RESUMEN
BACKGROUND: Microglial activation has been suggested to be involved in the pathogenesis of depression and Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a marker of microglial activation. The purpose of this study was to investigate the interrelationships of cerebrospinal fluid (CSF) sTREM2, AD pathology, as well as minimal depressive symptoms (MDSs), and cognition. METHODS: A total of 545 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative cohort were included in our study. The average age of the total population was 72.6 years and the percentage of females was 42.6%. Linear regression models were conducted to investigate the linear relationships of MDSs with CSF sTREM2, AD pathology, cognition, and brain structure. Mediation models and structural equation models (SEM) were conducted to examine whether CSF sTREM2 mediated the relationships of MDSs with AD pathology and cognition. RESULTS: Results revealed that individuals with MDSs had lower CSF sTREM2 levels than normal controls. Linear regression showed that MDSs were linearly associated with CSF sTREM2 (PFDR = 0.012) and amyloid biomarkers (PFDR < 0.05), as well as cognitive scores (PFDR < 0.05) and hippocampal volume (PFDR = 0.003). Mediation analyses revealed that CSF sTREM2 mediated the association between MDSs and amyloid pathology, with the mediating proportions ranging from 6.030 to 18.894%. However, SEM failed to reveal that MDS affected cognition through CSF amyloid pathology and CSF sTREM2. CONCLUSIONS: MDSs are associated with amyloid pathology and cognition. CSF sTREM2 may potentially be an intervenable target between depression and AD pathology.
Asunto(s)
Enfermedad de Alzheimer , Depresión , Glicoproteínas de Membrana , Receptores Inmunológicos , Humanos , Femenino , Masculino , Glicoproteínas de Membrana/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Depresión/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Cognición/fisiología , Anciano de 80 o más Años , Estudios de Cohortes , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Péptidos beta-Amiloides/líquido cefalorraquídeo , Persona de Mediana EdadRESUMEN
BACKGROUND: Depression is known as the "mental cold" and is also considered a major cause of disability worldwide. It is estimated that over 300 million people worldwide suffer from severe depression, equivalent to 4.4% of the world's population. The monoamine hypothesis of depression predicts the underlying pathophysiological mechanisms of depression, but in-depth research has failed to find convincing evidence. METHOD: In this study, we will dynamically and strictly quantitatively monitor the concentration changes of monoamine transmitters in the cerebrospinal fluid (CSF) of macaques, based on our previous work. In the experiment, timed and quantitative collection of CSF samples from macaques was performed and the concentration of monoamine transmitters was determined. RESULT: The results showed that after 2 months of chronic stress, the concentrations of high vanillin acid (HVA) and 3,4-dihydroxy-phenylacetic acid were significantly higher in the maternal separation (MS) group, whereas there was no significant difference in dopamine and 5-hydroxyindoleacetic acid. CONCLUSION: This study is the first to observe the long-term dynamic relationship between early adversity, chronic stress, adolescent depression, and CSF monoamine concentrations. The research suggests that MS and chronic stress play an undeniable role in the pathogenesis of depression and that concentrations of HVA and dihydroxyphenylacetic acid are likely to serve as early markers of depressive-like symptoms in macaques.
Asunto(s)
Depresión , Modelos Animales de Enfermedad , Macaca mulatta , Estrés Psicológico , Animales , Estrés Psicológico/líquido cefalorraquídeo , Estrés Psicológico/metabolismo , Masculino , Depresión/líquido cefalorraquídeo , Ácido 3,4-Dihidroxifenilacético/líquido cefalorraquídeo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Biomarcadores/líquido cefalorraquídeo , Benzaldehídos/farmacología , Privación Materna , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Dopamina/líquido cefalorraquídeo , Dopamina/metabolismo , Femenino , Monoaminas Biogénicas/líquido cefalorraquídeo , Monoaminas Biogénicas/metabolismo , Ácido Homovanílico/líquido cefalorraquídeoRESUMEN
OBJECTIVE: Previous studies demonstrated a significant protective effect of elevated cerebrospinal fluid (CSF) sTREM2 levels on brain structure and cognitive decline. Nonetheless, the role of sTREM2 in the depression progression remains unclear. This study aimed to investigate the association between CSF sTREM2 levels and longitudinal trajectories of depression. METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) Study were used. CSF sTREM2 levels and depression were measured using an ELISA-based assay and the Geriatric Depression Scale (GDS-15), respectively. Linear mixed-effect models were employed to assess the relationships between CSF sTREM2 levels and GDS scores. RESULTS: A total of 1,017 participants were enrolled at baseline, with a mean follow-up time of 4.65 years. Baseline CSF sTREM2 levels were negatively correlated with GDS scores (ß=-0.21, P=0.022) after adjustment for age, gender, race/ethnicity, education, APOE ε4 carrier status, TREM2 rare variant carrier status, marital status, smoking, and clinical cognitive status. CONCLUSION: Our findings suggested that a higher level of CSF sTREM2 was associated with a lower risk of depression.
Asunto(s)
Enfermedad de Alzheimer , Depresión , Glicoproteínas de Membrana , Receptores Inmunológicos , Humanos , Femenino , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Glicoproteínas de Membrana/líquido cefalorraquídeo , Masculino , Anciano , Depresión/líquido cefalorraquídeo , Neuroimagen , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Anciano de 80 o más AñosRESUMEN
Micronutrient deficiencies and excesses are closely related to developing and treating depression. Traditional and effective antidepressants include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and lithium. There is no consensus on the fluctuation of zinc (Zn2+), magnesium (Mg2+), calcium (Ca2+), copper (Cu2+), iron (Fe2+), and manganese (Mn2+) ion levels in depressed individuals before and after therapy. In order to determine whether there were changes in blood and cerebrospinal fluid (CSF) levels of these ions in depressed patients compared with healthy controls and depressed patients treated with TCAs, SSRIs, or lithium, we applied a systematic review and meta-analysis. Using the Stata 17.0 software, we performed a systematic review and meta-analysis of the changes in ion levels in human samples from healthy controls, depressive patients, and patients treated with TCAs, SSRIs, and lithium, respectively. By searching the PubMed, EMBASE, Google Scholar, Web of Science, China National Knowledge Infrastructure (CNKI), and WAN FANG databases, 75 published analyzable papers were chosen. In the blood, the levels of Zn2+ and Mg2+ in depressed patients had decreased while the Ca2+ and Cu2+ levels had increased compared to healthy controls, Fe2+ and Mn2+ levels have not significantly changed. After treatment with SSRIs, the levels of Zn2+ and Ca2+ in depressed patients increased while Cu2+ levels decreased. Mg2+ and Ca2+ levels were increased in depressed patients after Lithium treatment. The findings of the meta-analysis revealed that micronutrient levels were closely associated with the onset of depression and prompted more research into the underlying mechanisms as well as the pathophysiological and therapeutic implications.
Asunto(s)
Depresión , Humanos , Depresión/sangre , Depresión/tratamiento farmacológico , Depresión/líquido cefalorraquídeo , Iones/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-ß 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (pADJ < 0.05) and predementia AD (pADJ < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (pADJ < 0.001), BACE1 (pADJ < 0.05) and Ng/BACE1 ratio (pADJ < 0.01). All groups had significantly lower Aß 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as "predementia AD with depression".
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Secretasas de la Proteína Precursora del Amiloide/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Ácido Aspártico Endopeptidasas/líquido cefalorraquídeo , Depresión/líquido cefalorraquídeo , Neurogranina/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Sinapsis/metabolismo , Anciano , Enfermedad de Alzheimer/clasificación , Biomarcadores/líquido cefalorraquídeo , Estudios Transversales , Humanos , Persona de Mediana EdadRESUMEN
Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
Asunto(s)
Disfunción Cognitiva/diagnóstico , Depresión/diagnóstico , Síndrome de Down/diagnóstico , Enfermedades Neurodegenerativas/diagnóstico , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Factores de Edad , Anciano , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Estudios de Cohortes , Depresión/líquido cefalorraquídeo , Síndrome de Down/líquido cefalorraquídeo , Reacciones Falso Positivas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Valor Predictivo de las Pruebas , Valores de Referencia , Factores SexualesRESUMEN
BACKGROUND: Depressive symptoms often co-occur with Alzheimer's disease (AD) and can impact neuropsychological test results. In early stages of AD, disentangling cognitive impairments due to depression from those due to neurodegeneration often poses a challenge. OBJECTIVE: We aimed to identify neuropsychological tests able to detect AD-typical pathology while taking into account varying degrees of depressive symptoms. METHODS: A battery of neuropsychological tests (CERAD-NP) and the Geriatric Depression Scale (GDS) were assessed, and cerebrospinal fluid (CSF) biomarkers were obtained. After stratifying patients into CSF positive or negative and into low, moderate, or high GDS score groups, sensitivity and specificity and area under the curve (AUC) were calculated for each subtest. RESULTS: 497 participants were included in the analyses. In patients with low GDS scores (≤10), the highest AUC (0.72) was achieved by Mini-Mental State Examination, followed by Constructional Praxis Recall and Wordlist Total Recall (AUCâ=â0.714, both). In patients with moderate (11-20) and high (≥21) GDS scores, Trail Making Test-B (TMT-B) revealed the highest AUCs with 0.77 and 0.82, respectively. CONCLUSION: Neuropsychological tests showing AD-typical pathology in participants with low GDS scores are in-line with previous results. In patients with higher GDS scores, TMT-B showed the best discrimination. This indicates the need to focus on executive function rather than on memory task results in depressed patients to explore a risk for AD.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Depresión/diagnóstico , Depresión/psicología , Progresión de la Enfermedad , Pruebas Neuropsicológicas/normas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Estudios Transversales , Depresión/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Dysfunction in glutamate homeostasis contributes to the pathology of depression-like behavior. Using a chronic restraint stress (CRS) model of depression in C57BL/6 mice, we measured glutamate levels in the cerebrospinal fluid at different restraint time points (CRS 1 d, CRS 3 d, CRS 5 d, CRS 7 d, CRS 14 d, and CRS 21 d). Glutamate levels were increased in the early stage of stress (CRS 1 d and CRS 5 d) but returned to basal levels at the other time points (CRS 7 d-21 d). We hypothesized that glutamate-induced excitotoxicity is critical for the development of depression-like behavior in the CRS model. Treatment with sodium valproate (VPA) or lamotrigine (LTG), two drugs that prevent excitotoxicity in neurons by increasing inhibitory inputs or blocking sodium channels, in the early stage (CRS 1 d-5 d) was sufficient to correct depression-like behavior. In contrast, treatment with the classic antidepressant fluoxetine (FLX) during the same time period was not sufficient to correct depressive behavior. Western blot of two markers of dendritic spines PSD95 and VGluT1 showed that restraining mice for 5 d resulted in the loss of dendritic spines, which was rescued by VPA or LTG. In conclusion, an initial increase in glutamate levels plays an important role in the development of depression-like behavior in the CRS model.
Asunto(s)
Depresión/líquido cefalorraquídeo , Ácido Glutámico/líquido cefalorraquídeo , Restricción Física/fisiología , Estrés Psicológico/líquido cefalorraquídeo , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Biomarcadores/líquido cefalorraquídeo , Enfermedad Crónica , Depresión/tratamiento farmacológico , Depresión/psicología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Restricción Física/psicología , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/psicologíaRESUMEN
BACKGROUND: Delirium is a common and serious complication in geriatric patients. The pathophysiology of delirium is not known. OBJECTIVE: The objective of the current study was to test the hypothesis that cerebrospinal fluid (CSF) levels of inflammatory markers at the time of spinal anesthesia for hip surgery are associated with delirium. METHODS: In total 133 hip fracture patients and 125 cognitively healthy controls undergoing elective surgery, together with 73 Alzheimer's disease (AD) dementia patients, were recruited at Oslo University Hospital and Diakonhjemmet Hospital, Oslo, Norway. Delirium was evaluated daily in hip fracture patients by the Confusion Assessment Method (CAM). Depression was evaluated by Cornell Scale for Depression in Dementia (CSDD). Tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1ß), and interleukin-8 (IL-8) levels were measured in CSF using a Mesoscale Discovery (MSD) immunoassay. RESULTS: Hip fracture patients had significantly higher IL-8 levels (pâ<â0.001) compared to cognitively healthy controls or patients with stable AD dementia. Furthermore, preoperative IL-8 levels were significantly higher (pâ=â0.013) in hip fracture patients who developed delirium (incident delirium) after surgery as compared to patients with no delirium. However, subgroup analyses showed that IL-8 levels were only significantly higher in delirium patients without dementia (pâ=â0.006). In contrast, depression subgroup analysis showed that IL-8 concentration was significantly higher (pâ=â0.002) in delirium patients with depression. Both TNF-α and IL-1ß were undetected in most patients. CONCLUSIONS: Our study suggests that IL-8 levels are associated with delirium onset and that underlying depression or dementia influences IL-8 levels.
Asunto(s)
Delirio/líquido cefalorraquídeo , Demencia/líquido cefalorraquídeo , Interleucina-8/líquido cefalorraquídeo , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/psicología , Anestesia , Biomarcadores/líquido cefalorraquídeo , Delirio/psicología , Demencia/psicología , Depresión/líquido cefalorraquídeo , Depresión/complicaciones , Femenino , Voluntarios Sanos , Fracturas de Cadera/complicaciones , Fracturas de Cadera/cirugía , Humanos , Inflamación/líquido cefalorraquídeo , Interleucina-1beta/líquido cefalorraquídeo , Masculino , Pruebas de Estado Mental y Demencia , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeoRESUMEN
BACKGROUND: Major depressive disorder (MDD) is a pathophysiologically uncharacterized mental illness with complex etiology and clinical manifestations. Rodent depression-like models have been widely used to mimic the morbid state of depression. However, research on emotional disorders can also benefit from the use of models in non-human primates, which share a wide range of genetic and social similarities with humans. METHODS: To investigate the pathophysiological mechanisms of depression, we established two models, naturally occurring depression cynomolgus (NOD) and social plus visual isolation-induced depression cynomolgus (SVC), imitating chronic mild or acute intense stress, respectively. We used i-TRAQ (isobaric tags for relative and absolute quantitation)-based quantitative proteomics and shotgun proteomics to identify differentially expressed proteins in cerebrospinal fluid (CSF) of the two monkey models and human MDD patients. We also used DAVID and ingenuity pathway analysis (IPA) for further bioinformatic investigation. RESULTS: In behavioral tests, NOD monkeys achieved higher scores in depression-like and anxiety-like behavioral measures, and spent more time on ingesting, thermoregulatory, and locomotive actions than SVC monkeys. A total of 902 proteins were identified by i-TRAQ, and 40 differentially expressed proteins were identified in each of the NOD-CON1 and SVC-CON2 groups. Application of DAVID revealed dysregulation of energy metabolism in the NOD group, whereas lipid metabolism and inflammatory response pathways were significantly altered in the SVC group. Use of IPA and Cytoscape showed that the oxygen species metabolic process glycolysis I/gluconeogenesis I, accompanied by downregulation of tubulin beta 3 class III (TUBB3), RAC-alpha serine/threonine-protein kinase (AKT1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), was the most significantly affected pathway in the NOD group. Furthermore, 152 differentially expressed proteins in human MDD patients also revealed disruption of glucose energy metabolism. Significantly aberrant energy metabolism in various brain regions and the plasma and liver of chronic unpredictable mild stress rodent samples were also observed in a previous study. CONCLUSIONS: Our results reveal for the first time the overall CSF protein profiles of two cynomolgus monkey models of depression. We propose that chronic mild stress may affect the disruption of glucose energy metabolism in NOD cynomolgus monkeys and rodents. These findings promote our understanding of the pathophysiology of MDD and may help to identify novel therapeutic targets.
Asunto(s)
Depresión/metabolismo , Metabolismo Energético/fisiología , Glucosa/metabolismo , Adulto , Animales , Conducta Animal , Metabolismo de los Hidratos de Carbono/fisiología , Depresión/líquido cefalorraquídeo , Trastorno Depresivo Mayor/líquido cefalorraquídeo , Trastorno Depresivo Mayor/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Macaca fascicularis/líquido cefalorraquídeo , Macaca fascicularis/metabolismo , Masculino , Proteómica/métodos , Aislamiento Social , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatologíaRESUMEN
BACKGROUND: While perinatal depression is one of the most common complications of pregnancy, there is an insufficient understanding of the mechanistic underpinnings of disease. While an association between peripheral inflammatory cytokines and major depressive disorder has been demonstrated, cytokines cannot freely cross the blood-brain barrier, and thus, they give little insight into alternations in brain function. Because the brain is in direct communication with the cerebrospinal fluid, assessment of inflammation in the cerebrospinal fluid may be more directly related to the biologic markers of affective change. OBJECTIVE: Our objectives were to examine the association between perinatal depression and inflammatory cytokines in plasma, the association between perinatal depression and inflammatory cytokines in cerebrospinal fluid, and the correlations between plasma and cerebrospinal fluid inflammatory cytokines. STUDY DESIGN: This was a prospective, observational study of women with a singleton gestation at term undergoing a scheduled cesarean delivery. Women were screened for depression and those with depressive symptomatology preferentially enrolled. The Mini-International Neuropsychiatric Interview was administered to confirm the clinical diagnosis of depression. Maternal plasma and cerebrospinal fluid were collected preoperatively and cytokines measured via flow cytometry. Bivariable and multivariable analyses were used to determine the association between each cytokine and perinatal depression. Correlations were measured between the cytokines in plasma and cerebrospinal fluid. RESULTS: Of the 117 women who met inclusion criteria, 76 (65%) screened positive for depression, 15 (20%) of whom met the clinical diagnostic criteria for depression. There were no significant associations between any of the plasma cytokines and perinatal depression in our sample. Conversely, in multivariable analyses, higher cerebrospinal fluid interleukin-1ß (adjusted odds ratio, 232.7, 95% confidence interval, 5.9-9148.5), interleukin-23 (adjusted odds ratio, 22.1, 95% confidence interval, 1.7-294.5), and interleukin-33 (adjusted odds ratio, 1.7, 95% confidence interval, 1.1-2.6) concentrations were significantly associated with increased odds of perinatal depression. The plasma and cerebrospinal fluid cytokine concentrations were not strongly correlated. CONCLUSION: Higher concentrations of cerebrospinal fluid cytokines were associated with perinatal depression. These cerebrospinal fluid cytokines were not strongly correlated with plasma cytokines, and accordingly, plasma cytokines were not significantly associated with perinatal depression. Central neuroinflammation, as opposed to peripheral inflammation, may represent a mechanistic pathway that contributes to perinatal depression.
Asunto(s)
Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Depresión/etiología , Inflamación/diagnóstico , Complicaciones del Embarazo/etiología , Adulto , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Depresión/sangre , Depresión/líquido cefalorraquídeo , Depresión/diagnóstico , Femenino , Humanos , Inflamación/complicaciones , Inflamación/metabolismo , Inflamación/psicología , Modelos Logísticos , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/líquido cefalorraquídeo , Complicaciones del Embarazo/diagnóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) displays a promising antidepressant effects in patients with treatment-refractory depression; however, a clear consensus on underlying mechanisms is still enigmatic. Herein, we investigated the effects of MFB-DBS on anhedonic-like behavior using the Froot Loops® consumption in a chronic unpredictable mild stress (CUS) model of depression, biochemical estimation of peripheral and central inflammatory cytokines, stress hormone, and brain-derived neurotrophic factor (BDNF). Seven days of MFB-DBS significantly reversed the 42-day CUS-generated anhedonic-like phenotype (p < 0.02) indicated by an increase in Froot Loops® consumption. Gross locomotor activity and body weight remained unaffected across the different groups. A dramatic augmentation of adrenocorticotropic hormone levels was seen in the plasma and cerebrospinal fluid (CSF) samples of CUS rats, which significantly reduced following MFB-DBS treatment. However, C-reactive protein levels were found to be unaffected. Interestingly, decreased levels of BDNF in the CUS animals were augmented in the plasma, CSF, and hippocampus following MFB-DBS, but remained unaltered in the nucleus accumbens (NAc). While multiplex assay revealed no change in the neuronal levels of inflammatory cytokines including IL-1α, IL-4, IL-10, IL-12, IL-13, and IL-17 in the neuroanatomical framework of the hippocampus and NAc, increased levels of IL-1ß, IL-2, IL-5, IL-6, IL-7, IL-18, TNF-α, and INF-γ were seen in these brain structures after CUS and were differentially modulated in the presence of MFB stimulation. Here, we show that there is dysregulation of BDNF and neuroimmune mediators in a stress-driven chronic depression model, and that chronic MFB-DBS has the potential to undo these aberrations.
Asunto(s)
Anhedonia , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Citocinas/metabolismo , Estimulación Encefálica Profunda , Depresión/complicaciones , Mediadores de Inflamación/metabolismo , Haz Prosencefálico Medial/patología , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/líquido cefalorraquídeo , Animales , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Proteína C-Reactiva/líquido cefalorraquídeo , Proteína C-Reactiva/metabolismo , Depresión/sangre , Depresión/líquido cefalorraquídeo , Depresión/fisiopatología , Modelos Animales de Enfermedad , Conducta Alimentaria , Hipocampo/metabolismo , Masculino , Actividad Motora , Núcleo Accumbens/metabolismo , Ratas Wistar , Estrés Psicológico/sangre , Estrés Psicológico/líquido cefalorraquídeo , Estrés Psicológico/complicaciones , Estrés Psicológico/fisiopatologíaRESUMEN
Elevated systemic oxidative stress levels of 8-oxoGuo and 8-oxodG have been reported in individuals with severe mental illness (SMI). As no previous studies have addressed the link between local levels of 8-oxoGuo and 8-oxodG in the central nervous system (CNS), measured in cerebrospinal fluid (CSF), and urinary systemic levels, we employed autopsy-based material to elucidate this aspect. Additionally, we investigated the impact of 8-oxoGuo and 8-oxodG levels on the prevalence of somatic co-morbidities. Based on post mortem samples from deceased individuals with SMI (Nâ¯=â¯107), we found significantly elevated urinary levels of both 8-oxoGuo and 8-oxodG compared to mentally healthy living controls. While we found an association between urinary and CSF 8-oxodG levels (râ¯=â¯0.50, Pâ¯<â¯0.001), a similar correlation was not evident for 8-oxoGuo (râ¯=â¯0.15, Pâ¯=â¯0.16). Additionally, the two r-values were significantly different (Pâ¯<â¯0.001). Neither marker in urine or CSF was associated with obesity-related variables, metabolic syndrome or type 2 diabetes. The post mortem interval did not affect the results, but the agonal phase seemingly introduced bias. This study provided novel insights into the cellular oxidative stress levels in individuals with SMI. We demonstrated that increased oxidative stress locally and systemically is correlated and is a clear phenomenon in SMI. Although post mortem measurements contain some weaknesses, our study indicates DNA as the main site of oxidative stress modifications in the CNS in SMI. This may provide novel opportunities for treatment modalities. Additionally, our study demonstrated the applicability of post mortem material investigating systemic and local 8-oxoGuo and 8-oxodG levels.
Asunto(s)
Desoxiguanosina/análogos & derivados , Guanosina/análogos & derivados , Trastornos Mentales/líquido cefalorraquídeo , Estrés Oxidativo/genética , 8-Hidroxi-2'-Desoxicoguanosina , Anciano , Autopsia , Trastorno Bipolar/líquido cefalorraquídeo , Trastorno Bipolar/fisiopatología , Trastorno Bipolar/orina , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/fisiopatología , Desoxiguanosina/líquido cefalorraquídeo , Desoxiguanosina/orina , Depresión/líquido cefalorraquídeo , Depresión/fisiopatología , Depresión/orina , Femenino , Guanosina/líquido cefalorraquídeo , Guanosina/orina , Humanos , Masculino , Trastornos Mentales/fisiopatología , Trastornos Mentales/orina , Persona de Mediana Edad , Estrés Oxidativo/fisiología , Esquizofrenia/líquido cefalorraquídeo , Esquizofrenia/fisiopatología , Esquizofrenia/orinaRESUMEN
BACKGROUND: Depression is a common mental disorder with unknown mechanism. Emerging evidence shows that miRNAs play a critical role in the process of depression. Here we reported the cerebrospinal fluid (CSF) miR-16 expression and its association with miR-16 and serotonin transporter (SERT) in the raphe of a rat model of depression. METHODS: 20 rats were randomized to the control or CUMS (chronic unpredictable mild stress) group. The rats in the CUMS group underwent CUMS for 21 days, while those in the control group received no treatment. After anesthetization, CSF was collected for the measurement of miR-16. Then raphes from all rats were separated for determination of miR-16 and SERT protein. RESULTS: The expression levels of miR-16 in CSF and raphe of the CUMS group were significantly lower than those of the control group (Pâ¯=â¯0.007 and 0.031). However, SERT protein in raphe of the CUMS group was obviously increased as compared that of the control group (Pâ¯=â¯0.005). There was a positive correlation between CSF miR-16 and raphe miR-16 (râ¯=â¯0.95, Pâ¯=â¯0.000). Meanwhile, negative correlations between miR-16 and SERT protein in raphe (râ¯=â¯-0.70 Pâ¯=â¯0.02), between CSF miR-16 and raphe SERT protein (râ¯=â¯-0.86, Pâ¯=â¯0.002) were observed in the CUMS group. LIMITATIONS: We have not explored the reason why CSF miR-16 was decreased in the rat model of depression and only tested the association of miR-16 between CSF and raphe. CONCLUSIONS: CSF miR-16 was involved in the pathogenesis of depression via reflecting raphe miR-16 level, and thus affecting raphe SERT expression.
Asunto(s)
Depresión/líquido cefalorraquídeo , MicroARNs/líquido cefalorraquídeo , Núcleos del Rafe/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Distribución Aleatoria , Ratas , Estrés Psicológico/líquido cefalorraquídeoRESUMEN
BACKGROUND: Creutzfeldt-Jakob disease is a rare and rapidly fatal neurodegenerative disease. Since clinicians may see only very few cases during their professional career, it is important to be familiar with the clinical presentation and progression, to perform appropriate investigations, and allow for quick diagnosis. CASE PRESENTATION: A 73-year-old British Caucasian woman presented with acute confusion of 2 weeks' duration on a background of low mood following a recent bereavement. Her symptoms included behavioral change, visual hallucinations, vertigo, and recent falls. She was mildly confused, with left-sided hyperreflexia, a wide-based gait, and intention tremor in her left upper limb. Initial blood tests, computed tomography, and magnetic resonance imaging of her brain showed no significant abnormality. Following admission, she had rapid cognitive decline and developed florid and progressive neurological signs; a diagnosis of prion disease was suspected. A lumbar puncture was performed; cerebrospinal fluid was positive for 14-3-3 protein, real-time quaking-induced conversion, and raised levels of s-100b proteins were detected. An electroencephalogram showed bilateral periodic triphasic waves on a slow background. The diagnosis of probable Creutzfeldt-Jakob disease was made. CONCLUSIONS: This case report highlights key features in the initial presentation and clinical development of a rare but invariably rapidly progressive and fatal disease. It emphasizes the importance of considering a unifying diagnosis for multifaceted clinical presentations. Although it is very rare, Creutzfeldt-Jakob disease should be considered a diagnosis for a mixed neuropsychiatric presentation, particularly with rapid progressive cognitive decline and development of neurological signs. However, to avoid overlooking early signal change on magnetic resonance imaging, it is important to take diffusion-weighted magnetic resonance imaging for all patients with neuropsychological symptoms. Importantly, early diagnosis also ensures the arrangement of suitable contamination control measures to minimize the risk of infection to health care professionals and other patients.
Asunto(s)
Accidentes por Caídas , Síndrome de Creutzfeldt-Jakob/diagnóstico , Depresión/etiología , Alucinaciones/etiología , Anciano , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/fisiopatología , Síndrome de Creutzfeldt-Jakob/psicología , Depresión/líquido cefalorraquídeo , Depresión/diagnóstico , Diagnóstico Diferencial , Progresión de la Enfermedad , Electroencefalografía , Resultado Fatal , Femenino , Alucinaciones/líquido cefalorraquídeo , Alucinaciones/diagnóstico , Humanos , Imagen por Resonancia Magnética , Punción Espinal , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.
Asunto(s)
Quimiocinas/líquido cefalorraquídeo , Dolor Crónico/líquido cefalorraquídeo , Inflamación/líquido cefalorraquídeo , Neuralgia/líquido cefalorraquídeo , Adulto , Quimiocina CCL11/líquido cefalorraquídeo , Quimiocinas CC/líquido cefalorraquídeo , Estudios Transversales , Depresión/líquido cefalorraquídeo , Fatiga/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder, primarily affecting memory. That disorder is thought to be a consequence of neuronal network disturbances and synapse loss. Decline in cognitive function is associated with a high burden of neuropsychiatric symptoms (NPSs) such as depression. The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) are essential second messengers that play a crucial role in memory processing as well as synaptic plasticity and are potential therapeutic targets. Biomarkers that are able to monitor potential treatment effects and that reflect the underlying pathology are of crucial interest. METHODS: In this study, we measured cGMP and cAMP in cerebrospinal fluid (CSF) in a cohort of 133 subjects including 68 AD patients and 65 control subjects. To address the association with disease progression we correlated cognitive status with cyclic nucleotide levels. Because a high burden of NPSs is associated with decrease in cognitive function, we performed an exhaustive evaluation of AD-relevant marker combinations in a depressive subgroup. RESULTS: We show that cGMP, but not cAMP, levels in the CSF of AD patients are significantly reduced compared with the control group. Reduced cGMP levels in AD patients correlate with memory impairment based on Mini-Mental State Examination score (r = 0.17, p = 0.048) and tau as a marker of neurodegeneration (r = -0.28, p = 0.001). Moreover, we were able to show that AD patients suffering from current depression show reduced cGMP levels (p = 0.07) and exhibit a higher degree of cognitive impairment than non-depressed AD patients. CONCLUSION: These results provide further evidence for an involvement of cGMP in AD pathogenesis and accompanying co-morbidities, and may contribute to elucidating synaptic plasticity alterations during disease progression.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/psicología , GMP Cíclico/líquido cefalorraquídeo , Depresión/líquido cefalorraquídeo , Depresión/complicaciones , Anciano , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Cognición , Estudios de Cohortes , AMP Cíclico/líquido cefalorraquídeo , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
Fibroblast growth factor 21 (FGF21) is an important metabolic regulator of glucose homeostasis and lipid metabolism. Recently, FGF21 has been shown to play a robust neuroprotective role and act as a mediator of the effects of mood stabilizers. In the present study, we measured the concentration of FGF21 in human cerebrospinal fluid (CSF) and investigated the relationship of FGF21 levels with depression and anxiety emotions. Sixty-seven Chinese volunteers were recruited from Beijing Jishuitan Hospital. A significant negative association was found between CSF FGF21 levels and Beck Depression Inventory (BDI) scores in male subjects. Our findings provide evidence of the role of FGF21 in mood regulation.
Asunto(s)
Pueblo Asiatico/psicología , Depresión/líquido cefalorraquídeo , Factores de Crecimiento de Fibroblastos/líquido cefalorraquídeo , Escalas de Valoración Psiquiátrica , Adulto , Ansiedad/líquido cefalorraquídeo , China , Humanos , MasculinoRESUMEN
Systemic inflammation is accompanied by profound behavioral and mood changes that resemble symptoms of depression. Findings in animals suggest that pro-inflammatory cytokines released by activated immune cells in the periphery evoke these behavioral symptoms by driving inflammatory changes in the brain. However, experimental data in humans are lacking. Here we demonstrate in healthy male volunteers (10 endotoxin treated, 8 placebo treated) that intravenous administration of low-dose endotoxin (0.8 ng/kg body weight), a prototypical pathogen-associated molecular pattern that activates the innate immune system, not only induces a significant increase in peripheral blood cytokine concentrations (that is, tumor necrosis factor-α, interleukin (IL)-6, IL-10) but also results, with some latency, in a robust and selective increase of IL-6 in the cerebrospinal fluid (CSF). Moreover, we found a strong association between the endotoxin-induced increase of IL-6 in the CSF and the severity of mood impairment, with larger increases in CSF IL-6 concentration followed by a greater deterioration in mood. Taken together, these findings suggest that the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration, identifying IL-6 as a potential therapeutic target in mood disorders.