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Psychoneuroendocrinology Feb 2022Anxiety and depression are linked to both explicit and implicit memory biases, which are defined as the tendency to preferentially recall emotionally negative...
Anxiety and depression are linked to both explicit and implicit memory biases, which are defined as the tendency to preferentially recall emotionally negative information at conscious and subconscious levels, respectively. Functional connectivity (FC) of the basolateral amygdala (BLA) and related stress hormones (i.e., cortisol and norepinephrine) are purportedly implicated in these biases. However, previous findings on memory biases in anxiety and depression have been inconsistent, likely due to their symptomatic complications. Therefore, the underlying neurobiological mechanism remains unclear. We thus investigated whether anxiety and depression as premorbid predispositions are related to the memory biases, and whether FC of BLA, cortisol, and 3-methoxy-4-hydroxyphenylglycol (MHPG: a major metabolite of norepinephrine) would affect the anxiety/depression-related biased memory recall in 100 participants without psychiatric symptomatology. Psycho-behavioral assessment, resting-state fMRI scans, and saliva collection at 10-points-in-time across two days were conducted. Correlations of memory biases with anxiety/depression and neurobiological markers were explored. As a result, neither anxiety nor depression were correlated with explicit memory bias to negative (vs. positive) information, although depression was associated with better recall of the negative stimuli only when they were perceived as self-relevant. In contrast, both anxiety and depression were correlated with implicit memory bias; however, the effects were solely explained by anxiety. Furthermore, FC of the BLA with subgenual anterior cingulate cortex (sgACC) and the synergetic effect of cortisol and MHPG uniquely affected the implicit memory bias. These findings suggest that anxiety facilitates an initial snapshot of negative information and can be accompanied by depression when the information creates negative semantic associations with the self. The BLA-sgACC neural connectivity and cortisol-norepinephrine interaction that are associated with the implicit memory bias might be one of the important neurobiological targets in the prevention and treatment for comorbid anxiety and depressive disorders.
Topics: Anxiety; Basolateral Nuclear Complex; Depression; Humans; Hydrocortisone; Magnetic Resonance Imaging; Methoxyhydroxyphenylglycol; Norepinephrine
PubMed: 34894424
DOI: 10.1016/j.psyneuen.2021.105598 -
Gut Aug 2023Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of...
BACKGROUND AND AIMS
Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models.
METHODS
Two prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling.
RESULTS
Three prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality.
CONCLUSIONS
Models including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.
Topics: Humans; Prognosis; Prospective Studies; Methoxyhydroxyphenylglycol; Liver Cirrhosis; Acute-On-Chronic Liver Failure; Inflammation; Metabolomics; Mitochondria
PubMed: 36788015
DOI: 10.1136/gutjnl-2022-328708 -
Ageing Research Reviews Jan 2023Some studies point locus coeruleus cell loss, the central nervous system main source of norepinephrine, to be one of the earliest neuropathological events of Alzheimer's... (Meta-Analysis)
Meta-Analysis Review
Some studies point locus coeruleus cell loss, the central nervous system main source of norepinephrine, to be one of the earliest neuropathological events of Alzheimer's disease (AD). However, there are conflicting reports regarding the level of norepinephrine and its metabolites (3-Methoxy-4-hydroxyphenylglycol (MHPG), 3,5-dihydroxyphenylglycine (DHPG) and 3,4 -dihydroxyphenylglycolaldehyde (DOPEGAL)) in AD patients. Uncover these alterations may be a key factor for understanding cognitive deficits and AD pathology. We review the literature that compare norepinephrine and its metabolites between AD patients and non-demented controls. A meta-analysis did not reveal significant statistical differences, but there was a trend towards a lower level of norepinephrine of AD, with almost no difference in MHPG in the cerebrospinal fluid. Regarding MHPG in plasma, DHPG and DOPEGAL we only performed a qualitative analyse due to the small or absent number of studies. These findings point to a decrease in norepinephrine, what is in line with locus coeluleus cell loss in AD. The absence of statistical difference and an equal level of MHGP could indicate a compensatory mechanism.
Topics: Humans; Norepinephrine; Methoxyhydroxyphenylglycol; Alzheimer Disease
PubMed: 36368648
DOI: 10.1016/j.arr.2022.101784 -
Depression and Anxiety Oct 2014Low gamma-aminobutyric acid (GABA) is implicated in both anxiety and depression pathophysiology. They are often comorbid, but most clinical studies have not examined...
BACKGROUND
Low gamma-aminobutyric acid (GABA) is implicated in both anxiety and depression pathophysiology. They are often comorbid, but most clinical studies have not examined these relationships separately. We investigated the relationship of cerebrospinal fluid (CSF) free GABA to the anxiety and depression components of a major depressive episode (MDE) and to monoamine systems.
METHODS AND MATERIALS
Patients with a DSM-IV major depressive episode (N = 167: 130 major depressive disorder; 37 bipolar disorder) and healthy volunteers (N = 38) had CSF free GABA measured by gas chromatography mass spectroscopy. Monoamine metabolites were assayed by high performance liquid chromatography. Symptomatology was assessed by Hamilton depression rating scale.
RESULTS
Psychic anxiety severity increased with age and correlated with lower CSF free GABA, controlling for age. CSF free GABA declined with age but was not related to depression severity. Other monoamine metabolites correlated positively with CSF GABA but not with psychic anxiety or depression severity. CSF free GABA was lower in MDD compared with bipolar disorder and healthy volunteers. GABA levels did not differ based on a suicide attempt history in mood disorders. Recent exposure to benzodiazepines, but not alcohol or past alcoholism, was associated with a statistical trend for more severe anxiety and lower CSF GABA.
CONCLUSIONS
Lower CSF GABA may explain increasing severity of psychic anxiety in major depression with increasing age. This relationship is not seen with monoamine metabolites, suggesting treatments targeting the GABAergic system should be evaluated in treatment-resistant anxious major depression and in older patients.
Topics: Adult; Age Factors; Anxiety; Bipolar Disorder; Case-Control Studies; Chromatography, High Pressure Liquid; Depressive Disorder, Major; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Severity of Illness Index; Young Adult; gamma-Aminobutyric Acid
PubMed: 24865448
DOI: 10.1002/da.22278 -
Journal of Neurochemistry Jul 2021The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the...
The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p < .0001 each by Dunnett's post hoc test), DHPG (p = .004; p < .0001; p < .0001) and norepinephrine (p = .017; p = .0003; p = .044). CSF HVA and DOPAC were decreased in PD (p < .0001 each) and MSA (p < .0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency-prominent in PD and MSA, less apparent in PAF. Data from putamen F-DOPA and cardiac F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons.
Topics: 3,4-Dihydroxyphenylacetic Acid; Aged; Cohort Studies; Dopamine; Dopaminergic Neurons; Female; Homovanillic Acid; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Multiple System Atrophy; Neurons; Norepinephrine; Parkinson Disease; Pure Autonomic Failure; Retrospective Studies; Synucleinopathies
PubMed: 33894018
DOI: 10.1111/jnc.15371 -
International Journal of Environmental... Jan 2011Smoking is a major risk factor of morbidity and mortality. It is well established that monoamine oxidase (MAO) activity is decreased in smokers. Serotonin (5-HT), a... (Review)
Review
Smoking is a major risk factor of morbidity and mortality. It is well established that monoamine oxidase (MAO) activity is decreased in smokers. Serotonin (5-HT), a major substrate for MAO that circulates as a reserve pool stored in platelets, is a marker of platelet activation. We recently reported that smoking durably modifies the platelet 5-HT/MAO system by inducing a demethylation of the MAO gene promoter resulting in high MAO protein concentration persisting more than ten years after quitting smoking. The present data enlarges the results to another MAO substrate, norepinephrine (NE), further confirming the central role of MAO in tobacco use-induced diseases. Thus, MAO could be a readily accessible and helpful marker in the risk evaluation of smoking-related diseases, from cardiovascular and pulmonary diseases to depression, anxiety and cancer. The present review implements the new finding of epigenetic regulation of MAO and suggests that smoking-induced MAO demethylation can be considered as a hallmark of smoking-related cancers similarly to other aberrant DNA methylations.
Topics: Anxiety; Biomarkers; Cardiovascular Diseases; Depression; Epigenesis, Genetic; Humans; Hydroxyindoleacetic Acid; Lung Diseases; Methoxyhydroxyphenylglycol; Monoamine Oxidase; Neoplasms; Norepinephrine; Risk Factors; Serotonin; Smoking
PubMed: 21318020
DOI: 10.3390/ijerph8010136 -
Journal of Alzheimer's Disease : JAD 2021The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We...
The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-β is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer's disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial Alzheimer's disease-related processes.
Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Cohort Studies; Disease Progression; Female; Humans; Learning; Locus Coeruleus; Male; Memory Disorders; Methoxyhydroxyphenylglycol; Middle Aged; Neuropsychological Tests; Norepinephrine; Predictive Value of Tests; tau Proteins
PubMed: 33554915
DOI: 10.3233/JAD-201411 -
Journal of Neurovirology Aug 2023Depression is a common illness in people with HIV (PWH) and is associated with substantial morbidity and mortality. The mechanisms that underpin depression in PWH remain...
Depression is a common illness in people with HIV (PWH) and is associated with substantial morbidity and mortality. The mechanisms that underpin depression in PWH remain incompletely elucidated, and more research is therefore needed to develop effective treatments. One hypothesis is that neurotransmitter levels may be altered. These levels could be influenced by the chronic inflammation and viral persistence that occurs in PWH. We examined a panel of cerebrospinal fluid (CSF) neurotransmitters in PWH on suppressive antiretroviral therapy (ART), many of whom had a current depression diagnosis. CSF monoamine neurotransmitters and their metabolites were measured from participants in studies at the Emory Center for AIDS Research (CFAR). Only participants on stable ART with suppressed HIV RNA from both plasma and CSF were analyzed. Neurotransmitter levels were measured with high-performance liquid chromatography (HPLC). Neurotransmitters and their metabolites included dopamine (DA), homovanillic acid (HVA, a major metabolite of dopamine), serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA, a major metabolite of serotonin), and 4-hydroxy-3-methoxyphenylglycol (MHPG, a major metabolite of norepinephrine). Multivariable logistic regression was used to evaluate factors associated with depression. There were 79 PWH with plasma and CSF HIV RNA levels < 200 copies/mL at the time of the visit, and 25 (31.6%) carried a current diagnosis of depression. Participants with depression were significantly older (median age 53 years versus 47 years, P = 0.014) and were significantly less likely to be African American (48.0% versus 77.8%, P = 0.008). Participants with depression had significantly lower dopamine levels (median 0.49 ng/mL versus 0.62 ng/mL, P = 0.03) and significantly lower 5-HIAA levels (median 12.57 ng/mL versus 15.41 ng/mL, P = 0.015). Dopamine and 5-HIAA were highly correlated. In the multivariable logistic regression models, lower 5-HIAA was significantly associated with the depression diagnosis when accounting for other significant demographic factors. The associations between lower 5-HIAA, lower dopamine, and depression in PWH suggest that altered neurotransmission may contribute to these comorbid conditions. However, the effects of antidepressants on neurotransmitters cannot be ruled out as a factor in the 5-HIAA results.
Topics: Humans; Middle Aged; Dopamine; Serotonin; Hydroxyindoleacetic Acid; Depression; Methoxyhydroxyphenylglycol; Neurotransmitter Agents
PubMed: 37289360
DOI: 10.1007/s13365-023-01142-2 -
Parkinsonism & Related Disorders Jun 2015Parkinson disease (PD) and multiple system atrophy (MSA) share some neuropathologic features (nigrostriatal dopaminergic lesion, alpha-synuclein deposition) but not...
BACKGROUND
Parkinson disease (PD) and multiple system atrophy (MSA) share some neuropathologic features (nigrostriatal dopaminergic lesion, alpha-synuclein deposition) but not others (Lewy bodies in PD, glial cytoplasmic inclusions in MSA). In PD evidence has accrued for a vesicular storage defect and decreased aldehyde dehydrogenase (ALDH) activity in residual dopaminergic terminals, resulting in accumulation of the toxic dopamine (DA) metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). In this study we asked whether MSA entails a similar abnormal neurochemical pattern.
METHODS
DA and its main neuronal metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and its main neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG), the catecholamine precursor DOPA, and DOPAL were measured in striatal and frontal cortical tissue from patients with pathologically proven end-stage MSA (N = 15), sporadic PD (N = 17), and control subjects (N = 18).
RESULTS
Compared to the control group, the MSA and PD groups had similarly decreased putamen DA (by 96% and 93%, p < 0.0001), DOPAC (97% and 95%, p < 0.0001), NE (91% and 74%, p < 0.0001), and DHPG (81% and 74%, p < 0.0001). In the MSA and PD groups, ratios of DOPAL:DA were 2.3 and 3.5 times control and DHPG:NE 3.1 and 2.6 times control, while DOPAC:DOPAL ratios were decreased by 61% and 74%. In both diseases cortical NE and DHPG were decreased, while DA and DOPAC were not.
CONCLUSIONS
MSA and PD entail a catecholamine metabolic profile indicating impaired vesicular storage, decreased ALDH activity, and DOPAL buildup, which might be part of a common pathway in catecholamine neuronal death. Targeting this pathway by interfering with catecholaldehyde production or effects constitutes a novel treatment approach.
Topics: 3,4-Dihydroxyphenylacetic Acid; Aged; Aged, 80 and over; Aldehyde Dehydrogenase; Corpus Striatum; Dihydroxyphenylalanine; Dopamine; Female; Frontal Lobe; Humans; Male; Methoxyhydroxyphenylglycol; Multiple System Atrophy; Neurons; Norepinephrine; Parkinson Disease
PubMed: 25829070
DOI: 10.1016/j.parkreldis.2015.03.006 -
Glia Apr 2017Astrocytes play crucial roles in brain homeostasis and are emerging as regulatory elements of neuronal and synaptic physiology by responding to neurotransmitters with Ca...
Astrocytes play crucial roles in brain homeostasis and are emerging as regulatory elements of neuronal and synaptic physiology by responding to neurotransmitters with Ca elevations and releasing gliotransmitters that activate neuronal receptors. Aging involves neuronal and astrocytic alterations, being considered risk factor for neurodegenerative diseases. Most evidence of the astrocyte-neuron signaling is derived from studies with young animals; however, the features of astrocyte-neuron signaling in adult and aging brain remain largely unknown. We have investigated the existence and properties of astrocyte-neuron signaling in physiologically and pathologically aging mouse hippocampal and cortical slices at different lifetime points (0.5 to 20 month-old animals). We found that astrocytes preserved their ability to express spontaneous and neurotransmitter-dependent intracellular Ca signals from juvenile to aging brains. Likewise, resting levels of gliotransmission, assessed by neuronal NMDAR activation by glutamate released from astrocytes, were largely preserved with similar properties in all tested age groups, but DHPG-induced gliotransmission was reduced in aged mice. In contrast, gliotransmission was enhanced in the APP/PS1 mouse model of Alzheimer's disease, indicating a dysregulation of astrocyte-neuron signaling in pathological conditions. Disruption of the astrocytic IP R2 mediated-signaling, which is required for neurotransmitter-induced astrocyte Ca signals and gliotransmission, boosted the progression of amyloid plaque deposits and synaptic plasticity impairments in APP/PS1 mice at early stages of the disease. Therefore, astrocyte-neuron interaction is a fundamental signaling, largely conserved in the adult and aging brain of healthy animals, but it is altered in Alzheimer's disease, suggesting that dysfunctions of astrocyte Ca physiology may contribute to this neurodegenerative disease. GLIA 2017 GLIA 2017;65:569-580.
Topics: Acetylcholine; Adenosine Triphosphate; Aging; Amyloid beta-Protein Precursor; Animals; Astrocytes; Brain; Calcium; Cell Communication; Excitatory Amino Acid Agents; Membrane Potentials; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Presenilin-1; Signal Transduction; Synapses; Synaptic Potentials
PubMed: 28130845
DOI: 10.1002/glia.23112