Aline Silva de Miranda

Ontogeny and Functions of Central Nervous System Macrophages

Microglia, the only nonneuroepithelial cells found in the parenchyma of the CNS, originate during embryogenesis from the yolk sac and enter the CNS quite early (embryonic day 9.5–10 in mice). Thereafter, microglia are maintained independently of any input from the blood and, in particular, do not require hematopoietic stem cells as a source of replacement for senescent cells. Monocytes are hematopoietic cells, derived from bone marrow. The ontogeny of microglia and monocytes is important for understanding CNS pathologies. Microglial functions are distinct from those of blood-derived monocytes, which invade the CNS only under pathological conditions. Recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions. In this article, we discuss the physiology of microglia and the functions of monocytes in CNS pathology. We address the roles of microglia and monocytes in neurodegenerative diseases as an example of CNS pathology.

Functional Performance and Inflammatory Cytokines After Squat Exercises and Whole-Body Vibration in Elderly Individuals With Knee Osteoarthritis

OBJECTIVE To investigate the effects of squat exercises combined with whole-body vibration on the plasma concentration of inflammatory markers and the functional performance of elderly individuals with knee osteoarthritis (OA). DESIGN Clinical, prospective, randomized, single-blinded study. SETTING Exercise physiology laboratory. PARTICIPANTS Elderly subjects with knee OA (N=32) were divided into 3 groups: (1) squat exercises on a vibratory platform (platform group, n=11); (2) squat exercises without vibration (squat group, n=10); and (3) the control group (n=11). INTERVENTIONS The structured program of squat exercises in the platform and squat groups was conducted 3 times per week, on alternate days, for 12 weeks. MAIN OUTCOME MEASURES Plasma soluble tumor necrosis factor-α receptors 1 (sTNFR1) and 2 (sTNFR2) were measured using immunoassays (the enzyme-linked immunosorbent assay method). The Western Ontario and McMaster Universities Osteoarthritis Index questionnaire was used to evaluate self-reported physical function, pain, and stiffness. The 6-minute walk test, the Berg Balance Scale, and gait speed were used to evaluate physical function. RESULTS In the platform group, there were significant reductions in the plasma concentrations of the inflammatory markers sTNFR1 and sTNFR2 (P<.001 and P<.05, respectively) and self-reported pain (P<.05) compared with the control group, and there was an increase in balance (P<.05) and speed and distance walked (P<.05 and P<.001, respectively). In addition, the platform group walked faster than the squat group (P<.01). CONCLUSIONS The results suggest that whole-body vibration training improves self-perception of pain, balance, gait quality, and inflammatory markers in elderly subjects with knee OA.

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 Glial-derived neurotrophic factor is reduced in late-life depression

BACKGROUND The Glial cell-line derived neurotrophic factor (GDNF) is part of the TGF-β superfamily and is abundantly expressed in the central nervous system. Changes in GDNF homeostasis have been reported in affective disorders. AIM To assess serum GDNF concentration in elderly subjects with late-life depression, before antidepressant treatment, as compared to healthy elderly controls. METHODS Thirty-four elderly subjects with major depression and 37 age and gender-matched healthy elderly controls were included in this study. Diagnosis of major depression was ascertained by the SCID interview for DSM-IV and the severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale (HDRS-21). Serum GDNF concentration were determined by sandwich ELISA. RESULTS Patients with major depression showed a significant reduction in GDNF levels as compared to healthy elderly controls (p < 0.001). Also, GDNF level was negatively correlated with HDRS-21 scores (r = -0.343, p = 0.003). DISCUSSION Our data provide evidence that GDNF may be a state marker of depressive episode in older adults. Changes in the homeostatic control of GDNF production may be a target to development of new antidepressant strategies.

Inflammatory changes in the central nervous system are associated with behavioral impairment in Plasmodium berghei (strain ANKA)-infected mice

Experimental cerebral malaria is a neuroinflammatory condition that results from the host immune response to the parasite. Using intravital microscopy, we investigated leukocyte recruitment in the brain microcirculation and the temporal relationship of this process to the behavioral changes observed in Plasmodium berghei (strain ANKA)-infected C57Bl/6 mice. We found that leukocyte recruitment was increased from day 5 post-infection (p.i.) onwards. Histopathological changes and increased levels of inflammatory cytokines in the brain were also observed. Behavioral performance evaluated by the SHIRPA protocol showed functional impairment from day 6 p.i. onwards. Thus, early leukocyte migration into the brain and associated inflammatory changes may be involved in neurological impairment in parasite-infected C57Bl/6 mice.

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.

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.

Intracerebral infection with dengue-3 virus induces meningoencephalitis and behavioral changes that precede lethality in mice

BackgroundDengue, one of the most important arboviral diseases of humans, may cause severe systemic disease. Although dengue virus (DENV) has been considered to be a non-neurotropic virus, dengue infection has been associated recently with a series of neurological syndromes, including encephalitis. In this work, we evaluated behavioral changes and inflammatory parameters in C57BL/6 mice infected with non-adapted dengue virus 3 (DENV-3) genotype I.MethodsC57BL/6 mice received 4 × 103 PFU of DENV-3 by an intracranial route. We evaluated the trafficking of leukocytes in brain microvasculature using intravital microscopy, and evaluated chemokine and cytokine profiling by an ELISA test at 3 and 6 days post infection (p.i.). Furthermore, we determined myeloperoxidase activity and immune cell populations, and also performed histopathological analysis and immunostaining for the virus in brain tissue.ResultsAll animals developed signs of encephalitis and died by day 8 p.i. Motor behavior and muscle tone and strength parameters declined at day 7 p.i. We observed increased leukocyte rolling and adhesion in brain microvasculature of infected mice at days 3 and 6 p.i. The infection was followed by significant increases in IFN-γ, TNF-α, CCL2, CCL5, CXCL1, and CXCL2. Histological analysis showed evidence of meningoencephalitis and reactive gliosis. Increased numbers of neutrophils, CD4+ and CD8+ T cells were detected in brain of infected animals, notably at day 6 p.i. Cells immunoreactive for anti-NS-3 were visualized throughout the brain.ConclusionIntracerebral infection with non-adapted DENV-3 induces encephalitis and behavioral changes that precede lethality in mice.

Usual gait speed assessment in middle-aged and elderly Brazilian subjects

OBJECTIVES To evaluate the usual gait speed of asymptomatic adult and elderly Brazilians with a 10-meter walk test and to compare the results with foreign reference values. METHODS Seventy-nine asymptomatic volunteers ≥40 years old of both genders were assessed. After anamnesis, anthropometry and the application of a habitual physical activity questionnaire, the volunteers were submitted to a 10-meter walk test at usual speed by means of which gait speed, the number of steps and length of stride were calculated. RESULTS Except for age, all study variables were significantly lower in women. Subjects ≥70 years old presented a significantly lower gait speed than subjects between 40 and 49 years old and between 50 and 59 in both men (1.09±0.18 m/s, 1.35±0.11 m/s and 1.34±0.22 m/s, respectively) and women (1.02±0,10 m/s, 1.27±0.20 m/s and 1.27±0,15 m/s), respectively). Gait speed showed moderate correlations with age (r=-0.41, p<0.001) and height (r=0.35, p=0.001). After multiple regression analysis, age and gender were selected as relevant attributes of gait speed in that they explained 24.6% of this variable. The gait speed values in this study were significantly lower than foreign reference values (p<0.05). CONCLUSIONS The gait speed presented age-related decline and values significantly lower than those described for foreign populations. This finding indicates the need for comprehensive investigation of gait speed reference values for the Brazilian population.