RESUMEN
BACKGROUND: Neurofilament light (NfL) has previously been highlighted as a potential biomarker for Huntington's Disease (HD) using cross-sectional analyses. Our study aim was to investigate how longitudinal trajectories of plasma NfL relate to HD disease stage. METHODS: 108 participants [78 individuals with the HD mutation, and 30 healthy controls (HC)] were included in this study. Individuals with the HD mutation were categorised separately by both HD-Integrated Staging System (HD-ISS) (Study 1) and PIN score-Approximated Staging System (PASS) (Study 2) criteria. Plasma NfL trajectories were examined using Mixed Linear Modeling (MLM); associations with symptom presentation were assessed using Spearman's rho correlations. FINDINGS: The MLM coefficients for disease stage (HD-ISS ß = 32.73, p < 0.0001; PASS ß = 33.00, p < 0.0001) and disease stage∗time (HD-ISS ß = 7.85, p = 0.004; PASS ß = 6.58, p = 0.0047) suggest these are significant contributors to plasma NfL levels. In addition, the plasma NfL rate of change varied significantly across time (HD-ISS ß = 3.14, p = 0.04; PASS ß = 2.94, p = 0.050). The annualised rate of change was 8.32% for HC; 10.55%, 12.75% and 15.62% for HD-ISS Stage ≤1, Stage 2, and Stage 3, respectively; and 12.13%, 10.46%, 10.33%, 17.52%, for PASS Stage 0, Stage 1, Stage 2, and Stage 3, respectively. Plasma NfL levels correlated with the Symbol Digit Modalities Test (SDMT) in HD-ISS Stage ≤1, and both SDMT and Total Motor Score in Stage 3 (ps < 0.01). INTERPRETATION: Our findings suggest that plasma NfL levels increase linearly across earlier disease stages, correlating with the cognitive SDMT measure. Thereafter, an increase or surge in plasma NfL levels, paired with correlations with both cognitive and motor measures, suggest a late acceleration in clinical and pathological progression. FUNDING: NIH (NS111655); the UCSD HDSA CoE; the UCSD ADRC (NIH-NIA P30 AG062429).
Asunto(s)
Biomarcadores , Progresión de la Enfermedad , Enfermedad de Huntington , Proteínas de Neurofilamentos , Humanos , Enfermedad de Huntington/sangre , Enfermedad de Huntington/patología , Masculino , Proteínas de Neurofilamentos/sangre , Femenino , Persona de Mediana Edad , Biomarcadores/sangre , Estudios Longitudinales , Adulto , Anciano , Índice de Severidad de la EnfermedadAsunto(s)
Biomarcadores , Enfermedad de Huntington , Proteínas de Neurofilamentos , Humanos , Enfermedad de Huntington/sangre , Enfermedad de Huntington/patología , Enfermedad de Huntington/diagnóstico , Biomarcadores/sangre , Proteínas de Neurofilamentos/sangre , Femenino , Masculino , Persona de Mediana Edad , AdultoRESUMEN
The main trend of current research in neurodegenerative diseases (NDDs) is directed towards the discovery of novel biomarkers for disease diagnostics and progression. The pathological features of NDDs suggest that diagnostic markers can be found in peripheral fluids and cells. Herein, we investigated the thermodynamic behavior of the peripheral red blood cells (RBCs) derived from patients diagnosed with three common NDDs-Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) and compared it with that of healthy individuals, evaluating both fresh and aged RBCs. We established that NDDs can be differentiated from the normal healthy state on the basis of the variation in the thermodynamic parameters of the unfolding of major RBCs proteins-the cytoplasmic hemoglobin (Hb) and the membrane Band 3 (B3) protein. A common feature of NDDs is the higher thermal stability of both Hb and B3 proteins along the RBCs aging, while the calorimetric enthalpy can distinguish PD from ALS and AD. Our data provide insights into the RBCs thermodynamic behavior in two complex and tightly related phenomena-neurodegenerative pathologies and aging, and it suggests that the determined thermodynamic parameters are fingerprints of the altered conformation of Hb and B3 protein and modified RBCs' aging in the studied NDDs.
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Envejecimiento/sangre , Biomarcadores/sangre , Enfermedades Neurodegenerativas/sangre , Termodinámica , Envejecimiento/patología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/patología , Eritrocitos/patología , Hemoglobinas/metabolismo , Humanos , Enfermedad de Huntington/sangre , Enfermedad de Huntington/patología , Enfermedades Neurodegenerativas/patología , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/patologíaRESUMEN
Suppressor of cytokine signaling (SOCS) proteins are primarily feedback inhibitors of cytokine signaling. The two conserved domains of SOCS proteins have distinct functions. Src homology 2 (SH2) domain inhibits cytokine receptor, while SOCS box acts as an E3 ubiquitin ligase. SOCS2, a cytokine signaling suppressor, has been primarily implicated in regulating inflammatory conditions in neuronal diseases. However, SOCS proteins have been suggested to play diverse roles in healthy and diseased nervous system including neurodegenerative disorders. In this study, SOCS2 was found to be upregulated in Huntington's disease and was substantially induced in extended polyglutamine (polyQ)-expressing striatal cells. The induced level was augmented under aging conditions. In extended polyQ-expressing cells, downregulated SOCS2 improved autophagic dysfunction rather than altered inflammatory conditions. Overall, we suggest that SOCS2 involves in regulating autophagy by functioning as an E3 ligase in extended polyQ conditions, and consequently regulates cell damage and cell death type.
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Autofagia , Enfermedad de Huntington/genética , Proteínas Supresoras de la Señalización de Citocinas/genética , Envejecimiento , Animales , Línea Celular , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Humanos , Enfermedad de Huntington/sangre , Enfermedad de Huntington/patología , Masculino , Ratones , Proteínas Supresoras de la Señalización de Citocinas/sangre , Regulación hacia ArribaRESUMEN
Recent work on Huntington disease (HD) suggests that somatic instability of CAG repeat tracts, which can expand into the hundreds in neurons, explains clinical outcomes better than the length of the inherited allele. Here, we measured somatic expansion in blood samples collected from the same 50 HD mutation carriers over a twenty-year period, along with post-mortem tissue from 15 adults and 7 fetal mutation carriers, to examine somatic expansions at different stages of life. Post-mortem brains, as previously reported, had the greatest expansions, but fetal cortex had virtually none. Somatic instability in blood increased with age, despite blood cells being short-lived compared to neurons, and was driven mostly by CAG repeat length, then by age at sampling and by interaction between these two variables. Expansion rates were higher in symptomatic subjects. These data lend support to a previously proposed computational model of somatic instability-driven disease.
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Envejecimiento , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Expansión de Repetición de Trinucleótido/genética , Feto Abortado , Adulto , Edad de Inicio , Anciano , Progresión de la Enfermedad , Femenino , Lóbulo Frontal/patología , Humanos , Enfermedad de Huntington/sangre , Enfermedad de Huntington/patología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación/genéticaRESUMEN
BACKGROUND: Huntington's disease (HD) starts its pathology long before clinical manifestation, however, there is no therapy to cure it completely and only a few studies have been reported for delaying the progression of HD. Recently, it has been shown that heterochronic parabiosis can modulate the neurodegenerative diseases. Despite the importance of the transportation process of positive factors during heterochronic parabiosis, there were limited understandings because the transportation process is nanoscale, which makes it difficult to identify the messenger unit. We demonstrated that heterochronic parabiosis could modulate HD in R6/2 mice model, and identified the messenger unit for transferring positive factors in the young blood serum. METHODS: R6/2 mice were surgically connected with young wild-type mice (n = 13), old wild-type mice (n = 8), or R6/2 mice (n = 6) to examine the effect of heterochronic parabiosis. Parabionts composed of 5- to 6-week-old transgenic and wild-type mice were observed for 6 weeks in a single cage. The in vitro cellular model of HD cells were treated by the blood serum of the young or old mice, and by the exosomes isolated from thereof. The in vitro cellular model of HD were developed by differentiating neural stem cells cultured from SVZ of the brain. RESULTS: After the heterochronic parabiosis, the weight loss and survival of HD mice was improved. Also, mutant Huntingtin aggregation (EM48 p < 0.005), improvement of mitochondria dysfunction (PGC-1a p < 0.05, p-CREB/CREB p < 0.005), cell death (p53 p < 0.05, Bax p < 0.05, Cleaved-caspase3 p < 0.05), and cognition (DCX p < 0.5) showed a near complete restoration. In addition, treating in vitro cellular model of HD by the exosomes from young blood serum improved mutant Huntingtin aggregation (EM48 p < 0.05), mitochondria biogenesis (p-CREB/CREB p < 0.005), cell death (p53 p < 0.05, Bax p < 0.005, Cleaved-caspase3 p < 0.05, Bcl-2 p < 0.05), and cell proliferation (WST-1 p < 0.005). CONCLUSIONS: We found that the overall pathology of HD could be improved by the shared blood circulation through heterochronic parabiosis, furthermore, we demonstrated that the exosomes could be messengers for transferring positive factors, showing the potential of exosomes from young blood for the amelioration of HD.
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Exosomas/genética , Exosomas/metabolismo , Enfermedad de Huntington/sangre , Enfermedad de Huntington/genética , Parabiosis/métodos , Animales , Encéfalo/patología , Femenino , Enfermedad de Huntington/terapia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Ratones Transgénicos , Grabación en Video/métodosRESUMEN
OBJECTIVE: To investigate whether plasma NfL levels correlate with clinical symptom severity in premanifest (PM) and manifest HD (HD) individuals, and whether a NfL cut-point could distinguish PM from HD patients with reasonable accuracy. METHOD: 98 participants (33 control, 26 PM, 39 HD), underwent blood sample collection and clinical assessment, using both UHDRS and non-UHDRS measures, at one academic HD Center. Years to onset (YTO), probability of disease onset in 5 years, and predicted years until 60% onset probability were also calculated. NfL levels were measured using a Meso Scale Discovery assay. RESULTS: Cohorts differed by age. NfL levels differed significantly across diagnostic groups and were significantly correlated with age. Age-adjusted NfL levels were not correlated with clinical measures in either HD or PM cohorts, but were correlated when cohorts were combined. In PM subjects, NfL levels correlated with YTO, probability of onset in 5 years, and years until 60% onset probability. Using ROC analysis, a NfL cut-point of <53.15 pg/ml distinguished HD from control; <74.84 pg/ml distinguished HD from PM. CONCLUSIONS: These findings implicate plasma NfL as a peripheral prognostic marker for premanifest-HD. Notably, we show that significant correlations between NfL and clinical symptoms are detected only when PM + HD subjects are combined, but not within HD subjects alone. To date, prior studies have investigated the clinical usefulness of NfL exclusively in merged PM + HD cohorts. Our data suggests a biasing of these previous correlations, and hence potentially limited usefulness of plasma NfL in monitoring HD symptom progression, for example, in clinical trials.
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Enfermedad de Huntington/sangre , Enfermedad de Huntington/diagnóstico , Proteínas de Neurofilamentos/sangre , Síntomas Prodrómicos , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Converging lines of evidence from several models, and post-mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single-site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high-performance liquid-chromatography to measure the levels of KP metabolites-tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid-in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short-term stability, intergroup differences, associations with clinical and imaging measures and derived sample-size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient-derived biofluids.
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Enfermedad de Huntington/sangre , Enfermedad de Huntington/líquido cefalorraquídeo , Quinurenina/sangre , Quinurenina/líquido cefalorraquídeo , Transducción de Señal , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Cromatografía Líquida de Alta Presión , Estudios de Cohortes , Femenino , Humanos , Enfermedad de Huntington/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fenotipo , Estudios ProspectivosRESUMEN
INTRODUCTION: Huntington's disease (HD) is a severe neurodegenerative disorder with no effective treatment. Minimally-invasive biomarkers such as blood neurofilament light chain (NfL) in HD are therefore needed to quantitatively characterize neuronal loss. NfL levels in HD are known to correlate with disease progression and striatal atrophy, but whether they also reflect cortical degeneration remains elusive. METHODS: In a sample of 35 HD patients, we characterized the cortical macro (cortical thickness) and microstructural (increased intracortical diffusivity) correlates of plasma NfL levels. We further investigated whether NfL-related cortical alterations correlated with clinical indicators of disease progression. RESULTS: Increased plasma NfL levels in HD reflected posterior-cortical microstructural degeneration, but not reduced cortical thickness (p < 0.05, corrected). Importantly, these imaging alterations correlated, in turn, with more severe motor, cognitive and behavioral symptoms. CONCLUSION: Plasma NfL levels may be useful for tracking clinically-meaningful cortical deterioration in HD. Additionally, our results further reinforce the role of intracortical diffusivity as a valuable imaging indicator in movement disorders.
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Corteza Cerebral/patología , Enfermedad de Huntington/sangre , Enfermedad de Huntington/patología , Proteínas de Neurofilamentos/sangre , Adulto , Biomarcadores/sangre , Corteza Cerebral/diagnóstico por imagen , Imagen de Difusión Tensora , Femenino , Humanos , Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Huntington/fisiopatología , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
Kynurenine 3-monooxygenase (KMO) regulates the levels of neuroactive metabolites in the kynurenine pathway (KP), dysregulation of which is associated with Huntington's disease (HD) pathogenesis. KMO inhibition leads to increased levels of neuroprotective relative to neurotoxic metabolites, and has been found to ameliorate disease-relevant phenotypes in several HD models. Here, we crossed KMO knockout mice to R6/2 HD mice to examine the effect of KMO depletion in the brain and periphery. KP genes were dysregulated in peripheral tissues from R6/2 mice and KMO ablation normalised levels of a subset of these. KP metabolites were also assessed, and KMO depletion led to increased levels of neuroprotective kynurenic acid in brain and periphery, and dramatically reduced neurotoxic 3-hydroxykunurenine levels in striatum and cortex. Notably, the increased levels of pro-inflammatory cytokines TNFa, IL1ß, IL4 and IL6 found in R6/2 plasma were normalised upon KMO deletion. Despite these improvements in KP dysregulation and peripheral inflammation, KMO ablation had no effect upon several behavioural phenotypes. Therefore, although genetic inhibition of KMO in R6/2 mice modulates several metabolic and inflammatory parameters, these do not translate to improvements in primary disease indicators-observations which will likely be relevant for other interventions targeted at peripheral inflammation in HD.
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Citocinas/sangre , Enfermedad de Huntington/genética , Inflamación/sangre , Quinurenina 3-Monooxigenasa/genética , Animales , Modelos Animales de Enfermedad , Femenino , Eliminación de Gen , Enfermedad de Huntington/sangre , Inflamación/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington's disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. We quantified BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. We conclude that BDNF in CSF and plasma is unlikely to be a biomarker of HD progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.
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Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Enfermedad de Huntington/sangre , Enfermedad de Huntington/líquido cefalorraquídeo , Adulto , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoensayo , Masculino , Persona de Mediana EdadRESUMEN
Huntington's Disease (HD) is a progressive, fatal neurodegenerative condition. While generally considered for its devastating neurological phenotype, disturbances in other organ systems and metabolic pathways outside the brain have attracted attention for possible relevance to HD pathology, potential as therapeutic targets, or use as biomarkers of progression. In addition, it is not established how metabolic changes in the HD brain correlate to progression across the full spectrum of early to late-stage disease. In this pilot study, we sought to explore the metabolic profile across manifest HD from early to advanced clinical staging through metabolomic analysis by mass spectrometry in plasma and cerebrospinal fluid (CSF). With disease progression, we observed nominally significant increases in plasma arginine, citrulline, and glycine, with decreases in total and D-serine, cholesterol esters, diacylglycerides, triacylglycerides, phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins. In CSF, worsening disease was associated with nominally significant increases in NAD+, arginine, saturated long chain free fatty acids, diacylglycerides, triacylglycerides, and sphingomyelins. Notably, diacylglycerides and triacylglyceride species associated with clinical progression were different between plasma and CSF, suggesting different metabolic preferences for these compartments. Increasing NAD+ levels strongly correlating with disease progression was an unexpected finding. Our data suggest that defects in the urea cycle, glycine, and serine metabolism may be underrecognized in the progression HD pathology, and merit further study for possible therapeutic relevance.
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Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Evaluación de la Discapacidad , Enfermedad de Huntington/sangre , Enfermedad de Huntington/líquido cefalorraquídeo , Metabolómica , Adulto , Arginina/sangre , Arginina/líquido cefalorraquídeo , Creatina/sangre , Creatina/líquido cefalorraquídeo , Estudios Transversales , Femenino , Glicina/sangre , Glicina/líquido cefalorraquídeo , Humanos , Enfermedad de Huntington/metabolismo , Masculino , Persona de Mediana Edad , Proyectos Piloto , Resultado del Tratamiento , Adulto JovenRESUMEN
Although Huntington's disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10-7) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10-26). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10-8) and in the transgenic sheep model (p = 2.4 × 10-88). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10-7) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10-9), GRIK4 (p = 3.0 × 10-8), and COX4I2 (p = 6.5 × 10-8). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.
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Metilación de ADN , Epigénesis Genética , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Animales Modificados Genéticamente , Conducta Animal , Islas de CpG/genética , Estudios Transversales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Técnicas de Sustitución del Gen , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Carga Global de Enfermedades , Humanos , Enfermedad de Huntington/sangre , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/epidemiología , Estudios Longitudinales , Masculino , Ratones , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Proteínas Recombinantes/genética , Sistema de Registros/estadística & datos numéricos , Índice de Severidad de la Enfermedad , Ovinos , Adulto JovenRESUMEN
Huntington's disease (HD) is a hereditary autosomal dominant neurodegenerative disease. Although studies have shown that blood oxidative stress markers are dysregulated in HD patients, clinical data on the blood oxidative stress markers of HD patients is inconsistent. To better understand the pathogenesis of HD, we performed a systematic review and meta-analysis of blood oxidative stress markers in HD patients and healthy control (HC) subjects. A database search from PubMed and Web of Science identified 12 studies with 375 HD patients and 447 HC subjects in this meta-analysis. A random-effects meta-analysis showed that blood lipid peroxidation products (Hedges' g = 0.883, 95%CI = 0.637 to 1.130, p < 0.001), 8-hydroxyguanosine (Hedges' g = 1.727, 95%CI = 0.489 to 2.965, p = 0.006) levels, and the activity of glutathione peroxidase (Hedges' g = 2.026, 95%CI = 0.570 to 3.482, p = 0.006) were significantly increased in HD patients compared to controls. In contrast, reduced glutathione levels were lower in HD patients than in controls (Hedges' g = -0.611, 95%CI = -1.016 to - 0.207, p = 0.003). However, blood superoxide dismutase, cholesterol, high-density lipoproteins, low-density lipoproteins, and triglycerides did not show significant differences between cases and controls. Taken together, this study clarified the associations between blood oxidative stress markers and HD, supporting the clinical evidence that HD is accompanied by increased oxidative stress.
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Biomarcadores/sangre , Enfermedad de Huntington/sangre , Enfermedad de Huntington/patología , Estrés Oxidativo , Adulto , Eritrocitos/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Chorea-ballism is a neurological syndrome characterised by violent involuntary movements of one or both extremities. In the last decades, several patients with these involuntary movements were reported in association with hyperglycaemia. Here, we present a unique case of possible Huntington's disease, which could have been unmasked by the hyperglycaemic insult to the basal ganglia in a 64-year-old man who presented with chorea-ballism.
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Cetoacidosis Diabética/diagnóstico , Enfermedad de Huntington/diagnóstico , Hiperglucemia/diagnóstico , Anciano , Cetoacidosis Diabética/sangre , Cetoacidosis Diabética/complicaciones , Cetoacidosis Diabética/tratamiento farmacológico , Diagnóstico Diferencial , Discinesias/etiología , Humanos , Enfermedad de Huntington/sangre , Enfermedad de Huntington/complicaciones , Enfermedad de Huntington/tratamiento farmacológico , Hiperglucemia/sangre , Hiperglucemia/complicaciones , Hiperglucemia/tratamiento farmacológico , Insulina/uso terapéutico , MasculinoRESUMEN
Emerging evidence indicates that gut dysbiosis may play a regulatory role in the onset and progression of Huntington's disease (HD). However, any alterations in the fecal microbiome of HD patients and its relation to the host cytokine response remain unknown. The present study investigated alterations and host cytokine responses in patients with HD. We enrolled 33 HD patients and 33 sex- and age- matched healthy controls. Fecal microbiota communities were determined through 16S ribosomal DNA gene sequencing, from which we analyzed fecal microbial richness, evenness, structure, and differential abundance of individual taxa between HD patients and healthy controls. HD patients were evaluated for their clinical characteristics, and the relationships of fecal microbiota with these clinical characteristics were analyzed. Plasma concentrations of interferon gamma (IFN-γ), interleukin 1 beta (IL-1ß), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor alpha were measured by Meso Scale Discovery (MSD) assays, and relationships between microbiota and cytokine levels were analyzed in the HD group. HD patients showed increased α-diversity (richness), ß-diversity (structure), and altered relative abundances of several taxa compared to those in healthy controls. HD-associated clinical characteristics correlated with the abundances of components of fecal microbiota at the genus level. Genus Intestinimonas was correlated with total functional capacity scores and IL-4 levels. Our present study also revealed that genus Bilophila were negatively correlated with proinflammatory IL-6 levels. Taken together, our present study represents the first to demonstrate alterations in fecal microbiota and inflammatory cytokine responses in HD patients. Further elucidation of interactions between microbial and host immune responses may help to better understand the pathogenesis of HD.
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Bacterias/inmunología , Citocinas/sangre , Microbioma Gastrointestinal , Enfermedad de Huntington/microbiología , Mediadores de Inflamación/sangre , Intestinos/microbiología , Adulto , Bacterias/genética , Estudios de Casos y Controles , China , Disbiosis , Heces/microbiología , Femenino , Interacciones Huésped-Patógeno , Humanos , Enfermedad de Huntington/sangre , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/inmunología , Masculino , Persona de Mediana Edad , Filogenia , RibotipificaciónRESUMEN
Huntington' disease (HD) is an autosomal dominant neurodegenerative disease characterized by progressive motor, psychiatric, and cognitive deterioration. HD is, together with spinocerebellar ataxias, spinobulbar muscular atrophy and dentatorubral-pallido- luysian atrophy, one of the nine disorders caused by an expansion of glutamine residues in the causative protein where the polyglutamine expansion cause aberrant protein folding. Since an excessive metal's accumulation in organs may induce protein misfolding and oxidative stress, we have studied the blood concentration of essential (Cr, Co, Cu, Fe, Mn, Mo, Ni, Se, Zn) and nonessential (As, Cd, Sb, Sn, V) trace elements in HD patients. We found increased levels of the essential elements iron, chromium, selenium and zinc and of the nonessential element arsenic in the blood of HD patients. Since alteration in metals homeostasis may contribute to the pathogenesis of neurodegenerative disease and could eventually constitute a target for therapy, we may suggest the utilize of the blood metal profile as a further in vivo tool to study and characterize Huntington disease.
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Enfermedad de Huntington/sangre , Oligoelementos/sangre , Cadmio/sangre , Cobalto/sangre , Femenino , Humanos , Masculino , Molibdeno/sangre , Níquel/sangre , Estaño/sangreRESUMEN
BACKGROUND: Hypothalamic pathology is a well-documented feature of Huntington's disease (HD) and is believed to contribute to circadian rhythm and habitual sleep disturbances. Currently, no therapies exist to combat hypothalamic changes, nor circadian rhythm and habitual sleep disturbances in HD. OBJECTIVE: To evaluate the effects of multidisciplinary rehabilitation on hypothalamic volume, brain-derived neurotrophic factor (BDNF), circadian rhythm and habitual sleep in individuals with preclinical HD. METHODS: Eighteen individuals with HD (ten premanifest and eight prodromal) undertook a nine-month multidisciplinary rehabilitation intervention (intervention group), which included exercise, cognitive and dual task training and social events, and were compared to a community sample of eleven individuals with premanifest HD receiving no intervention (control group). Hypothalamic volume, serum BDNF, salivary cortisol and melatonin concentrations, subjective sleep quality, daytime somnolence, habitual sleep-wake patterns, stress and anxiety and depression symptomatology were evaluated. RESULTS: Hypothalamus grey matter volume loss was significantly attenuated in the intervention group compared to the control group after controlling for age, gender, Unified Huntington's Disease Rating Scale-Total Motor Score and number of cytosine-adenine-guanine repeats. Serum BDNF levels were maintained in the intervention group, but decreased in the control group following the study period. Both groups exhibited decreases in cortisol and melatonin concentrations. No changes were observed in sleep or mood outcomes. CONCLUSIONS: This exploratory study provides evidence that multidisciplinary rehabilitation can reduce hypothalamic volume loss and maintain peripheral BDNF levels in individuals with preclinical HD but may not impact on circadian rhythm. Larger, randomised controlled trials are required to confirm these findings.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Sustancia Gris/diagnóstico por imagen , Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Huntington/rehabilitación , Hipotálamo/diagnóstico por imagen , Síntomas Prodrómicos , Adulto , Factor Neurotrófico Derivado del Encéfalo/sangre , Ritmo Circadiano/fisiología , Femenino , Estudios de Seguimiento , Sustancia Gris/fisiología , Humanos , Enfermedad de Huntington/sangre , Hipotálamo/fisiología , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Proyectos Piloto , Sueño/fisiología , Factores de TiempoRESUMEN
Melatonin is a pleiotrophic hormone, synthesised primarily by the pineal gland under the control of the suprachiasmatic nuclei (SCN). It not only provides a hormonal signal of darkness but also has neuroprotective properties. Huntington's disease (HD) is a progressive neurodegenerative disorder characterised by abnormal motor, cognitive and psychiatric symptoms. There is growing evidence, particularly from animal models, that circadian rhythms may also be disturbed in HD. We measured two circadian-regulated hormones, melatonin and cortisol, in plasma samples collected around-the-clock from normal and presymptomatic transgenic HD sheep (Ovis aries) at 5 and 7 years of age, to assess SCN-driven rhythms and the effect of genotype, sex and age. Melatonin-related precursors and metabolites (tryptophan, serotonin, kynurenine) were also measured by liquid chromatography (LC)-mass spectrometry (MS). At 5 years of age in both rams and ewes, plasma melatonin levels were significantly elevated in HD sheep. In ewes measured 2 years later, there was still a significant elevation of nocturnal melatonin. Furthermore, the daytime baseline levels of melatonin were significantly higher in HD sheep. Since increased melatonin could have global beneficial effects on brain function, we suggest that the increased melatonin measured in presymptomatic HD sheep is part of an autoprotective response to mutant huntingtin toxicity that may account, at least in part, for the late onset of disease that characterises HD.
Asunto(s)
Ritmo Circadiano , Enfermedad de Huntington/sangre , Melatonina/sangre , Neuroprotección , Ovinos/sangre , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , MasculinoRESUMEN
The expanded CAG repeat results in somatic mosaicism and genetic anticipation in Huntington's disease (HD). Here we report a longitudinal study examining CAG repeat instability in lymphocytes and sperm of three HD monkeys throughout their whole life-span that encompass the prodromal to symptomatic stages of HD. We demonstrate a progressive increase in CAG repeat length in lymphocytes and sperm as the animals aged. We also examined the impact of CAG repeat length on expansion rate, which showed a clear linear correlation up to 62Q, and high instability after. Our findings stress the importance of further investigation in CAG instability in peripheral blood cells longitudinally.