BRENO SATLER DE OLIVEIRA DINIZ
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- 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.
- Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: A preliminary 4-week study(2011) SOUSA, Rafael T. de; BILT, Martinus T. van de; DINIZ, Breno S.; LADEIRA, Rodolfo B.; PORTELA, Luis V.; SOUZA, Diogo O.; FORLENZA, Orestes V.; GATTAZ, Wagner F.; MACHADO-VIEIRA, RodrigoSeveral studies have suggested an important role for brain-derived neurotrophic factor (BDNF) in the pathophysiology and therapeutics of bipolar disorder (BPD). The mechanisms underlying the therapeutic effects of lithium in BPD seem to involve a direct regulation of neurotrophic cascades. However, no clinical study evaluated the specific effects of lithium on BDNF levels in subjects with BPD. This study aims to investigate the effects of lithium monotherapy on BDNF levels in acute mania. Ten subjects with bipolar I disorder in a manic episode were evaluated at baseline and after 28 days of lithium therapy. Changes in plasma BDNF levels and Young Mania Rating Scale (YMRS) scores were analyzed. A significant increase in plasma BDNF levels was observed after 28 days of therapy with lithium monotherapy (510.9 +/- 127.1 pg/mL) compared to pre-treatment (406.3 +/- 69.5 pg/mL) (p = 0.03). Although it was not found a significant association between BDNF levels and clinical improvement (YMRS), 87% of responders presented an increase in BDNF levels after treatment with lithium. These preliminary data showed lithium's direct effects on BDNF levels in bipolar mania, suggesting that short-term lithium treatment may activate neurotrophic cascades. Further studies with larger samples and longer period may confirm whether this biological effect is involved in the therapeutic efficacy of lithium in BPD.
- Platelet GSK3B activity in patients with late-life depression: Marker of depressive episode severity and cognitive impairment?(2011) DINIZ, Breno Satler; TALIB, Leda Leme; JOAQUIM, Helena Passarelli Giroud; PAULA, Vanessa Rodrigues Jesus de; GATTAZ, Wagner Farid; FORLENZA, Orestes VicenteObjective. Increased GSK3B activity has been reported as a state marker of major affective episodes in patients with depression and bipolar disorder. No study so far has addressed GSK3B activity in late-life depression. The aims of the present study were to determine GSK3B activity in platelets of elderly patients with major depression, and the association between GSK3B activity and the severity of depressive symptoms and cognitive impairment. Methods. Forty drug-free elderly patients with major depressive episode were compared to healthy older adults (n == 13). Severity of the depressive episode and current cognitive state were determined by the Hamilton Depression Scale (HAM-D) and the Cambridge Cognitive Test (CAMCOG), respectively. Total- and ser-9-phosphorylated GSK3B (tGSK3B and pGSK3B) were determined in platelets by enzyme immunometric assays (EIA). GSK3B activity was indirectly inferred by the GSK3B ratio (i.e. pGSK3B/tGSK3B). Results. Elderly depressed patients had significantly lower pGSK3B levels (P == 0.03) and GSK3B ratio (P == 0.03), indicating higher GSK3B activity. Higher GSK3B activity were observed in patients with severe depressive episode (HAM-D scores > 22, P == 0.03) and with cognitive impairment (CAMCOG scores < 86, P == 0.01). Conclusion. The present findings provide additional evidence of the involvement of GSK3B in the pathophysiology of late-life major depression. Higher GSK3B activity may be more relevant in those patients with more severe depressive symptoms and cognitive impairment.
- 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.
- Optimizing the CAMCOG test in the screening for mild cognitive impairment and incipient dementia: saving time with relevant domains(2011) APRAHAMIAN, Ivan; DINIZ, Breno Satler; IZBICKI, Rafael; RADANOVIC, Marcia; NUNES, Paula Villela; FORLENZA, Orestes VicenteObjective: To identify the CAMCOG sub-items that best contribute for the identification of patients with mild cognitive impairment (MCI) and incipient Alzheimer's disease (AD) in clinical practice. Methods: Cross-sectional assessment of 272 older adults (98 MCI, 82 AD, and 92 controls) with a standardized neuropsychological battery and the CAMCOG schedule. Backward logistic regression analysis with diagnosis (MCI and controls) as dependent variable and the sub-items of the CAMCOG as independent variable was carried out to determine the CAMCOG sub-items that predicted the diagnosis of MCI. Results: Lower scores on Language, Memory, Praxis, and Calculation CAMCOG sub-items were significantly associated with the diagnosis of MCI. A composite score obtained by the sum of these scores significantly discriminated MCI patients from comparison groups. This reduced version of the CAMCOG showed similar diagnostic accuracy than the original schedule for the identification of patients with MCI as compared to controls (AUC = 0.80 +/- 0.03 for the reduced CAMCOG; AUC = 0.79 +/- 0.03 for the original CAMCOG). Conclusion: This reduced version of the CAMCOG had similar diagnostic properties as the original CAMCOG and was faster and easier to administer, rendering it more suitable for the screening of subtle cognitive deficits in general clinical practice.
- Understanding the neuroprotective mechanisms of lithium may have clinical significance Reply(2011) FORLENZA, Orestes V.; DINIZ, Breno S.; GATTAZ, Wagner F.
- 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.
- Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial(2011) FORLENZA, Orestes V.; DINIZ, Breno S.; RADANOVIC, Marcia; SANTOS, Franklin S.; TALIB, Leda L.; GATTAZ, Wagner F.Background Two recent clinical studies support the feasibility of trials to evaluate the disease-modifying properties of lithium in Alzheimer's disease, although no benefits were obtained from short-term treatment. Aims To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI). Method Forty-five participants with aMCI were randomised to receive lithium (0.25-0.5mmol/l) (n=24) or placebo (n = 21) in a 12-month, double-blind trial. Primary outcome measures were the modification of cognitive and functional test scores, and concentrations of cerebrospinal fluid (CSF) biomarkers (amyloid-beta peptide (A beta(42)), total tau (T-tau), phosphorylated-tau) (P-tau). Trial registration: NCT01055392. Results Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P=0.03) and better perform-ance on the cognitive subscale of the Alzheimer's Disease Assessment Scale and in attention tasks. Overall tolerability of lithium was good and the adherence rate was 91%. Conclusions The present data support the notion that lithium has disease-modifying properties with potential clinical implications in the prevention of Alzheimer's disease.