Inflammatory cytokines and white matter microstructure in the acute phase of first-episode psychosis: A longitudinal study.

OBJECTIVES: Schizophrenia-related psychosis is associated with abnormalities in white matter (WM) microstructure and structural brain dysconnectivity. However, the pathological process underlying such changes is unknown. We sought to investigate the potential association between peripheral cytokine levels and WM microstructure during the acute phase of first-episode psychosis (FEP) in a cohort of drug-naïve patients. METHODS: Twenty-five non-affective FEP patients and 69 healthy controls underwent MRI scanning and blood collection at study entry. After achieving clinical remission, 21 FEP were reassessed; 38 age and biological sex-matched controls also had a second assessment. We measured fractional anisotropy (FA) of selected WM regions-of-interest (ROIs) and plasma levels of four cytokines (IL-6, IL-10, IFN-γ, and TNF-α). RESULTS: At baseline (acute psychosis), the FEP group showed reduced FA relative to controls in half the examined ROIs. Within the FEP group, IL-6 levels were negatively correlated with FA values. Longitudinally, patients showed increments of FA in several ROIs affected at baseline, and such changes were associated with reductions in IL-6 levels. CONCLUSIONS: A state-dependent process involving an interplay between a pro-inflammatory cytokine and brain WM might be associated with the clinical manifestation of FEP. This association suggests a deleterious effect of IL-6 on WM tracts during the acute phase of psychosis.

Cannabinoids in Late Life Parkinson's Disease and Dementia: Biological Pathways and Clinical Challenges.

The use of cannabinoids as therapeutic drugs has increased among aging populations recently. Age-related changes in the endogenous cannabinoid system could influence the effects of therapies that target the cannabinoid system. At the preclinical level, cannabidiol (CBD) induces anti-amyloidogenic, antioxidative, anti-apoptotic, anti-inflammatory, and neuroprotective effects. These findings suggest a potential therapeutic role of cannabinoids to neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer. Emerging evidence suggests that CBD and tetrahydrocannabinol have neuroprotective therapeutic-like effects on dementias. In clinical practice, cannabinoids are being used off-label to relieve symptoms of PD and AD. In fact, patients are using cannabis compounds for the treatment of tremor, non-motor symptoms, anxiety, and sleep assistance in PD, and managing responsive behaviors of dementia such as agitation. However, strong evidence from clinical trials is scarce for most indications. Some clinicians consider cannabinoids an alternative for older adults bearing Parkinson's disease and Alzheimer's dementia with a poor response to first-line treatments. In our concept and experience, cannabinoids should never be considered a first-line treatment but could be regarded as an adjuvant therapy in specific situations commonly seen in clinical practice. To mitigate the risk of adverse events, the traditional dogma of geriatric medicine, starting with a low dose and proceeding with a slow titration regime, should also be employed with cannabinoids. In this review, we aimed to address preclinical evidence of cannabinoids in neurodegenerative disorders such as PD and AD and discuss potential off-label use of cannabinoids in clinical practice of these disorders.

COX-2 pathway is upregulated in ultra-high risk individuals for psychosis.

BACKGROUND: The identification of Ultra-High Risk (UHR) individuals is thought to be useful for early intervention to improve psychosis outcomes. However, transition rates vary widely, and there is an effort to make these criteria more specific and accurate. Neuroinflammation has been discussed in the pathophysiology of psychosis. The metabolism of eicosanoids is a key process in inflammatory states. Therefore, we investigated whether the study of the inflammatory COX-2 pathway through the quantification of the eicosanoid levels can be a useful approach for the characterisation of UHR individuals. METHODS: One hundred and twenty-two individuals were included in this study (67 UHR and 55 controls) based on performance on the Prodromal Questionnaire. UHR status was assessed by Structured Interview for Prodromal Syndromes (SIPS). We determined the levels of Prostaglandin F2α (PGF2α), Prostaglandin E2 (PGE2), and Thromboxane B2 (TxB2) in plasma using ELISA assays. RESULTS: Concentrations of PGE2 and TxB2 were increased in UHR compared to controls (p = 0.01 and p < 0.05, respectively). PGE2 and PGF2α levels were correlated to negative symptoms (p < 0.01 and p < 0.05), whereas TxB2 correlated with positive symptoms (p = 0.05) as assessed by the SIPS. CONCLUSIONS: Our findings suggest that overactivation of the COX-2 pathway may be related to an increased risk for psychosis. However, our data do not allow us to draw conclusions related to the cause-effect mechanisms. Future studies should determine whether the levels of the eicosanoids have a predictive value for the transition of UHR to frank psychosis.

Plasmatic endocannabinoids are decreased in subjects with ultra-high risk of psychosis.

The onset of frank psychosis is usually preceded by a prodromal phase characterized by attenuated psychotic symptoms. Currently, research on schizophrenia prodromal phase (ultra-high risk for psychosis [UHR]) has focused on the risk of developing psychosis, on the transition to full blown psychosis and on its prediction. Neurobiological differences between UHR individuals who fully recover (remitters) versus those who show persistent/progressive prodromal symptoms (nonremitters) have been little explored. The endocannabinoid system constitutes a neuromodulatory system that plays a major role in brain development, synaptic plasticity, emotional behaviours and cognition. It comprises two cannabinoid receptors (CB1/CB2), two endocannabinoid ligands, arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2AG) along with their inactivation enzymes. Despite much evidence that the endocannabinoid system is imbalanced during psychosis, very little is known about it in UHR. Therefore, we aimed to quantify the plasma endocannabinoid levels in UHR and healthy controls (HC) and verify if these metabolites could differentiate between remitters and nonremitters. Circulating concentrations of AEA (p = .003) and 2AG (p < .001) were lower in UHR when compared with HC, with no difference between remitters and nonremitters. Regarding clinical evolution, it was observed that out of 91 UHRs initially considered, 16 had psychiatric complaints (3 years of follow-up). Considering those subjects, there were weak correlations between clinical parameters and plasma concentrations of endocannabinoids. Our results suggest that the endocannabinoids are imbalanced before frank psychosis and that changes can be seen in plasma of UHR individuals. These molecules proved to be potential biomarkers to identify individuals in the prodromal phase of psychosis.

Increased PLA2 activity in individuals at ultra-high risk for psychosis.

Phospholipase A2 is the main enzyme in the metabolism of membrane phospholipids. It comprises a family of enzymes divided into iPLA2, cPLA2 and sPLA2. Studies have reported increased PLA2 activity in psychotic patients, which suggests an accelerated breakdown of membrane phospholipids. In the present study we investigated whether increased PLA2 activity is also present in individuals at ultra-high risk (UHR) for psychosis. One-hundred fifty adults were included in this study (85 UHR and 65 controls). UHR was assessed using the "structured interview for prodromal syndromes". PLA2 activity was determined in platelets by a radio-enzymatic assay. We found in UHR individuals increased activities of iPLA2 (p < 0.001) and cPLA2 (p = 0.012) as compared to controls. No correlations were found between socio-demographic and clinical parameters and PLA2 activity. Our findings suggest that increased PLA2 activities may be useful as a biological risk-marker for psychotic disorders.

Plasma Metabolite Profiles in First Episode Psychosis: Exploring Symptoms Heterogeneity/Severity in Schizophrenia and Bipolar Disorder Cohorts.

INTRODUCTION: The first symptoms of psychosis are frequently shared amongst several neuropsychiatry disorders, which makes the differentiation by clinical diagnosis challenging. Early recognition of symptoms is important in the management of psychosis. Therefore, the implementation of molecular biomarkers will be crucial for transforming the currently used diagnostic and therapeutic approach, improving insights into the underlying biological processes and clinical management. OBJECTIVES: To define a set of metabolites that supports diagnosis or prognosis of schizophrenia (SCZ) and bipolar disorder (BD) at first onset psychosis. METHODS: Plasma samples from 55 drug-naïve patients, 28 SCZ and 27 BD, and 42 healthy controls (HC). All participants underwent a seminaturalistic treatment regimen, clinically evaluated on a weekly basis until achieving clinical remission. All clinical or sociodemographic aspects considered for this study were equivalent between the groups at first-onset psychosis time point. The plasma samples were analyzed by untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) using reversed-phase and hydrophilic interaction chromatography. The acquired molecular features were analyzed with MetaboAnalyst. RESULTS: We identified two patient groups with different metabolite profiles. Both groups are composed of SCZ and BD patients. We found differences between these two groups regarding general symptoms of PANSS score after remission (p = 0.008), and the improvement of general symptoms (delta of the score at remission minus the baseline) (-0.50 vs. -0.33, p = 0.019). CONCLUSION: Our results suggest that plasma metabolite profiles cluster clinical remission phenotypes based on PANSS general psychopathology scores.

Cognitive impairment in remitted late-life depression is not associated with Alzheimer's disease-related CSF biomarkers.

BACKGROUND: Cognitive impairment is a common feature of late-life depression (LLD). Early studies using Alzheimer's disease (AD) biomarkers inferred a biological link between AD pathology and LLD, but recent findings have challenged this association. The aim of this investigation was to determine a panel of AD-related cerebrospinal fluid (CSF) biomarkers in a cross-section of elders with mild cognitive impairment (MCI) with and without LLD. METHODS: Subjects comprised 102 older adults: 27 with 'pure' amnestic MCI (aMCI), 53 with major depression and cognitive impairment - encompassing 22 late-onset (LOD) and 31 early-onset depression (EOD), and 22 euthymic elders without cognitive impairment (controls). Participants underwent lumbar puncture for determination of CSF concentrations of Aß1-42, T-tau, and P-tau. Cut-off scores for suspected AD were: Aß1-42 < 416p g/mL, P-tau > 36.1 pg/mL and Aß/P-tau ratio < 9.53 (O. V. Forlenza et al. 2015). Statistical analyses consisted of analyses of variance (ANOVA), analyses of covariance (ANCOVA), Bonferroni post-hoc tests, and Pearson's chi-squared tests. RESULTS: ANCOVA (age and schooling as covariates) displayed statistically significant results with respect to CSF biomarkers' profiles regardless of the socio-demographic divergencies previously identified by one-way ANOVA. Mean Aß1-42 values (pg/mL) were: aMCI, 360.3 (p < 0.001); LOD, 486.6 (p < 0.001); EOD, 494.2 (p < 0.001); controls, 528.3 (p < 0.001); p< 0.05. Mean Aß1-42/P-tau ratio: aMCI, 7.9 (p < 0.001); LOD 14.2 (p < 0.001); EOD, 15.3 (p < 0.001); controls, 17.1 (p < 0.001); p < 0.05. Post-hoc tests indicated that patients with aMCI showed significant differences in biomarker profile compatible with AD signature. LIMITATION: The main limitation is the relatively small sample. CONCLUSION: Our findings suggest that, distinctively from aMCI, cognitive impairment in LLD is not associated with AD's CSF pathological signature.

Three plasma metabolites in elderly patients differentiate mild cognitive impairment and Alzheimer's disease: a pilot study.

The metabolomic profile of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) may suggest potential diagnostic biomarkers and provide information on the pathophysiology of dementia. Our aim was to quantify plasmatic metabolites of AD patients, MCI and controls. We investigated the metabolomic profile-using the AbsoluteIDQ®p180 assay-of 79 older adults with primary cognitive impairment (34 AD and 20 MCI) and 25 healthy elders (controls). A cluster analysis revealed that a combination C12-DC, C12 and PCaaC26:0 could differentiate the patients according to diagnostic. Future studies should combine metabolomic profiles with other biomarkers to identify diagnostic groups.

Reduced Annexin A3 in schizophrenia.

The cellular and molecular mechanisms underlying onset and development of schizophrenia have not yet been completely elucidated, but the association of disturbed neuroplasticity and inflammation has gained particular relevance recently. These mechanisms are linked to annexins functions. ANXA3, particularly, is associated to inflammation and membrane metabolism cascades. The aim was to determine the ANXA3 levels in first-onset drug-naïve psychotic patients. We investigated by western blot the protein expression of annexin A3 in platelets of first-onset, drug-naïve psychotic patients (diagnoses according to DSM-IV: 28 schizophrenia, 27 bipolar disorder) as compared to 30 age- and gender-matched healthy controls. Annexin A3 level was lower in schizophrenia patients as compared to healthy controls (p < 0.001) and to bipolar patients (p < 0.001). Twenty out of 28 schizophrenic patients had undetectable annexin A3 levels, as compared to none from the bipolar and none from the control subjects. ANXA3 was reduced in drug-naïve patients with schizophrenia. ANXA3 affects neuroplasticity, inflammation and apoptosis, as well as it modulates membrane phospholipid metabolism. All these processes have been discussed in regard to the biology of schizophrenia. In face of these data, we feel that further studies with larger samples are warranted to investigate the possible role of reduced ANXA3 as a possible risk marker for schizophrenia.

Decreased plasmatic spermidine and increased spermine in mild cognitive impairment and Alzheimer's disease patients

Abstract Background Current evidence suggests that upregulation of polyamines system plays a role both in cognitive deficit and synaptic loss observed in Alzheimer's disease (AD). Objective The aim of this study was to determine the plasmatic concentration of polyamines in mild cognitive impairment (MCI) and AD patients in comparison with healthy controls (HC). Methods Plasmatic polyamines were quantified using the AbsoluteIDQ® p180 and liquid chromatography coupled to tandem mass spectrometry (LC/MS-MS). Results The study group comprised 34 AD patients, 20 MCI and 25 HC. All individuals were followed for 4 years. During this period 8 amnestic MCI patients (40% of the MCI sample at baseline) converted to AD. Spermidine level was lower in both patient groups (AD; MCI) compared to HC (p = 0.007). Plasma levels of spermine were higher in the MCI group (p < 0.001), but decreased in the sub-sample of MCI patients who converted to AD (p = 0.043). No statistically significant differences were found in ornithine and putrescine levels (p = 0.056 and p = 0.126, respectively). Discussion Our results suggest dynamic changes in the expression of polyamines in the MCI-AD continuum.

Plasma lipids metabolism in mild cognitive impairment and Alzheimer's disease.

OBJECTIVES: Expression of phospholipids and related molecules could provide panels of multiple biomarkers searching for the signature of Alzheimer's disease (AD). The aim of the present study was to quantify ten phospholipids and simultaneously determine phospholipase A2 (PLA2) activity in blood of mild cognitive impairment (MCI) and AD patients. METHODS: Thirty-four AD, 20 MCI and 25 controls were enrolled. The phospholipids where analysed using the AbsoluteIDQ® p180 Kit. PLA2 activities were accessed in platelets by a radio-enzymatic assay. RESULTS: The study failed to fix the ten phospholipids as a panel to predict AD; the levels of PCaaC36:6, PCaaC40:6 and C16:1-OH were lower in MCI than in controls (P = 0.041, P = 0.012, P = 0.044 respectively). PCaaC40:2 levels were lower in MCI than in AD (P = 0.041). The converters MCI-AD showed at baseline lower levels of PCaaC40:2 (P = 0.050) and PCaaC40:6 (P = 0.037) than controls. iPLA2 activity was reduced in AD and MCI than in controls (P < 0.001). We found positive correlation in the control group between PCaaC38:6 and tPLA2 (r = 0.680; P = 0.001) and sPLA2 (r = 0.601; P = 0.004); PCaaC40:1 and iPLA2 (r = 0.503; P = 0.020); PCaaC40:6 and tPLA2 (r = 0.532; P = 0.013) and sPLA2 (r = 0.523; P = 0.015). CONCLUSIONS: Lipids metabolites in plasma might indirectly indicate changes in neuronal membrane and this deregulation can outline the transition between healthy and diseased brains.

Kynurenine is correlated with IL-1ß in plasma of schizophrenia patients.

The etiology of schizophrenia is still unclear. It is well-known that pro-inflammatory cytokines are higher in schizophrenia patients since the first episode psychosis comparing to healthy controls. Inflammatory downstream cascades influence different cellular pathways, like the displacement of the tryptophan (TRP) metabolism to the production of kynurenine (KYN) instead of serotonin, which results in the generation of several neuro and immunoactive metabolites. The aim of this study was to determine TRP, KYN and IL-1ß plasma levels in first-onset schizophrenia (n = 28) and healthy controls (n = 30). The plasmatic levels of TRP and KYN were decreased in schizophrenic patients (p = 0.004 and p = 0.002, respectively), but there was no difference in the ratio of KYN/TRP (p = 0.554) or either in IL-1ß (p = 0.101). Positive correlation was observed between KYN and IL-1ß only in the schizophrenia group (r = 0.461, p = 0.021). And, there was also positive correlation between KYN and Positive and Negative Symptoms Scale (PANSS) (r = 0.395, p = 0.037). There is no correlation between the other analytes and other parameters of PANSS. Although our results of KYN have been different than expected and there was no difference in the KYN/TRP ratio, we observed a positive correlation between IL-1ß and KYN, corroborating findings that pro-inflammatory agents hold up the KYN pathway.

Donepezil effects on cholesterol and oxysterol plasma levels of Alzheimer's disease patients.

Cholesterol is an essential component in the structure and function of cell membranes and has been associated with the major pathological signatures of Alzheimer's disease (AD). To maintain brain cholesterol homeostasis, it is converted into 24(S)-hydroxycholesterol (24OHC) which can be driven through the blood-brain barrier. Several studies have already described a decrease in 24OHC and an increase of 27(S)-hydroxycholesterol (27OHC) in AD, as a reflection of disease burden, the loss of metabolically active neurons and the degree of structural atrophy. It is also well known that peripheral cholesterol is altered in AD patients. However, there are no data regarding effects of AD treatment in this cholesterol pathway. Since a study from our group indicated a significant increase in membrane phospholipid metabolism by donepezil, the aim of this study was to evaluate the effect of short- and long-term donepezil treatment on cholesterol and metabolites 24OHC and 27OHC in plasma of AD patients and in healthy volunteers. At baseline, we found a decrease of 24OHC (p = 0.003) in AD patients. Cholesterol levels increased with donepezil treatment (p = 0.04) but no differences were observed regarding 24OHC and 27OHC. However, these results confirm and extend previous studies demonstrating disturbed cholesterol turnover in Alzheimer's disease.

Increased platelet glycogen sysnthase kinase 3beta in first-episode psychosis.

Past studies have linked intracellular pathways related to psychotic disorders to the GSK3B enzyme. This study aimed to investigate GSK3B protein expression and phosphorylation in drug-naïve first-episode psychosis patients (n=43) at baseline and following symptom remission, and in healthy controls (n=77). At baseline GSK3B total level was higher in patients (p<0.001). In schizophrenia spectrum patients (n=25) GSK3B total and phosphorylated levels were higher than in controls and patients with other non-affective psychotic disorders (n=18) (p<0.001; p=0.027; p=0.05 respectively). No enzyme changes were found after clinical remission. The implication of this finding for the biology of psychoses warrants further studies to clarify whether increased GSK3B may be useful as a biomarker for psychosis in general, and schizophrenia in particular.

Hippocampal serotonin depletion is related to the presence of generalized tonic-clonic seizures, but not to psychiatric disorders in patients with temporal lobe epilepsy.

OBJECTIVE: Previous studies suggest that concentration of serotonin ([5-HT]) plays a pathogenic role in various types of epilepsy inhibiting seizures. However, most have not considered the clinical variables of epilepsy, and all of these studies included small and heterogeneous samples with refractory epilepsy, regardless of etiology. In this work, we measured [5-HT]s in hippocampal tissues from a large series of patients with refractory temporal lobe epilepsy caused by hippocampal sclerosis who underwent epilepsy surgery and evaluated the relationship between [5HT] and epilepsy-related clinical variables and psychiatric disorders. METHODS: We included 44 patients with refractory unilateral TLE-HS who underwent surgical treatment for epilepsy. Hippocampal samples were collected, and serotonin concentrations were measured with high-pressure liquid chromatography (HPLC). RESULTS: Lower [5-HT]s were correlated with a history of GTC seizures (Student's t-test: p 0.041). There were no differences in [5-HT]s according to the other clinical variables and the presence of psychiatric disorders. SIGNIFICANCE: Our findings demonstrated that serotonin depletion in the hippocampus play an important role in some aspects of the severity of epilepsy (i.e., the presence of GTC seizures) in a homogeneous sample of patients with refractory temporal lobe epilepsy determined by hippocampal sclerosis, but not with the presence of psychiatric disorders.

Long-term sertraline treatment increases expression and decreases phosphorylation of glycogen synthase kinase-3B in platelets of patients with late-life major depression.

BACKGROUND: Abnormal regulation of glycogen synthase kinase 3-beta (GSK3B) activity has been implicated in the pathophysiology of mood disorders. Many pharmacological agents, including antidepressants, can modulate GSK3B. The aim of the present study was to investigate the effect of short-and long-term sertraline treatment on the expression and phosphorylation of GSK3B in platelets of patients with late-life major depression. METHODS: Thirty-nine unmedicated elderly adults with major depressive disorder (MDD) were initially included in this study. The comparison group comprised 18 age-matched, healthy individuals. The expression of total and Ser-9 phosphorylated GSK3B (pGSK3B) was determined by Enzyme Immunometric Assay (EIA) in platelets of patients and controls at baseline, and after 3 and 12 months of sertraline treatments for patients only. During this period, patients were continuously treated with therapeutic doses of sertraline. GSK3B activity was indirectly estimated by calculating the proportion of inactive (phosphorylated) forms (pGSK3B) in relation to the total expression of the enzyme (i.e., GSK3B ratio). RESULTS: Depressed patients had significantly higher levels of pGSK3B as compared to controls (p < 0.001). Within the MDD group, after 3 months of sertraline treatment no significant changes were observed in GSK3B expression and phosphorylation state, as compared to baseline levels. However, after 12 months of treatment we found a significant increase in the expression of total GSK3B (p = 0.05), in the absence of any significant changes in pGSK3B (p = 0.12), leading to a significant reduction in GSK3B ratio (p = 0.001). CONCLUSIONS: Our findings indicate that GSK3B expression was upregulated by the continuous treatment with sertraline, along with an increment in the proportion of active forms of the enzyme. This is compatible with an increase in overall GSK3B activity, which may have been induced by the long-term treatment of late-life depression with sertraline.

Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer's disease.

The disruption of glycogen synthase kinase 3-beta (GSK3B) homeostasis has implications in the pathophysiology of neuropsychiatric disorders, namely Alzheimer's disease (AD). GSK3B activity is increased within the AD brain, favoring the hyperphosphorylation of microtubule-associated protein Tau and the formation of neurofibrillary tangles. Such abnormality has also been detected in leukocytes of patients with cognitive disorders. The aim of the present study was to determine the expression of total and phosphorylated GSK3B at protein level in platelets of older adults with varying degrees of cognitive impairment, and to compare GSK3B activity in patients with AD, mild cognitive impairment (MCI) and healthy controls. Sixty-nine older adults were included (24 patients with mild to moderate AD, 22 patients with amnestic MCI and 23 elderly controls). The expression of platelet GSK3B (total- and Ser-9 phosphorylated GSK3B) was determined by Western blot. GSK3B activity was indirectly assessed by means of the proportion between phospho-GSK3B to total GSK3B (GSK3B ratio), the former representing the inactive form of the enzyme. Ser-9 phosphorylated GSK3B was significantly reduced in patients with MCI and AD as compared to controls (p=0.04). Platelet GSK3B ratio was significantly decreased in patients with MCI and AD (p=0.04), and positively correlated with scores on memory tests (r=0.298, p=0.01). In conclusion, we corroborate previous evidence of increased GSK activity in peripheral tissues of patients with MCI and AD, and further propose that platelet GSK may be an alternative peripheral biomarker of this abnormality, provided samples are adequately handled in order to preclude platelet activation.