[Show abstract][Hide abstract] ABSTRACT: Alzheimer’s disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.
Full-text · Article · May 2015 · Translational Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis is a chronic, inflammatory, immune-mediated disease of the central nervous system. Current evidence indicates that a complex genetic trait associated with environmental factors probably triggers MS. The hypothesis is that the inflammatory response starts when CNS protein-specific CD4+ T cells become activated in the periphery, cross the blood/brain barrier, and induce CNS autoimmunity. A disturbed balance between cells that induce or cause demyelination and regulatory T cells capable of suppressing these auto-reactive T cells underlie MS pathogenesis. Inflammation and oxidative stress are major causes of tissue damage in the CNS. Diagnostic criteria include paraclinical laboratory assessments emphasizing the principle of lesions disseminated in time and space. Cerebrospinal fluid analysis remains mandatory in order to support the diagnosis and differentiate MS from other diseases. Disease modifying therapies (DMT) are available for MS patients like recombinant Interferon β (IFN-β) and Glatiramer Acetate (GA) that present similar clinical outcomes showing reduction in patient’s annual number of relapses, MRI T2 lesion load reduction and delay of disability. Recently, a monoclonal humanized antibody, Natalizumab, was re-launched showing a larger reduction in annual number of relapses and MRI lesions in the CNS. Besides, Fingolimod (FTY720) was also introduced as the first oral drug with similar effects. Corticosteroids are the first line therapy for acute MS exacerbations. The parenteral use of Cyclophosphamide, Mitoxantrone and Cladribine may benefit some patients with aggressive disease. Oral immunosuppressive drugs (azathioprine, mycophenolatemofetil and methotrexate) have also been reserved for patients whose disease progression cannot be controlled by DMTs.
[Show abstract][Hide abstract] ABSTRACT: Background: Although aquaporin-4 (AQP4) is widely expressed in the human brain cortex, lesions are rare in neuromyelitis optica (NMO) spectrum disorders (NMOSD). Recently, however, several studies have demonstrated occult structural brain atrophy in NMO.
Objective: This study aims to investigate magnetic resonance imaging (MRI) patterns of gray matter (GM) and white matter (WM) abnormalities in patients with NMOSD and to assess the visual pathway integrity during disease duration correlation of the retinal nerve fiber layer (RNFL) and pericalcarine cortex thickness.
Methods: Twenty-one patients with NMOSD and 34 matched healthy controls underwent both high-field MRI (3T) high-resolution T1-weighted and diffusion-tensor MRI. Voxel-based morphometry, cortical analyses (Freesurfer) and diffusion-tensor imaging (DTI) analyses (TBSS-FSL) were used to investigate brain abnormalities. In addition, RNFL measurement by optic-coherence tomography (OCT) was performed.
Results: We demonstrate that NMOSD is associated with GM and WM atrophy, encompassing more frequently the motor, sensory and visual pathways, and that the extent of GM atrophy correlates with disease duration. Furthermore, we demonstrate for the first time a correlation between RNFL and pericalcarine cortical thickness, with cortical atrophy evolving over the course of disease.
Conclusions: Our findings indicate a role for retrograde and anterograde neurodegeneration in GM atrophy in NMOSD. However, the presence atrophy encompassing almost all lobes suggests that additional pathomechanisms might also be involved
Full-text · Article · Jan 2014 · Multiple Sclerosis
[Show abstract][Hide abstract] ABSTRACT: O líquor (Líquido Cefalorraquiano- LCR) é um fluído oligocelular, límpido e incolor que preenche os ventrículos cerebrais e o espaço subaracnóideo, circundando o encéfalo e a medula espinhal. Devido à proximidade do sistema nervoso, o estudo liquórico reflete o processo patológico que ocorre em diversos distúrbios neurológicos. O exame consiste principalmente na observação da composição físico-química, citológica, microbiológica e imunológica do LCR. As modificações detectadas na sua composição, fluxo e pressão auxiliam no diagnóstico e tratamento das patologias do sistema nervoso.
A via de acesso ao LCR preconizada pela Academia Brasileira de Neurologia é a punção lombar (PL), que foi descrita por Quincke, em 1891. Atualmente, a PL é considerada um ato médico de rotina para anestesia, diagnóstico, pesquisa ou tratamento de doenças que acometem o sistema nervoso central (SNC) e raízes nervosas. A compreensão dos aspectos anatômicos é fundamental para o sucesso e a segurança do procedimento.
Este capítulo tem por objetivo discorrer sobre aspectos relacionados à técnica da punção lombar, suas indicações, contraindicações, complicações e as principais síndromes liquóricas, especialmente em unidades de terapia intensiva (UTI).
[Show abstract][Hide abstract] ABSTRACT: Neuromyelitis optica (NMO) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are inflammatory diseases of the central nervous system. NMO is a syndrome of autoimmune etiology still not well defined and HAM/TSP is considered an immune-mediated disease associated with the infection of the HTLV-1 retrovirus, evolving with different clinical presentations. Recently, some acute cases of transverse myelitis and/or optic neuritis during the course of HAM/TSP were described, with a clinical evolution similar to NMO and were called acute variant of HAM/TSP. These reports raised the possibility that HTLV-1 is related to NMO attacks due to the fact that autoimmune diseases are frequently triggered by viral infections in genetically susceptible individuals and that both diseases present high prevalences, coincidently, in certain areas of the world. The objective of the present study is to review acute cases of HAM/ TSP and discuss clinical, pathological and laboratory features of HTLV-1-associated myelopathy and NMO.
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is a complex autoimmune disease mediated by an immune response to central nervous system antigens. Modern immunomodulatory therapies, however, do not ameliorate many of the symptoms, such as pain and depression. Patients thus seek alternative treatments, such as acupuncture, although the benefits of such treatments have not been objectively evaluated. The present study was thus designed to evaluate the effect of the use of acupuncture in the alleviation of the symptoms of patients with MS.
Thirty-one patients with Relapsing-Remitting Multiple Sclerosis undergoing treatment with immunomodulators were randomly distributed into sex-stratified experimental and placebo groups in a patient- and evaluator-blind design; they received either true or sham electroacupuncture during regular visits to the doctor in the university hospital outpatient clinic. Standardized questionnaires were used to evaluate the effect of electroacupuncture on the quality of life of these patients. Initial and follow-up assessment included the evaluation of clinical status (Expanded Disability Status Scale), pain (Visual Analogue Scale) and quality of life (Functional Assessment of multiple Sclerosis) to ascertain the impact of electroacupuncture on the quality of life of these patients.
Electroacupuncture improved various aspects of quality of life, including a reduction in pain and depression. The self-report scales were more sensitive to improvement than was the more objective clinical measure.
This paper provides evidence that electroacupuncture can significantly improve the quality of life of such patients. The results suggest that the routine use of a self-report scale evaluating quality of life should be included in regular clinical evaluations in order to detect changes more rapidly.
Full-text · Article · Nov 2012 · BMC Complementary and Alternative Medicine
[Show abstract][Hide abstract] ABSTRACT: Background:
Daily practice is still faced with uncertainty in predicting the long-term disability of multiple sclerosis (MS). Most information comes from northern hemisphere cohorts, but in South America this information is scarce, and race, genetic and environmental factors could play an important role in the heterogeneity observed in disease outcomes.
We evaluated 197 patients attending our MS Center gathering clinical and demographic information. Outcome measures analyzed were time from first clinical symptom to EDSS of 6, 7 and 8. For survival analysis we employed Cox regression models and the Kaplan-Meier method.
Time to EDSS 6 was 25.83 years (95% CI 15.36-36.31), and 36.25 years (95% CI 20.72-51.78) for EDSS 7. Male sex was associated with a 4.63 and 4.69 fold increased risk to EDSS 6 and 7, respectively (p<0.001 and p=0.006). Motor and brainstem symptoms at onset were also associated with an 8.1 and 13.1 fold increased risk to EDSS 6, respectively (p=0.04 and p=0.01). The number of relapses in five and ten years of disease onset was associated with a slightly increased risk to EDSS 8 (1.28 and 1.19, respectively; p=0.032 and p=0.015).
Male patients presenting with frequent relapses, especially those with motor and brainstem involvement, deserve close observation and should be cautiously monitored to early signs of treatment failure.
Full-text · Article · Oct 2012 · Journal of the neurological sciences
[Show abstract][Hide abstract] ABSTRACT: The seroprevalence of human T-cell leukemia virus type 1 (HTLV-1) is very high among Brazilians (1:200). HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP) is the most common neurological complication of HTLV-1 infection. HAM/TSP can present with an acute/subacute form of longitudinally extensive myelitis, which can be confused with lesions seen in aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorders (NMOSD) on MRI. Moreover, clinical attacks in patients with NMOSD have been shown to be preceded by viral infections in around 30% of cases.
To evaluate the frequency of AQP4-Ab in patients with HAM/TSP. To evaluate the frequency of HTLV-1 infection in patients with NMOSD.
23 Brazilian patients with HAM/TSP, 20 asymptomatic HTLV-1+ serostatus patients, and 34 with NMOSD were tested for AQP4-Ab using a standardized recombinant cell based assay. In addition, all patients were tested for HTLV-1 by ELISA and Western blotting.
20/34 NMOSD patients were positive for AQP4-Ab but none of the HAM/TSP patients and none of the asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1 antibodies. One patient with HAM/TSP developed optic neuritis in addition to subacute LETM; this patient was AQP4-Ab negative as well. Patients were found to be predominantly female and of African descent both in the NMOSD and in the HAM/TSP group; Osame scale and expanded disability status scale scores did not differ significantly between the two groups.
Our results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in populations with high HTLV-1 seroprevalence.
[Show abstract][Hide abstract] ABSTRACT: Depression is a highly prevalent disorder in the elderly and one of the risk factors for developing dementia. The present study involves patients with Alzheimer's disease (AD), geriatric major depressive disorder (MDD) and cognitively healthy controls aiming to compare baseline cerebrospinal fluid (CSF) biomarkers.
The study included 52 patients with more than 60 years of age with a diagnosis of MDD, AD, and healthy controls. All individuals underwent a medical history, physical, and neurologic examination, laboratory tests and neuropsychological assessment to rule out any clinical diseases or disorders. Measurement of CSF P-tau(181) , T-tau, and Aβ42 was performed using commercial assays (ELISA).
CSF Aβ42 levels of depressed patients and normal controls were significantly higher than in AD. There was not any significant difference in measures of P-tau among the groups. T-tau, however, showed to be significantly different among the groups, with higher measures in AD group. Higher levels of P-tau were observed in four MDD patients compared with controls.
CSF Aβ42, T-tau, and P-tau levels may differentiate between AD and depression in a Brazilian sample.
[Show abstract][Hide abstract] ABSTRACT: The pathological hallmarks of multiple sclerosis (MS) lesions are inflammation, demyelination, axon loss and gliosis. The aim of this study was to verify the relation of brain lesion load and volume of the cerebral hemisphere determined by brain MRI with intrathecal antibody synthesis.
A longitudinal study of 54 Brazilian patients with the relapsing-remitting form of MS was undertaken after an average of 6.3 ± 2.7 years of treatment. MRI scans were performed, and cerebrospinal fluid samples were collected both during the diagnostic process and after treatment with β-interferon or glatiramer acetate.
A positive correlation between the IgG index and total lesion volume was identified. Intrathecal IgG against Epstein-Barr virus (EBV) was observed in 21 patients. The number of contrast-enhanced lesions observed in these patients was correlated with intrathecal IgM synthesis. Brain atrophy was observed early in the disease, with the number of relapses inversely correlated with brain volume.
The high intrathecal IgG synthesis observed in these relapsing-remitting MS patients is associated with the brain lesion burden and the presence of antibodies to EBV, whereas intrathecal IgM synthesis is associated with the activity of the disease, as revealed by MRI.
Full-text · Article · Mar 2012 · NeuroImmunoModulation
[Show abstract][Hide abstract] ABSTRACT: Intrathecal immunoglobulin synthesis in an oligoclonal pattern is the most common immunologic abnormality detected in MS patients. Various treatments, such as immunomodulators and immunosuppressors, have not been found to modify it. Natalizumab hinders migration of encephalitogenic T-cells into the central nervous system (CNS), reducing inflammatory response. Its impact on CSF oligoclonal bands (OCBs) has not been demonstrated. This report describes its effect in four out of six patients with multiple sclerosis after a mean of 10 infusions: the CSF was negative for OCBs at the second lumbar puncture. In conclusion, natalizumab treatment can reduce CSF OCBs to undetectable levels, although the clinical significance of this observation is not yet known.
Full-text · Article · Oct 2011 · Multiple Sclerosis
[Show abstract][Hide abstract] ABSTRACT: The plasmacytoid dendritic cells (pDCs) express a high level of Toll-like receptor 9 (TLR-9), which recognizes viral DNA. Activated via TLR-9, pDCs also secrete large amounts of type I interferon which are involved either in stimulation or down regulation of immune response in multiple sclerosis (MS). In the present study, we determinate pDCs levels by flow cytometry in Cerebrospinal Fluid (CSF) and Peripheral Blood from MS patients in relapsing and in remitting phases of the disease, comparing with other non-inflammatory diseases (OND). We provide evidence that MS patients in relapse without any treatment have a significantly (p < 0.01) higher percentage of pDCs in CSF than do patients in remission or those with OND. No change in the percentage of pDCs was observed in the peripheral blood of any of these patients. The increase of pDCs in central nervous system during relapse may be explained either by a virus infection or a down regulatory process.
Full-text · Article · Jan 2011 · Journal of Neuroinflammation
[Show abstract][Hide abstract] ABSTRACT: Immunotherapy with Interferon-beta (IFNbeta) results in remarkably beneficial effects in patients with relapsing-remitting multiple sclerosis (MS), although the mechanisms by which it exerts these beneficial effects remain poorly understood. An investigation was made of the effects of IFNbeta on pro-inflammatory and anti-inflammatory cytokine production in peripheral blood cells in MS patients, both untreated and those undergoing immunotherapy, as well as in healthy controls. Results show a significant increase in the production of pro-inflammatory cytokines such as TNFalpha, IFNgamma and IL-12 in the plasma and in the supernatant of leukocyte cultures from MS patients with the untreated disease; IFNbeta administration significantly reduced the levels of TNFalpha and IFNgamma, with no changes in the level of IL-12. The Interferon-beta therapy also led to a significant increase in the production of IL-10, as well as a slight increase in that of TGFbeta. The reduction in pro-inflammatory cytokine production in the treated MS patient group, accompanied by a simultaneous increase in the production of anti-inflammatory cytokines and the reduction of relapse rates suggests that the beneficial effects of IFNbeta immunotherapy result, at least in part, from the modulation of cytokine patterns.
Full-text · Article · Apr 2009 · International immunopharmacology
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory disease of the white matter of the central nervous system (CNS) characterized by focal areas of demyelination. Interferon-beta (IFN-beta) provides an effective treatment that lessens the frequency and severity of exacerbations in relapsing-remitting multiple sclerosis (RRMS), but the mechanisms by which IFN-beta is efficient remain uncertain. The data presented here demonstrate that IFN-beta impairs the proliferative response to myelin basic protein (MBP) and myelin, as well as increasing the expression of the CTLA4 intracellular molecule. Moreover, this treatment increases the expression of surface Fas molecules and of the soluble form of these molecules. Our hypothesis is that the increase in Fas and CTLA4 molecules in MS patients may lead to lymphocyte apoptosis, which suggests possible mechanisms underlying the therapeutic response to IFN-beta.
Full-text · Article · Nov 2007 · Journal of Interferon & Cytokine Research
[Show abstract][Hide abstract] ABSTRACT: Central nervous system involvement is the most common neurological complication in the course of tuberculosis. The lack of rapid and sensitive tests delays the early diagnosis. Here, we retrospectively reviewed the cerebrospinal fluid (CSF) examination of 30 patients with tuberculous meningitis confirmed by bacteriological tests (culture and/or polymerase chain reaction). The purpose of the present study was to determine the CSF parameters associated to the positive CSF culture for Mycobacterium tuberculosis in tuberculous meningitis. We found higher frequency of positive CSF culture in patients infected with HIV as well in patients with high number of neutrophils and high protein content (characteristic in the early or acute-stage patients), which suggests that the positive culture found in these patients may be associated with the presence of high bacillary load in CSF occurring in these stages.
Preview · Article · Apr 2007 · Arquivos de Neuro-Psiquiatria
[Show abstract][Hide abstract] ABSTRACT: It was the aim of this study to evaluate if the quantitative intrathecal immunoglobulin G (IgG) synthesis correlates with the brain atrophy and the total lesion volume (TLV) in brain magnetic resonance imaging (MRI) of multiple sclerosis (MS) patients.
A total of 50 patients with relapsing-remitting MS were included in this study. MRIs were performed and cerebrospinal fluid samples were collected during the diagnostic determination when patients were in remission without treatment.
At study baseline, IgG index values were elevated in 36 patients (72%), and oligoclonal IgG bands were positive in 42 of 50 patients (84%). Brain MRI was abnormal in 94% of patients, and, compared with healthy controls, brain atrophy was observed in MS patients. A positive correlation among IgG index, cerebrospinal fluid leukocyte count and TLV was observed; the Expanded Disability Status Scale correlated positively with TLV and the number of lesions, although a significant relationship between disability and brain atrophy was not demonstrated.
Although new parameters will be necessary in longitudinal studies to characterize the axonal injury in various stages of the disease, the data suggest that the high intrathecal IgG synthesis may predict a greater brain lesion burden.
Full-text · Article · Feb 2006 · NeuroImmunoModulation
[Show abstract][Hide abstract] ABSTRACT: Cytokines and intrathecal IgG synthesis were determined in the cerebrospinal fluid (CSF) and sera to evaluate inflammatory activity in multiple sclerosis (MS) patients during clinical remission. Although the disease was stable, there had been a significant increase of proinflammatory cytokines such as TNFalpha and IFNgamma in the CSF and serum, with no significant changes of IL12 and IL10 production. The changes in the cytokine production patterns were associated with an increase of leukocytes in the CSF, as well as the presence of oligoclonal bands suggesting intrathecal IgG synthesis. These results suggest that even when the disease is clinically silent, one can observe inflammatory activity in these MS patients.
Full-text · Article · Jan 2006 · Arquivos de Neuro-Psiquiatria