Natália Pessoa Rocha

Executive dysfunction in euthymic bipolar disorder patients and its association with plasma biomarkers

BACKGROUND Despite the old Kraepelinean concept that bipolar disorder (BD) does not evolve with cognitive decline, the presence of cognitive impairment, especially executive dysfunction has been recognized in BD patients. Brain-derived neurotrophic factor (BDNF) and pro-inflammatory molecules are important contributors to the pathophysiology of BD, and imbalance in peripheral levels of these molecules may be implicated in the cognitive decline observed in BD patients. We aimed to investigate the executive performance of BD type I euthymic patients and its relation with the plasma levels of BDNF, TNF-α and its related soluble receptors (sTNFR1 and sTNFR2). METHODS We evaluated executive functioning through the Frontal Assessment Battery (FAB). Plasma levels of BDNF, TNF-α, sTNFR1 and sTNFR2 were measured using enzyme-linked immunosorbent assay (ELISA) in 25 euthymic type I BD patients and 25 age and gender matched healthy controls. RESULTS BD patients had an impairment in executive functioning (p<0.006), particularly sensitivity of interference (p=0.02), inhibitory control (p=0.02), and increased BDNF plasma levels (p=0.001) in comparison with controls. Plasma levels of TNF-α were correlated with inhibitory control in BD patients (ρ=0.50, p=0.02) while motor programming was negatively correlated with sTNFR2 plasma levels (ρ=-0.47, p=0.02) in controls. Executive function correlated with age and MMSE, but not with BDNF, neither was influenced by psychiatric and clinical comorbidities nor medications in use. CONCLUSION BDNF is altered in BD but do not correlate with executive functioning.

Insights into Neuroinflammation in Parkinson's Disease: From Biomarkers to Anti-Inflammatory Based Therapies.

Parkinsons disease (PD) is the second most common neurodegenerative disorder worldwide, being characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Among several putative factors that may contribute to PD pathogenesis, inflammatory mechanisms may play a pivotal role. The involvement of microglial activation as well as of brain and peripheral immune mediators in PD pathophysiology has been reported by clinical and experimental studies. These inflammatory biomarkers evaluated by imaging techniques and/or by biological sample analysis have become valuable tools for PD diagnosis and prognosis. Regardless of the significant increase in the number of people suffering from PD, there are still no established disease-modifying or neuroprotective therapies for it. There is growing evidence of protective effect of anti-inflammatory drugs on PD development. Herein, we reviewed the current literature regarding the central nervous system and peripheral immune biomarkers in PD and advances in diagnostic and prognostic tools as well as the neuroprotective effects of anti-inflammatory therapies.

Increased levels of adipokines in bipolar disorder.

Bipolar disorder (BD) is associated with considerable higher chronic medical comorbidities, overweight and obesity. Adipokines are adipocyte-derived secretory factors which have functions in immune response and seem to be associated with both BD and overweight. The aim of this study was to evaluate the plasma levels of adipokines (adiponectin, resistin and leptin) and TNF-α and its receptors (sTNFR1 and sTNFR2) in BD overweight patients in comparison with overweight controls. Thirty euthymic BD type-I patients and thirty controls matched by age, gender and body-mass index (BMI) were assessed by Mini-International Neuropsychiatric Interview, Young Mania and Hamilton Depression rating scales (YMRS and HDRS, respectively). Plasma levels of adiponectin, resistin, leptin, TNF-α and its soluble receptors were measured by ELISA. BD patients presented increased plasma levels of adiponectin (p < 0.001), leptin (p < 0.001) and sTNFR1 (p = 0.01). Plasma levels of adipokines were not correlated neither with clinical parameters nor TNF-α, sTNFR1 and sTNFR2 plasma levels. This study provides further support to the hypothesis of the immune/inflammatory imbalance in BD.

Circulating levels of GDNF in bipolar disorder

Neurotrophic factors regulate the survival and growth of neurons, and influence synaptic efficiency and plasticity. Several studies suggest the existence of a relationship between changes in neurotrophic levels and bipolar disorder (BD). The glial cell-line derived neurotrophic factor (GDNF) influences monoaminergic neurons and glial cells, but its role in BD patients is controversial. In order to elucidate it we evaluated plasma levels of GDNF in a sample of 70 BD patients (35 in mania and 35 in euthymia) and compared with 50 healthy controls matched for age, gender and educational levels. GDNF plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients were assessed by a Mini-International Neuropsychiatric Interview (MINI-plus), Young Mania and Hamilton Depression Rating Scales. Plasma GDNF levels were significantly increased in BD patients in euthymia compared with BD patients in mania and healthy controls (p<0.05). GDNF plasma levels were correlated with age (ρ=0.30, p<0.05) and negatively correlated with manic symptoms in BD patients (ρ=-0.54, p<0.05). Our results provide evidence that peripheral levels of GDNF are related with different mood states in BD, reinforcing the involvement of neurotrophic factors in its physiopathology.

Effects of Physical Exercise on Plasma Levels of Brain-Derived Neurotrophic Factor and Depressive Symptoms in Elderly Women—A Randomized Clinical Trial

OBJECTIVES To investigate the effect of 2 standardized exercise programs, muscle strength exercises (SE) and aerobic exercises (AE), on the plasma levels of brain-derived neurotrophic factor (BDNF) and depressive symptoms in 451 elderly women. DESIGN A randomized controlled trial. SETTING Belo Horizonte/MG-Brazil. PARTICIPANTS Community-dwelling older women (N=451; age, 65-89y). INTERVENTION The participants were divided into 2 groups: SE and AE. Both protocols lasted 10 weeks, and 30 sessions (1-h sessions) in total were performed 3 times a week under the direct supervision of physical therapists. MAIN OUTCOME MEASURES Plasma levels of BDNF (enzyme-linked immunosorbent assay) and depressive symptoms (Geriatric Depression Scale). RESULTS There was a significant difference for BDNF plasma levels between the SE and AE groups (P=.009). Post hoc analysis revealed a pre-post intervention difference in BDNF levels only for the SE group (P=.008). A statistically significant difference was found for the pre- and postintervention Geriatric Depression Scale scores in both groups (P=.001), showing that the effects of both exercise protocols were comparable regarding depressive symptoms (P=.185). CONCLUSIONS The present findings have demonstrated the positive effect of muscle strengthening and aerobic intervention on depressive symptoms in community-dwelling elderly women. Interestingly, only SE significantly increased the plasma levels of BDNF in our sample. The positive effects of physical exercise on depressive symptoms in the elderly were not mediated by BDNF.

Complexidade do regime terapêutico prescrito para idosos

OBJECTIVE: To examine factors associated with therapeutic regimen complexity of drug prescriptions for elderly people in Belo Horizonte, Minas Gerais, Brazil. METHODS: A household survey of elderly people selected by simple random sampling from Brazils social security register. The medication complexity index (MCI), a direct measurement of actions required to administer medication, was derived from information in the latest prescription. Univariate and bivariate analyses were performed to identify factors associated with the MCI. RESULTS: Of the 667 interviewees, 56.5% had prescriptions meeting the inclusion criteria; most (69.2%) were females aged 72.4 years (mean); 35.5% self-rated their health good or very good; and 37.4% reported five or more diseases. In the 15 days prior to interview, 1873 drugs were used (mean=5.1), of which 942 appeared on the prescriptions examined (mean=2.5). Over the same period, 22.3% of interviewees failed to use some prescribed drug. The MCI ranged from 1 to 24 (mean=6.1). Number of drugs prescribed (>2), less schooling, worse perception of health and a lower benefit payment associated positively with greater complexity (p<0.05). An association was observed between regimen complexity and failure to use some drug in the preceding 15 days (p=0.034). CONCLUSION: Elderly people in worse socio-economic and health conditions seem more likely to receive more complex therapeutic regimens, which are associated with non-compliance to the proposed treatment. This is an important consideration in the healthcare of elderly. Simplification of therapy could aid self-care among the elderly.

Neurotrophic factors in obsessive-compulsive disorder

In this cross-sectional study, we assessed the levels of neurotrophins (NF) of patients with obsessive-compulsive disorder (OCD) in different stages of treatment and their relationship with OCD clinical features. Forty patients with OCD and 40 healthy controls had Brain-Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF), and Glial Cell-Derived Neurotrophic Factor (GNDF) plasma levels measured by enzyme-linked immunosorbent assay (ELISA). Patients with OCD were further examined with the Obsessive-Compulsive Inventory-Revised, the Beck Depression Inventory, the Beck Anxiety Inventory, and the Sheehan Disability Scale (SDS). Patients with OCD exhibited significantly lower levels of BDNF and significantly increased levels of NGF as compared to healthy controls. In OCD, statistically significant negative correlations between BDNF levels and number of working days lost per week were found. Additional analyses revealed a statistically significant positive correlation between both NGF and GDNF and severity of washing symptoms. Plasma levels of NF were not affected by age, age at OCD onset, gender, major depressive disorder, the relative dose of serotonin-reuptake inhibitors being prescribed, or the use of antipsychotics. Our findings suggest that patients with OCD may exhibit a particular NF profile, with functional impairment correlating with BDNF levels and severity of washing symptoms correlating with NGF and GDNF levels.

Plasma levels of soluble tumor necrosis factor receptors are associated with cognitive performance in Parkinson's disease.

Inflammatory mechanisms have been implicated in a series of neuropsychiatric conditions, including behavioral disturbances, cognitive dysfunction, and affective disorders. Accumulating evidence also strongly suggests their involvement in the pathophysiology of Parkinsons disease (PD). This study aimed to evaluate plasma levels of inflammatory biomarkers, and their association with cognitive performance and other non‐motor symptoms of PD. PD patients and control individuals were subjected to various psychometric tests, including the Mini‐Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Becks Depression Inventory (BDI). Biomarker plasma levels were measured by enzyme‐linked immunosorbent assay (ELISA). PD patients exhibited worse performance on MMSE and the programming task of FAB, and presented higher soluble tumor necrosis factor receptor (sTNFR) plasma levels than control individuals. Among PD patients, increased sTNFR1 and sTNFR2 concentrations were associated with poorer cognitive test scores. After multiple linear regression, sTNFR1 and education remained a significant predictor for FAB scores. Our data suggest that PD is associated with a proinflammatory profile, and sTNFRs are putative biomarkers of cognitive performance, with elevated sTNFR1 levels predicting poorer executive functioning in PD patients.

Monocyte and lymphocyte activation in bipolar disorder: a new piece in the puzzle of immune dysfunction in mood disorders.

Background: This study tested the hypothesis that the low-grade inflammation presented in patients with bipolar disorder (BD) is associated with expansion of activated T cells, and this activated state may be due to a lack of peripheral regulatory cells. Methods: Specifically, we investigated the distribution of monocytes and lymphocyte subsets, and investigated Th1/Th2/Th17 cytokines in plasma by flow cytometry. Twenty-one BD type I patients and 21 age- and sex-matched controls were recruited for this study. Results: BD patients had increased proportions of monocytes (CD14+). Regarding lymphocyte populations, BD patients presented reduced proportions of T cells (CD3+) and cytotoxic T cells (CD3+CD8+). BD patients also exhibited a higher percentage of activated T CD4+CD25+ cells, and a lower percentage of IL-10 expressing Treg cells. Conclusions: Our data shed some light into the underlying mechanisms involved with the chronic low-grade inflammatory profile described in BD patients.

Altered intracellular signaling cascades in peripheral blood mononuclear cells from BD patients

Bipolar disorder (BD) is a severe psychiatric disorder of complex physiopathology that has been associated with a pro-inflammatory state. The aim of the present study was to investigate intracellular pathways associated with inflammatory signaling, assessing the phosphorylation levels of transcription factor nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPKs) in peripheral blood mononuclear cells of euthymic BD patients and healthy controls. Fifteen BD euthymic type I patients, and 12 healthy controls matched by age and gender were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatry Interview and the patients also by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. Phosphorylation levels of p65 NF-κB subunit, and MAPK ERK1/2, and p38 were assessed by Western blot and flow cytometry. Plasma cytokines (IL-2, IL-4, IL6, IL-10, IFN-γ, TNF-α, and IL-17A) were measured using cytometric bead arrays. Western blot and flow cytometry analyses showed increased phosphorylation levels of p65 NF-κB subunit, and MAPKs ERK1/2, and p38 in BD patients in euthymia in comparison with controls. BD patients presented increased pro-inflammatory cytokines levels in comparison with controls, and TNF-α correlated with the levels of phosphorylated p65 NF-κB. The present study found increased activation of MAPK and NF-κB pathways in BD patients, which is in line with a pro-inflammatory status.