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1.
Clin Chim Acta ; 495: 13-24, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30922855

RESUMO

Mutations on the GBA gene, encoding for the lysosomal enzyme ß-glucocerebrosidase (GCase), have been identified as the most common genetic risk factor involved in the development of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), indicating a direct contribution of this enzyme to the pathogenesis of synucleinopathies. Decreased GCase activity has been observed repeatedly in brain tissues and biological fluids of both GBA mutation carrier and non-carrier PD and DLB patients, suggesting that lower GCase activity constitutes a typical feature of these disorders. Additional genetic, pathological and biochemical data on other lysosomal enzymes (e.g., Acid sphingomyelinase, Cathepsin D, α-galactosidase A and ß-hexosaminidase) have further strengthened the evidence of a link between lysosomal dysfunction and synucleinopathies. A few studies have been performed for assessing the potential value of lysosomal enzyme activities in cerebrospinal fluid (CSF) as biomarkers for synucleinopathies. The reduction of GCase activity in the CSF of PD and DLB patients was validated in several of them, whereas the behaviour of other lysosomal enzyme activities was not consistently reliable among the studies. More in-depth investigations on larger cohorts, following stringent standard operating procedures should be committed to really understand the diagnostic utility of lysosomal enzymes as biomarkers for synucleinopathies. In this review, we reported the evidences of the association between the defective function of lysosomal proteins and the pathogenesis of synucleinopathies, and examined the role of lysosomal enzyme activities in CSF as reliable biomarkers for the diagnosis of PD and related neurodegenerative disorders.


Assuntos
Lisossomos/enzimologia , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/enzimologia , alfa-Sinucleína/química , Biomarcadores/líquido cefalorraquidiano , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Agregados Proteicos
2.
Mass Spectrom Rev ; 38(1): 22-33, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29130504

RESUMO

Metabolomics seeks to take a "snapshot" in a time of the levels, activities, regulation and interactions of all small molecule metabolites in response to a biological system with genetic or environmental changes. The emerging development in mass spectrometry technologies has shown promise in the discovery and quantitation of neuroactive small molecule metabolites associated with gut microbiota and brain. Significant progress has been made recently in the characterization of intermediate role of small molecule metabolites linked to neural development and neurodegenerative disorder, showing its potential in understanding the crosstalk between gut microbiota and the host brain. More evidence reveals that small molecule metabolites may play a critical role in mediating microbial effects on neurotransmission and disease development. Mass spectrometry-based metabolomics is uniquely suitable for obtaining the metabolic signals in bidirectional communication between gut microbiota and brain. In this review, we summarized major mass spectrometry technologies including liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and imaging mass spectrometry for metabolomics studies of neurodegenerative disorders. We also reviewed the recent advances in the identification of new metabolites by mass spectrometry and metabolic pathways involved in the connection of intestinal microbiota and brain. These metabolic pathways allowed the microbiota to impact the regular function of the brain, which can in turn affect the composition of microbiota via the neurotransmitter substances. The dysfunctional interaction of this crosstalk connects neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. The mass spectrometry-based metabolomics analysis provides information for targeting dysfunctional pathways of small molecule metabolites in the development of the neurodegenerative diseases, which may be valuable for the investigation of underlying mechanism of therapeutic strategies.


Assuntos
Encéfalo/metabolismo , Microbioma Gastrointestinal , Espectrometria de Massas/métodos , Metabolômica/métodos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/microbiologia , Animais , Bactérias/metabolismo , Fezes/microbiologia , Humanos , Espectrometria de Massas/instrumentação , Metaboloma , Metabolômica/instrumentação , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano
3.
J Steroid Biochem Mol Biol ; 188: 86-89, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30586624

RESUMO

In contrast to cholesterol itself the side-chain oxidized metabolites 24S-hydroxycholesterol (24OH) and 27-hydroxycholesterol (27OH) are able to pass the blood-brain barrier and the blood-CSF barrier. Most 27OH in circulation is formed extracerebrally and according to catheterization experiments about 5 mg of it is taken up by the brain per 24 h. 24OH is almost exclusively produced in the brain and about 6 mg fluxes from the brain into the circulation per 24 h. In addition to these major fluxes a very minor fraction of these two oxysterols flux from the circulation into CSF. Isotope experiments have shown that almost all 27OH in CSF originates from the circulation and evidence has been presented that this is the case also with a substantial part of 24OH. The levels of both 24OH and 27OH in CSF are thus affected by the integrity of the blood-CSF barrier with higher levels when the barrier is defect. Both levels of 24OH and 27OH in CSF are increased in connection with neurodegeneration and in general the increase in 24OH levels is higher than the increase in 27OH levels. A number of observations in different type of patients including measurements of other biochemical markers support that the increase in levels of 24OH due to neurodegeneration is due to a release of this oxysterol or its precursor cholesterol from dying neuronal cells. In contrast the increase in levels of 27OH is likely to be a consequence of reduced metabolism due to loss of the neuronal enzyme CYP7B1. We discuss the driving forces behind the fluxes of oxysterols in the brain, the limitations in the flux across the barriers and the diagnostic potential for side-chain oxidized oxysterols in CSF.


Assuntos
Barreira Hematoencefálica/metabolismo , Hidroxicolesteróis/metabolismo , Animais , Família 7 do Citocromo P450/metabolismo , Humanos , Hidroxicolesteróis/sangue , Hidroxicolesteróis/líquido cefalorraquidiano , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Oxirredução , Esteroide Hidroxilases/metabolismo
4.
PLoS One ; 13(12): e0208636, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30543686

RESUMO

OBJECTIVE: To identify the specific domains of the presynaptic protein synapsin targeted by recently described autoantibodies to synapsin. METHODS: Sera of 20 and CSF of two patients with different psychiatric and neurological disorders previously tested positive for immunoglobulin (Ig)G antibodies to full-length synapsin were screened for IgG against synapsin I domains using HEK293 cells transfected with constructs encoding different domains of rat synapsin Ia. Additionally, IgG subclasses were determined using full-length synapsin Ia. Serum and CSF from one patient were also screened for IgA autoantibodies to synapsin I domains. Sera from nine and CSF from two healthy subjects were analyzed as controls. RESULTS: IgG in serum from 12 of 20 IgG synapsin full-length positive patients, but from none of the healthy controls, bound to synapsin domains. Of these 12 sera, six bound to the A domain, five to the D domain, and one to the B- (and possibly A-), D-, and E-domains of synapsin I. IgG antibodies to the D-domain were also detected in one of the CSF samples. Determination of IgG subclasses detected IgG1 in two sera and one CSF, IgG2 in none of the samples, IgG3 in two sera, and IgG4 in eight sera. One patient known to be positive for IgA antibodies to full-length synapsin had IgA antibodies to the D-domain in serum and CSF. CONCLUSIONS: Anti-synapsin autoantibodies preferentially bind to either the A- or the D-domain of synapsin I.


Assuntos
Autoanticorpos/sangue , Epitopos/imunologia , Imunoglobulina G/sangue , Sinapsinas/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Células HEK293 , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/classificação , Masculino , Transtornos Mentais/líquido cefalorraquidiano , Transtornos Mentais/patologia , Pessoa de Meia-Idade , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/patologia , Domínios Proteicos/imunologia , Sinapsinas/química , Sinapsinas/metabolismo , Adulto Jovem
5.
Brain Behav ; 8(12): e01160, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30468006

RESUMO

INTRODUCTION: The aim of this study was the assessment of neuron-specific enolase (NSE) and S-100 concentration in serum and cerebrospinal fluid (CSF) in patients with different clinical forms of tick-borne encephalitis (TBE). MATERIAL AND METHODS: The serum and CFS concentrations of S100B and NSE of 43 patients with TBE were measured with ELISA method using commercial kits: NSE and S100B Elisa Kit (DRG, Germany). Subjects were divided into: Group I-patients with meningoencephalitis (n = 17) and Group II-patients with meningitis (n = 26). None of the patients reported any neurodegenerative disorder that could affect the results of the study. The control group (CG) consisted of 13 patients. These patients were admitted to the hospital because of headache, and the CSF examination excluded inflammatory process. Samples were collected on admission (sample 1) and after treatment (sample 2). RESULTS: Neuron-specific enolase concentration in CSF was higher in group I than in group II (p = 0.0002) and controls (p = 0.04). NSE concentration was higher in the second serum and CSF sample in both groups. S100B concentration did not differ between TBE patients and controls. NSE concentration in serum after 14 days was higher in the sequelae group (34.3 ± 9.7 vs. 16.7 ± 15, p = 0.04). Also, NSE serum sample 2/serum sample 1 ratio was significantly higher in the sequelae group (3.57 ± 0.92 vs. 1.53 ± 1.99, p = 0.04). Receiver Operating Characteristic curve analysis indicated that NSE concentration in serum II differentiates sequelae group from other meningoencephalitis patients (p = 0.0001). S100B serum sample 2/CSF sample 2 ratio was lower in the sequelae group (0.05 ± 0.1 vs. 0.37 ± 0.28, p = 0.02). CONCLUSIONS: (a) Neurodegeneration process is present in TBE encephalitis. (b) NSE concentration correlates with inflammatory parameters in CSF in TBE. (c) Neurodegeneration is present even after clinical recovery of TBE. (d) NSE could be used in the prediction of TBE course. (e) S-100 did not differ between TBE patients and controls.


Assuntos
Encefalite Transmitida por Carrapatos/virologia , Doenças Neurodegenerativas/virologia , Fosfopiruvato Hidratase/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Encefalite Transmitida por Carrapatos/sangue , Encefalite Transmitida por Carrapatos/líquido cefalorraquidiano , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano , Curva ROC
6.
Neurología (Barc., Ed. impr.) ; 33(7): 449-458, sept. 2018. ilus
Artigo em Espanhol | IBECS | ID: ibc-175953

RESUMO

Introducción: Desde la descripción hace 5 décadas de la hidrocefalia crónica del adulto idiopática (HCAi), su fisiopatología ha sido considerada básicamente relacionada con el efecto que la dilatación ventricular ejerce sobre las estructuras adyacentes al sistema ventricular. Sin embargo, las alteraciones en el flujo sanguíneo cerebral (FSC) y, sobre todo, la reducción en el recambio licuoral parecen emerger como componentes fisiopatológicos principales de esta enfermedad. Desarrollo: En la HCAi se observa una compresión del tracto piramidal, de los circuitos cortico-subcorticales fronto-estriatales y fronto-reticulares, y de las fibras profundas del fascículo longitudinal superior. En el cuerpo calloso se objetiva un descenso en el número de fibras comisurales, que son reemplazadas por gliosis. El FSC se encuentra alterado, con un patrón de última pradera en la región subcortical adyacente a los ventrículos, correspondiente a la intersección entre las arterias subependimarias y las arterias perforantes dependientes de los grandes troncos arteriales de la circulación anterior. El recambio diario del LCR se ve disminuido en un 75%, lo que conlleva una reducción del aclaramiento de neurotóxicos y la interrupción de las señalizaciones neuroendocrinas y paracrinas que ocurren a través del LCR. Conclusiones: La HCAi emerge como una entidad nosológica compleja, en la que los efectos de la microangiopatía subcortical y la disminución del recambio de LCR desempeñan un papel fundamental. Esta base fisiopatológica aleja la HCAi del concepto clásico de hidrocefalia y la acerca al perfil de otras enfermedades neurodegenerativas, como la enfermedad de Alzheimer o la enfermedad de Binswanger


Introduction: Since its description five decades ago, the pathophysiology of idiopathic chronic adult hydrocephalus (iCAH) has been traditionally related to the effect that ventricular dilatation exerts on the structures surrounding the ventricular system. However, altered cerebral blood flow, especially a reduction in the CSF turnover rate, are starting to be considered the main pathophysiological elements of this disease. Development: Compression of the pyramidal tract, the frontostriatal and frontoreticular circuits, and the paraventricular fibres of the superior longitudinal fasciculus have all been reported in iCAH. At the level of the corpus callosum, gliosis replaces a number of commissural tracts. Cerebral blood flow is also altered, showing a periventricular watershed region limited by the subependymal arteries and the perforating branches of the major arteries of the anterior cerebral circulation. The CSF turnover rate is decreased by 75%, leading to the reduced clearance of neurotoxins and the interruption of neuroendocrine and paracrine signalling in the CSF. Conclusions: iCAH presents as a complex nosological entity, in which the effects of subcortical microangiopathy and reduced CSF turnover play a key role. According to its pathophysiology, it is simpler to think of iCAH more as a neurodegenerative disease, such as Alzheimer disease or Binswanger disease than as the classical concept of hydrocephalus


Assuntos
Humanos , Hidrocefalia de Pressão Normal/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Ventrículos Cerebrais/fisiopatologia , Pressão do Líquido Cefalorraquidiano/fisiologia , Circulação Cerebrovascular/fisiologia , Doença Crônica , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico
7.
J Psychiatr Res ; 104: 183-191, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30103065

RESUMO

Behavioural variant frontotemporal dementia (bvFTD) is characterized by behavioural and social cognitive disturbances, while various psychiatric and neurodegenerative disorders may have similar clinical symptoms. Since neurodegenerative disorders are eventually progressive, whereas primary psychiatric disorders are not, this study aimed to investigate whether the change in clinical symptoms over time differed between groups and which biomarkers predicted rate of decline. Disease trajectories (median follow-up = 3 years) of frontal and stereotyped behaviour, general and frontal cognitive functioning, and social cognition were examined in bvFTD (n = 34), other neurodegenerative (n = 28) and primary psychiatric disorders (n = 43), all presenting with late-onset frontal lobe syndrome (45-75 years), using linear mixed models. To gain more insight in underlying pathological processes driving disease progression, we studied the association of baseline cerebrospinal fluid (CSF) (neurofilament light (NfL) and YKL-40 levels, phosphotau181 to total tau ratio) and neuroimaging markers with disease trajectories. Frontal behavioural symptoms (e.g., disinhibition, apathy) worsened over time in bvFTD, whereas they improved in psychiatric disorders and remained stable in other neurodegenerative disorders. General and frontal cognitive decline was observed in bvFTD and other neurodegenerative disorders, but not in psychiatric disorders. None of the groups showed change in stereotypy and social cognition. For all diagnostic groups, higher CSF NfL levels were associated with faster frontal cognitive decline. A modest association was observed between caudate volume and stereotyped behaviour. Tracking frontal behavioural symptoms and cognition has potential to distinguish bvFTD from other disorders. CSF NfL levels seem to be associated with decline in frontal cognitive functioning.


Assuntos
Apatia/fisiologia , Transtornos Cognitivos/etiologia , Demência Frontotemporal/complicações , Transtornos Mentais/complicações , Doenças Neurodegenerativas/complicações , Comportamento Estereotipado/fisiologia , Idoso , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/diagnóstico por imagem , Progressão da Doença , Feminino , Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Transtornos Mentais/líquido cefalorraquidiano , Transtornos Mentais/diagnóstico por imagem , Pessoa de Meia-Idade , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico por imagem , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica
8.
Neurology ; 91(5): e436-e443, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-29959263

RESUMO

OBJECTIVE: To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation. METHODS: In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3-like protein 1 [YKL-40]). Participants were divided into 3 groups based on diagnosis and p-tau/ß-amyloid42 (Aß42): those with low p-tau/Aß42 and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aß42 diagnosed with AD-dementia or AD-mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aß42 but unimpaired cognition were classified as mismatches (n = 14). A similar, secondary analysis was performed with no age exclusion criteria (n = 411). RESULTS: In both the primary and secondary analyses, biomarker levels between groups were compared with the use of analysis of covariance while controlling for age and demographic variables. Despite p-tau/Aß42 and Aß42/Aß40 levels comparable to those of the AD-Dementia group, mismatches had significantly lower levels of NFL and total tau. While not significantly lower than the AD-Dementia group on YKL-40 and neurogranin, mismatches were also not significantly different from controls. CONCLUSIONS: These results provide evidence that, in the absence of significant neurodegenerative processes, individuals who harbor AD neuropathology may remain cognitively unimpaired. This finding provides insight into the biological processes phenotypic of dementia and supports monitoring multiple biomarkers in individuals positive for AD neuropathology.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Gliose/líquido cefalorraquidiano , Gliose/diagnóstico , Fenótipo , Sinapses/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Feminino , Gliose/genética , Humanos , Masculino , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Sinapses/genética , Proteínas tau/líquido cefalorraquidiano
9.
Methods Mol Biol ; 1768: 111-126, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29717440

RESUMO

Cerebrospinal fluid (CSF) contains molecules directly linked with brain function because it permeates brain tissue. The analysis of protein biomarkers in CSF is currently recommended for the diagnosis of neurodegenerative disorders, but the clinical sensitivity and specificity are still being investigated. A major drawback is that most of the currently used biomarkers of neurodegenerative diseases are proteins that are found at very low concentrations in CSF and need to be measured by immunoassays that provide relative values, which sometimes are difficult to reproduce between laboratories. In contrast, the recent availability of digital PCR platforms allows the absolute quantification of nucleic acids at single-molecule resolution, but their presence in CSF has not been characterized. CSF contains cell-free mitochondrial DNA (mtDNA) and changes in the concentration of this nucleic acid are linked to neurodegeneration. Here we describe a method to measure the concentration of cell-free circulating mtDNA directly in unpurified CSF using droplet digital PCR with either hydrolysis probes or fluorescent DNA-binding dye methods. This protocol allows the detection and absolute quantification of mtDNA content in the CSF with high analytical sensitivity, specificity, and accuracy.


Assuntos
Ácidos Nucleicos Livres/isolamento & purificação , DNA Mitocondrial/isolamento & purificação , Reação em Cadeia da Polimerase Multiplex/métodos , Doenças Neurodegenerativas/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Ácidos Nucleicos Livres/líquido cefalorraquidiano , Ácidos Nucleicos Livres/genética , DNA Mitocondrial/líquido cefalorraquidiano , DNA Mitocondrial/genética , Corantes Fluorescentes/química , Humanos , Reação em Cadeia da Polimerase Multiplex/instrumentação , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/genética , Sensibilidade e Especificidade
11.
J Neurol Sci ; 388: 150-154, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29627011

RESUMO

INTRODUCTION: Idiopathic basal ganglia calcification (IBGC), also called Fahr's disease or recently primary familial brain calcification (PFBC), is characterized by abnormal deposits of minerals including calcium mainly and phosphate in the brain. Mutations in SLC20A2 (IBGC1 (merged with former IBGC2 and IBGC3)), which encodes PiT-2, a phosphate transporter, is the major cause of IBGC. Recently, Slc20a2-KO mice have been showed to have elevated levels of inorganic phosphorus (Pi) in cerebrospinal fluid (CSF); however, CSF Pi levels in patients with IBGC have not been fully examined. METHODS: We investigated the cases of 29 patients with IBGC including six patients with SLC20A2 mutation and three patients with PDGFB mutation, and 13 controls. The levels of sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and Pi in sera and CSF were determined by potentiometry and colorimetry. Moreover, clinical manifestations were investigated in the IBGC patients with high Pi levels in CSF. RESULTS: The study revealed that the average level of Pi in the CSF of the total group of patients with IBGC is significantly higher than that of the control group, and the levels of Pi in CSF of the IBGC patients with SLC20A2 mutations are significantly higher than those of the IBGC patients with PDGFB mutations, the other IBGC patients and controls. CONCLUSION: Results of this study suggest that the levels of CSF Pi will be a good biomarker for IBGC1.


Assuntos
Doenças dos Gânglios da Base/líquido cefalorraquidiano , Doenças dos Gânglios da Base/genética , Calcinose/líquido cefalorraquidiano , Calcinose/genética , Mutação , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/genética , Fósforo/líquido cefalorraquidiano , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Adolescente , Adulto , Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/diagnóstico por imagem , Biomarcadores/líquido cefalorraquidiano , Calcinose/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico por imagem , Proteínas Proto-Oncogênicas c-sis/genética , Adulto Jovem
12.
Cancer ; 124(12): 2607-2620, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29624648

RESUMO

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.


Assuntos
Neoplasias Encefálicas/diagnóstico , Histiocitose de Células de Langerhans/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Osteopontina/líquido cefalorraquidiano , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biópsia , Encéfalo/patologia , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Células-Tronco Hematopoéticas/patologia , Histiocitose de Células de Langerhans/líquido cefalorraquidiano , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Recém-Nascido , Leucócitos Mononucleares/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos Retrospectivos , Adulto Jovem
13.
Acta Neuropathol ; 136(3): 363-376, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29700597

RESUMO

Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer's disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson's disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid ß (Aß), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aß neuritic plaque (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with ß-amyloid plaque pathology.


Assuntos
Hipocampo/patologia , Doenças Neurodegenerativas/líquido cefalorraquidiano , Neurogranina/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/patologia , Emaranhados Neurofibrilares/patologia , Fenótipo , Estudos Prospectivos , alfa-Sinucleína/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano
14.
Exp Gerontol ; 108: 181-188, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29704639

RESUMO

Cerebrospinal fluid (CSF) circulates through the brain and has a unique composition reflecting the biological processes of the brain. Identifying ageing CSF biomarkers can aid in understanding the ageing process and interpreting CSF protein changes in neurodegenerative diseases. In this study, ovine CSF proteins from young (1-2 year old), middle aged (3-6 year old) and old (7-10 year old) sheep were systemically studied. CSF proteins were labelled with iTRAQ tagging reagents and fractionated by 2-dimensional high performance, liquid chromatography. Tryptic peptides were identified using MS/MS fragmentation ions for sequencing and quantified from iTRAQ reporter ion intensities at m/z 114, 115, 116 and 117. Two hundred thirty one peptides were detected, from which 143 proteins were identified. There were 52 proteins with >25% increase in concentrations in the old sheep compared to the young. 33 of them increased >25% but <50%, 13 increased >50% but <1 fold, 6 increased >1 fold [i.e. haptoglobin (Hp), haemoglobin, neuroendocrine protein 7B2, IgM, fibrous sheath interacting protein 1, vimentin]. There were 18 proteins with >25% decrease in concentrations in the old sheep compared to the young. 17 of them decreased >25% but <50%, and histone deacetylase 7 (HDAC7) was gradually decreased for over 80%. Glutathione S-transferase was decreased in middle aged CSF compared to both young and old CSF. The differential expressions of 3 proteins (Hp, neuroendocrine protein 7B2, IgM) were confirmed by immunoassays. These data expand our current knowledge regarding ovine CSF proteins, supply the necessary information to understand the ageing process in the brain and provide a basis for diagnosis of neurodegenerative diseases.


Assuntos
Envelhecimento/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteômica , Animais , Cromatografia Líquida de Alta Pressão , Feminino , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico , Ovinos , Espectrometria de Massas em Tandem
15.
Brain Behav ; 8(2): e00903, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29484263

RESUMO

Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results: Aß1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aß1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions: Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aß1-40 and p-tau181 as potentially valuable biomarkers of these processes.


Assuntos
Envelhecimento , Peptídeos beta-Amiloides , Encéfalo/patologia , Angiopatia Amiloide Cerebral , Doenças dos Macacos , Fragmentos de Peptídeos , Proteínas tau , Envelhecimento/líquido cefalorraquidiano , Envelhecimento/genética , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/genética , Animais , Biomarcadores/líquido cefalorraquidiano , Angiopatia Amiloide Cerebral/líquido cefalorraquidiano , Angiopatia Amiloide Cerebral/genética , Cromossomos de Mamíferos , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Masculino , Modelos Animais , Doenças dos Macacos/líquido cefalorraquidiano , Doenças dos Macacos/genética , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/genética , Neuroimagem/métodos , Tamanho do Órgão , Linhagem , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/genética , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética
16.
World J Biol Psychiatry ; 19(4): 244-328, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29076399

RESUMO

In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-ß positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.


Assuntos
Psiquiatria Biológica/normas , Biomarcadores , Consenso , Demência/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Sociedades Médicas/normas , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Demência/sangue , Demência/líquido cefalorraquidiano , Humanos , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano
17.
Eur J Neurol ; 25(3): 542-548, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29222955

RESUMO

BACKGROUND AND PURPOSE: This cross-sectional study aims to compare gait changes after the cerebrospinal fluid (CSF) tap test between normal pressure hydrocephalus patients with and without brain comorbidities (NPH+ and NPH- respectively) and then to identify significant contributors to a poor CSF tap test amongst individuals with NPH+. METHODS: Gait changes (during the single task and the dual task of backward counting) were quantified before and 24 h after the CSF tap test with an optoelectronic system in 52 NPH patients (77.4 ± 6.0 years; 34.6% women). Changes after the CSF tap test in stride time variability (STV, %) were our main outcome. CSF Alzheimer's disease biomarkers, cerebrovascular white matter changes assessed with brain imaging and neurodegenerative diseases with parkinsonian syndrome represented the three individual brain comorbidities. RESULTS: Brain comorbidities were frequently identified, NPH+ patients representing 40 patients of our sample (76.9%). NPH- patients improved their STV better in the single task (delta of STV = -58.6% ± 54.3% vs. -14.1% ± 62.0%; P = 0.031) and in the dual task (delta of STV =-32.2% ± 33.7% vs. 6.3% ± 58.4%; P = 0.028) after the CSF tap test than NPH+ patients. Amongst NPH+ individuals, only comorbid Alzheimer's disease was associated with STV increase (i.e. deterioration of gait) in the dual task [ß 38.4; 95% confidence interval (5.64; 71.24); P = 0.023] after the CSF tap test, whilst it was borderline in the single task [ß 35.0; 95% confidence interval (-1.97; 71.90); P = 0.063]. CONCLUSIONS: Brain comorbidities affect gait improvement after the CSF tap test in NPH patients; this influence is driven by Alzheimer's disease-related pathology.


Assuntos
Doença de Alzheimer , Transtornos Neurológicos da Marcha , Hidrocefalia de Pressão Normal , Leucoencefalopatias , Doenças Neurodegenerativas , Doença de Parkinson , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/fisiopatologia , Biomarcadores/líquido cefalorraquidiano , Comorbidade , Estudos Transversais , Feminino , Transtornos Neurológicos da Marcha/líquido cefalorraquidiano , Transtornos Neurológicos da Marcha/diagnóstico por imagem , Transtornos Neurológicos da Marcha/epidemiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico por imagem , Hidrocefalia de Pressão Normal/epidemiologia , Hidrocefalia de Pressão Normal/fisiopatologia , Leucoencefalopatias/líquido cefalorraquidiano , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/epidemiologia , Leucoencefalopatias/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/epidemiologia , Doença de Parkinson/fisiopatologia
18.
Neurology ; 90(4): e282-e290, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29282337

RESUMO

OBJECTIVE: To assess the relationships between fluid and imaging biomarkers of tau pathology and compare their diagnostic utility in a clinically heterogeneous sample. METHODS: Fifty-three patients (28 with clinical Alzheimer disease [AD] and 25 with non-AD clinical neurodegenerative diagnoses) underwent ß-amyloid (Aß) and tau ([18F]AV1451) PET and lumbar puncture. CSF biomarkers (Aß42, total tau [t-tau], and phosphorylated tau [p-tau]) were measured by multianalyte immunoassay (AlzBio3). Receiver operator characteristic analyses were performed to compare discrimination of Aß-positive AD from non-AD conditions across biomarkers. Correlations between CSF biomarkers and PET standardized uptake value ratios (SUVR) were assessed using skipped Pearson correlation coefficients. Voxelwise analyses were run to assess regional CSF-PET associations. RESULTS: [18F]AV1451-PET cortical SUVR and p-tau showed excellent discrimination between Aß-positive AD and non-AD conditions (area under the curve 0.92-0.94; ≤0.83 for other CSF measures), and reached 83% classification agreement. In the full sample, cortical [18F]AV1451 was associated with all CSF biomarkers, most strongly with p-tau (r = 0.75 vs 0.57 for t-tau and -0.49 for Aß42). When restricted to Aß-positive patients with AD, [18F]AV1451 SUVR correlated modestly with p-tau and t-tau (both r = 0.46) but not Aß42 (r = 0.02). On voxelwise analysis, [18F]AV1451 correlated with CSF p-tau in temporoparietal cortices and with t-tau in medial prefrontal regions. Within AD, Mini-Mental State Examination scores were associated with [18F]AV1451-PET, but not CSF biomarkers. CONCLUSION: [18F]AV1451-PET and CSF p-tau had comparable value for differential diagnosis. Correlations were robust in a heterogeneous clinical group but attenuated (although significant) in AD, suggesting that fluid and imaging biomarkers capture different aspects of tau pathology. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, in a clinical sample of patients with a variety of suspected neurodegenerative diseases, both CSF p-tau and [18F]AV1451 distinguish AD from non-AD conditions.


Assuntos
Encéfalo/diagnóstico por imagem , Carbolinas , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico por imagem , Compostos Radiofarmacêuticos , Proteínas tau/líquido cefalorraquidiano , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Área Sob a Curva , Biomarcadores/líquido cefalorraquidiano , Encéfalo/metabolismo , Encéfalo/patologia , Estudos Transversais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/patologia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença
19.
Neurologia ; 33(7): 449-458, 2018 Sep.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-27296497

RESUMO

INTRODUCTION: Since its description five decades ago, the pathophysiology of idiopathic chronic adult hydrocephalus (iCAH) has been traditionally related to the effect that ventricular dilatation exerts on the structures surrounding the ventricular system. However, altered cerebral blood flow, especially a reduction in the CSF turnover rate, are starting to be considered the main pathophysiological elements of this disease. DEVELOPMENT: Compression of the pyramidal tract, the frontostriatal and frontoreticular circuits, and the paraventricular fibres of the superior longitudinal fasciculus have all been reported in iCAH. At the level of the corpus callosum, gliosis replaces a number of commissural tracts. Cerebral blood flow is also altered, showing a periventricular watershed region limited by the subependymal arteries and the perforating branches of the major arteries of the anterior cerebral circulation. The CSF turnover rate is decreased by 75%, leading to the reduced clearance of neurotoxins and the interruption of neuroendocrine and paracrine signalling in the CSF. CONCLUSIONS: iCAH presents as a complex nosological entity, in which the effects of subcortical microangiopathy and reduced CSF turnover play a key role. According to its pathophysiology, it is simpler to think of iCAH more as a neurodegenerative disease, such as Alzheimer disease or Binswanger disease than as the classical concept of hydrocephalus.


Assuntos
Hidrocefalia de Pressão Normal/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Adulto , Ventrículos Cerebrais/fisiopatologia , Pressão do Líquido Cefalorraquidiano/fisiologia , Circulação Cerebrovascular/fisiologia , Doença Crônica , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico
20.
Clin Immunol ; 189: 29-33, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-27664933

RESUMO

Eotaxins are C-C motif chemokines first identified as potent eosinophil chemoattractants. They facilitate eosinophil recruitment to sites of inflammation in response to parasitic infections as well as allergic and autoimmune diseases such as asthma, atopic dermatitis, and inflammatory bowel disease. The eotaxin family currently includes three members: eotaxin-1 (CCL11), eotaxin-2 (CCL24), and eotaxin-3 (CCL26). Despite having only ~30% sequence homology to one another, each was identified based on its ability to bind the chemokine receptor, CCR3. Beyond their role in innate immunity, recent studies have shown that CCL11 and related molecules may directly contribute to degenerative processes in the central nervous system (CNS). CCL11 levels increase in the plasma and cerebrospinal fluid of both mice and humans as part of normal aging. In mice, these increases are associated with declining neurogenesis and impaired cognition and memory. In humans, elevated plasma levels of CCL11 have been observed in Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and secondary progressive multiple sclerosis when compared to age-matched, healthy controls. Since CCL11 is capable of crossing the blood-brain barrier of normal mice, it is plausible that eotaxins generated in the periphery may exert physiological and pathological actions in the CNS. Here, we briefly review known functions of eotaxin family members during innate immunity, and then focus on whether and how these molecules might participate in the progression of neurodegenerative diseases.


Assuntos
Quimiocina CCL11/imunologia , Quimiocina CCL24/imunologia , Quimiocina CCL26/imunologia , Imunidade Inata/imunologia , Doenças Neurodegenerativas/imunologia , Envelhecimento/imunologia , Animais , Quimiocina CCL11/sangue , Quimiocina CCL11/líquido cefalorraquidiano , Quimiocina CCL24/sangue , Quimiocina CCL24/líquido cefalorraquidiano , Quimiocina CCL26/sangue , Quimiocina CCL26/líquido cefalorraquidiano , Humanos , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano , Receptores CCR3/imunologia , Receptores CCR3/metabolismo
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