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Multiple Sclerosis; HERV; MSRV; Epstein Barr Virus
Online: 19 April 2020 (02:36:17 CEST)
Multiple Sclerosis (MS) has a well established link with Epstein-Barr virus (EBV) and a growing association with human endogenous retroviruses (HERVs). In this review, we described how these two pieces may interact in MS pathogenesis
Wed, 19 August 2020
CASE REPORT | doi:10.20944/preprints202008.0404.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: neurobrucellosis; gait disturbance; flaccid paraprasia; weakness
Online: 19 August 2020 (08:41:47 CEST)
Brucellosis is a multi-system infectious disease that exhibits with various manifestations and complications. Neurobrucellosis is a rare but serious presentation of brucellosis that can be discovered in every stages of the disease. Laboratory tests and physical examination and patient history are generally the basis for diagnosing the disease. It has both insidious and prolonged clinical course of the disease and long-term therapies. Also the most common pattern of exhibition is subacute or chronic. We reported a case of young female who had history of painless weakness in the right lower limb (proximal and distal) that started gradually and had progressed over the time, and after a month she felt weakness in the left lower limb with the same pattern. Lumbosacral Magnetic resonance imaging (MRI) with and without contrast was shown evidence of enhancement thickening of caudal equina ventral roots. Brucella antigen titer was positive, the result was 1/160. And other clinical tests were normal. Patient treated with Intravenous injection (IV) Rifampicin and Intravenous Cotrimoxazole. patient was discharged with good health and continuinng all two medications for 5 months. The descision was taken to report this case as a result of entire respond in patient’s illness after a enduring disease. Neurobrucellosis is a treatable disease in which it would be better to consider a high indication of suspicion. Due to if ignored, it may cause significant morbidity and mortality.
Mon, 31 August 2020
REVIEW | doi:10.20944/preprints202007.0737.v2
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: oxidative stress; redox; antioxidant; multiple sclerosis; biomarker; neurodegenerative disease; personalized medicine
Online: 31 August 2020 (04:01:49 CEST)
Worldwide, over 2.2 million people are suffered from multiple sclerosis (MS), a multifactorial demyelinating disease of the central nervous system. MS is characterized by multifocal inflammatory or demyelinating attacks associated with neuroinflammation and neurodegeneration. The blood, cerebrospinal fluid, and postmortem brain samples of MS patients evidenced the disturbance of reduction-oxidation (redox) homeostasis such as the alterations of oxidative and antioxidative enzyme activities and the presence of degradation products. This review article discussed the components of redox homeostasis including reactive chemical species, oxidative enzymes, antioxidative enzymes, and degradation products. The reactive chemical species covered frequently discussed reactive oxygen/nitrogen species, infrequently featured reactive chemicals such as sulfur, carbonyl, halogen, selenium, and nucleophilic species that potentially act as reductive as well as pro-oxidative stressors. The antioxidative enzyme systems covered the nuclear factor erythroid-2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) signaling pathway. The NRF2 and other transcriptional factors potentially become a biomarker sensitive to the initial phase of oxidative stress. Altered components of the redox homeostasis in MS were discussed in search of a diagnostic, prognostic, predictive, and/or therapeutic biomarker. Finally, monitoring a battery of reactive chemical species, oxidative enzymes, antioxidative enzymes and degradation products helps evaluate the redox status of MS patients, expediting prolongation of remission, prevention of relapse, and thus building personalized treatment plans.
Tue, 15 December 2020
ARTICLE | doi:10.20944/preprints202012.0373.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Intensity standardisation; FSL-SIENA; longitudinal atrophy quantification; brain magnetic resonance imaging
Online: 15 December 2020 (11:03:11 CET)
Atrophy quantification is fundamental for understanding brain development and diagnosing and monitoring brain diseases. FSL-SIENA is a well-known fully-automated method that has been widely used in brain magnetic resonance imaging studies. However, intensity variations arising during image acquisition that may compromise evaluation, analysis and even diagnosis. In this work, we study whether intensity standardisation can improve longitudinal atrophy quantification. We considered seven methods comprising z-score, fuzzy c-means, Gaussian mixture model, kernel density, histogram matching, white stripe, and removal of artificial voxel effects by linear regression (RAVEL). We used a total of 330 scans from two publicly-available datasets, ADNI and OASIS. In scan-rescan assessments, that measures robustness to subtle imaging variations, intensity standardisation did not compromise the robustness of FSL-SIENA significantly (p>0.1). In power analysis assessments, that measures the ability to discern between two groups of subjects, three methods led to consistent improvements in both datasets with respect to the original: fuzzy c-means, Gaussian mixture model, and kernel density estimation. Reduction in sample size using these three methods ranged from 17% to 95%. The performance of the other four methods was affected by spatial normalisation, skull stripping errors, presence of periventricular white matter hyperintensities, or tissue proportion variations over time. Our work evinces the relevance of appropriate intensity standardisation in longitudinal cerebral atrophy assessments using FSL-SIENA.
Mon, 27 May 2019
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.
Fri, 4 June 2021
ARTICLE | doi:10.20944/preprints202010.0172.v2
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: kynurenines; tryptophan; indoleamine 2,3-dioxygenase; single nucleotide polymorphisms; Parkinson’s diseases; neurodegenerative diseases
Online: 4 June 2021 (09:41:35 CEST)
Aims Earlier studies reported alterations of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism in Parkinson’s disease (PD). The first rate-limiting enzymes indoleamine 2,3- dioxygenase (IDO) and tryptophan dioxygenase were observed upregulated, resulting elevated KYN/TRP ratios in the serum and cerebrospinal fluid samples of patients with PD. An increasing number of single nucleotide polymorphisms (SNPs) has been identified in a population of PD. However, little is known if genetic variations of the IDO contribute to disturbance of the KYN metabolism in and the pathogenesis of PD. Main methods SNP analysis of IDO1 was performed by allelic discrimination assay with fluorescently labelled TaqMan probes and a subgroup analysis was conducted according to the age of PD onset. The frame shifts variant rs34155785, intronic variant rs7820268, and promotor region variant rs9657182 SNPs of 105 PD patients without comorbidity were analyzed and compared to 129 healthy controls. Key findings No significant correlation was found in three SNPs between PD patients and healthy controls. However, the subgroup analysis revealed that A alleles of rs7820268 SNP or rs9657182 SNP carriers contribute to later onset of PD than non-carriers. Significance The study suggested that SNPs of IDO1 influenced the age onset of PD and genotyping of SNPs in certain alleles potentially serves as a risk biomarker of PD.
Mon, 6 September 2021
ARTICLE | doi:10.20944/preprints202107.0134.v2
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Diffusion Magnetic Resonance Imaging; White Matter; Fractional anisotropy; Multi-centre; Reproducibility; Imaging artefacts; Ageing
Online: 6 September 2021 (13:20:18 CEST)
In clinical diagnostics and longitudinal studies, the reproducibility of MRI assessments is of high importance in order to detect pathological changes, but developments in MRI hard- and software often outrun extended periods of data acquisition and analysis. This could potentially introduce artefactual changes or mask pathological alterations. However, if and how changes of MRI hardware, scanning protocols or preprocessing software affect complex neuroimaging outcomes from e.g. diffusion weighted imaging (DWI) remains largely understudied. We therefore compared DWI outcomes and artefact severity of 121 healthy participants (age range 19-54 years) who underwent two matched DWI protocols (Siemens product and Center for Magnetic Resonance Research sequence) at two sites (Siemens 3T Magnetom Verio and Skyrafit). After different preprocessing steps, fractional anisotropy (FA) and mean diffusivity (MD) maps,obtained by tensor fitting, were processed with tract-based spatial statistics (TBSS). Inter-scanner and inter-sequence variability of skeletonised FA values reached up to 5% and differed largely in magnitude and direction across the brain. Skeletonised MD values differed up to 14% between scanners. We here demonstrate that DTI outcome measures strongly depend on imaging site and software, and that these biases vary between brain regions. These regionally inhomogeneous biases may exceed and considerably confound physiological effects such as ageing, highlighting the need to harmonise data acquisition and analysis. Future studies thus need to implement novel strategies to augment neuroimaging data reliability and replicability.
Wed, 18 August 2021
ARTICLE | doi:10.20944/preprints202108.0376.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Migraine; Headache; Irritable Bowel Syndrome; Chronic Pain; Saudi Arabia
Online: 18 August 2021 (11:21:40 CEST)
Migraine is a primary headache disorder with a prevalence of 11.6% globally and 27% in Saudi Arabia. Irritable bowel syndrome has a prevalence of 9.2% worldwide. The prevalence of IBS has not been established nationally. However, provincial studies for both migraine and IBS have been conducted across the nation. There is a significant link between migraines and IBS globally. This identifies an association that needs to be investigated in a nationwide manner. This study aims to observe the association and the relationship between migraine and irritable bowel syndrome in Saudi Arabia. A cross-sectional study was conducted between March 2021 to June 2021 among the general population of Saudi Arabia, whose ages are 15 years old or greater. The data collection tools included MS-Q for migraine symptoms, MIGSEV scale for severity of migraine, and The IBS module of the Rome IV Diagnostic Questionnaire (R4DQ) for IBS symptoms and its subtype. With a total of 2802 participants, the majority of the study sample were males, who constituted 52.5%. Among the study's sample, the prevalence of migraine consisted of 27.4%, and the prevalence of IBS was 16.4%. The odds of having IBS in migraineurs were much higher than in those without migraines (OR 4.127; 95% CI 3.325-5.121), and the association was statistically significant (P<0.001). In conclusion, there is a strong association between migraine and irritable bowel syndrome in Saudi Arabia.
Mon, 10 May 2021
ARTICLE | doi:10.20944/preprints202105.0167.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Heart arrest; optic nerve sheath diameter; Patient outcome assessment
Online: 10 May 2021 (10:51:42 CEST)
Optic nerve sheath diameter (ONSD) can help predict the neurologic outcome of patients with post-cardiac arrest (CA) return of spontaneous circulation (ROSC). We aimed to investigate the effect of ONSD changes before and after CA on neurologic outcomes in patients with ROSC after CA using brain computed tomography (CT). The study included patients hospitalized after CA, who had undergone pre- and post-CA brain CT from January 2001 to September 2020. The patients were divided into good and poor neurologic outcome (GNO and PNO, respectively) groups based on the neurologic outcome at hospital discharge. We performed between-group comparisons of the amount and rate of ONSD changes on brain CT and calculated the area under the curve (AUC) to determine their predictive value for neurologic outcomes. Among the 96 enrolled patients, 25 had GNO. Compared to the GNO group, the PNO group showed significantly higher amount (0.30 vs. 0.63 mm; p=0.030) and rate of change (5.26 vs. 12.29 %; p=0.041). The AUC for predicting PNO was 0.64 (95% CI=0.53–0.73; p=0.04) and patients with a rate of ONSD change >27.2% had PNO with 100% specificity and positive predictive value. Hence, ONSD changes may predict neurologic outcomes in patients with post-CA ROSC.
Tue, 29 June 2021
ARTICLE | doi:10.20944/preprints202106.0716.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: intracranial compliance; intracranial pressure; decompressive craniectomy; acute brain damage
Online: 29 June 2021 (23:58:09 CEST)
Background: Morphological alterations in intracranial pressure pulse waveform (ICPPW) secondary to intracranial hypertension (ICP >20 mmHg) and reduction in intracranial compliance (ICC) are well known indicators of neurological severity. To date, no studies have documented the ICPPW modifications after intracranial hypertension resolution with decompressive craniectomy (DC). The present study aimed to assess the morphological alterations in ICPPW among neurocritical care patients with and without DC, by comparing the variations of ICPPW features according to elevations in mean ICP values. Methods: Patients requiring ICP monitoring because of severe traumatic or spontaneous conditions were included. Mean ICP values were compared with ICPPW features (P2/P1 ratio, TTP and pulse amplitude). Elevation in ICP was produced by means of ultrasound-guided manual internal jugular veins compression. Results were distributed for three groups: intact skull (exclusive burr hole for ICP monitoring), craniotomy/large fractures (group 2) or DC (group 3). Results: 57 patients were analyzed. 21 (36%) presented no skull defects, whereas 15 (26%) had DC. ICP was not significantly different between groups: ±13.59 for intact and ±17.66 mmHg for DC, with ICP induced elevation also similar between groups (p= 0.56). Significant elevation was observed for P2/P1 ratio for groups 1 and 2, whereas reduction was observed in group 3 (elevation of ±0.09 for groups 1 and 2, whereas reduction of 0.03 for group 3, p=0.01). Conclusion: In the present study, intracranial pressure pulse waveform analysis indicated that intracranial compliance was significantly more impaired among decompressive craniectomy patients, although ICPPW indicated DC to be protective for further influences of ICP elevations over the brain. Analysis of ICPPW seems to be an alternative to real time ICC assessment.
Wed, 23 September 2020
REVIEW | doi:10.20944/preprints202009.0539.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: brain aging; energy metabolism; neurodegeneration; neurodegenerative disorders
Online: 23 September 2020 (04:55:21 CEST)
A growing body of evidence indicates that aging of the brain is strictly related to the decline of energy metabolism. In particular, in older adults, the neuronal metabolism of glucose declines steadily resulting in a growing deficit of ATP production. The decline is evoked by deficient NAD recovery in the salvage pathway and subsequent impairment of the Krebs cycle. NAD deficit impairs also the activity of NAD-dependent enzymes. All these open vicious circles of neurodegeneration and neuronal death. Some brain structures are particularly prone to aging and neurodegeneration. These are pathological foci of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. This review article summarizes the impacts and mutual relationships between metabolic processes both on neuronal and brain levels. It also provides directions on how to reduce the risk of neurodegeneration and protect the elderly against neurodegenerative diseases.
Fri, 14 August 2020
CASE REPORT | doi:10.20944/preprints202008.0319.v1
Online: 14 August 2020 (10:19:11 CEST)
Late onset Pompe disease is a recessive lysosomal storage disease. Clinical features include skeletal muscles deficiency and diaphragm weakness. Clinical management relies on supportive treatment and mechanical ventilation in patents with chronic respiratory failure. M mode ultrasound and tissue Doppler imaging can be used to assess and to follow up diaphragm function.
Tue, 15 October 2019
ARTICLE | 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.
Thu, 21 May 2020
REVIEW | doi:10.20944/preprints202005.0334.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Human Bregs; IL-10; IL-35; TGF- ß; myasthenia gravis; Bregs expansion
Online: 21 May 2020 (03:55:17 CEST)
Regulatory B cells (Bregs) with immunosuppressive function are critical in maintaining immune tolerance. In recent years, Bregs is an essential part of the study due to its therapeutic relevance and function in immune tolerance. The positive and negative regulatory role of human Bregs in immune tolerance is being discussed in several pathologies, including in autoimmune diseases, cancers, chronic infections, strokes in multiple reports. The negative regulatory roles of human Bregs are associated with lesser numbers and functional abnormalities in most of these studies, including myasthenia gravis (MG). In this review, the potential findings regarding human Bregs in MG, and Bregs mediated potential therapeutic strategies with its pros and cons have been discussed based on previous and current reports.
Mon, 13 May 2019
ARTICLE | 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.
Thu, 19 December 2019
REVIEW | doi:10.20944/preprints201912.0261.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: huntington disease; cag repeat; mutant huntingtin (mhtt); therapeutics; neurodegeneration
Online: 19 December 2019 (13:18:38 CET)
Huntington disease (HD) is an autosomal dominantly inherited fatal neurodegenerative disease. It affects motor, cognitive and psychiatric functions, and ultimately leads to death. The pathology of the disease is due to an expansion of CAG repeats in exon 1 of the huntingtin gene on chromosome 4, which produces a mutant huntingtin protein (mhtt). HD patients manifest a typical phenotype of sporadic, rapid, involuntary control of limb movement, stiffness of limbs, impaired cognition and severe psychiatric disturbances. A variety of symptomatic treatments (which target excitotoxicity, the dopamine pathway, caspases, aggregation, mitochondrial dysfunction, transcriptional dysregulation, mHtt, nucleic acid, neurodegeneration, fetal neural transplants, etc.) are currently available, and new symptomatic and potentially disease-modifying therapies are being actively developed. Recent advances in novel therapeutic strategies, including targeting mutant huntingtin (mhtt) and the htt gene, promise another wave of disease-modifying trials in the near future. A better appreciation of heterogeneous clinical phenomenology and immediate tractable treatment goals coupled with advances in new therapeutics heralds a golden age of HD treatment that will positively impact the quality of life and longevity of HD patients and inform advances in other inherited and neurodegenerative neurological disorders. In the present review literature, our aims to address the latest research on promising therapeutics based on influencing the hypothesized pathological mechanisms associated with HD.
Thu, 20 August 2020
CASE REPORT | doi:10.20944/preprints202008.0435.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: balance; sensory substitution; neuroprosthesis; peripheral neuropathy; fall risk; diabetes
Online: 20 August 2020 (06:06:06 CEST)
Background:Peripheral neuropathy (PN) can result in either partial or complete loss of distal sensation resulting in an increased fall risk. Walkasins® uses a shoe insert to detect the magnitude and direction of sway and sends signals to a leg unit that provides sensory balance cues. The objective of this case report is to describe the long-term influence of the Walkasins® lower limb sensory neuroprosthesis on balance and gait for an individual with diabetic PN.Case Description:A fifty-one-year-old male with a 3-year history of PN and a 10-year history of type II diabetes mellitus was fitted with Walkasins® and utilized the shoe inserts 8-10 hours/day for more than 1 year. Although, vibration and tactile thresholds were severely impaired at his 1st metatarsophalangeal joint and the lateral malleolus bilaterally he could perceive tactile stimuli from the Walkasins® above the ankles.Outcomes:Following Walkasins® use, his Activities-specific Balance Confidence Scale (ABC) scores improved from 33% to 80%. His mean Vestibular Activities of Daily Living (VADL) scores decreased from 3.54 to 1. His Functional Gait Assessment (FGA) scores increased from 13/30 to 28/30 and his miniBESTest scores improved from 15/28 to 26/28. Gait speed increased from 0.23 m/sec to 1.5 m/sec. The patient described a decrease in pain and cramping throughout his lower extremities and an increase in function.Discussion:Gait and balance improved with the use of the Walkasins® and participation in the Neuro Wellness Program. This improvement suggests that the use of sensory substitution devices, such as the Walkasins®, may replace sensory deficits related to gait and balance dysfunction experienced by patients with PN. Further research is needed to determine if other patients will have a similar response and what the necessary threshold of sensory function is to benefit from use of the Walkasins®.
Thu, 24 September 2020
HYPOTHESIS | doi:10.20944/preprints202009.0588.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: electromagnetic hypersensitivity; multiple chemical sensitivity; migraine; TRPA1
Online: 24 September 2020 (18:22:45 CEST)
According to the French Agency for Food, Environmental and Occupational Health & Safety, electromagnetic hypersensitivity affects more than 3 million people in France, and headaches are a very frequent cause of complaint in electrohypersensitive patients, to the point of dominating the clinical picture. These headaches share characteristics with migraine pathology, and clinical improvement with anti-migraine therapy has led us to consider that the headache in the electrohypersensitive patient may be a variant of the migraine disease mediated by the TRPA1 receptor, which if confirmed, would offer effective therapeutic possibilities to relieve the electrohypersensitive patient.
Sun, 29 December 2019
ARTICLE | doi:10.20944/preprints201912.0382.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: glioblastoma multiforme; MGMT; IDH1; EGFR; P53; ATRX; Ki67; neurosurgery; oncology; epilepsy
Online: 29 December 2019 (13:04:12 CET)
Glioblastoma is a solid, infiltrating and the most frequent highly malignant primary brain tumor. Our aim was to find the prognostic value of mutations of IDH1, MGMT, EGFR, p53, ATRX, Ki67 genes and the correlation between sex, age, presenting with seizures, number of interventions, extent of resection with Overall Survival (OS), Progression Free Survival (PFS) and Karnofsky performance status (KPS) score. A randomized retrospective analysis of 122 patients treated by a single operator at Sapienza University of Rome, was carried out. After surgery patients followed standard treatment Stupp protocol . Exclusion criteria were: patients with primitive brainstem and spinal cord gliomas and patients who underwent partial resections (resection < 90%) and cases of brain biopsy exclusively for diagnostic purposes. Statistical analysis with a simultaneous regression model was carried on by SPSS 25 ® (IBM) program. Results showed statistically significant survival increase in four groups: 1) patients treated with gross total resection (p< 0.03); 2) patients with methylated MGMT promoter (p<0.005); 3) patients with non EGFR amplification or EGFRvIII mutation (p<0.035); 4) mutated IDH1/IDH2 (p<0.0161). Higher survival rates (but not statistically significant) were observed also in patients with: age < 75 years, Ki 67 <10%, lesions in non eloquent areas, ATRX gene mutation and presentation with seizures.
Mon, 24 May 2021
ARTICLE | doi:10.20944/preprints202105.0558.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Cerebrospinal fluid; Total protein; Reference interval; Older population; Japanese healthy volunteer
Online: 24 May 2021 (10:38:05 CEST)
The concentration of cerebrospinal fluid total protein (CSF-TP) is important for the diagnosis of neurological emergencies. Recently, some Western studies have shown that the current upper reference limit of CSF-TP is quite low for older patients. However, little is reported about the concentration of CSF-TP in older Asian population. In this study, we retrospectively analyzed the CSF-TP concentrations in Japanese healthy older volunteers. CSF samples in 69 healthy Japanese volunteers (age range: 55–73 years) were collected by lumbar puncture, and the data of CSF were retrospectively analyzed. The mean (standard deviation) CSF-TP was 41.7 (12.3) mg/dL. The older group (≥ 65 years old) had higher CSF-TP concentration than the younger group (55–64 years old). The 2.5th percentile and 97.5th percentile of CSF-TP were estimated as 22.5 and 73.2 mg/dL, respectively, which were higher than the current reference range in Japan (10–40 mg/dL).
Fri, 17 April 2020
REVIEW | doi:10.20944/preprints202004.0303.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: chronic-ataxic neuropathy; anti-disialosyl; IgM monoclonal gammopathy; CANOMAD
Online: 17 April 2020 (15:15:12 CEST)
Objective: Elucidate the main clinical aspects of the CANOMAD spectrum. Methods: Bibliographical review trough databases (PubMed, Google Scholar, Orphanet, Oxford Academic) of articles from 1985 (1) to 2019 and later selection of the most applicable of the above, in order to construct a non-systematic review. Conclusion: CANOMAD is a chronic-ataxic autoimmune neuropathy associated with IgM monoclonal gammopathy. The correct diagnosis of this rare and multi-faceted disease will help optimal treatment.
Sun, 30 August 2020
CASE REPORT | doi:10.20944/preprints202008.0669.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Miller Fisher Syndrome; Guillain Barré Syndrome variant; Dysphonia; Dysphagia
Online: 30 August 2020 (14:41:29 CEST)
Miller Fisher Syndrome (MFS) is a rare variant of Guillain-Barré Syndrome (GBS). It is largely a clinical diagnosis based on the classical features of ataxia, areflexia, and opthalmoplegia. Its clinical evolution is most often favorable. However, other neurological signs and symptoms may also be present. Supportive laboratory studies (positivity of antibodies, CSF albumin-cytological dissociation and nerve conduction studies) are useful especially in uncommon presentations. We report a case of a 74-year-old patient who exhibited dysphonia and difficulty to swallowing previously to the classic triad of ataxia, areflexia, and opthalmoplegia, characteristic of MFS. CSF analysis demonstrates an albumin-cytological dissociation but anti-GQ1b antibody were negative. The patient has spontaneously and completely recovered after several weeks.
Sun, 20 October 2019
ARTICLE | doi:10.20944/preprints201910.0230.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: carotid intraplaque hemorrhage; carotid atherosclerosis; semi-automatic quantification; MPRAGE
Online: 20 October 2019 (01:39:19 CEST)
Purpose: Carotid intraplaque hemorrhage (IPH) increases risk of territorial cerebral ischemic events, but different sequences or criteria have been used to diagnose or quantify carotid IPH. The purpose of this study was to compare manual segmentation and semi-automatic segmentation for quantification of carotid IPH on magnetization-prepared rapid acquisition with gradient-echo (MPRAGE) sequences. Methods: Forty patients with 16–79% carotid stenosis and IPH on MPRAGE sequences were reviewed by two trained radiologists with more than five years of specialized experience in carotid plaque characterization with carotid plaque MRI. Initially, the radiologists manually viewed the IPH based on the MPRAGE sequence. IPH volume was then measured by three different semi-automatic methods, with high signal intensity 150%, 175%, and 200%, respectively, above that of adjacent muscle on the MPRAGE sequence. Agreement on measurements between manual segmentation and semi-automatic segmentation was assessed using the intraclass correlation coefficient (ICC). Results: There was near-perfect agreement between manual segmentation and the 150% and 175% criteria for semi-automatic segmentation in quantification of IPH volume. The ICC of each semi-automatic segmentation were as follows: 150% criteria: 0.861, 175% criteria: 0.809, 200% criteria: 0.491. The ICC value of manual vs. 150% criteria and manual vs. 175% criteria were significantly better than the manual vs. 200% criteria (p < 0.001). Conclusions: The ICC of 150% and 175% criteria for semi-automatic segmentation are more reliable for quantification of IPH volume. Semi-automatic classification tools may be beneficial in large-scale multicenter studies by reducing image analysis time and avoiding bias between human reviewers.
Sun, 7 June 2020
ARTICLE | doi:10.20944/preprints202006.0093.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: myasthenia gravis; thymic stromal lymphopoietin; regulatory T cells; TGF- β; IL-10
Online: 7 June 2020 (15:00:37 CEST)
Thymic stromal lymphopoietin (TSLP) is a cytokine and is closely related to Interleukin (IL) - 7, and hTSLP can activation through the human thymus dendritic cell in thymic to indirectly promote the differentiation of natural Regulatory T cells (Tregs) of the thymus. In this study, we focused on recombinant TSLP to determine its effects on the differentiation of CD4+CD25-T cells separated from the thymus of myasthenia gravis (MG) patients. Our results demonstrated that exogenous TSLP could increase CD4+CD25+T/CD4+T cells ratio, up-regulate the expression of Foxp3 mRNA and protein expression in CD4+CD25+Treg cells. Furthermore, we found that CD4+CD25+ Treg cells induced by exogenous TSLP could secrete IL - 10, Transforming growth factor (TGF) - β and the ability to inhibit CD4+T cell proliferation improved. These results indicate that TSLP may promote the differentiation of thymic CD4+CD25-T cells of MG patient to CD4+CD25+Foxp3+ regulatory T cells and enhance the function of immune suppression.
Sat, 2 May 2020
REVIEW | doi:10.20944/preprints202005.0021.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: anti-IgLON5 disease; sleep disorders; tau protein accumulation; immunotherapy; neurodegenerative diseases
Online: 2 May 2020 (16:26:03 CEST)
The objective of this review is to do an overview about the current knowledge of Anti Iglon5 Syndrome, a disease that was first described in 2014. The IgLON proteins are a family of cell adhesion molecules and the presence of antibodies against IgLON5 are crucial for diagnosis of Anti IgLON5 Syndrome. This syndrome has an expanded clinical spectrum that involves prominent sleep disorder, progressive bulbar dysfunction, gait instability with abnormal eye movements reminiscent and cognitive deterioration sometimes associated with chorea. The main neuropathological finding is the neuronal loss with hyperphosphorylated tau (p-Tau) protein accumulation at hypothalamus, brainstem tegmentum, hippocampus, periaqueductal gray matter, medulla oblongata and upper cervical cord. The exact pathogenesis is still unclear and involves a neurodegenerative process and autoimmune response. The early diagnosis is important to avoid unnecessary tests and prevent complications. Important resources for diagnosis are the antibody testing of serum and CSF for IgLON5-IgG. The mortality of anti IgLON5 syndrome is high and new studies published described a good response to immune therapy. However, the response to immune therapy depends of some clinical and analytical characteristic. In addition, future studies are needed to thoroughly study the aspects of pathogene