BRENO SATLER DE OLIVEIRA DINIZ
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conferenceObject Body awareness therapy reduces residual depressive symptoms in elderly subjects.(2012) COSTA, Ana Carolina O.; KAMKHAGI, Dorli; SUPINO, Deborah; KUSMISKY, Sandra; FORLENZA, Orestes V.; DINIZ, Breno S.- Reduced serum levels of adiponectin in elderly patients with major depression(2012) DINIZ, Breno S.; TEIXEIRA, Antonio L.; CAMPOS, Alline C.; MIRANDA, Aline S.; ROCHA, Natalia P.; TALIB, Leda L.; GATTAZ, Wagner F.; FORLENZA, Orestes V.Recent studies have implicated adiponectin and other adipocytokines in brain function, particularly in processes related to memory and cognition. Blood levels of adiponectin are reduced in patients with primary cognitive disorders, such as Alzheimer's disease and mild cognitive impairment, and in adult patients with major depression. The aim of the present study is to determine serum levels of adiponectin in a sample of elderly patients with major depressive disorder (MOD) as compared to healthy older adults, and to examine the correlations between adiponectin levels and parameters indicative of mood and cognitive state. We recruited fifty-one unmedicated outpatients with late-life depression (LLD) and 47 age-matched controls in this study. The diagnosis of MDD was made according to the DSM-IV criteria, and the severity of depressive episode was determined with the 21-item Hamilton Depression Scale (HORS). Cognitive state was ascertained with the Cambridge Cognitive Test (CAMCOG) and the Mini-Mental State Examination (MMSE). Serum concentrations of adiponectin were determined using a sandwich ELISA method. Serum levels of adiponectin were significantly reduced in individuals with LLD (F = p < 0.001). Adiponectin level remained significantly reduced in after controlling for BMI index, scores on the CAMCOG, MMSE and HDRS and educational level (p < 0.001). Adiponectin levels showed a negative correlation with HORS scores (r = -0.59, p < 0.001) and BMI index (r = -0.42, p < 0.001); and showed a positive correlation with CAMCOG (r = 0.34, p < 0.01) and MMSE scores (r = 0.20, p = 0.05). The availability of circulating adiponectin is reduced in older adults with major depression, with likely implications on cognitive and mood state. Additional studies are required to determine whether this abnormality pertains to the pathophysiology of geriatric depression per se, or is a consequence of the morbid state.
- Does Lithium Prevent Alzheimer's Disease?(2012) FORLENZA, Orestes V.; PAULA, Vanessa J. de; MACHADO-VIEIRA, Rodrigo; DINIZ, Breno S.; GATTAZ, Wagner F.Lithium salts have a well-established role in the treatment of major affective disorders. More recently, experimental and clinical studies have provided evidence that lithium may also exert neuroprotective effects. In animal and cell culture models, lithium has been shown to increase neuronal viability through a combination of mechanisms that includes the inhibition of apoptosis, regulation of autophagy, increased mitochondrial function, and synthesis of neurotrophic factors. In humans, lithium treatment has been associated with humoral and structural evidence of neuroprotection, such as increased expression of anti-apoptotic genes, inhibition of cellular oxidative stress, synthesis of brain-derived neurotrophic factor (BDNF), cortical thickening, increased grey matter density, and hippocampal enlargement. Recent studies addressing the inhibition of glycogen synthase kinase-3 beta (GSK3B) by lithium have further suggested the modification of biological cascades that pertain to the pathophysiology of Alzheimer's disease (AD). A recent placebo-controlled clinical trial in patients with amnestic mild cognitive impairment (MCI) showed that long-term lithium treatment may actually slow the progression of cognitive and functional deficits, and also attenuate Tau hyperphosphorylation in the MCI-AD continuum. Therefore, lithium treatment may yield disease-modifying effects in AD, both by the specific modification of its pathophysiology via inhibition of overactive GSK3B, and by the unspecific provision of neurotrophic and neuroprotective support. Although the clinical evidence available so far is promising, further experimentation and replication of the evidence in large scale clinical trials is still required to assess the benefit of lithium in the treatment or prevention of cognitive decline in the elderly.
- Redução dos níveis séricos de ácido fólico em pacientes com a doença de Alzheimer(2012) ALMEIDA, Cesar C.; BRENTANI, Helena P.; FORLENZA, Orestes V.; DINIZ, Breno S.Background: Complex B vitamin deficiency has been associated to cognitive impairment and dementing disorders in the elderly. Objective: This work aims to assess whether patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) have lower levels of folic acid and cobalamin (vitamin B-12) compared to age and gender-matched controls. Methods: One hundred and forty six elderly subjects (40 AD, 56 MCI and 49 healthy older adults) were recruited for this study. Serum folic acid and vitamin B-12 levels were measured by electrochemoluminescence. Results: Compared to MCI and healthy controls a statistically significant reduction in serum concentrations of folic acid in AD patients was found (p = 0.02). This result remained statistically significant after controlling for socio-demographic and cognitive performance variables (p = 0.01). No significant differences were found in serum concentrations of vitamin B-12 in patients with AD, MCI and healthy controls. No significant changes in hematologic parameters were observed across these diagnostic groups. Discussion: The present study provides additional evidence that folic acid is reduced in patients with AD and reinforces the importance of nutritional changes, in particular the one-carbon metabolism, in the physiopathology of AD.
- Circulating Glial-derived neurotrophic factor is reduced in late-life depression(2012) DINIZ, Breno S.; TEIXEIRA, Antonio L.; MIRANDA, Aline S.; TALIB, Leda L.; GATTAZ, Wagner F.; FORLENZA, Orestes V.Background: The Glial Cell-line derived neurotrophic factor (GDNF) is part of the TGF-beta 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.
- A radioenzymatic assay to identify three groups of phospholipase A(2) in platelets(2012) TALIB, Leda L.; DINIZ, Breno S.; ZAINAGHI, Isis A.; FORLENZA, Orestes V.; GATTAZ, Wagner F.Phospholipases A(2) (PLA(2)) are key enzymes in membrane metabolism. The release of fatty acids and lysophospholipids by PLA(2) activates several intra-cellular second messenger cascades that regulate a wide variety of physiological responses. The aim of the present study is to describe a radioenzymatic assay to determine the activity of three main PLA(2) subtypes in platelets, namely extracellular calcium-dependent PLA(2) (sPLA(2)) and intracellular calcium-dependent (cPLA(2)) and calcium-independent PLA(2) (iPLA(2)). The differentiation of these distinct PLA(2) subtypes was based on the enzyme substrate preference (arachdonic acid or palmitoyl acid) and calcium concentration. Our results indicate that this new assay is feasible, precise and specific to measure the activity of the aforementioned subtypes of PLA(2). Therefore, this protocol can be used to investigate modifications of PLA(2) homeostasis in distinct biological models addressing the pathophysiology of many medical and neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.
- Reduced platelet amyloid precursor protein ratio (APP ratio) predicts conversion from mild cognitive impairment to Alzheimer's disease(2012) ZAINAGHI, Isis A.; TALIB, Leda L.; DINIZ, Breno S.; GATTAZ, Wagner F.; FORLENZA, Orestes V.Studies have shown that platelet APP ratio (representing the percentage of 120-130 kDa to 110 kDa isoforms of the amyloid precursor protein) is reduced in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we sought to determine if baseline APP ratio predicts the conversion from MCI to AD dementia after 4 years of longitudinal assessment. Fifty-five older adults with varying degrees of cognitive impairment (34 with MCI and 21 with AD) were assessed at baseline and after 4 years. MCI patients were re-classified according to the conversion status upon follow-up: 25 individuals retained the diagnostic status of MCI and were considered as stable cases (MCI-MCI); conversely, in nine cases the diagnosis of dementia due to AD was ascertained. The APP ratio (APPr) was determined by the Western blot method in samples of platelets collected at baseline. We found a significant reduction of APPr in MCI patients who converted to dementia upon follow-up. These individuals had baseline APPr values similar to those of demented AD patients. The overall accuracy of APPr to identify subjects with MCI who will progress to AD was 0.74 +/- A 0.10, p = 0.05. The cut-off of 1.12 yielded a sensitivity of 75 % and a specificity of 75 %. Platelet APPr may be a surrogate marker of the disease process in AD, with potential implications for the assessment of abnormalities in the APP metabolism in patients with and at risk for dementia. However, diagnostic accuracy was relatively low. Therefore, studies in larger samples are needed to determine whether APPr may warrant its use as a biomarker to support the early diagnosis of AD.
bookPart 0 Citação(ões) na Scopus Predementic diagnosis and biomarkers of dementia in Alzheimer's disease(2012) FORLENZA, O. V.; DINIZ, B. S.; GATTAZ, W. F.In next decades, Alzheimer's disease (AD) will reach an epidemic status unless more effective therapeutic interventions are made available. These treatments should target the modification of specific pathological cascades that lead to neurodegeneration in AD. There is evidence of a long pre-clinical stage in AD, in which neuritic plaques and neurofibrillary tangles gradually accumulate in affected brain areas. At the earliest stages of this process, no significant cognitive or functional impairment is detected by conventional clinical methods. New technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid may depict correlates of intracerebral pathology in individuals with mild, pre-dementia symptoms. These methods are commonly referred to as AD-related biomarkers. Therefore, the combination of clinical and biological information yields better diagnostic accuracy to identify individuals at high risk of AD. The relevance of this diagnosis relies on the hypothesis that pharmacological interventions with disease-modifying compounds are likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. In this paper, we review the clinical characteristics of the prodromal and transitional states from normal cognitive ageing to dementia in AD. We further address recent developments in biomarker research to support the early diagnosis and prediction of dementia, and discuss the challenges and perspectives for the development of disease-modifying therapies. © 2012 by Nova Science Publishers, Inc. All rights reserved.conferenceObject Circulating Nerve Growth Factor in elderly subjects: state marker of depression?(2012) DINIZ, Breno S.; TEIXEIRA, Antonio L.; TALIB, Leda L.; GATTAZ, Wagner F.; FORLENZA, Orestes V.- Long-term sertraline treatment increases expression and decreases phosphorylation of glycogen synthase kinase-3B in platelets of patients with late-life major depression(2012) JOAQUIM, Helena P. G.; TALIB, Leda L.; FORLENZA, Orestes V.; DINIZ, Breno S.; GATTAZ, Wagner F.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 (MOD) 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.