RESUMO
Previous studies reported significantly altered tryptophan catabolite concentrations in major depression. Thus, tryptophan catabolites were considered as potential biomarkers of depression and their modulators as potential targets for psychopharmacotherapy. However, the results were based mainly on studies with small sample sizes limiting their generalizability. Against this background, we investigated the relationship of peripheral tryptophan catabolites with depression in a population-based sample with n = 3,389 participants (with fasting status ≥ 8 h and C-reactive protein < 10 mg/L). N = 248 had clinically significant depression according to a PHQ-9 score of ≥ 10, n = 1,101 subjects had mild depressive symptoms with PHQ-9 scores between 5 and 9, and n = 2,040 had no depression. After multivariable adjustment, clinically significant depression was associated with lower kynurenine and kynurenic acid. Spearman correlation coefficients of the tryptophan catabolites with the severity of depression were very small (rho ≤ 0.080, p ≤ 0.015). None of the tryptophan catabolites could diagnostically separate depressed from not depressed persons. Concerning linear associations, kynurenine and kynurenic acid were associated only with the severity and the cognitive dimension of depression but not its somatic dimension. Tryptophan catabolites were not associated with persistence or recurrence of depression at the 5 year follow-up. The results replicated the association between kynurenine and kynurenic acid with depression. However, the associations were small raising doubts about their clinical utility. Findings underline the complexity of the relationships between depression and tryptophan catabolites. The search for subgroups of depression with a potentially higher impact of depression might be warranted.
Assuntos
Transtorno Depressivo Maior , Triptofano , Humanos , Proteína C-Reativa , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/metabolismo , Ácido Cinurênico/química , Ácido Cinurênico/metabolismo , Cinurenina/química , Cinurenina/metabolismo , Triptofano/química , Triptofano/metabolismo , BiomarcadoresRESUMO
BACKGROUND: Tryptophan catabolites ("TRYCATs") produced by the kynurenine pathway (KP) may play a role in depression pathophysiology. Studies comparing TRYCATs levels in depressed subjects and controls provided mixed findings. We examined the association of TRYCATs levels with 1) the presence of Major Depressive Disorder (MDD), 2) depressive symptom profiles and 3) inflammatory markers. METHODS: The sample from the Netherlands Study of Depression and Anxiety included participants with current (n = 1100) or remitted (n = 753) MDD DSM-IV diagnosis and healthy controls (n = 642). Plasma levels of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KynA), quinolinic acid (QA), C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured. Atypical/energy-related symptom (AES), melancholic symptom (MS) and anxious-distress symptom (ADS) profiles were derived from questionnaires. RESULTS: After adjustment for age, sex, education, smoking status, alcohol consumption and chronic diseases, no significant differences in TRYCATs were found comparing MDD cases versus controls. The MS profile was associated (q < 0.05) with lower KynA (ß = -0.05), while AES was associated with higher KYN (ß = 0.05), QA (ß = 0.06) and TRP (ß = 0.06). Inflammatory markers were associated with higher KYN (CRP ß = 0.12, IL-6 ß = 0.08, TNF ß = 0.10) and QA (CRP ß = 0.21, IL-6 ß = 0.12, TNF ß = 0.18). Significant differences against controls emerged after selecting MDD cases with high (top 30%) CRP (KYN d = 0.20, QA d = 0.33) and high TNF (KYN d = 0.24; QA d = 0.39). CONCLUSIONS: TRYCATs levels were related to specific clinical and biological features, such as atypical symptoms or a proinflammatory status. Modulation of KP may potentially benefit a specific subset of depressed patients. Clinical studies should focus on patients with clear evidence of KP dysregulations.
Assuntos
Transtorno Depressivo Maior , Triptofano , Depressão , Humanos , Inflamação , Ácido Cinurênico , CinureninaRESUMO
OBJECTIVES: To evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on rapid efficacy readouts for disease-modifying trials. METHODS: 40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies. RESULTS: Longitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision. CONCLUSIONS: To exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months.
Assuntos
Doença de Huntington/terapia , Projetos de Pesquisa , Adulto , Idoso , Estudos de Casos e Controles , Córtex Cerebral/patologia , Cognição , Progressão da Doença , Feminino , Humanos , Doença de Huntington/patologia , Doença de Huntington/psicologia , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
BACKGROUND: This study investigated the hypothesis that AFQ056 (mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntington's disease (HD). METHODS: This 32-day randomized, double-blind, parallel-group, proof-of-concept study investigated AFQ056 (25-150 mg [incremental doses], twice-daily) versus placebo in patients with HD. Primary efficacy assessments were the chorea-sum score and orientation index (nondominant hand) from the quantitative motor (Q-Motor) grasping task at day 28. Key secondary efficacy assessments included finger-tapping in the Unified Huntington's Disease Rating Scale-Total Motor Score and Q-Motor measures. Safety and tolerability were assessed. RESULTS: Overall, 42 patients were randomized. At day 28, no improvement was observed on the primary efficacy assessments (P > 0.10) with AFQ056 versus placebo. The Q-Motor speeded-tapping interonset interval variability was reduced with AFQ056 versus placebo for the nondominant hand (P = 0.01). The incidence of adverse events was 66.7% with AFQ056 and 57.1% with placebo. CONCLUSIONS: AFQ056 did not reduce choreatic movements in HD, but was well tolerated. The clinical relevance of the Q-Motor findings (speeded-tapping) are unknown and may warrant further investigation.
Assuntos
Coreia/tratamento farmacológico , Coreia/etiologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Doença de Huntington/complicações , Indóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Avaliação da Deficiência , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
AIMS: Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers. RESULTS: Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen. CONCLUSIONS: Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.
Assuntos
Carbazóis/uso terapêutico , Doença de Huntington/tratamento farmacológico , Sirtuína 1/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Carbazóis/administração & dosagem , Carbazóis/efeitos adversos , Carbazóis/sangue , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Doença de Huntington/sangue , Doença de Huntington/psicologia , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Índice de Gravidade de Doença , Distribuição Tecidual , Resultado do Tratamento , Adulto JovemRESUMO
Posterior cortical volume changes and abnormal visuomotor performance are present in patients with Huntington's disease (HD). However, it is unclear whether posterior cortical volume loss contributes to abnormal neural activity, and whether activity changes predict cognitive dysfunction. Using magnetic resonance imaging (MRI), we investigated brain structure and visual network activity at rest in patients with early HD (n = 20) and healthy controls (n = 20). The symbol digit modalities test (SDMT) and subtests of the Visual Object and Space Perception Battery were completed offline. For functional MRI data, a group independent component analysis was used. Voxel-based morphometry was employed to assess regional brain atrophy, and 'biological parametric mapping' analyses were included to investigate the impact of atrophy on neural activity. Patients showed significantly worse visuomotor and visual object performance than controls. Structural analyses confirmed occipitotemporal atrophy. In patients and controls, two spatiotemporally distinct visual systems were identified. Patients showed decreased activity in the left fusiform cortex, and increased left cerebellar activity. These findings remained stable after correction for brain atrophy. Lower fusiform cortex activity was associated with lower SDMT performance and with higher disease burden scores. These associations were absent when cerebellar function was related to task performance and disease burden. The results of this study suggest that regionally specific functional abnormalities of the visual system can account for the worse visuomotor cognition in HD patients. However, occipital volume changes cannot sufficiently explain abnormal neural function in these patients.
Assuntos
Cognição , Doença de Huntington/fisiopatologia , Lobo Occipital/fisiopatologia , Reconhecimento Visual de Modelos , Percepção Espacial , Cerebelo/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Temporal/fisiopatologiaRESUMO
INTRODUCTION: Glutaric aciduria type II (GAII) is a rare autosomal recessive disorder with variable clinical course. The disorder is caused by a defect in the mitochondrial electron transfer flavoprotein or the electron transfer flavoprotein dehydrogenase (ETFDH). METHODS: We performed clinical characterization, brain and whole body MRI, muscle histopathology, and genetic analysis of the ETFDH gene in a young woman. RESULTS: She presented with rhabdomyolysis and severe quadriparesis. We identified a novel homozygous missense mutation in ETFDH (c.1544G>T, p.Ser515Ile). Body fat MRI revealed a large amount of subcutaneous fat but no increase in visceral fat despite steatosis of liver and muscle. Diffusion tensor imaging (DTI) of cerebral MRI revealed reduced directionality of the white matter tracts. Histopathological findings showed lipid storage myopathy. CONCLUSIONS: In this study, we highlight diagnostic clues and body fat MRI in this rare metabolic disorder.
Assuntos
Flavoproteínas Transferidoras de Elétrons/genética , Proteínas Ferro-Enxofre/genética , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Mutação/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Adulto , Anisotropia , Encéfalo/patologia , Imagem de Tensor de Difusão , Feminino , Humanos , Imageamento por Ressonância Magnética , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Deficiência Múltipla de Acil Coenzima A Desidrogenase/fisiopatologia , Imagem Corporal TotalRESUMO
BACKGROUND: Corrupted gradient directions (GD) in diffusion weighted images may seriously affect reliability of diffusion tensor imaging (DTI)-based comparisons at the group level. In the present study we employed a quality control (QC) algorithm to eliminate corrupted gradient directions from DTI data. We then assessed effects of this procedure on comparisons between Huntington disease (HD) subjects and controls at the group level. METHODS: Sixty-one HD patients in early stages and forty matched healthy controls were studied in a longitudinal design (baseline and two follow-ups at three time points over 15 months), in a multicenter setting with similar acquisition protocols on four different MR scanners at four European study sites. A QC algorithm was used to identify corrupted GD in DTI data sets. Differences in fractional anisotropy (FA) maps at the group level with and without elimination of corrupted GD were analyzed. RESULTS: The elimination of corrupted GD had an impact on individual FA maps as well as on cross-sectional group comparisons between HD subjects and controls. Following application of the QC algorithm, less small clusters of FA changes were observed, compared to the analysis without QC. However, the main pattern of regional reductions and increases in FA values with and without QC-based elimination of corrupted GD was unchanged. CONCLUSION: An impact on the result patterns of the comparison of FA maps between HD subjects and controls was observed depending on whether QC-based elimination of corrupted GD was performed. QC-based elimination of corrupted GD in DTI scans reduces the risk of type I and type II errors in cross-sectional group comparison of FA maps contributing to an increase in reliability and stability of group comparisons.
Assuntos
Encéfalo/ultraestrutura , Imagem de Tensor de Difusão/métodos , Doença de Huntington/diagnóstico , Algoritmos , Anisotropia , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Estudos Transversais , Humanos , Modelos Teóricos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Huntington's disease (HD) is a monogenic disorder caused by an aberrant expansion of CAG repeats in the huntingtin gene (HTT). Pathogenesis is associated with expression of the mutant (mHTT) protein in the CNS, with its levels most likely related to disease progression and symptom severity. Since non-invasive methods to quantify HTT in the CNS do not exist, measuring amount of soluble HTT in peripheral cells represents an important step in development of disease-modifying interventions in HD. RESULTS: An ELISA assay using commercially available antibodies was developed to quantify HTT levels in complex matrices like mammalian cell cultures lysates and human samples. The immunoassay was optimized using a recombinant full-length HTT protein, and validated both on wild-type and mutant HTT species. The ability of the assay to detect significant variations of soluble HTT levels was evaluated using an HSP90 inhibitor that is known to enhance HTT degradation. Once optimized, the bioassay was applied to peripheral blood mononuclear cells (PBMCs) from HD patients, demonstrating good potential in tracking the disease course. CONCLUSIONS: The method described here represents a validated, simple and rapid bio-molecular assay to evaluate soluble HTT levels in blood cells as useful tool in disease and pharmacodynamic marker identification for observational and clinical trials.
Assuntos
Análise Química do Sangue/métodos , Ensaio de Imunoadsorção Enzimática , Leucócitos Mononucleares/metabolismo , Proteínas do Tecido Nervoso/sangue , Anticorpos/imunologia , Ensaio de Imunoadsorção Enzimática/normas , Células HEK293 , Humanos , Proteína Huntingtina , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Espectrometria de Massas , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/normas , Controle de Qualidade , Proteínas Recombinantes/análise , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/normasRESUMO
BACKGROUND: Anhedonia and other deficits in reward- and motivation-related processing in psychiatric patients, including patients with major depressive disorder (MDD), represent a high unmet medical need. Neurobiologically, these deficits in MDD patients are mainly associated with low dopamine function in a frontostriatal network. In this study, alterations in brain activation changes during reward processing and at rest in MDD patients compared with healthy subjects are explored and the effects of a single low dose of the dopamine D2 receptor antagonist amisulpride are investigated. METHODS: This is a randomized, controlled, double-blind, single-dose, single-center parallel-group clinical trial to assess the effects of a single dose of amisulpride (100 mg) on blood-oxygenation-level-dependent (BOLD) responses during reward- and motivation-related processing in healthy subjects (n = 60) and MDD patients (n = 60). Using functional magnetic resonance imaging (fMRI), BOLD responses are assessed during the monetary incentive delay (MID) task (primary outcome). Exploratory outcomes include BOLD responses and behavioral measures during the MID task, instrumental learning task, effort-based decision-making task, social incentive delay task, and probabilistic reward task as well as changes in resting state functional connectivity and cerebral blood flow. DISCUSSION: This study broadly covers all aspects of reward- and motivation-related processing as categorized by the National Institute of Mental Health Research Domain Criteria and is thereby an important step towards precision psychiatry. Results regarding the immediate effects of a dopaminergic drug on deficits in reward- and motivation-related processing not only have the potential to significantly broaden our understanding of underlying neurobiological processes but might eventually also pave the way for new treatment options. TRIAL REGISTRATION: ClinicalTrials.gov NCT05347199. April 12, 2022.
Assuntos
Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Motivação , Amissulprida/efeitos adversos , Imageamento por Ressonância Magnética/métodos , Voluntários Saudáveis , Encéfalo/diagnóstico por imagem , Recompensa , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Patients with schizophrenia experience cognitive impairment related to neural network dysfunction and deficits in sensory processing. These deficits are thought to be caused by N-methyl-D-aspartate receptor hypofunction and can be assessed in patient populations using electroencephalography (EEG). This substudy from a Phase II, randomized, double-blind, placebo-controlled, parallel-group study investigating the safety and efficacy of the novel glycine transporter-1 inhibitor, iclepertin (BI 425809), assessed the potential of EEG parameters as clinically relevant biomarkers of schizophrenia and response to iclepertin treatment. Eligible patients were randomized to once-daily add-on iclepertin (2, 5, 10, or 25 mg), or placebo (1:1:1:1:2 ratio) for 12 weeks. EEG data were recorded from a subgroup of patients (n = 79) at baseline and end of treatment (EoT). EEG parameters of interest were mismatch negativity (MMN), auditory steady-state response (ASSR), and resting state gamma power, and their correlations with clinical assessments. At baseline, MMN and ASSR exhibited consistent correlations with clinical assessments, indicating their potential value as neurophysiological biomarkers of schizophrenia-related deficits. ASSR measures were positively correlated to the MATRICS Consensus Cognitive Battery overall and neurocognitive composite scores; MMN amplitude was positively correlated with Positive and Negative Syndrome Scale scores. However, correlations between change from baseline (CfB) at EoT in clinical assessments, and baseline or CfB at EoT for EEG parameters were modest and inconsistent between dose groups, which might indicate low potential of these EEG parameters as predictive and treatment response biomarkers. Further methodological refinement is needed to establish EEG parameters as useful drug development tools for schizophrenia.
Assuntos
Esquizofrenia , Biomarcadores , Eletroencefalografia , Potenciais Evocados Auditivos/fisiologia , Humanos , Compostos Orgânicos/uso terapêutico , Esquizofrenia/tratamento farmacológicoRESUMO
To evaluate cerebrospinal fluid (CSF) proteins reflecting processes of neurodegeneration and glial activation in progressive supranuclear palsy (PSP; Richardson's syndrome, n = 20; PSP-Parkinsonism, n = 7) and multiple system atrophy (MSA, n = 25), we analyzed tau, phosphorylated tau, amyloid-beta(1-42) (Abeta1-42), Abeta1-40, glial fibrillary acidic protein (GFAP), and CSF routine variables. Individuals with PSP-Parkinsonism and MSA had elevated tau levels when compared with Richardson's syndrome, Parkinson's disease (PD), and age-matched controls (P Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano
, Transtornos Parkinsonianos/líquido cefalorraquidiano
, Fragmentos de Peptídeos/líquido cefalorraquidiano
, Proteínas tau/líquido cefalorraquidiano
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Feminino
, Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Estatísticas não Paramétricas
RESUMO
Elevated cerebrospinal fluid (CSF)/serum quotients of albumin (Q(Alb)) may occur in motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS), but the pathophysiologic mechanisms underlying these alterations are unclear. Evidence from animal experiments suggests that the arterial carbon dioxide level might affect the Q(Alb), i.e. the function of the blood-CSF barrier (BCB). We therefore compared basic CSF parameters in different forms of MND (ALS, n = 105; lower motor neuron diseases, n = 12; and upper motor neuron diseases, n = 7) and investigated the relationship between elevated Q(Alb) and the arterial partial pressure of carbon dioxide (pCO(2)) in ALS where respiratory insufficiency leads to hypercapnia in the course of the disease. Pathologic elevations of Q(Alb) occurred in 32 of 124 MND patients. In ALS, Q(Alb) significantly correlated with the arterial pCO(2) (r = 0.454; P = 0.001; n = 45). These data indicate that BCB dysfunction is a frequent finding in different forms of MND and may reflect distinct pathophysiological mechanisms. In ALS, an important underlying mechanism might be the influence of the arterial pCO(2) which may alter the CSF flow.
Assuntos
Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Barreira Hematoencefálica , Hipercapnia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/líquido cefalorraquidiano , Albumina Sérica/metabolismo , Paraplegia Espástica Hereditária/líquido cefalorraquidiano , Adulto JovemRESUMO
To investigate whether and how cerebrospinal fluid (CSF) findings can contribute to distinguish tick-borne encephalitis (TBE) from herpes simplex virus (HSV) and varicella zoster virus (VZV) induced central nervous system (CNS) infections (HSV-I, VZV-I). Chart review and identification of TBE, HSV- I, and VZV-I was carried out, fulfilling the following criteria: (1) clinical signs of encephalitis and/or meningitis, (2) complete CSF analysis and confirmed viral etiology by either PCR or antibody testing in CSF, (3) hospitalized patients, and (4) available brain magnetic resonance imaging (MRI). Fifty-nine patients with 118 CSF/serum pairs were included. These comprised 21 with TBE (35 CSF/serum pairs), 20 (40 CSF/serum pairs) with HSV-I, and 18 (43 CSF/serum pairs) with VZV-I. In contrast to HSV-I and VZV-I, CSF cell differentiation in TBE showed more often an increased (>20%) proportion of granulocytes (p < 0.01) and a more frequent quantitative intrathecal IgM synthesis (p = 0.001 and p < 0.01, respectively), while the second was even more pronounced when follow-up CSF analyses were included (p < 0.001). CSF findings help to distinguish TBE from other viral infections. In cases with CSF pleocytosis and a positive history for a stay in or near an endemic area, TBE antibodies in CSF and serum should be determined, especially if granulocytes in CSF cell differentiation and/or an intrathecal IgM synthesis is present.
Assuntos
Infecções do Sistema Nervoso Central/diagnóstico , Diagnóstico Diferencial , Encefalite Transmitida por Carrapatos/diagnóstico , Meningite/diagnóstico , Adulto , Idoso , Infecções do Sistema Nervoso Central/sangue , Infecções do Sistema Nervoso Central/líquido cefalorraquidiano , Infecções do Sistema Nervoso Central/virologia , Encefalite Transmitida por Carrapatos/sangue , Encefalite Transmitida por Carrapatos/líquido cefalorraquidiano , Encefalite Transmitida por Carrapatos/virologia , Feminino , Herpesvirus Humano 3/patogenicidade , Humanos , Imunidade Humoral/genética , Imunidade Humoral/imunologia , Imunoglobulina M/sangue , Leucocitose/sangue , Leucocitose/líquido cefalorraquidiano , Leucocitose/diagnóstico , Leucocitose/virologia , Imageamento por Ressonância Magnética , Masculino , Meningite/sangue , Meningite/líquido cefalorraquidiano , Meningite/virologia , Pessoa de Meia-Idade , Simplexvirus/imunologia , Simplexvirus/patogenicidadeRESUMO
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron diseases (MND) characterized by progressive selective degeneration of motor neurons. Although several mutations underlying rare cases of familial ALS were identified during the last decade, the pathogenesis of ALS remains poorly understood. Various mechanisms have been suggested to contribute to disease pathology such as excitotoxicity, oxidative stress, protein aggregation, and inflammation. Accordingly, several candidate biochemical markers related to these pathomechanisms were investigated in cerebrospinal fluid (CSF). Although none of these markers gained clinical importance so far, CSF might reflect pathophysiological alterations in the course of the disease and could therefore provide an insight into pathomechanisms in vivo. It is suggested that cellular and proteinchemical processes are better reflected in the CSF than in other body fluids such as blood or urine due to the proximity of the affected motor neurons to the CSF compartment. Accordingly, alterations in protein expression, post-translational modification or turnover within the tissue of the central nervous system may be mirrored in corresponding changes in CSF protein content. Research on biomarkers in CSF using novel discovery technologies such as proteomics allows to search for a set of proteins that reflect different disease specific molecular pathways and might therefore be of relevance for the establishment of biomarkers for therapeutic monitoring and the development of novel therapies. In this review, an updated overview is given on CSF biomarkers related to the pathomechanisms supposed to be participating in the complex disease process of ALS.
Assuntos
Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Antioxidantes/metabolismo , Proteínas do Líquido Cefalorraquidiano/análise , DNA/química , Humanos , Inflamação , Peroxidação de Lipídeos , Modelos Biológicos , Modelos Químicos , Neurônios Motores/patologia , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo , Proteômica/métodos , Proteínas tau/metabolismoRESUMO
BACKGROUND: Chemotherapy-induced polyneuropathy (CIPN) is a common toxicity after chemotherapy, immunomodulatory drugs or proteasome inhibitors, which is difficult to treat and may also have impact on quality of life. The objective of the study was to evaluate whole-body vibration (WBV) on the background of an integrated program (IP) including massage, passive mobilization and physical exercises on CIPN. PATIENTS AND METHODS: In an exploratory phase-2 study patients with CIPN (NCI CTC grade 2/3) were randomized for WBV plus IP (experimental) to IP alone (standard). 15 training sessions within 15 weeks were intended. As primary endpoint we used chair-rising test (CRT) to assess physical fitness and coordination. In addition, locomotor and neurological tests and self-assessment tools were performed. RESULTS: A total 131 patients with CIPN were randomized (standard, n = 65; experimental, n = 66). The median age was 60 (range 24-71) years; 44 patients had haematological neoplasms and 87 solid tumors. At baseline, all patients presented with an abnormal CRT. Fifteen (standard) and 22 (experimental) patients left the program due to progression/relapse or concomitant disease. There was no significant difference in the proportion of patients with normal CRT (<10 s) at follow up between experimental (68%) and standard (56%) (p = 0.20). All patients experienced less symptoms and pain (p < 0.001) and had improved CRT (p < 0.001) over time. WBV was significantly associated with a higher reduction of time needed for CRT (p = 0.02) and significantly improved warm-detection-threshold comparing baseline to follow-up assessment (p = 0.02). CONCLUSION: Whole-body vibration on the background of an IP may improve physical fitness and coordination in patients suffering from CIPN. Trial registration Retrospectively registered at http://www.iscrtn.com (ISRCTN 51361937) and http://www.clinicaltrials.gov (NCT02846844).
RESUMO
In Huntington's disease, the relationship of brain structure, brain function and clinical measures remains incompletely understood. We asked how sensory-motor network brain structure and neural activity relate to each other and to motor performance. Thirty-four early stage HD and 32 age- and sex-matched healthy control participants underwent structural magnetic resonance imaging (MRI), diffusion tensor, and intrinsic functional connectivity MRI. Diffusivity patterns were assessed in the cortico-spinal tract and the thalamus-somatosensory cortex tract. For the motor network connectivity analyses the dominant M1 motor cortex region and for the basal ganglia-thalamic network the thalamus were used as seeds. Region to region structural and functional connectivity was examined between thalamus and somatosensory cortex. Fractional anisotropy (FA) was higher in HD than controls in the basal ganglia, and lower in the external and internal capsule, in the thalamus, and in subcortical white matter. Between-group axial and radial diffusivity differences were more prominent than differences in FA, and correlated with motor performance. Within the motor network, the insula was less connected in HD than in controls, with the degree of connection correlating with motor scores. The basal ganglia-thalamic network's connectivity differed in the insula and basal ganglia. Tract specific white matter diffusivity and functional connectivity were not correlated. In HD sensory-motor white matter organization and functional connectivity in a motor network were independently associated with motor performance. The lack of tract-specific association of structure and function suggests that functional adaptation to structural loss differs between participants.
Assuntos
Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Córtex Motor/diagnóstico por imagem , Vias Neurais/diagnóstico por imagem , Tratos Piramidais/patologia , Substância Branca/patologia , Adulto , Idoso , Anisotropia , Mapeamento Encefálico , Estudos de Casos e Controles , Imagem de Tensor de Difusão , Feminino , Humanos , Doença de Huntington/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tratos Piramidais/diagnóstico por imagem , Substância Branca/diagnóstico por imagemRESUMO
Impairments of emotion recognition have been widely documented in Huntington's disease (HD), but little is known concerning how these relate to other aspects of social cognition, including first impressions of traits such as trustworthiness and dominance. Here, we introduce a novel and sensitive method to investigate the ability to evaluate trustworthiness and dominance from facial appearance, with control tasks measuring ability to perceive differences between comparable stimuli. We used this new method together with standard tests of face perception to investigate social cognition in HD. We found that a subgroup of people with HD was impaired at perceiving trustworthiness and dominance, and that perceiving trustworthiness and dominance were correlated with impaired facial expression recognition. In addition, we used diffusion tensor imaging (DTI) to provisionally identify candidate brain regions associated with social cognition by contrasting regional functional anisotropy (FA) measures between subgroups of HD participants showing normal or impaired perception of trustworthiness and dominance, and by correlating these regional brain abnormalities with behavioural performance on tests of emotion recognition. In this way we show for the first time alterations in perception of trustworthiness and dominance in people with HD and link these to regions which may map the boundaries of the social brain. The pattern of breakdown seen in this neurodegenerative disease can thus be used to explore potential inter-relationships between different components of social cognition.
Assuntos
Encéfalo/fisiopatologia , Emoções/fisiologia , Expressão Facial , Doença de Huntington/fisiopatologia , Percepção/fisiologia , Reconhecimento Psicológico/fisiologia , Adulto , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Doença de Huntington/psicologia , Masculino , Pessoa de Meia-Idade , Neuropsicologia/métodos , Comportamento SocialRESUMO
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to progressive cell death of upper and lower motor neurons and reactive astrogliosis. Two proteins which may be relevant in this respect (tau and S100 beta) were studied in cerebrospinal fluid (CSF) next to routine parameters in 20 patients with sporadic ALS and 20 age-matched controls. Serum levels of creatine kinase (CK) were also determined to monitor the muscular involvement. S100 beta showed a significant decrease in CSF over the disease course (P=0.024). CSF tau as well as serum CK were elevated in 70% of the ALS patients. While highest CSF tau levels were found rather in the early disease stages, serum CK showed a shift of the peak values to several months later. Elevation of the CSF/serum albumin quotient occurred in 20% of the cases most likely representing a non-specific finding in ALS.
Assuntos
Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Creatina Quinase/sangue , Fatores de Crescimento Neural/líquido cefalorraquidiano , Proteínas S100/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Adulto , Idade de Início , Idoso , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculos/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100 , Estatísticas não Paramétricas , Fatores de TempoRESUMO
Functional compensation demonstrated as mechanism to offset neuronal loss in early Alzheimer disease may also occur in other adult-onset neurodegenerative diseases, particularly Huntington disease (HD) with its genetic determination and gradual changes in structural integrity. In HD, neurodegeneration typically initiates in the dorsal striatum, successively affecting ventral striatal areas. Investigating carriers of the HD mutation with evident dorsal, but only minimal or no ventral striatal atrophy, we expected to find evidence for compensation of ventral striatal functioning. We investigated 14 pre- or early symptomatic carriers of the mutation leading to HD and 18 matched healthy controls. Participants underwent structural T1 magnetic resonance imaging (MRI) and functional MRI during a reward task that probes ventral striatal functioning. Motor functioning and attention were assessed with reaction time (RT) tasks. Structural images confirmed a specific decrease of dorsal striatal but only marginal ventral striatal volume in HD relative to control subjects, paralleling prolonged RT in the motor response tasks. While behavioral performance in the reward task during fMRI scanning was unimpaired, reward-related fMRI signaling in the HD group was differentially enhanced in the bilateral ventral striatum and in bilateral orbitofrontal cortex/anterior insula, as another region sensitive to reward processing. We provide evidence for the concept of functional compensation in premanifest HD which may suggest a defense mechanism in neurodegeneration. Given the so far inevitable course of HD with its genetically determined endpoint, this disease may provide another model to study the different aspects of the concept of functional compensation.